Novel antibodies that bind to antigenic polypeptides, nucleic acids encoding the antigens, and methods of use

Abstract
Disclosed herein are nucleic acid sequences that encode polypeptides. Also disclosed are antibodies, which immunospecifically-bind to the polypeptide, as well as derivatives, variants, mutants, or fragments of the aforementioned polypeptide, polynucleotide, or antibody. The invention further discloses therapeutic, diagnostic and research methods for diagnosis, treatment, and prevention of disorders involving any one of these novel human nucleic acids, polypeptides, or antibodies, or fragments thereof.
Description


FIELD OF THE INVENTION

[0002] The present invention relates to novel antibodies that bind immunospecifically to antigenic polypeptides, wherein the polypeptides have characteristic properties related to biochemical or physiological responses in a cell, a tissue, an organ or an organism. The novel polypeptides are gene products of novel genes, or are specified biologically active fragments or derivatives thereof. Methods of use of the antibodies encompass procedures for diagnostic and prognostic assay of the polypeptides, as well as methods of treating diverse pathological conditions.



BACKGROUND OF THE INVENTION

[0003] Eukaryotic cells are characterized by biochemical and physiological processes which under normal conditions are exquisitely balanced to achieve the preservation and propagation of the cells. When such cells are components of multicellular organisms such as vertebrates, or more particularly organisms such as mammals, the regulation of the biochemical and physiological processes involves intricate signaling pathways. Frequently, such signaling pathways are constituted of extracellular signaling proteins, cellular receptors that bind the signaling proteins and signal transducing components located within the cells.


[0004] Signaling proteins may be classified as endocrine effectors, paracrine effectors or autocrine effectors. Endocrine effectors are signaling molecules secreted by a given organ into the circulatory system, which are then transported to a distant target organ or tissue. The target cells include the receptors for the endocrine effector, and when the endocrine effector binds, a signaling cascade is induced. Paracrine effectors involve secreting cells and receptor cells in close proximity to each other, for example two different classes of cells in the same tissue or organ. One class of cells secretes the paracrine effector, which then reaches the second class of cells, for example by diffusion through the extracellular fluid. The second class of cells contains the receptors for the paracrine effector; binding of the effector results in induction of the signaling cascade that elicits the corresponding biochemical or physiological effect. Autocrine effectors are highly analogous to paracrine effectors, except that the same cell type that secretes the autocrine effector also contains the receptor. Thus the autocrine effector binds to receptors on the same cell, or on identical neighboring cells. The binding process then elicits the characteristic biochemical or physiological effect.


[0005] Signaling processes may elicit a variety of effects on cells and tissues including by way of nonlimiting example induction of cell or tissue proliferation, suppression of growth or proliferation, induction of differentiation or maturation of a cell or tissue, and suppression of differentiation or maturation of a cell or tissue.


[0006] Many pathological conditions involve dysregulation of expression of important effector proteins. In certain classes of pathologies the dysregulation is manifested as elevated or excessive synthesis and secretion of protein effectors. In a clinical setting a subject may be suspected of suffering from a condition brought on by elevated or excessive levels of a protein effector of interest.


[0007] Antibodies are multichain proteins that bind specifically to a given antigen, and poorly or not at all to substances deemed not to be a cognate antigen. Antibodies are comprised of two short chains termed light chains and two long chains termed heavy chains. These chains are constituted of immunoglobulin domains, of which generally there are two classes: one variable domain per chain and one constant domain in light chains and three or more constant domains in heavy chains. The antigen-specific portion of the immunoglobulin molecules resides in the variable domains; the variable domains of one light chain and one heavy chain associate with each other to generate the antigen-binding moiety. Antibodies that bind immunospecifically to a cognate or target antigen bind with high affinities. Accordingly, they are useful in assaying specifically for the presence of the antigen in a sample. In addition, they have the potential of inactivating the activity of the antigen.


[0008] Therefore there is a need to assay for the level of the protein effector of interest in a biological sample from such a subject, and to compare the level with that characteristic of a nonpathological condition. In particular, there is a need for such an assay based on the use of an antibody that binds immunospecifically to the antigen. There further is a need to inhibit the activity of the protein effector in cases where a pathological condition arises from elevated or excessive levels of the effector based on the use of an antibody that binds immunospecifically to the effector. Thus there is a need for the antibody as a product of manufacture. There further is a need for a method of treatment of a pathological condition brought on by an elevated or excessive level of the protein effector of interest based on administering the antibody to the subject.



SUMMARY OF THE INVENTION

[0009] The invention is based in part upon the discovery of nucleic acid sequences encoding novel polypeptides. The novel nucleic acids and polypeptides are referred to herein as NOVX, or NOV1, NOV2, NOV3, etc. nucleic acids and polypeptides. These nucleic acids and polypeptides, as well as derivatives, homologs, analogs and fragments thereof, will hereinafter be collectively designated as “NOVX” nucleic acid or polypeptide sequences.


[0010] In one aspect, the invention provides an isolated polypeptide comprising a mature form of a NOVX amino acid. The polypeptide can be, for example, a NOVX amino acid sequence or a variant of a NOVX amino acid sequence, wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed. The invention also includes fragments of any of NOVX polypeptides. In another aspect, the invention also includes an isolated nucleic acid that encodes a NOVX polypeptide, or a fragment, homolog, analog or derivative thereof.


[0011] Also included in the invention is a NOVX polypeptide that is a naturally occurring variant of a NOVX sequence. In one embodiment, the variant includes an amino acid sequence that is the translation of a nucleic acid sequence differing by a single nucleotide from a NOVX nucleic acid sequence. In another embodiment, the NOVX polypeptide is a variant polypeptide described therein, wherein any amino acid specified in the chosen sequence is changed to provide a conservative substitution.


[0012] In another aspect, invention provides a method for determining the presence or amount of the NOVX polypeptide in a sample by providing a sample; introducing the sample to an antibody that binds immunospecifically to the polypeptide; and determining the presence or amount of antibody bound to the NOVX polypeptide, thereby determining the presence or amount of the NOVX polypeptide in the sample.


[0013] In yet another aspect, the invention includes a method for determining the presence of or predisposition to a disease associated with altered levels of a NOVX polypeptide in a mammalian subject by measuring the level of expression of the polypeptide in a sample from the first mammalian subject; and comparing the amount of the polypeptide in the sample of the first step to the amount of the polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, the disease. An alteration in the expression level of the polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.


[0014] In another aspect, the invention includes pharmaceutical compositions that include therapeutically- or prophylactically-effective amounts of a therapeutic and a pharmaceutically-acceptable carrier. The therapeutic can be, e.g., a NOVX nucleic acid, a NOVX polypeptide, or an antibody specific for a NOVX polypeptide. In a further aspect, the invention includes, in one or more containers, a therapeutically- or prophylactically-effective amount of this pharmaceutical composition.


[0015] In still another aspect, the invention provides the use of a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease that is associated with a NOVX polypeptide.


[0016] In a further aspect, the invention provides a method for modulating the activity of a NOVX polypeptide by contacting a cell sample expressing the NOVX polypeptide with antibody that binds the NOVX polypeptide in an amount sufficient to modulate the activity of the polypeptide.


[0017] The invention also includes an isolated nucleic acid that encodes a NOVX polypeptide, or a fragment, homolog, analog or derivative thereof. In a preferred embodiment, the nucleic acid molecule comprises the nucleotide sequence of a naturally occurring allelic nucleic acid variant. In another embodiment, the nucleic acid encodes a variant polypeptide, wherein the variant polypeptide has the polypeptide sequence of a naturally occurring polypeptide variant. In another embodiment, the nucleic acid molecule differs by a single nucleotide from a NOVX nucleic acid sequence. In one embodiment, the NOVX nucleic acid molecule hybridizes under stringent conditions to the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n−1, wherein n is an integer between 1 and 101, or a complement of the nucleotide sequence. In one embodiment, the invention provides a nucleic acid molecule wherein the nucleic acid includes the nucleotide sequence of a naturally occurring allelic nucleic acid variant.


[0018] Also included in the invention is a vector containing one or more of the nucleic acids described herein, and a cell containing the vectors or nucleic acids described herein. The invention is also directed to host cells transformed with a vector comprising any of the nucleic acid molecules described above.


[0019] In yet another aspect, the invention provides for a method for determining the presence or amount of a nucleic acid molecule in a sample by contacting a sample with a probe that binds a NOVX nucleic acid and determining the amount of the probe that is bound to the NOVX nucleic acid. For example the NOVX nucleic may be a marker for cell or tissue type such as a cell or tissue type that is cancerous.


[0020] In yet a further aspect, the invention provides a method for determining the presence of or predisposition to a disease associated with altered levels of a nucleic acid molecule in a first mammalian subject, wherein an alteration in the level of the nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.


[0021] The invention further provides an antibody that binds immunospecifically to a NOVX polypeptide. The NOVX antibody may be monoclonal, humanized, or a fully human antibody. Preferably, the antibody has a dissociation constant for the binding of the NOVX polypeptide to the antibody less than 1×10−9 M. More preferably, the NOVX antibody neutralizes the activity of the NOVX polypeptide.


[0022] In a further aspect, the invention provides for the use of a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease, associated with a NOVX polypeptide. Preferably the therapeutic is a NOVX antibody.


[0023] In yet a further aspect, the invention provides a method of treating or preventing a NOVX-associated disorder, a method of treating a pathological state in a mammal, and a method of treating or preventing a pathology associated with a polypeptide by administering a NOVX antibody to a subject in an amount sufficient to treat or prevent the disorder.


[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.


[0025] Other features and advantages of the invention will be apparent from the following detailed description and claims.



DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention provides novel nucleotides and polypeptides encoded thereby. Included in the invention are the novel nucleic acid sequences, their encoded polypeptides, antibodies, and other related compounds. The sequences are collectively referred to herein as “NOVX nucleic acids” or “NOVX polynucleotides” and the corresponding encoded polypeptides are referred to as “NOVX polypeptides” or “NOVX proteins.” Unless indicated otherwise, “NOVX” is meant to refer to any of the novel sequences disclosed herein. Table 1 provides a summary of the NOVX nucleic acids and their encoded polypeptides.
1TABLE 1NOVX Polynucleotide and Polypeptide Sequences and CorrespondingSEQ ID NumbersSEQ IDSEQ IDNOVXNONOAssign-Internal(nucleic(poly-mentIdentificationacid)peptide)Homology 1aCG58546-0112Adlican 1b17430791834Adlican 1c17430792456Adlican 1d16967919778Adlican 1e169679219910Adlican 1f2077046551112Adlican 2aCG58598-011314Brain Specific Trans-membrane-like 2bCG58598-021516Brain Specific Trans-membrane-like 2c2097704591718Brain Specific Trans-membrane-like 3aCG57833-011920Amino Acid Transporter-like 4aCG57853-012122Heal Na(+)/Bile Cotrans-porter-like 4bCG57853-022324Heal Na(+)/Bile Cotrans-porter-like 4cCG57853-032526Heal Na(+)/Bile Cotrans-porter-like 5aCG57829-012728ADAM-TS 1 Precursor-like 5bCG57829-052930ADAM-TS 1 Precursor-like 5c1750704953132ADAM-TS 1 Precursor-like 5d1750705043334ADAM-TS 1 Prccursor-like 5e1750705123536ADAM-TS 1 Precursor-like 5f1750705193738ADAM-TS 1 Precursor-like 6aCG59197-013940TULIP 2-like (Tuberin) 6b1888220754142TULIP 2-like (Tuberin) 7aCG58524-014344T cell receptor beta chainprecursor V region-like 8aCG56512-014546Oncofetal AntigenPrecursor -like 9aCG58180-014748Prohibitin-like10aCG59199-014950Natriuretic Peptide Receptor11aCG59249-015152Metalloproteinase Disintegrinbeta (ADAM)11bCG59249-025354Metalloproteinase Disintegrinbeta (ADAM)12aCG58577-015556CASPR412b1743079715758CASPR412c1743079755960CASPR412d1743079796162CASPR412e1743079836364CASPR412f1743079876566CASPR412g1743079966768CASPR412h1698949296970CASPR413aCG59237-0171721 g, ring finger andfibronectin domains13bCG59237-0273741 g, ring finger andfibronectin domains14aCG58575-017576phosphatidylserine synthase2-like15aCG59256-017778MHC class 1-like16aCG59239-017980MHC class 1-like17aCG59295-018182Otogelin-like18aCG59293-018384renal organic anion transportprotein 1-like19aCG59284-018586solute carrier family 22-like20aCG59278-018788GPCR P2-like21aCG59274-018990lipoma HMGIC fusionpartner-like21bCG59274-029192lipoma HMGIC fusionpartner-like22a1728855109394lipoma HMGIC fusionpartner-like23aCG57734-019596lipid associated protein-like23bCG57734-029798lipid associated protein-like23c19836360199100lipid associated protein-like24aCG59389-01101102galactose binding lectin-like24bCG59389-02103104galactose binding lectin-like24cCG59389-04105106galactose binding lectin-like24d174308481107108galactose binding lectin-like24e174308497109110galactose binding lectin-like24f174308507111112galactose binding lectin-like24g174308517113114galactose binding lectin-like24h174308525115116galactose binding lectin-like25aCG59885-01117118HGFR26aCG93443-01119120LIV-127aCG50838-01121122Leucine-rich repeat trans-membrane protein FLRT328aCG58567-01123124Protocadherin28bCG58567-05125126Protocadherin28cCG58567-06127128Protocadherin29aCG59243-01129130Mitochondrial carrier-like29b188822080131132Mitochondrial carrier-like29cCG59243-02133134Mitochondrial carrier like30aCG59534-01135136membrane glycoprotein-like31aCG59289-01137138Crumbs-like31bCG59289-02139140Crumbs-like32aCG57111-01141142Protocadherin 13-like33aCG59363-01143144BAB26184-like33bCG59363-02145146BAB26184-like33cCG59363-03147148BAB26184-like34aCG59301-01149150androgen receptor like35aCG59525-01151152carcinoembryonic antigencgml-like36aCG59484-01153154wd-repeat protein-like37aCG57245-02155156CD40L Receptor Precursor-like37bCG57245-04157158CD40L Receptor Precursor-like37c174308232159160CD40L Receptor Precursor-like38aCG59454-01161162Butyrophilin-like38bCG59454-03163164Butyrophilin-like38cCG59454-04165166Butyrophilin-like39aCG59307-01167168DNA-binding protein-like40aCG59713-01169170Van Gogh-like40b170645777171172Van Gogh-like41aCG59570-01173174Aquaporin-like42aCG56162-02175176Lysophospholipase-like42b174228465177178Lysophospholipase-like43aCG59681-01179180immunoglobulin domaincontaining protein43b174308213181182immunoglobulin domaincontaining protein43c174308218183184immunoglobulin domaincontaining protein43d174308224185186immunoglobulin domaincontaining protein44aCG59869-01187188Leucine rich repeat membraneprotein-like44bCG59869-02189190Leucine rich repeat membraneprotein-like44cCG59869-03191192Leucine rich repeat membraneprotein-like45aCG59859-01193194Testis expressed protein 261(TEG-261)-like45bCG59859-02195196Testis expressed protein 261(TEG-261)-like46aCG59913-01197198ATP-binding cassette trans-porter (ABC transporter)-like47aCG59909-01199200ATP-binding cassette trans-porter (ABC transporter)-like48aCG59945-01201202Steroid Hormone Receptor-like


[0027] Table 1 indicates homology of NOVX nucleic acids to known protein families. Thus, the nucleic acids and polypeptides, antibodies and related compounds according to the invention corresponding to a NOVX as identified in column 1 of Table 1 will be useful in therapeutic and diagnostic applications implicated in, for example, pathologies and disorders associated with the known protein families identified in column 5 of Table 1.


[0028] NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts. The various NOVX nucleic acids and polypeptides according to the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the NOVX polypeptides belong.


[0029] Consistent with other known members of the family of proteins, identified in Column 5 of Table 1, the NOVX polypeptides of the present invention show homology to, and contain domains that are characteristic of other members of such protein families. Details of the sequence relatedness and domain analysis for each NOVX are presented in Example A.


[0030] The NOVX nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOVX activity or function. Specifically, the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit diseases associated with the protein families listed in Table 1.


[0031] The NOVX nucleic acids and polypeptides are also useful for detecting specific cell types. Details of the expression analysis for each NOVX are presented in Example B. Accordingly, the NOVX nucleic acids, polypeptides, antibodies and related compounds according to the invention will have diagnostic and therapeutic applications in the detection of a variety of diseases with differential expression in normal vs. diseased tissues, e.g. a variety of cancers.


[0032] Additional utilities for NOVX nucleic acids and polypeptides according to the invention are disclosed herein.


[0033] NOVX Clones


[0034] NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts. The various NOVX nucleic acids and polypeptides according to the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the NOVX polypeptides belong.


[0035] The NOVX genes and their corresponding encoded proteins are useful for preventing, treating or ameliorating medical conditions, e.g., by protein or gene therapy. Pathological conditions can be diagnosed by determining the amount of the new protein in a sample or by determining the presence of mutations in the new genes. Specific uses are described for each of the NOVX genes, based on the tissues in which they are most highly expressed. Uses include developing products for the diagnosis or treatment of a variety of diseases and disorders.


[0036] The NOVX nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool. These include serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) biological defense weapon.


[0037] In one specific embodiment, the invention includes an isolated polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101; (b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101, wherein any amino acid in the mature form is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; (c) an amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101; (d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 101 wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; and (e) a fragment of any of (a) through (d).


[0038] In another specific embodiment, the invention includes an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form of the amino acid sequence given SEQ ID NO: 2n, wherein n is an integer between 1 and 101; (b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101 wherein any amino acid in the mature form of the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; (c) the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101; (d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101, in which any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; (e) a nucleic acid fragment encoding at least a portion of a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101 or any variant of said polypeptide wherein any amino acid of the chosen sequence is changed to a different amino acid, provided that no more than 10% of the amino acid residues in the sequence are so changed; and (f) the complement of any of said nucleic acid molecules.


[0039] In yet another specific embodiment, the invention includes an isolated nucleic acid molecule, wherein said nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of: (a) the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n−1, wherein n is an integer between 1 and 101; (b) a nucleotide sequence wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n−1, wherein n is an integer between 1 and 101 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed; (c) a nucleic acid fragment of the sequence selected from the group consisting of SEQ ID NO: 2n−1, wherein n is an integer between 1 and 101; and (d) a nucleic acid fragment wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n−1, wherein i is an integer between 1 and 101 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed.


[0040] NOVX Nucleic Acids and Polypeptides


[0041] One aspect of the invention pertains to isolated nucleic acid molecules that encode NOVX polypeptides or biologically active portions thereof. Also included in the invention are nucleic acid fragments sufficient for use as hybridization probes to identify NOVX-encoding nucleic acids (e.g., NOVX mRNA's) and fragments for use as PCR primers for the amplification and/or mutation of NOVX nucleic acid molecules. As used herein, the term “nucleic acid molecule” is intended to include DNA molecules (e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA), analogs of the DNA or RNA generated using nucleotide analogs, and derivatives, fragments and homologs thereof. The nucleic acid molecule may be single-stranded or double-stranded, but preferably is comprised double-stranded DNA.


[0042] A NOVX nucleic acid can encode a mature NOVX polypeptide. As used herein, a “mature” form of a polypeptide or protein disclosed in the present invention is the product of a naturally occurring polypeptide or precursor form or proprotein. The naturally occurring polypeptide, precursor or proprotein includes, by way of nonlimiting example, the full-length gene product, encoded by the corresponding gene. Alternatively, it may be defined as the polypeptide, precursor or proprotein encoded by an ORF described herein. The product “mature” form arises, again by way of nonlimiting example, as a result of one or more naturally occurring processing steps as they may take place within the cell, or host cell, in which the gene product arises. Examples of such processing steps leading to a “mature” form of a polypeptide or protein include the cleavage of the N-terminal methionine residue encoded by the initiation codon of an ORF, or the proteolytic cleavage of a signal peptide or leader sequence. Thus a mature form arising from a precursor polypeptide or protein that has residues 1 to N, where residue 1 is the N-terminal methionine, would have residues 2 through N remaining after removal of the N-terminal methionine. Alternatively, a mature form arising from a precursor polypeptide or protein having residues 1 to N, in which an N-terminal signal sequence from residue 1 to residue M is cleaved, would have the residues from residue M+1 to residue N remaining. Further as used herein, a “mature” form of a polypeptide or protein may arise from a step of post-translational modification other than a proteolytic cleavage event. Such additional processes include, by way of non-limiting example, glycosylation, myristylation or phosphorylation. In general, a mature polypeptide or protein may result from the operation of only one of these processes, or a combination of any of them.


[0043] The term “probes”, as utilized herein, refers to nucleic acid sequences of variable length, preferably between at least about 10 nucleotides (nt), 100 nt, or as many as approximately, e.g., 6,000 nt, depending upon the specific use. Probes are used in the detection of identical, similar, or complementary nucleic acid sequences. Longer length probes are generally obtained from a natural or recombinant source, are highly specific, and much slower to hybridize than shorter-length oligomer probes. Probes may be single- or double-stranded and designed to have specificity in PCR, membrane-based hybridization technologies, or ELISA-like technologies.


[0044] The term “isolated” nucleic acid molecule, as utilized herein, is one, which is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid. Preferably, an “isolated” nucleic acid is free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5′- and 3′-termini of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. For example, in various embodiments, the isolated NOVX nucleic acid molecules can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturally flank the nucleic acid molecule in genomic DNA of the cell/tissue from which the nucleic acid is derived (e.g., brain, heart, liver, spleen, etc.). Moreover, an “isolated” nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material or culture medium when produced by recombinant techniques, or of chemical precursors or other chemicals when chemically synthesized.


[0045] A nucleic acid molecule of the invention, e.g., a nucleic acid molecule having the nucleotide sequence of SEQ ID NO:2n−1, wherein n is an integer between 1-101, or a complement of this aforementioned nucleotide sequence, can be isolated using standard molecular biology techniques and the sequence information provided herein. Using all or a portion of the nucleic acid sequence of SEQ ID NO:2n−1, wherein n is an integer between 1-101, as a hybridization probe, NOVX molecules can be isolated using standard hybridization and cloning techniques (e.g., as described in Sambrook, et al., (eds.), MOLECULAR CLONING: A LABORATORY MANUAL 2nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989; and Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, N.Y., 1993.)


[0046] A nucleic acid of the invention can be amplified using cDNA, mRNA or alternatively, genomic DNA, as a template and appropriate oligonucleotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis. Furthermore, oligonucleotides corresponding to NOVX nucleotide sequences can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer.


[0047] As used herein, the term “oligonucleotide” refers to a series of linked nucleotide residues, which oligonucleotide has a sufficient number of nucleotide bases to be used in a PCR reaction. A short oligonucleotide sequence may be based on, or designed from, a genomic or cDNA sequence and is used to amplify, confirm, or reveal the presence of an identical, similar or complementary DNA or RNA in a particular cell or tissue. Oligonucleotides comprise portions of a nucleic acid sequence having about 10 nt, 50 nt, or 100 nt in length, preferably about 15 nt to 30 nt in length. In one embodiment of the invention, an oligonucleotide comprising a nucleic acid molecule less than 100 nt in length would further comprise at least 6 contiguous nucleotides of SEQ ID NO:2n−1, wherein n is an integer between 1-101, or a complement thereof. Oligonucleotides may be chemically synthesized and may also be used as probes.


[0048] In another embodiment, an isolated nucleic acid molecule of the invention comprises a nucleic acid molecule that is a complement of the nucleotide sequence SEQ ID NO:2n−1, wherein n is an integer between 1-101, or a portion of this nucleotide sequence (e.g., a fragment that can be used as a probe or primer or a fragment encoding a biologically-active portion of a NOVX polypeptide). A nucleic acid molecule that is complementary to the nucleotide sequence of SEQ ID NO:2n−1, wherein n is an integer between 1-101, is one that is sufficiently complementary to the nucleotide sequence of SEQ ID NO:2n−1, wherein n is an integer between 1-101, that it can hydrogen bond with little or no mismatches to the nucleotide sequence of SEQ ID NO:2n−1, wherein n is an integer between 1-101, thereby forming a stable duplex.


[0049] As used herein, the term “complementary” refers to Watson-Crick or Hoogsteen base pairing between nucleotides units of a nucleic acid molecule, and the term “binding” means the physical or chemical interaction between two polypeptides or compounds or associated polypeptides or compounds or combinations thereof. Binding includes ionic, non-ionic, van der Waals, hydrophobic interactions, and the like. A physical interaction can be either direct or indirect. Indirect interactions may be through or due to the effects of another polypeptide or compound. Direct binding refers to interactions that do not take place through, or due to, the effect of another polypeptide or compound, but instead are without other substantial chemical intermediates.


[0050] Fragments provided herein are defined as sequences of at least 6 (contiguous) nucleic acids or at least 4 (contiguous) amino acids, a length sufficient to allow for specific hybridization in the case of nucleic acids or for specific recognition of an epitope in the case of amino acids, respectively, and are at most some portion less than a full length sequence. Fragments may be derived from any contiguous portion of a nucleic acid or amino acid sequence of choice. Derivatives are nucleic acid sequences or amino acid sequences formed from the native compounds either directly or by modification or partial substitution. Analogs are nucleic acid sequences or amino acid sequences that have a structure similar to, but not identical to, the native compound but differs from it in respect to certain components or side chains. Analogs may be synthetic or from a different evolutionary origin and may have a similar or opposite metabolic activity compared to wild type. Homologs are nucleic acid sequences or amino acid sequences of a particular gene that are derived from different species.


[0051] A full-length NOVX clone is identified as containing an ATG translation start codon and an in-frame stop codon. Any disclosed NOVX nucleotide sequence lacking an ATG start codon therefore encodes a truncated C-terminal fragment of the respective NOVX polypeptide, and requires that the corresponding full-length cDNA extend in the 5′ direction of the disclosed sequence. Any disclosed NOVX nucleotide sequence lacking an in-frame stop codon similarly encodes a truncated N-terminal fragment of the respective NOVX polypeptide, and requires that the corresponding full-length cDNA extend in the 3′ direction of the disclosed sequence.


[0052] Derivatives and analogs may be full length or other than full length, if the derivative or analog contains a modified nucleic acid or amino acid, as described below. Derivatives or analogs of the nucleic acids or proteins of the invention include, but are not limited to, molecules comprising regions that are substantially homologous to the nucleic acids or proteins of the invention, in various embodiments, by at least about 70%, 80%, or 95% identity (with a preferred identity of 80-95%) over a nucleic acid or amino acid sequence of identical size or when compared to all aligned sequence in which the alignment is done by a computer homology program known in the art, or whose encoding nucleic acid is capable of hybridizing to the complement of a sequence encoding the aforementioned proteins under stringent, moderately stringent, or low stringent conditions. See e.g. Ausubel, et al., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, N.Y., 1993, and below.


[0053] A “homologous nucleic acid sequence” or “homologous amino acid sequence,” or variations thereof, refer to sequences characterized by a homology at the nucleotide level or amino acid level as discussed above. Homologous nucleotide sequences encode those sequences coding for isoforms of NOVX polypeptides. Isoforms can be expressed in different tissues of the same organism as a result of, for example, alternative splicing of RNA. Alternatively, isoforms can be encoded by different genes. In the invention, homologous nucleotide sequences include nucleotide sequences encoding for a NOVX polypeptide of species other than humans, including, but not limited to: vertebrates, and thus can include, e.g., frog, mouse, rat, rabbit, dog, cat cow, horse, and other organisms. Homologous nucleotide sequences also include, but are not limited to, naturally occurring allelic variations and mutations of the nucleotide sequences set forth herein. A homologous nucleotide sequence does not, however, include the exact nucleotide sequence encoding human NOVX protein. Homologous nucleic acid sequences include those nucleic acid sequences that encode conservative amino acid substitutions (see below) in SEQ ID NO:2n−1, wherein n is an integer between 1-101, as well as a polypeptide possessing NOVX biological activity. Various biological activities of the NOVX proteins are described below.


[0054] A NOVX polypeptide is encoded by the open reading frame (“ORF”) of a NOVX nucleic acid. An ORF corresponds to a nucleotide sequence that could potentially be translated into a polypeptide. A stretch of nucleic acids comprising an ORF is uninterrupted by a stop codon. An ORF that represents the coding sequence for a full protein begins with an ATG “start” codon and terminates with one of the three “stop” codons, namely, TAA, TAG, or TGA. For the purposes of this invention, an ORF may be any part of a coding sequence, with or without a start codon, a stop codon, or both. For an ORF to be considered as a good candidate for coding for a bona fide cellular protein, a minimum size requirement is often set, e.g., a stretch of DNA that would encode a protein of 50 amino acids or more.


[0055] The nucleotide sequences determined from the cloning of the human NOVX genes allows for the generation of probes and primers designed for use in identifying and/or cloning NOVX homologues in other cell types, e.g. from other tissues, as well as NOVX homologues from other vertebrates. The probe/primer typically comprises substantially purified oligonucleotide. The oligonucleotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 12, 25, 50, 100, 150, 200, 250, 300, 350 or 400 consecutive sense strand nucleotide sequence of SEQ ID NO:2n−1, wherein n is an integer between 1-101; or an anti-sense strand nucleotide sequence of SEQ ID NO:2n−1, wherein n is an integer between 1-101; or of a naturally occurring mutant of SEQ ID NO:2n−1, wherein n is an integer between 1-101.


[0056] Probes based on the human NOVX nucleotide sequences can be used to detect transcripts or genomic sequences encoding the same or homologous proteins. In various embodiments, the probe further comprises a label group attached thereto, e.g. the label group can be a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used as a part of a diagnostic test kit for identifying cells or tissues which mis-express a NOVX protein, such as by measuring a level of a NOVX-encoding nucleic acid in a sample of cells from a subject e.g., detecting NOVX mRNA levels or determining whether a genomic NOVX gene has been mutated or deleted.


[0057] “A polypeptide having a biologically-active portion of a NOVX polypeptide” refers to polypeptides exhibiting activity similar, but not necessarily identical to, an activity of a polypeptide of the invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. A nucleic acid fragment encoding a “biologically-active portion of NOVX” can be prepared by isolating a portion of SEQ ID NO:2n−1, wherein n is an integer between 1-101, that encodes a polypeptide having a NOVX biological activity (the biological activities of the NOVX proteins are described below), expressing the encoded portion of NOVX protein (e.g., by recombinant expression in vitro) and assessing the activity of the encoded portion of NOVX.


[0058] NOVX Nucleic Acid and Polypeptide Variants


[0059] The invention further encompasses nucleic acid molecules that differ from the nucleotide sequences of SEQ ID NO:2n−1, wherein n is an integer between 1-101, due to degeneracy of the genetic code and thus encode the same NOVX proteins as that encoded by the nucleotide sequences of SEQ ID NO:2n−1, wherein n is an integer between 1-101. In another embodiment, an isolated nucleic acid molecule of the invention has a nucleotide sequence encoding a protein having an amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1-101.


[0060] In addition to the human NOVX nucleotide sequences of SEQ ID NO:2n−1, wherein n is an integer between 1-101, it will be appreciated by those skilled in the art that DNA sequence polymorphisms that lead to changes in the amino acid sequences of the NOVX polypeptides may exist within a population (e.g., the human population). Such genetic polymorphism in the NOVX genes may exist among individuals within a population due to natural allelic variation. As used herein, the terms “gene” and “recombinant gene” refer to nucleic acid molecules comprising an open reading frame (ORF) encoding a NOVX protein, preferably a vertebrate NOVX protein. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence of the NOVX genes. Any and all such nucleotide variations and resulting amino acid polymorphisms in the NOVX polypeptides, which are the result of natural allelic variation and that do not alter the functional activity of the NOVX polypeptides, are intended to be within the scope of the invention.


[0061] Moreover, nucleic acid molecules encoding NOVX proteins from other species, and thus that have a nucleotide sequence that differs from any one of the human SEQ ID NO:2n−1, wherein n is an integer between 1-101, are intended to be within the scope of the invention. Nucleic acid molecules corresponding to natural allelic variants and homologues of the NOVX cDNAs of the invention can be isolated based on their homology to the human NOVX nucleic acids disclosed herein using the human cDNAs, or a portion thereof, as a hybridization probe according to standard hybridization techniques under stringent hybridization conditions.


[0062] Accordingly, in another embodiment, an isolated nucleic acid molecule of the invention is at least 6 nucleotides in length and hybridizes under stringent conditions to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2n−1, wherein n is an integer between 1-101. In another embodiment, the nucleic acid is at least 10, 25, 50, 100, 250, 500, 750, 1000, 1500, or 2000 or more nucleotides in length. In yet another embodiment, an isolated nucleic acid molecule of the invention hybridizes to the coding region. As used herein, the term “hybridizes under stringent conditions” is intended to describe conditions for hybridization and washing under which nucleotide sequences at least 60% homologous to each other typically remain hybridized to each other.


[0063] Homologs (i.e., nucleic acids encoding NOVX proteins derived from species other than human) or other related sequences (e.g., paralogs) can be obtained by low, moderate or high stringency hybridization with all or a portion of the particular human sequence as a probe using methods well known in the art for nucleic acid hybridization and cloning.


[0064] As used herein, the phrase “stringent hybridization conditions” refers to conditions under which a probe, primer or oligonucleotide will hybridize to its target sequence, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures than shorter sequences. Generally, stringent conditions are selected to be about 5° C. lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength, pH and nucleic acid concentration) at which 50% of the probes complementary to the target sequence hybridize to the target sequence at equilibrium. Since the target sequences are generally present at excess, at Tm, 50% of the probes are occupied at equilibrium. Typically, stringent conditions will be those in which the salt concentration is less than about 1.0 M sodium ion, typically about 0.01 to 1.0 M sodium ion (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30° C. for short probes, primers or oligonucleotides (e.g., 10 nt to 50 nt) and at least about 60° C. for longer probes, primers and oligonucleotides. Stringent conditions may also be achieved with the addition of destabilizing agents, such as formamide.


[0065] Stringent conditions are known to those skilled in the art and can be found in Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York (1989), 6.3.1-6.3.6. Preferably, the conditions are such that sequences at least about 65%, 70%, 75%, 85%, 90%, 95%, 98%, or 99% homologous to each other typically remain hybridized to each other. A non-limiting example of stringent hybridization conditions are hybridization in a high salt buffer comprising 6× SSC, 50 mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 mg/ml denatured salmon sperm DNA at 65° C., followed by one or more washes in 0.2× SSC, 0.01% BSA at 50° C. An isolated nucleic acid molecule of the invention that hybridizes under stringent conditions to any one of the sequences of SEQ ID NO:2n−1, wherein n is an integer between 1-101, corresponds to a naturally-occurring nucleic acid molecule. As used herein, a “naturally-occurring” nucleic acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs in nature (e.g., encodes a natural protein).


[0066] In a second embodiment, a nucleic acid sequence that is hybridizable to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2n−1, wherein n is an integer between 1-101, or fragments, analogs or derivatives thereof, under conditions of moderate stringency is provided. A non-limiting example of moderate stringency hybridization conditions are hybridization in 6× SSC, 5× Reinhardt's solution, 0.5% SDS and 100 mg/ml denatured salmon sperm DNA at 55° C., followed by one or more washes in 1× SSC, 0.1% SDS at 37° C. Other conditions of moderate stringency that may be used are well-known within the art. See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, and Krieger, 1990; GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, New York.


[0067] In a third embodiment, a nucleic acid that is hybridizable to the nucleic acid molecule comprising the nucleotide sequences of SEQ ID NO:2n−1, wherein n is an integer between 1-101, or fragments, analogs or derivatives thereof, under conditions of low stringency, is provided. A non-limiting example of low stringency hybridization conditions are hybridization in 35% formamide, 5× SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 mg/ml denatured salmon sperm DNA, 10% (wt/volt) dextran sulfate at 40° C., followed by one or more washes in 2× SSC, 25 mM Tris-HCl (pH 7.4), 5 mM EDTA, and 0.1% SDS at 50° C. Other conditions of low stringency that may be used are well known in the art (e.g., as employed for cross-species hybridizations). See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, and Kriegler, 1990, GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, New York; Shilo and Weinberg, 1981. Proc Natl Acad Sci USA 78: 6789-6792.


[0068] Conservative Mutations


[0069] In addition to naturally-occurring allelic variants of NOVX sequences that may exist in the population, the skilled artisan will further appreciate that changes can be introduced by mutation into the nucleotide sequences of SEQ ID NO:2n−1, wherein n is an integer between 1-101, thereby leading to changes in the amino acid sequences of the encoded NOVX proteins, without altering the functional ability of said NOVX proteins. For example, nucleotide substitutions leading to amino acid substitutions at “non-essential” amino acid residues can be made in the sequence of SEQ ID NO:2n, wherein n is an integer between 1-101. A “non-essential” amino acid residue is a residue that can be altered from the wild-type sequences of the NOVX proteins without altering their biological activity, whereas an “essential” amino acid residue is required for such biological activity. For example, amino acid residues that are conserved among the NOVX proteins of the invention are particularly non-amenable to alteration. Amino acids for which conservative substitutions can be made are well-known within the art.


[0070] Another aspect of the invention pertains to nucleic acid molecules encoding NOVX proteins that contain changes in amino acid residues that are not essential for activity. Such NOVX proteins differ in amino acid sequence from any one of SEQ ID NO:2n−1, wherein n is an integer between 1-101, yet retain biological activity. In one embodiment, the isolated nucleic acid molecule comprises a nucleotide sequence encoding a protein, wherein the protein comprises an amino acid sequence at least about 45% homologous to the amino acid sequences of SEQ ID NO:2n, wherein n is an integer between 1-101. Preferably, the protein encoded by the nucleic acid molecule is at least about 60% homologous to SEQ ID NO:2n, wherein n is an integer between 1-101; more preferably at least about 70% homologous to SEQ ID NO:2n, wherein n is an integer between 1-101; still more preferably at least about 80% homologous to SEQ ID NO:2n, wherein n is an integer between 1-101; even more preferably at least about 90% homologous to SEQ ID NO:2n, wherein n is an integer between 1-101; and most preferably at least about 95% homologous to SEQ ID NO:2n, wherein n is an integer between 1-101.


[0071] An isolated nucleic acid molecule encoding a NOVX protein homologous to the protein of SEQ ID NO:2n, wherein n is an integer between 1-101, can be created by introducing one or more nucleotide substitutions, additions or deletions into the nucleotide sequence of SEQ ID NO:2n−1, wherein n is an integer between 1-101, such that one or more amino acid substitutions, additions or deletions are introduced into the encoded protein.


[0072] Mutations can be introduced into any of SEQ ID NO:2n−1, wherein n is an integer between 1-101, by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. Preferably, conservative amino acid substitutions are made at one or more predicted, non-essential amino acid residues. A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined within the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a predicted non-essential amino acid residue in the NOVX protein is replaced with another amino acid residue from the same side chain family. Alternatively, in another embodiment, mutations can be introduced randomly along all or part of a NOVX coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for NOVX biological activity to identify mutants that retain activity. Following mutagenesis of any one of SEQ ID NO:2n−1, wherein n is an integer between 1-101, the encoded protein can be expressed by any recombinant technology known in the art and the activity of the protein can be determined.


[0073] The relatedness of amino acid families may also be determined based on side chain interactions. Substituted amino acids may be fully conserved “strong” residues or fully conserved “weak” residues. The “strong” group of conserved amino acid residues may be any one of the following groups: STA, NEQK, NHQK, NDEQ, QHRK, MILV, MILF, HY, FYW, wherein the single letter amino acid codes are grouped by those amino acids that may be substituted for each other. Likewise, the “weak” group of conserved residues may be any one of the following: CSA, ATV, SAG, STNK, STPA, SGND, SNDEQK, NDEQHK, NEQHRK, VLIM, HFY, wherein the letters within each group represent the single letter amino acid code.


[0074] In one embodiment, a mutant NOVX protein can be assayed for (i) the ability to form protein:protein interactions with other NOVX proteins, other cell-surface proteins, or biologically-active portions thereof, (ii) complex formation between a mutant NOVX protein and a NOVX ligand; or (iii) the ability of a mutant NOVX protein to bind to an intracellular target protein or biologically-active portion thereof; (e.g. avidin proteins).


[0075] In yet another embodiment, a mutant NOVX protein can be assayed for the ability to regulate a specific biological function (e.g., regulation of insulin release).


[0076] Antisense Nucleic Acids


[0077] Another aspect of the invention pertains to isolated antisense nucleic acid molecules that are hybridizable to or complementary to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2n−1, wherein n is an integer between 1-101, or fragments, analogs or derivatives thereof. An “antisense” nucleic acid comprises a nucleotide sequence that is complementary to a “sense” nucleic acid encoding a protein (e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence). In specific aspects, antisense nucleic acid molecules are provided that comprise a sequence complementary to at least about 10, 25, 50, 100, 250 or 500 nucleotides or an entire NOVX coding strand, or to only a portion thereof. Nucleic acid molecules encoding fragments, homologs, derivatives and analogs of a NOVX protein of SEQ ID NO:2n, wherein n is an integer between 1-101, or antisense nucleic acids complementary to a NOVX nucleic acid sequence of SEQ ID NO:2n−1, wherein n is an integer between 1-101, are additionally provided.


[0078] In one embodiment, an antisense nucleic acid molecule is antisense to a “coding region” of the coding strand of a nucleotide sequence encoding a NOVX protein. The term “coding region” refers to the region of the nucleotide sequence comprising codons which are translated into amino acid residues. In another embodiment, the antisense nucleic acid molecule is antisense to a “noncoding region” of the coding strand of a nucleotide sequence encoding the NOVX protein. The term “noncoding region” refers to 5′ and 3′ sequences which flank the coding region that are not translated into amino acids (i.e., also referred to as 5′ and 3′ untranslated regions).


[0079] Given the coding strand sequences encoding the NOVX protein disclosed herein, antisense nucleic acids of the invention can be designed according to the rules of Watson and Crick or Hoogsteen base pairing. The antisense nucleic acid molecule can be complementary to the entire coding region of NOVX mRNA, but more preferably is an oligonucleotide that is antisense to only a portion of the coding or noncoding region of NOVX mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of NOVX mRNA. An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides in length. An antisense nucleic acid of the invention can be constructed using chemical synthesis or enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally-occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids (e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used).


[0080] Examples of modified nucleotides that can be used to generate the antisense nucleic acid include: 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyl adenine, 1-methylguanine, 1-methylinosine 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminoethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).


[0081] The antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a NOVX protein to thereby inhibit expression of the protein (e.g., by inhibiting transcription and/or translation). The hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface (e.g., by linking the antisense nucleic acid molecules to peptides or antibodies that bind to cell surface receptors or antigens). The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To achieve sufficient nucleic acid molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred.


[0082] In yet another embodiment, the antisense nucleic acid molecule of the invention is an α-anomeric nucleic acid molecule. An α-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual β-units, the strands run parallel to each other. See, e.g., Gaultier, el al., 1987. Nucl. Acids Res. 15: 6625-6641. The antisense nucleic acid molecule can also comprise a 2′-o-methylribonucleotide (See, e.g., Inoue, et al. 1987. Nucl. Acids Res. 15: 6131-6148) or a chimeric RNA-DNA analogue (See. e.g., Inoue, et al., 1987. FEBS Lett. 215: 327-330.


[0083] Ribozymes and PNA Moieties


[0084] Nucleic acid modifications include, by way of non-limiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability of the modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject.


[0085] In one embodiment, an antisense nucleic acid of the invention is a ribozyme. Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes as described in Haselhoff and Gerlach 1988. Nature 334: 585-591) can be used to catalytically cleave NOVX mRNA transcripts to thereby inhibit translation of NOVX mRNA. A ribozyme having specificity for a NOVX-encoding nucleic acid can be designed based upon the nucleotide sequence of a NOVX cDNA disclosed herein (i.e., any one of SEQ ID NO:2n−1, wherein n is an integer between 1-101). For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide any of whose residues may be changed from the corresponding residues shown in any one of SEQ ID NO:2n, wherein n is an integer between 1-101, while still encoding a protein that maintains its NOVX activities and physiological functions, or a functional fragment thereof.


[0086] In general, a NOVX variant that preserves NOVX-like function includes any variant in which residues at a particular position in the sequence have been substituted by other amino acids, and further include the possibility of inserting an additional residue or residues between two residues of the parent protein as well as the possibility of deleting one or more residues from the parent sequence. Any amino acid substitution, insertion, or deletion is encompassed by the invention. In favorable circumstances, the substitution is a conservative substitution as defined above.


[0087] One aspect of the invention pertains to isolated NOVX proteins, and biologically-active portions thereof, or derivatives, fragments, analogs or homologs thereof. Also provided are polypeptide fragments suitable for use as immunogens to raise anti-NOVX antibodies. In one embodiment, native NOVX proteins can be isolated from cells or tissue sources by an appropriate purification scheme using standard protein purification techniques. In another embodiment, NOVX proteins are produced by recombinant DNA techniques. Alternative to recombinant expression, a NOVX protein or polypeptide can be synthesized chemically using standard peptide synthesis techniques.


[0088] An “isolated” or “purified” polypeptide or protein or biologically-active portion thereof is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the NOVX protein is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized. The language “substantially free of cellular material” includes preparations of NOVX proteins in which the protein is separated from cellular components of the cells from which it is isolated or recombinantly-produced. In one embodiment, the language “substantially free of cellular material” includes preparations of NOVX proteins having less than about 30% (by dry weight) of non-NOVX proteins (also referred to herein as a “contaminating protein”), more preferably less than about 20% of non-NOVX proteins, still more preferably less than about 10% of non-NOVX proteins, and most preferably less than about 5% of non-NOVX proteins. When the NOVX protein or biologically-active portion thereof is recombinantly-produced, it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, more preferably less than sequence of the active site is complementary to the nucleotide sequence to be cleaved in a NOVX-encoding mRNA. See, e.g., U.S. Pat. No. 4,987,071 to Cech, et al. and U.S. Pat. No. 5,116,742 to Cech, et al. NOVX mRNA can also be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., (1993) Science 261:1411-1418.


[0089] Alternatively, NOVX gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the NOVX nucleic acid (e.g., the NOVX promoter and/or enhancers) to form triple helical structures that prevent transcription of the NOVX gene in target cells. See, e.g., Helene, 1991. Anticancer Drug Des. 6: 569-84; Helene, et al. 1992. Ann. N.Y. Acad. Sci. 660: 27-36; Maher, 1992. Bioassays 14: 807-15.


[0090] In various embodiments, the NOVX nucleic acids can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids. See, e.g., Hyrup, et al., 1996. Bioorg Med Chem 4: 5-23. As used herein, the terms “peptide nucleic acids” or “PNAs” refer to nucleic acid mimics (e.g., DNA mimics) in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleotide bases are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomer can be performed using standard solid phase peptide synthesis protocols as described in Hyrup, et al., 1996. supra; Perry-O'Keefe, et al., 1996. Proc. Natl. Acad. Sci. USA 93: 14670-14675.


[0091] PNAs of NOVX can be used in therapeutic and diagnostic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. PNAs of NOVX can also be used, for example, in the analysis of single base pair mutations in a gene (e.g., PNA directed PCR clamping; as artificial restriction enzymes when used in combination with other enzymes, e.g., S1 nucleases (See, Hyrup, et al., 1996.supra); or as probes or primers for DNA sequence and hybridization (See, Hyrup, et al., 1996, supra; Perry-O'Keefe, et al., 1996. supra).


[0092] In another embodiment, PNAs of NOVX can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA-DNA chimeras of NOVX can be generated that may combine the advantageous properties of PNA and DNA. Such chimeras allow DNA recognition enzymes (e.g., RNase H and DNA polymerases) to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity. PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleotide bases, and orientation (see, Hyrup, et al., 1996. supra). The synthesis of PNA-DNA chimeras can be performed as described in Hyrup, et al., 1996. supra and Finn, et al., 1996. Nucl Acids Res 24: 3357-3363. For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry, and modified nucleoside analogs, e.g., 5′-(4-methoxytrityl)amino-5′-deoxy-thymidine phosphoramidite, can be used between the PNA and the 5′ end of DNA. See, e.g., Mag, et al., 1989. Nucl Acid Res 17: 5973-5988. PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5′ PNA segment and a 3′ DNA segment. See, e.g., Finn, et al., 1996. supra. Alternatively, chimeric molecules can be synthesized with a 5′ DNA segment and a 3′ PNA segment. See, e.g., Petersen, et al., 1975. Bioorg. Med. Chem. Lett. 5: 1119-11124.


[0093] In other embodiments, the oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger, et al., 1989. Proc. Natl. Acad. Sci. U.S.A. 86: 6553-6556; Lemaitre, et al., 1987. Proc. Natl. Acad. Sci. 84: 648-652; PCT Publication No. WO88/09810) or the blood-brain barrier (see, e.g., PCT Publication No. WO 89/10134). In addition, oligonucleotides can be modified with hybridization triggered cleavage agents (see, e.g., Krol, et al., 1988. BioTechniques 6:958-976) or intercalating agents (see, e.g., Zon, 1988. Pharm. Res. 5: 539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, a hybridization triggered cross-linking agent, a transport agent, a hybridization-triggered cleavage agent, and the like.


[0094] NOVX Polypeptides


[0095] A polypeptide according to the invention includes a polypeptide including the amino acid sequence of NOVX polypeptides whose sequences are provided in any one of SEQ ID NO:2n, wherein n is an integer between 1-101. The invention also includes a mutant or variant protein about 10%, and most preferably less than about 5% of the volume of the NOVX protein preparation.


[0096] The language “substantially free of chemical precursors or other chemicals” includes preparations of NOVX proteins in which the protein is separated from chemical precursors or other chemicals that are involved in the synthesis of the protein. In one embodiment, the language “substantially free of chemical precursors or other chemicals” includes preparations of NOVX proteins having less than about 30% (by dry weight) of chemical precursors or non-NOVX chemicals, more preferably less than about 20% chemical precursors or non-NOVX chemicals, still more preferably less than about 10% chemical precursors or non-NOVX chemicals, and most preferably less than about 5% chemical precursors or non-NOVX chemicals.


[0097] Biologically-active portions of NOVX proteins include peptides comprising amino acid sequences sufficiently homologous to or derived from the amino acid sequences of the NOVX proteins (e.g., the amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1-101) that include fewer amino acids than the full-length NOVX proteins, and exhibit at least one activity of a NOVX protein. Typically, biologically-active portions comprise a domain or motif with at least one activity of the NOVX protein. A biologically-active portion of a NOVX protein can be a polypeptide which is, for example, 10, 25, 50, 100 or more amino acid residues in length.


[0098] Moreover, other biologically-active portions, in which other regions of the protein are deleted, can be prepared by recombinant techniques and evaluated for one or more of the functional activities of a native NOVX protein.


[0099] In an embodiment, the NOVX protein has an amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1-101. In other embodiments, the NOVX protein is substantially homologous to SEQ ID NO:2n, wherein n is an integer between 1-1 01, and retains the functional activity of the protein of SEQ ID NO:2n, wherein n is an integer between 1-101, yet differs in amino acid sequence due to natural allelic variation or mutagenesis, as described in detail, below. Accordingly, in another embodiment, the NOVX protein is a protein that comprises an amino acid sequence at least about 45% homologous to the amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1-101, and retains the functional activity of the NOVX proteins of SEQ ID NO:2n, wherein n is an integer between 1-101.


[0100] Determining Homology Between Two or More Sequences


[0101] To determine the percent homology of two amino acid sequences or of two nucleic acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are homologous at that position (i.e., as used herein amino acid or nucleic acid “homology” is equivalent to amino acid or nucleic acid “identity”).


[0102] The nucleic acid sequence homology may be determined as the degree of identity between two sequences. The homology may be determined using computer programs known in the art, such as GAP software provided in the GCG program package. See, Needleman and Wunsch, 1970. J Mol Biol 48: 443-453. Using GCG GAP software with the following settings for nucleic acid sequence comparison: GAP creation penalty of 5.0 and GAP extension penalty of 0.3, the coding region of the analogous nucleic acid sequences referred to above exhibits a degree of identity preferably of at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%, with the CDS (encoding) part of the DNA sequence of SEQ ID NO:2n−1, wherein n is an integer between 1-101.


[0103] The term “sequence identity” refers to the degree to which two polynucleotide or polypeptide sequences are identical on a residue-by-residue basis over a particular region of comparison. The term “percentage of sequence identity” is calculated by comparing two optimally aligned sequences over that region of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I, in the case of nucleic acids) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the region of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. The term “substantial identity” as used herein denotes a characteristic of a polynucleotide sequence, wherein the polynucleotide comprises a sequence that has at least 80 percent sequence identity, preferably at least 85 percent identity and often 90 to 95 percent sequence identity, more usually at least 99 percent sequence identity as compared to a reference sequence over a comparison region.


[0104] Chimeric and Fusion Proteins


[0105] The invention also provides NOVX chimeric or fusion proteins. As used herein, a NOVX “chimeric protein” or “fusion protein” comprises a NOVX polypeptide operatively-linked to a non-NOVX polypeptide. An “NOVX polypeptide” refers to a polypeptide having an amino acid sequence corresponding to a NOVX protein of SEQ ID NO:2n, wherein n is an integer between 1-101, whereas a “non-NOVX polypeptide” refers to a polypeptide having an amino acid sequence corresponding to a protein that is not substantially homologous to the NOVX protein, e.g., a protein that is different from the NOVX protein and that is derived from the same or a different organism. Within a NOVX fusion protein the NOVX polypeptide can correspond to all or a portion of a NOVX protein. In one embodiment, a NOVX fusion protein comprises at least one biologically-active portion of a NOVX protein. In another embodiment, a NOVX fusion protein comprises at least two biologically-active portions of a NOVX protein. In yet another embodiment, a NOVX fusion protein comprises at least three biologically-active portions of a NOVX protein. Within the fusion protein, the term “operatively-linked” is intended to indicate that the NOVX polypeptide and the non-NOVX polypeptide are fused in-frame with one another. The non-NOVX polypeptide can be fused to the N-terminus or C-terminus of the NOVX polypeptide.


[0106] In one embodiment, the fusion protein is a GST-NOVX fusion protein in which the NOVX sequences are fused to the C-terminus of the GST (glutathione S-transferase) sequences. Such fusion proteins can facilitate the purification of recombinant NOVX polypeptides.


[0107] In another embodiment, the fusion protein is a NOVX protein containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression and/or secretion of NOVX can be increased through use of a heterologous signal sequence.


[0108] In yet another embodiment, the fusion protein is a NOVX-immunoglobulin fusion protein in which the NOVX sequences are fused to sequences derived from a member of the immunoglobulin protein family. The NOVX-immunoglobulin fusion proteins of the invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between a NOVX ligand and a NOVX protein on the surface of a cell, to thereby suppress NOVX-mediated signal transduction in vivo. The NOVX-immunoglobulin fusion proteins can be used to affect the bioavailability of a NOVX cognate ligand. Inhibition of the NOVX ligand/NOVX interaction may be useful therapeutically for both the treatment of proliferative and differentiative disorders, as well as modulating (e.g. promoting or inhibiting) cell survival. Moreover, the NOVX-immunoglobulin fusion proteins of the invention can be used as immunogens to produce anti-NOVX antibodies in a subject, to purify NOVX ligands, and in screening assays to identify molecules that inhibit the interaction of NOVX with a NOVX ligand.


[0109] A NOVX chimeric or fusion protein of the invention can be produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, e.g., by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive gene fragments that can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, e.g., Ausubel, et al. (eds.) CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide). A NOVX-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the NOVX protein.


[0110] NOVX Agonists and Antagonists


[0111] The invention also pertains to variants of the NOVX proteins that function as either NOVX agonists (i.e., mimetics) or as NOVX antagonists. Variants of the NOVX protein can be generated by mutagenesis (e.g., discrete point mutation or truncation of the NOVX protein). An agonist of the NOVX protein can retain substantially the same, or a subset of, the biological activities of the naturally occurring form of the NOVX protein. An antagonist of the NOVX protein can inhibit one or more of the activities of the naturally occurring form of the NOVX protein by, for example, competitively binding to a downstream or upstream member of a cellular signaling cascade which includes the NOVX protein. Thus, specific biological effects can be elicited by treatment with a variant of limited function. In one embodiment, treatment of a subject with a variant having a subset of the biological activities of the naturally occurring form of the protein has fewer side effects in a subject relative to treatment with the naturally occurring form of the NOVX proteins.


[0112] Variants of the NOVX proteins that function as either NOVX agonists (i.e., mimetics) or as NOVX antagonists can be identified by screening combinatorial libraries of mutants (e.g., truncation mutants) of the NOVX proteins for NOVX protein agonist or antagonist activity. In one embodiment, a variegated library of NOVX variants is generated by combinatorial mutagenesis at the nucleic acid level and is encoded by a variegated gene library. A variegated library of NOVX variants can be produced by, for example, enzymatically ligating a mixture of synthetic oligonucleotides into gene sequences such that a degenerate set of potential NOVX sequences is expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g., for phage display) containing the set of NOVX sequences thereini. There are a variety of methods which can be used to produce libraries of potential NOVX variants from a degenerate oligonucleotide sequence. Chemical synthesis of a degenerate gene sequence can be performed in an automatic DNA synthesizer, and the synthetic gene then ligated into an appropriate expression vector. Use of a degenerate set of genes allows for the provision, in one mixture, of all of the sequences encoding the desired set of potential NOVX sequences. Methods for synthesizing degenerate oligonucleotides are well-known within the art. See, e.g., Narang, 1983. Tetrahedron 39: 3; Itakura, et al., 1984. Annu. Rev. Biochem. 53: 323; Itakura, et al., 1984. Science 198: 1056; Ike, et al., 1983. Nucl. Acids Res. 11: 477.


[0113] Polypeptide Libraries


[0114] In addition, libraries of fragments of the NOVX protein coding sequences can be used to generate a variegated population of NOVX fragments for screening and subsequent selection of variants of a NOVX protein. In one embodiment, a library of coding sequence fragments can be generated by treating a double stranded PCR fragment of a NOVX coding sequence with a nuclease under conditions wherein nicking occurs only about once per molecule, denaturing the double stranded DNA, renaturing the DNA to form double-stranded DNA that can include sense/antisense pairs from different nicked products, removing single stranded portions from reformed duplexes by treatment with S1 nuclease, and ligating the resulting fragment library into an expression vector. By this method, expression libraries can be derived which encodes N-terminal and internal fragments of various sizes of the NOVX proteins.


[0115] Various techniques are known in the art for screening gene products of combinatorial libraries made by point mutations or truncation, and for screening cDNA libraries for gene products having a selected property. Such techniques are adaptable for rapid screening of the gene libraries generated by the combinatorial mutagenesis of NOVX proteins. The most widely used techniques, which are amenable to high throughput analysis, for screening large gene libraries typically include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates isolation of the vector encoding the gene whose product was detected. Recursive ensemble mutagenesis (REM), a new technique that enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify NOVX variants. See, e.g., Arkin and Yourvan, 1992. Proc. Natl. Acad. Sci. USA 89: 7811-7815; Delgrave, et al., 1993. Protein Engineering 6:327-331.


[0116] NOVX Antibodies


[0117] The term “antibody” as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen binding site that specifically binds (immunoreacts with) an antigen. Such antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, Fab, Fab′ and F(ab′)2 fragments, and an Fab expression library. In general, antibody molecules obtained from humans relates to any of the classes IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature of the heavy chain present in the molecule. Certain classes have subclasses as well, such as IgG1, IgG2, and others. Furthermore, in humans, the light chain may be a kappa chain or a lambda chain. Reference herein to antibodies includes a reference to all such classes, subclasses and types of human antibody species.


[0118] An isolated protein of the invention intended to serve as an antigen, or a portion or fragment thereof, can be used as an immunogen to generate antibodies that immunospecifically bind the antigen, using standard techniques for polyclonal and monoclonal antibody preparation. The full-length protein can be used or, alternatively, the invention provides antigenic peptide fragments of the antigen for use as immunogens. An antigenic peptide fragment comprises at least 6 amino acid residues of the amino acid sequence of the full length protein, such as an amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1-101, and encompasses an epitope thereof such that an antibody raised against the peptide forms a specific immune complex with the full length protein or with any fragment that contains the epitope. Preferably, the antigenic peptide comprises at least 10 amino acid residues, or at least 15 amino acid residues, or at least 20 amino acid residues, or at least 30 amino acid residues. Preferred epitopes encompassed by the antigenic peptide are regions of the protein that are located on its surface; commonly these are hydrophilic regions.


[0119] In certain embodiments of the invention, at least one epitope encompassed by the antigenic peptide is a region of NOVX that is located on the surface of the protein, e.g., a hydrophilic region. A hydrophobicity analysis of the human NOVX protein sequence will indicate which regions of a NOVX polypeptide are particularly hydrophilic and, therefore, encode surface residues useful for targeting antibody production. As a means for targeting antibody production, hydropathy plots showing regions of hydrophilicity and hydrophobicity may be generated by any method well known in the art, including, for example, the Kyte Doolittle or the Hopp Woods methods, either with or without Fourier transformation. See, e.g., Hopp and Woods, 1981, Proc. Nat. Acad. Sci. USA 78: 3824-3828; Kyte and Doolittle 1982, J. Mol. Biol. 157: 105-142, each incorporated herein by reference in their entirety. Antibodies that are specific for one or more domains within an antigenic protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein.


[0120] The term “epitope” includes any protein determinant capable of specific binding to an immunoglobulin or T-cell receptor. Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three dimensional structural characteristics, as well as specific charge characteristics. A NOVX polypeptide or a fragment thereof comprises at least one antigenic epitope. An anti-NOVX antibody of the present invention is said to specifically bind to antigen NOVX when the equilibrium binding constant (KD) is ≦1 μM, preferably ≦100 nM, more preferably ≦10 nM, and most preferably ≦100 pM to about 1 pM, as measured by assays such as radioligand binding assays or similar assays known to those skilled in the art.


[0121] A protein of the invention, or a derivative, fragment, analog, homolog or ortholog thereof, may be utilized as an immunogen in the generation of antibodies that immunospecifically bind these protein components.


[0122] Various procedures known within the art may be used for the production of polyclonal or monoclonal antibodies directed against a protein of the invention, or against derivatives, fragments, analogs homologs or orthologs thereof (see, for example, Antibodies: A Laboratory Manual, Harlow E, and Lane D, 1988, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, incorporated herein by reference). Some of these antibodies are discussed below.


[0123] Polyclonal Antibodies


[0124] For the production of polyclonal antibodies, various suitable host animals (e.g., rabbit, goat, mouse or other mammal) may be immunized by one or more injections with the native protein, a synthetic variant thereof, or a derivative of the foregoing. An appropriate immunogenic preparation can contain, for example, the naturally occurring immunogenic protein, a chemically synthesized polypeptide representing the immunogenic protein, or a recombinantly expressed immunogenic protein. Furthermore, the protein may be conjugated to a second protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. The preparation can further include an adjuvant. Various adjuvants used to increase the immunological response include, but are not limited to, Freund's (complete and incomplete), mineral gels (e.g., aluminum hydroxide), surface active substances (e.g., lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, dinitrophenol, etc.), adjuvants usable in humans such as Bacille Calmette-Guerin and Corynebacterium parvum, or similar immunostimulatory agents. Additional examples of adjuvants which can be employed include MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).


[0125] The polygonal antibody molecules directed against the immunogenic protein can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as affinity chromatography using protein A or protein G, which provide primarily the IgG fraction of immune serum. Subsequently, or alternatively, the specific antigen which is the target of the immunoglobulin sought, or an epitope thereof, may be immobilized on a column to purify the immune specific antibody by immunoaffinity chromatography. Purification of immunoglobulins is discussed, for example, by D. Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia Pa., Vol. 14, No. 8 (Apr. 17, 2000), pp. 25-28).


[0126] Monoclonal Antibodies


[0127] The term “monoclonal antibody” (MAb) or “monoclonal antibody composition”, as used herein, refers to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product. In particular, the complementarity determining regions (CDRs) of the monoclonal antibody are identical in all the molecules of the population. MAbs thus contain an antigen binding site capable of immunoreacting with a particular epitope of the antigen characterized by a unique binding affinity for it.


[0128] Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975). In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes can be immunized in vitro.


[0129] The immunizing agent will typically include the protein antigen, a fragment thereof or a fusion protein thereof. Generally, either peripheral blood lymphocytes are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell [Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-103]. Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells can be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (“HAT medium”), which substances prevent the growth of HGPRT-deficient cells.


[0130] Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, Calif. and the American Type Culture Collection, Manassas, Va. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies [Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51-63].


[0131] The culture medium in which the hybridoma cells arc cultured can then be assayed for the presence of monoclonal antibodies directed against the antigen. Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, Such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107:220 (1980). It is an objective, especially important in therapeutic applications of monoclonal antibodies, to identify antibodies having a high degree of specificity and a high binding affinity for the target antigen.


[0132] After the desired hybridoma cells are identified, the clones can be subcloned by limiting dilution procedures and grown by standard methods (Goding, 1986). Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal.


[0133] The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.


[0134] The monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Pat. No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells of the invention serve as a preferred source of such DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences (U.S. Pat. No. 4,816,567; Morrison, Nature 368, 812-13 (1994)) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.


[0135] Humanized Antibodies


[0136] The antibodies directed against the protein antigens of the invention can further comprise humanized antibodies or human antibodies. These antibodies are suitable for administration to humans without engendering an immune response by the human against the administered immunoglobulin. Humanized forms of antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab′, F(ab′)2 or other antigen-binding subsequences of antibodies) that are principally comprised of the sequence of a human immunoglobulin, and contain minimal sequence derived from a non-human immunoglobulin. Humanization can be performed following the method of Winter and co-workers (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. (See also U.S. Pat. No. 5,225,539.) In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies can also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al., 1986; Riechmann et al., 1988; and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992)).


[0137] Human Antibodies


[0138] Fully human antibodies essentially relate to antibody molecules in which the entire sequence of both the light chain and the heavy chain, including the CDRs, arise from human genes. Such antibodies are termed “human antibodies”, or “fully human antibodies” herein. Human monoclonal antibodies can be prepared by the trioma technique; the human B-cell hybridoma technique (see Kozbor, et al., 1983 Immunol Today 4: 72) and the EBV hybridoma technique to produce human monoclonal antibodies (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96). Human monoclonal antibodies may be utilized in the practice of the present invention and may be produced by using human hybridomas (see Cote, et al., 1983. Proc Natl Acad Sci USA 80: 2026-2030) or by transforming human B-cells with Epstein Barr Virus in vitro (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96).


[0139] In addition, human antibodies can also be produced using additional techniques, including phage display libraries (Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)). Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et al. (Bio/Techology 10, 779-783 (1992)); Lonberg et al. (Nature 368 856-859 (1994)); Morrison (Nature 368, 812-13 (1994)); Fishwild et al, (Nature Biotechnology 14, 845-51 (1996)); Neuberger (Nature Biotechnology 14, 826 (1996)); and Lonberg and Huszar (Intern. Rev. Immunol. 13 65-93 (1995)).


[0140] Human antibodies may additionally be produced using transgenic nonhuman animals which are modified so as to produce fully human antibodies rather than the animal's endogenous antibodies in response to challenge by an antigen. (See PCT publication WO94/02602). The endogenous genes encoding the heavy and light immunoglobulin chains in the nonhuman host have been incapacitated, and active loci encoding human heavy and light chain immunoglobulins are inserted into the host's genome. The human genes are incorporated, for example, using yeast artificial chromosomes containing the requisite human DNA segments. An animal which provides all the desired modifications is then obtained as progeny by crossbreeding intermediate transgenic animals containing fewer than the full complement of the modifications. The preferred embodiment of such a nonhuman animal is a mouse, and is termed the Xenomouse™ as disclosed in PCT publications WO 96/33735 and WO 96/34096. This animal produces B cells which secrete fully human immunoglobulins. The antibodies can be obtained directly from the animal after immunization with an immunogen of interest, as, for example, a preparation of a polyclonal antibody, or alternatively from immortalized B cells derived from the animal, such as hybridomas producing monoclonal antibodies. Additionally, the genes encoding the immunoglobulins with human variable regions can be recovered and expressed to obtain the antibodies directly, or can be further modified to obtain analogs of antibodies such as, for example, single chain Fv molecules.


[0141] An example of a method of producing a nonhuman host, exemplified as a mouse, lacking expression of an endogenous immunoglobulin heavy chain is disclosed in U.S. Pat. No. 5,939,598. It can be obtained by a method including deleting the J segment genes from at least one endogenous heavy chain locus in an embryonic stem cell to prevent rearrangement of the locus and to prevent formation of a transcript of a rearranged immunoglobulin heavy chain locus, the deletion being effected by a targeting vector containing a gene encoding a selectable marker; and producing from the embryonic stem cell a transgenic mouse whose somatic and germ cells contain the gene encoding the selectable marker.


[0142] A method for producing an antibody of interest, such as a human antibody, is disclosed in U.S. Pat. No. 5,916,771. It includes introducing an expression vector that contains a nucleotide sequence encoding a heavy chain into one mammalian host cell in culture, introducing an expression vector containing a nucleotide sequence encoding a light chain into another mammalian host cell, and fusing the two cells to form a hybrid cell. The hybrid cell expresses an antibody containing the heavy chain and the light chain.


[0143] In a further improvement on this procedure, a method for identifying a clinically relevant epitope on an immunogen, and a correlative method for selecting an antibody that binds immunospecifically to the relevant epitope with high affinity, are disclosed in PCT publication WO 99/53049.


[0144] Fab Fragments and Single Chain Antibodies


[0145] According to the invention, techniques can be adapted for the production of single-chain antibodies specific to an antigenic protein of the invention (see e.g., U.S. Pat. No. 4,946,778). In addition, methods can be adapted for the construction of Fab expression libraries (see e.g., Huse, et al., 1989 Science 246: 1275-1281) to allow rapid and effective identification of monoclonal Fab fragments with the desired specificity for a protein or derivatives, fragments, analogs or homologs thereof. Antibody fragments that contain the idiotypes to a protein antigen may be produced by techniques known in the art including, but not limited to: (i) an F(ab′)2 fragment produced by pepsin digestion of an antibody molecule; (ii) an Fab fragment generated by reducing the disulfide bridges of an F(ab′)2 fragment; (iii) an Fab fragment generated by the treatment of the antibody molecule with papain and a reducing agent and (iv) Fv fragments.


[0146] Bispecific Antibodies


[0147] Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for an antigenic protein of the invention. The second binding target is any other antigen, and advantageously is a cell-surface protein or receptor or receptor subunit.


[0148] Methods for making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature, 305:537-539 (1983)). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO 93/08829, published May 13, 1993, and in Traunecker et al., EMBO J., 10:3655-3659 (1991).


[0149] Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region (CH1) containing the site necessary for light-chain binding present in at least one of the fusions. DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology, 121:210 (1986).


[0150] According to another approach described in WO 96/27011, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH3 region of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g. tyrosine or tryptophan). Compensatory “cavities” of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers.


[0151] Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g. F(ab′)2 bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al., Science 229:81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab′)2 fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab′ fragments generated are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab′-TNB derivatives is then reconverted to the Fab′-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab′-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.


[0152] Additionally, Fab′ fragments can be directly recovered from E. coli and chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175:217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab′)2 molecule. Each Fab′ fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.


[0153] Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al., J. Immunol. 148(5):1547-1553 (1992). The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab′ portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers. The “diabody” technology described by Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments. The fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See, Gruber et al., J. Immunol. 152:5368 (1994).


[0154] Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991).


[0155] Exemplary bispecific antibodies can bind to two different epitopes, at least one of which originates in the protein antigen of the invention. Alternatively, an anti-antigenic arm of an immunoglobulin molecule can be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2, CD3, CD28, or B7), or Fc receptors for IgG (FcγR), such as FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD16) so as to focus cellular defense mechanisms to the cell expressing the particular antigen. Bispecific antibodies can also be used to direct cytotoxic agents to cells which express a particular antigen. These antibodies possess an antigen-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. Another bispecific antibody of interest binds the protein antigen described herein and further binds tissue factor (TF).


[0156] Heteroconjugate Antibodies


[0157] Heteroconjugate antibodies arc also within the scope of the present invention. Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Pat. No. 4,676,980), and for treatment of HIV infection (WO 91/00360; WO 92/200373; EP 03089). It is contemplated that the antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxinis can be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S. Pat. No. 4,676,980.


[0158] Effector Function Engineering


[0159] It can be desirable to modify the antibody of the invention with respect to effector function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer. For example, cysteine residue(s) can be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated can have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et al., J. Exp Med., 176: 1191-1195 (1992) and Shopes, J. Immunol., 148: 2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers as described in Wolff et al. Cancer Research, 53: 2560-2565 (1993). Alternatively, an antibody can be engineered that has dual Fc regions and can thereby have enhanced complement lysis and ADCC capabilities. See Stevenson et al., Anti-Cancer Drug Designs 3: 219-230 (1989).


[0160] Immunoconjugates


[0161] The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).


[0162] Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above. Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas acruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include 212Bi, 131I, 131In, 90Y, and 186Re.


[0163] Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as gluitareldehlyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepenitaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO94/11026.


[0164] In another embodiment, the antibody can be conjugated to a “receptor” (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a “ligand” (e.g., avidin) that is in turn conjugated to a cytotoxic agent.


[0165] Immunoliposomes


[0166] The antibodies disclosed herein can also be formulated as immunoliposomes. Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., Proc. Natl Acad. Sci. USA, 77:4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Pat. No. 5,013,556.


[0167] Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter. Fab′ fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin et al ., J. Biol. Chem., 257: 286-288 (1982) via a disulfide-interchange reaction. A chemotherapeutic agent (such as Doxorubicin) is optionally contained within the liposome. See Gabizon ct al., J. National Cancer Inst., 81(19): 1484 (1989).


[0168] Diagnostic Applications of Antibodies Directed Against the Proteins of the Invention


[0169] Antibodies directed against a protein of the invention may be used in methods known within the art relating to the localization and/or quantitation of the protein (e.g., for use in measuring levels of the protein within appropriate physiological samples, for use in diagnostic methods, for use in imaging the protein, and the like). In a given embodiment, antibodies against the proteins, or derivatives, fragments, analogs or homologs thereof, that contain the antigen binding domain, are utilized as pharmacologically-active compounds (see below).


[0170] An antibody specific for a protein of the invention can be used to isolate the protein by standard techniques, such as immunoaffinity chromatography or immunoprecipitation. Such an antibody can facilitate the purification of the natural protein antigen from cells and of recombinantly produced antigen expressed in host cells. Moreover, such an antibody can be used to detect the antigenic protein (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the antigenic protein. Antibodies directed against the protein can be used diagnostically to monitor protein levels in tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include 125I, 131I, 35S or 3H.


[0171] Antibody Therapeutics


[0172] Antibodies of the invention, including polyclonal, monoclonal, humanized and fully human antibodies, may used as therapeutic agents. Such agents will generally be employed to treat or prevent a disease or pathology in a subject. An antibody preparation, preferably one having high specificity and high affinity for its target antigen, is administered to the subject and will generally have an effect due to its binding with the target. Such an effect may be one of two kinds, depending on the specific nature of the interaction between the given antibody molecule and the target antigen in question. In the first instance, administration of the antibody may abrogate or inhibit the binding of the target with an endogenous ligand to which it naturally binds. In this case, the antibody binds to the target and masks a binding site of the naturally occurring ligand, wherein the ligand serves as an effector molecule. Thius the receptor mediates a signal transduction pathway for which ligand is responsible.


[0173] Alteratively, the effect may be one in which the antibody elicits a physiological result by virtue of binding to an effector binding site on the target molecule. In this case the target, a receptor having an endogenous ligand which may be absent or defective in the disease or pathology, binds the antibody as a surrogate effector ligand, initiating a receptor-based signal transduction event by the receptor.


[0174] A therapeutically effective amount of an antibody of the invention relates generally to the amount needed to achieve a therapeutic objective. As noted above, this may be a binding interaction between the antibody and its target antigen that, in certain cases, interferes with the functioning of the target, and in other cases, promotes a physiological response. The amount required to be administered will furthermore depend on the binding affinity of the antibody for its specific antigen, and will also depend on the rate at which an administered antibody is depleted from the free volume other subject to which it is administered. Common ranges for therapeutically effective dosing of an antibody or antibody fragment of the invention may be, by way of nonlimiting example, from about 0.1 mg/kg body weight to about 50 mg/kg body weight. Common dosing frequencies may range, for example, from twice daily to once a week.


[0175] Pharmaceutical Compositions of Antibodies


[0176] Antibodies specifically binding a protein of the invention, as well as other molecules identified by the screening assays disclosed herein, can be administered for the treatment of various disorders in the form of pharmaceutical compositions. Principles and considerations involved in preparing such compositions, as well as guidance in the choice of components are provided, for example, in Remington: The Science And Practice Of Pharmacy 19th ed. (Alfonso R. Gennaro, et al., editors) Mack Pub. Co., Easton, Pa.: 1995; Drug Absorption Enhancement Concepts, Possibilities, Limitations, And Trends, Harwood Academic Publishers, Langhorne, Pa., 1994; and Peptide And Protein Drug Delivery (Advances In Parenteral Sciences, Vol. 4), 1991, M. Dekker, New York.


[0177] If the antigenic protein is intracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred. However, liposomes can also be used to deliver the antibody, or an antibody fragment, into cells. Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred. For example, based upon the variable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target protein sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA technology. See, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA, 90: 7889-7893 (1993). The formulation herein can also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the composition can comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.


[0178] The active ingredients can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions.


[0179] The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.


[0180] Sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and γ ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods.


[0181] ELISA Assay


[0182] An agent for detecting an analyte protein is an antibody capable of binding to an analyte protein, preferably an antibody with a detectable label. Antibodies can be polygonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F(ab)2) can be used. The term “labeled”, with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labelinig of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term “biological sample” is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. Included within the usage of the term “biological sample”, therefore, is blood and a fraction or component of blood including blood serum, blood plasma, or lymph. That is, the detection method of the invention can be used to detect an analyte mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of an analyte mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of an analyte protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of an analyte genomic DNA include Southern hybridizations. Procedures for conducting immunoassays are described, for example in “ELISA: Theory and Practice: Methods in Molecular Biology”, Vol. 42, J. R. Crowther (Ed.) Human Press, Totowa, N.J., 1995; “Immunoassay”, E. Diamandis and T. Christopoulus, Academic Press, Inc., San Diego, Calif., 1996; and “Practice and Thory of Enzyme Immunloassays”, P. Tijssen, Elsevier Science Publishers, Amsterdam, 1985. Furthermore, in vivo techniques for detection of an analyte protein include introducing into a subject a labeled anti-an analyte protein antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.


[0183] NOVX Recombinant Expression Vectors and Host Cells


[0184] Another aspect of the invention pertains to vectors, preferably expression vectors, containing a nucleic acid encoding a NOVX protein, or derivatives, fragments, analogs or homologs thereof. As used herein, the term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a “plasmid”, which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively-linked. Such vectors are referred to herein as “expression vectors”. In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, “plasmid” and “vector” can be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.


[0185] The recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, that is operatively-linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, “operably-linked” is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner that allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell).


[0186] The term “regulatory sequence” is intended to includes promoters, enhancers and other expression control elements (e.g., polyadenylationl signals). Such regulatory sequences are described, for example, in Coeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence in many types of host cell and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein (e.g., NOVX proteins, mutant forms of NOVX proteins, fusion proteins, etc.).


[0187] The recombinant expression vectors of the invention can be designed for expression of NOVX proteins in prokaryotic or eukaryotic cells. For example, NOVX proteins can be expressed in bacterial cells such as Escherichia coli, insect cells (using baculovirus expression vectors) yeast cells or mammalian cells. Suitable host cells are discussed further in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.


[0188] Expression of proteins in prokaryotes is most often carried out in Escherichia coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein. Such fusion vectors typically serve three purposes: (i) to increase expression of recombinant protein; (ii) to increase the solubility of the recombinant protein; and (iii) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant protein to enable separation of the recombinant protein from the fusion moiety subsequent to purification of the fusion protein. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith and Johnson, 1988. Gene 67: 31-40), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) that fuse glutathionc S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein.


[0189] Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amrann et al., (1988) Gene 69:301-315) and pET 11d (Studier et al., GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 60-89).


[0190] One strategy to maximize recombinant protein expression in E. coli is to express the protein in a host bacteria with an impaired capacity to proteolytically cleave the recombinant protein. See, e.g., Gottesman, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 119-128. Another strategy is to alter the nucleic acid sequence of the nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E. coli (see, e.g., Wada, et al., 1992. Nucl. Acids Res. 20: 2111-2118). Such alteration of nucleic acid sequences of the invention can be carried out by standard DNA synthesis techniques.


[0191] In another embodiment, the NOVX expression vector is a yeast expression vector. Examples of vectors for expression in yeast Saccharomyces cerivisae include pYepSec1 (Baldari, et al., 1987. EMBO J. 6: 229-234), pMFa (Kurjan and Herskowitz, 1982. Cell 30: 933-943), pJRY88 (Schultz et al., 1987. Gene 54: 113-123), pYES2 (Invitrogen Corporation, San Diego, Calif.), and picZ (InVitrogen Corp, San Diego, Calif.).


[0192] Alternatively, NOVX can be expressed in insect cells using baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., SF89 cells) include the pAc series (Smith, et al., 1983. Mol. Cell. Biol. 3: 2156-2165) and the pVL series (Lucklow and Summers, 1989. Virology 170: 31-39).


[0193] In yet another embodiment, a nucleic acid of the invention is expressed in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include pCDM8 (Seed, 1987. Nature 329: 840) and pMT2PC (Kaufman, et al., 1987. EMBO. J. 6: 187-195). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, adenovirus 2, cytomegalovirus, and simian virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 of Sambrook, et al., MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989.


[0194] In another embodiment, the recombinant mammalian expression vector is capable of directing expression of the nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert, et al., 1987. Genes Dev. 1: 268-277), lymphoid-specific promoters (Calame and Eaton, 1988. Adv. Immunol. 43: 235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989. EMBO. J. 8: 729-733) and immunoglobulins (Banerji, et al., 1983. Cell 33: 729-740; Queen and Baltimore, 1983. Cell 33: 741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle, 1989. Proc. Natl. Acad. Sci. USA 86: 5473-5477), pancreas-specific promoters (Edlund, et al., 1985. Science 230: 912-916), and mammary gland-specific promoters (e g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are also encompassed, e.g., the murine hox promoters (Kessel and Gruss, 1990. Science 249: 374-379) and the α-fetoprotein promoter (Campes and Tilghman, 1989. Genes Dev. 3: 537-546).


[0195] The invention further provides a recombinant expression vector comprising a DNA molecule of the invention cloned into the expression vector in an antisense orientation. That is, the DNA molecule is operatively-linked to a regulatory sequence in a manner that allows for expression (by transcription of the DNA molecule) of an RNA molecule that is antisense to NOVX mRNA. Regulatory sequences operatively linked to a nucleic acid cloned in the antisense orientation can be chosen that direct the continuous expression of the antisense RNA molecule in a variety of cell types, for instance viral promoters and/or enhancers, or regulatory sequences can be chosen that direct constitutive, tissue specific or cell type specific expression of antisense RNA. The antisense expression vector can be in the form of a recombinant plasmid, phagemid or attenuated virus in which antisense nucleic acids are produced under the control of a high efficiency regulatory region, the activity of which can be determined by the cell type into which the vector is introduced. For a discussion of the regulation of gene expression using antisense genies see, e.g., Weintraub, et al., “Antisense RNA as a molecular tool for genetic analysis,” Reviews-Trends in Genetics, Vol. 1(1) 1986.


[0196] Another aspect of the invention pertains to host cells into which a recombinant expression vector of the invention has been introduced. The terms “host cell” and “recombinant host cell” are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.


[0197] A host cell can be any prokaryotic or eukaryotic cell. For example, NOVX protein can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are known to those skilled in the art.


[0198] Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms “transformation” and “transfection” are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989), and other laboratory manuals.


[0199] For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Various selectable markers include those that confer resistance to drugs, such as G418, hygromycin and methotrexate. Nucleic acid encoding a selectable marker can be introduced into a host cell on the same vector as that encoding NOVX or can be introduced on a separate vector. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die).


[0200] A host cell of the invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (i.e., express) NOVX protein. Accordingly, the invention further provides methods for producing NOVX protein using the host cells of the invention. In one embodiment, the method comprises culturing the host cell of invention (into which a recombinant expression vector encoding NOVX protein has been introduced) in a suitable medium such that NOVX protein is produced. In another embodiment, the method further comprises isolating NOVX protein from the medium or the host cell.


[0201] Transgenic NOVX Animals


[0202] The host cells of the invention can also be used to produce non-human transgenic animals. For example, in one embodiment, a host cell of the invention is a fertilized oocyte or an embryonic stem cell into which NOVX protein-coding sequences have been introduced. Such host cells can then be used to create non-human transgenic animals in which exogenous NOVX sequences have been introduced into their genome or homologous recombinant animals in which endogenous NOVX sequences have been altered. Such animals are useful for studying the function and/or activity of NOVX protein and for identifying and/or evaluating modulators of NOVX protein activity. As used herein, a “transgenic animal” is a non-human animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in which one or more of the cells of the animal includes a transgene. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, amphibians, etc. A transgene is exogenous DNA that is integrated into the genome of a cell from which a transgenic animal develops and that remains in the genome of the mature animal, thereby directing the expression of an encoded gene product in one or more cell types or tissues of the transgenic animal. As used herein, a “homologous recombinant animal” is a non-human, animal, preferably a mammal, more preferably a mouse, in which an endogenous NOVX gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal, e.g., an embryonic cell of the animal, prior to development of the animal.


[0203] A transgenic animal of the invention can be created by introducing NOVX-encoding nucleic acid into the male pronuclei of a fertilized oocyte (e.g., by microinjection, retroviral infection) and allowing the oocyte to develop in a pseudopregnant female foster animal. The human NOVX cDNA sequences, i.e., any one of SEQ ID NO:2n−1, wherein n is an integer between 1-101, can be introduced as a transgene into the genome of a non-human animal. Alternatively, a non-human homologue of the human NOVX gene, such as a mouse NOVX gene, can be isolated based on hybridization to the human NOVX cDNA (described further supra) and used as a transgene. Intronic sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression of the transgene. A tissue-specific regulatory sequence(s) can be operably-linked to the NOVX transgene to direct expression of NOVX protein to particular cells. Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866; 4,870,009; and 4,873,191 ; and Hogan, 1986. In: MANIPULATING THE MOUSE EMBRYO, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. Similar methods arc used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the NOVX transgene in its genome and/or expression of NOVX mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene-encoding NOVX protein can further be bred to other transgenic animals carrying other transgenes.


[0204] To create a homologous recombinant animal, a vector is prepared which contains at least a portion of a NOVX gene into which a deletion, addition or substitution has been introduced to thereby alter, e.g., functionally disrupt, the NOVX gene. The NOVX gene can be a human gene (e.g., the cDNA of any one of SEQ ID NO:2n−1, wherein n is an integer between 1-101), but more preferably, is a non-human homologue of a human NOVX gene. For example, a mouse homologue of human NOVX gene of SEQ ID NO:2n−1, wherein n is an integer between 1-101, can be used to construct a homologous recombination vector suitable for altering an endogenous NOVX gene in the mouse genome. In one embodiment, the vector is designed such that, upon homologous recombination, the endogenous NOVX gene is functionally disrupted (i.e., no longer encodes a functional protein; also referred to as a “knock out” vector).


[0205] Alternatively, the vector can be designed such that, upon homologous recombination, the endogenous NOVX gene is mutated or otherwise altered but still encodes functional protein (e.g., the upstream regulatory region can be altered to thereby alter the expression of the endogenous NOVX protein). In the homologous recombination vector, the altered portion of the NOVX gene is flanked at its 5′- and 3′-termini by additional nucleic acid of the NOVX gene to allow for homologous recombination to occur between the exogenous NOVX gene carried by the vector and an endogenous NOVX gene in an embryonic stem cell. The additional flanking NOVX nucleic acid is of sufficient length for successful homologous recombination with the endogenous gene. Typically, several kilobases of flanking DNA (both at the 5′- and 3′-termini) are included in the vector. See, e.g., Thomas, et al., 1987. Cell 51: 503 for a description of homologous recombination vectors. The vector is ten introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced NOVX gene has homologously-recombined with the endogenous NOVX gene are selected. See, e.g., Li, et al., 1992. Cell 69: 915.


[0206] The selected cells are then injected into a blastocyst of an animal (e.g., a mouse) to form aggregation chimeras. See, e.g., Bradley, 1987. In: TERATOCARCINOMAS AND EMBRYONIC STEM CELLS: A PRACTICAL APPROACH, Robertson, ed. IRL, Oxford, pp. 113-152. A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term. Progeny harboring the homologously-recombined DNA in their germ cells can be used to breed animals in which all cells of the animal contain the homologously-recombined DNA by germline transmission of the transgene. Methods for constructing homologous recombination vectors and homologous recombinant animals are described further in Bradley, 1991. Curr. Opin. Biotechnol. 2: 823-829; PCT International Publication Nos.: WO 90/11354; WO 91/01140; WO 92/0968; and WO 93/04169.


[0207] In another embodiment, transgenic non-humans animals can be produced that contain selected systems that allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage PI. For a description of the cre/loxP recombinase system, See, e.g., Lakso, et al., 1992. Proc. Natl. Acad. Sci. USA 89: 6232-6236. Another example of a recombinase system is the FLP recombinase system of Saccharomyces cerevisiae. See, O'Gorman, et al., 1991. Science 251:1351-1355. If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are required. Such animals can be provided through the construction of “double” transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase.


[0208] Clones of the non-human transgenic animals described herein can also be produced according to the methods described in Wilmut, et al., 1997. Nature 385: 810-813. In brief, a cell (e.g., a somatic cell) from the transgenic animal can be isolated and induced to exit the growth cycle and enter G0 phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyte and then transferred to pseudopregnant female foster animal. The offspring borne of this female foster animal will be a clone of the animal from which the cell (e.g., the somatic cell) is isolated.


[0209] Pharmaceutical Compositions


[0210] The NOVX nucleic acid molecules, NOVX proteins, and anti-NOVX antibodies (also referred to herein as “active compounds”) of the invention, and derivatives, fragments, analogs and homologs thereof, can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the nucleic acid molecule, protein, or antibody and a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compound(s can also be incorporated into the compositions.


[0211] A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabeins; anitioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.


[0212] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.


[0213] Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a NOVX protein or anti-NOVX antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.


[0214] Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.


[0215] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.


[0216] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.


[0217] The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.


[0218] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.


[0219] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.


[0220] The nucleic acid molecules of the invention can be inserted into vectors and used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see, e.g., U.S. Pat. No. 5,328,470) or by stereotactic injection (see, e.g., Chen, et al., 1994. Proc. Natl. Acad. Sci. USA 91: 3054-3057). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells that produce the gene delivery system.


[0221] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.


[0222] Screening and Detection Methods


[0223] The isolated nucleic acid molecules of the invention can be used to express NOVX protein (e.g., via a recombinant expression vector in a host cell in gene therapy applications), to detect NOVX mRNA (e.g., in a biological sample) or a genetic lesion in a NOVX gene, and to modulate NOVX activity, as described further, below. In addition, the NOVX proteins can be used to screen drugs or compounds that modulate the NOVX protein activity or expression as well as to treat disorders characterized by insufficient or excessive production of NOVX protein or production of NOVX protein forms that have decreased or aberrant activity compared to NOVX wild-type protein (e.g.; diabetes (regulates insulin release); obesity (binds and transport lipids); metabolic disturbances associated with obesity, the metabolic syndrome X as well as anorexia and wasting disorders associated with chronic diseases and various cancers, and infectious disease (possesses antimicrobial activity) and the various dyslipidemias. In addition, the anti-NOVX antibodies of the invention can be used to detect and isolate NOVX proteins and modulate NOVX activity. In yet a further aspect, the invention can be used in methods to influence appetite, absorption of nutrients and the disposition of metabolic substrates in both a positive and negative fashion.


[0224] The invention further pertains to novel agents identified by the screening assays described herein and uses thereof for treatments as described, supra.


[0225] Screening Assays


[0226] The invention provides a method (also referred to herein as a “screening assay”) for identifying modulators, i.e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, small molecules or other drugs) that bind to NOVX proteins or have a stimulatory or inhibitory effect on, e.g., NOVX protein expression or NOVX protein activity. The invention also includes compounds identified in the screening assays described herein.


[0227] In one embodiment, the invention provides assays for screening candidate or test compounds which bind to or modulate the activity of the membrane-bound form of a NOVX protein or polypeptide or biologically-active portion thereof. The test compounds of the invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the “one-bead one-compound” library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds. See, e.g., Lam, 1997. Anticancer Drug Design 12: 145.


[0228] A “small molecule” as used herein, is meant to refer to a composition that has a molecular weight of less than about 5 kD and most preferably less than about 4 kD. Small molecules can be, e.g., nucleic acids, peptides, polypeptides, peptidomlimetics, carbohydrates, lipids or other organic or inorganic molecules. Libraries of chemical and/or biological mixtures, such as fungal, bacterial, or algal extracts, are known in the art and can be screened with any of the assays of the invention.


[0229] Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt, et al., 1993. Proc. Natl. Acad. Sci. USA. 90: 6909; Erb, et al., 1994. Proc. Natl. Acad. Sci. USA. 91: 11422; Zuckermann, et al., 1994.,J. Med. Chem. 37: 2678; Cho, et al., 1993. Science 261: 1303; Carrell, et al., 1994. Angew. Chem. Int. Ed. Engl. 33: 2059; Carell, et al., 1994. Angew. Chem. Int. Ed. Engl. 33: 2061; and Gallop, et al., 1994. J. Med. Chem. 37: 1233.


[0230] Libraries of compounds may be presented in solution (e.g., Houghten, 1992. Biotechniques 13: 412-421), or on beads (Lam, 1991. Nature 354: 82-84), on chips (Fodor, 1993. Nature 364: 555-556), bacteria (Ladner, U.S. Pat. No. 5,223,409), spores (Ladner, U.S. Pat. No. 5,233,409), plasmids (Cull, et al., 1992. Proc. Natl. Acad. Sci. USA 89: 1865-1869) or on phage (Scott and Smith, 1990. Science 249: 386-390; Devlin, 1990. Science 249: 404-406; Cwirla, et al., 1990. Proc. Natl. Acad. Sci. U.S.A. 87: 6378-6382; Felici, 1991. J. Mol. Biol. 222: 301-310; Ladner, U.S. Pat. No. 5,233,409.).


[0231] In one embodiment, an assay is a cell-based assay in which a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface is contacted with i test compound and the ability of the test compound to bind to a NOVX protein determined. The cell, for example, can of mammalian origin or a yeast cell. Determining the ability of the test compound to bind to the NOVX protein can be accomplished, for example, by coupling the test compound with a radioisotope or enzymatic label such that binding of the test compound to the NOVX protein or biologically-active portion thereof can be determined by detecting the labeled compound in a complex. For example, test compounds can be labeled with 125I, 35S, 14C, or 3H, either directly or indirectly, and the radioisotope detected by direct counting of radioemission or by scintillation counting. Alternatively, test compounds can be enzymatically-labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product. In one embodiment, the assay comprises contacting a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with a NOVX protein, wherein determining the ability of the test compound to interact with a NOVX protein comprises determining the ability of the test compound to preferentially bind to NOVX protein or a biologically-active portion thereof as compared to the known compound.


[0232] In another embodiment, an assay is a cell-based assay comprising contacting a cell expressing a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a test compound and determining the ability of the test compound to modulate (e.g., stimulate or inhibit) the activity of the NOVX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of NOVX or a biologically-active portion thereof can be accomplished, for example, by determining the ability of the NOVX protein to bind to or interact with a NOVX target molecule. As used herein, a “target molecule” is a molecule with which a NOVX protein binds or interacts in nature, for example, a molecule on the surface of a cell which expresses a NOVX interacting protein, a molecule on the surface of a second cell, a molecule in the extracellular milieu, a molecule associated with the internal surface of a cell membrane or a cytoplasmic molecule. A NOVX target molecule can be a non-NOVX molecule or a NOVX protein or polypeptide of the invention. In one embodiment, a NOVX target molecule is a component of a signal transduction pathway that facilitates transduction of an extracellular signal (e.g. a signal generated by binding of a compound to a membrane-bound NOVX molecule) through the cell membrane and into the cell. The target, for example, can be a second intercellular protein that has catalytic activity or a protein that facilitates the association of downstream signaling molecules with NOVX.


[0233] Determining the ability of the NOVX protein to bind to or interact with a NOVX target molecule can be accomplished by one of the methods described above for determining direct binding. In one embodiment, determining the ability of the NOVX protein to bind to or interact with a NOVX target molecule can be accomplished by determining the activity of the target molecule. For example, the activity of the target molecule can be determined by detecting induction of a cellular second messenger of the target (i.e. intracellular Ca2+, diacylglycerol, IP3, etc.), detecting catalytic/enzymatic activity of the target an appropriate substrate, detecting the induction of a reporter gene (comprising a NOVX-responsive regulatory element operatively linked to a nucleic acid encoding a detectable marker, e.g., luciferase), or detecting a cellular response, for example, cell survival, cellular differentiation, or cell proliferation.


[0234] In yet another embodiment, an assay of the invention is a cell-free assay comprising contacting a NOVX protein or biologically-active portion thereof with a test compound and determining the ability of the test compound to bind to the NOVX protein or biologically-active portion thereof. Binding of the test compound to the NOVX protein can be determined either directly or indirectly as described above. In one such embodiment, the assay comprises contacting the NOVX protein or biologically-active portion thereof with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with a NOVX protein, wherein determining the ability of the test compound to interact with a NOVX protein comprises determining the ability of the test compound to preferentially bind to NOVX or biologically-active portion thereof as compared to the known compound.


[0235] In still another embodiment, an assay is a cell-free assay comprising contacting NOVX protein or biologically-active portion thereof with a test compound and determining the ability of the test compound to modulate (e.g. stimulate or inhibit) the activity of the NOVX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of NOVX can be accomplished, for example, by determining the ability of the NOVX protein to bind to a NOVX target molecule by one of the methods described above for determining direct binding. In an alternative embodiment, determining the ability of the test compound to modulate the activity of NOVX protein can be accomplished by determining the ability of the NOVX protein further modulate a NOVX target molecule. For example, the catalytic/enzymatic activity of the target molecule on an appropriate substrate can be determined as described, supra.


[0236] In yet another embodiment, the cell-free assay comprises contacting the NOVX protein or biologically-active portion thereof with a known compound which binds NOVX protein to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with a NOVX protein, wherein determining the ability of the test compound to interact with a NOVX protein comprises determining the ability of the NOVX protein to preferentially bind to or modulate the activity of a NOVX target molecule.


[0237] The cell-free assays of the invention are amenable to use of both the soluble form or the membrane-bound form of NOVX protein. In the case of cell-free assays comprising the membrane-bound form of NOVX protein, it may be desirable to utilize a solubilizing agent such that the membrane-bound form of NOVX protein is maintained in solution. Examples of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside, octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton® X-100, Triton® X-114, Thesit®, Isotridecypoly(ethylene glycol ether)n, N-dodecyl-N,N-dimethyl-3-ammonio-1-propane sulfonate, 3-(3-cholamidopropyl) dimethylamminiol-1-propane sulfonate (CHAPS), or 3-(3-cholamidopropyl)dimethylamminiol-2-hydroxy-1 1-propane sulfonate (CHAPSO).


[0238] In more than one embodiment of the above assay methods of the invention, it may be desirable to immobilize either NOVX protein or its target molecule to facilitate separation of complexed from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay. Binding of a test compound to NOVX protein, or interaction of NOVX protein with a target molecule in the presence and absence of a candidate compound, can be accomplished in any vessel suitable for containing the reactants. Examples of such vessels include microtiter plates, test tubes, and micro-centrifuge tubes. In one embodiment, a fusion protein can be provided that adds a domain that allows one or both of the proteins to be bound to a matrix. For example, GST-NOVX fusion proteins or GST-target fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatized microtiter plates, that are then combined with the test compound or the test compound and either the non-adsorbed target protein or NOVX protein, and the mixture is incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, the matrix immobilized in the case of beads, complex determined either directly or indirectly, for example, as described, supra. Alternatively, the complexes can be dissociated from the matrix, and the level of NOVX protein binding or activity determined using standard techniques.


[0239] Other techniques for immobilizing proteins on matrices can also be used in the screening assays of the invention. For example, either the NOVX protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Biotinylated NOVX protein or target molecules can be prepared from biotin-NFIS (N-hydroxy-succinimide) using techniques well-known within the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). Alternatively, antibodies reactive with NOVX protein or target molecules, but which do not interfere with binding of the NOVX protein to its target molecule, can be derivatized to the wells of the plate, and unbound target or NOVX protein trapped in the wells by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the NOVX protein or target molecule, as well as enzyme-linked assays that rely on detecting an enzymatic activity associated with the NOVX protein or target molecule.


[0240] In another embodiment, modulators of NOVX protein expression are identified in a method wherein a cell is contacted with a candidate compound and the expression of NOVX mRNA or protein in the cell is determined. The level of expression of NOVX mRNA or protein in the presence of the candidate compound is compared to the level of expression of NOVX mRNA or protein in the absence of the candidate compound. The candidate compound can then be identified as a modulator of NOVX mRNA or protein expression based upon this comparison. For example, when expression of NOVX mRNA or protein is greater (i.e., statistically significantly greater) in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of NOVX mRNA or protein expression. Alternatively, when expression of NOVX mRNA or protein is less (statistically significantly less) in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of NOVX mRNA or protein expression. The level of NOVX mRNA or protein expression in the cells can be determined by methods described herein for detecting NOVX mRNA or protein.


[0241] In yet another aspect of the invention, the NOVX proteins can be used as “bait proteins” in a two-hybrid assay or three hybrid assay (see, e.g., U.S. Pat. No. 5,283,317; Zervos, et al., 1993. Cell 72: 223-232; Madura, et al., 1993. J. Biol. Chem. 268: 12046-12054; Bartel, et al., 1993. Biotechniques 14: 920-924; Iwabuchii, et al., 1993. Oncogene 8: 1693-1696; and Brent WO 94/10300), to identify other proteins that bind to or interact with NOVX (“NOVX-binding proteins” or “NOVX-bp”) and modulate NOVX activity. Such NOVX-binding proteins are also involved in the propagation of signals by the NOVX proteins as, for example, upstream or downstream elements of the NOVX pathway.


[0242] The two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. Briefly, the assay utilizes two different DNA constructs. In one construct, the gene that codes for NOVX is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein (“prey” or “sample”) is fused to a gene that codes for the activation domain of the known transcription factor. If the “bait” and the “prey” proteins are able to interact, in vivo, forming a NOVX-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) that is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene that encodes the protein which interacts with NOVX.


[0243] The invention further pertains to novel agents identified by the aforementioned screening assays and uses thereof for treatments as described herein.


[0244] Detection Assays


[0245] Portions or fragments of the cDNA sequences identified herein (and the corresponding complete gene sequences) can be used in numerous ways as polynucleotide reagents. By way of example, and not of limitation, these sequences can be used to: (i) map their respective genes on a chromosome; and, thus, locate gene regions associated with genetic disease; (ii) identify an individual from a minute biological sample (tissue typing); and (iii) aid in forensic identification of a biological sample. Some of these applications are described in the subsections, below.


[0246] Chromosome Mapping


[0247] Once the sequence (or a portion of the sequence) of a gene has been isolated, this sequence can be used to map the location of the gene on a chromosome. This process is called chromosome mapping. Accordingly, portions or fragments of the NOVX sequences of SEQ ID NO:2n−1, wherein n is an integer between 1-101, or fragments or derivatives thereof, can be used to map the location of the NOVX genes, respectively, on a chromosome. The mapping of the NOVX sequences to chromosomes is an important first step in correlating these sequences with genes associated with disease.


[0248] Briefly, NOVX genes can be mapped to chromosomes by preparing PCR primers (preferably 15-25 bp in length) from the NOVX sequences. Computer analysis of the NOVX, sequences can be used to rapidly select primers that do not span more than one exon in the genomic DNA, thus complicating the amplification process. These primers can then be used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the NOVX sequences will yield an amplified fragment.


[0249] Somatic cell hybrids are prepared by fusing somatic cells from different mammals (e.g., human and mouse cells). As hybrids of human and mouse cells grow and divide, they gradually lose human chromosomes in random order, but retain the mouse chromosomes. By using media in which mouse cells cannot grow, because they lack a particular enzyme, but in which human cells can, the one human chromosome that contains the gene encoding the needed enzyme will be retained. By using various media, panels of hybrid cell lines can be established. Each cell line in a panel contains either a single human chromosome or a small number of human chromosomes, and a full set of mouse chromosomes, allowing easy mapping of individual genes to specific human chromosomes. See, e.g., D'Eustachio, et al., 1983. Science 220: 919-924. Somatic cell hybrids containing only fragments of human chromosomes can also be produced by using human chromosomes with translocations and deletions.


[0250] PCR mapping of somatic cell hybrids is a rapid procedure for assigning a particular sequence to a particular chromosome. Three or more sequences can be assigned per day using a single thermal cycler. Using the NOVX sequences to design oligonucleotide primers, sub-localization can be achieved with panels of fragments from specific chromosomes.


[0251] Fluorescence in situ hybridization (FISH) of a DNA sequence to a metaphase chromosomal spread can further be used to provide a precise chromosomal location in one step. Chromosome spreads can be made using cells whose division has been blocked in metaphase by a chemical like colcemid that disrupts the mitotic spindle. The chromosomes can be treated briefly with trypsin, and then stained with Giemsa. A pattern of light and dark bands develops on each chromosome, so that the chromosomes can be identified individually. The FISH technique can be used with a DNA sequence as short as 500 or 600 bases. However, clones larger than 1,000 bases have a higher likelihood of binding to a unique chromosomal location with sufficient signal intensity for simple detection. Preferably 1,000 bases, and more preferably 2,000 bases, will suffice to get good results at a reasonable amount of time. For a review of this technique, see, Verma, et al., HUMAN CHROMOSOMES: A MANUAL OF BASIC TECHNIQUES (Pergamon Press, New York 1988).


[0252] Reagents for chromosome mapping can be used individually to mark a single chromosome or a single site on that chromosome, or panels of reagents can be used for marking multiple sites and/or multiple chromosomes. Reagents corresponding to noncoding regions of the genes actually are preferred for mapping purposes. Coding sequences are more likely to be conserved within gene families, thus increasing the chance of cross hybridizations during chromosomal mapping.


[0253] Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. Such data are found, e.g., in McKusick, MENDELIAN INHERITANCE IN MAN, available on-line through Johns Hopkins University Welch Medical Library). The relationship between genes and disease, mapped to the same chromosomal region, can then be identified through linkage analysis (co-inheritance of physically adjacent genes), described in, e.g., Egeland, el al., 1987. Nature, 325: 783-787.


[0254] Moreover, differences in the DNA sequences between individuals affected and unaffected with a disease associated with the NOVX gene, can be determined. If a mutation is observed in some or all of the affected individuals but not in any unaffected inindividuals, then the mutation is likely to be the causative agent of the particular disease. Comparison of affected and unaffected individuals generally involves first looking for structural alterations in the chromosomes, such as deletions or translocations that are visible from chromosome spreads or delectable using PCR based on that DNA sequence. Ultimately, complete sequencing of genes from several individuals can be performed to confirm the presence of a mutation and to distinguish mutations from polymorphisms.


[0255] Tissue Typing


[0256] The NOVX sequences of the invention can also be used to identify individuals from minute biological samples. In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identification. The sequences of the invention are useful as additional DNA markers for RFLP (“restriction fragment length polymorphisms,” described in U.S. Pat. No. 5,272,057).


[0257] Furthermore, the sequences of the invention can be used to provide an alternative technique that determines the actual base-by-base DNA sequence of selected portions of an individual's genome. Thus, the NOVX sequences described herein can be used to prepare two PCR primers from the 5′- and 3′-termini of the sequences. These primers can then be used to amplify an individual's DNA and subsequently sequence it.


[0258] Panels of corresponding DNA sequences from individuals, prepared in this manner, can provide unique individual identifications, as each individual will have a unique set of such DNA sequences due to allelic differences. The sequences of the invention can be used to obtain such identification sequences from individuals and from tissue. The NOVX sequences of the invention uniquely represent portions of the human genome. Allelic variation occurs to some degree in the coding regions of these sequences, and to a greater degree in the noncoding regions. It is estimated that allelic variation between individual humans occurs with a frequency of about once per each 500 bases. Much of the allelic variation is due to single nucleotide polymorphisms (SNPs), which include restriction fragment length polymorphisms (RFLPs).


[0259] Each of the sequences described herein can, to some degree, be used as a standard against which DNA from an individual can be compared for identification purposes. Because greater numbers of polymorphisms occur in the noncoding regions, fewer sequences are necessary to differentiate individuals. The noncoding sequences can comfortably provide positive individual identification with a panel of perhaps 10 to 1,000 primers that each yield a noncoding amplified sequence of 100 bases. If coding sequences, such as those of SEQ ID NO:2n−1, wherein n is an integer between 1-101, are used, a more appropriate number of primers for positive individual identification would be 500-2,000.


[0260] Predictive Medicine


[0261] The invention also pertains to the field of predictive medicine in which diagnostic assays, prognostic assays, pharmacogenomics, and monitoring clinical trials are used for prognostic (predictive) purposes to thereby treat an individual prophylactically. Accordingly, one aspect of the invention relates to diagnostic assays for determining NOVX protein and/or nucleic acid expression as well as NOVX activity, in the context of a biological sample (e.g., blood, serum, cells, tissue) to thereby determine whether an individual is afflicted with a disease or disorder, or is at risk of developing a disorder, associated with aberrant NOVX expression or activity. The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers. The invention also provides for prognostic (or predictive) assays for determining whether an individual is at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. For example, mutations in a NOVX gene can be assayed in a biological sample. Such assays can be used for prognostic or predictive purpose to thereby prophylactically treat an individual prior to the onset of a disorder characterized by or associated with NOVX protein, nucleic acid expression, or biological activity.


[0262] Another aspect of the invention provides methods for determining NOVX protein, nucleic acid expression or activity in an individual to thereby select appropriate therapeutic or prophylactic agents for that individual (referred to herein as “pharmacogenomics”). Pharmacogenomics allows for the selection of agents (e.g., drugs) for therapeutic or prophylactic treatment of an individual based on the genotype of the individual (e.g., the genotype of the individual examined to determine the ability of the individual to respond to a particular agent.)


[0263] Yet another aspect of the invention pertains to monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of NOVX in clinical trials.


[0264] These and other agents are described in further detail in the following sections.


[0265] Diagnostic Assays


[0266] An exemplary method for detecting the presence or absence of NOVX in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting NOVX protein or nucleic acid (e.g., mRNA, genomic DNA) that encodes NOVX protein such that the presence of NOVX is detected in the biological sample. An agent for detecting NOVX mRNA or genomic DNA is a labeled nucleic acid probe capable of hybridizing to NOVX mRNA or genomic DNA. The nucleic acid probe can be, for example, a full-length NOVX nucleic acid, such as the nucleic acid of SEQ ID NO:2n−1, wherein n is an integer between 1-101, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to NOVX mRNA or genomic DNA. Other suitable probes for use in the diagnostic assays of the invention are described herein.


[0267] An agent for detecting NOVX protein is an antibody capable of binding to NOVX protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F(ab′)2) can be used. The term “labeled”, with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term “biological sample” is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. That is, the detection method of the invention can be used to detect NOVX mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of NOVX mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of NOVX protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of NOVX genome DNA include Southern hybridizations. Furthermore, in vivo techniques for detection of NOVX protein include introducing into a subject a labeled anti-NOVX antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.


[0268] In one embodiment, the biological sample contains protein molecules from the test subject. Alternatively, the biological sample can contain mRNA molecules from the test subject or genomic DNA molecules from the test subject. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject.


[0269] In another embodiment, the methods further involve obtaining a control biological sample from a control subject, contacting the control sample with a compound or agent capable of detecting NOVX protein, mRNA, or genomic DNA, such that the presence of NOVX protein, mRNA or genomic DNA is detected in the biological sample, and comparing the presence of NOVX protein, mRNA or genomic DNA in the control sample with the presence of NOVX protein, mRNA or genomic DNA in the test sample.


[0270] The invention also encompasses kits for detecting the presence of NOVX in a biological sample. For example, the kit can comprise: a labeled compound or agent capable of detecting NOVX protein or mRNA in a biological sample; means for determining the amount of NOVX in the sample; and means for comparing the amount of NOVX in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect NOVX protein or nucleic acid.


[0271] Prognostic Assays


[0272] The diagnostic methods described herein can furthermore be utilized to identify subjects having or at risk of developing a disease or disorder associated with aberrant NOVX expression or activity. For example, the assays described herein, such as the preceding diagnostic assays or the following assays, can be utilized to identify a subject having or at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. Alternatively, the prognostic assays can be utilized to identify a subject having or at risk for developing a disease or disorder. Thus, the invention provides a method for identifying a disease or disorder associated with aberrant NOVX expression or activity in which a test sample is obtained from a subject and NOVX protein or nucleic acid (e.g., mRNA, genomic DNA) is detected, wherein the presence of NOVX protein or nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with aberrant NOVX expression or activity. As used herein, a “test sample” refers to a biological sample obtained from a subject of interest. For example, a test sample can be a biological fluid (e.g., serum), cell sample, or tissue.


[0273] Furthermore, the prognostic assays described herein can be used to determine whether a subject can be administered an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate) to treat a disease or disorder associated with aberrant NOVX expression or activity. For example, such methods can be used to determine whether a subject can be effectively treated with an agent for a disorder. Thus, the invention provides methods for determining whether a subject can be effectively treated with an agent for a disorder associated with aberrant NOVX expression or activity in which a test sample is obtained and NOVX protein or nucleic acid is detected (e.g., wherein the presence of NOVX protein or nucleic acid is diagnostic for a subject that can be administered the agent to treat a disorder associated with aberrant NOVX expression or activity).


[0274] The methods of the invention can also be used to detect genetic lesions in a NOVX gene, thereby determining if a subject with the lesioned gene is at risk for a disorder characterized by aberrant cell proliferation and/or differentiation. In various embodiments, the methods include detecting, in a sample of cells from the subject, the presence or absence of a genetic lesion characterized by at least one of an alteration affecting the integrity of a gene encoding a NOVX-protein, or the misexpression of the NOVX gene. For example, such genetic lesions can be detected by ascertaining the existence of at least one of: (i) a deletion of one or more nucleotides from a NOVX gene; (ii) an addition of one or more nucleotides to a NOVX gene; (iii) a substitution of one or more nucleotides of a NOVX gene, (iv) a chromosomal rearrangement of a NOVX gene; (v) an alteration in the level of a messenger RNA transcript of a NOVX gene, (vi) aberrant modification of a NOVX gene, such as of the methylation pattern of the genomic DNA, (vii) the presence of a non-wild-type splicing pattern of a messenger RNA transcript of a NOVX gene, (viii) a non-wild-type level of a NOVX protein, (ix) allelic loss of a NOVX gene, and (x) inappropriate post-translational modification of a NOVX protein. As described herein, there are a large number of assay techniques known in the art which can be used for detecting lesions in a NOVX gene. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.


[0275] In certain embodiments, detection of the lesion involves the use of a probe/primer in a polymerase chain reaction (PCR) (see, e.g., U.S. Pat. Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g, Landegran, et al., 1988. Science 241:1077-1080; and Nakazawa, et al., 1994. Proc. Natl. Acad Sci. USA 91: 360-364), the latter of which can be particularly useful for detecting point mutations in the NOVX-gene (see, Abravaya, et al., 1995. Nucl. Acids Res. 23:675-682). This method can include the steps of collecting a sample of cells from a patient, isolating nucleic acid (e.g., genomic, mRNA or both) from the cells of the sample, contacting the nucleic acid sample with one or more primers that specifically hybridize to a NOVX gene under conditions such that hybridization and amplification of the NOVX gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any of the techniques used for detecting mutations described herein.


[0276] Alternative amplification methods include: self sustained sequence replication (see, Guatelli, et al., 1990. Proc. Natl. Acad. Sci. USA 87:1874-1878), transcriptional amplification system (see, Kwoh, et al., 1989. Proc. Natl. Acad. Sci. USA 86:1173-1177); Qβ Replicase (see, Lizardi, et al, 1988. BioTechnology 6:1197), or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers.


[0277] In an alternative embodiment, mutations in a NOVX gene from a sample cell can be identified by alterations in restriction enzyme cleavage patterns. For example, sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined by gel electrophoresis and compared. Differences in fragment length sizes between sample and control DNA indicates mutations in the sample DNA. Moreover, the use of sequence specific ribozymes (see, e.g., U.S. Pat. No. 5,493,531) can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site.


[0278] In other embodiments, genetic mutations in NOVX can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high-density arrays containing hundreds or thousands of oligonucleotides probes. See, e.g., Cronin, et al., 1996. Human Mutation 7: 244-255; Kozal, et al., 1996. Nat. Med. 2: 753-759. For example, genetic mutations in NOVX can be identified in two dimensional arrays containing light-generated DNA probes as described in Cronin, et al., supra. Briefly, a first hybridization array of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential overlapping probes. This step allows the identification of point mutations. This is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or mutations detected. Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene.


[0279] In yet another embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence the NOVX gene and detect mutations by comparing the sequence of the sample NOVX with the corresponding wild-type (control) sequence. Examples of sequencing reactions include those based on techniques developed by Maxim and Gilbert, 1977. Proc. Natl. Acad. .Sci. USA 74: 560 or Sanger, 1977. Proc. Natl. Acad. Sci. USA 74: 5463. It is also contemplate(d that any of a variety of automated sequencing procedures can be utilized when performing the diagnostic assays (see, e.g., Naeve, et al., 1995. Biotechniques 19: 448), including sequencing by mass spectrometry (see, e.g., PCT International Publication No. WO 94/16101; Cohen, et al., 1996. Adv. Chromatography 36: 127-162; and Griffin, et al., 1993. Appl. Biochem. Biotechnol. 38: 147-159).


[0280] Other methods for detecting mutations in the NOVX gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA heteroduplexes. See, e.g., Myers, et al., 1985. Science 230: 1242. In general, the art technique of “mismatch cleavage” starts by providing heteroduplexes of formed by hybridizing (labeled) RNA or DNA containing the wild-type NOVX sequence with potentially mutant RNA or DNA obtained from a tissue sample. The double-stranded duplexes are treated with an agent that cleaves single-stranded regions of the duplex such as which will exist due to basepair mismatches between the control and sample strands. For instance, RNA/DNA duplexes can be treated with RNase and DNA/DNA hybrids treated with S1 nuclease to enzymatically digesting the mismatched regions. In other embodiments, either DNA/DNA or RNA/DNA duplexes can be treated with hydroxylamine or osmium tetroxide and with piperidine in order to digest mismatched regions. After digestion of the mismatched regions, the resulting material is then separated by size on denaturing polyacrylamide gels to determine the site of mutation. See, e.g., Cotton, et al., 1988. Proc. Natl. Acad. Sci. USA 85: 4397; Saleeba, et al., 1992. Methods Enzymol. 217: 286-295. In an embodiment, the control DNA or RNA can be labeled for detection.


[0281] In still another embodiment, the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called “DNA mismatch repair” enzymes) in defined systems for detecting and mapping point mutations in NOVX cDNAs obtained from samples of cells. For example, the mutY enzyme of E. coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T at G/T mismatches. See, e.g., Hsu, et al., 1994. Carcinogenesis 15: 1657-1662. According to an exemplary embodiment, a probe based on a NOVX sequence, e.g., a wild-type NOVX sequence, is hybridized to a cDNA or other DNA product from a test cell(s). The duplex is treated with a DNA mismatch repair enzyme, and the cleavage products, if any, can be detected from electrophoresis protocols or the like. See, e.g., U.S. Pat. No. 5,459,039.


[0282] In other embodiments, alterations in electrophoretic mobility will be used to identify mutations in NOVX genes. For example, single strand conformation. polymorphism (SSCP) may be used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids. See, e.g., Orita, et al., 1989. Proc. Natl. Acad. Sci. USA: 86: 2766; Cotton, 1993. Mutat. Res. 285: 125-144; Hayashi, 1992. Genet. Anal. Tech. Appl. 9: 73-79. Single-stranded DNA fragments of sample and control NOVX nucleic acids will be denatured and allowed to renature. The secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in electrophoretic mobility enables the detection of even a single base change. The DNA fragments may be labeled or detected with labeled probes. The sensitivity of the assay may be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In one embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility. See, e.g., Keen, et al., 1991. Trends Genet. 7:5.


[0283] In yet another embodiment, the movement of mutant or wild-type fragments in polyacrylanide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE). See, e.g., Myers, et al., 1985. Nature 313: 495. When DGGE is used as the method of analysis, DNA will be modified to insure that it does not completely denature, for example by adding a GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR. In a further embodiment, a temperature gradient is used in place of a denaturing gradient to identify differences in the mobility of control and sample DNA. See, e.g., Rosenbaum and Reissner, 1987. Biophys. Chem. 265: 12753.


[0284] Examples of other techniques for detecting point mutations include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide primers may be prepared in which the known mutation is placed centrally and then hybridized to target DNA under conditions that permit hybridization only if a perfect match is found. See, e.g., Saiki, et al., 1986. Nature 324: 163; Saiki, et al., 1989. Proc. Natl. Acad. Sci. USA 86: 6230. Such allele specific oligonucleotides are hybridized to PCR amplified target DNA or a number of different mutations when the oligonucleotides are attached to the hybridizing membrane and hybridized with labeled target DNA.


[0285] Alternatively, allele specific amplification technology that depends on selective PCR amplification may be used in conjunction with the instant invention. Oligonucleotides used as primers for specific amplification may carry the mutation of interest in the center of the molecule (so that amplification depends on differential hybridization; see, e.g., Gibbs, et al., 1989. Nucl. Acids Res. 17: 2437-2448) or at the extreme 3′-terminus of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (see, e.g., Prossner, 1993. Tibtech. 11: 238). In addition it may be desirable to introduce a novel restriction site in the region of the mutation to create cleavage-based detection. See, e.g., Gasparini, et al., 1992. Mol. Cell Probes 6:1. It is anticipated that in certain embodiments amplification may also be performed using Taq ligase for amplification. See, e.g., Barany, 1991. Proc. Natl. Acad. Sci. USA 88: 189. In such cases, ligation will occur only if there is a perfect match at the 3′-terminus of the 5′ sequence, making it possible to detect the presence of a known mutation at a specific site by looking for the presence or absence of amplification.


[0286] The methods described herein may be performed, for example, by utilizing pre-packaged diagnostic kits comprising at least one probe nucleic acid or antibody reagent described herein, which may be conveniently used, e.g., in clinical settings to diagnose patients exhibiting symptoms or family history of a disease or illness involving a NOVX gene.


[0287] Furthermore, any cell type or tissue, preferably peripheral blood leukocytes, in which NOVX is expressed may be utilized in the prognostic assays described herein. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.


[0288] Pharmacogenomics


[0289] Agents, or modulators that have a stimulatory or inhibitory effect on NOVX activity (e.g., NOVX gene expression), as identified by a screening assay described herein can be administered to individuals to treat (prophylactically or therapeutically) disorders (The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers.) In conjunction with such treatment, the pharmacogenomics (i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) of the individual may be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, the pharmacogenomics of the individual permits the selection of effective agents (e.g., drugs) for prophylactic or therapeutic treatments based on a consideration of the individual's genotype. Such pharmacogenomics can further be used to determine appropriate dosages and therapeutic regimens. Accordingly, the activity of NOVX protein, expression of NOVX nucleic acid, or mutation content of NOVX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual.


[0290] Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See e.g., Eichelbaum, 1996. Clin. Exp. Pharmacol. Physiol., 23: 983-985; Linder, 1997. Clin. Chem., 43: 254-266. In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body (altered drug action) or genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur either as rare defects or as polymorphisms. For example, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzymopathy in which the main clinical complication is hemolysis after ingestion of oxidant drugs (anti-malarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans.


[0291] As an illustrative embodiment, the activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action. The discovery of genetic polymorphisms of drug metabolizing enzymes (e.g., N-acetyltransferase 2 (NAT 2) and cytochhrome PREGNANCY ZONE PROTEIN PRECURSOR enzymes CYP2D6 and CYP2C19) has provided an explanation as to why some patients do not obtain the expected drug effects or show exaggerated drug response and serious toxicity after taking the standard and safe dose of a drug. These polymorphisms are expressed in two phenotypes in the population, the extensive metabolizer (EM) and poor metabolizer (PM). The prevalence of PM is different among different populations. For example, the gene coding for CYP2D6 is highly polymorphic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quite frequently experience exaggerated drug response and side effects when they receive standard closes. If a metabolite is the active therapeutic moiety, PM show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its CYP2D6-formed metabolite morphine. At the other extreme are the so called ultra-rapid metabolizers who do not respond to standard doses. Recently, the molecular basis of ultra-rapid metabolism has been identified to be due to CYP2D6 gene amplification.


[0292] Thus, the activity of NOVX protein, expression of NOVX nucleic acid, or mutation content of NOVX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual. In addition, pharmacogenetic studies can be used to apply genotyping of polymorphic alleles encoding drug-metabolizing enzymes to the identification of an individual's drug responsiveness phenotype. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating a subject with a NOVX modulator, such as a modulator identified by one of the exemplary screening assays described herein.


[0293] Monitoring of Effects During Clinical Trials


[0294] Monitoring the influence of agents (e.g., drugs, compounds) oil the expression or activity of NOVX (e.g., the ability to modulate aberrant cell proliferation and/or differentiation) can be applied not only in basic drug screening, but also in clinical trials. For example, the effectiveness of an agent determined by a screening assay as described herein to increase NOVX gene expression, protein levels, or upregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting decreased NOVX gene expression, protein levels, or downregulated NOVX activity. Alternatively, the effectiveness of an agent determined by a screening assay to decrease NOVX gene expression, protein levels, or downregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting increased NOVX gene expression, protein levels, or upregulated NOVX activity. In such clinical trials, the expression or activity of NOVX and, preferably, other genes that have been implicated in, for example, a cellular proliferation or immune disorder can be used as a “read out” or markets of the immune responsiveness of a particular cell.


[0295] By way of example, and not of limitation, genes, including NOVX, that are modulated in cells by treatment with an agent (e.g., compound, drug or small molecule) that modulates NOVX activity (e.g., identified in a screening assay as described herein) can be identified. Thus, to study the effect of agents on cellular proliferation disorders, for example, in a clinical trial, cells can be isolated and RNA prepared and analyzed for the levels of expression of NOVX and other genes implicated in the disorder. The levels of gene expression (i.e., a gene expression pattern) can be quantified by Northern blot analysis or RT-PCR, as described herein, or alternatively by measuring the amount of protein produced, by one of the methods as described herein, or by measuring the levels of activity of NOVX or other genes. In this manner, the gene expression pattern can serve as a marker, indicative of the physiological response of the cells to the agent. Accordingly, this response state may be determined before, and at various points during, treatment of the individual with the agent.


[0296] In one embodiment, the invention provides a method for monitoring the effectiveness of treatment of a subject with an agent (e.g., an agonist, antagonist, protein, peptide, peptidomimetic, nucleic acid, small molecule, or other drug candidate identified by the screening assays described herein) comprising the steps of (i) obtaining a pre-administration sample from a subject prior to administration of the agent; (ii) detecting the level of expression of a NOVX protein, mRNA, or genomic DNA in the preadministrational sample; (iii) obtaining one or more post-administration samples from the subject; (iv) detecting the level of expression or activity of the NOVX protein, mRNA, or genomic DNA in the post-administration samples; (v) comparing the level of expression or activity of the NOVX protein, mRNA, or genomic DNA in the pre-administration sample with the NOVX protein, mRNA, or genomic DNA in the post administration sample or samples; and (vi) altering the administration of the agent to the subject accordingly. For example, increased administration of the agent may be desirable to increase the expression or activity of NOVX to higher levels than detected, i.e., to increase the effectiveness of the agent. Alternatively, decreased administration of the agent may be desirable to decrease expression or activity of NOVX to lower levels than detected, i.e., to decrease the effectiveness of the agent.


[0297] Methods of Treatment


[0298] The invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder or having a disorder associated with aberrant NOVX expression or activity. The disorders include cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, adrenoleukodystrophy, congenital adrenal hyperplasia, prostate cancer, neoplasm; adenocarcinoma, lymphoma, uterus cancer, fertility, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, graft versus host disease, AIDS, bronchial asthma, Crohn's disease; multiple sclerosis, treatment of Albright Hereditary Osteodystrophy, and other diseases, disorders and conditions of the like.


[0299] These methods of treatment will be discussed more fully, below.


[0300] Disease and Disorders


[0301] Diseases and disorders that are characterized by increased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that antagonize (i.e., reduce or inhibit) activity. Therapeutics that antagonize activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to: (i) an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; (ii) antibodies to an aforementioned peptide; (iii) nucleic acids encoding an aforementioned peptide; (iv) administration of antisense nucleic acid and nucleic acids that are “dysfunctional” (i.e., due to a heterologous insertion within the coding sequences of coding sequences to an aforementioned peptide) that are utilized to “knockout” endogenous function of an aforementioned peptide by homologous recombination (see, e.g., Capecchi, 1989. Science 244:1288-1292); or (v) modulators ( i.e., inhibitors, agonists and antagonists, including additional peptide mimetic of the invention or antibodies specific to a peptide of the invention) that alter the interaction between an aforementioned peptide and its binding partner.


[0302] Diseases and disorders that are characterized by decreased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that increase (i.e., are agonists to) activity. Therapeutics that upregulate activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to, an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; or an agonist that increases bioavailability.


[0303] Increased or decreased levels can be readily detected by quantifying peptide and/or RNA, by obtaining a patient tissue sample (e.g., from biopsy tissue) and assaying it in vitro for RNA or peptide levels, structure and/or activity of the expressed peptides (or mRNAs of an aforementioned peptide). Methods that are well-known within the art include, but are not limited to, immunoassays (e.g., by Western blot analysis, immunoprecipitation followed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis, immunocytochemistry, etc.) and/or hybridization assays to detect expression of mRNAs (e.g., Northern assays, dot blots, in situ hybridization, and the like).


[0304] Prophylactic Methods


[0305] In one aspect, the invention provides a method for preventing, in a subject, a disease or condition associated with an aberrant NOVX expression or activity, by administering to the subject an agent that modulates NOVX expression or at least one NOVX activity. Subjects at risk for a disease that is caused or contributed to by aberrant NOVX expression or activity can be identified by, for example, any or a combination of diagnostic or prognostic assays as described herein. Administration of a prophylactic agent can occur prior to the manifestation of symptoms characteristic of the NOVX aberrancy, such that a disease or disorder is prevented or, alternatively, delayed in its progression. Depending upon the type of NOVX aberrancy, for example, a NOVX agonist or NOVX antagonist agent can be used for treating the subject. The appropriate agent can be determined based on screening assays described herein. The prophylactic methods of the invention are further discussed in the following subsections.


[0306] Therapeutic Methods


[0307] Another aspect of the invention pertains to methods of modulating NOVX expression or activity for therapeutic purposes. The modulatory method of the invention involves contacting a cell with an agent that modulates one or more of the activities of NOVX protein activity associated with the cell. An agent that modulates NOVX protein activity can be an agent as described herein, such as a nucleic acid or a protein, a naturally-occurring cognate ligand of a NOVX protein, a peptide, a NOVX peptidomimetic, or other small molecule. In one embodiment, the agent stimulates one or more NOVX protein activity. Examples of such stimulatory agents include active NOVX protein and a nucleic acid molecule encoding NOVX that has been introduced into the cell. In another embodiment, the agent inhibits one or more NOVX protein activity. Examples of such inhibitory agents include antisense NOVX nucleic acid molecules and anti-NOVX antibodies. These modulatory methods can be performed in vitro (e.g., by culturing the cell with the agent) or, alternatively, in vivo (e.g., by administering the agent to a subject). As such, the invention provides methods of treating an individual afflicted with a disease or disorder characterized by aberrant expression or activity of a NOVX protein or nucleic acid molecule. In one embodiment, the method involves administering an agent (e.g., an agent identified by a screening assay described herein), or combination of agents that modulates (e.g., up-regulates or down-regulates) NOVX expression or activity. In another embodiment, the method involves administering a NOVX protein or nucleic acid molecule as therapy to compensate for reduced or aberrant NOVX expression or activity.


[0308] Stimulation of NOVX activity is desirable in situations in which NOVX is abnormally downregulated and/or in which increased NOVX activity has a beneficial effect. One example of such a situation is where a subject has a disorder characterized by aberrant cell proliferation and/or differentiation (e.g., cancer or immune associated disorders). Another example of such a situation is where the subject has a gestational disease (e.g., preclampsia).


[0309] Determination of the Biological Effect of the Therapeutic


[0310] In various embodiments of the invention, suitable in vitro or in vivo assays are performed to determine the effect of a specific Therapeutic and whether its administration is indicated for treatment of the affected tissue.


[0311] In various specific embodiments, in vitro assays may be performed with representative cells of the type(s) involved in the patient's disorder, to determine if a given Therapeutic exerts the desired effect upon the cell type(s). Compounds for use in therapy may be tested in suitable animal model systems including, but not limited to rats, mice, chicken, cows, monkeys, rabbits, and the like, prior to testing in human subjects. Similarly, for in vivo testing, any of the animal model system known in the art may be used prior to administration to human subjects.


[0312] Prophylactic and Therapeutic Uses of the Compositions of the Invention


[0313] The NOVX nucleic acids and proteins of the invention are useful in potential prophylactic and therapeutic applications implicated in a variety of disorders including, but not limited to: metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers.


[0314] As an example, a cDNA encoding the NOVX protein of the invention may be useful in gene therapy, and the protein may be useful when administered to a subject in need thereof. By way of non-limiting example, the compositions of the invention will have efficacy for treatment of patients suffering from: metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias.


[0315] Both the novel nucleic acid encoding the NOVX protein, and the NOVX protein of the invention, or fragments thereof, may also be useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed. A further use could be as an anti-bacterial molecule (i.e., some peptides have been found to possess anti-bacterial properties). These materials are further useful in the generation of antibodies, which immunospecifically-bind to the novel substances of the invention for use in therapeutic or diagnostic methods.







EXAMPLES


Example A

[0316] Polynucleotide and Polypeptide Sequences, and Homology Data



Example 1

[0317] The NOV1 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 1A.
2TABLE 1ANOV1 Sequence AnalysisSEQ ID NO: 18554bpNOV1aGCACCCCGACAAGATGCCCAAGCGCGCGCACTGGGGGGCCCTCTCTGTGGTGCTGATCCG58546-01 DNASequenceCTGCTTTGGGGTCTCCGCGAGTGGCGCTGGCCTGCCCTCATCCTTGTGCCTGCTACGTCCCCAGCGAGGTCCACTGCACGTTCCGATCCCTGGCTTCTGTGCCCGCTGGCATTGCTAAACACTGTGGAAAGAATCAATTTGGGGTTTGGAAATAGCATACAGGCCCTGTCAGAAACCTCATTTGCAGGACTGACCAAGTTGGAGCTACTTATGATTCACGGCAATGAGATCCCAAGCATCCCCGATGGAGCTTTAAGAGACCTCAGCTCTCTTCAGGTTTTCAAGTTCAGCTACAACAAGCTGACAGTGATCACAGGACAGACCCTCCAGCGTCTCTCTAACTTAATGAGGCTGCACATTGACCACAACAAGATCGAGTTTATCCACCCTCAAGCTTTCAACGGCTTAACCTCTCTGAGGCTACTCCATTTGGAAGGAAATCTCCTCCACCAGCTGCACCCCAGCACCTTCTCCACGTTCACATTTTTGGATTATTTCAGACTCTCCACCATAAGGCACCTCTACTTAGCAGAGAACATGGTTAGAACTCTTCCTGCCAGCATGCTTCGGAACATGCCGCTTCTGGAGAATCTTTACTTGCAGGGAAATCCGTGGACCTGCGATTGTGAGATGAGATGGTTTTTGGAATGGGATGCAAAATCCAGAGGAATTCTGAAGTGTAAAAGGACAAAGCTTATGAAGGCGGTCAGTTGTGTGCAATGTGCTTCAGTCCAAAGAAGTTGTACAAACATGAGATTCACAAGCTGAAGGACCTGACTTGTCTGAAGCCTTCCATAGAGTCTCCTCTGAGACAGAACAGGAGCACGAGTATTGAGGAGGAGCAACAAGAAGAGAATGGTGACAGCCAGCTCATCCTGGAGAAAATCCAACTTCCCCAGTGGAGCATCTCTTTGATATGACTGATGAGCACGGGAACCTGGTGAACTTGGTGTGTGACATCAAGAAACCAATGGATGTGTACAAATTCACTTGAACCAAACAGATCCTCCAGATATTGACATAAATGCAATGGTTGCCTTGGACTTTGAGTATCCAATGACCCAGGAAAACTATGAAAATCTATGGAAATTGATAGCATACTACAGTGAAGTTCCCATGAAGCTACACAGAGAGCTCATGCTCAGCAAACACCCCAGAGTCAGCTACCAGTACAGGCAAGATGCCGATCAAGAAGCTCTTTACTACACAGGTGTGAGAGCCCAGATTCTTGCAGAACCAGAATGGATCATGCAGCCATCCATAGATATCCAGCTGAACCGACCTCAGAGTACCCCCAGAJGGTGCTACTTTCCTACTACAACCAGTATTCTCAAACAATAGCCACCAAGATACAGGCAGGCTCGGGGCAGAAGCTGGGTAATGATTGAGCCTAGTAGAGCTGTGCAAAAAGATCAGACTGTCCTGGAAGGGGGTCGATGCCAGTTGAGCTGCAATGTGAAACCTTCTGAGAGTCCATCTATCTTCTGGGTGCTTCCAGATGGCTCCATCCTGAAAGTGCCTGTCGATGACCCAGACAGCAAGTTCTCCATTCTCAGCAGTGGCTGCCTGAGGATCAAGTCCATGCAAGCCATCTGACTCGGGCTTCTACCAGTGCATTGCTCAAGTGAGGGATGAAATGGACCGCATGGTATATAGGGTACTTGTGCAGTCTCCCTCCACTCAGCCAGCCGAGAAGACACAGTGACAAATTGGCAAGAACCCAGGGGAGCCAGTGATGTTGCCTTGCAATGCTTTAGCTATACCCGAAGCCCACCTTAGCTGGATTCTTCCAACAGAAGGATAATTAATGATTTGGCTAACACATCACATGTATACATGCTGCCAAATGGAACTCTTTCCATCCCAAAGGTCCAAGTCAGTGACAGTGGTTACCACAGATGTGTGGCTGTCAACCAGCATGGGGCAGACCATATCACGGTGGGAATCACAGTCACCAAGAAAGGTTCTGGCTCGCCATCCAAAAGAGGCAGATGGCCAGGTCCAAAGGCTCTTTCCAGATCCAAAGGCTCTTTCCAGATGAGAGAAGACATCGTGGACCATGAAGGGGTCTCAGCCACGCGAGATGAAGAGAACACTTCAAGGAGACTTCTACATCCAAAGCACCAAGAGGCGTTCCTCAAAACAAAGGATGATGCCATCAATGGAGATAAGAGCCAAGAAAGGGAGAAGAAAGCTCAAACTCTGGAAGCATTCACAAAAGAACCAGAGACCACTGTTCCAGAAGATCTCACTGGGCTGATATTTT AGAGTGTTTGAATCAAGACGAAGGATAAACGTGGCAAACAAACAGATTAATCCGGAGCATCCCCAATTATTAAAAGCCAAAGTCTTTGGGAAAAATCTCCCTACAGGCACAGAAGTTTGCCTGCTGTTTCTCACCACAAGTTCTCCATTCTTGAGCCTAGTAGTCACACCACCTAATCCTCAGCAGATGTCCCCCTTGGCATCTCCAATACAGACAGCAAACAAGTGCTGAACCTCAGCCAGCATGGGAACCTCTACTCAGCGAAGGAAAGCACATTTTGAGTACCATTTCGAACAAGCACACCTCTCTAGAACACCACAACAITGGAGTTATTCTTGTTGAACCTGAAXTCACTTCCACTGAAGGCGAAGAAGTTGTTGATGAGTATTCCAAGAAGACTGAGGAGATTATGAACAATCTCCTCGACCTGAAGGGCACTGCAGCCTCTACACTTATATCTGAGCCGAAGAGACGGAAACAGACTCTACACACCTTAGACACAGTCTATGAAGAGCCCACCCATCATCCAGTGAGTATGAAGGGTTGGTCTGCAGCAGATGTTGGATCCTCACCAGATCCCAGCAATACTTTGACCCAGCTTCCATTGGTTGTTGTCTCCTTCCCTGAGTCTAGCCTGTGAATACAGTTTTGCACGATTTGGAGACTAATTCACAACCACATGAGGATAACATAAAACATCACTGTCATTTGAACCTTACTCCAACCGCCATCATCTGGTTTAATGACTCTAGTATCTACAAGGACCGACAGGATTCTACTGTAGGGGAACAAGGTGTCCCAGGCAAATCACAACCTTATTGATTAAAAGAGAACATCCAGCTTGTGAAAAGTAGTTTTAGCACTCAAGACTGCTAGAGGGAGACCCAACGTATGAAAGAGATGTCTCAGACACTACAGGGACGATAATCCATCACTTTACCTTACACACTCCAGAAGTTCTGAGATGAGGGCCAAGAGAGCAAAAGCCTGCGGAAACCAGACTCCACACTGGGTATAACCAGCAGTACGTCTCCAGTTAAGCTCCAAGGCAAAAAGTCAGTTGTCACCTGCTACACAAAGACACCACAACAGAAACAAACCCAATGGGAGAAAAGGCTTCATCATCCACCATGAGCACTCACCCTTCTCGAAGAAACCCACAACTTTTGCTCTTACACCCTCACAAATTCCACCACCCGACAAGCAAACCCCATTAAGATTTCAAATCACATTAGAGACTTTTTCTACTCACCACTCAACCAACTGACAAGTTAATACCCCCAAAAATGGAGAGTTCTCTGGTTCCTACATCTTGGGACATTAACACACTCCACGGAGAAAACCAGCTGGMATGGAGAAGAATGTACAGCTCATATCAAAAGCAATGAGTTCAAGAGCATCACGGGAAGAGGCCAAACAAACATCGATATACCCCTTCTACAGCATTGTTACTCCCAGTTGCATCCAAGCCCAGCCCTTCTCCAGATAACATAGAAGAGGGCGTTTATGATTTCAGAAACTACACTTTTGCCTAGAAATGTTTCTCTGAAAACTACCATAAAGTCCAAGACCTTAGATTACACGACAACCACCAGAAAAATACATTCATCTCAATTCAGGATGATGTTCACACTTCCAGTCATGTATAAACCCACATCAGATGGAAAAGAGGTGAGTCAATTACAAGCCACAAATGTTGACAAACATAAAAGTGACATTTTAGTCCCTAATTTAAGGAAGAATCATGTCACACkACTTCTCGCTCCTTGGTCTCCACTATGGGAGAAGGAAAGCTCAGCCTCTCTCCTGTGGGCTTTCCAGGAATTCCAACCTGGAATCCCTCACCCCTACAGACCCTCGGGAGGCTACAGACAGACATACATGTTACCACTTCTGGGGAATTTTGTCCTCTGTGACCCCTTGTTAACGAGCTTGAGGATGTGGATTTTACTTCTGAGTAATTCTCTCAAGCATAAGTCTCCACACCATTTCACCAGGAAGAAGCTGGTTTTTCCACGGTCAAGATCATCATGAAAGTGGAGATGGCTTCAAGTCACGTAGAAACTACCACCCTTATCACATCCTTACTGCAAACCACTGTGGCTATTCTCCACTCTGAAACTAGACCACAGATCTCCTGTCTTTGGGATGCCTGGATGAAGGAGCCAGCATCTTTGTCCCCTCCCATGATTCTCAAATATGTAAAGCAAACCACCACCACTAAGCCAGAACTTCTCAGTCCAAGAACAAAACAGAAGCAACCCCATTCCAAGGAAAATGTTTTCTTGAATTACATGGGGAAACCAGATTATCAACACCATCTAGTGAAAATGAAGGAACACAGCGTATGTCAGGGCCAAATGAGAAAAGCAAGTATTTGTCTGACCACGATGCATTTAACTTGTCTACAAAGCTAGAATTGATGGAAGAGTTCATGCATAGTAGGAGTCTAACACGTGGCCCACATAGCCACCACCAGGAACAGGAACAGTGAGGTTCTCATCAACTAACCAGAATCCCTGCCAAACCCATCCTACCACTTTCCAGCCACCTCCTGCCTGAAATGTCCACACAAAGCACTTCCAGATACTTTGTAGGGCTTTGCCAGAGAGATCACGGGACCAACAAACCAGAAATAACTACATATCCTTCTACCTATCACACATGTCCCAACAGTTTACAACTCCAAGAGTAGCAAGTACACTCCTCTCAATCCAATGGCTCCTAACCCAGCATTTCTAGTAAGTTTCCTGACCTAAGAACTGACCAGTTGGAAAGCCTCTACAAAGTGTTTGGAAATAGCAACATCCCTGAGGCAAGAAACTCTTTACCAACAGGACTCAGTCCAAGAATTTATCATTATTCCAATGGAAGACTCCCTTTCCCTCTTCTCCTGTCCCTTTCTTTTTCACAGTTGGGAGTCACCCGGAGACCCCAGATAGGATATATTCCCATAGCAGTAATGAGAGAGAGAAAAGTTAATCCAGGTTCCTACAATAGCACACTCCATGGACCCACCTTCCATCTGGACTTTGGCCTTCCAGCACCTCCACTGTTTCATCCACCCAGAGTTATGGTATCACCCCCAACTAACTTACAGAATATCCCTATGGTCTCCACCAAAGCGGCTCCTGTCTCCTTTATAACATCTTCTGTCCAGTCCTCAGGAAGCATCTTGGGCAAAAGCCCAAAGTTCTTTGCAGGAGGACCGCCTGCATCCAAATTCTGGCCCAAATCCTCACCAAGTCCCCACAGACTGTGTCTGTCACTGCTGAAACGGACGCTGTGTTCCCGTGTGAGGCAATAGGAACCAAAAGCCTTTCGTTACTTGGACAAAAGTTTCCACATCTCCAGGAGTTCTTATGACTCCGAATACCAGGATACAACGGTTTGAGGTTCTCAAGAACCGTACCTTAGTGATAAGGAAGTTTCAAGTGCAAGATCGAGGCCAGTATATGTGCACCGCCAGCAACCTGTACGGCCTGGACAGGATGGTGGTCTTTCTCTGGGTCACCGTGCAGCAACCTCAAATCCTAGCCTCCCACTACCAGGACGTCACCGTCTACCTGGGAGACACCATTACAATGGAGTGTCTGGCGAAAGGGACCCCAGCCCCCCAAAATTTCCTGGATCTTCCGTGACAGGAGGGTGTGGCAAACTCTGTCCTCCGTGGAGGGCCGGATCACCCTGCACCAAAACCGGACCCTTTCCATCAAGGAGGCGTCCTTCTCAGACAGAGGCGTCTATAAGTGCGTGGCCAGCAACGCAACCCGGGCGGACAGCGTGTCCATCCGCCTACACGTGGCGGCACTGCCCCCCATTATCCACCAGGAGAAGCTGGAGAACATCTCGCTGCCCCCGGGGCTCAGCATTCACATTCACTGCACTGCCAAAGCTGCGCCCCTGCCCAGCGTGCTCTGGGTGCTCGGGGATGCATACCCAAATCCGCCCCTCGCATTTCCTCCACCGGAACTTGTTTGTTTTCCCCAACGGGACGCTCTACATCTGCAACCTCGCGCCCAAGAAAAGCGGGCGCTATGAGTGCGTGGCCGCCAACCTGATCGGCTCCGCGCGCAGTACGGTGCAGCTGAACGTGCAGCGCGCAGCAGCGAACGTGCAGCGCGCAGCAGCGAACGTGCAGCGCGCCAACGCGCGCATCACGGGCACCTCCTCGCAGAGGACGGACGTCAGCTACGGAGGGACCCTCAAGCTGGACTGCAGCGCCTCGGGGGATCCCTGGCCGCGCATCCTCTGGAGGCTGCCGTCCAAGAGGACGATCGACGCGCTTTTCAGTTTTGATAGTAGAATCAAGGTGTTTGCCAACAGGACCCTGGTGGTGAAATCAATGACAGACAAAGACGCCGGAGATTACCTGTGTGTAGCTCGAATAAGCTTCGTGATGACTGCGTGGTGCTCAGGTGGATGTGATGATGAAACCGGCCAAGATTGAACACAAGGAGGAGAACGACCACAPAAGTCTTCTACAGGGGTGACCTCAAAGTGGACTGTGTGGCCACTGCACTTCCCAITCCCGAGATCTCCTGGAGCCTCCTGGATGCGAGTCTGGTGAACTCCTTCATCCAGTCAGATGACAGTGGTGGACCCACCAAGCACTATGTGGTCTTCAACAATGGGACACTCTACTTCAGTGAAGTGGGGATGAGGGAGGAAGGAGACTACACCTGCTTTGCTGAAAATCAGGTTGGGAAGGATGAGATGAGAGTCAGAGTCAAGATGGTGACACCTGCCACCATCTGGAACAAGACTTACTTGGCAGTTCAGGTACCCTATGGAGATCTGGTCACTGTAACCTGTGAGGCCAAACGAGAACCCATGCCCAAGGTGACTTGGTTGTCCCCAGCCAACAGGGTGATCCCCACCTCCTCTGAGAAAGTATCAGATATACCAATATGGCACTCTCCTTATTCAGAAAGCCCAGTGCTCTGACAGCGGCPACTACACCTGCCTGGTCAGGAACAGTGCCGGAGAGGATACGAAGACAGTGTGGATTCACGTCAACCTCCAGCCACCCAAGATCAATGGTAACCCCAACCCCATCACCACCGTGTGGGAGATAGCAGCCGCGGCCAGTCGGAAACTGATTGACTGCAAAGCTGAAGGCATCCCCACCCCGAGGGTGTTATGGGCTTTTCCCCAGGGTGTGGTTCTGCCAGATCCATACTATGGAAACCGGATCACTGTCCATGGCAACGGTTCCCTGCACATCAGGAGTTTGAGGAAGAGCGACTCCGTCCAGCTGGTATGCATGGCACGCAACGAGGGAGCGGAGGCGAGGTTGATCGTGCAGCTCACTGTCCTGGAGCCCATGGAGAAACCCATCTTCCACCACCCGATCAGCGAGAAGATCACGGCCATGGCGGGCCACACCATCACCCTCAACTGCTCTGCCGCGGGGACCCTGACACCCAGCCTGGTGTGGGTCCTTCCCAATGGCACCGATCTGCAGAGTGGACAGCAGCTGCAGCGCTTCTACCACAAGGCTGACGGCATGCTACACATTAGCGGTCTCTCCTCGGTGGACGCCGGGGCCTACCGCTGCGTGGCCCGCAATGCCGCGGCCCACACGGAGAGGCTGGTCTCCCTGAAGGTGGGACTGAAGCCAGAAGCAAACAAGCAGTATCATAACCTGGTCAGCATCATCAATGGTGAGACCCTGAAGCTCCCCTGCACCCCTCCTGCAGCTGGGCAGGGACATTTCTCCTGGACACTCCCCAATGGCATGCATCTOGAGGGCCCCCAAACCCTGGGACGCGTTTCTCTTCTCGACAATGGCACCCTCACGGTTCGTGAGGCCTCGGTGTTTGACAGCGGTACCTATGTATGCAGCATGGAGACGGCGTACGGCCCTTCCGTCACCAGCATCCCCGTGATTGTCATCGCCTATCCTCCCCGGATCACCAGCGAGCCTACCCCAGTCATCTACACCCGTCCCCGGAACACCGTGAACTGAACTGCATGGCTATGGGGATTCCCAAAGGTGACATCACGTGGGAGTTACCGGATAAGTTGCATCTGAACGCAGGGGTTCAGGCTCGTCTGTATGGAAACAGATTTCTTCACCCCCAGGGATCACTGACCATCCAGCAGGCCAGACCGAGACACGCTGGCTTCTACAAGTGCACGGCAAAAAACATTCTCAGCAGTGACTCCAAAACAACTTATATCCATGTCTTCTGAAATORE Start: ATG at 14ORE Stop: TGA at 8549SEQ ID NO: 22845 aaMW at 31 5664.5kDNOV 1a,MPKRAHWGALSVVLILLWGHPRVALACPHPCACYVPSEVHCTFRSLASVPAGIAKHVECG58546-01 ProteinSequenceRINLGFGNSIQALSETSFAGLTKLELLMIHGNEIPSIPDGALRDLSSLQVFKSYNKLRVITGQTLQGLSNLMRLHIDHNKIEFIHPQAFNGLTSLRLLHLEGNLLHQLHPSTFSTFTFLDYFRLSTIRHLYLAENMVRTLPASMLRNMPLLENLYLQGNPWTCDCEMRWFLEWDAKSRGILKCKKDKAYEGGQLCAMCFSPKKLYKHETHKLKDLTCLKPSIESPLRQNRSRSIEEEQKQEENGDSQLILEKIQLPQWSISLNMTDEHGNLVNLVCDIKKPMDVYKIHLNQTDPPDIDINAMVALDFEYPMTQENYENLWKLIAYYSEVPMKLHRELMLSKIPRVSYQYRQDADEEALYYTGVRAQILAEPEWIMQPSIDIQLNRPQSTAKKVLLSYYNQYSQTIATKDTRQARGRSWVMIEPSRAVQKDTVLEGGRCQLSCVKASESPSIFWVLPDGSILKVPVDDPDSKFSILSSGWLRIKSMEPSDGLYQCIAQVRDEMDRVYRVLVQSPSTQPAEKDTVTIGKNPGEPVMLPCNALAIPEAHLWILPNRRIINDLANTSHVYMLPNGTLSIPKVQVSDSYHRCVAVNQHGADHITVGITVTKKGSGSPSKRGRWPGPKALSRSKGSFQMREDIVEDEGVSGTGDEENTSRRLLHPHQEAFLKTKDDAINGDKKAKKGRRKLKLWKHSEKEPETSVAEDLRVFESRRRINVANKQINPEHWADILAKVFGKNLPTGTEVSPIIKTTSSPFLSLVVTPPLPAVSPPLASPIQTATSAEESSADVPLLSEGKHILSTISSASMGLEHHNNGVILVEPEVTSTPLEEVVDEYSKKTEEMTSTEGDLKGTAASTLISEPYEQSPTLHTLDTVYEEPTHEETETEGWSAADVGSSPDPTSSEYELPLVVVSLAESKPVQYFDPDLETNSQPHEDNIKEYSFAHLTPTAIIWFNDSSTSLSFEDSTVGEQGVPGKSHLQGPTENIQLVKSSFSTQDTLLIKKGMKEMSQTLQGGNMLEGDPTHSRSSENEGQESKSITLPDSTLGITSSTSPVKKPAETTVVTLLHKDTTTETTPRQKVASSSTMSTHPSRRRPNGRKLHPHKFHHRHKQTPPTTFAPLETFSTQPTQATDIKISNQMESSLVPTWEINTVNTPKQLEMEKNVELISKGTPPPKHGKRPNKHRYTPSTVSSRASASKPSPSPENKHRNIVTPSSETTLLPRNVSLKTEGVYDSLDYTTTTRKIHSSHHKVQDTLPVMYKPTSDGKEIQDDVATNVDKHKSDILVPGESITNVTQTSRSLVSTMGEFKEESSPVGFGIPTWNPSRKAQPGRLQTDIHVTTSGETPTDPPLVNELEDVDFTSEFLSSVTVSTPFHQEEAGFSTILSSIKVEMASSQVETTTLGQDHHETTVAILHSETRPQNHILTAAWMKEPASLSPPMILLSLGQTTTTKPELLSRTSQICKDSKENVFLNYMGNPETEATPVKEGTQRMSGPNELSTPHVFSEQ ID NO: 3762 bpNOV1b, CGGCCGTGCCCTCATCCTTGTGCCTGCTACGTCCCCAGCOAGGTCCACTGCACGTTCC174307918 DNA SequenceGATCCCTGGCTTCCGTGCCCGCTGGCATTGCTAACACGTGGAAAAGAATCAATTTGGGGTTTAATAGCATACAGGCCCTGTCAGAAACCTCATTTGCAGGACTGACCAAGTTGCAGCTACTTATGATTCACGGCAATGAGATCCCAAGCATCCCCGATGGAGCTTTAAGAGACCTCAGCTCTCTTCAGGTTTTCAAGTTCAGCTACAACAAGCTGAGAGTGATCACAGGACAGACCCTCCAGGGTCTCTCTAACTTAATGAGGCTGCACATTGACCACAACAAGATCGAGTTTATCCACCCTCAAGCTTTCACGGCTTAACGTCTCTGAGGCTACTCCATTTGGAAGGAAATCTCCTCCACCAGCTGCACCCCAGCACCTTCTCCACGTTCACATTTTTGGATTATTTCAGACTCTCCACCATAAGGCACCTCTACTTCGCAGAGAAACATGGTTAGAACTCTTCCTGCCAGCATGCTTCGGAACATGCCGCTTCTGGAGAATCTTTACTTGCAGGGAAATCCGTGGACCTGCGATTGTGAGATGAGATGGTTTTTGGAATGGGATGCAAAATCCAGAGGAATTCTGAAGTGTAAAAAGGACAAAGCTTATGAAGGCGGTCAGTTGTGTGCAATGTGCTTCAGTCCAAAGAAGTTGTACAAACATGAGATTCACAAGCTGAAGGACCTGACTTGTCTGCTCGAGORF Start: CGG at 1ORF Stop: it at 763SEQ ID NO: 41254 aaMW at 29088.6kDNOV 1b,RPCPHPCACYVPSEVIICTFRSLASVPAGIAKHVERINLGFNSIQALSETSFAGLTKLE174307918 ProteinSequence LLMTHGNEIPSIPDGALRDLSSLQVFKFSYNKLRVITGQTLQGLSNLMRLHIDHNKIEFIHPQAFNGLTSLRLLHLEGNLLHQLHPSTFSTFTFLDYFRLSTIRHLYFAENMVRTLPASMLRNMPLLENLYLQGNPWTCDCEMRWFLEWDAKSRIGILKCKKDKAYEGGQLCAMCFSPKKLYKHEIHKLKDLTCLLESEQ ID NO: 5 762 bp NOV 1c,CGGCCGTGCCCTCATCCTTGTGCCTGCTACGTCCCCAGCGAGGTCCACTGCACGTTCC174307924 DNASequenceGATCCCTGCCTTCCGTGCCCGCTGGCATTGCTAAACACGTGGAAAGAATCAATTTGGGGTTTAATAGCATACAGGCCCTGTCAGAAACCTCATTTGCAGGACTGACCAAGTTGGAGCTACTTATGATTCACGGCAATGAGATCCCAAGCATCCCCGATGGACCTTTAAGAGACCTCAGCTCTCTTCAGGTTTTCAAGTTCAGCTACAACAAGCTGAGAGTGATCACAGGACAGACCCTCCAGGGTCTCTCTAACTTAATGAGGCTGCACATTGACCACAACAAGATCAAATTTATCCACCCTCAAGCTTTCAACGGCTTAACGTCTCTGAGGCTACTCCATTTGGAAGGAAATCTCCTCCACCAGCTGCACCCCAGCACCTTCTCCACGTTCACATTTTTGGATTATTTCAGACTCTCCACCATAAGGCACCTCTACTTAGCAGAGAACATGGTTAGAACTCTTCCTGCCAGCATGCTTCCGAACATGCCGCTTCTGGAGAATCTTTACTTGCAGGGAAATCCGTGGACCTGCGATTGTGAGATGAGATGGTTTTTGGAATGGGATGCAAAGTCCAGAGGAATTCTGAAGTGTAAAAAGGGCAAAGCTTATGAAGGCGGTCAGTTGTGTGCATGTGCTTCAGTCCAAAGAAGTTGTACAAACATGAGATTCACAAGCTGAAGGACCTGACTTGTCTGCTCGAGORF Start: CCC at 1AORF Stop: it at 763SEQ ID NO:6254 aaMW at 28996.5kDNOV 1c,RPCPHPCACYVPSEVHCTFRSLASVPAGIAKHVERINLGFNSIQALSETSFAGLTKLE174307924 ProteinSequenceLLMIHGNEIPSIPDGALRDLSSLQVFKFSYNKLRVITGQTLQGLSNLMRLHIDHNKIEFIHPQAFNGLTSLRLLHLEGNLLHQLHPSTFSTFTFLDYFRLSTIRHLYLAENMVRTLPASMLRNNPLLENLYLQGNPWTCDCEMRWFLEWDAKSRGILKCKKGAYEGGQLCAMCFSPKKLYKHEIHKLKDLTCLLESEQ ID NO:7762bpNOV 1d,CGGCCGTGCCCTCATCCTTGTGCCTGCTACGTCCCCAGCGAGGTCCACTGCACGTTCC169679197 DNASequence CTACTTATGATTCACGGCAATGAGATCCCAAGCATCCCCGATCGAGCTTTAAGAGACCGATCCCTCGCTTCCGTGCCCGCTGGCATTGCTAAACACGTGGAAAGAATCATTTGGGGTTTAATAGCATACAGGCCCTGTCAGAAACCTCATTTGCAGGACTGACCAAGTTGGAGTCAGCTCTCTTCAGGTTTTCAAGTTCAGCTACAACAAGCTGAGAGTGATCACAGGACAGACCCTCCAGGGTCTCTCTAACTTAATGAGGCTGCACATTGACCACAACAAGATCGAGTTTATCCACCCTCAGCTTTCAACGGCTTAACGTCTCTGAGGCTACTCCATTTGGAGGAAATCTCCTCCACCAGCTGCACCCCAGCACCTTCTCCACCTTCACATTTTTGGATTATTTCAGACTCTCCACCATAAGGCACCTCTACTTAGCAGAGAACATGGTTAGAACTCTTCCTGCCAGCATGCTTCGGAACATGCCGCTTCTGGAGAATCTTTACTTGCAGGGAAATCCGTGGACCTGCGATTGTGAGATGAGATGGTTTTTGGAATGGGATGCAAAATCCAGAGGAATTCTGAAGTGTAAAAAGGACAAAGCTTATGAAGGCGGTCACTTGTGTACATGTGCTTCAGTCCAAAGAAGTTGTACAACATGAGATTCACAAAGCTGAGGACCTGACTTGTCTTGCTCGAGORF Start: CGG at 1ORF Stop: it at 763SEQ ID NO: 8254 aaMW at 29084.6kDNOV 1d,RPCPHPCACYVPSEVHCTFRSLASVPAGIAKHVERINLGFNSIQALSETSFAGLTKLE169679197 ProteinSequenceLLMIHGNEIPSIPDGALRDLSSLQVFKFSYNKLRVITGQTLQGLSNLMRLHIDHNKIEFIHPQAFNGLTSLRLLHLEGNLLHQLHPSTFSTFTFLDYFRLSTIRHLYLAENMAARTLPASMLRNNPLLENLYLQGNPWTCDCEMRWFLEWDAKSRGILKCKKDKAYEGGQLCTMCFSPKKLYKHEIHKLKDLTCLLESEQ ID NO: 9762 bpNOV 1c,CGGCCGTGCCCTCATCCTTCTGCCTGCTACGTCCCCAGCGAGGTCCACTGCACGTTCC169679219 DNASequenceGATCCCTGGCTTCCGTGCCCGCTGGCATTGCTAACACGTGGAAAGAATCAATTTGGGGTTTAATAGCATACAGGCCCTGTCAGAAACCTCATTTGCAGGACTGACCAAGTTGGAGCTACTTATGATTCACGGCAATGAGATCCCAAGCATCCCCGATGGAGCTTTAAGAGACCTCAGCTCTCTTCAGGTTTTCAAGTTCAGCTACAACAAGCTGAGAGTGATCACAGGACAGACCCTCCAGGGTCTCTCTAACTTAATGAGGCTGCACATTGACCACMA.CIAGATCGAGTTTATCCACCCTCAAGCTTTCAACGGCTTAACGTCTCTGAGGCTACTCCATTTGGAAGGAAATCTCCTCCACCAGCTGCACCCCAGCACCTTCTCCACGTTCACATTTTTGGATTATTTCAGACTCTCCACCATAAGGCACCTCTACTTAGCAGAGAACATGGTTAGAACTCTTCCTGCCAGCATGCTTCGGAACATGCCGCTTCTGGAGAATCTTTACTTGCAGGGAAATCCGTGGACCTGCGATTGTGAGATGAGATGGTTTTTGGAATGGGATGCAAAATCCAGAGGAATTCTGAAGTGTAAAAAGGACAAAAGCTTATGAAGGCGGTCAGTTGTGTGCPATGTGCTTCAGTCCAAAGAAGTTGTACAACATGAGATTCACAIGCTGAAGGACCTGACTTGTCTGCTCGAGORE Start: COG at 1ORF Stop: it at 763SEQ ID NO: 10254aaMW at 29054.6kDNOV 1e,RPCPHPCACYVPSEVHICTFRSLASVPAGIAKIVERINLGFNSIQALSETSFAGLTKLE169679219 ProteinSequenceLLMIHCNEIPSIPDGALRDLSSLQVFKFSYNKLRVITGQTLQGLSNLMRLHIDHNKIEFIHPQAFNGLTSLRLLHLEGNLLHQLHPSTFSTFTFLDYFRLSTIRHLYLAENNVRTLPASMLRNNPLLENLYLQGNPWTCDCEMRWFLEWDAKSRG ILKCKKDKAYEGGQLCAMCFSPKKLYKHEIHKLKDLTCLLESEQ ID NO: 11762 bpNOV 1fGGATCCTGCCCTCATCCTTGTGCCTGCTACGTCCCCAGCGAGGTCCACTGCACGTTCC207704655 DNASequenceGATCCCTGGCTTCCGTGCCCGCTGGCATTGCTAAACACGTGGAAAGAATCAATTTGGGGTTTAATAGCATACAGGCCCTGTCAGAAACCTCATTTGCAGGACTGACCAAGTTGGAGCTACTTATGATTCACGGCATGAGATCCCAAGCATCCCCGATCGAGCTTTAAGAGACCTCAGCTCTCTTCAGGTTTTCAAGTTCAGCTACAACAAGCTGAGAGTGATCACAGGACAGACCCTCCAGGGTCTCTCTAACTTAATGAGGCTGCACATTGACCACAACAAGATCGAGTTTATCCACCCTCAGCTTTCIVAACGGCTTIAACGTCTCTGAGGCTACTCCATTTGGAAGGAAATCTCCTCCACCAGCTGCACCCCAGCACCTTCTCCACGTTCACATTTTTGGATTATTTCAGACTCTCCACCATAAGGCACCTCTACTTAGCAGAGAACATGGTTAGAACTCTTCCTGCCAGCATGCTTCGGAACATGCCGCTTCTGGAGAATCTTTACTTGCAGGGAAIATCCGTGGACCTGCCATTGTGAGATGAGATGGTTTTTGGAATGGGATGCAAAATCCAGAGGAATTCTGAAGTGTAAAAAGGACAAAGCTTATGAAGGCGGTCAGTTGTGTACAATGTGCTTCAGTCCAAGAAGTTGTACAAACATGAGATTCACAAGCTGAAGGACCTGACTTGTCTGCTCGAGORF Start: OGA at 1ORE Stop: it at 763SEQ ID NO: 12254 aaAMW at 28975.4kDNOV 1f,GSCPHPCACYTPSEVHCTFRSLASVPAGIAKHVERINLGFNSIQALSETSFAGLTKLE207704655 ProteinSequenceLLMIHGNEIPSIPDGALRDLSSLQVFKFSYNKLRVITGQTLQGLSNLMRLHIDHNKIEFIHPQAFNGLTSLRLLNLEGNLLHQLHPSTFSTFTFLDYFRLSTIRHLYLAENMVRTLPASMLRNMPLLENLYLQGNPWTCDCEMRWFLEWDAKSRGILKCKKDKAYEGGQLCTMCFSPKKLYKHEIEHKLKDLTCLLE


[0318] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 1B.
3TABLE 1BComparison of NOV1a against NOV1b through NOV1f.ProteinNOV1a Residues/Identities/SequenceMatch ResiduesSimilarities for the Matched RegionNOV1b27 . . . 277234/251 (93%) 3 . . . 252234/251 (93%)NOV1c27 . . . 277234/251 (93%) 3 . . . 252234/251 (93%)NOV1d27 . . . 277234/251 (93%) 3 . . . 252234/251 (93%)NOV1e27 . . . 277235/251 (93%) 3 . . . 252235/251 (93%)NOV1f26 . . . 277234/252 (92%) 2 . . . 252235/252 (92%)


[0319] Further analysis of the NOV1a protein yielded the following properties in Table 1C.
4TABLE 1CProtein Sequence Properties NOV1aPSort0.4371 probability located in outside; 0.1900 probabilityanalysis:located in lysosome (lumen); 0.1800 probability located innucleus; 0.1000 probability located in endoplasmic reticulum(membrane)SignalPCleavage site between residues 27 and 28analysis:


[0320] A search of the NOV1 a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 1D.
5TABLE 1DGeneseq Results for NOV1aNOV1aIdentities/Protein/Organism/Residues/Similarities forGeneseqLength [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAM41498Human polypeptide SEQ ID NO 6429 -2211 . . . 2845605/636 (95%)0.0Homo sapiens, 666 aa. 31 . . . 666612/636 (96%)[WO200153312-A1, 26 JUL. 2001]AAM39712Human polypeptide SEQ ID NO 2857 -2258 . . . 2845561/589 (95%)0.0Homo sapiens, 589 aa.  1 . . . 589567/589 (96%)[WO200153312-A1, 26 JUL. 2001]AAB42539Human ORFX ORF2303 polypeptide2263 . . . 2845556/584 (95%)0.0sequence SEQ ID NO: 4606 - Homo  1 . . . 584562/584 (96%)sapiens, 584 aa. [WO200058473-A2,05 OCT. 2000]ABB19814Protein #1813 encoded by probe for 841 . . . 1349509/509 (100%)0.0measuring heart cell gene expression -  1 . . . 509509/509 (100%)Homo sapiens, 509 aa.[WO200157274-A2, 09 AUG. 2001]AAM67586Human bone marrow expressed probe 841 . . . 1349509/509 (100%)0.0encoded protein SEQ ID NO: 27892 -  1 . . . 509509/509 (100%)Homo sapiens, 509 aa.[WO200157276-A2, 09 AUG. 2001]


[0321] In a BLAST search of public sequence databases, the NOV1a protein was found to have homology to the proteins shown in the BLASTP data in Table 1E.
6TABLE 1EPublic BLASTP Results for NOV1aNOV1aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ9NR99ADLICAN - Homo sapiens (Human),  1 . . . 28452568/2849 (90%)0.02828 aa.  1 . . . 28282641/2849 (92%)Q9Y3Y8HYPOTHETICAL 63.9 KDA2263 . . . 2845 554/584 (94%)0.0PROTEIN - Homo sapiens (Human),  1 . . . 584 562/584 (95%)584 aa (fragment).Q96SC3FIBULIN-6 - Homo sapiens1787 . . . 2844 284/1075 (26%)8e−81(Human), 2673 aa (fragment). 28 . . . 1022 443/1075 (40%)Q96RW7HEMICENTIN - Homo sapiens1861 . . . 2844 268/991 (27%)1e−80(Human), 5636 aa.3064 . . . 3985 416/991 (41%)Q96DN3CDNA FLJ31995 FIS, CLONE1854 . . . 2831 263/988 (26%)4e−73NT2RP7009236, WEAKLY 147 . . . 1066 416/988 (41%)SIMILAR TO BASEMENTMEMBRANE-PROTEOGLYCANCORE PROTEIN PRECURSOR -Homo sapiens (Human),1252 aa (fragment).


[0322] PFam analysis indicated that the NOV1 a protein contains the domains shown in the Table 1F.
7TABLE 1FDomain Analysis of NOV1aIdentities/Similaritiesfor theNOV1aMatchedExpectedPfam DomainMatch RegionRegionValueLRRNT: domain 1 of 1 26 . . . 5411/31 (35%)0.07822/31 (71%)LRR: domain 1 of 6 56 . . . 80 6/26 (23%)2.4e+0220/26 (77%)LRR: domain 2 of 6 81 . . . 104 7/25 (28%)0.3620/25 (80%)LRR: domain 3 of 6105 . . . 128 5/25 (20%)4.218/25 (72%)LRR: domain 4 of 6129 . . . 152 7/25 (28%)0.01521/25 (84%)LRR: domain 5 of 6153 . . . 176 8/25 (32%)0.8418/25 (72%)LRR: domain 6 of 6185 . . . 208 7/25 (28%)3.317/25 (68%)LRRCT: domain 1 of 1218 . . . 27718/64 (28%)4.1e−0540/64 (62%)ig: domain 1 of 13495 . . . 55815/67 (22%)3.7e−0646/67 (69%)ig: domain 2 of 13593 . . . 65415/65 (23%)1.8e−0644/65 (68%)ig: domain 3 of 131011 . . . 1295 5/286 (2%)5.9e+04221/286(77%)ig: domain 4 of 131872 . . . 193613/68 (19%)2.5e−0645/68 (66%)ig: domains 5 of 131971 . . . 203314/66 (21%)1.1e−0643/66 (65%)IF3: domain 1 of 12110 . . . 21223.511/13 (85%)ig: domain 6 of 132073 . . . 213014/61 (23%)0.0002638/61 (62%)ig: domain 7 of 132179 . . . 224118/66 (27%)1.8e−0844/66 (67%)ig: domain 8 of 132276 . . . 234412/72 (17%)0.0008943/72 (60%)ig: domain 9 of 132378 . . . 243721/63 (33%)2.4e−1145/63 (71%)ig: domain 10 of 132476 . . . 253714/65 (22%)0.1139/65 (60%)ig: domain 11 of 132574 . . . 263514/65 (22%)2.1e−0645/65 (69%)ig: domain 12 of 132669 . . . 273012/65 (18%)7.3e−0544/65 (68%)ig: domain 13 of 132765 . . . 282917/68 (25%)8.9e−0947/68 (69%)



Example 2

[0323] The NOV2 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 2A.
8TABLE 2ANOV2 Sequence AnalysisSEQ ID NO: 131055 bpNOV2a,CCAAGAAACAGAATCAAGGCTCGATGCCTGTCCTGCACGTCCATGGTTCTGAAGGGCATCTGGGGACTCTTGATCATCTTGTCAGTATCATCATCTTGGTCTATTATTCTGGTCATCTAGCCACTGCTCAAGAAAAGCAATCTCCAATGAAAAAATTCAGGGAATGCAGTCGGATTTTTGGTGAAGATGGTCTGACGCTGAAACTCTTTCTTAAAAGAACTGCTCCCTTTTCTATTCTATGGACTTTGACTAATTACCTTTATTTACTGGCTTTAAAGAAGCTGACGGCCACGGATGTCTCCGCTCTGTTCTGTTGTAACAAAGCCTTTGTCTTCTTGCTGTCATGGATTGTGCTGAAAGACAGGTTCATGGGAGTGAGGATAGTTGCTGCAATAATGGCAATTACCGGCATTGTCATGATGGCATATGCAGATAATTTCCACGCTGATTCCATCATAGGAGTGGCATTTGCGGTGGGCTCAGCCTCTACATCTGCATTATATAAGGTATTGTTTAAAATGTTTCTTGGAAGTGCCAACTTTGGGGAAGCTGCACACTTTGTCTCCACCTTGGGTTTCTTCAATTTGATCTTCATCTCCTTCACCCCAGTCATCTTGTATTTCACCAAGGTGGAGCACTGGTCCTCTTTTGCTGCTCTGCCATGGGGCTGTCTCTGTGGGATGGCAGGGCTGTGGCTGGCCTTCAACATCCTGGTGAATGTTGGGGTGGTGCTGACATACCCAATCCTAATCTCCATTGGGACAGTGCTCAGCGTTCCTGGAAATGCAGCTGTGGATCTCCTAAAGCAGGAGGTGATATTCAATGTTGTCCGCCTGGCTGCTACCATCATCATCTGCATTGGGTTTCTGCTGATGCTGTTGCCTGAGGAATGGGATGAAATCACCCTGAGGTTCATCAACAGCCTGAAGGAAAAGAAGAGTGAGGAGCATGTGGATGATGTGACTGATCCCAGCATACACCTGCGGGGCAGAGGCAGAGCCAATGGGACAGTGTCTATACCACTGGCTTAGAGAGGGACATATTTTGAATGCACORF Start: ATG at 25ORF Stop: TAG at 1030SEQ ID NO: 14335 aaMW at 36928.2kDNOV 2aMPVLHVHGSEGHLGTLDHLVSIIILVYYSGHLATAQEKQSPMKKFRECSRIFGEDGLTCG58598-01 ProteinSequenceLKLFLKRTAPFSILWTLTNYLYLLALKKLTATDVSALFCCNKAFVFLLSWIVLKDRFMGVRIVAAIMAIGIVMMAYADNFHADSIIGVAFAVGSASTSALYKVLFKMFLGSANFGEAAHFVSTLGFFNLIFISFTPVILYFTKVEHWSSFAALPWGCLCGMAGLWLAFNILVNVGVVLTYPILISIGTVLSVPGNAAVDLLKQEVIFNVVRLAATIIICIGFLLMLLPEEWDEITLRFINSLKEKKSEEHVDDVTDPSIHLRGRGRANGTVSIPLASEQ ID NO: 151154 bpNOV2b,CCAAGAAAACAGAATCAAGGCTCGCTGCCATGGTTCTGAAGGGCCG58598-02 DNAATCTGGGACCCTTGATCATCTTGTCAGTATCATCATCTTGGGTTGGAACTACACAGATTGTAAAAAATTACTTATAAGAACTTCTATTGCCCATTTTTCATGACTTGGTTTTCAACAAACTGAACATTATGTTTTTCCCAGTCTATTATTCTGGTCATCTAGCCACTGCTCAAGAAAAGCAATCTCCAATGAAAAAATTCAGGGAATGCAGTCGGATTTTTGGTGAAGATGGTCTGACGCTGAAACTTTCTTAAAAGAACTGCTCCCTTTTCTATTCTATGGACTTTGACTAATTACCTTTATTTACTCCCTTTAAACAACCTGACGGCCACGGATGTCTCCGCTCTGTTCTGTTGTAACAAGCCTTTGTCTTCTTGCTGTCATGGATTGTCCTGAAAGACAGGTTCATGGGAGTGAGGATAGTTGCTGCAATAATGGCAATTACCCCCAAGACAAAAAGGCATATGCAGATAATTTCCACGCTGATTCCATCATAGGACTGGCATTTGCGGTGGGCTCAGCCTCTACATCTGCATTATATAAGGTCTTGTTTAAAATGTTTCTTGGAGTGCCAACTTTGGGGAAGCTGCACACTTTGTCTCCACCTTGGGTTTCTTCAATTTGATCTTCATCTCCTTCACCCCAGTCATCTTGTATTTCACCAAGGTGGAGCACTGGTCCTCTTTTGCTGCTCTGCCATGCGGCTGTCTCTGTGGGATGGCAGGGCTGTGGCTGGCCTTCACATCCTGGTGAATGTTGGGGTGGTGCTGACATACCCAATCCTAAACTCCATTGGGACAATAAACAGCGTTCCTGGAAATGCAGCTGTGGATCTCCTAAAGCAGGAGGTGATATTCAATGTTGTCCGCCTGGCTGCTACCATCATCATCTGCATTGGGTTTCTGCTGATGCTGTTGCCTGAGGAATGGGATGAAATCACCCTGAGGTTCATCAACAGCCTGAAGGAAACAAAGTAAGGAGCATGTGGATGATGTGACTGATCCCAGCATACACCTGCGGGGCAGAGCCAGAGCCAATGGGACAGTGTCTATACCACTGGCTTAGAGAGGGACATATTTTGAATGCAORF Start: ATG at 44ORF Stop: TAG at 1130SEQ ID NO: 16362 aaMW at 40382.4kDNOV2b,MVLKGIWGPLIILSVSSSWVGTTQIVKITYKNFYCPFFMTWFSTNWNIMFFPVYYSGHCG58598-02 ProteinSequenceLATAQEKQSPMKKFRECSRIFGEDGLTLKLFLKRTAPFSILWTLTNYLYLLALKKLTATDVSALFCCNKAFVFLLSWIVLKDRFMGVRIVAIMAITGIVMMAYADNFAASIIGVAFAVGSASTSALYKVLFKNFLGSANFGEAAAAFVSTLGFFNLIFISFTPVILYFTKVEHWSSFAALPWGCLCGMAGLWLAFNILVNVGVVLTYPILISIGTVLSVPGNAAVDLLKQEVIFNVVRLAATIIICIGFLLMLLPEEWDEITLRFINSLKEKKSEEHVATDDVTDPS IHLRGRGRANGTVSIPLASEQ ID NO: 17324 bpNOV2c,GGATCCTGGGTTGGAACTACACAGATTGTMAAAATTACTTATAAGAAIACTTCTATTGCC209770459 DNASequenceCATTTTTCATGACTTGGTTTTCAACIAAACTGGAACATTATGTTTTTCCCAGTCTATTATTCTGGTCATCTAGCCACTGCTCAAGAAAAGCAATCTCCAATGAAAAAATTCAGGGAA TGCAGTCGGATTTTTGGTGAAGATGGTCTGACGCTGAAACTCTTTCTTAAAAGAACTGCTCCCTTTTCTATTCTATGGACTTTGACTAATTACCTTATTTACTGGCTTTAAAGAAGCTGACGGCCACGGATGTCTCCGCTCTGCTCGAGORF Start: GGA at 1ORF Stop: 32 at 325SEQ ID NO: 18108 aaMW at 12629.7kDNOV2c,GSWVGTTQIVKITYKNFYCPFFMTWFSTNWNIMFFPVYYSGHLATAQEKQSPMKKFRE209770459 ProteinSequenceCSRIFGEDGLTLKLFLKRTAPFSILWTLTNYLYLLALKKLTATDVSALLE


[0324] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 2B.
9TABLE 2BComparison of NOV2a against NOV2b through NOV2c.ProteinNOV2a Residues/Identities/SequenceMatch ResiduesSimilarities for the Matched RegionNOV2b26 . . . 335291/310 (93%)53 . . . 362291/310 (93%)NOV2c26 . . . 95 51/70 (72%)37 . . . 106 51/70 (72%)


[0325] Further analysis of the NOV2a protein yielded the following properties shown in Table 2C.
10TABLE 2CProtein Sequence Properties NOV2aPSort0.6850 probability located in endoplasmic reticulumanalysis:(membrane); 0.6400 probability located in plasma membrane;0.4600 probability located in Golgi body; 0.1000 probabilitylocated in endoplasmic reticulum (lumen)SignalPCleavage site between residues 36 and 37analysis:


[0326] A search of the NOV2a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 2D.
11TABLE 2DGeneseq Results for NOV2aNOV2aIdentities/Protein/Organism/Residues/Similarities forGeneseqLength [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAG28842Arabidopsis thaliana protein fragment73 . . . 289 55/231 (23%)4e−09SEQ ID NO: 34212 - Arabidopsis14 . . . 240104/231 (44%)thaliana, 278 aa. [EP1033405-A2,06 SEP. 2000]AAG28841Arabidopsis thaliana protein fragment73 . . . 289 55/231 (23%)4e−09SEQ ID NO: 34211 - Arabidopsis94 . . . 320104/231 (44%)thaliana, 358 aa. [EP1033405-A2,06 SEP. 2000]AAG28840Arabidopsis thaliana protein fragment73 . . . 289 55/231 (23%)4e−09SEQ ID NO: 34210 - Arabidopsis174 . . . 400 104/231 (44%)thaliana, 438 aa. [EP1033405-A2,06 SEP. 2000]AAG38623Arabidopsis thaliana protein fragment73 . . . 289 55/231 (23%)6e−09SEQ ID NO: 47675 - Arabidopsis14 . . . 240103/231 (43%)thaliana, 305 aa. [EP1033405-A2,06 SEP. 2000]AAG38622Arabidopsis thaliana protein fragment73 . . . 289 55/231 (23%)6e−09SEQ ID NO: 47674 - Arabidopsis94 . . . 320103/231 (43%)thaliana, 385 aa. [EP1033405-A2,06 SEP. 2000]


[0327] In a BLAST search of public sequence databases, the NOV2a protein was found to have homology to the proteins shown in the BLASTP data in Table 2E.
12TABLE 2EPublic BLASTP Results for NOV2aNOV2aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ9JJG8BRAIN CDNA, CLONE MNCB- 1 . . . 335323/335 (96%)0.00335 - Mus musculus (Mouse), 335 1 . . . 335330/335 (98%)aa.AAL39312GH20388P - Drosophila26 . . . 301 97/278 (34%)5e−41melanogaster (Fruit fly), 578 aa.265 . . . 539 157/278 (55%)Q95XC7HYPOTHETICAL 37.3 KDA47 . . . 287 84/242 (34%)4e−34PROTEIN - Caenorhabditis elegans,87 . . . 326138/242 (56%)339 aa.Q9VDJ2CG15688 PROTEIN - Drosophila26 . . . 127 45/103 (43%)7e−13melanogaster (Fruit fly), 365 aa.265 . . . 365  62/103 (59%)Q9VDJ0CG15689 PROTEIN - Drosophila143 . . . 298  42/169 (24%)5e−12melanogaster (Fruit fly), 195 aa. 9 . . . 176 82/169 (47%)


[0328] PFam analysis indicates that the NOV2a protein contains the domains shown in the Table 2F.
13TABLE 2FDomain Analysis of NOV2aNOV2aIdentities/MatchSimilaritiesExpectPfam DomainRegionfor the Matched RegionValueDUF6: domain 1 of 125 . . . 13518/127 (14%)0.8978/127 (61%)



Example 3

[0329] The NOV3 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 3A.
14TABLE 3ANOV3 Sequence AnalysisSEQ ID NO: 191681 bpNOV3a,AAAGCGCTGACAGCTCAAATGGATCCCATGGAACTGAGAAATGTCAACATCGAACCAGCG57833-01 DNASequenceATGATGAGAGCAGCAGTGGACAAAGTGCTCCAGATAGCTACATCGGGATAGGAAATTCAGAAAGGCAGCAATGAGTCAATTTGCTPATGAAGACACTGIAAAGTCAGAATTCCTGACAAATGGATTTTTGGGGAAAAAGAAGCTGGCAGATTATGCTGATGAACACCATCCCGGAACCACTTCCTTTGGAATGTCTTCATTTAACCTGAGTAATGCCATCATCCCCACTCCGATCCTGGGCTTGTCCTATGCCATGGCCAACACAGGGATCATACTTTTTATGATCATGCTGCTTGCTGTGGCAATATTATCACTGTATTCAGTTCACCTTTTATTAAAAACAGCCAAGGAAGGAGGTTCTTTGATTTATGAAAAATTAGGAGAAAAGGCATTTGGATGGCCCGGAAAAATTGGAGCTTTTGTTTCCATTACAATGCAGAACATTGGAGCAATGTCAAGCTACCTCTTTATCATTAAATATGAACTACCTGAAGTAATCAGAGCATTCATGGGACTTGAAGAAAATACTGGGGAATGGTACCTCAATGGCAACTACCTCATCATATTTGTGTCTGTTCGAATTATTCTTCCACTTTCGCTCCTTAAAAATTTAGGTTATCTTGGCTATACCAGTGGATTTTCTCTTACCTGCATGGTGTTTTTTGTTAGTGTGGTAATTTACAAGATTCCAAAAATACCCTGCCCTCTACCTGTTTTGGATCACAGTGTTGGAATCTGTCATTCAACAACACGCTTCCAATGCATGTGGTAATGTTACCCAACAACTCTGACAGTTCTGATGTGAACTTCATGATGGATTACACCCACCGCAATCCTGCAGGGCTGGATGAGAACCAGGCCAGGGCTCTCTTCATGACAGTGGAGTAGAATATGAAGCTCATAGTGATGACAAGTGTGAACCCAAATACTTTGTATTCAACTCCCGGACGGCCTATGCAATTCCTATCCTAGTATTTGCTTTTGTATGCCACCCTGAGCTCCTTCCCATCTACAGTGAACTTAAAAGAGCGGTCCCGGAGAAAAATGCAAACGGTGTCAAAATATTTCCATCACGGGGATGCTTGTCATGTACCTGCTTGCCGCCCTCTTTGGTTACCTACCTTCTATGGTGAGTTGIAGATGAATTACTTCATGCCTACAGCAAAGTGTATACATTAGACATCCCCCTTCTCATGGTTCGCCTGGCACTCCTTGTGGCAGTAACACTAACTCTCCCCATTGTCCTCTTCCCAATTCGTACATCAGTGATCACACTGTTATTTCCCAAACGACCCTTCAGCTGGATACGACATTTCCTGATTGCAGCTGTGCTTATTGCACTTAATAATGTTCTGGTCATCCTTGTGCCAACTATAAAATACATCTTCGGATTCATAGGTGCTTCTTCTGCCACTATGCTGATTTTTATTCTTCCAGCAGTTTTTTATCTTAAACTTGTCAAGAAAGAAACTTTTAGGTCACCCCAAAAGGTCGGGGCTTTAATTTTCCTTGTGGTTGGAIATATTCTTCATGATTGGAAGCATGGCACTCATTATAAAAATTGACTGGATTTATGATCCTCCAAATTCCAACCATCACTAACACAAGGAAAATACTTTCTTTORF Start: ATG at 19ORF Stop: TAA at 1657SEQ ID NO: 20546 aaMW at 60708.4kDNOV3a, MDPMELRNVNIEPDDESSSGESAPDSYIGIGNSEKAAMSQFANEDTESQKFLTNGFLGCG57833-01 ProteinSequenceKKKLADYADEHHPGTTSFCMSSFNLSNAIMGSGILGLSYAIVIANTGIILFMIMLLAVAILSLYSVHLLLKTAKEGGSLIYEKLGEKAFGWPGKIGAFVSITMQNIGAMSSYLFIIKYELPEVIRAFMGLEENTGEWYLNGNYLIIFVSVGIILPLSLLKNLGYLGYTSCFSLTCMVFFVSVVIYKKFQIPCPLPVLDHSVGNLSFNNTLPMHVATMLPNSESSDVNFAAVIDYTHRNPAGLDENQAKGSLHDSGVEYEAHSDDKCEPKYFVFNSRTAYAIPILVFAFVCHPEVLPIYSELKERSRRKMQTVSNISITGMLVMYLLALFGYLTFYCEVEDELLHAYSKVYTLDIPLLMRLAVLVAVTLTVPIVLFPIRTSVITLLFPKRPFSWIRHFLIAAVLIALNNVLVILVPTIKYIFGFIGASSATMLIFILPAVFYLKLVKKETFRSPQKGALIFLVVGIFFMIGSMALIIIDWIYDPPNSKHH


[0330] Further analysis of the NOV3a protein yielded the following properties shown in Table 3B.
15TABLE 3BProtein Sequence Properties NOV3aPSort0.6000 probability located in plasma membrane; 0.4000analysis:probability located in Golgi body; 0.3000 probabilitylocated in endoplasmic reticulum (membrane); 0.0300probability located in mitochondrial inner membraneSignalPNo Known Signal Sequence Indicatedanalysis:


[0331] A search of the NOV3a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 3C.
16TABLE 3CGeneseq Results for NOV3aNOV3aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAY79188Haematopoietic stem cell specific 1 . . . 546474/547 (86%)0.0protein - Mus musculus, 547 aa. 1 . . . 547509/547 (92%)[WO200011168-A2, 02-MAR-2000]AAB93237Human protein sequence SEQ ID108 . . . 545255/438 (58%)e−140NO: 12239 - Homo sapiens, 406 aa. 5 . . . 406310/438 (70%)[EP1074617-A2, 07-FEB-2001]AAB81002Rat neuronal glutamine transporter 5 . . . 546258/542 (47%)e−134(NGT) amino acid sequence - Rattus 12 . . . 485347/542 (63%)norvegicus, 485 aa. [CN1272545-A,08-NOV-2000]AAB92592Human protein sequence SEQ ID 1 . . . 243241/244 (98%)e−133NO: 10833 - Homo sapiens, 259 aa. 1 . . . 244242/244 (98%)[EP1074617-A2, 07-FEB-2001]AAM93430Human polypeptide, SEQ ID NO: 5 . . . 546256/542 (47%)e−1333060 - Homo sapiens, 487 aa. 12 . . . 487346/542 (63%)[EP1130094-A2, 05-SEP-2001]


[0332] In a BLAST search of public sequence databases, the NOV3a protein was found to have homology to the proteins shown in the BLASTP data in Table 3D.
17TABLE 3DPublic BLASTP Results for NOV3aResidues/Similarities forAccessionMatchthe MatchedNumberProtein/Organism/LengthResiduesPortionValueQ96916AMINO ACID TRANSPORTER1 . . . 546544/547 (99%)0.0HNAT3 (AMINO ACID1 . . . 547546/547 (99%)TRANSPORTER SYSTEM A3) -Homo sapiens (Human), 547 aa.Q9EQ25AMINO ACID TRANSPORT1 . . . 546481/547 (87%)0.0SYSTEM A3 - Rattus norvegicus (Rat),1 . . . 547511/547 (92%)547 aa.BAB84091SYSTEM A AMINO ACID1 . . . 546473/547 (86%)0.0TRANSPORTER 3 - Mus musculus1 . . . 547508/547 (92%)(Mouse), 547 aa.Q9HAV3AMINO ACID TRANSPORTER1 . . . 545313/545 (57%)e−170SYSTEM A (AMINO ACID1 . . . 506379/545 (69%)TRANSPORTER SYSTEM A2) -Homo sapiens (Human), 506 aa.Q96QD8PUTATIVE 40-9-1 PROTEIN - Homo1 . . . 545312/545 (57%)e−170sapiens (Human), 506 aa.1 . . . 506379/545 (69%)


[0333] PFam analysis indicates that the NOV3a protein contains the domains shown in the Table 3E.
18TABLE 3EDomain Analysis of NOV3aNOV3aIdentities/SimilaritiesMatchforExpectPfam DomainRegionthe Matched RegionValuesec Y: domain 1 of 1112 . . . 475 61/479 (13%)7.5224/479 (47%)Aa_trans: domain 1 of 1 98 . . . 528107/510 (21%)2.3e−51318/510 (62%)



Example 4

[0334] The NOV4 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 4A.
19TABLE 4ANOV4 Sequence AnalysisSEQ ID NO: 211152 bpNOV4a, ATCCTAAATACTACAATGGTGAATGTGGCCAAGAAGATCTCATCAGATGCTACACG57853-01 DNASequenceCTTTACCATAATCTGGTGACTGATGAAGAAGGAGACATGTGACTATTCACTCTGGGATTCTGAAGGTAGGCAAGAAAGACTCATTGAAGAAATCAAGAATGTGAAAGTCAAAGTGCTCAAACAAAAAGACAGTCTACTCCAGGCACCAATGCATATTGATAGACATCCTAATGCTTATTTTACCACTAATACTATTGATAAGTGTGCATTTGGTTGTA.AGATTGAATTACAGCTGTTTCAAZACAGTATGGAAGAGACCTTTGCCAGTIAAATTCTTGGGGCAGTTACACAGTTTTTTCTGATGCCATTTTGCGGGTTTCTTTTGTCTCAGATTOTCCCATTGCCTGAGGCGCAAGCTTTTGGAGTTGTAATGACCTGCACGTGCCCAGGAGGGGGTGGGGGCTATCTCTTTGCTCTGCTTCTAGATGGAGATTTCACATTGGCCATTTTGATGACTTGCACATCAACATTATTGGCTCTGATCATGATGCCTGTCAATTCTTATATATACAGTAGGATATTAGGGTTGTCAGGTACATTCCATATTCCTGTTTCTAAATTGTGTCAACACTCCTTTTCATACTTGTGCCAGTATCAATTGGAATAGTCATCAAGCATAGAATACCTGAAAAAGCAAGCTTCTTAGAGAGAATAATTAGACCTCTGAGTTTTATTTTAAATGTTCGTAGGAATTTATTTGACTTTCACAGTGGGATTAGTGTTCTTAAAAACAGATAATCTAGAGGTGATTCTGTTGGGTCTCTTAGTTCCTGCTTTGGGTTTGCTGTTTGGGTACTCCTTTGCTAAAGTTTGTACGCTGCCTCTTCCTGTTTGTAAAACTGTTGCTATTGAAAGTGGGATGTTAATAGTTTCTTAGCTCTTGCCGTTATTCAGCTGTCTTTTCCACAGTCCAAGGCCAATTTAGCTTCTGTGGCTCCTTTTACAGTAGCCATGTGTTCTGGATGTGAAATGTTACTGATCATTCTAGTTTACAAGGCTAAGAAAAGATGTATCTTTTTCTTACAAGATAAAAGGAAAAGAATTTCCTAATCTAACAATTAAAGCATTACTGAATTCCTACTCTGGORF Start: ATG at 18ORF Stop: TAA at 1119SEQ ID NO: 22367 aaMW at 40588.5kDNOV4a,MVNVAKKISSDATNFTINLVTDEEGETNVTIQLWDSEGRQERLIEEIKNVKVKVLKQKCG57853-01 ProteinSequenceDSLLQAPMHIDRNILMLILPLILLNKCAFGCKIELQLFQTVWKRPLPVILGAVTQFFLMPFCGFLLSQIVALPEAQAFGVVNTCTCPGGGGGYLFALLLDGDFTLAILMTCTSTLLALIMNPVNSYIYSRILGLSGTFHIPVSKIVSTLLFILVPVSIGIVIKHRIPEAFLARIIRPLSFILMFVGIYLTFTVGLVFLKTDILEVILLGLLVPALGLLFGYSFAKVCTLPLPVCKTVAIESGMLNSFLALAVIQLSFPQSKANLASVAFTVANCGCEMLLIILVYKAKKRCIFFLQDKRKRNFLISEQ ID NO:2311355 bpNOV4b,TTTCAAATTTCAAAATGATTAGAAAACTTTTTATTGTTCTACTTTTGTTGCTTGTGACTATAGAACG57853-02 DNASequenceGAAGCAAGGATGTCATCGCTCAGTTTTCTGAATATAGAGAAGACTGATACTATTTTTCACAAAGACTGAAGAAACCATCCTTGTAAGTTCAAGCTACGAAATAAAACGGCCTAAGCCAAGAAGATCTCATCAGATGCTACAAACTTTACCATA3AATCTGGTGACTGATGAACAAGCAGAACAAATGTGACTATTCAACTCTGGGATTCTGAAGGTAGGCAAGAAAAGACTCATTGAAGAAATCAAGAATGTGAAAGTCAAAGTGCTCAAACAAAAAACACAGTCTACTCCAGGCACCAATGCATATTGATAGAACATCCTAATGCTTATTTTACCACTATACTATTGAATAAGTGTGCATTTGGTTGTAGATTGATTACAGCTGTTTCAACAGTATGGAGAGACCTTTGCCAGTAATTCTTGGGGCAGTTACACAGTTTTTTCTGATGCCATTTTGCGGGTTTCTTTTGTCTCAGATTGTGGCATTGCCTGAGGCGCAAGCTTTTGGAGTTGTAATGACCTGCACGTGCCCAGGAGGCGGTGGOGGCTATCTCTTTGCTCTGCTTCTAGATCGAGATTTCACATTGGCCATTTTGATGACTTGCACATCAACATTATTGGCTCTGATCATGATGCCTGTCAATTCTTATATATACAGTAGGATATTAGGGTTGTCACGTACATTCCATATTCCTGTTTCTAAAATTGTGTCAACACTCCTTTTCATACTTCTGCCAGTATCATTGGAATAGTCATCAAGCATAGAATACCTGAGCAAAGCTTCTTAGAGAGAAATTAGACCTCTGAGTTTTATTTTAATGTTCGTAGGAATTTATTTGACTTTCACAGTGGGATTACTGTTCTTAAAAACAGATAATCTAGAGGTGATTCTGTTCGGTCTCTTAGTTCCTGCTTTGCGTTTGCTGTTTGGGTACTCCTTTGCTAAAGTTTGTACGCTGCCTCTTCCTGTTTGTAAAACTGTTGCTATTGAAAGTGGGATGTTAAATAGTTTCTTAGCTCTTGCCGTTATTCAGCTGTCTTTTCCACAGTCCAACGCCAATTTAGCTTCTGTGGCTCCTTTTACAGTAGCCATGTGTTCTGGATGTGAAATCTTACTGATCATTCTAGTTTACICGCTAGAAAAGATGTATCTTTTTCTTACAAGATAAAGGAAAAGAAATTTCCTAATCTAACAATTAAAGCATTACTGAATTCCTACTCTGGORF Start: ATG at 8ORF Stop: TAA at 1322SEQ ID NO: 24438 aaMW at 48870.2kDNOV4b,MIRKLFIVLLLLLVTIEEARMSSLSFLNIEKTEILFFTKTEETILVSSSYENKRPNSSCG57853-02 ProteinSequenceHLFVKIEDPKILQMVNVAKKISSDATNFTINLVTDEEGETNVTIQLWDSEGRQERLIEEIKNVKVKVLKQKDSLLQAPMHIDRNILMLILPLILLNKCAFGCKIELQLFQTVWKRPLPVILGAVTQFFLMPFCGFLLSQIVALPEAQAFGWAMTCTCPGGGGGYLFALLLDGDFTLAILMTCTSTLLALIMMPVNSYIYSRILGLSGTFHIPVSKIVSTLLFILVPVSIGIVIKHRIPEKASFLERIIRPLSFILMFVGIYLTFTVGLVFLKTDNLEVILLGLLVPALGLLFGYSFAKVCTLPLPVCKTVAIESGMLNSFLALAVIQLSFPQSKANLASVAPFTVAMCSGCEMLLIILVYKAKKRCIFFLQDKRKRNFLISEQ ID NO: 251152 bpNOV4e,ATCCTAAAATACTACAAATGGTGAATGTGGCCAAGAAGATCTCATCAGATGCTACAAAACG57853-03SequenceDNACTTTACCATAAATCTGGTGACTGATGAAGAAGGAGAAACAAIAGTGACTATTCAACTCTGGGATTCTGAAGGTAGGCAGAGACTCATTGAAGATCAAGAATGTGAAAGTCAAGTGCTCAAACAAAAAGACAGTCTACTCCAGGCACCAATGCATATTGATAGAAACATCCTAATGCTTATTTTACCACTAATACTATTGAATAAGTGTGCATTTGGTTGTAGATTGAATTACAGCTGTTTCAAACAGTATGGAAGAGACCTTTGCCAGTAATTCTTGGGGCAGTTACACAGTTTTTTCTGATGCCATTTTGCGGGTTTCTTTTGTCTCAGATTGTGGCATTGCCTGAGGCGCAAGCTTTTGGAGTTGTAATGACCTGCACGTGCCCAGGAGGGGGTGGGGGCTATCTCTTTGCTCTGCTTCTAGATGGAGATTTCACATTGGCCATTTTGATGACTTGCACATCAACATTATTGGCTCTGATCATGATGCCTGTCAATTCTTATATATACAGTAGGATATTAGGGTTGTCAGGTACATTCCATATTCCTGTTTCTAAAITTGTGTCAACACTCCTTTTCATACTTGTGCCAGTATCAATTGGAATAGTCATCATGCATAGAATACCTGAAAAAGCAAGCTTCTTAGAGAGAATAATTAGACCTCTGAGTTTTATTTTAATGTTCGTACGAATTTATTTGACTTTCACAGTGGGATTAGTGTTCTTAIAAACAGATAATCTAGAGGTGATTCTGTTGGGTCTCTTAGTTCCTGCTTTGGGTTTGCTGTTTGGGTACCCTTGCTAAAGTTTGTACGCTGCCTCTTCCTGTTTGTAAAACTGTTGCTATTGAAAGTGGGATGTTAATAGTTTCTTAGCTCTTGCCGTTATTCAGCTGTCTTTTCCACAGTCCAAGACCATTTAGCTTCTGTGGCTCCTTTTACAGTAGCCATGTGTTCTGGATGTGAAATGTTACTGATCATTCTAGTTTACAAGGCTAAGAAAAGATGTATCTTTTTCTTACAAGATAAAAGGAAAAGAAATTTCCTAATCTACAATTAAAGCATTACTGAATTCCTACTCTGGORF Start: ATG at 18ORF Stop: TAA at 1119SEQ ID NO: 26367 aaMW at 40588.5kDNOV4c,MVNVAKKISSDATNFTINLVTDEEGETNVTIQLWDSEGRQERLIEEIKNVKVKVLKQKCG5 7853-03 ProteinSequenceDSLLQAPMHIDRNILMLILPLILLNKCAFGCKIELQLFQTVWKRPLPVILGAVTQFFLMPFCGFLLSQIVALPEAQAFGVVMTCTCPGGGGGYLFALLLDGDFTLAILMTCTSTL ALIMMPVNSYIYSRILGLSGTFHIPVSKIVSTLLFILVPVSIGIVIKIRIPEKASFLERIIRPLSFILMFVGIYLTFTVGLVFLKTDNLEVILLGLLVPALGLLFGYSFAKVCTLPLPVCKTVAIESGMLNSFLALAVIQLSFPQSKANLASVAPFTVAiAICsGCEMLLIILVYKAKKRCIFFLQDKRKRNFLI


[0335] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 4B.
20TABLE 4BComparison of NOV4a against NOV4b through NOV4c.NOV4a Residues/Identities/SimilaritiesProtein SequenceMatch Residuesfor the Matched RegionNOV4b1 . . . 367324/367 (88%)72 . . . 438 324/367 (88%)NOV4c1 . . . 367324/367 (88%)1 . . . 367324/367 (88%)


[0336] Further analysis of the NOV4a protein yielded the following properties shown in Table 4C.
21TABLE 4CProtein Sequence Properties NOV4aPSort0.6000 probability located in plasma membrane; 0.4318analysis:probability located in mitochondrial inner membrane; 0.4000probability located in Golgi body; 0.3000probability located in endoplasmic reticulum (membrane)SignalPNo Known Signal Sequence Indicatedanalysis:


[0337] A search of the NOV4a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 4D.
22TABLE 4DGeneseq Results for NOV4aNOV4aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAR77224Hamster ileal/renal bile acid72 . . . 353 90/284 (31%)2e−37cotransporter - Cricetulus griseus, 34837 . . . 314155/284 (53%)aa. [WO9517905-A1, 06-JUL-1995]AAR77225Human ileal/renal bile acid72 . . . 353 93/285 (32%)2e−36cotransporter - Homo sapiens, 348 aa.37 . . . 314155/285 (53%)[WO9517905-A1, 06-JUL-1995]AAG91138C glutamicum protein fragment SEQ ID71 . . . 309 79/249 (31%)1e−19NO: 4892 - Corynebacterium44 . . . 278127/249 (50%)glutamicum, 335 aa. [EP1108790-A2,20-JUN-2001]AAG42824Arabidopsis thaliana protein fragment80 . . . 317 63/246 (25%)5e−19SEQ ID NO: 53452 - Arabidopsis18 . . . 251114/246 (45%)thaliana, 288 aa. [EP1033405-A2,06-SEP-2000]AAG42823Arabidopsis thaliana protein fragment80 . . . 317 63/246 (25%)5e−19SEQ ID NO: 53451 - Arabidopsis131 . . . 364 114/246 (45%)thaliana, 401 aa. [EP1033405-A2,06-SEP-2000]


[0338] In a BLAST search of public sequence databases, the NOV4a protein was found to have homology to the proteins shown in the BLASTP data in Table 4E.
23TABLE 4EPublic BLASTP Results for NOV4aNOV4aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueP09131P3 protein - Homo sapiens (Human),15 . . . 345142/335 (42%)3e−74477 aa.131 . . . 465 225/335 (66%)Q9BSL2SIMILAR TO PROTEIN P3 - Homo20 . . . 345141/330 (42%)4e−73sapiens (Human), 448 aa.107 . . . 436 220/330 (65%)Q60414Ileal sodium/bile acid cotransporter (Ileal72 . . . 353 90/284 (31%)7e−37Na(+)/bile acid cotransporter) (Na+37 . . . 314155/284 (53%)dependent ileal bile acid transporter) (Ilealsodium-dependent bile acid transporter)(ISBT) (Sodium/taurocholatecotransporting polypeptide, ileal) -Cricetulus griseus (Chinese hamster),348 aa.Q62633Ileal sodium/bile acid cotransporter (Ileal72 . . . 353 93/285 (32%)2e−36Na(+)/bile acid cotransporter) (Na+37 . . . 314154/285 (53%)dependent ileal bile acid transporter) (Ilealsodium-dependent bile acid transporter)(ISBT) (Sodium/taurocholatecotransporting polypeptide, ileal) - Rattusnorvegicus (Rat), 348 aa.CAC39447BA11L8.1 (SOLUTE CARRIER FAMILY72 . . . 353 93/285 (32%)8e−3610 (SODIUM/BILE ACID37 . . . 314155/285 (53%)COTRANSPORTER FAMILY),MEMBER 2) - Homo sapiens (Human),348 aa.


[0339] PFam analysis indicates that the NOV4a protein contains the domains shown in the Table 4F.
24TABLE 4FDomain Analysis of NOV4aNOV4aIdentities/MatchSimilaritiesExpectPfam DomainRegionfor the Matched RegionValueSBF: domain 1 of 1 77 . . . 261 48/208 (23%)1.5e−37145/208 (70%)ABC-3: domain 1 of 1126 . . . 323 32/283 (11%)9.2125/283 (44%)



Example 5

[0340] The NOV5 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 5A.
25TABLE 5ANOV5 Sequence AnalysisSEQ ID NO: 272804 bpNOV5a,CGCGGCGGTGCGCTGCCCGGCGCCATGCTTCTGCTGGGCATCCTAACCCTGGCTTTCGCG57829-01 DNASequenceCCGGGCGAACCGCTGGAGGCTCTGAGCCAGAGCGGGAGGTAGTCGTTCCCATCCGACTGGACCCGGACATTAACGGCCGCCGCTACTACTGGCGGGGTCCCGACGACTCCGGGGATCAGGGACTCATTTTTCAGATCACAGCATTTCAGGAGGACTTTTACCTACACCTGACGCCGGATGCTCAGTTCTTGGCTCCCGCCTTCTCCACTGAGCATCTGGGCGTCCCCCTCCAGGGCTCACCGGGGGCTCTTCAGACCTGCGACGCTGCTTCTATTCTGGGGACGTGAACGCCGAGCCGGACTCGTTCGCTGCTCTGAGCCTGTGCGGGGGGCTCCGCGGACCCTTTGGCTACCGAGGCGCCGAGTATGTCATTAGCCCGCTGCCCAATGCTAGCCCGCCCGCGGCGCACCGCAACAGCCAGGGCGCACACCTTCTCCAGCGCCGGGGTGTTCCGGGCGGGCCTTCCGGAGACCCCACCTCTCGCTCCGCGGTGGCCTCGGGCTGGAACCCCGCCATCCTACGGGCCCTGGACCCTTACAAGCCGCGGCGGGCGGGCTTCGGGGAGAGTCGTACCCGGCGCAGGTCTGGGCGCGCCAAGCGTTTCGTGTCTATCCCGCGGTACGTGGAGACGCTGGTGGTCGCGGACGAGTCAATGGTCAAGTTCCACGGCGCGGACCTGGAACATTATCTGCTGACGCTGCTGGCAACGGCGGCGCGACTCTACCGCCATCCCAGCATCCTCAACCCCATCAACATCGTTGTGGTCAAGGTGCTGCTTCTTAGAGATCGTGACTCCGGGCCCAAGGTCACCGGCAATGCGGCCCTGACGCTGCGCAACTTCTGTGCCTGGCAGAAGAAGCTGAACAAAGTGAGTGACAAGCACCCCGAGTACTGGGACACTGCCATCCTCTTCACCAGGCAGGACCTGTGTGGACCCACCACCTGTGACACCCTGGGCATGGCTGATGTGGGTACCATGTGTGACCCCAAGAGAAGCTGCTCTGTCATTGAGGACGATGGGCTTCCATCAGCCTTCACCACTGCCCACGAGCTGGGTCACGTGTTCAACATGCCCCATGACAATGTGAAAGTCTGTGAGGAGGTGTTTGGGAAGCTCCGAGCCAACCACATGATGTCCCCGACCCTCATCCAGATCGACCGTGCCAACCCCTGGTCAGCCTGCAGTGCTGCCATCATCACCGACTTCCTGGACAGCGGGCACGGTGACTGCCTCCTGGACCAACCCAGCAAGCCCATCTCCCTGCCCGAGGATCTGCCGGCCGCCAGCTACACCCTGAGCCAGCAGTGCGAGCTGGCTTTTGGCGTGGGCTCCAAGCCCTGTCCTTACATGCACTACTGCACCAAGCTGTGGTGCACCGGGAAGGCCAAGGGACAGATGGTGTGCCAGACCCGCCACTTCCCCTGGGCCGATCGCACCAGCTGTCGCGAGGGCAAGCTCTGCCTCAAAGGGGCCTGCGTGGAGAGACACAACCTCAACAAGCACTCTTCCTCACAGGTGGATGGTTCCTGGGCCAAATGGGATCCCTATGGCCCCTGCTCGCGCACATGTGGTCGGGGCGTGCAGCTGGCCAGGAGGCAGTGCACCAACCCCACCCCTGCCAACGGGGGCAAGTACTGCGAGGGAGTGAGGGTGAAATACCGATCCTGCAATCTGGAGCCCTGCCCCAGCTCCGGAAAGAGCTTCCGGGAGGAGCAGTGTGAGGCTTTCAACGGCTACAACCACAGCACCAACCGGCTCACTCTCGCCGTGGCATGGGTGCCCAAGTACTCCGGCGTGTCTCCCCGGGACAAGTGCAAGCTCATCTGCCGAGCCAATGGCACTGGCTACTTCTATGTGCTGGCACCCAAGGTGGTGGACGCCACGCTGTGCTCTCCTGACTCCACCTCCGTCTGTGTCCAAGGCAAGTGCATCAAGGCTGGCTGTGATGGGAACCTGGGCTCCAAGAAGAGATTCGACAAGTGTGGGGTGTGTGGGGGAGACAATAAGAGCTGCAAGAAGGTGACTGGACTCCTTTCCCCCGCCAGGCATGGCTACAATTTCGTGGTGGCCATCCCCGCACGCGCCTCAAGCATCGACATCCGCCAGCGCGGTTACAAAGGGCTGATCGGGCATGACAACTACCTGGCTCTGAAGAACAGCCAAGGCAAGTACCTGCTCAACGGGCATTTCGTGGTGTCGGCGGTCGAGCGGCACCTGGTGGTGAAGGGCAGTCTGCTGCGGTACAGCGGCACGGGCACAGCGGTGGAGAGCCTGCAGGCTTCCCCGCCCATCCTCGAGCCGCTGACCGTGGAGGTCCTCTCCGTGGGGAAGATGACACCGCCCCCGGTCCGCTACTCCTTCTATCTGCCCAAAGAGCCTCGGGAGGACAAGTCCTCTCATCCCCCGGCACGCTGGGTGGCTGGCAGCTGGGGGCCGTGCTCCGCGAGCTGCGGCAGTGGCCTGCAGAAGCGGGCGGTGGACTGGCGGCGCTCCGCCGGGCAGCGCACGGTCCCTGCCTGTGATGCAGCCCATCGGCCCGTGGAGACACAAGCCTGCGGGGAGCCCTGCCCCACCTGGGAGCTCAGCGCCTGGTCACCCTGCTCCAAGAGCTGCGGCCGGGGATTTCAGAGGCGCTCACTCAAGTGTGTGGGCCACGGAGGCCCCCTGCTGGCCCGGGACCAGTGCAACTTGCACCGCAAGCCCCAGGAGCTGGACTTCTCCGTCCTGAGGCCGTGCTGAGTGGGORF Start: ATG at 25ORF Stop: TGA at 2797SEQ ID NO: 28924aaMW at 100396.3kDNOV5a,MLLLGILTLAFAGRTAGGSEPEREVVVPIRLDPDINGRRYYWRGPEDSGDQGLIFQITCG57829-01 ProteinSequenceAFQEDFYLHLTPDAQFLAPAFSTEHLGVPLQGLTGGSSDLRRCFYSGDVNAEPDSFAAVSLCGGLRGAFGYRGAEYVISPLPNASAPAAQRNSQGAHLLQRRGVPGGPSGDPTSRCGVASGWNPAILRALDPYKPRRAGFGESRSRRRSGRAKRFVSIPRYVETLVVADESMVKFHGADLEIIYLLTLLATAARLYRHPSILNPINIVVVKVLLLRDRDSGPKVTGNAALTLRNFCAWQKKLNKVSDKAIPEYWDTAILFTRQDLCCATTCDTLGMADVGTMCDPKRSCSVIEDDCLPSAFTTAHELGHVFNMPHDNVKVCEEVFGKLRANHMMSPTLIQIDRANPWSACSAAIITDFLDSGHGDCLLDQPSKPISLPEDLPGASYTLSQQCELAFGVGSKPCPYMQYCTKLWCTGKAKGQMVCQTRHFPWADGTSCGEGKLCLKGACVERHNLNKHSSSQVDGSWAKWDPYGPCSRTCGGGVQLARRQCTNPTPANGGKYCEGVRVKYRSCNLEPCPSSGKSFREEQCEAFNGYNHSTNRLTLAVAWVPKYSGVSPRDKCKLICRANGTGYFYVLAPKVVDGTLCSPDSTSVCVQGKCIKAGCDGNLGSKKRFDKCGVCGGDNKSCKKVTGLLSPARHOYNFVVAIPAGASS IDIRQRGYKGLIGDDNYLALKNSQGKYLLNGHFVVSAVERDLVVKGSLLRYSGTGTAVESLQASRPILEPLTVEVLSVGKMTPPRVRYSFYLPKEPREDKSSHPPARWVACSWCPCSASCGSGLQKRAVDWRGSAGQRTVPACDAAHRPVETQACGEPCPTWELSAWSPCSKSCGRGFQRRSLKCVGHGGRLLARDQCNLHRKPQELDFCVLRPCSEQ ID NO: 292297bpNOV5b,CGCGGCGGTGCGCTGCCCGGCGCCATGCTTCTGCTGGGCATCCTAACCCTGGCTTTCGCG57829-05 DNASequenceCCGGGCGAACCGCTGGAGGCTCTGAGCCAGAGCGGGAGGTAGTCGTTCCCATCCGACTGGACCCGGACATTAACGGCCGCCGCTACTACTGGCGGGGTCCCGAGGACTCCGGGGATCAGGGACTCATTTTTCAGATCACAGCATTTCAGGAGGACTTTTACCTACACCTGACGCCGGATGCTCAGTTCTTGGCTCCCGCCTTCTCCACTGAGCATCTGCGCGTCCCCCTCCAGGGGCTCACCGGCGGCTCTTCAGACCTGCGACGCTGCTTCTATTCTGGGGACGTGAACGCCGAGCCGGACTCGTTCGCTGCTGTGAGCCTGTGCGGGGGGCTCCGCGGAGCCTTTGGCTACCGAGGCGCCGAGTATGTCATTAGCCCGCTGCCCAATGCTAGCGCGCCGGCGGCGCAGCGCAACAGCCAGCGCGCACACCTTCTCCAGCGCCGGGGTGTTCCGGGCGGCCCTTCCGGAGACCCCACCTCTCGCTGCGGGGTGGCCTCGGGCTGGAACCCCGCCATCCTACGGGCCCTGGACCCTTACAAGCCGCGGCGGGCGGGCTTCGGGGAGAGTCGTAGCCGGCGCAGGTCTGGGCGCGCCAAGCGTTTCGTGTCTATCCCGCGGTACGTGGAGACGCTGGTGGTCGCGGACGAGTCAATGGTCAAGTTCCACGGCGCGGACCTGGAACATTATCTGCTGACGCTGCTGGCAACGGCGGCGCGACTCTACCGCCATCCCAGCATCCTCAACCCCATCAACATCGTTGTGGTCAAGGTGCTGCTTCTTAGAGATCGTGACTCCGGGCCCAAGGTCACCGGCAATGCGGCCCTGACGCTGCGCAACTTCTGTGCCTGGCAGAAGAAGCTGAACAAAGTGAGTGACAAGCACCCCGAGTACTGGGACACTGCCATCCTCTTCACCAGGCAGGTGGATGGTTCCTGGGCCAAATGGGATCCCTATGGCCCCTGCTCGCGCACATGTGGTGGGGGCGTGCAGCTGGCCAGGAGGCAGTGCACCAACCCCACCCCTGCCAACGGGGGCAAGTACTGCGAGGGAGTGAGGGTGAAATACCGATCCTGCAATCTGGAGCCCTGCCCCAGCTCAGCCTCCGGAAAGAGCTTCCGGGAGGAGCAGTGTGAGGCTTTCAACGGCTACAACCACAGCACCAACCGGCTCACTCTCGCCGTGGCATGGGTGCCCAAGTACTCCGGCGTGTCTCCCCGGGACAAGTCCAAGCTCATCTGCCCAGCCAATGGCACTGGCTACTTCTATGTGCTGGCACCCAAGGTGGTGGACGCCACGCTGTGCTCTCCTGACTCCACCTCCGTCTGTCTCCAAGGCAAGTGCATCAAGGCTGGCTGTGATGGGAACCTGGGCTCCAAGAAGAGATTCGACAAGTGTGGGGTGTGTGGGGGAGACAATAAGAGCTGCAAGAAGGTGACTGGACTCTTCACCAAGCCCATGCATGGCTACAATTTCGTGGTGGCCATCCCCGCAGGCGCCTCAAGCATCGACATCCGCCAGCGCGGTTACAAAGGGCTGATCGGGGATGACAACTACCTGGCTCTGAAGAACAGCCAAGGCAAGTACCTGCTCAACGGGCATTTCCTGGTGTCGGCGGTGGAGCGGGACCTGGTGGTGAAGGGCAGTCTGCTGCGGTACAGCGGCACGGGCACAGCGGTGGAGAGCCTCCAGGCTTCCCGGCCCATCCTGGAGCCGCTGACCGTGGAGGTCCTCTCCGTGGGGAAGATGACACCGCCCCGGGTCCGCTACTCCTTCTATCTGCCCAAAGAGCCTCGGGAGGACAAGTCCTCTCATCCCAAGGACCCCCGGGGACCCTCTGTCTTGCACAACACCGTCCTCAGCCTCTCCAACCAGGTGGAGCAGCCGGACGACAGGCCCCCTGCACGCTGGGTGGCTGGCAGCTGGGGGCCGTGCTCCGCGAGCTGCGGCAGTGGCCTGCAGAAGCGGGCGGTGGACTGCCGGGGCTCCGCCGGGCAGCGCACGGTCCCTGCCTGTGATCCAGCCCATCCGCCCGTGGAGACACAAGCCTGCGGGGAGCCCTGCCCCACCTGGGAGCTCAGCGCCTGCTCACCCTGCTCCAAGAGCTGCGGCCGGGGATTTCAGAGGCGCTCACTCAAGTGTGTGGGCCACGGAGGCCGGCTGCTGGCCCGGGACCAGTGCAACTTGCACCGCAAGCCCCAGGAGCTGGACTTCTGCGTCCTCAGCCCGTGCTGAGTGGGORF Start: ATG at 25ORF Stop: TGA at 2290SEQ ID NO: 30755 aaMW at 82147.6kDNOV5b,MLLLGILTLAFAGRTAGGSEPEREVVVPIRLDPDINGRRYYWRGPEDSGDQGLIFQITCG57829-05 ProteinSequenceAFQEDFYLHLTPDAQFLAPAFSTEHLGVPLQGLTGGSSDLRRCFYSGDVNAEPDSFAAVSLCGGLRGAFGYRGAEYVISPLPNASAPAAQRNSQGAHLLQRRGVPGGPSGDPTSRCGVASGWNPATLRALDPYKPRRAGFGESRSRRRSGRAKRFVSIPRYVETLVVADESMVK FHGADLEHYLLTLLATAARLYRHPSILNPINIVVVKVLLLRDRDSGPKVTGNAALTLRNFCAWQKKLNKVSDKHPEYWDTAILFTRQVDGSWAKWDPYGPCSRTCGGGVQLARRQCTNPTPANGGKYCECVRVKYRSCNLEPCPSSASGKSFREEQCEAFNGYNHSTNRLTLAVAWVPKYSGVSPRDKCKLICRANGTGYFYVLAPKVVDGTLCSPDSTSVCVQGKCIKAGCDGNLGSKKRFDKCGVCGGDNKSCKKVTGLFTKPMHGYNFVVAIPAGASSIDIRQRGYKGLIGDDNYLALKNSQGKYLLNGHFVVSAVERDLVVKGSLLRYSGTGTAVESLQASRPILEPLTVEVLSVGKNTPPRVRYSFYLPKEPREDKSSHPKDPRGPSVLHNSVLSLSNQVEQPDDRPPARWVAGSWGPCSASCGSGLQKRAVDCRGSAGQRTVPACDAAHRPVETQACGEPCPTWELSAWSPCSKSCCRGFQRRSLKCVGHGGRLLARDQCNLHRKPQELDFCvLRpCSEQ ID NO: 31555 bpNOV5c,AGATCTCGGTACGTGGAGACGCTGGTGGTCGCGGACGAGTCAATGGTCAGTTCCACG175070495 DNASequenceGCGCGGACCTGGAACATTATCTGCTGACGCTGCTGGCAACGGCGGCGCGACTCTACCGCCATCCCAGCATCCTCAACCCCATCAACATCGTTGTGGTCAAGGTGCTGCTTCTTAGAGATCGTGACTCCGGGCCCAAGGTCACCGGCAATACGGCCCTGACGCrGCGCAACTTCTGTGCCTGGCAGAAGAAGCTGAACAAAGTGAGTGACAAGCACCCCGAGTACTGGGACACTGCCATCCTCTTCACCAGGCAGGACCTGTGTGGAGCCACCACCTGTGACACCCTGGGCATGGCTGATGTCGGTACCATGTGTGACCCCAAGAGAAGCTGCTCTGTCATTGAGGACCATGGGCTTCCATCAGCCTTCACCACTGCCCACGAGCTGGGCCACGTGTTCPACATGCCCCATGACAATGTGAAAGTCTGTGAGGAGGTGTTTGGGAAGCTCCGAGCCAACCACATGATGTCCCCGACCCTCATCCAGATCGACCTCGAGORF Start: AGA at 1ORF Stop: ig at 556SEQ ID NO: 32185 aaMW at 20725.7kDNOV5c,RSRYVETLVVADESMVKFHGADLEHYLLTLLATAARLYRHPS ELNPINIVVVKVLLLR175070495 ProteinSequenceDRDSGPKATTGNTALTLRNFCAWQKKLNKVSDKHPEYWDTAILFTRQDLCGATTCDTLGMADVGTMCDPKRSCSVIEDDGLPSAFTTA1IELGHVFNMPHDNVKVCEEVFGKLRANHMMSPTLIQIDLESEQ ID NO: 33555 bpNOV5d,AGATCTCGGTACGTGGAGACGCTGGTGGTCGCGGACGAGTCAATGGTCAAGTTCCACG175070504 SequenceDNAGCGCGGACCTGGAACATTATCTGCTGACGCTGCCGGCAACGGCGGCGCGACTCTACCGCCATCCCAGCATCCTCAACCCCATCAACATCGTTGTGGTCAAGGTGCTGCTTCTTAGAGATCGTGACTCCGGGCCCAACGTCACCGGCAATGCGGCCCTGACGCTGCGCAACTTCTGTGCCTGGCAGAAGAAGCTGAACAAAGTGAGTCACAAGCACCCCGAGTACTGGGACACTGCCATCCTCTTCACCAGGCAGGACCTGTGTGGAGCCACCACCTGTGACACCCTGGGCATGGCTGATGTGGGTACCATGTGTGACCCCAAGAGAAGCTGCTCTGTCATTGAGGACGATGGGCTTCCATCAGCCTTCACCACTGCCCACGAGCTGGGCCACGTGTTCAACATGCCCATGACAATGTGAAAGTCTGTGAGGAGGTGTTTGGGAAGCTCCGAGCCAACCACATGATGTCCCCGACCCTCATCCAGATCGACCTCGAGORF Start: AGA at 1ORF Slop: ig at 556SEQ ID NO: 34185 aaMW at 20679.6kDNOV5d,RSRYVETLVVADESMVKFHGADLEHYLLTLPATAARLYRHPSILNPINIVVVKVLLLR175070504 ProteinSequenceDRDSGPKVTGNAALTLRNFCAWQKKLNKVSDKHPEYWDTAILFTRQDLCGATTCDTLGMADVGTMCDPKRSCSVIEDDGLPSAFTTAHELGHVFNMPHDNVKVCEEVFGKLRAIIHMMSPTLIQIDLESEQ ID NO:35556 bpNOV5e,AGATCTCGGTACGTGGAGACGCTGGTGGTCGCGGACGAGTCAATGGTCAAGTTCCACG175070512 DNASequenceGCGCGGACCTGGAACATTATCTGCTGACGCTGCTGGCAACGGCGGCGCGACTCTACCGCCATCCCAGCATCCTCAACCCCATCAACATCGTTGTGGTCAAGGTGCTGCTTCTTACAGATCGTGACTCCGGGCCCAAGGTCACCGGCAATGCGGCCCTGACGCTGCGCAACTTCTGTGCCTGGCAGAAGAAGCTGAACAAAGTGAGTGACAAGCACCCCGAGTACTGGGACACTGTUCCTGGCAGAAGAAACTGAACAAAGTGAGTGACAAGCACCCCGAGTACTGGGACACATGGCTGATGTGGGTACCATGTGTGACCCCAAGAGAAGCTGCTCTGTCATTGAGGACGATGGGCTTCCATCAGCCTTCACCACTGCCCACGAGCTGGGCCACGTGTTCAACATGCCCCATGACAATGTGAAAGTCTGTGAGGAGGTGTTTGGGAAGCTCCGAGCCAACCACATGATGTCCCCGACCCTCATCCAGATCGACCTCGAGORF Start: AGA at 1ORF Stop: ig at 556SEQ ID NO: 36185 aaMW at 20695.6kDNOV5e, RSRYVETLVVADESMVKFHGADLEHYLLTLLATAARLYRHPSILNPINIVVVKVLLLR175070512 ProteinSequenceDRDSGPKVTGNAALTLRNFCAWQKKLNKVSDKHPEYWDTAILFTRQDLCGATTCDTLGMADVGTMCDPKRSCSVIEDDGLPSAFTTAHELGHVFNMPHDNVKVCEEVFGKLRANIMMSPTLIQIDLESEQ ID NO: 37555 bpNOV5f,AGATCTCGGTACGTGGAGACGCTGGTGGTCGCGGACCAGTCAATGGTCAAGCTCCACG175070519 DNASequenceGCGCGGACCTGGAACATTATCTGCTGACGCTGCTGGCAACGGCGGCGCGACTCTACCGCCATCCCAGCATCCTCAACCCCATCAACATCGTTGTGGTCAAGGTGCTGCTTCTTAGACATCGTGACTCCGGGCCCAAGGTCACCGGCAATGCGGCCCTGACGCTGCGCAACTTCTCTGCCTGGCAGAAAGAAGCTGAACAAAGTGAGTGACAAGCACCCCGAGTACTGGGACACTGCCATCCTCTTCACCAGGCAGGACCTGTGTGGAGCCACCACCTGTGACACCCTGGGCATGGCTGATGTGGGTACCATGTGTGACCCCAAGAGAAGCTGCTCTGTCATTGAGGACGATGGGCTTCCATCAGCCTTCACCACTGCCCACGAGCTGGGCCACGTGTTCAACATGCCCCATGACAATGTGAAAGTCTGTCACGAGGTGTTTGGGAAGCTCCGAGCCAACCACATGATGTCCCCGACCCTCATCCAGATCGACCTCGAGORF Start: AGA at 1ORF Stop: ig at 556SEQ ID NO: 38185aaMW at 20661.6kDNOV5f,RSRYVETLVVADESMVKLHGADLEHYLLTLLATAARLYRHPSILNPINIVVVKVLLLR175070519 ProteinSequenceDRDSGPKVTGNAALTLRNFCAWQKKLNKVSDKHPEYWDTAILFTRQDLCGATTCDTLGMADVGTMCDPKRSCSVIEDDGLPSAFTTAHELGHVFNMPHDNVKVCEEVFGKLRANHMMSPTLIQIDLE


[0341] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 5B.
26TABLE 5BComparison of NOV5a against NOV5b through NOV5f.NOV5a Residues/Identities/SimilaritiesProtein SequenceMatch Residuesfor the Matched RegionNOV5b494 . . . 924410/473 (86%)283 . . . 755413/473 (86%)NOV5c218 . . . 398158/181 (87%) 3 . . . 183158/181 (87%)NOV5d218 . . . 398172/181 (95%) 3 . . . 183172/181 (95%)NOV5e218 . . . 398159/181 (87%) 3 . . . 183159/181 (87%)NOV5f218 . . . 398158/181 (87%) 3 . . . 183158/181 (87%)


[0342] Further analysis of the NOV5a protein yielded the following properties shown in Table 5C.
27TABLE 5CProtein Sequence Properties NOV5aPSort0.5469 probability located in outside; 0.1900analysis:probability located in lysosome (lumen); 0.1000 probabilitylocated in endoplasmic reticulum (membrane); 0.1000probability located in endoplasmic reticulum (lumen)SignalPCleavage site between residues 18 and 19analysis:


[0343] A search of the NOV5a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 5D.
28TABLE 5DGeneseq Results for NOV5aNOV5aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAG62299Human metalloprotease MDTS6 1 . . . 924913/953 (95%)0.0protein - Homo sapiens, 950 aa. 1 . . . 950915/953 (95%)[WO200134785-A1, 17-MAY-2001]AAB21257Rat metalloproteinase ADAMTS-5 -89 . . . 581459/497 (92%)0.0Rattus norvegicus, 505 aa.13 . . . 505468/497 (93%)[WO200053774-A2, 14-SEP-2000]AAB73549Human ADAM-type metalloprotease 1 . . . 924477/955 (49%)0.0MDTS4, SEQ ID NO: 4 - Homo19 . . . 949631/955 (65%)sapiens, 950 aa. [JP2001017183-A,23-JAN-2001]AAB50011Protein; SEQ ID 125 - Homo sapiens, 1 . . . 924477/955 (49%)0.0968 aa. [WO200071577-A1,37 . . . 967631/955 (65%)30-NOV-2000]AAB50002Human METH1 - Homo sapiens, 950 1 . . . 924477/955 (49%)0.0aa. [WO200071577-A1, 30-NOV-2000]19 . . . 949631/955 (65%)


[0344] In a BLAST search of public sequence databases, the NOV5a protein was found to have homology to the proteins shown in the BLASTP data in Table 5E.
29TABLE 5EPublic BLASTP Results for NOV5aNOV5aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ9UH18ADAMTS-1 precursor (EC 3.4.24.-) (A 1 . . . 924477/955 (49%)0.0disintegrin and metalloproteinase with36 . . . 966631/955 (65%)thrombospondin motifs 1)(ADAM-TS 1)(ADAM-TS1) (METH-1) -Homo sapiens (Human), 967 aa.T00017gene ADAMTS-1 protein - mouse, 1 . . . 924478/953 (50%)0.0951 aa.20 . . . 950636/953 (66%)P97857ADAM-TS 1 precursor (EC 3.4.24.-) (A 1 . . . 924478/953 (50%)0.0disintegrin and metalloproteinase with37 . . . 967636/953 (66%)thrombospondin motifs 1)(ADAMTS-1)(ADAM-TS1) - Mus musculus (Mouse),968 aa.Q9WUQ1ADAMTS-1 precursor (EC 3.4.24.-) (A 1 . . . 924472/952 (49%)0.0disintegrin and metalloproteinase with37 . . . 966638/952 (66%)thrombospondin motifs 1)(ADAM-TS 1)(ADAM-TS 1) - Rattusnorvegicus (Rat), 967 aa.Q9UP79ADAMTS-8 precursor (EC 3.4.24.-) (A 1 . . . 869423/902 (46%)0.0disintegrin and metalloproteinase with16 . . . 889569/902 (62%)thrombospondin motifs 8)(ADAM-TS 8)(ADAM-TS8) (METH-2) (METH-8) —Homo sapiens (Human), 890 aa.


[0345] PFam analysis indicates that the NOV5a protein contains the domains shown in the Table 5F.
30TABLE 5FDomain Analysis of NOV5aIdentities/SimilaritiesNOV5a Matchfor the MatchedExpectPfam DomainRegionRegionValuePep_M12B_propep: 67 . . . 18130/120 (25%) 2.3e−06domain 1 of 169/120 (58%) Reprolysin: domain 1 of 1218 . . . 42769/226 (31%) 7.4e−09135/226 (60%) tsp_1: domain 1 of 3523 . . . 57319/54 (35%)1.5e−0732/54 (59%)tsp_1: domain 2 of 3817 . . . 86816/55 (29%)0.04229/55 (53%)tsp_1: domain 3 of 3871 . . . 92416/61 (26%)0.001736/61 (59%)



Example 6

[0346] The NOV6 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 6A.
31TABLE 6ANOV6 Sequence AnalysisSEQ ID NO: 39j2633 bpNOV6a,ATTTTCTAACACATTTCTACAATATAATGCATTGTGGATTACTTCATATTGACCAGGACG59197-01 DNASequenceTATTGTCAATACAATCATCAAACACTGCTCACCTCAATTTTTTTCACTTGGTTTGCCTGGTGCCACAATGCTTATTATGGATTTTATTGTAGCAGCTGGTAGAGTGGCTTCTTCAGCTTTTCTCAATGCACCAAGAGTAGAAGCACAAGTTCTTCTOGGATCTTTGGTTTGCTTTCCCAACTTATATTGTGAACTGCCTTCTCTTCATCCCAACATTCCTGATGTTGCTGTGTCTCAGTTTACAGATGTTAAGGAACTTATAATCAAAACTGTATTAAGCTCGGCAAGAGATGAGCCCTCTGGTCCTCCACGGTGTGTAGCACTTTGTAGTTTAGGTATTTGGATTTGTGAAGAACTAGTCCATGAGTCTCATCATCCTCAAATTAAGGAAGCTCTGAATGTGATTTGTGTTTCCTTAAAGTTTACTAATAAAAACAGTAGCCCACGTAGCTTGTAACATGCTTCACATGCTGGTTCATTATGTACCTAGACTTCAGATTTACCAGCCTGATTCTCCCTTCAAAATTATTCAAATCCTAATAGCTACCATCACCCATCTTTTACCAAGTACAGAGGCTTCATCTTATGAAATGGACAAGAGGTTGCTACTATCTTTACTTCTCTGCCTTCTGGACTGGATCATGGCCTTACCTCTAAGACACTGCTCCAACCATTTCATGCTACGGGAGCAGAAAGCGATAAAACAGAAAAATCTGTTCTCAATTGCATTTATAAGGTATTACATGGGTGTGTTTATGGAGCTCAGTGTTTTAGCAATCCAAGGTATTTTCCCATCAGCCTCTCTGATTTGGCATCTCTACATTATGATCCTTTTATGCATTTGGAAAGTCTGAAAAGAGCCTGAGCCTCTGCACTCTCCTGACTCAGAACGATCTTCTAACTCCAGCCAGTAACAGAAGTGATAAACTCAAATGCAGCATGGATTAATCTCTATAGCAGCCCGCACTGTTATTACACATCTGGTAATCACCTGGGCCATTATCCAATGAGCGGTGGTCCTGCTATGCTAACAAGTCAGGTGTGTGAAAATCACGACAATCATTACAGTGAGTACTCAACTTTCTCCTGAACTCTTTGAGAGTCCAAATATCCAGTTCTTTGTGTTAAATAATACAACCTTAGTGTCCTGTATCCAGATCAGATCAGAAGAGAATATGCCTGGAGGAGGTTTATCTCCTGGCCTTGCATCAGCCAATTCAAATGTCAGAATCATAGTACGTGATCTCTCTGGAAAATATTCATGGGATTCTGCTATACTCTATGGCCCACCTCCTGTAAGTGGCTTGTCAGAACCTACATCTTTCATGCTTTCATTGTCTCACCAAGAGAAGCCAGAACAGCCTCCGACATCTAATGAATGCTTAGAAGATATAACCGTAAAAGATGCACTTTCTCTCCAGTTTAAAAGATTTAGAGAAACTGTACCAACTTGGGATACAATAAGAGATGAAGAAGATGTTCTTGATGAGCTCTTGCAGTATTTGGGTGTTACTACTCCTGAATGCTTACAGAGAACTGGAATCTCACTTAATATTCCTGCTCCACAACCTGTGTGCATTTCTGAAAAACAAGAAAATGATGTTATTAATGCTATCCTTAAGCAACATACAGAAGAAAAAGAATTTGTTGAGAAGCACTTTAATGACTTAAACATGAAAGCTGTGGAACAAGATGAACCAATACCTCAAAAACCTCAGTCAGCATTTTATTATTGCAGATTGCTTCTTAGTATATTGGGAATGAATTCCTGGGACAAACGGAGGAGCTTTCATCTCCTGAAGAAAAATGAAAAGCTACTTAGAGAACTTAGGAACTTGGATTCAAGGCAGTGGCGAGAGACACACAAGATTGCAGTATTTTATGTTGCTGAAGGACAAGAAGACAAACACTCCATTCTCACCAATACAGGAGGAAGTCAAGCATATGAAGATTTTCTAGCTGGTCTTGGTTGGGAGGTAAATCTTACAAACCATTGTGGTTTTATGGCACCACTACAAAAAAACAAAAGCACTGGATTGACCACTCCATATTTTGCTACCTCTACAGTAGAGGTAATATTTCACGTGTCAACAAGAATGCCTTCTGATTCTGATGATTCTTTGACCAAAAAATTGAGACATTTGGGAAATGATGAAGTGCACATTGTTTGGTCAGAGCATACTAGAGACTACAGGAGAGGAATTATTCCCACAGAATTTGGTGATGTCCTTATTCTAATATATCCAATGAAAAATCACATGTTCAGTATTCAGATAATGAAAAAACCAGAGGTACCCTTCTTTGGTCCCCTTTTTGATGGTGCTATTGTGAATGCAAAGGTTCTACCCATTATGGTTAGAGCAACAGCTATAAATGCAAGCCGTGCTCTGAAATCTCTGATTCCATTGTATCAAAACTTGTATGAGGAGAGAGCACGATACCTGCAAACAATTGTCCAGCACCACTTAGAACCACAACATTTGAAGATTTTGCAGCACAGGTTTTTTCTCCAGCTCCCTACCACCATTTACCATCTGATGCCGCTAAGATTAAAAGCGAGTATTAGTTACTTORF Start: ATG at 27ORF Stop: TAG at 2625SEQ ID NO: 401866 aaMW at 97197.4kDNOV6a,MHCGLLHIDQDIVNTIIKHCSPQFFSLGLPGATMLIMDFIVAAGRVASSAFLNAPRVECG59197-01 ProteinSequenceAQVLLGSLVCFPNLYCELPSLHPNIPDVAVSQFTDVKELIIKTVLSSARDEPSGPARCVALCSLGIWICEELVHESHHPQIKEALNVICVSLKFTNKTVAHVACNMLHMLVHYVPRLQIYQPDSPLKIIQILIATITHLLPSTEASSYEMDKRLVVSLLLCLLDWIMALPLKTLLQPFHATGAESDKTEKSVLNCIYKVLHGCVYGAQCFSNPRYFPMSLSDLASVDYDPFMHLESLKEPEPLHSPDSERSSKLQPVTEVKTQMQHGLISIAARTVITHLVNHLGHYPMSGGPAMLTSQVCENHDNHYSESTELSPELFESPNIQFFVLNNTTLVSCIQIRSEENMPGGGLSAGLASANSNVRIIVRDLSCKYSWDSAILYGPPPVSGLSEPTSFMLSLSHQEKPEEPPTSNECLEDITVKDGLSLQFKRFRETVPTWDTIRDEEDVLDELLQYLGVTSPECLQRTGISLNIPAPQPVCISEKQENDVINAILKQHTEEKEFVEKHFNDLNMKAVEQDEPIPQKPQSAFYYCRLLLSILGMNSWDKRRSPHLLKKNEKLLRELRNLDSRQWRETHKIAVFYVAEGQEDKRSILTNTGGSQAYEDFVAGLGWEVNLTNHCGFMGGLQKNKSTGLTTPYFATSTVEVIFHVSTRMPSDSDDSLTKKLRHLGADEVHIVWSEHTRDYRRGIIPTEFGDVLIVIYPMKNHMFSIQIMKKPEVPFFGPLFDGAIVNGKVLPIMVRATAINASRALKSLIPLYQNLYEERARYLQTIVQHHLEPTTFEDFAAQVFSPAPYHHLPSDAGKIKSEYSEQ ID NO: 411923 bpNOV6b,GGATCCAAGACACTGCTCCAACCATTTCATGCTACGGGAGCAGAAAGCGATAAACAG188822075 DNASequenceAAAAATCTGTTCTCAATTGCATTTATAAGGTTTTACATGGGTGTGTTTATGGAGCTCAGTGTTTTAGCAATCCAAGGTATTTTCCCATGAGCCTCTCTGATTTGGCATCTGTAGATTATGATCCTTTTATGCATTTGGAAAGTCTGAAAGAGCCTGAGCCTCTGCACTCTCCTGACTCAGAACGATCTTCTAAACTCCAGCCAGTAACAGAAGTGAAAACTCAAATGCAGCATGGATTAATCTCTATAGCAGCCCGCACTGTTATTACACATCTGGTAAATCACCTGGGCCATTATCCAATGAGCGGTGGTCCTGCTATGCTAACAAGTCAGGTGTGTGAAAATCACGACAATCATTACAGTGAAAGTACTGAACTTTCTCCTGAACTCTTTGAGAGTCCAAATATCCAGTTCTTTGTGTTAAATAATACAACCTTAGTGTCCTGTATCCAGATCAGATCAGAGAGAATATGCCTGGAGGAGGTTTATCTGCTGGCCTTGCATCAGCCAATTCAAATGTCAGAATCATAGTACGTGATCTCTCTGGAAAATATTCATGGGATTCTGCTATACTGTATGGCCCACCTCCTGTAAGTGGCTTGTCACAACCTACATCTTTCATGCTTTCATTGTCTCACCAAGAGAAGCCAGAAGAGCCTCCGACATCTAATGAATGCTTAGAAGATATACCGTAAAAGATGGACTTTCTCTCCAGTTTAAAAGATTTAGAGAAACTGTACCAACTTGGGATACAATAAGAGATGAAGAAGATGTTCTTGATGAGCTCTTGCAGTATTTGGGTGTTACTAGTCCTGATGCTTACAGAGAACTGGAATCTCACTTAATATTCCTGCTCCACAACCTGTGTGCATTTCTGAAAAACAAGAAAATGATGTTATTAATGCTATCCTTAAGCAACATACAGAAGAAAAGAATTTGTTGAGAAGCACTTTAATGACTTAACATGAAAGCTGTCCAACAAGATGAACCAATACCTCAAAAACCTCAGTCAGCATTTTATTATTGCAGATTGCTTCTTAGTATATTGGGAATGAATTCCTGGGACAAACGGAGGAGCTTTCATCTCCTGAAGAAAAAATGAAAAGCTACTTAGAGAACTTAGGAACTTGGATTCAAGGCAGTGCCGAGAGACACACAGATTGCAGTATTTTATGTTGCTGAGGACAACAAGACAAACACTCCATTCTCACCAATACAGGAGGAAGTCAAGCATATGAAGATTTTGTAGCTGCTCTTCGTTGGGACCTATCTTACAAACCATTGTGGTTTTATGGGAGGACTACAAAAAAACAAAAGCACTGGATTGACCACTCCATATTTTGCTACCTCTACAGTAGAGGTAATATTTCACGTGTCAACAGAATGCCTTCTGATTCTGATGATTCTTTGACCAAAAAATTGAGACATTTGGGAAATGATGAAGTGCACATTGTTTGGTCAGAGCATACTAGAGACTACAGGAGAGGAATTATTCCCACAGAATTTGGTGATGTCCTTATTGTAATATATCCAATGAAAAATCACATGTTCAGTATTCAGATAATGAIAAAAACCAGAGGTTCCCTTCTTTGGTCCCCTTTTTGATGGTGCTATTTGAATGGAAGGTTCTACCCATTATGGTTAGAGCAACAGCTATAAATGCAAGCCGTGCTCTGAAATCTCTGATTCCATTCATATCAAACTTCTATGAGGAGAGAGCCGATACCTGCAAACAATTGTCCAGCACCACTTAGAACCAACAACATTTGAAGATTTTGCAGCACAGGTTTTTTCTCCAGCTCCCTACCACCATTTACCATCTGATGCCGGTAAGATTAAAAGCGAGTATCTCGAGORF Start: OGA at 1ORF Stop: 47 at 1924SEQ ID NO: 42641 aaMW at 72273.2kDNOV6b,GSKTLLQPFHATGAESDKTEKSVLNCIYKVLHGCVYGAQCFSNPRYFPMSLSDLASVD188822075 ProteinSequenceYDPFMHLESLKEPEPLHSPDSERSSKLQPVTEVKTQMQHGLISIARTVITHLAAAHLGHYPMSGGPANLTSQCENDNHYSESTELSPELFESPNIQFFVLNNTTLVSCIQIRSEENMPGGGLSAGLASANSNVRHVRDLSGKYSWDSAILYGPPPVSGLSEPTSFMLSLSHQEKPEEPPTSNECLEDITVKDGLSLQFKRFRETVPTWDTIRDEEDVLDELLQYLGVTSPECLQRTGISLNIPAPQPVCISEKQENDVINAILKQHTEEKEFVEKHFNDLNNKAVEQDEPIPQKPQSAFYYCRLLLSILGMNSWDKRRSFHLLKKNEKLLRELRNLDSRQCRETHKIAVFYVAEGQEDKHSILTNTGGSQAYEDFVAGLGWEVNLTNHCGFMGOLQKNKSTGLTTPYFATSTVEVIFHVSTRMPSDSDDSLTKKLRHLGNDEVHIVWSEHTRDYRRGIIPTEFGDVLIVIYPMKNHMFSIQIMKKPEVPFPGPLFDGAIVNCKVLPIMVAATAINASRALKSLIPLYQNFYEERARYLQTIVQHHLEPTTFEDFAAQVFSPAPYHHLPSDAGKIKSEYLE


[0347] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 6B.
32TABLE 6BComparison of NOV6a against NOV6b and NOV6c.NOV6a Residues/Identities/SimilaritiesProtein SequenceMatch Residuesfor the Matched RegionNOV6b230 . . . 866606/637 (95%) 3 . . . 639606/637 (95%)


[0348] Further analysis of the NOV6a protein yielded the following properties shown in Table 6C.
33TABLE 6CProtein Sequence Properties NOV6aPSort0.7900 probability located in plasma membrane; 0.3000analysis:probability located in microbody (peroxisome); 0.3000probability located in Golgi body; 0.2000probability located in endoplasmic reticulum (membrane)SignalPNo Known Signal Sequence Indicatedanalysis:


[0349] A search of the NOV6protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 6D.
34TABLE 6DGeneseq Results for NOV6aNOV6aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent#, Date]ResiduesRegionValueAAB41763Human ORFX ORF1527 polypeptide445 . . . 859410/415 (98%)0.0sequence SEQ ID NO: 3054 - Homo 1 . . . 415410/415 (98%)sapiens, 417 aa. [WO200058473-A2,05-OCT-2000]AAB93704Human protein sequence SEQ ID177 . . . 864389/693 (56%)0.0NO: 13287 - Homo sapiens, 704 aa. 1 . . . 658491/693 (70%)[EP 1074617-A2, 07-FEB-2001]AAB95195Human protein sequence SEQ ID599 . . . 819186/221 (84%)e−107NO: 17282 - Homo sapiens, 227 aa. 1 . . . 221203/221 (91%)[EP1074617-A2, 07-FEB-2001]AAR77223Tuberous sclerosis 2 TSC2 gene610 . . . 857 70/260 (26%)3e−20product - Homo sapiens, 1784 aa.1497 . . . 1755128/260 (48%)[WO9518226-A, 06-JUL-1995]AAW95629Homo sapiens secreted protein gene616 . . . 781 50/172 (29%)1e−14clone gm196_4 - Homo sapiens, 17 . . . 188 89/172 (51%)322 aa. [WO9856805-A1,17-DEC-1998]


[0350] In a BLAST search of public sequence databases, the NOV6a protein was found to have homology to the proteins shown in the BLASTP data in Table 6E.
35TABLE 6EPublic BLASTP Results for NOV6aProteinNOV6aIdentities/AccessionResidues/Similarities forExpectNumberProtein/Organism/LengthResiduesPortionValueO55008TULIP 2 - Rattus norvegicus (Rat), 1 . . . 865815/865 (94%)0.0866 aa. 1 . . . 865843/865 (97%)O55007TULIP 1 - Rattus norvegicus (Rat), 1 . . . 723680/723 (94%)0.0747 aa. 1 . . . 723705/723 (97%)Q9BQT6BA287B20.1.1 (KIAA1272 SIMILAR 11 . . . 855483/852 (56%)0.0TO RAT TULIP PROTEINS 1 AND 2, 1 . . . 817613/852 (71%)ISOFORM 1) - Homo sapiens (Human),820 aa (fragment).Q9ULE8KIAA1272 PROTEIN - Homo sapiens 1 . . . 817464/824 (56%)0.0(Human), 1023 aa (fragment). 231 . . . 1019590/824 (71%)Q9JMC4TULIP 1 PROTEIN - Mus musculus131 . . . 570407/440 (92%)0.0(Mouse), 446 aa. 7 . . . 446423/440 (95%)


[0351] PFam analysis indicates that the NOV6a protein contains the domains shown in the Table 6F.
36TABLE 6FDomain Analysis of NOV6aNOV6aIdentities/MatchSimilarities forExpectPfam DomainRegionthe Matched RegionValueRap_GAP: domain 1 of 1650 . . . 82952/192 (27%)2.5e−1898/192 (51%)



Example 7

[0352] The NOV7 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 7A.
37TABLE 7ANOV7 Sequence AnalysisSEQ ID NO: 43570 bpNOV7a,CTCATCCCTTTGCGACGTCAATGCGACCACGGGCACCAGGCTTCTCGGCTGGGTAGCTCG58524-11 DNASequenceCTTTGTCTCCTGCCAGCAGGTGAGCTCTGAGCACAGAATAAAAACCCTTGTCCTGGGCTGGCCAACCCCCAGATCCAAGCTTTGCTGTTGTTGTTIAAGGTCTTTCCTGGACTCTGTCTACAGCATCTGTTTCTTTCTCTTACAGGCTGTTTTCATGCCAAAGTCACACAGACTCCAGGATATTTGGTCAAAGGAAAAGCAAAGGAACAAAGATGTATTGTACCCCCAApAAACGGACATACTTTTGTTTGTTGGTATCAGCAGAATCAGAATAAAGAGTTTATGTTTTTGATTTCCTTTCAGAATGAACAAGTTCTTCAAGAAATCGAGATGCACAAGAGCGATTCTCATCTCAATGCCCCAAGAACCCACCCTGCAGCCTGGCAAATCCTGTCCTCGGAACCGGGAGACACCGCACTGTATCTCTGTGCCACCAGTCCGTCCACAGCACTGAAAATGTCAGTTCCTGTTAGCACACAAACTTGCCACAGACCCAGCTCAGGAGCAGGTGATORF Start: AAA at 100ORF Stop: DF at 571SEQ ID NO: 44157aaMW at 17470.1kDNOV7a, KPLSWAGQPPDPSFAVVVKVFPGLCLQHLFLSLTGCFHAKVTQTPGYLVKGKGRKTKMCG58524-01 ProteinSequenceYCTPKNGHTFVCWYQQNQNKEFMFLISFQNEQVLQEMEMHKKRFSSQCPKIAPPCSLAILSSEPGDTALYLCATSPSTALKCQFLLAHKLATDPAQEAGD


[0353] Further analysis of the NOV7a protein yielded the following properties shown in Table 7B.
38TABLE 7BProtein Sequence Properties NOV7aPSort0.5500 probability located in endoplasmic reticulumanalysis:(membrane); 0.1900 probability located in lysosome (lumen);0.1421 probability located in microbody (peroxisome);0.1000 probability located in endoplasmic reticulum (lumen)SignalPCleavage site between residues 40 and 41analysis:


[0354] A search of the NOV7a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 7C.
39TABLE 7CGeneseq Results for NOV7aNOV7aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueABB25859Protein #7858 encoded by probe for36 . . . 155120/120 (100%)5e−69measuring heart cell gene expression - 1 . . . 120120/120 (100%)Homo sapiens, 120 aa.[WO200157274-A2, 09-AUG-2001]AAM76093Human bone marrow expressed probe36 . . . 155120/120 (100%)5e−69encoded protein SEQ ID NO: 36399 - 1 . . . 120120/120 (100%)Homo sapiens, 120 aa.[WO200157276-A2, 09-AUG-2001]AAM63281Human brain expressed single exon36 . . . 155120/120 (100%)5e−69probe encoded protein SEQ ID NO: 1 . . . 120120/120 (100%)35386 - Homo sapiens, 120 aa.[WO200157275-A2, 09-AUG-2001]AAM36201Peptide #10238 encoded by probe for36 . . . 155120/120 (100%)5e−69measuring placental gene expression - 1 . . . 120120/120 (100%)Homo sapiens, 120 aa.[WO200157272-A2, 09-AUG-2001]AAY80643Canine TCR V-beta 54 protein, SEQ ID24 . . . 13560/112 (53%)1e−27[WO200006732-A2, 10-FEB-2000] 6 . . . 11775/112 (66%)


[0355] In a BLAST search of public sequence databases, the NOV7a protein was found to have homology to the proteins shown in the BLASTP data in Table 7D.
40TABLE 7DPublic BLASTP Results for NOV7aNOV7aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueC32578T-cell receptor beta chain precursor V14 . . . 132102/119 (85%) 2e−55region (HBVT72) - human, 120 aa. 2 . . . 120108/119 (90%) AAD15201T-CELL RECEPTOR BETA14 . . . 132102/119 (85%) 2e−55PRECURSOR - Homo sapiens 2 . . . 120108/119 (90%) (Human), 143 aa (fragment).CAB99345BA255A11.11 (PUTATIVE NOVEL T36 . . . 131 96/96 (100%)3e−54CELL RECEPTOR BETA CHAIN V1 . . . 96 96/96 (100%)REGION PROTEIN) - Homo sapiens(Human), 96 aa (fragment).AAA36721T-CELL RECEPTOR BETA CHAIN -26 . . . 114 88/89 (98%)5e−49Homo sapiens (Human), 89 aa1 . . . 89 88/89 (98%)(fragment).CAB35951TCRBV19S1P PROTEIN - Homo29 . . . 13489/106 (83%)1e−46sapiens (Human), 116 aa (fragment).11 . . . 11693/106 (86%)


[0356] PFam analysis indicates that the NOV7a protein contains the domains shown in the Table 7E.
41TABLE 7EDomain Analysis of NOV7aIdentities/SimilaritiesNOV7afor thePfam DomainMatch RegionMatched RegionExpect Valueig: domain 1 of 153 . . . 13112/83 (14%)0.0009653/83 (64%)



Example 8

[0357] The NOV8 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 8A.
42TABLE 8ANOV8 Sequence AnalysisSEQ ID NO:451156 bpNOV8a,CTAGCGCTCGTACTCCTGGGCTGGGTCTCCTCGTCTTCTCCCACCTCCTCGGCATCCTCG56512-02 DNASequenceCCTTCTCCTCCTCGGCGCCGTTCCTGGCTTCCGCCGTGTCCGCCCAGCCCCCGCTGCCGGACCAGTGCCCCGCGCTGTGCGAGTGCTCCGAGGCAGCGCGCACAGTCAAGTGCGTTAACCGCAATCTGACCGAGGTGCCCACGGACCTGCCCGCCTACGTGCGCAACCTCTTCCTTACCGGCAACCAGCTGGCCGCGCTCAACCTCAGCGGCAGCCGCCTGGACGAGGTGCGCGCGGGCGCCTTCGAGCATCTGCCCAGCCTGCGCCAGCTCGACCTCAGCCACAACCCACTGGCCGACCTCAGTCCCTTCGCTTTCTCGGGCAGCAATGCCAGCGTCTCGGCCCCCAGTCCCCTTGTGGAACTGATCCTGAACCACATCGTGCCCCCTGAAGATGAGCGGCAGACCGGAGCTTCGAGGGCATGGTGGTGGCGGCCCTGCTGGCGGGCCGTGCACTGCAGGGGCTCCGCCGCTTGGAGCTGGCCAGCAACCACTTCCTTTACCTGCCGCGGGATGTGCTGGCCCAACTGCCCAGCCTCAGGCACCTGGACTTAAGTAATAATTCGCTGGTGAGCCTGACCTACGTGTCCTTCCCCAACCTGACACATCTAGAAAGCCTCCACCTGGAGGACAATGCCCTCAAGGTCCTTCACAATGGCACCCTGGCTGAGTTGCAAGGTCTACCCCACATTAGGCTTTTCCTGGACAACAATCCCTGGGTCTGCGACTGCCACATGGCAGACATGGTGACCTGGCTCAAGGAAACAGAGGTAGTGCAGGGCAAAGACCGGCTCACCTGTGCATATCCGGAAAAAAATGAGGAATCGGGTCCTCTTGGAACTCAACAGTGCTGACCTGGACTGTGACCCGATTCTTCCCCCATCCCTCACAAACCTCTTATGTCTTCCTGGGTATTGTTTTAGCCCTGATAGGCGCTATTTTCCTCCTGGTTTTGTATTTGAACCGCAAGGGGATAAAAAAGTGGATGCATAACATCAGAGATGCCTGCAGGGATCACATGGAACCGTATCATTACAGATATGAAAATCAATGCGGACCCCAGATTAACGAACCTCAGTTCTAACTCGGATGTCTGAGAAAORF Start: CTA at 1IORF Stop: TGA at 1150SEQ ID NO: 46383 aaMW at 42319.8kDNOV8a,LALVLLGNVSSSSPTSSASSFSSSAPFLASAVSAQPPLPDQCPALCECSEAARTVKCVCG56512-02 ProteinSequenceNRNLTEVPTDLPAYVRNLFLTGNQLAALNLSGSRLDEVRAGAFEHLPSLRQLDLSHNPLADLSPFAFSGSNASVSAPSPLVELILNHIVPPEDERQNRSFEGMVVAALLAGRALQGLRRLELASNIFLYLPRDVLAQLPSLRHLDLSNNSLVSLTYVSFRNLTHLESLHLEDNALKVLHNGTLAELQGLPHIRVFLDNNPWVCDCHMADMVTWLKETEVVQGKDRLTCAYPEKNRNRVLLELNSADLDCDPILPPSLQTSYVFLGIVLALIGAIFLLVLYLNRKGIKKWMHNIRDACRDHMEGYHYRYEINADPRLTNLSSNSDV


[0358] Further analysis of the NOV8a protein yielded the following properties shown in Table 8B.
43TABLE 8BProtein Sequence Properties NOV8aPSort0.4600 probability located in plasma membrane; 0.1000 prob-analysis:ability located in endoplasmic reticulum (membrane); 0.1000probability located in endoplasmic reticulum (lumen); 0.1000probability located in outsideSignalPCleavage site between residues 19 and 20analysis:


[0359] A search of the NOV8a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 8C.
44TABLE 8CGeneseq Results for NOV8aNov8aIdentities/GeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAM93334Human polypeptide, SEQ ID NO: 2867 - 1 . . . 383383/400 (95%)0.0Homo sapiens, 420 aa. [EP1130094- 21 . . . 420383/400 (95%)A2, 05-SEP-2001]AAM93333Human polypeptide, SEQ ID NO: 2865 - 1 . . . 346346/363 (95%)0.0Homo sapiens, 383 aa. [EP1130094- 21 . . . 383346/363 (95%)A2, 05-SEP-2001]AAB83839Amino acid sequence of canine 5T4 1 . . . 383333/400 (83%)0.0protein - Canis sp, 420 aa. 21 . . . 420345/400 (86%)[WO200136486-A2, 25-MAY-2001]AAY94351Canine 5T4 tumour-associated antigen -146 . . . 383215/238 (90%) e−123Canis sp, 238 aa. [WO200029428-A2, 1 . . . 238221/238 (92%)25-MAY-2000]AAE13006Human leucine-rich repeat (LRR) 28 . . . 307 94/321 (29%)2e−20 family member protein - Homo sapiens, 43 . . . 361130/321 (40%)713 aa. [WO200175105-A2, 11-OCT-2001]


[0360] In a BLAST search of public sequence databases, the NOV8a protein was found to have homology to the proteins shown in the BLASTP data in Table 8D.
45TABLE 8DPublic BLASTP Results for NOV8aNOV8aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ136415T4 ONCOFETAL ANTIGEN 1 . . . 383383/400 (95%)0.0PRECURSOR - Homo sapiens21 . . . 420383/400 (95%)(Human), 420 aa.Q9Z0L05T4 ONCOFETAL TROPHOBLAST 1 . . . 383322/407 (79%) e−179GLYCOPROTEIN PRECURSOR -21 . . . 426345/407 (84%)Mus musculus (Mouse), 426 aa.Q9QYD95T4 ONCOFETAL ANTIGEN 1 . . . 383318/407 (78%) e−176HOMOLOG - Rattus norvegicus21 . . . 426340/407 (83%)(Rat), 426 aa.CAD10322SEQUENCE 1 FROM PATENT28 . . . 307 94/321 (29%)6e−20 WO0175105 - Homo sapiens43 . . . 361130/321 (40%)(Human), 713 aa.Q9VK54KEK1 PROTEIN - Drosophila 9 . . . 313 83/309 (26%)1e−19 melanogaster (Fruit fly), 880 aa.55 . . . 333135/309 (42%)


[0361] PFam analysis indicates that the NOV8a protein contains the domains shown in the Table 8E.
46TABLE 8EDomain Analysis of NOV8aIdentities/SimilaritiesPfam DomainNOV8a Match Regionfor the Matched RegionExpect ValueLRRNT: domain 1 of 141 . . . 7016/31 (52%)3.5e−0825/31 (81%)LRR: domain 1 of 5 82 . . . 105 8/25 (32%)7.119/25 (76%)LRR: domain 2 of 5106 . . . 12910/25 (40%)0.0418/25 (72%)LRR: domain 3 of 5174 . . . 197 8/25 (32%)1.118/25 (72%)LRR: domain 4 of 5198 . . . 22114/25 (56%)0.001620/25 (80%)LRR: domain 5 of 5222 . . . 245 8/25 (32%)0.3620/25 (80%)LRRCT: domain 1 of 1257 . . . 30820/54 (37%)2.8e−1848/54 (89%)



Example 9

[0362] The NOV9 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 9A.
47TABLE 9ANOV9 Sequence AnalysisSEQ ID NO:47958 bpNOV9a,AAAACATGGCAGCCAAAGTGTTTGAGTCCACGGGTAAGTTTGGCTTGGCCTTACCTGTCG58180-01 DNATGCACGACTTGGCCTTAGCTGTTGCAGGAGACCTGTGAACTCTGCCTTATATAATGTGSequenceGATGTTGGGCACAGAGCTGTCATCTTTGACAGATTCCAGGACAAACAGGACATTGTGGTAGGCGACTCACTTTCTCATCCCATGGGTACAGAAACCAATTATCTTTGCCTTTCTCCACCACGTAATGTACCAATCATCACTGGTACCAAACATTTACAGAATGTCAATATCACACTGCGCATCATCTTCCAGCCTGTTGCTAGCCAGCTTCCTCGCATCTTCACCAGCATCGGAGAGGACTATGATGAGCCTGTGCTGACGTACATCACGACCGAGATCCTCAAGTCAGTGGTGGCTCGCTTTGATGCTGGAGAAGTTATCACTCAGAGAGAGCTGGTCTCCAGGCAGCTGAGCAACGACCTTACGGAGCAAGCAGCCACATTTGGGCTCATCCTGGACGACGTGTCCTTGACATATCTGACCTTTGGAAAGGAGTTCACAGAAGCAGTGGAAGCCAAACAGGTGGCTCAGCAGGAAGCAGACAGGGCCAGATTTGTGAAGGAAAAGGCTGAGCAGCAGAAAAAGGCTGAGCAGCAGAAAAAGGTTGAGCAGCAGAAAAAGGCAGCCGTGATCTCTGCTGAGGGCGACTCCAAGGCAACCGAGCTGATTGCCAACTCACTGGCCACCGCGGGGGACGGCCTGATGGAGCTGTGCAAGTTGCAAGCCGCGGAGTCTCGGAACATGACCTACCTGCCGGCGGGGCAGTCCGCTCCTCCGGCTGCCCCATGAGGGCCCACCCTGCCTGCACCTCCGCAGGCTGACTGGGCCACAGCCCCAATGATTCTTAACACTGCCTTACCCCCCTACCCCAGAAATCACTGAAATTTCATAATTGGCTTAAAORF Start: ATG at 6ORF Stop: TGA at 843SEQ ID NO:48279 aa MW at 30368.2 kDNOV9a,MAAKVFESTGKFGLALAVAGLGLSCCRRPVNSALYNVDVGHRAVIFDRFQDKQDIVVGCG58180-01 ProteinDSLSHPMGTETNYLCLSPPRNVPIITGSKDLQNVNITLRIIFQPVASQLPRIFTSIGESequenceDYDEPVLTYITTEILKSVVARFDAGEVITQRELVSRQVSNDLTEQAATFGLILDDVSLTYLTFGKEFTEAVEAKQVAQQEAERARFVKEKAEQQKKAEQQKKVEQQKKAAVISAEGDSKATELIANSLATAGDGLMELCKLEAAESRNNTYLPAGQSAPPAAP


[0363] Further analysis of the NOV9a protein yielded the following properties shown in Table 9B.
48TABLE 9BProtein Sequence Properties NOV9aPSort0.3700 probability located in outside; 0.1900 probabilityanalysis:located in lysosome (lumen); 0.1000 probability located inendoplasmic reticulum (membrane); 0.1000 probabilitylocated in endoplasmic reticulum (lumen)SignalPCleavage site between residues 33 and 34analysis:


[0364] A search of the NOV9a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 9C.
49TABLE 9CGeneseq Results for NOV9aNOV9aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAG73845Human colon cancer antigen protein1 . . . 273216/284 (76%)e−104SEQ ID NO:4609 - Homo sapiens, 2798 . . . 272230/284 (80%)aa. [WO200122920-A2, 05-APR-2001]AAB43874Human cancer associated protein1 . . . 273216/284 (76%)e−104sequence SEQ ID NO:1319 - Homo8 . . . 272230/284 (80%)sapiens, 279 aa. [WO200055350-A1,21-SEP-2000]AAW54352Heat shock 27 kD protein and1 . . . 273216/284 (76%)e−104prohibitin (admixture) - Homo sapiens,200 . . . 464 230/284 (80%)1998]AAR42215Human prohibitin - Homo sapiens, 2721 . . . 273216/284 (76%)e−104aa. [JP05271294-A, 19-OCT-1993]1 . . . 265230/284 (80%)AAR13466Prohibitin - Rattus rattus, 272 aa.1 . . . 273215/284 (75%)e−104[US7612674-A, 16-JUL-1991]1 . . . 265230/284 (80%)


[0365] In a BLAST search of public sequence databases, the NOV9a protein was found to have homology to the proteins shown in the BLASTP data in Table 9D.
50TABLE 9DPublic BLASTP Results for NOV9aNOV9aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ96CH8HYPOTHETICAL 22.1 KDA65 . . . 262 196/198 (98%) e−104PROTEIN - Homo sapiens (Human),1 . . . 198197/198 (98%)201 aa.P35232Prohibitin - Homo sapiens (Human),1 . . . 273216/284 (76%) e−104272 aa.1 . . . 265230/284 (80%)P24142Prohibitin (B-cell receptor associated1 . . . 273215/284 (75%) e−103protein 32) (BAP 32) - Mus musculus1 . . . 265230/284 (80%)(Mouse), and, 272 aa.Q9VIZ4LETHAL (2) 37CC PROTEIN -1 . . . 273159/284 (55%)7e−75Drosophila melanogaster (Fruit fly),1 . . . 265200/284 (69%)276 aa.Q9BKU4HYPOTHETICAL 30.0 KDA1 . . . 272145/283 (51%)3e−64PROTEIN - Caenorhabditis elegans,1 . . . 267188/283 (66%)275 aa.


[0366] PFam analysis indicates that the NOV9a protein contains the domains shown in the Table 9E.
51TABLE 9EDomain Analysis of NOV9aIdentities/NOV9aSimilarities forExpectPfam DomainMatch Regionthe Matched RegionValueBand_7: domain 1 of 112 . . . 211 46/213 (22%)1.3e−42162/213 (76%)



Example 10

[0367] The NOV10 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 10A.
52TABLE 10ANOV10 Sequence AnalysisSEQ ID NO:492482 bpNOV 10a,CGGCCACATAAOATATTATCTACACAAAAGCTTATTTAGGAATGACCAATGAGCTCAACG59 199-01 DNACTTAAATTTATTAGAAATCTGATTAGCATTATAAATCAACTGACTTTTAGGAGCATAGSequenceGCTTTGGCGCTACAGGGATCTGGCTTGAACCTCATTGAGGCCACTGATTGGTGAGTGACCTTAAGCAAGTCTCTTTACCTTGTTAGGGCACAATTTCCTCTCGGAATTGTGAAATGGGTTTAATTACACCAGCTTACATCCCAACCATCAGCAAGTCCTCTTGTATGTAACCATCTCCAACACAGAAAGGGGATCTGCCCATGTTCTACCATCCTCACCTTTCTCCAAGCCACTACAACCTCTCACAACAGCCTTCCAATTGGTCTCCCTAAACTCTTATCCCCCCTACACCCCGTTCTCAGTCCTCAGTCCTTGCCCTAGGCTGGTAGCCCACTCCTTGCCCGCCCCCCGCCTTCCTCCCATCTCCCCCTCCTCTCCCCGGCCCCCAGCACCTTCTGCATCCCAGCCTACCTAGCCTACTCCTCCTCTTCCTGGCCCTCTTCCCCAGGCTCCAGGCTGGGGGGTGCTCGCGTCTCCCCTGTAGGCCAGAGCAGCCCCAAGTTCTGGGGGCGGTCGGCCTGCTGCTTTATCCCCATGGCCCTGCCATCACTTCTGCTGTTGGTGGCAGCCCTGGCAGGTGGGGTGCGTCCTCCCGGGGCGCGGAACCTGACGCTGGCGGTGGTGCTGCCAGAACACAACCTGAGCTATGCCTGGCCCTGCCCACCGGTGGGACCCGCTGTGGCACTAGCTGTGGAGGCTCTGGGCCGGGCACTGCCCGTGGACCTGCGGTTTGTCAGCTCCGAACTGGAAGGCGCCTGCTCTGAGTACCTGGCACCGCTGAGCGCTGTGGACCTCAAGCTGTACCATGACCCCGACCTGCTGTTAGGTCCCGGTTGCGTGTACCCTGCTGCCTCTCTCGCCCGCTTTGCCTCCCACTGGCGCCTTCCCCTGCTGACTGCGGGTGCTGTGGCCTCTGGTTTTTCGGCTAAGAATGACCATTATCGTACCCTGGTTCGCACTGGCCCCTCTGCTCCCAAGCTGGGTGAGTTTGTGGTGACACTACACGGGCACTTCAATTGGACTGCCCGTGCTGCCTTGCTCTACCTGGATGCTCGCACAGATGACCGGCCTCACTACTTCACCATCGAGGGCGTCTTTGAGGCCCTGCAGGCCAGCAACCTCAGTGTGCAGCACCAGGTGTATGCCCGAGAGCCAGGGGGCCCCGAGCAGGCCACCCACTTCATCCGCGCCAACGGGCGCATTGTGTATATCTGCGGCCCTCTGGAGATGCTGCATGAGATCCTGCTTCAGGCCCAGAGGGAGAATCTGACCAATGGGGATTATGTCTTCTTTTACCTGGATGTCTTTGGGGAGAGTCTCCGTGCAGGCCCCACAAGTGATACAGGCCGGCCCTGGCAGGACAATCGCACCCGGGAACAGGCCCAGGCCCTCAGAGAGGCCTTTCAGACTGTATTGGTGATCACGTACCGAGAACCCCCAAATCCTGAGTATCAGGAATTCCAGAATCGTCTGCTGATAAGAGCCCGGGAAGACTTTGGTGTGGAGCTGGCCCCTTCCCTGATGAACCTCATCGCTGGCTGCTTCTATGATGGGATCCTGCTATATGCTGAAGTCCTGAATGAGACAATACAGGAAGGAGGCACCCGGGAGGATGGACTTCGAATTGTGGAAAAGATGCAGGGACGAAGATATCACGGAGTAACTGGGCTGGTTGTCATGGACAAGAACAATGACCGAAATGGTCAACGCCATGCACCAGAAATTGCTCGTATGGCCCTAGCATTACTAGATGCAGTTTCTTCCTTTCGCATCCGCCACCGACCCCATGACCAGCTGAGGCTACGCATAGGGGTCCATACTGGGCCAGTCTGTGCTCGGGTTGTTCGCCTGAAGATGCCCCGTTATTGTCTTTTTGGAGACACAGTGAACACTGCTTCTCGAATGGAGTCTAATGGTCAAGCGCTGAAGATCCATGTCTCCTCTACCACCAAGGATGCCCTAGATGAGCTAGGATGCTTCCAGCTAGAGCTTCGGGGGGATGTGGAAATGAAGGGAAAAGGAAAGATGCGAACATACTGGCTCTTAGCAGAGCCGAAAGGACCTCCTGGACTCCTGTAAACCCCCATTCTTTCCAAGTCAGATACTCTTCTGCTGCTGGTACCTGCCTGGGCAATCGCCACCATGTCTGCACACACCAGAAATGGACATTTTCATATGCAATCGAAAACAGCCACAAAAAAACCTACCTTATATGGAAGTTGTAGCCCTCTGCAGCTCAGCCCTGTACATATATCTGTCCCTCTCTGGCTTGGTCCCCTTCCTCCCTACTTTCTGTAAATATCTGTATCTAAACCAGAATATTTTGGTCAAATATAAAACAATAATAAAAAAAGTTCTGATGTCATORF Start: ATG at 651ORF Stop: TAA at 2193SEQ ID NO:50514 aa MW at 56836.4 kDNOV 10a,MALPSLLLLVAALAGGVRPPGARNLTLAVVLPEHNLSYAWAWPRVGPAVALAVEALGRCG59199-01 ProteinALPVDLRFVSSELEGACSEYLAPLSAVDLKLYHDPDLLLGPGCVYPAASVARFASHWRSequenceLPLLTAGAVASGFSAKNDHYRTLVRTGPSAPKLGEFVVTLHGHFNWTARAALLYLDARTDDRPHYFTIEGVFEALQGSNLSVQHQVYAREPGGPEQATHFIRANCRIVYICGPLEMLHEILLQAQRENLTNGDYVFFYLDVFCESLRAGPTSDTGRPWQDNRTREQAQALREAFQTVLVITYREPPNPEYQEFQNRLLIRAREDFGVELGPSLMNLIAGCFYDGILLYAEVLNETIQEGGTREDGLRIVEKMQGRRYHGVTGLVVNDKNNDRNGQRHAPEIARMALALLDAVSSFRIRHRPHDQLRLRIGVHTGPVCAGVVGLKMPRYCLFGDTVNTASRMESNGQALKIHVSSTTKDALDELGCFQLELRGDVEMKCKGKMRTYWLLGERKGPPGLL


[0368] Further analysis of the NOV10a protein yielded the following properties shown in Table 10B.
53TABLE 10BProtein Sequence Properties NOV10aPSort0.8650 probability located in lysosome (lumen); 0.5517 prob-analysis:ability located in outside; 0.1000 probability located inendoplasmic reticulum (membrane); 0.1000 probabilitylocated in endoplasmic reticulum (lumen)SignalPCleavage site between residues 17 and 18analysis:


[0369] A search of the NOV10a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 10C.
54TABLE 10CGeneseq Results for NOV10aNOV10aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAR10867NPRB (Pro655, Glu656, Leu663,1 . . . 388386/388 (99%)0.0Phe664, Ala682) - Homo sapiens, 10471 . . . 388386/388 (99%)aa. [WO9100292-A, 10-JAN-1991]AAR10399Human Natriuretic Peptide Receptor B -1 . . . 388386/388 (99%)0.0Homo sapiens, 1047 aa. [WO9100292-1 . . . 388386/388 (99%)A, 10-JAN-1991]AAR38863GC-B - Rattus rattus, 1025 aa.23 . . . 388 352/366 (96%)0.0[US5237051-A, 17-AUG-1993]1 . . . 366357/366 (97%)AAR38862GC-A - Rattus rattus, 1029 aa.24 . . . 389 169/377 (44%)7e−83[US5237051-A, 17-AUG-1993]2 . . . 373227/377 (59%)ABB11783Human ANP-A receptor homologue,6 . . . 388171/397 (43%)2e−79SEQ ID NO:2153 - Homo sapiens,30 . . . 418 227/397 (57%)1075 aa. [WO200157188-A2, 09-AUG-2001]


[0370] In a BLAST search of public sequence databases, the NOV10a protein was found to have homology to the proteins shown in the BLASTP data in Table 10D.
55TABLE 10DPublic BLASTP Results for NOV10aNOV10aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueP20594Atrial natriuretic peptide receptor B1 . . . 388386/388 (99%)0.0precursor (ANP-B) (ANPRB) (GC-B)1 . . . 388386/388 (99%)(Guanylate cyclase) (EC 4.6.1.2) (NPR-B)(Atrial natriuretic peptide B-type receptor) -Homo sapiens (Human), 1047 aa.P16067Atrial natriuretic peptide receptor B1 . . . 388376/388 (96%)0.0precursor (ANP-B) (ANPRB) (GC-B)1 . . . 388382/388 (97%)(Guanylate cyclase) (EC 4.6.1.2) (NPR-B)(Atrial natriuretic peptide B-type receptor) -Rattus norvegicus (Rat), 1047 aa.P46197Atrial natriuretic peptide receptor B1 . . . 388376/388 (96%)0.0precursor (ANP-B) (ANPRB) (GC-B)1 . . . 388381/388 (97%)(Guanylate cyclase) (EC 4.6.1.2) (NPR-B)(Atrial natriuretic peptide B-type receptor) -Bos taurus (Bovine), 1047 aa.Q9PWG9GUANYLYL CYCLASE-2 - Xenopus25 . . . 389 233/372 (62%)e−133laevis (African clawed frog), 1082 aa.59 . . . 425 291/372 (77%)Q9Y117C-TYPE NATRIURETIC PEPTIDE6 . . . 389197/395 (49%)e−105RECEPTOR PRECURSOR - Squalus8 . . . 398258/395 (64%)acanthias (Spiny dogfish), 1056 aa.


[0371] PFam analysis indicates that the NOV10a protein contains the domains shown in the Table 10E.
56TABLE 10EDomain Analysis of NOV10aIdentities/SimilaritiesNOV10afor theMatchMatchedExpectPfam DomainRegionRegionValueANF_receptor: domain 1 of 1 21 . . . 391121/427 (28%)5.9e−123322/427 (75%)guanylate_cyc: domain 1 of 1376 . . . 505 65/157 (41%)6.8e−54 110/157 (70%)



Example 11

[0372] The NOV11 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 11A.
57TABLE 11ANOV11 Sequence AnalysisSEQ ID NO:512372 bpNOV11a,TCCCATTTGACTCCATTTTCTTTGGTCAAAGGCTTCCTTATTCATGGGACCTGCCTGGCG59249-01 DNAGTCCAGGACCCCTTGACAGGTGCTCTCTGGCTGCCTGTCCTCTGGGCACTCTTGTCCCSequenceAGGTCTATTGTTTTCATGACCCACCAGGATGGCGCTTCACTTCCTCAGAAATTGTGATCCCCAGGAAAGTGCCCCACAAGAGGGGTGGAGTTGAGATGCCAGACCAGCTCTcTTACAGCATGCGTTTCCGGGGCCAAAGACACGTGATTCACATGAAGCTCAAGAAGAACATGATGCCCAGACATTTACCTGTTTTTACTGATAATGACCAAGGGGCCATGCAGGAGAACTACCCTTTTGTCCCACGAGACTGTTACTATGACTGCTACCTGGAAGGGGTTCCTGGGTCTAGCATGCGTTTCCGGGGCCAAAGACACGTGATTCACATGAAGCTCAAGAAGAACATGATGACTTACGAAATCAAACACCTGGAGGCTTCTTCCAAATTTGAGCATGTAGTATCTCTGCTTGTGTCAGAAGAAAGACCAGGAGAGGCTAGTAGATGTAAGACTGAAGGGCAAGAGATAGATCAAGAATCTGAAAAGGTAAAACTGGCTGAAACTCCCAGAGCAGGCCACGTTTATTTGTGGACGCATCATAGAAAAAACTTGAAAATTCACTACACGGTTACTCGTGGATTATTCATGCGGAACCCTAATGTGTCACATATAATAGAGAATGTAGTGATTATTAACAGCATCATACATACCATTTTCAAACCAGTTTATTTAAATGTCTATATATGTGTTTTGTGCATATGGAATCAAAAGGATGCACTACTATTTTCTGCTAGCAGGCCAGGCCACGTTGCTGTAGAACTGTTTGGTGTGTCGAAATATCACAATTTGTATTCACAAATTTCACATGATACCTCAGTTGTTTTTACATCAAATCGACTTGGAAACAGTGAGTGTTATGCCAGCTTTGATGGAATATGCACCCCCAACTGGGGAGCAATGTTTGTGTATATAATGAGGTATCACCTATTTAGGGGGGCATGTGTTACAGCACATGCACTAGGTCATAACATGGGCTTGAGACATGATTCTGTTGGTTGTTATTGTTTTCGACGAACCAACTGTCTCATGAGCAATTGTTCTTATGAGATAATTCAACGCAAGTTTAATCAATGGGATCCTTGTTTGAGTGCTCCAAATGTTCCATACACTAATTTTCCATACGTAGCTCCTCGTTGTGGAGACAAGATCAAAAATCAGAGGGAAGAATGTGACTGTGGCTCCCTTAAAGATTGTGCCAGTGATAGATGTTGTGAGACCTCTTGTACCCTTTCTCTTGGCAGTGTTTGCAATACAGGACTTTGCTGCCATAAGTGTAAATATGCTGCCCCTGGAGTGGTTTGCAGAGACTTGGGTGGTATATGTGATCTACCGGAATACTGTGATGGGAAAAAGGAAGAGTGTCCAAATGACATCTACATCCAGGATGGAACCCCATGTTCAGCAGTATCTGTTTGTATAACAGGAAACTGCAGTGACCGTGATATGCAGTGTCAAGCCCTTTTTGGCTACCAAGTGAAACACCGTTCCCCAGCGTGCTATCGAAAATTGAATAGGATTGGTAACCGATTTGGAAACTGTGGGGTTATTCTACGGCGACCGGGAAGTACACCTTTTCCATGTGAAGAAGATGATGTTTTTTGTGGAATGTTGCACTGTAGCGGTGTCAGCCACATTCCCGGTGGAGGTGAGCACACTACATTTTGTAATATATTAGTACACGACATAAAAGAAGAAAAATGCTTTGGCTATGAAGCACACCAGGGGACAGACTTGCCAGAAATGGGGCTGGTAGTGGATGGTGCAACCTGTGGCCCAGGGAGCTACTGTCTTAAACGCAATTGTACTTTTTATCAAGACCTGCATTTTGAGTGTGATCTTAAAACATGCAATTACAAAGGAGTATGTAACAACAAAAAACATTGTCATTGTCTGCATGAGTGGCAACCACCAACATGTGAACTGAGAGGAAAAGGAGGTAGTATAGATAGTGGCCCTCTACCTGACAAACAATATCGTATTGCAGGCAGCATACTTGTAAATACAAACCGAGCACTAGTTTTAATATGTATTCGTTACATCCTTTTTGTGGTTTCGCTTCTCTTTGGTGGCTTTTCACAAGCAATACAATGTTAGGGAAGAGAAAGCAAAAGAGCCCACACAATGGAGTAAATTACATTGACACTTACTGGCAGATATAATCAATAGTCACTCTGACAATTACATCATCTTTTAGCAATTCTCATGTCATCTTGAAATAAAATCACTTGGCAATTTAAAAAGGTCTGTGTGTTTAAATORF Start: ATG at 44ORF Stop: TAG at 2207SEQ ID NO:52721 aa MW at 81098.2 kDNOV11a,MGPAWVQDPLTGALWLPVLWALLSQVYCFHDPPGWRFTSSEIVIPRKVPHKRGGVEMPCG59249-01 ProteinDQLSYSMRFRGQRHVIHMKLKKNMMPRHLPVFTDNDQGANQENYPFVPRDCYYDCYLESequenceGVPGSAATLDTCRGGLHGMLQVDDLTYEIKHLEASSKFEHVVSLLVSEERPGEASRCKTEGEEIDQESEKVKLAETPRAGHVYLWRHHRKNLKIHYTVTRGLFMRNPNVSHIIENVISHDTSVVFTSNRLGNSECYASFDGICTPNWGANFVYIMRYHLFRGACVTAHALGHNMGLRHDSVGCYCFRRTNCLMSNCSYEIIQRKFNQWDPCLSAPNVPYTNFPYVAPRCGDKIKNQREECDCGSLKDCASDRCCETSCTLSLGSVCNTGLCCHKCKYAAPGVVCRDLGGICDLPEYCDGKKEECPMDTYIQDGTPCSAVSVCIRCNCSDRDMQCQALFGYQVKDGSPACYRKLNRIGNRFGNCGVILRRGGSRPFPCEEDDVFCGMLHCSGVSHIPGGGEHTTFCNILVHDIKEEKCFGYEAHQGTDLPEMGLVVDGATCGPGSYCLKRNCTFYQDLHFECDLKTCNYKGVCNNKKHCHCLHEWQPPTCELRGKGGSIDSGPLPDKQYRIAGSILVNTNRALVLICIRYILFVVSLLFGGFSQAIQCSEQ ID NO:532429 bpNOV11b,TCCCATTTGACTGCATTTTCTTTGGTCAAAGGCTTCCTTATTCATGGGACCTGCCTGGCG59249-02 DNAGTCCAGGACCCCTTGACAGGTGCTCTCTGGCTGCCTGTCCTCTGGGCACTCTTGTCCCSequenceAGGTCTATTGTTTTCATGACCCACCAGGATGGCGCTTCACTTCCTCAGAAATTGTGATCCCCAGGAAAGTGCCCCACAAGAGGGGTGGAGTTGAGATGCCAGACCAGCTCTCTTACAGCATGCGTTTCCGGGGCCAAAGACACGTGATTCACATGAAGCTCAAGAAGAACATGATGCCCAGACATTTACCTGTTTTTACTGATAATGACCAAGGGGCCATGCAGGAGAACTACCCTTTTGTCCCACCACACTCTTACTATGACTGCTACCTGGAAGGGGTTCCTGGGTCTGCGGCCACATTGGACACCTGCCGTGGAGGTCTGCATGGCATGCTGCAGCTGGATGACTTGACTTACGAAATCAAACCCCTGGAGGCTTCTTCCAAATTTGAGCATGTAGTATCTCTGCTTGTGTCAGAAGAAACACCAGGAGAGGCTAGTGGATGTATGACTGAAGGGGAAGAGATAGATCAAGAATCTGAAAAGGTAAAACTGGCTGAAACTCCCAGAGCAGGCCACGTTTATTTGTGGAGGCATCATAGAAAAAACTTGAAAATTCACTACACGGTTACTCGTGGATTATTCATGCGGAACCCTAATGTGTCACATATAATAGAGAATGTAGTGATTATTAACAGCATCATACATACCATTTTCAAACCAGTTTATTTAAATGTCTATATATGTGTTTTGTGCATATGGAATCAAAAGGATGCAGTACTATTTTCTGCTAGCAGGCCGGCCCACGTTGCTGTAGAACTGTTTGGTGTGTGGAAATATCACAATTTGTATTCAGAGATTTCACATGATGCCTCAGTTGTTTTTACATCAAATCGACTTGGAAACAGTGAGTGTTATGCCAGCTTTGATGGAATATGCACCCCCAACTGGGGAGCAATGTTTGTGTATATAATGAGGTATCACCTATTTAGGGGGGCATGTCTTACAGCACATGCACTAGGTCATAACATGGGCTTGAGACATGATTCTGTTGGTTGTTATTGTTTTCGACGAACCAACTATCTCATGGCTCCTGTTCCTGATCTTAATGATATGATGAGCAATTGTTCTTATGAGATAATTCAACGCAAGTTTAATCAATGGGATCCTTGTTTGAGTGCTCCAAATGTTCCATACACTAATTTTCCATACGTAGCTCCTCGTTGTGGAGACAAGATCAAAAATCAGAGGGAAGAATGTGACTGTGGCTCCCTTAAAGATTGTGCCAGTGATAGATGTTGTGAGACCTCTTGTACCCTTTCTCTTGGCAGTGTTTGCAATACAGGACTTTGCTGCCATAAGTGTAAATATGCTGCCCCTGGAGTGGTTTGCAGAGACTTGGGTGGTATATGTGATCTACCGGAATACTGTGATGGGAAAAAGGAAGAGTGTCCAAATGACATCTACATCCAGGATGGAACCCCATGTTCAGCAGTATCTGTTTGTATAAGAGGAAACTGCAGTGACCGTGATATGCAGTGTCAAGCCCTTTTTGGCTACCAAGTGAAAGACGGTTCCCCAGCGTGCTATCGAAAATTGAATAGGATTGGTAACCGATTTGGAAACTGTGGGGTTATTCTACGGCGAGGGGGAAGTAGACCTTTTCCATGTGAAGAAGATGATGTTTTTTGTGGAATGTTGCACTGTAGCGGTGTCAGCCACATTCCCGGTGGAGGTGAGCACACTACATTTTGTAATATATTAGTACACGACATAAAAGAAGAAAAATCCTTTGGCTATGAAGCACACCAGGGGACAGACTTGCCAGAAATGGGGCTGGTAGTGGATGGTGCAACCTGTGGCCCAGGGAGCTACTGTCTTAAACGCAATTGTACTTTTTATCAAGACCTGCATTTTGAGTGTGATCTTAAAACATGCAATTACAAAGGAGTATGTAGCAACAAAAAACATTGTCATTGTCTGCATGAGTGGCAACCACCAACATGTGAACTGAGAGGAAAAGGAGGTAGTATAGATAGTCGCCCTCTACCTGACAAACAATATCGTATTGCAGGCAGCATACTTGTAAATACAAACCGAGCACTAGTTTTAATATGTATTCGTTACATCCTTTTTGTGGTTTCGCTTCTCTTTGGTGGCTTTTCACAAGCAATACAATGTTAGGGAAGAGAAAGGAAAAGAGCCCACACAATGGAGTAAATTACATTGACACTTACTGGGAGATATAATCAATAGTCACTCTGACAATTACATCATCTTTTAGCAATTCTGATGTCATCTTGAAATAAAATCACTTGGCAATTTAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGGORF Start: ATG at 44ORF Stop: TAG at 2237SEQ ID NO:54731 aa MW at 82049.3 kDNOV11b,MGPAWVQDPLTGALWLPVLWALLSQVYCFHDPPGWRFTSSEIVIPRKVPHKRGGVEMPCG59249-02 ProteinDQLSYSMRFRGQRHVIHMKLKKNMMPRHLPVFTDNDQGAMQENYPFVPRDCYYDCYLESequenceGVPGSAATLDTCRGGLHGMLQVDDLTYEIKPLEASSKFEHVVSLLVSEERPGEASGCMTEGEEIDQESEKVKLAETPRAGHVYLWRHHRKNLKIHYTVTRGLFMRNPNVSHIIENVVIINSIIHTIFKPVYLNVYICVLCIWNQKDAVLFSASRPGHVAVELFGVWKYHNLYSEISHDASVVFTSNRLGNSECYASFDGICTPNWGAMFVYIMRYHLFRGACVTAHALGHNMGLRHDSVGCYCFRRTNYLMAPVPDLNDMNSNCSYEIIQRKFNQWDPCLSAPNVPYTNFPYVAPRCGDKIKNQREECDCGSLKDCASDRCCETSCTLSLGSVCNTGLCCHKCKYAAPGVVCRDLGGICDLPEYCDGKKEECPNDIYIQDGTPCSAVSVCIRGNCSDRDMQCQALFGYQVKDGSPACYRKLNRIGNRFGNCGVILRRGGSRPFPCEEDDVFCGMLHCSGVSHIPGGGEHTTFCNILVHDIKEEKCFGYEAHQGTDLPEMGLVVDGATCGPGSYCLKRNCTFYQDLHFECDLKTCNYKGVCSNKKHCHCLHEWQPPTCELRGKGGSIDSGPLPDKQYRIAGSILVNTNRALVLICIRYILFVVSLLFGGFSQAIQC


[0373] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 11B.
58TABLE 11BComparison of NOV11a against NOV11b and NOV11c.ProteinNOV11a Residues/Identities/SequenceMatch ResiduesSimilarities for the Matched RegionNOV11b1 . . . 721698/731 (95%)1 . . . 731699/731 (95%)


[0374] Further analysis of the NOV11a protein yielded the following properties shown in Table 11C.
59TABLE 11CProtein Sequence Properties NOV11aPSort:0.8056 probability located in plasma membrane; 0.2800 prob-analysis:ability located in endoplasmic reticulum (membrane); 0.2000probability located in lysosome (membrane); 0.1000probability located in endoplasmic reticulum (lumen)SignalPCleavage site between residues 29 and 30analysis:


[0375] A search of the NOV11a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 11D.
60TABLE 11DGeneseq Results for NOV11aNOV11aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAY17413sapiens, 726 aa. [WO9923228-A1, 14-33 . . . 714378/704 (53%)e−135MAY-1999]AAY03223Amino acid sequence of the novel33 . . . 712250/704 (35%)e−134metalloprotease ADAM 16a - Homo33 . . . 714377/704 (53%)sapiens, 726 aa. [WO9907856-A1, 18-FEB-1999]AAB07741A snake venom protease (SVPH-1)29 . . . 681250/673 (37%)e−132polypeptide variant SVPH-1c - Homo27 . . . 671360/673 (53%)sapiens, 820 aa. [WO200043525-A2,27-JUL-2000]AAB07740A snake venom protease (SVPH-1)29 . . . 681250/673 (37%)e−132polypeptide variant SVPH-1b - Homo27 . . . 671360/673 (53%)sapiens, 787 aa. [WO200043525-A2,27-JUL-2000]AAB07739A snake venom protease (SVPH-1)29 . . . 681250/673 (37%)e−132polypeptide variant SVPH-1a - Homo27 . . . 671360/673 (53%)sapiens, 766 aa. [WO200043525-A2,27-JUL-2000]


[0376] In a BLAST search of public sequence databases, the NOV11a protein was found to have homology to the proteins shown in the BLASTP data in Table 11E.
61TABLE 11EPublic BLASTP Results for NOV11aNOV11aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ95LW7HYPOTHETICAL 52.8 KDA PROTEIN -271 . . . 719390/459 (84%)0.0Macaca fascicularis (Crab eating 2 . . . 460415/459 (89%)macaque) (Cynomolgus monkey), 474 aa.Q60815ADAM 4 PROTEIN - Mus musculus279 . . . 719241/454 (53%)e−151(Mouse), 473 aa (fragment). 1 . . . 449309/454 (67%)Q28484TESTICULAR METALLOPROTEASE- 19 . . . 713268/711 (37%)e−137LIKE, DISINTEGRIN-LIKE, 19 . . . 710378/711 (52%)CYSTEINE-RICH PROTEIN IVA -Macaca fascicularis (Crab eatingmacaque) (Cynomolgus monkey), 732 aa.O43506ADAM 20 precursor (EC 3.4.24.-) (A 33 . . . 712250/704 (35%)e−134disintegrin and metalloproteinase domain 33 . . . 714377/704 (53%)20) - Homo sapiens (Human), 726 aa.Q9UKF5ADAM 29 precursor (A disintegrin and 29 . . . 681250/673 (37%)e−131metalloproteinase domain 29) - Homo 27 . . . 671360/673 (53%)sapiens (Human), 820 aa.


[0377] PFam analysis indicates that the NOV11a protein contains the domains shown in the Table 11F.
62TABLE 11FDomain Analysis of NOV11aIdentities/NOV11aSimilaritiesMatchfor the MatchedExpectPfam DomainRegionRegionValuePep_M12B_propep: 75 . . . 19134/119 (29%)2.2e−29domain 1 of 191/119 (76%)Reprolysin: domain 1 of 1206 . . . 39251/210 (24%)1.7e−06115/210 (55%) disintegrin: domain 1 of 1409 . . . 484 30/77 (39%)3.3e−15 50/77 (65%)EGF: domain 1 of 1635 . . . 663 8/47 (17%)2.7 20/47 (43%)



Example 12

[0378] The NOV12 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 12A.
63TABLE 12ANOV12 Sequence AnalysisSEQ ID NO:553874 bpNOV12a,ACAACTGTGATGATCCACTAGCATCCCTGCTCTCTCCAATGGCTTTTTCCAGTTCCTCCG58577-01 DNAAGACCTCACTGGCACTCACAGCCCAGCTCAACTCAACTGGAGAGTTGGAACTGGCGGTSequenceTGGTCCCCACCAGATTCCAATGCTCAACAGTGGCTCCAGATGGACCTGGGAAACAGAGTAGAGATTACAGCAGTGGCCACGCAGGGAAGATACGGAAGCTCTGACTGGGTGACGAGTTACAGCCTGATGTTCAGTGACACAGGACGCAACTGGAAACAGTACAAACAAGAAGACAGCATCTGGACCTTTGCAGGAAACATGAATGCTGACAGCGTGGTGCACCACAAGCTATTGCACTCAGTGAGAGCCCGATTTGTTCGCTTTGTGCCCCTGGAATGGAATCCCAGTGGGAAGATTGGCATCAGACTCGAGGTCTACGGATGTTCCTATAATGTTGCTGACTTTGATGGCCGAAGCTCACTTCTGTACAGGTTCAATCAGAAGTTGATGAGTACTCTCAAAGATGTGATCTCCCTGAAGTTCAAGAGCATGCAAGGAGATGGGGTCCTGTTCCATGGAGAAGGTCAGCGTGGAGACCACATCACCTTGGAACTCCAGAAGGGGAGGCTCGCCCTACACCTCAATTTGGGTGACAGCAAAGCGCGGCTCAGCAGCAGCTTGCCCTCTGCCACCCTGCGCAGCCTCCTGGATGACCACCACTGGCACTCGGTCCTCATTGAGCGGGTGGGCAAGCAGGTGAACTTCACGGTGGACAAGCACACACAGCACTTCCGCACCAAGGGCGAGACGGATGCCTTAGACATTGACTATGAOCTTAGTTTTGGAGGAATTCCACTACCAGGAAAACcTGGGACCTTTTTAAAGAAAAACTTCCATGGATGCATCGAAAACCTTTACTACAATGGAGTAAACATAATTGACCTGGCTAAGAGACGAAAGCATCAGATCTATACTGTGGGCAATGTCACTTTTTCCTGCTCCGAACCACAGATTGTGCCCATCACATTTGTCAACTCCAGCGGCAGCTATTTGCTGCTGCCCGGCACCCCCCAAATTGATGGGCTCTCAGTGAGTTTCCAGTTTCGAACATGGAACAAGGATGGTCTCCTTCTGTCCACAGAGCTGTCTGAGGGCTCGGGAACCCTGCTGCTGAGCCTGGAGGGTGGAATCCTGAGACTCGTGATTCAGAAAATGACAGAACGCGTAGCTGAAATCCTCACAGGCAGCAACTTGAATGATCGCCTGTGGCACTCGGTTAGCATCAACGCCAGGAGGAACCGCATCACGCTCACTCTGGATGATGAAGCAGCACCCCCGGCTCCAGACAGCACTTGGGTGCAGATTTATTCTGGAAATAGCTACTATTTTGGAGGTTGCCCCGACAATCTCACCGATTCCCAATGTTTAAATCCCATTAAGGCTTTCCAAGGCTGCATGAGGCTCATCTTTATTGATAACCAGCCCAAGGACCTCATTTCAGTTCAGCAAGGTTCCCTGGGCAATTTTAGTGATTTACACATTGATCTGTGTAGCATCAAAGACAGGTGTTTGCCAAACTACTGTGAACATGGAAGGAAGTTGTTCCCAGTCCTGGACTACCTTTTCTATTGTAACTGCAGTGACACAAGTTACACTGGTGCCACCTGCCACAACTCCATCTACGAGCAATCCTGCGAGGTGTACAGGCACCAGGGGAATACAGCCGGCTTCTTCTACATCGACTCAGATGGCAGCGGCCCACTGGGACCTCTCCAGGTGTACTGCAATATCACTCAGGACAACATCTGGACATCAGTGCAGCACAACAATACAGAGCTGACCCGAGTGCGGGGCGCTAACCCTGAGAAGCCCTATGCCATGGCCTTGGACTACGGGGGCAGCATGGAACAGCTGGAGGCCGTGATCGACGGCTCTGAGCACTGTGAGCAGGAGGTGGCCTACCACTGCAGGAGGTCCCGCCTGCTCAACACGCCGGATGGAACACCATTTACCTGGTGGATTGGGCGGTCCAATGAAAGGCACCCTTACTGGGGAGGTTCCCCTCCTGGGGTCCAGCAGTGTGAGTGTGGCCTAGACGAGAGCTGCCTGGACATTCAGCACTTTTGCAATTGCGACGCTGACAAGGAAAATGATACTGGCTTTCTTTCCTTCAAAGACCACTTGCCTGTCACTCAGATAGTTATCACTGATACCGACAGATCAAACTCAGAAGCCGCTTGGAGAATTGGTCCCTTGCGTTGCTATGGTGACCCACCCTTCTGGAACGCCGTCTCATTTTATACAGAAGCCTCTTACCTCCACTTTCCTACCTTCCATGCGGAATTCAGTGCCGATATTTCCTTCTTTTTTAAAACCACAGCATTATCCGGAGTTTTCCTAGAAAATCTTGGCATTAAAGACTTCATTCGACTCGAAATAAGCTCTCCTTCAGAGATCACCTTTGCCATCGATGTTGGGAATGGTCCTGTGGAGCTTGTAGTCCAGTCTCCTTCTCTTCTGAATGACAACCAATGGCACTATGTCCGGGCTGAGAGGAACCTCAAGGAGACCTCCCTGCAGGTGGACAACCTTCCAAGGAGCACCAGGGAGACGTCGGAGGAGGGCCATTTTCGACTGCAGCTGAACAGCCAGTTGTTTGTAGGCGGAACGTCATCCAGACAGAAAGGCTTCCTAGGATGCATTCGCTCCTTACACTTGAATGGACAGAAAATGGACCTGGAAGAGAGGGCAAAGGTCACATCTGGAGTCAGGCCAGGCTGCCCCGGCCACTGCAGCAGCTACGGCAGCATCTGCCACAACGGGGGCAAGTGTGTGGAGAAGCACAATGGCTACCTGTGTGATTGCACCAATTCACCTTATGAAGGGCCCTTTTGCAAAAAAGAGGTTTCTCCTGTTTTTGAGGCTGGCACGTCGGTTACTTACATGTTTCAAGAACCCTATCCTGTGACCAAGAATATAAGCCTCTCATCCTCAGCTATTTACACAGATTCAGCTCCATCCAAGGAAAACATTGCACTTAGCTTTGTGACAACCCAGGCACCCAGTCTTTTGCTCTTTATCAATTCTTCTTCTCAGGACTTCGTGGTTGTTCTGCTCTGCAAGAATGGAAGCTTACAGGTTCCCTATCACCTAAACAAGGAAGAAACCCATGTATTCACCATTGATGCAGATAACTTTGCTAACAGAAGGATGCACCACTTGAAGATTAACCGAGAGGGAAGAGAGCTTACCATTCAGGTACCTTCCTTACTTTCTCCTGCTTCAGCCAATATGGACCAGCAACTTCGACTCAGTTATAACTTCTCTCCGGAAGTAGAGTTCAGGGTTATAAGGTCACTCACCTTGGGCAAAGTCACAGAGAATCTTGGTTTGGATTCTGAAGTTGCTAAAGCAAATGCCATGGGTTTTGCTGGATGCATGTCTTCCGTCCAGTACAACCACATAGCACCACTGAAGGCTGCCCTGCGCCATGCCACTGTCGCGCCTCTCACTGTCCATGGGACCTTGACGGAATCCAGCTGTGGCTTCATGGTGGACTCAGATGTGAATGCAGTGACCACGGTGCATTCTTCATCAGATCCTTTTGGGAAGACAGATGAGCGGGAACCACTCACAAATGCTGTTCGAAGTGATTCGGCAGTCATCCGAGGGGTGATAGCAGTGGTGATATTCATCATCTTCTGTATCATCGGCATCATGACCCGGTTCCTCTACCAGCACAAGCAGTCACATCGTACGAGCCAGATGAAGGAGAAGGAATATCCAGAAAATTTGGACAGTTCCTTCAGAAATGAAATTGACTTGCAAAACACAGTGAGCGAGTGTAAACGGGAATATTTCATCTGAGAAACTGCAGGORF Start: AAC at 3ORF Stop: TGA at 3861SEQ ID NO:561286 aa MW at 143343.7 kDNOV12a,NCDDPLASLLSPMAFSSSSDLTGTHSPAQLNWRVGTGGWSPADSNAQQWLQMDLGNRVCG58577-01 ProteinEITAVATQGRYGSSDWVTSYSLMFSDTGRNWKQYKQEDSIWTFAGNMNADSVVHHKLLSequenceHSVRARFVRFVPLEWNPSGKIGMRVEVYGCSYNVADFDGRSSLLYRFNQKLMSTLKDVISLKFKSMQGDGVLFHGEGQRGDHITLELQKGRLALHLNLGDSKARLSSSLPSATLGSLLDDQHWHSVLIERVGKQVNFTVDKHTQHFRTKGETDALDIDYELSFGGIPVPGKPGTFLKKNFHGCIENLYYNCVNIIDLAKRRKHQIYTVGNVTFSCSEPQIVPITFVNSSGSYLLLPGTPQIDGLSVSFQFRTWNKDGLLLSTELSEGSGTLLLSLEGGILRLVIQKNTERVAEILTGSNLNDGLWHSVSINARRNRITLTLDDEAAPPAPDSTWVQIYSCNSYYFGGCPDNLTDSQCLNPIKAFQGCMRLIFIDNQPKDLISVQQGSLGNFSDLHIDLCSIKDRCLPNYCEHGRKLFPVLDYLFYCNCSDTSYTGATCHNSIYEQSCEVYRHQGNTAGFFYIDSDGSGPLGPLQVYCNITEDKIWTSVQHNNTELTRVRGANPEKPYAMALDYGGSMEQLEAVIDGSEHCEQEVAYHCRRSRLLNTPDGTPFTWWIGRSNERHPYWGGSPPGVQQCECGLDESCLDIQHFCNCDADKENDTGFLSFKDHLPVTQIVITDTDRSNSEAAWRIGPLRCYGDRRFWNAVSFYTEASYLHFPTFHAEFSADISFFFKTTALSGVFLENLGIKDFIRLEISSPSEITFAIDVGNGPVELVVQSPSLLNDNQWHYVRAERNLKETSLQVDNLPRSTRETSEEGHFRLQLNSQLFVGGTSSRQKGFLGCIRSLHLNGQKMDLEERAKVTSGVRPGCPGHCSSYGSICHNGGKCVEKHNGYLCDCTNSPYEGPFCKKEVSAVFEAGTSVTYMFQEPYPVTKNISLSSSAIYTDSAPSKENIALSFVTTQAPSLLLFINSSSQDFVVVLLCKNGSLQVRYHLNKEETHVFTIDADNFANRRMHHLKINREGRELTIQVPSLLSPASANMDQQLRLSYNFSPEVEFRVIRSLTLGKVTENLGLDSEVAKANANGFAGCMSSVQYNHIAPLKAALRHATVAPVTVHGTLTESSCGFMVDSDVNAVTTVHSSSDPFGKTDEREPLTNAVRSDSAVIGGVIAVVIFIIFCIIGIMTRFLYQHKQSHRTSQMKEKEYPENLDSSFRNEIDLQNTVSECKREYFISEQ ID NO:57429 bpNOV12b,GGATCCCCACTAGCATCCCTGCTCTCTCCAATGGCTTTTTCCAGTTCCTCAGACCTCA174307971 DNACTGGCACTCACAGCCCAGCTCAACTCAACTGGAGAGTTGGAACTGGCGGTTGGTCCCCSequenceACCAGATTCCAATGCTCAACAGTGGCTCCAGATGGACCTGGGAAACAGAGTAGAGATTACAGCAGTGGCCACGCAGGGAAGATACGGAAGCTCTGACTGGGTGACGAGTTACAGCCTGATGTTCAGTGACACAGGACGCAACTGGAAACAGTACAAACAAGAAGACAGCATCTGGACCTTTGCAGGAAACATGAATGCTGACAGCGTGGTGCACCACAAGCTATTGCACTCAGTGAGAGCCCGATTTGTTCGCTTTGTGCCCCTGGAATCGAATCCCAGTGGGAAGATTGGCATGAGAGTCGAGGTCCTCGAGORF Start: GGA at 1ORF Stop: al at 430SEQ ID NO:58143 aa MW at 15889.6 kDNOV12b,GSPLASLLSPMAFSSSSDLTGTHSPAQLNWRVGTGGWSPADSNAQQWLQMDLGNRVEI174307971 ProteinTAVATQGRYGSSDWVTSYSLMFSDTGRNWKQYKQEDSIWTFAGNMNADSVVHHKLLHSSequenceVRARFVRFVPLEWNPSGKIGMRVEVLESEQ ID NO:59429 bpNOV12c,GGATCCCCACTAGCATCCCTGCTCTCTCCAATCGCTTTTTCCAGTTCCTCAGACCTCA174307975 DNACTGGCACTCACAGCCCAGCTCAACTCAACTGGAGAGTTGGAACTGGCGGTTGGTCCCCSequenceAGCAGATTCCAATGCTCAACAGTGGCTCCAGATGGACCTGGGAAACAGAGTAGAGATTACAGCAGTGGCCACGCAGGGAAGGTACGGAAGCTCTGACTGGGTGACGAGTTACAGCCTGATGTTCAGTGACACAGGACGCAACTGGAAACAGTACAAACAAGAAGACAGCATCTGGACCTTTGCAGGAAACATGAATGCTGACAGCGTCGTGCACCACAAGCTATTGCACTCAGTGAGAGCCCGATTTGTTCGCTTTGTGCCCCTGGAATGGAATCCCAGTGGGAAGATTGGCATOAGAGTCGAGGTCCTCGAGORF Start: GGA at 1ORF Stop: al at 430SEQ ID NO:60143 aa MW at 15889.6 kDNOV12c,GSPLASLLSPMAFSSSSDLTGTHSPAQLNWRVGTGGWSPADSNAQQWLQMDLGNRVEI174307971 ProteinTAVATQGRYGSSDWVTSYSLMFSDTGRNWKQYKQEDSIWTFAGNMNADSVVHHKLLHSSequenceVRARFVRFVPLEWNPSGKIGMRVEVLESEQ ID NO:61429 bpNOV12d,GGATCCCCACTAGCATCCCTGCTCTCTCCAATCGCTTTTTCCAGTTCCTCAGACCTCA174307979 DNACTGGCACTCACAGCCCAGCTCAACTCAACTGGAGAGTTGGAACTGGCGGTTGGTCCCCSequenceAGCAGATTCCAATGCTCAACAGTGGCTCCAGATGGACCTGGGAAACAGAGTAGAGATTACAGCAGTGGCCACGCAGGGAAGATACGGAAGCTCTGACTGGGTGACGAGTTACAGCCTGATGTTCAGTGACACAGGACGCAACTGGAAACAGTACAAACAAGAAGACAGCATCTGGACCTTTGCAGGAAACATGAATGCTGACAGCGTGGTGCACCACAAGCTATTGCGCTCAGTGAGAGCCCGATTTGTTCGCTTTGTGCCCCTGGAATGGAATCCCACTGGGAAGATTGGCATGAGAGTCGAGGTCCTCGAGORF Start: GGA at 1ORF Stop: al at 430SEQ ID NO:62143 aa MW at 15908.7 kDNOV12d,GSPLASLLSPMAFSSSSDLTGTHSPAQLNWRVGTGGWSPADSNAQQWLQMDLGNRVEI174307979 ProteinTAVATQGRYGSSDWVTSYSLMFSDTGRNWKQYKQEDSIWTFAGNMNADSVVHHKLLRSSequenceVRARFVRFVPLEWNPSGKIGMRVEVLESEQ ID NO:63429 bpNOV12e,GGATCCCCACTAGCATCCCTGCTCTCTCCAATGGCTTTTTCCAGTTCCTCAGACCTCA174307983 DNACTGGCACTCACAGCCCAGCTCAACTCAACTGGAGAGTTGGAACTGGCGGTTGGTCCCCSequenceAGCAGATTCCAATGCTCAACAGTGGCTCCAGATGGACCTCGGAAACAGAGTAGAGATTACAGCAGTGGCCACGCAGGGAAGATACGGAAGCTCTGACTGGGTGACGAGTTACAGCCTGATGTTCAGTGACACAGGACGCAACTGGAAACAGTACAAACAGGAAGACAGCATCTGGACCTTTGCAGGAAACATGAATGCTGACAGCGTGGTGCACCACAAGCTATTGCACTCAGTGAGAGCCCGATTTGTTCGCTTTGTGCCCCTGGAATGGAATCCCAGTGGGAAGATTGGCATGAGAGTCCAGGTCCTCCAGORF Start: GGA at 1ORF Stop: al at 430SEQ ID NO:64143 aa MW at 15889.6 kDNOV12e,GSPLASLLSPMAFSSSSDLTGTHSPAQLNWRVGTGGWSPADSNAQQWLQMDLGNRVEI174307983 ProteinTAVATQGRYGSSDWVTSYSLMFSDTGRNWKQYKQEDSIWTFAGNMNADSVVHHKLLHSSequenceVRARFVRFVPLEWNPSGKIGMRVEVLESEQ ID NO:651429 bpNOV12f,GGATCCCCACTAGCATCCCTGCTCTCTCCAATGGCTTTTTCCAGTTCCTCAGACCTCA174307987 DNACTGGCACTCACAGCCCAGCTCAACTCAACTGGAGAGTTGGAACTGGCGGTTGGTCCCCSequenceAGCAGATTCCAATGCTCAACAGTGGCTCCAGATGGACCTGGGAAACAGAGTAGAGATTACAGCAGTGGCCACGCGGGGAAGATACGGAAGCTCTGACTGGGTGACGAGTTACAGCCTGATGTTCAGTGACACAGGACGCAACTGGAAACAGTACAAACAAGAAGACAGCATCTGGACCTTTGCAGGAAACATGAATGCTGACACCGTGGTGCACCACGAGCTATTGCACTCAGTGAGAGCCCGATTTGTTCGCTTTGTGCCCCTGGAATGGAATCCCAGTGGGAAGATTGGCATGAGAGTCGAGGTCCTCGAGORF Start: GGA at 1ORF Stop: al at 430SEQ ID NO:66143 aa MW at 15918.6 kDNOV12f,GSPLASLLSPMAFSSSSDLTGTHSPAQLNWRVGTGGWSPADSNAQQWLQMDLGNRVEI174307987 ProteinTAVATRGRYGSSDWVTSYSLMFSDTGRNWKQYKQEDSIWTFAGNMNADSVVHHELLHSSequenceVRARFVRFVPLEWNPSGKIGMRVEVLESEQ ID NO:67429 bpNOV12g,GGATCCCCACTAGCATCCCTGCTCTCTCCAATGGCTTTTTCCAGTTCCTCAGACCTCA174307996 DNACTGGCACTCACAGCCCAGCTCAACTCAACTGGAGAGTTGGAACTGGCGGTTGGTCCCCSequenceAGCAGATTCCAATGCTCAACAGTGGCTCCAGATGGACCTGGGAAACAGAGTAGAGATTACAGCAGTGGCCACGCAGGGAAGATACGGAAGCTCTGACTGGGTGACGAGTTACAGCCTGATGTTCAGTGACACAGGACGTAACTGGAAACAGTACAAACAAGAAGACAGCATCTGGACCTTTGCAGGAAACATGAATGCTGACAGCGTGGTGCACCACAAGCTATTGCACTCAGTGAGAGCCCGATTTGTTCGCTTTGTGCCCCTGGAATGGAATCCCAGTGGGAAGATTGGCATGAGAGTCGAGGTCCTCGAGORF Start: GGA at 1ORF Stop: al at 430SEQ ID NO:68143 aa MW at 15889.6 kDNOV12g,GSPLASLLSPMAFSSSSDLTGTHSPAQLNWRVGTGGWSPADSNAQQWLQMDLGNRVEI174307996 ProteinTAVATQGRYGSSDWVTSYSLMFSDTGRNWKQYKQEDSIWTFAGNNNADSVVHHKLLHSSequenceVRARFVRFVPLEWNPSGKIGMRVEVLESEQ ID NO:69429 bpNOV12h,GGATCCCCACTAGCATCCCTGCTCTCTCCAATGGCTTTTTCCAGTTCCTCAGACCTCA169894929 DNACTGGCACTCACAGCCCAGCTCAACTCAACTGGAGAGTTGGAACTGGCGGTTGGTCCCCSequenceAGCACATTCCAATGCTCAACAGTGGCTCCAGATGGACCTGGGAAGCAGAGTAGAGATTACAGCAGTGGCCACGCAGGGAAGATACGGAAGCTCTGACTGGGTGACGAGTTACAGCCTGATGTTCAGTGACACAGGACGCAACTGGAAACAGTACAAACAAGAAGACAGCATCTGGACCTTTGCAGGAAACATCAACGCTGACAGCGTGGTGCACCACAAGCTATTGCACTCAGTGAGAGCCCCGATTTGTTCGCTTTGTGCCCCTGGAATGGAATCCAGTGGGAAGATTGGCATGAGAGTCGAGGTCCTCGAGORF Start: GGA at 1ORF Stop: al at 430SEQ ID NO:70143 aa MW at 15862.6 kDNOV12h,GSPLASLLSPMAFSSSSDLTGTHSPAQLNWRVGTCGWSPADSNAQQWLQMDLGSRVEI169894929 ProteinTAVATQGRYGSSDWVTSYSLMFSDTGRNWKQYKQEDSIWTFAGNNNADSVVHHKLLHSSequenceVRARFVRFVPLEWNPSGKIGMRVEVLE


[0379] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 12B.
64TABLE 12BComparison of NOV12a against NOV12b through NOV12h.NOV12a Residues/Identities/SimilaritiesProtein SequenceMatch Residuesfor the Matched RegionNOV12b22 . . . 143122/122 (100%)20 . . . 141122/122 (100%)NOV12c22 . . . 143122/122 (100%)20 . . . 141122/122 (100%)NOV12d22 . . . 143121/122 (99%) 20 . . . 141121/122 (99%) NOV12e22 . . . 143122/122 (100%)20 . . . 141122/122 (100%)NOV12f22 . . . 143120/122 (98%) 20 . . . 141122/122 (99%) NOV12g20 . . . 141122/122 (100%)NOV12h22 . . . 143121/122 (99%) 20 . . . 141122/122 (99%) 


[0380] Further analysis of the NOV12a protein yielded the following properties shown in Table 12C.
65TABLE 12CProtein Sequence Properties NOV12aPSort0.7000 probability located in plasma membrane; 0.4467 prob-analysis:ability located in microbody (peroxisome); 0.3000 probabilitylocated in nucleus; 0.2000 probability located inendoplasmic reticulum (membrane)SignalPNo Known Signal Sequence Indicatedanalysis:


[0381] A search of the NOV12a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 12D.
66TABLE 12DGeneseq Results for NOV12aNOV12aResidues/Identities/GeneseqProtein/Organism/Length [PatentMatchSimilarities for theExpectIdentifier#, Date]ResiduesMatched RegionValueAAE07293Human neurexin-like protein #12 - 1 . . . 12861263/1291 (97%)0.0Homo sapiens, 1298 aa. 20 . . . 12981265/1291 (97%)[WO200158938-A2, 16-AUG-2001]AAE07282Human neurexin-like protein #1 - 1 . . . 12861261/1291 (97%)0.0Homo sapiens, 1307 aa. 29 . . . 13071263/1291 (97%)[WO200158938-A2, 16-AUG-2001]AAE07283Human neurexin-like protein #2 - 1 . . . 12861214/1291 (94%)0.0Homo sapiens, 1259 aa. 29 . . . 12591216/1291 (94%)[WO200158938-A2, 16-AUG-2001]AAE07294Human neurexin-like protein #13 -105 . . . 12861159/1187 (97%)0.0Homo sapiens, 1175 aa. 1 . . . 11751161/1187 (97%)[WO200158938-A2, 16-AUG-2001]AAE07291Human neurexin-like protein #10 - 1 . . . 797 749/802 (93%)0.0Homo sapiens, 839 aa.29 . . . 829 755/802 (93%)[WO200158938-A2, 16-AUG-2001]


[0382] In a BLAST search of public sequence databases, the NOV12a protein was found to have homology to the proteins shown in the BLASTP data in Table 12E.
67TABLE 12EPublic BLASTP Results for NOV12aNOV12aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueBAB83897CASPR5 - Homo sapiens (Human), 1 . . . 12861262/1291 (97%)0.01306 aa.29 . . . 13061264/1291 (97%)Q96MS7CDNA FLJ31966 FIS, CLONE1 . . . 925 912/930 (98%)0.0NT2RP7007925, WEAKLY SIMILAR29 . . . 957  914/930 (98%)TO HOMO SAPIENS CONTACTINASSOCIATED PROTEIN (CASPR)MRNA - Homo sapiens (Human), 963aa.AAL68839CELL RECOGNITION PROTEIN 1 . . . 1285 747/1293 (57%)0.0CASPR4 - Homo sapiens (Human),33 . . . 1310 961/1293 (73%)1311 aa.Q9C0A0Contactin associated protein-like 4 1 . . . 1285 747/1293 (57%)0.0precursor (Cell recognition molecule30 . . . 1307 961/1293 (73%)Caspr4) - Homo sapiens (Human), 1308aa.Q99P47Contactin associated protein-like 4 1 . . . 1285 725/1293 (56%)0.0precursor (Cell recognition molecule32 . . . 1309 955/1293 (73%)Caspr4) - Mus musculus (Mouse), 1310aa.


[0383] PFam analysis indicates that the NOV12a protein contains the domains shown in the Table 12F.
68TABLE 12FDomain Analysis of NOV12aIdentities/NOV12aSimilaritiesMatchfor the MatchedExpectPfam DomainRegionRegionValueF5_F8_type_C: 5 . . . 14348/167 (29%)  1e−41domain 1 of 1115/167 (69%) laminin_G: domain 1 of 4179 . . . 31140/168 (24%)3.6e−1193/168 (55%)laminin_G: domain 2 of 4366 . . . 49540/161 (25%)3.5e−1288/161 (55%)EGF: domain 1 of 2521 . . . 554 22/47 (47%)3.5TSPN: domain 1 of 1729 . . . 90835/225 (16%)8.5115/225 (51%) laminin_G: domain 3 of 4788 . . . 91044/164 (27%)4.5e−1592/164 (56%)EGF: domain 2 of 2929 . . . 963 14/47 (30%)0.0044 27/47 (57%)laminin_G: domain 4 of 41014 . . . 1085 20/87 (23%)0.0019 51/87 (59%)



Example 13

[0384] The NOV13 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 13A.
69TABLE 13ANOV13 Sequence AnalysisSEQ ID NO:7114109 bpNOV13a,TGTCGCTCAACGGGATGCCCCTGTACAACGACAGCTTCCATGAGATCTCACACAAGGGCG59237-01 DNACCGCCGCCACACGCTGGTACTCAAGACCATCCAGCGGGCTCATGCCGGCATAGTACGCSequenceGCCTCCTCCCTGAAGGTGTCGACCTCTGCCCGCCTGGAGGTCCGAGTGAAGCCCGTGGTGTTCCTGAAGGCGCTGGATGACCTGTCCGCAGAGGAGCGCGGCACCCTGGCCCTGCAGTGTGAAGTCTCTGACCCCGAGGCCCATGTGGTGTGGCGCAAAGATGGCGTGCAGCTGGGCCCCAGTGACAAGTATGACTTCCTGCACACGGCGGGCACGCGGGGGCTCGTGGTGCATGACGTGAGCCCTGAAGACGCCGGCCTGTACACCTGCCACGTGGGCTCCGAGGAGACCCGGGCCCGGGTCCGCGTGCACGATCTGCACGTGGGCATCACCAACAGGCTGAAGACAATGGAGGTGCTGGAAGGGGAAAGCTGCAGCTTTGAGTGCGTCCTGTCCCACGAGAGTGCCAGCGACCCGGCCATGTGGACAGTCGGTGGGAAGACAGTGGCCAGCTCCAGCCGCTTCCAGGCCACACGTCAGGGCCGAAAATACATCCTGGTGGTCCGGGAGGCTGCACCAAGTGATGCCGGGGAGGTGGTCTTCTCTGTGCGGGGCCTCACCTCCAAGGCCTCACTCATTGTCAGAGAGAGGCCGGCCGCCATCATCAAGCCCCTGGAAGACCAGTGGGTGGCGCCAGGGGAGGACGTGGAGCTGCGCTGTGAGCTGTCACGGGCCGGAACGCCCCTGCACTGGCTGAAGGACAGGAAGGCCATCCGCAAGAGCCAGAAGTATGATGTGGTCTGCGACGGCACGATGGCCATGCTGGTCATCCGCGGGGCCTCGCTCAAGGACGCGGGCGAGTACACGTGTGAGGTGCAGGCTTCCAAGAGCACAGCCAGCCTCCATGTGGAAGAAAAAGCAAACTGCTTCACAGAGGAGCTGACCAATCTGCACGTGCAGGACAAAGGCACAGCTGTGTTCACGTGCAAGACGGAGCACCCCGCGGCCACAGTGACCTGGCGCAAGGGCCTCTTGGAGCTACGGGCCTCAGGGAAGCACCAGCCCAGCCAGGAGGGCCTGACCCTGCGCCTCACCATCAGTGCCCTGGAGAAGGCAGACAGCGACACCTATACCTGCGACATTGGCCAGGCCCAGTCCCGGGCCCAGCTCCTAGTGCAAGGCCGGAGAGTGCACATCATCCAGGACCTGGAGGATGTGGATGTGCACGAGGGCTCCTCGGCCACCTTCCGTTCCCGGATCTCCCCGGCCAACTACGAGCCTGTGCACTGGTTCCTGGACAAGACACCCCTGCATGCCAACGAGCTCAATGAGATCGATGCCCAGCCCGGGCGCTACCACGTGCTGACCCTGCGGCAGCTGGCGCTCAAGGACTCGGGCACCATCTACTTTGAGGCGGGTGACCAGCGGGCCTCGGCCGCCCTGCGGGTCACTGAGAAGCCAAGCGTCTTCTCCCGGGAGCTCACAGATGCCACCATCACAGAGGGTGAGGACTTGACCCTGGTGTGCGAGACCAGCACCTGCGACATTCCTGTGTGCTGGACCAAGGATGGGAAGACCCTGCGGGGGTCTGCCCGGTGCCAGCTGAGCCATGAGGGCCACCGGGCCCAGCTGCTCATCACTGGGGCCACCCTGCAGGACAGTGGACGCTACAAGTGTGAGGCTGGGGGCGCCTGCAGCAGCTCCATTGTCAGGGTCCATGCGCGGCCAGTGCGGTTCCAGGAGGCCCTGAAGGACCTGGAGGTGCTGGAGGGTGGTGCTGCCACACTGCGCTGTGTGCTGTCATCTGTGGCTCCCCCCGTGAAGTGGTGCTATGGAAACAACGTCCTGAGGCCAGGTGACAAATACAGCCTACGCCAGGAGGGTGCCATGCTGGAGCTGGTCGTCCGGAACCTCCGGCCGCAGGACAGCGGGCGGTACTCATGCTCCTTCGGCGACCAGACTACTTCTGCCACCCTCACAGTGACTGCCCTCCCTGCCCAGTTCATCGGGAAACTGAGPAACAAGGAGGCCACAGAAGGGGCCACGGCCACGCTGCGGTGTGAGCTGAGCAAGGCAGCCCCTGTGGAGTGGAGAAAGGGGTCCGAGACCCTCAGAGATGGGGACAGATACTGTCTGAGGCAGGACGGGGCCATGTGTGAGCTGCAGATCCGTCGCCTGGCCATGGTGGATGCCGCGGAGTACTCGTGTGTGTGTGGAGAGGAGAGGACCTCACCCTCACTCACCATCAGGCCCATGCCTGCCCACTTCATAGGAAGACTGAGACACCAAGAGAGCATAGAAGGGGCCACAGCCACGCTGCGGTGTGAGCTGAGCAAGGCGGCCCCCGTGGAGTGGAGGAAGGGGCGTGAGAGCCTCAGAGATGGGGACAGACATAGCCTGAGGCAGGACGGGGCTGTGTGCGAGCTGCAGATCTGTGGCCTGGCTGTGGCAGATGCTGGGGAGTACTCCTGTGTGTGTGGGGACGAGAGGACCTCTGCCACTCTCACCGTGAAGGCCCTGCCAGCCAAGTTCACAGAGGGTCTGAGGAATGAAGAGGCCGTGGAAGGGGCCACAGCCATGTTGTGGTGTGAACTGAGCAAGGTGGCCCCTGTGGAGTGGAGGAAGGGGCCCGAGAACCTCAGAGATGGGGACAGATACATCCTGAGGCAGGAGGGGACCAGGTGTGAGCTGCAGATCTGTGGCCTGGCCATGGCGGACGCCGGGGAGTACTTGTGTGTGTGCGGGCAGGAGAGGACCTCAGCCACGCTCACCATCAGGCCTCTGCCTGCCAGGTTCATAGAAGATGTGAAAAACCAGGAGGCCAGAGAAGGGGCCACGGCTGTGCTGCAGTGTGAGCTGAACAGTGCAGCCCCTGTGGAGTGGAGAAAGGGGTCTGAGACCCTTAGACATGGGCACAGATACACCCTGAGGCAGGACGGGACTAAATGTGAGCTGCAGATTCGTGGCCTGGCCATGCCAGACACTGGGGAGTACTCGTGCGTGTGCGGGCAGGAGAGGACCTCGGCTATCCTCACCGTCAGGGCTCTACCCATCAAGTTCACAGAGGGTCTGAGGAACGAAGAGGCCACAGAAGGGGCAACAGCCGTGCTGCGGTGTGAGCTGAGCAAGATGCCCCCCGTGGAGTGGTGGAAGGGGCATGAGACCCTCAGAGATGGAGACAGACACAGCCTGAGGCAGGACGGGGCCAGGTGTGAGCTGCAGATCCGCGGCCTCGTGGCAGAGGACGCTGGGGAGTACCTGTGCATGTGCCGGAAGGAGAGGACCTCAGCCATGCTCACCGTCAGGGCCATGCCTTCCAAGTTCATAGAGGGTCTGAGGAATGAAGAGGCCACAGAAGGGGACACGGCCACGCTGTGGTGTGAGCTGAGCAAGGCCGCACCGGTGGAGTGGAGGAAGGGGCATGAGACCCTCAGAGATGGGGACAGACACAGCCTGAGGCAGGATGGGTCCAGGTGTGAGCTGCAGATCCGTGGCCTGGCTGTGGTGGATGCCGGGGAGTACTCGTGTGTGTGCGGGCAGCAGAGGACCTCAGCCACACTCACTGTCAGGGCCCTGCCTGCCAGATTCATAGAAGATGTGAAAAACCAGGAGGCCAGAGAAGGGGCCACGGCCGTGCTGCAATGTGAGCTGAGCAAGGCGGCCCCCGTGGAGTGGAGGAAGGGGTCTGAGACCCTCAGAGGTGGGCACAGATACAGCCTGACGCAGGATGGGACCAGATGTGAGCTGCAGATTCATGGCCTGTCTGTGGCAGACACTGGCGAGTACTCGTGTGTGTGCGGGCAGGAGAGGACCTCGGCCACACTCACCGTCAGGGCCCTGCCTGCACGATTCACTCAAGATCTGAAGACCAAGGAGGCCTCAGAAGGGGCCACAGCTACACTGCAGTGTGAGCTGAGCAAGGTGGCCCCTGTGGAATGGAAGAAGGGTCCTGAGACCCTCAGAGATGGGGGCAGATACAGCCTGAAGCAGGATGGGACGAGGTGTGAGCTGCAGATCCATGACCTGTCTGTGGCGGATGCTGGGGAATACTCATGCATGTGTGGACAAGAGAGGACCTCGGCCACGCTCACTGTCAGGGCCCTGCCTGCCAGGTTCACAGAGGGTCTGAGGAATGAACAGGCCATGGAAGGGGCCACAGCCACACTGCAATGTGAGCTGAGCAAGGCAGCCCCTGTGGAGTGGAGGAAAGGCCTTGAGGCTCTCAGAGATGGGGACAAATACAGCCTGAGACAAGACGGGGCTGTGTGTGAGCTGCAGATTCATGGCCTGGCTATGGCAGATAACGGGGTGTACTCATGTGTGTGTGGGCACGAGAGCACCTCAGCTACACTCACTGTCAGGGCCCTGCCTGCCAGATTCATAGAGGATATGAGAAACCAGAAGGCCACAGAAGGGCCTACAGTCACATTGCAATGTAAGCTGAGAAAGGCGGCCCCCGTGGAGTCGAGAAAGGGGCCCAACACCCTCAAAGATGGGGACAGGTACAGCCTGAAGCAGGATGGGACCAGTTGTGAGCTGCAGATTCGTGGCCTGGTCATAGCAGATGCTGGAGAATACTCGTGCATATGTGAGCAGGAGAGGACCTCGGCCACGCTCACTGTCAGGGCCCTGCCGGCCAGATTCATAGAAGATGTGAGAAATCACGAGGCCACAGAAGGGGCCACAGCTGTGCTGCAGTGTGAGCTGAGCAAGGCGGCCCCCGTGGACTGGCGGAAGGGGTCTCAGACCCTCAGAGATGGGCACAGATATAGCCTGAGGCAGGACGCGACCAGGTGTGAGCTGCAGATTCGTGGCCTGGCTGTGGAGGACACTGCAGAGTATTTGTGTGTGTGCGGGCAGGAGAGAACCTCAGCTACACTCACTGTCAGGGCCCTGCCAGCCAGATTCATAGACAACATGACAAACCAGGAAGCCAGAGAAGGCGCCACGGCCACACTGCACTGTGAACTGAGCAAGGTCGCCCCTGTGGAGTGGAGGAAGGGACCTGAAACCCTCCGAGATGGGGACAGACACAGCCTGAGGCAGGATGGGTCCAGGTGTGAGCTGCAGATCCGTGGCCTGGCTGTGGTGGATGCCGGGGAGTACTCGTGTGTGTGCGGGCAGGAGAGGACCTCAGCCACACTCACTGTCAGGGCCCTGCCTGCCAGATTCATAGAAGATGTGAAAAACCAGGAGGCCAGAGAAGGGGCCACGGCCGTGCTGCAATGTGAGCTGAGCAAGGCGGCCCCCGTGGAGTGGAGGAAGGGGTCTGAGACCCTCAGAGGTGGGGACAGATACAGCCTGAGGCAGGATGGGACCAGATGTGAGCTGCAGATTCATGGCCTGTCTGTGGCAGACACTGGGGAGTACTCGTGTGTGTGCGGGCAGGAGAGGACCTCGGCCACACTCACCGTCAGGGCCCTGCCTGCACGATTCACTCAAGATCTGAAGACCAAGGAGGCCTCAGAAGGGGCCACAGCTACACTGCAGTGTGAGCTGAGCAAGGTGGCCCCTGTGGAATGGAAGAAGGGTCCTGAGACCCTCAGAGATGGGGGCAGATACAGCCTGAAGCAGGATGGGACGAGGTGTGAGCTGCAGATCCATGACCTGTCTGTGGCGGATGCTGGGGAATACTCATGCATGTGTGGACAAGAGAGGACCTCGGCCACGCTCACTGTCAGGGACTGCCACACTCTTCACGTCATGCCACACTATCCCTTCCAGCTTCCTGGGCTGCTGAAGGAACCAGAAGAAACTCTCATCTACATCCAGATTCCCTCTCCTGTGATACTGTTCACAGAGGGTCTGAGGAATGAAGAGGCCATGGAAGGGGCCACAGCCACACTGCAATGTGAGCTGAGCAAGGCAGCCCCTGTGGAGTGGAGGAAACCCCTTGAGGCTCTCAGAGATGGGGACAAATACAGCCTGAGACAAGACGGGGCTGTGTGTGAGCTGCAGATTCATGGCCTGGCTATGGCAGATAACGGGGTGTACTCATCCCTGCCTGCCAGATTCATAGAGGATATGAGAAACCAGAAGGCCACAGAAGGGGCTACAGTCACATTGCAATGTAAGCTGAGAAAGGCGGCCCCCGTGCAGTCCACAAAGGGGCCCAACACCCTCAAAGATGGGGACAGGTACAGCCTGAAGAATACTCGTGCATATGTGAGCAGGAGAGGACCTCGGCCACGCTCACTGTCAGGGCCCTGCCGGCCAGATTCATAGAAGATGTGAGAAATCACGAGGCCACAGAAGGGGCCACAGCTGTGCTGCAGTGTOACCTGAGCAAGGCGGCCCCCGTGGAGTGGCGGAAGGGGTCTGAGACCCTCAGAGATGGGGACAGATATAGCCTCAGGCAGGACGGGACGAGGTGTGAGCTGCAGATTCGTGGCCTGGCTGTGGAGGACACTGGAGAGTATTTGTGTGTGTGCGGGCAGGAGAGAACCTCAGCTACACTCACTGTCAGGGCCCTGCCAGCCAGATTCATAGACAACATGACAAACCAGGAAGCCACAGAACGGGCCACGCCCACACTGCACTGTGAACTGAGCAAGGTGGCCCCTGTGGAGTGGAGGAAGGGACCTGAAACCCTCCGAGATGGGGACAGACACAGCCTGAGGCAGGATGGGACCAGGTGTGAGCTGCAGATTCGTGGCCTGTCTGTGGCAGATGCCGGGGAGTACTCGTGCGTGTGTGGGCAGGAGAGGACCTCAGCCACACTCACGATCAGGGCCCTGCCCGCCAAGTTCACAAAGGGTCTGAGGAATGAAGAGGCCACAGAAGGGGCCACGGCTATGTTGCAGTGTCAGCTGAGCAAGGTGGCCCCTGTTGAGTGGAGGAAGGGACCTGAAACCCTCAGAGATGGGGACAGATACAACCTGAGGCAGGATGGGACCAGATGTGAGCTGCAGATTCATGGCCTGTCCGTGGCAGACACTGGGGAGTACTCATGTGTATGTGGTCAGGAGAAGACGTCGGCCACTCTCACTGTCAAGGCCCCACAGCCACTGTTCCGGGAGCCGCTGCAGAGTCTGCAGGCGGAGGAGGGCTCCACGGCCACCCTGCAGTGTGACCTGTCTGAGCCCACTGCTACAGTGGTCTGGAGCAAGGGTGGCCTGCAGCTGCAGGCCAATGGGCGCCGGGAGCCACGGCTTCAGGGCTGCACCGCGGAGCTGGTGTTACAGGACCTACAACGTGAAGACACTGGCGAATACACTTGCACCTGTGGCTCCCAGGCCACCAGTGCCACCCTCACTGTCACAGCTGCGCCTGTGCGGTTCCTCCGAGAGCTGCAGCACCAGGAGGTGGATGAGGGAGGCACCGCACACTTATGCTGCGAGCTGAGCCGGGCGGGTGCGAGCGTGGAGTGGCCCAAGGGCTCCCTACAGCTCTTCCCTTGTGCCAAGTACCAGATGGTGCAGGATGGTGCAGCTGCAGAGCTCCTGGTACGCGGAGTGGAGCAGGAGGATGCGGGTGACTACACGTGTGACACGGGCCACACGCAGAGCATGGCCAGCCTCTCTGTCCGTGGAGGGCGTGGAGCTGCATGCGGGCCCCAAGTACGAGATGCGGCGCAGGGGGCCACGCGGGAGCTGCTGATCCACCAACTGGAGGCCAAGGACACGGGCGAGTATGCCTGTGTGACAGGCGGCCAGAAAACCGCTGCCTCCCTCAGGGTCACAGAGCCTGAGGTGACCATTGTACGGGGGCTGGTTGATGCGCAGGTGACGGCCGATGAGCATGTTGAGTTCAGCTCTGAGGTGTCCAGGGCTGGAGCCACAGGCGTGCAGTGGTGCCTACAGGGCCTGCCACTGCAAAGCAATGAGGTGACAGAGGTGGCTGTGCGGGATGGCCGCATCCACACCCTGCCGCTGAAGGGCGTGACGCCCGAGGACGCTGGCACTGTCTCCTTCCATTTGGGAAACCATGCTTCCTCTGCCCAGCTCACCGTCAGAGCTCCTGAGGTGACCATCCTGGAGCCCCTGCAGGACGTGCAGCTCAGAGGGGTGCCCCTGCAGGCCAACGAGATGAATGACATCACTGTGGAGCAGGGCACACTCCACCTGCTCACCCTGCACAAGGTGACCCTTGAGGATCCTGGAACTGTCAGTTTCCACGTGGGCACGTGTAGCTCTGAGGCCCAGCTGAAAGTCACAGAGGCAGTGCCGTGCCTGGTACGTGGCTTGCAGAATGTGGATGTCTTCGCGGGGGAGGTGGCCACGTTCTCCTGTGAGGATGGCCCCCAGAGCGCCATCGCTGTGCGAGATGGGATCTTTCACTCCCTCATGCTCTCGGGCCTGGGGGTGGCCGACTCCGCCACTGTCATCTTCCGCGCAGGGCCCCTGGTCTCCACGGCCAAGTTGTTGATCAAAGATCCCGTCGTGGAGGTGGTCAGTGCCATGCAGGACTTGGCCGTGGAGGAGGGTGGCTCGGCTGAGCTCCTCTGCCAGTATTCACGGCCCGTGCAGGCCACGTGGAAGATGGACGAGCGGGAGGTGCACACGGATGGGCACCGTGTCATCATAGAGCAGGACTGGAACGTGGCCAGGCTGACCTTCAGGCCGGCCTTGCCCTGTGACAGTGGCATCTATTCTTGTGAGGCTGCGGGCACCCGCGTAGTGGCCCTGCTGCAAGTGCAAGCCAAGAACACGGTGGTGCGAGGGCTGGAGAATGTGGAGGCGCTGGAGGGCGGCGAGGCGCTGTTCGAGTGCCAGCTGTCCCAGCCCGAGGTGGCCGCCCACACCTGGCTGCTGGACGACGAACCCGTGCGCACCTCGGAGAACGCCGAGGTGGTCTTCTTCGAGAACGGCCTGCGCCACCTGCTGCTGCTCAAAAACTTGCGGCCACAAGACAGCTGCCGGGTGACCTTCCTGGCTGGGGATATGGTGACGTCCGCATTCCTCACGGTCCGAGGTGACTGCGCTGTGCTGGTGCAGGGCTGGCGCCTGGAGATCCTGGAGCCTCTGAAAAACGCGGCGGTCCGGGCCGGCGCACAGGCACGCTTCACCTGCACGCTCAGCGAGGCGGTGCCCGTGGGAGAGGCGTCCTGGTACATCAATGGCGCGGCAGTGCAGCCGGATGACAGCGACTGGACTGTCACCGCCGACGGCAGTCACCACGCCCTACTGCTGCGCAGCGCCCAGCCCCACCACGCCGGGGAGGTCACCTTCGCTTGCCGCGACGCCGTGGCCTCTGCGCGGCTCACCGTGCTGGGCCTCCCTGATCCCCCAGAGGATGCTGAGGTGGTGGCTCGCAGCAGCCACACTGTGACACTGTCTTGGGCAGCTCCCATGAGTGATGGAGGCGGTGGTCTCTGTGGCTACCGCGTGGAGGTGAAGGAGGGGGCCACAGGCCAGTGGCGGCTGTGCCACGAGCTGGTGCCTGGACCCGAGTGTGTGGTGGATGGCCTGGCCCCCGGGGAGACCTACCGCTTCCGTGTGGCAGCTGTGGGCCCTGTGGGTGCTGGGGAACCGGTTCACCTGCCCCAGACAGTGCGGCTTGAGCCACCGAAGCCTGTGCCTCCCCAGCCCTCAGCCCCTGAGAGCCGGCAGGTGGCAGCTGGTGAAGATGTCTGTCTGCAGCTTGAGGTCGTGGCTGAGGCTGGCGAGGTCATCTGGCACAAGGGAATGGAGCGCATCCAGCCCGGTGGGCGGTTCGAGGTGGTCTCCCAGGGTCGGCAACAGATGCTGGTGATCAAGGGCTTCACGGCAGAAGACCAGGGCGAGTACCACTGTGGCCTGGCTCAGGGCTCCATCTGCCCTGCGGCTGCCACCTTCCAGGTGGCACTCAGCCCAGCCTCTGTGGATGAGGCCCCTCAGCCCAGCTTGCCCCCCGAGGCAGCCCAGGAGGGTGACCTGCACCTACTGTGGGAGGCCCTGGCTCGGAAACGTCGCATGAGCCGTGAGCCCACGCTGGACTCCATTAGCGAGCTGCCAGAGGAGGACGGCCGCTCGCAGCGCCTGCCACAGGAGGCAGAGGAGGTGGCACCTGATCTCTCTGAAGGCTACTCCACGGCCGATGAGCTGGCCCGCACTGGAGATGCTGACCTCTCACACACCAGCTCTGATGATGAGTCCCGGGCAGGCACCCCTTCCCTGGTCACCTACCTCAAGAAGGCTGGGAGGCCAGGCACCTCACCACTGGCCAGCAAGGTGAGCCCCCCCAACTTGGCCTGCAAGGAGAGGTTCCCCACGCCCCGGGCCGGCCGCAGCCTCCTGGGCTTCGTGGGGGCAGACCCAGCCTTTCCCGGCAGCGAGCGCTCGGCCAGGTGCACTAGGCGCTGTGCGGCCCCCCCTCCCCGCGAGTCCCTCAAGCGGGAACCTGCCTCGTGTCTCCCAGGAGCCATGGAGGCTGTGGAACTCGCCAGAAAACTGCAGGAGGAAGCTACGTGCTCCATCTGTCTGGATTACTTCACAGACCCTGTGATGACCACCTGTGGCCACAACTTCTGCCGAGCGTGCATCCAGCTGAGCTGGGAAAAGGCGAGGGGCAAGAAGGGGAGGCGGAAGCGGAAGGGCTCCTTCCCCTGCCCCGAGTGCAGAGACATGTCCCCCCACAGGAACCTGCTGCCCAACCGGCTGCTGACCAAGGTGGCCGAGATGGCGCAGCAGCATCCTCGTCTGCAGAAGCAAGACCTGTGCCAGGAGCACCACGAGCCCCTCAAGCTTTTCTGCCAGAAGGACCAGAGCCCCATCTGTGTGGTGTGCAGGGAGTCCCGGGAGCACCGGCTGCACAGGGTGCTGCCCGCCGAGGAGGCAGTGCAGGGGTACAAGTTGAACCTGGAGGAGGACATGGAGTACCTTCGGGAGCAGATCACCAGGACAGGGAATCTGCAGGCCAGGGAGGAGCAGAGCTTAGCCGAGTGGCAGGGCAAGGTGAAGGAGCGGAGAGAACGCATTGTGCTGGAGTTTGAGAAGATGAACCTCTACCTGGTGGAAGAAGAGCAGAGGCTCCTCCAGGCTCTGGAGACCGAAGAAGAGGAGACTCCCACCAGGCTCCGGGAGAGCGTGGCCTGCCTGGACCGGCAGGGTCACTCTCTGGAGCTGCTGCTGCTGCAGCTGCAGGAGCCGAGCACACAGGGGCCCCTCCAGATGCTGCAGGACATGAAGCAACCCCTGACCAGGGCGGCGTTACTGGTGGTTCTAATTCATGGGATGAATCTTGTTGAGTTCCCAGTGGTCTCTCTGCCCAGCCCCCTGTACCTTATTGCCACCAAGGCCCACACACAATTGGGCCCGGGGACTCCCACCTTTGACCCTGAATGCCCCACACCTCTCCCCATCTCTCCACCACCACGCCCATCTACAGAGGATGTGGTGCCTGATGCCACCTCCGCGTACCCCTACCTCCTCCTGTATGAGAGCCGCCAGAGGCGCTACCTCGGCTCTTCGCCGGAGGGCAGTGGGTTCTGCAGCAAGGACCGATTTGTGGCTTACCCCTGTGCTGTGCGCCAGACGGCCTTCTCCTCTGGGAGGCACTACTGGGAGGTGGGCATGAACATCACCGGGGACGCGTTGTGGGCCCTGGGTGTGTGCAGGGACAACGTGAGCCGGAAAGACAGGGTCCCCAAGTGCCCCGAAAACGGCTTCTGGGTGGTGCAGCTGTCCAAGGGGACCAAGTACTTATCCACCTTCTCTGCCCTAACCCCGGTCATGCTGATGGAGCCTCCCAGCCACATGGGCATCTTCCTGGACTTCGAAGCCCGGGAAGTGTCCTTCTACAGTGTAAGCGATGGGTCCCACCTGCACACCTACTCCCAGGCCACCTTCCCAGGCCCCCTGCAGCCTTTCTTCTGCCTGGGGGCTCCGAAGTCTGGTCAGATGGTCATCTCCACAGTGACCATGGCAGGGGTAAAAGACCTGGCCACAAGAACCGGAGCGGTGGTGACGCCAGCGCTCGGAGCCTACGCGCCCAGCGCTACCGAAACCCAGAGTCCTGCGCCCTGGAGTCCCCGCGCCCCGGAGCCCGAGCACCCGGGAGTCCCGAGCCTCGCGCCCCGGAGTGCCCGAGCCTGCGCCGCCGCACCCGGATACCCCGGGTCCCCGCGAGCTGCCGAGGCCGCCCGCCGCCGCCCCGCGGACAGTACCGCCTTCCTCCCCTCTGTCCGCGCCATGGCCGCCCCCGACCTGTCCACCAACCTCCAGGAGCAGGCCACCTGCGCCATCTGCCTCGACTACTTCACGGATCCGGTGATGACCGACTGCGGCCACAACTTCTGCCGCGAGTGCATCCGGCGCTGCTGGGGCCAGCCCGAGGCCCGTACGCGTGCCCCGAGTGCCGCGAGCTGTCCCCGCAGAGGAACCTGCGGCCCAACCGCCCGCTTGCTAAGATGGCCGAGATGGCGCGGCGCCTGCACCCGCCGTCGCCGGTCCCGCAGGCGTGTGCCCGCGCACCGCGAGCCACTGGCCGCCTTCTGTGGCGACGAGCTGCGCCTCCTGTGTGCGGCCTGCGAGCGCTCTGGGGAGCACTGGGCGCACCGCGTTGGCCGCTGCAGGACGCGGCCGAAGACCTCAAGGCCCCTTGAGGCTGGGACCATGGCCGCCAATGAGACCCTGCTCTCGGGGGCGAAGCTGGAGAAGTCACTGGAGCATCTCCGGAAGCAGATGCAGGATGCGTTGCTGTTCCAAGCCCAGGCGGATGAGACCTGCGTCTTGTGGCAGGCAGAAGATGGTGGAGAGCAGCGGCACAACCTGCTGCCTGAGTTCGAGCGTCTTCGCCGTTTGCTGGCAGAGGGAGGGACAGCAGCTGCTGCAGAGGCTGGAGAGGAGGAGCTGAAGCAGAGCGCCCACCTAGCTGAGCTCATCGCCGAGCTCGAGAGGCCGCTGCCAGCTGCCTGCGCTGGGGCTGCTGCAGGAGAGTCTTTTCCCATGTGTGGGCTCCACTCCCTGAGCCGGCCCCCTGGCGTGGGCTTTCCTTGGTGCACCCCCAAACCAGAACCAGTGGACGCCCTGGCCTGTGCGTGGCGGCAGGGCTGCCAGACCCAGGTGGAGCCCACAATGCTGCAGATGTGGCTGGGCGGCTTTGCACAGGGGGTGACACTGCTGCCGGCCTCTGGAGCCCAGCAGAACATCAGTCCAGGCACCGGCTCCTGGTTTCGATTGTCATTTCTATTATTTAAGGGGTACAAGTGCAGTCAGAGTGTAGCCATCACCCGAATGGTGCACACTGTACCCAAGACCAAACCCCCTTGTCGAGGCCAAGGTTCTCCTCTACCCCCAAGCCCTTCTCCTGCCGCCCCTGCACCCGGCCTTGTGACAGCCACCACCTGTTTCCAAATGACACCAGGGGTGGGCCGCCCACCCCAGGACATCAAGGACGCCCTGCGCAGGGTCCAGGATGTGAAGCTGCAGCCCCCAGAAGTTGTGCCTATGGAGCTGAGGACCGTGTGCAGGGTCCCGGGACTGGTAGAGACACTGCGCAGGTTTCGAGGGGACGTGACCTTGGACCCGGACACCGCCAACCCTGACCTGATCCTGTCTGAAGACAGGCGGAGCGTGCAGCGGGGGGACCTACGGCAGGCCCTGCCGGACAGCCCAGAGCGCTTTGACCCCGGCCCCTGCGTGCTGGCCCAGGAGCGCTTCACCTCAGGCCGCCACTACTGGGAGGTGGAGGTTGGGGACCGCACCAGCTGGGCCCTGGGGGTGTGCAGGGAGAACGTGAACAGGAAGGAGAAGGGCGAGCTGTCCGCGGGCAACGGCTTCTGGATCCTGGTCTTCCTGGGGAGCTATTACAATTCCTCGGAACGGGCCTTGGCTCCACTCCGGGACCCACCCAGGCGCGTGGGGATCTTTCTGGACTACGAGGCTGGACATCTCTCTTTCTACAGTGCCACCGATGGGTCACTGCTATTCATCTTTCCCGAGATCCCCTTCTCGGGGACCCTGCGGCCCCTCTTCTCACCCCTGTCCAGCAGCCCGACCCCGATGACTATCTGCCGGCCGAAAGGTGGGTCCGOGGACACCCTGGCTCCCCAGTGACTCGGGCCCTCCTGGAGGAORF Start: ATG at 15ORF Stop: TGA at 14088SEQ ID NO:724691 aa MW at 512894.2 kDNOV13a,MPLYNDSFHEISHKGRRHTLVLKSIQRADAGIVRASSLKVSTSARLEVRVKPVVFLKACG59237-01 ProteinLDDLSAEERGTLALQCEVSDPEAHVVWRKDGVQLGPSDKYDFLHTAGTRGLVVHDVSPSequenceEDAGLYTCHVGSEETRARVRVHDLHVGITKRLKTMEVLEGESCSFECVLSHESASDPAMWTVGGKTVGSSSRFQATRQGRKYILVVREAAPSDAGEVVFSVRGLTSKASLIVRERPAAIIKPLEDQWVAPGEDVELRCELSRAGTPVHWLKDRKAIRKSQKYDVVCEGTMAMLVIRGASLKDAGEYTCEVEASKSTASLHVEEKANCFTEELTNLQVEEKGTAVFTCKTEHPAATVTWRKGLLELRASGKHQPSQEGLTLRLTISALEKADSDTYTCDIGQAQSRAQLLVQGRRVHIIEDLEDVDVQEGSSATFRCRISPANYEPVHWFLDKTPLHANELNEIDAQPGGYHVLTLRQLALKDSGTIYFEAGDQRASAALRVTEKPSVFSRELTDATITEGEDLTLVCETSTCDIPVCWTKDGKTLRGSARCQLSHEGHRAQLLITGATLQDSGRYKCEAGGACSSSIVRVHARPVRFQEALKDLEVLEGGAATLRCVLSSVAAPVKWCYGNNVLRPGDKYSLRQEGANLELVVRNLRPQDSCRYSCSFGDQTTSATLTVTALPAQFIGKLRNKEATEGATATLRCELSKAAPVEWRKGSETLRDGDRYCLRQDGAMCELQIRGLAMVDAAEYSCVCCEERTSASLTIRPMPAHFIGRLRHQESIEGATATLRCELSKAAPVEWRKGRESLRDGDRHSLRQDGAVCELQICGLAVADAGEYSCVCGEERTSATLTVKALPAKFTEGLRNEEAVEGATANLWCELSKVAPVEWRKGPENLRDGDRYILRQEGTRCELQICGLAMADAGEYLCVCGQERTSATLTIRALPARFIEDVKNQEAREGATAVLQCELNSAAPVEWRKGSETLRDGDRYSLRQDGTKCELQIRGLAMADTGEYSCVCGQERTSANLTVRALPIKFTEGLRNEEATEGATAVLRCELSKMAPVEWWKGHETLRDGDRHSLRQDGARCELQIRGLVAEDAGEYLCMCGKERTSAMLTVRAMPSKFIEGLRNEEATEGDTATLWCELSKAAPVEWRKGHETLRDGDRHSLRQDGSRCELQIRGLAVVDAGEYSCVCGQERTSATLTVRALPARFIEDVKNQEAREGATAVLQCELSKAAPVEWRKGSETLRGGDRYSLRQDGTRCELQIHGLSVADTGEYSCVCGQERTSATLTVRALPARFTQDLKTKEASEGATATLQCELSKVAPVEWKKGPETLRDGGRYSLKQDGTRCELQIHDLSVADAGEYSCMCGQERTSATLTVRALPARFTEGLRMEEANEGATATLQCELSKAAPVEWRKGLEALRDGDKYSLRQDGAVCELQIHGLAMADNGVYSCVCGQERTSATLTVRALPARFIEDMRNQKATEGATVTLQCKLRKAAPVEWRKGPNTLKDGDRYSLKQDGTSCELQIRGLVIADAGEYSCICEQERTSATLTVRALPARFIEDVRNHEATEGATAVLQCELSKAAPVEWRKGSETLRDCDRYSLRQDGTRCELQIRGLAVEDTGEYLCVCGQERTSATLTVRALPARFIDNMTNQEAREGATATLHCELSKVAPVEWRKGPETLRDGDRHSLRQDGSRCELQIRGLAVVDAGEYSCVCGQERTSATLTVRALPARFIEDVKNQEAREGATAVLQCELSKAAPVEWRKGSETLRGGDRYSLRQDGTRCELQIHGLSVADTGEYSCVCGQERTSATLTVRALPARFTQDLKTKEASEGATATLQCELSKVAPVEWKKGPETLRDGGRYSLKQDGTRCELQIHDLSVADAGEYSCMCGQERTSATLTVRDCHTLHVMPHYPFQLPGLLKEPEETLIYIQIPSPVILFTEGLRNEEANEGATATLQCELSKAAPVEWRKGLEALRDGDKYSLRQDGAVCELQIHGLAMADNGVYSSLPARFIEDMRNQKATEGATVTLQCKLRKAAPVEWRKGPNTLKDGDRYSLKQDGTSCELQIRGLVIADAGEYSCICEQERTSATLTVRALPARFIEDVRNHEATEGATAVLQCELSKAAPVEWRKGSETLRDGDRYSLRQDGTRCELQIRGLAVEDTGEYLCVCGQERTSATLTVRALPARFIDNNTNQEAREGATATLHCELSKVAPVEWRKGPETLRDGDRHSLRQDGTRCELQIRGLSVADAGEYSCVCGQERTSATLTIRALPAKFTKGLRNEEATEGATAMLQCELSKVAPVEWRKGPETLRDGDRYNLRQDGTRCELQIHGLSVADTGEYSCVCGQEKTSATLTVKAPQPVFREPLQSLQAEEGSTATLQCELSEPTATVVWSKGGLQLQANGRREPRLQGCTAELVLQDLQREDTGEYTCTCGSQATSATLTVTAAPVRFLRELQHQEVDEGGTARLCCELSRAGASVEWRKGSLQLFPCAKYQMVQDGAAAELLVRGVEQEDAGDYTCDTGHTQSMASLSVRGGRGARCGPQVRDAAQGATRELLIHQLEAKDTGEYACVTGGQKTAASLRVTEPEVTIVRGLVDAEVTADEDVEFSCEVSRAGATGVQWCLQGLPLQSNEVTEVAVRDGRIHTLRLKGVTPEDAGTVSFHLGNHASSAQLTVRAPEVTILEPLQDVQLRGVPLQANEMNDITVEQGTLHLLTLHKVTLEDAGTVSFHVGTCSSEAQLKVTEAVPCLVRGLQNVDVFAGEVATFSCEDGPQSAIAVRDGIFHSLMLSGLGVADSGTVIFRAGPLVSTAKLLIKDPVVEVVSAMQDLAVEEGGSAELLCQYSRPVQATWKMDEREVHTDGHRVIIEQDWNVARLTFRPALPCDSGIYSCEAAGTRVVALLQVQAKNTVVRGLENVEALEGGEALFECQLSQPEVAAHTWLLDDEPVRTSENAEVVFFENGLRHLLLLKNLRPQDSCRVTFLAGDMVTSAFLTVRGDCAVLVQGWRLEILEPLKNAAVRAGAQARFTCTLSEAVPVGEASWYINGAIWQPDDSDWTVTADGSHHALLLRSAQPHHAGEVTFACRDAVASARLTVLGLPDPPEDARVVARSSHTVTLSWAAPMSDGGCGLCGYRVEVKEGATGQWRLCHELVPGPECVVDGLAPGETYRFRVAAVGPVGAGEPVHLPQTVRLEPPKPVPPQPSAPESRQVAAGEDVCLELEVVAEAGEVIWHKGMERIQPGGRFEVVSQGRQQMLVIKGFTAEDQGEYHCGLAQGSICPAAATFQVALSPASVDEAPQPSLPPEAAQEGDLHLLWEALARKRRMSREPTLDSISELPEEDGRSQRLPQEAEEVAPDLSEGYSTADELARTGDADLSHTSSDDESRAGTPSLVTYLKKAGRPGTSPLASKVSPPNLACKERFPTPRAGRSLLGFVCADPAFPGSERSARCTRRCAAPPPRESLKREPASCLPGAMEAVELARKLQEEATCSICLDYFTDPVMTTCGHNFCRACIQLSWEKARGKKGRRKRKGSFPCPECREMSPQRNLLPNRLLTKVAEMAQQHPGLQKQDLCQEHHEPLKLFCQKDQSPICVVCRESREHRLHRVLPAEEAVQGYKLKLEEDMEYLREQITRTGNLQAREEQSLAEWQGKVKERRERIVLEFEKMNLYLVEEEQRLLQALETEEEETASRLRESVACLDRQGHSLELLLLQLEERSTQGPLQMLQDMKEPLSPAALLVVLIHGMNLVEFPVVSLPSPLYLIATKAHTQLGPGTPTFDPECPTPLPISPPPRPSTEDVVPDATSAYPYLLLYESRQRRYLGSSPEGSGFCSKDRFVAYPCAVGQTAFSSGRHYWEVGMNITGDALWALGVCRDNVSRKDRVPKCPENGFWVVQLSKGTKYLSTFSALTPVMLMEPPSHMGIFLDFEAGEVSFYSVSDGSHLHTYSQATFPGPLQPFFCLGAPKSGQMVISTVTMAGVKDLATRTGAVVTPALGAYAPSATETQSPAPWSPRAPEPEHPGVPSLAPRSARACAAAPGYPGSPRAAEAARRRPADSTAFLPSVRAMAAPDLSTNLQEEATCAICLDYFTDPVMTDCGHNFCRECIRRCWGQPEARTRAPSAASCPRRGTCGPTARLLRWPRWRGACTRRRRSRRRVPAHREPLAAFCGDELRLLCAACERSGEHWAHRVGRCRTRPKTSRPLEAGTMAANETLLSGAKLEKSLEHLRKQMQDALLFQAQADETCVLWQAEDGGEQRQNVLREFERLRRLLAEGGTAAAAEAGEEELKQSAHLAELIAELERPLPAACAGAAAGESFPMCGLHSLSRPPGVGFPWCTPKPEPVDALACAWRQGCQTQVEPTMLQMWLGGFAQGVTLLPASGAQQNISPGTGSWFRLSFLLFKGYKCSQSVAITRMVHTVPKTKPPCRGQGSPLPPSPSPAAPAPGLVTATTCFQMTPGVGRPPQDIKDALRRVQDVKLQPPEVVPMELRTVCRVPGLVETLRRFRGDVTLDPDTANPELILSEDRRSVQRGDLRQALPDSPERFDPGPCVLGQERFTSCRHYWEVEVGDRTSWALGVCRENVNRKEKGELSAGNGFWILVFLGSYYNSSERALAPLRDPPRRVGIFLDYEAGHLSFYSATDGSLLFIFPEIPFSGTLRPLFSPLSSSPTPMTICRPKGGSGDTLAPQSEQ ID NO:7314061 bpNOV13b,TGTCGCTCAACGGGATGCCCCTGTACAACGACAGCTTCCATGAGATCTCACACAAGGGCG59237-02 DNACCGGCGCCACACGCTGGTACTGAAGAGCATCCAGCGGGCTGATGCGCGCATAGTACGCSequenceGCCTCCTCCCTGAAGGTGTCGACCTCTGCCCGCCTGGAGGTCCGAGTGAAGCCGGTGGTGTTCCTGAAGGCGCTGGATGACCTGTCCGCAGAGGAGCGCGGCACCCTGGCCCTGCAGTGTGAAGTCTCTGACCCCGAGGCCCATGTGGTGTGGCGCAAAGATGGCGTGCAGCTGGGCCCCAGTGACAAGTATGACTTCCTGCACACGGCGGGCACGCGGGGGCTCGTGGTGCATGACGTGAGCCCTGAAGACGCCGGCCTGTACACCTGCCACGTGGGCTCCGAGGAGACCCGGGCCCGCGTCCGCCTCCACGATCTGCACGTGGGCATCACCAAGAGGCTGAAGACAATGGAGGTGCTGGAAGGGGAAAGCTGCAGCTTTGAGTGCGTCCTGTCCCACGAGAGTGCCAGCGACCCGGCCATGTGGACAGTCGGTGGGAAGACAGTGGGCAGCTCCAGCCGCTTCCAGGCCACACGTCAGGGCCGAAAATACATCCTGGTGGTCCGGGAGGCTGCACCAAGTGATGCCGGGGAGGTGGTCTTCTCTGTGCGGGGCCTCACCTCCAAGGCCTCACTCATTGTCAGAGAGAGGCCGGCCGCCATCATCAAGCCCCTGGAAGACCAGTGGGTGGCGCCAGGGGAGGACGTGGAGCTGCCCTGTGAGCTGTCACGGGCGGGAACGCCCGTGCACTGGCTGAAGGACAGGAAGGCCATCCGCAAGAGCCAGAAGTATGATGTGGTCTGCGAGGGCACGATGGCCATGCTGGTCATCCGCGGGGCCTCGCTCAAGGACGCGGGCGAGTACACGTGTGAGGTGGAGGCTTCCAAGAGCACAGCCAGCCTCCATGTGGAAGAAAAAGCAAACTGCTTCACAGAGGAGCTGACCAATCTGCAGGTGGAGGAGAAAGGCACAGCTGTGTTCACGTGCAAGACGGAGCACCCCGCGGCCACAGTGACCTGGCGCAAGGGCCTCTTGGAGCTACGGGCCTCAGGGAAGCACCAGCCCAGCCAGGAGGGCCTGACCCTGCGCCTCACCATCAGTGCCCTGGAGAAGGCAGACAGCGACACCTATACCTGCGACATTGGCCAGGCCCAGTCCCGGGCCCAGCTCCTAGTGCAAGGCCGGAGAGTGCACATCATCGAGGACCTGGACGATGTGGATGTGCAGGAGGGCTCCTCGGCCACCTTCCGTTGCCGGATCTCCCCGGCCAACTACGAGCCTGTGCACTGGTTCCTGGACAAGACACCCCTGCATGCCAACGAGCTCAATGAGATCGATGCCCAGCCCGGGGGCTACCACGTGCTGACCCTGCGCCAGCTGGCGCTCAAGGACTCGGGCACCATCTACTTTGAGGCGGGTGACCAGCGGGCCTCGGCCGCCCTGCGGGTCACTCAGAAGCCAAGCGTCTTCTCCCGGGAGCTCACAGATGCCACCATCACAGAGGGTGAGGACTTGACCCTGGTGTGCGAGACCAGCACCTGCGACATTCCTGTGTGCTGGACCAAGGATGGCAAGACCCTGCGGGGGTCTGCCCGGTGCCAGCTGAGCCATGAGGGCCACCGGGCCCAGCTGCTCATCACTGGGGCCACCCTGCAGGACAGTGGACGCTACAAGTGTGAGGCTGGGGGCGCCTGCAGCACCTCCATTGTCAGCGTGCATGCGCGGCCAGTGCGGTTCCAGGAGGCCCTGAAGGACCTGGAGGTGCTGGAGGCTGGTGCTGCCACACTCCGCTGTGTGCTGTCATCTGTGGCTGCGCCCGTGAAGTGGTGCTATGGAAACAACGTCCTGAGGCCAGGTGACAAATACAGCCTACGCCAGGAGGGTGCCATGCTGGAGCTGGTGGTCCGGAACCTCCGGCCGCAGGACAGCGGGCGGTACTCATGCTCCTTCGGGGACCAGACTACTTCTGCCACCCTCACAGTGACTGCCCTGCCTGCCCAGTTCATCGGGAAACTGAGAAACAAGGAGGCCACAGAAGGGGCCACGGCCACGCTGCGGTGTGAGCTGAGCAAGGCAGCCCCTGTGGAGTGGAGAAAGGGGTCCGAGACCCTCAGAGATGGGGACAGATACTGTCTGAGGCATTACGGGGCCATGTGTGAGCTGCAGATCCGTGGCCTGGCCATGGTGGATGCCGCGGAGTACTCGTGTGTGTGTGGAGAGGAGAGGACCTCAGCCTCACTCACCATCAGGCCCATGCCTGCCCACTTCATAGGAAGACTGAGACACCAAGAGAGCATAGAACGGGCCACAGCCACGCTGCGGTGTGAGCTGAGCAAGGCGGCCCCCGTGGAGTGGAGGAAGGGGCGTGAGAGCCTCAGAGATGGGCACAGACATAGCCTGAGGCAGGACGGGGCTGTGTGCGAGCTGCAGATCTGTGGCCTGGCTGTGGCAGATGCTGGGGAGTACTCCTCTGTGTGTGGGGAGGAGAGGACCTCTGCCACTCTCACCGTGAAGGCCCTGCCAGCCAAGTTCACAGAGCCTCTGAGGAATGAAGACGCCGTGGAAGGGGCCACAGCCATGTTGTGGTGTGAACTGAGCAAGGTGGCCCCTGTGGAGTGGAGGAAGGGGCCCGAGAACCTCAGAGATGGGGACAGATACATCCTGAGGCAGGAGGGGACCAGGTGTGAGCTGCAGATCTGTGGCCTGGCCATGGCGGACGCCGGGOAGTACTTGTGTGTGTGCGGGCAGGAGAGGACCTCAGCCACGCTCACCATCAGGGCTCTGCCTGCCAGGTTCATAGAAGATGTGAAAAACCAGGAGGCCAGAGAAGGGGCCACGGCTGTGCTGCAGTGTGAGCTGAACAGTGCAGCCCCTGTGGAGTGGAGAAAGGGGTCTGAGACCCTTAGAGATGCGGACAGATACAGCCTGAGGCAGGACGGGACTAAATGTGAGCTGCAGATTCGTGGCCTGGCCATCGCAGACACTGGGGAGTACTCGTGCGTGTGCGGGCAGGAGAGGACCTCGGCTATGCTCACCGTCAGGGCTCTACCCATCAAGTTCACAGAGGGTCTGAGGAACGAAGAGGCCACAGAAGGGGCAACAGCCGTGCTGCGGTGTGACCTGAGCAAGATGGCCCCCGTGGAGTGGTGGAAGGGGCATGAGACCCTCAGAGATGGAGACACACACAGCCTCAGGCAGGACGGGGCCAGGTGTGAGCTGCAGATCCGCGGCCTCGTGGCAGAGGACGCTGGGGAGTACCTGTGCATGTGCGGGAAGGAGAGGACCTCAGCCATGCTCACCGTCAGGGCCATGCCTTCCAAGTTCATAGAGGGTCTGAGGAATGAAGAGGCCACAGAAGGGGACACGGCCACGCTGTGGTGTGAGCTGAGCAAGGCGGCACCGGTGGAGTGGAGGAAGGGGCATGAGACCCTCAGAGATGGGGACAGACACAGCCTGAGGCAGGATGGGTCCAGGTGTGAGCTGCAGATCCGTGGCCTGGCTGTGGTGGATGCCGGGGAGTACTCGTGTGTGTGCGCCCAGGAGAGGACCTCAGCCACACTCACTGTCAGGGCCCTGCCTGCCAGATTCATAGAAGATGTGAAAAACCAGGAGGCCAGAGAAGGGGCCACGGCCGTGCTGCAATGTGAGCTGAGCAAGGCGGCCCCCGTGGAGTGGAGGAAGGGGTCTGAGACCCTCAGAGGTGGGGACAGATACAGCCTGAGGCAGGATGGGACCAGATGTGAGCTGCAGATTCATGGCCTGTCTGTGGCAGACACTGGGGAGTACTCGTGTGTGTGCGGGCAGGAGAGGACCTCGGCCACACTCACCGTCAGGGCCCTGCCTGCACGATTCACTCAAGATCTGAAGACCAAGGAGGCCTCAGAAGGGGCCACAGCTACACTGCAGTGTGAGCTGAGCAAGGTGGCCCCTGTGGAATGGAAGAAGGGTCCTGAGACCCTCAGAGATGGGGGCAGATACAGCCTGAAGCAGGATGGGACGAGGTGTGAGCTGCAGATCCATGACCTGTCTGTGGCGGATGCTGGGGAATACTCATGCATGTGTGGACAAGAGAGGACCTCGGCCACGCTCACTGTCAGGGCCCTGCCTGCCAGGTTCACAGAGGGTCTGAGGAATGAAGAGGCCATGGAAGGGGCCACAGCCACACTGCAATGTGAGCTGAGCAAGGCAGCCCCTGTGGAGTGGAGGAAAGGCCTTGAGGCTCTCAGAGATGCGGACAAATACAGCCTGAGACAAGACGGGGCTGTGTGTGAGCTGCAGATTCATGGCCTGGCTATGGCAGATAACGGGGTGTACTCATGTGTGTGTGGGCAGGAGAGGACCTCAGCTACACTCACTGTCAGGGCCCTGCCTGCCAGATTCATAGAGGATATGAGAAACCAGAAGGCCACAGAAGGGGCTACAGTCACATTGCAATGTAAGCTGAGAAAGGCGGCCCCCGTGGAGTGGAGAAAGGGGCCCAACACCCTCAAAGATGGGGACAGGTACAGCCTGAACCAGGATGGGACCAGTTGTGAGCTGCAGATTCGTGGCCTGGTCATAGCAGATGCTGGAGAATACTCGTGCATATGTGAGCAGGAGAGCACCTCGGCCACGCTCACIGTCAGGGCCCTGCCGGCCAGATTCATAGAAGATGTGAGAAATCACGAGGCCACAGAAGGGGCCACAGCTGTGCTCCAGTGTGAGCTGAGCAAGGCGGCCCCCGTGGAGTGGCGGAAGGGGTCTGAGACCCTCAGAGATGGGGACAGATATAGCCTGAGGCAGGACGGGACGAGGTGTGAGCTGCACATTCGTGGCCTGGCTGTGGAGGACACTGGAGAGTATTTGTGTGTGTGCGGGCAGGAGAGAACCTCAGCTACACTCACTGTCAGGGCCCTGCCAGCCAGATTCATAGACAACATGACAAACCACGPAGCCAGAGAAGGGGCCACGGCCACACTGCACTGTGAACTGAGCAAGGTGGCCCCTGTGCAGTGGAGGAAGGGACCTGAAACCCTCCGAGATGGGGACAGACACAGCCTGAGGCAGCATGGGTCCAGGTGTGAGCTGCAGATCCGTGGCCTGGCTGTGGTGGATGCCGGGCACTACTCGTGTGTGTGCGGGCAGGAGAGGACCTCAGCCACACTCACTGTCAGGGCCCTGCCTGCCAGATTCATAGAAGATGTGAAAAACCAGGAGGCCAGAGAACGGGCCACGGCCGTGCTGCAATGTGAGCTGAGCAAGGCGGCCCCCGTGGAGTGGAGGAAGGGGTCTGAGACCCTCAGAGGTGGGGACAGATACAGCCTGAGGCAGGATGGGACCAGATGTGAGCTGCAGATTCATGGCCTGTCTGTGGCAGACACTGGGGAGTACTCGTGTGTGTGCGGGCAGCAGAGGACCTCGGCCACACTCACCGTCAGGGCCCTGCCTCCACGATTCACTCAAGATCTGAAGACCAAGCAGGCCTCAGAAGGGGCCACAGCTACACTGCAGTGTGAGCTGAGCAAGGTGGCCCCTGTGGAATGGAAGAAGGGTCCTGAGACCCTCAGAGATGGGGGCAGATACAGCCTGAAGCAGGATGGGACGAGGTGTGAGCTGCAGATCCATGACCTGTCTGTGGCGGATGCTGGGGAATACTCATGCATGTGTGGACAAGAGAGGACCTCGGCCACGCTCACTGTCAGGGACTGCCACACTCTTCACGTCATGCCACACTATCCCTTCCAGCTTCCTGGGCTGCTGAACGAACCAGAAGAAACTCTCATCTACATCCAGATTCCCTCTCCTGTGATACTGTTCACAGAGGGTCTGAGGAATGAAGAGGCCATGGAAGGGGCCACAGCCACACTCCAATGTGAGCTGAGCAAGGCAGCCCCTGTGGAGTGGAGGAAAGGCCTTGAGGCTCTCAGAGATGGGGACAAATACAGCCTGAGACAAGACGGGGCTGTGTGTGAGCTGCAGATTCATGGCCTGGCTATGCCAGATAACGGGGTGTACTCATCCCTGCCTGCCAGATTCATAGAGGATATGAGAAACCAGAAGGCCACAGAAGGGGCTACAGTCACATTGCAATGTAACCTGAGAAAGGCGGCCCCCGTGGAGTGGAGAAAGGGGCCCAACACCCTCAAAGATGGGGACAGGTACAGCCTGAAGCAGGATGGGACCAGTTGTGAGCTGCAGATTCGTGGCCTGGTCATAGCAGATGCTGGAGAATACTCGTGCATATGTGAGCAGGAGAGGACCTCGGCCACGCTCACTGTCAGGGCCCTGCCCGCCAGATTCATAGAAGATGTGAGAAATCACGAGGCCACAGAAGGGGCCACAGCTGTGCTGCAGTGTOAGCTGAGCAAGGCGGCCCCCGTGGAGTGGCGGAAGGGGTCTGAGACCCTCAGAGATGGGGACAGATATAGCCTGACGCAGGACGGGACGAGGTGTGAGCTGCACAAACCAGGAAGCCAGAGAAGGGGCCACGGCCACACTGCACTGTGAACTGAGCAAGGTGGCCCCTGTGGAGTGGAGGAAGGGACCTGAAACCCTCCGAGATGGGGACAGACACAGCCTGAGGCAGGATGGGACCAGGTGTGAGCTGCAGATTCGTGGCCTGTCTGTGGCAGATCCCGGCGAGTACTCGTGCGTGTGTGGGCAGGAGAGGACCTCAGCCACACTCACGATCAGGGCCCTGCCCGCCAAGTTCACAAAGCGTCTGAGGAATGAAGAGGCCACAGAAGGGGCCACGGCTATGTTGCAGTGTGAGCTGAGCAAGGTGGCCCCTGTTGAGTGGAGGAAGGGACCTGAAACCCTCAGAGATGGGGACAGATACAACCTGAGGCAGGATGGGACCAGATGTGAGCTGCAGATTCATGOCCTGTCCGTGGCAGACACTGCGGAGTACTCATGTGTATGTGGTCAGGAGAAGACGTCGGCCACTCTCACTGTCAAGGCCCCACAGCCAGTGTTCCGGGAGCCGCTGCAGAGTCTGCAGGCGGAGGAGGGCTCCACGGCCACCCTGCAGTGTGAGCTGTCTGAGCCCACTGCTACAGTGGTCTGGAGCAAGGGTGGCCTGCAGCTGCAGCCCAATGGGCGCCGGGAGCCACGGCTTCAGGGCTGCACCGCGGAGCTGGTGTTACAGGACCTACAACGTGAAGACACTGGCGAATACACTTGCACCTGTGGCTCCCAGGCCACCAGTGCCACCCTCACTGTCACAGCTGCGCCTGTGCGGTTCCTCCGAGAGCTGCAGCACCAGGAGGTGGATGAGGGAGGCACCGCACACTTATGCTGCGAGCTGAGCCGGGCGGGTGCGAGCGTGGAGTGGCGCAAGGGCTCCCTACAGCTCTTCCCTTGTGCCAAGTACCAGATGGTGCAGGATGGTGCAGCTGCAGAGCTGCTGGTACGCGGAGTGGACCAGGAGGATGCGGGTGACTACACGTGTGACACGGGCCACACGCAGAGCATGGCCAGCCTCTCTGTCCGTGGAGGGCGTGGAGCTGCATGCGGGCCCCAAGTACGAGATGCGGCGCAGGGGGCCACGCGGGAGCTGCTGATCCACCAACTGGAGGCCAAGGACACGGGCGAGTATGCCTGTGTGACAGGCGGCCAGAAAACCGCTGCCTCCCTCAGGGTCACAGAGCCTGAGGTGACCATTGTACGGGGGCTGGTTGATGCGGAGGTGACGGCCGATGAGGATGTTGAGTTCAGCTGTGAGGTGTCCAGGGCTGGAGCCACAGGCGTGCAGTGGTGCCTACAGGGCCTGCCACTGCAAAGCAATGAGGTGACAGAGCTGGCTGTGCGGGATGGCCGCATCCACACCCTGCGGCTGAAGGGCGTGACGCCCGAGGACGCTGGCACTGTCTCCTTCCATTTGGGAAACCATGCTTCCTCTGCCCAGCTCACCGTCAGAGCTCCTGAGGTGACCATCCTGGAGCCCCTGCAGGACGTGCAGCTCAGAGGGGTGCCCCTGCAGGCCAACGAGATGAATGACATCACTGTGGAGCAGGGCACACTCCACCTGCTCACCCTGCACAAGGTGACCCTTGAGGATGCTGGAACTGTCAGTTTCCACGTGGGCACGTGTAGCTCTGAGGCCCAGCTGAAAGTCACAGAGGCAGTGCCGTGCCTGGTACGTGGCTTGCAGAATGTGGATGTCTTCGCGGGGGAGGTGGCCACGTTCTCCTGTGAGGATGGCCCCCAGAGCGCCATCGCTGTCCGAGATGGGATCTTTCACTCCCTCATGCTCTCGGGCCTGGGGGTGGCCGACTCCGGCACTGTCATCTTCCGCGCAGGGCCCCTGGTCTCCACGGCCAAGTTGTTGATCAAAGATCCCGTGGTGGAGGTGGTCAGTGCCATGCAGGACTTGGCCGTGGAGGAGGGTGGCTCGGCTGAGCTCCTCTGCCAGTATTCACGGCCCGTGCAGGCCACGTGGAAGATGGACGAGCGGGAGGTGCACACGGATGGGCACCGTGTCATCATAGAGCAGGACTGGAACGTGGCCAGGCTGACCTTCAGGCCGGCCTTGCCCTGTGACAGTGGCATCTATTCTTGTGAGGCTGCGGGCACCCGCGTAGTGGCCCTGCTGCAAGTCCAAGCCAAGAACACGGTGGTGCGAGGGCTGGAGGATGTGGAGGCGCTGGAGGGCGGCGAGGCGCTGTTCGAGTGCCAGCTGTCCCAGCCCGAGGTGGCCGCCCACACCTGGCTGCTGGACGACGAACCCGTGCGCACCTCGGAGAACGCCGAGGTGGTCTTCTTCGAGAACGGCCTGCGCCACCTGCTGCTGCTCAAAAACTTGCGGCCACAAGACAGCTGCCGGGTGACCTTCCTGGCTGGGGATATGGTGACGTCCGCATTCCTCACGGTCCGAGGTGACTGCGCTGTGCTGGTGCAGGGCTGGCGCCTGGAGATCCTGGAGCCTCTGAAAAACGCGGCGGTCCGGGCCGGCGCACAGGCACGCTTCACCTGCACGCTCAOCGAGGCGGTGCCCGTGGGAGAGGCGTCCTGGTACATCAATGGCGCGGCAGTGCAGCCGGATGACAGCGACTGGACTGTCACCGCCGACGGCAGTCACCACGCCCTACTGCTGCGCAGCGCCCAGCCCCACCACGCCGGGGAGGTCACCTTCGCTTGCCGCGACGCCGTGGCCTCTGCGCGGCTCACCGTGCTGGGCCTCCCTGATCCCCCAGAGGATGCTGAGGTGGTGGCTCGCAGCAGCCACACTGTGACACTGTCTTGGGCAGCTCCCATGAGTGATGGAGGCGGTGGTCTCTGTGCCTACCGCGTGGAGGTGAAGGAGGGGGCCACAGGCCAGTGGCGGCTGTGCCACGAGCTCGTGCCTGGACCCGAGTGTGTGGTGGATGGCCTGGCCCCCGGGGAGACCTACCGCTTCCGTGTGGCAGCTGTGGGCCCTGTGGGTGCTGGGGAACCGGTTCACCTGCCCCAGACAGTGCGGCTTGAGCCACCGAAGCCTGTGCCTCCCCAGCCCTCAGCCCCTGAGAGCCGGCAGGTGGCAGCTGGTGAAGATGTCTGTCTGGAGCTTGAGGTGGTGGCTGAGGCTGGCGAGGTCATCTGGCACAAGGGAATGGAGCGCATCCAGCCCGGTGGGCGGTTCGAGGTGGTCTCCCAGGGTCGGCAACAGATGCTGGCTCCATCTGCCCTGCGGCTGCCACCTTCCAGGTGGCACTGAGCCCAGCCTCTGTGGATGAGGCCCCTCAGCCCAGCTTGCCCCCCGAGGCAGCCCAGGAGGGTGACCTGCACCTACTGTGGGAGGCCCTGGCTCGGAAACGTCGCATGAGCCGTGAGCCCACGCTGGACTCCATTAGCGAGCTGCCAGAGGAGGACGGCCGCTCGCAGCGCCTGCCACAGGAGGCAGAGGAGGTGGCACCTGATCTCTCTGAAGGCTACTCCACGGCCGATGAGCTGGCCCGCACTGGAGATGCTCACCTCTCACACACCAGCTCTGATGATGAGTCCCGGGCAGGCACCCCTTCCCTGGTCACCTACCTCAAGAAGGCTGGGAGGCCAGGCACCTCACCACTGGCCAGCAAGGTGAGCCCCCCCAACTTGGCCTGCAAGGAGAGGTTCCCCACGCCCCGGGCCGGCCCCAGCCTCCTGGGCTTCGTGGGGGCAGACCCAGCCTTTCCCGGCAGCGAGCGCTCGGCCAGGTGCACTAGGCGCTGTGCGGCCCCCCCTCCCCGCGAGTCCCTCAAGCGGGAACCTGCCTCGTGTCTCCCAGGAGCCATGGAGGCTGTGGAACTCGCCAGAAAACTGCAGGAGGAAGCTACGTGCTCCATCTGTCTGGATTACTTCACAGACCCTGTGATGACCACCTGTGGCCACAACTTCTGCCGAGCGTGCATCCAGCTGAGCTGGGAAAAGGCGAGGGGCAAGAAGGGGAGGCGGAAGCGGAAGGGCTCCTTCCCCTGCCCCGAGTGCAGAGAGATGTCCCCGCAGAGGAACCTGCTGCCCAACCGGCTGCTGACCAAGGTGGCCGAGATGGCGCAGCAGCATCCTGGTCTGCAGAAGCAAGACCTGTGCCAGGAGCACCACGAGCCCCTCAAGCTTTTCTGCCAGAAGGACCAGAGCCCCATCTGTGTGGTGTGCAGGGAGTCCCGGGAGCACCGGCTGCACAGGGTGCTGCCCGCCGAGCAGGCAGTGCAGGGGTACAAGTTGAAGCTGGAGGAGGACATGGAGTACCTTCGGGAGCAGATCACCAGGACAGGGAATCTGCAGGCCAGGGAGGAGCAGAGCTTAGCCGAGTGGCAGGGCAAGGTGAAGGAGCGGAGAGAACGCATTGTGCTGGAGTTTGAGAAGATGAACCTCTACCTGGTGGAAGAAGAGCAGAGGCTCCTCCACGCTCTCGAGACGGAAGAAGAGGAGACTGCCAGCAGGCTCCGGGAGAGCGTGGCCTGCCTGGACCGGCAGGGTCACTCTCTGGAGCTGCTGCTGCTGCAGCTGGAGGAGCGGAGCACACAGGGGCCCCTCCAGATGCTGCAGGACATGAAGGAACCCCTGAGCAGGGCGGCGTTACTGGTGGTTCTAATTCATGGGATGAATCTTGTTGAGTTCCCAGTGGTCTCTCTGCCCAGCCCCCTGTACCTTATTGCCACCAACCCCCACACACAATTGGGCCCGGGGACTCCCACCTTTGACCCTGAATGCCCCACACCTCTCCCCATCTCTCCACCACCACGCCCATCTACAGAGGATGTGGTGCCTGATGCCACCTCCGCGTACCCCTACCTCCTCCTGTATGAGAGCCGCCAGACGCGCTACCTCGGCTCTTCGCCGGAGGGCAGTGGGTTCTGCAGCAAGGACCGATTTGTGCCTTACCCCTGTGCTGTGGGCCAGACGGCCTTCTCCTCTGGGAGGCACTACTGGGAGGTGGGCATGAACATCACCGGGGACGCGTTGTGGGCCCTGGGTGTGTCCAGGGACAACGTGAGCCGGAAAGACAGGGTCCCCAAGTGCCCCGAAAACGGCTTCTGGGTGGTGCAGCTGTCCAAGGGGACCAAGTACTTATCCACCTTCTCTGCCCTAACCCCGGTCATGCTGATGGAGCCTCCCAGCCACATGGGCATCTTCCTGGACTTCGAAGCCGGGGAAGTGTCCTTCTACAGTGTAAGCGATGGGTCCCACCTGCACACCTACTCCCAGGCCACCTTCCCAGGCCCCCTGCAGCCTTTCTTCTGCCTGGGGGCTCCCAAGTCTGGTCAGATGGTCATCTCCACAGTGACCATGGCAGGGGTAAAAGACCTGGCCACAAGAACCGGAGCGGTCGTGACGCCAGCGCTCGGAGCCTACGCGCCCAGCGCTACCGAAACCCAGAGTCCTGCGCCCTGGAGTCCCCGCGCCCCGGAGCCCGAGCACCCGGCAGTCCCGACCCTCGCCCCCCGGAGTGCCCGAGCCTGCGCCGCCGCACCCGGATACCCCGGGTCCCCGCGAGCTCCCCAGGCCGCCCGCCGCCGCCCCGCGGACAGTACCGCCTTCCTCCCCTCTGTCCGCGCCATGGCCGCCCCCGACCTGTCCACCAACCTCCAGGAGGAGGCCACCTGCGCCATCTGCCTCGACTACTTCACGGATCCGGTGATGACCGACTGCGGCCACAACTTCTGCCGCGAGTGCATCCGGCGCTGCTGGGGCCAGCCCGAGGGCCCGTACGCGTGCCCCGAGTGCCGCGAGCTGTCCCCGCAGAGGAACCTGCGGCCCAACCGCCCGCTTGCTAAGATGGCCGAGATGGCGCGGCGCCTGCACCCGCCGTCGCCGGTCCCGCAGGGCGTGTGCCCCGCGCACCGCGAGCCACTGGCCGCCTTCTGTGGCGACGAGCTGCGCCTCCTGTGTGCGGCCTGCGAGCGCTCTGGGGAGCACTGGGCGCACCGCGTGCGGCCGCTGCAGGACGCGGCCGAAGACCTCAAGGCGAAGCTGGAGAAGTCACTGGAGCATCTCCGGAAGCAGATGCAGGATGCGTTGCTGTTCCAAGCCCAGGCGCATGAGACCTGCGTCTTGTGGCAGAAGATGGTGGAGAGCCAGCGGCAGAACGTGCTGGGTGAGTTCGAGCGTCTTCGCCGTTTGCTGGCAGAGGGAGGGACAGCAGCTGCTGCAGAGGCTGGAGAGGAGGAGCTGAAGCAGAGCGCCCACCTAGCTGAGCTCATCGCCGAGCTCGAGAGGCCGCTGCCAGCTGCCTGCGCTGGGGCTGCTGCAGCAGAGTCTTTTCCCATGTGTGGGCTCCACTCCCTGAGCCGGCCCCCTGGCGTGGGCTTTCCTTGGTGCACCCCCTGGAGCCCACAATGCTGCAGATGTGGCTGGGCGGCTTTGCACAGGGGGTGACACTGCTGCCGGCCTCTGGAGCCCACCAGAACATCAGTCCAGGCACCGGCTCCTGGTTTCGATTGTCATTTCTATTATTTAAGGGGTACAAGTGCAGTCAGAGTGTAGCCATCACCCCAATGGTCCACACTGTACCCAAGACCAAACCCCCTTGTCGAGGCCAAGGTTCTCCTCTACCCCCAAGCCCTTCTCCTGCCGCCCCTGCACCCGGCCTTGTGACAGCCACCACCTGTTTCCAAATGACACCAGGGGTGGGCCGCCCACCCCAGGACATCAAGGACGCCCTGCGCAGGGTCCAGGATGTGAAGCTGCAGCCCCCAGAAGTTGTGCCTATGGAGCTGAGGACCGTGTGCAGGGTCCCGGGACTGGTAGAGACACTGCGGAGGTTTCGAGGGGACGTGACCTTGGACCCGGACACCGCCAACCCTGAGCTGATCCTGTCTGAAGACAGGCGGAGCGTGCAGCGGGGGGACCTACGGCAGGCCCTGCCGGACAGCCCAGAGCGCTTTGACCCCGGCCCCTGCGTGCTGGGCCAGGAGCGCTTCACCTCAGGCCGCCACTACTGGGAGGTGGAGGTTGGGGACCGCACCAGCTGGGCCCTGGGGGTGTGCAGGGAGAACGTGAACAGGAAGGAGAAGGGCGAGCTGTCCGCGGGCAACGGCTTCTGGATCCTGGTCTTCCTGGGGAGCTATTACAATTCCTCGGAACGGGCCTTGGCTCCACTCCGGGACCCACCCAGGCGCGTGGGGATCTTTCTGGACTACOAGGCTGGACATCTCTCTTTCTACAGTGCCACCGATCGGTCACTGCTATTCATCTTTCCCGAGATCCCCTTCTCGGGGACGCTGCGGCCCCTCTTCTCACCCCTGTCCAGCAGCCCGACCCCGATGACTATCTGCCGGCCGAAAGGTGGGTCCGGGGACACCCTGGCTCCCCAGTGACTCGGGCCCTCCTGGAGGAORF Start: ATG at 15ORF Stop: TGA at 14040SEQ ID NO:744675 aa MW at 511097.3 kDNOV13b,MPLYNDSFHEISHKGRRHTLVLKSIQRADAGIVRASSLKVSTSARLEVRVKPVVFLKACG59237-02 ProteinLDDLSAEERGTLALQCEVSDPEAHVVWRKDGVQLGPSDKYDFLHTAGTRGLVVHDVSPSequenceEDAGLYTCHVGSEETRARVRVHDLHVGITKRLKTMEVLEGESCSFECVLSHESASDPAMWTVGGKTVGSSSRFQATRQGRKYILVVREAAPSDAGEVVFSVRGLTSKASLIVRERPAAIIKPLEDQWVAPCEDVELRCELSRAGTPVHWLKDRKAIRKSQKYDVVCEGTMAMLVIRGASLKDAGEYTCEVEASKSTASLHVEEKANCFTEELTNLQVEEKGTAVFTCKTEHPAATVTWRKGLLELPASGKHQPSQEGLTLRLTISALEKADSDTYTCDIGQAQSRAQLLVQGRRVHIIEDLEDVDVQEGSSATFRCRISPANYEPVHWFLDKTPLHANELNEIDAQPGGYHVLTLRQLALKDSGTIYFEAGDQRASAALRVTEKPSVFSRELTDATITEGEDLTLVCETSTCDIPVCWTKDGKTLRGSARCQLSHEGHRAQLLITGATLQDSGRYKCEAGGACSSSIVRVHARPVRFQEALKDLEVLEGGAATLRCVLSSVAAPVKWCYGNNVLRPGDKYSLRQEGAMLELVVRNLRPQDSGRYSCSFGDQTTSATLTVTALPAQFIGKLRNKEATEGATATLRCELSKAAPVEWRKGSETLRDGDRYCLRQDGAMCELQIRGLAMVDAAEYSCVCGEERTSASLTIRPMPAHFIGRLRHQESIEGATATLRCELSKAAPVEWRKGRESLRDGDRHSLRQDGAVCELQICGLAVADAGEYSCVCGEERTSATLTVKALPAKFTEGLRNEEAVEGATANLWCELSKVAPVEWRKGPENLRDGDRYILRQEGTRCELQICGLAHADAGEYLCVCGQERTSATLTIRALPARFIEDVKNQEAREGATAVLQCELNSAAPVEWRKGSETLRDGDRYSLRQDGTKCELQIRGLAMADTGEYSCVCGQERTSAMLTVRALPIKFTEGLRNEEATEGATAVLRCELSKMAPVEWWKGHETLRDGDRHSLRQDGARCELQIRGLVAEDAGEYLCMCGKERTSAMLTVRAMPSKEIEGLRNEEATEGDTATLWCELSKAAPVEWRKGHETLRDGDRHSLRQDGSRCELQIRGLAVVDAGEYSCVCGQERTSATLTVRALPARFIEDVKNQEAREGATAVLQCELSKAAPVEWRKGSETLRGGDRYSLRQDGTRCELQIHGLSVADTGEYSCVCGQERTSATLTVRALPARFTQDLKTKEASEGATATLQCELSKVAPVEWKKGPETLRDGGRYSLKQDGTRCELQIHDLSVADAGEYSCMCGQERTSATLTVRALPARFTEGLRNEEAMEGATATLQCELSKAAPVEWRKGLEALRDGDKYSLRQDGAVCELQIHGLAMADNGVYSCVCGQERTSATLTVRALPARFIEDMRNQKATEGATVTLQCKLRKAAPVEWRKGPNTLKDGDRYSLKQDGTSCELQIRGLVIADAGEYSCICEQERTSATLTVRALPARFIEDVRNHEATEGATAVLQCELSKAAPVEWRKGSETLRDGDRYSLRQDGTRCELQIRGLAVEDTGEYLCVCGQERTSATLTVRALPARFIDNNTNQEAREGATATLHCELSKVAPVEWRKGPETLRDGDRHSLRQDGSRCELQIRGLAVVDAGEYSCVCGQERTSATLTVRALPARFIEDVKNQEAREGATAVLQCELSKAAPVEWRKGSETLRGGDRYSLRQDGTRCELQIHGLSVADTGEYSCVCGQERTSATLTVRALPARFTQDLKTKEASEGATATLQCELSKVAPVEWKKGPETLRDGGRYSLKQDGTRCELQIHDLSVADAGEYSCMCGQERTSATLTVRDCHTLHVMPHYPFQLPGLLKEPEETLIYIQIPSPVILFTEGLRNEEANEGATATLQCELSKAAPVEWRKGLEALRDGDKYSLRQDGAVCELQIHGLAMADNGVYSSLPARFIEDMRNQKATEGATVTLQCKLRKAAPVEWRKGPNTLKDGDRYSLKQDGTSCELQIRGLVIADAGEYSCICEQERTSATLTVRALPARFIEDVRNEEATEGATAVLQCELSKAAPVEWRKGSETLRDGDRYSLRQDGTRCELQIRGLAVEDTGEYLCVCGQERTSATLTVRALPARFIDNNTNQEAREGATATLHCELSKVAPVEWRKGPETLRDGDRHSLRQDGTRCELQIRGLSVADAGEYSCVCGQERTSATLTIRALPAKFTKGLRNEEATEGATANLQCELSKVAPVEWRKGPETLRDGDRYNLRQDGTRCELQIHGLSVADTGEYSCVCGQEKTSATLTVKAPQPVFREPLQSLQAEEGSTATLQCELSEPTATVVWSKGGLQLQANGRREPRLQGCTAELVLQDLQREDTGEYTCTCGSQATSATLTVTAAPVRFLRELQHQEVDEGGTAHLCCELSRAGASVEWRKGSLQLFPCAKYQMVQDGAAAELLVRGVEQEDAGDYTCDTGHTQSMASLSVRGGRGAACGPQVRDAAQGATRELLIHQLEAKDTGEYACVTGGQKTAASLRVTEPEVTIVRGLVDAEVTADEDVEFSCEVSRAGATGVQWCLQGLPLQSNEVTEVAVRDGRIHTLRLKGVTPEDAGTVSFHLGNUASSAQLTVRAPEVTILEPLQDVQLRCVPLQANEMNDITVEQGTLHLLTLHKVTLEDAGTVSFHVGTCSSEAQLKVTEAVPCLVRGLQNVDVFAGEVATFSCEDGPQSAIAVRDGIFHSLMLSGLGVADSGTVIFRAGPLVSTAKLLIKDPVVEVVSAMQDLAVEEGGSAELLCQYSRPVQATWKMDEREVHTDGHRVIIEQDWNVARLTFRPALPCDSGIYSCEAAGTRVVALLQVQAKNTVVRGLENVEALEGGEALFECQLSQPEVAAHTWLLDDEPVRTSENAEVVFFENGLRHLLLLKNLRPQDSCRVTFLAGDMVTSAFLTVRGDCAVLVQGWRLEILEPLKNAAVRAGAQARFTCTLSEAVPVGEASWYINCAAVQPDDSDWTVTADGSHHALLLRSAQPHHAGEVTFACRDAVASARLTVLGLPDPPEDAEVVARSSHTVTLSWAAPMSDGGGGLCGYRVEVKEGATGQWRLCHELVPGPECVVDGLAPGETYRFRVAAVGPVGAGEPVHLPQTVRLEPPKPVPPQPSAPESRQVAAGEDVCLELEVVAEAGEVIWHKGMERIQPGGRFEVVSQGRQQMLVIKGFTAEDQGEYHCGLAQGSICPAAATFQVALSPASVDEAPQPSLPPEAAQEGDLHLLWEALARKRRMSREPTLDSISELPEEDGRSQRLPQEAEEVAPDLSEGYSTADELARTGDADLSHTSSDDESRAGTPSLVTYLKKAGRPGTSPLASKVSPPNLACKERFPTPRAGRSLLGFVGADPAFPGSERSARCTRRCAAPPPRESLKREPASCLPGAMEAVELARKLQEEATCSICLDYFTDPVNTTCGHNFCRACIQLSWEKARGKKGRRKRKCSFPCPECREMSPQRNLLPNRLLTKVAEMAQQHPGLQKQDLCQEHHEPLKLFCQKDQSPICVVCRESREHRLHRVLPAEEAVQGYKLKLEEDMEYLREQITRTGNLQAREEQSLAEWQGKVKERRERIVLEFEKMNLYLVEEEQRLLQALETEEEETASRLRESVACLDRQGHSLELLLLQLEERSTQGPLQMLQDMKEPLSRAALLVVLIHGMNLVEFPVVSLPSPLYLIATKAHTQLGPGTPTFDPECPTPLPISPPPRPSTEDVVPDATSAYPYLLLYESRQRRYLGSSPEGSGFCSKDRFVAYPCAVCQTAFSSGRHYWEVGMNITGDALWALGVCRDNVSRKDRVPKCPENGFWVVQLSKGTKYLSTFSALTPVMLMEPPSHMGIFLDFEAGEVSFYSVSDGSHLHTYSQATFPGPLQPFFCLGAPKSGQMVISTVTMAGVKDLATRTGAVVTPALGAYAPSATETQSPAPWSPRAPEPEHPGVPSLAPRSARACAAAPGYPGSPRAAEAARRRPADSTAFLPSVRANAAPDLSTNLQEEATCAICLDYFTDPVMTDCGHNFCRECIRRCWGQPEGPYACPECRELSPQRNLRPNRPLAKMAEMARRLHPPSPVPQGVCPAHREPLAAFCGDELRLLCAACERSGEHWAHRVRPLQDAAEDLKAKLEKSLEHLRKQMQDALLFQAQADETCVLWQKNVESQRQNVLGEFERLRRLLAEGGTAAAAEAGEEELKQSAHLAELIAELERPLPAACAGAAAGESFPMCGLHSLSRPPGVGFPWCTPKPEPVDALACAWRQGCQTQVEPTMLQMWLGGFAQGVTLLPASGAQQNISPGTGSWERLSFLLFKGYKCSQSVAITRMVHTVPKTKPPCRGQGSPLPPSPSPAAPAPGLVTATTCFQMTPGVCRPPQDIKDALRRVQDVKLQPPEVVPMELRTVCRVPGLVETLRRFRGDVTLDPDTANPELILSEDRRSVQRGDLRQALPDSPERFDPGPCVLGQERFTSGRHYWEVEVGDRTSWALGVCRENVNRKEKGELSAGNGFWILVFLGSYYNSSERALAPLRDPPRRVGIFLDYEACHLSFYSATDGSLLFIFPEIPFSGTLRPLFSPLSSSPTPMTICRPKGGSGDTLAPQ


[0385] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 13B.
70TABLE 13BComparison of NOV13a against NOV13b and NOV13c.NOV13a Residues/Identities/SimilaritiesProtein SequenceMatch Residuesfor the Matched RegionNOV13b1 . . . 46914399/4696 (93%)1 . . . 46754403/4696 (93%)


[0386] Further analysis of the NOV13a protein yielded the following properties shown in Table 13C.
71TABLE 13CProtein Sequence Properties NOV13aPSort0.8500 probability located in endoplasmic reticulumanalysis:(membrane); 0.4400 probability located in plasma membrane;0.3500 probability located in nucleus; 0.3000probability located in microbody (peroxisome)SignalPNo Known Signal Sequence Indicatedanalysis:


[0387] A search of the NOV13a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 13D.
72TABLE 13DGeneseq Results for NOV13aNOV13aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length/[Patent#,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAB42919Human ORFX ORF2683 polypeptide3482 . . . 3981 448/500 (89%)0.0sequence SEQ ID NO:5366 - Homo 1 . . . 473 452/500 (89%)sapiens, 477 aa. [WO200058473-A2,05-OCT-2000]AAY53666from an alignment with protein 608 - 264 . . . 34431270/3235 (38%) 0.0Unidentified, 4412 aa. [WO9960164-A1, 25-NOV-1999]AAU05396Human titin (connectin) protein  9 . . . 1892526/1918 (27%)0.0sequence - Homo sapiens, 26926 aa.4667 . . . 6570859/1918 (44%)[WO200151666-A1, 19-JUL-2001]AAB43498Human cancer associated protein3480 . . . 3992 193/536 (36%)5e−84sequence SEQ ID NO:943 - Homo 66 . . . 570  285/536 (53%)sapiens, 580 aa. [WO200055350-A1,21-SEP-2000]AAY53667Sequence gi/3328186 from an 70 . . . 2452586/2595 (22%)3e−80alignment with protein 608 - 446 . . . 2900977/2595 (37%)Unidentified, 3117 aa. [WO9960164-A1, 25-Nov-1999]


[0388] In a BLAST search of public sequence databases, the NOV13a protein was found to have homology to the proteins shown in the BLASTP data in Table 13E.
73TABLE 13EPublic BLASTP Results for NOV13aNOV13aProteinResidues/Identities/AccessionMatchSimilarities for theExpectNumberProtein/Organisation/LengthResiduesMatched PortionValueQ9HCL6KIAA1556 PROTEIN - Homo 132 . . . 16971565/1566 (99%)0.0sapiens (Human), 1596 aa  1 . . . 15661566/1566 (99%)(fragment).Q96AA2OBSCURIN - Homo sapiens  1 . . . 23681605/2430 (66%)0.0(Human), 6620 aa.2595 . . . 49921764/2430 (72%)Q9Y577RING FINGER PROTEIN TERF -3482 . . . 3981 449/500 (89%)0.0Homo sapiens (Human), 477 aa. 1 . . . 473 453/500 (89%)CAD12456TITIN - Homo sapiens (Human), 41 . . . 3323 811/3501 (23%)0.034350 aa.5588 . . . 89211361/3501 (38%)Q9WV59RING FINGER PROTEIN TERF -3482 . . . 3981 341/500 (68%)0.0Rattus norvegicus (Rat), 477 aa. 1 . . . 473 400/500 (79%)


[0389] PFam analysis indicates that the NOV13a protein contains the domains shown in the Table 13F.
74TABLE 13FDomain Analysis of NOV13aSimilaritiesfor the MatchedPfam DomainRegionRegionValueig: domain 1 of 3467 . . . 2618/64 (28%)1.3e−0947/64 (73%)ig: domain 2 of 34156 . . . 21212/59 (20%)3040/59 (68%)PEP-utilizers: domain 1 of178 . . . 26022/105 (21%) 2.4150/105 (48%) ig: domain 3 of 34247 . . . 30618/64 (28%)6.5e−1043/64 (67%)MAM: domain 1 of 1159 . . . 30635/191 (18%) 4.189/191 (47%) ig: domain 4 of 34336 . . . 39516/64 (25%)5.7e−0743/64 (67%)ig: domain 5 of 34425 . . . 48113/60 (22%)0.002539/60 (65%)ig: domain 6 of 34516 . . . 57518/64 (28%)1.5e−0847/64 (73%)ig: domain 7 of 34605 . . . 66415/64 (23%)1.1e−0741/64 (64%)ig: domain 8 of 34694 . . . 75213/64 (20%)6.2e−0542/64 (66%)ig: domain 9 of 34782 . . . 84014/64 (22%)  1e−0542/64 (66%)ig: domain 10 of 34870 . . . 92813/64 (20%)0.001240/64 (62%)ig: domain 11 of 34 958 . . . 101612/64 (19%)0.0001144/64 (69%)ig: domain 12 of 341046 . . . 110413/64 (20%)8.5e−0644/64 (69%)ig: domain 13 of 341134 . . . 119214/64 (22%)3.3e−0646/64 (72%)ig: domain 14 of 341222 . . . 128013/64 (20%)4.5e−0645/64 (70%)ig: domain 15 of 341310 . . . 136813/64 (20%)8.5e−0746/64 (72%)ig: domain 16 of 341398 . . . 145614/64 (22%)  3e−0541/64 (64%)ig: domain 17 of 341486 . . . 154413/64 (20%)0.0008541/64 (64%)ig: domain 18 of 341574 . . . 163214/64 (22%)8.6e−0644/64 (69%)ig: domain 19 of 341662 . . . 172014/64 (22%)3.6e−0544/64 (69%)ig: domain 20 of 341750 . . . 180813/64 (20%)4.5e−0645/64 (70%)ig: domain 21 of 341838 . . . 189613/64 (20%)8.5e−0746/64 (72%)ig: domain 22 of 341958 . . . 201312/61 (20%)0.01439/61 (64%)ig: domain 23 of 342031 . . . 208913/64 (20%)0.0008541/64 (64%)ig: domain 24 of 342119 . . . 217714/64 (22%)8.6e−0644/64 (69%)ig: domain 25 of 342207 . . . 226514/64 (22%)5.3e−0645/64 (70%)ig: domain 26 of 342295 . . . 235313/64 (20%)1.4e−0545/64 (70%)ig: domain 27 of 342383 . . . 244216/64 (25%)  1e−0948/64 (75%)ig: domain 28 of 342472 . . . 253114/64 (22%)0.001439/64 (61%)ig: domain 29 of 342565 . . . 2582 7/19 (37%)0.9213/19 (68%)ig: domain 30 of 342612 . . . 266816/60 (27%)5.5e−0542/60 (70%)ig: domain 31 of 342842 . . . 290116/65 (25%)0.0003546/65 (71%)ig: domain 32 of 342930 . . . 298813/66 (20%)0.1838/66 (58%)ig: domain 33 of 343030 . . . 308913/62 (21%)0.2242/62 (68%)fn3: domain 1 of 13107 . . . 319229/89 (33%)1.2e−1463/89 (71%)ig: domain 34 of 343237 . . . 328010/47 (21%)4.629/47 (62%)zf-C3HC4: domain 1 of 23497 . . . 354620/61 (33%)2.1e−1448/61 (79%)PHD: domain 1 of 13496 . . . 354913/59 (22%)1.937/59 (63%)zf-B_box: domain 1 of 23575 . . . 361622/48 (46%)3.1e−1538/48 (79%)zf-UBR1: domain 1 of 13578 . . . 362913/80 (16%)9.834/80 (42%)SPRY: domain 1 of 23856 . . . 398041/157 (26%) 1.9e−3295/157 (61%) zf-C3HC4: domain 2 of 24086 . . . 411616/41 (39%)3.8e−1228/41 (68%)Flu_M1: domain 1 of 14178 . . . 4189 6/12 (50%)4.7 9/12 (75%)zf-B_box: domain 2 of 24156 . . . 419718/48 (38%)0.03126/48 (54%)Idh_C: domain 1 of 14222 . . . 4242 8/21 (38%)8.917/21 (81%)SPRY: domain 2 of 24562 . . . 468136/157 (23%)5.6e−2990/157 (57%)



Example 14

[0390] The NOV14 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 14A.
75TABLE 14ANOV14 Sequence AnalysisSEQ ID NO:751617 bpNOV14a,CTCTCTCGCCGGTGACCCGGTGTGCGTGGGGTCGAGGCGCCGGGCGGAGTGGCTCCGGCG58575-01 DNAGCCGAAACGCCATGCGGAGGGGCGAGCGCAGGGACGCCGGAGGTCCGCGGCCCGAGTCSequenceCCCGGTGCCCGCGGGCAGGGCCTCCCTGGAGGAGCCGCCTGACCGCCCGTCTGCCGGCCAAGCCACCGGGCCGGGGCGAGGCCGCAGCACCGAGTCCGAGGTCTACGACGACGGCACCAACACCTTCTTCTGGCGAGCCCACACCTTAACCGTGCTCTTCATCCTCACCTGTACGCTTGGCTATGTGACGCTGCTGGAGGAAACACCTCAGGACACGGCCTACAACACCAAGAGAGGTATTGTGGCCAGTATTTTGGTTTTCTTATGTTTTGGAGTCACACAAGCTAAAGACGGGCCATTTTCCAGACCTCATCCAGCTTACTGGAGGTTTTGGCTCTGCGTGAGTGTGGTCTACGAGCTGTTTCTCATCTTTATACTCTTCCAGACTGTCCACGACGGCCGGCAGTTTCTAAAGTATGTTGACCCCAAGCTGGGAGTCCCACTGCCAGAGAGAGACTACGGGGGAAACTGCCTCATCTACGACCCAGACAATGAGACTGACCCCTTTCACAACATCTGGGACAAGTTGGATGGCTTTGTTCCCGCGCACTTTCTTGGCTGGTACCTGAAGACCCTGATGATCCGAGACTGGTGGATGTGCATGATCATCAGCGTGATGTTCGAGTTCCTGGAGTACAGCCTGGAGCACCAGCTGCCCAACTTCAGCGAGTGCTGGTGGGATCACTGGATCATGGACGTGCTCGTCTGCAACGGGCTGGGCATCTACTGCGGCATGAAGACCCTTGAGTGGCTGTCCCTGAAGACGTACAAGGGCAAGATGAAGAGGATCGCCTTCCAGTTCACGCCGTACAGCTGGGTTCGCTTCGAGTGGAAGCCGGCCTCCAGCCTGCGTCGCTGGCTGGCCGTGTGCGGCATCATCCTGGTGTTCCTGTTGGCAGAACTGAACACGTTCTACCTGAAGTTTGTGCTGTGGATGCCCCCGGAGCACTACCTGGTCCTCCTGCGGCTCGTCTTCTTCGTGAACGTGGGTGGCGTGGCCATGCGTGAGATCTACGACTTCATGGATGACCCGAAGCCCCACAAGAAGCTGGGCCCGCAGGCCTGGCTGGTGGCGGCCATCACGGCCACGGAGCTGCTCATCGTGGTGAAGTACGACCCCCACACGCTCACCCTGTCCCTGCCCTTCTACATCTCCCAGTGCTGGACCCTCGGCTCCGTCCTGGCGCTCACCTGGACCGTCTGGCGCTTCTTCCTGCGGGACATCACATTGAGGTACAAGGAGACCCGGTGGCAGAAGTGGCAGAACAAGGATGACCAGGGCAGCACCGTCGGCAACGGGGACCAGCACCCACTGGGGCTGGACGAAGACCTGCTGGGGCCTGGGGTGGCCGAGGGCGAGGGAGCACCAACTCCAAACTGACCTGGGCCGTGGCTGCCTCGTGAGCCTCCCAGAGCCCAGGCCTCCGTGGCCTCCTCCTGTCTCGTGTGGGCGCTCGTCCACAAACACTCCGTGGCTGAGAGGCAGCGGATCCAGGCAGCGORF Start: ATG at 70ORF Stop: TCA at 1495SEQ ID NO: 76475 aa MW at 54735.7 kDNOV14a,MRRCERRDAGGPRPESPVPACRASLEEPPDCPSAGQATGPGRCRSTESEVYDDGTNTFC058575-01 ProteinFWRAHTLTVLFILTCTLGYVTLLEETPQDTAYNTKRGIVASILVFLCFGVTQAKDGPFSequenceSRPHPAYWRFWLCVSVVYELFLIFILFQTVQDGRQFLKYVDPKLGVPLPERDYGGNCLIYDPDNETDPFHNIWDKLDGFVPAHFLGWYLKTLMIRDWWMCMIISVMFEFLEYSLEHQLPNFSECWWDHWIMDVLVCNGLGIYCGMKTLEWLSLKTYKGKMKRIAFQFTPYSWVRFEWKPASSLRRWLAVCGIILVFLLAELNTFYLKFVLWMPPEHYLVLLRLVFFVNVGGVAMREIYDFMDDPKPHKKLGPQAWLVAAITATELLIVVKYDPHTLTLSLPFYISQCWTLGSVLALTWTVWRFFLRDITLRYKETRWQKWQNKDDQGSTVGNGDQHPLGLDEDLLGPGVAEGEGAPTPN


[0391] Further analysis of the NOV14a protein yielded the following properties shown in Table 14B.
76TABLE 14BProtein Sequence Properties NOV14aPSort0.6000 probability located in plasma membrane; 0.4000analysis:probability located in Golgi body; 0.3000 probability locatedin endoplasmic reticulum (membrane); 0.0300probability located in mitochondrial inner membraneSignalPCleavage site between residues 8 and 9analysis:


[0392] A search of the NOV14a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 14C.
77TABLE 14CGeneseq Results for NOV14aNOV14aIdentities/GeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAM79907Human protein SEQ ID NO 3553 - 1 . . . 475474/487 (97%)0.0Homo sapiens, 529 aa.19 . . . 505474/487 (97%)[WO200157190-A2, 09-AUG-2001]AAM78923Human protein SEQ ID NO 1585 - 1 . . . 475474/487 (97%)0.0Homo sapiens, 487 aa. 1 . . . 487474/487 (97%)[WO200157190-A2, 09-AUG-2001]AAB73515Human transferase HTFS-22, SEQ ID 1 . . . 475473/487 (97%)0.0NO: 22 - Homo sapiens, 487 aa. 1 . . . 487473/487 (97%)[WO200132888-A2, 10-MAY-2001]AAG30975Arabidopsis thaliana protein fragment41 . . . 387141/363 (38%)2e−73SEQ ID NO: 37124 - Arabidopsis 3 . . . 363209/363 (56%)thaliana, 436 aa. [EP1033405-A2,06-SEP-2000]AAG30974Arabidopsis thaliana protein fragment41 . . . 387141/363 (38%)2e−73SEQ ID NO: 37123 - Arabidopsis21 . . . 381209/363 (56%)thaliana, 454 aa. [EP1033405-A2,06-SEP-2000]


[0393] In a BLAST search of public sequence databases, the NOV14a protein was found to have homology to the proteins shown in the BLASTP data in Table 14D.
78TABLE 14DPublic BLASTP Results for NOV14aNOV14aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ9BVG9SIMILAR TO1 . . . 475474/487 (97%)0.0PHOSPHATIDYLSERINE SYNTHASE1 . . . 487474/487 (97%)2 - Homo sapiens (Human), 487 aa.O08888PHOSPHATIDYLSERINE SYNTHASE1 . . . 471408/482 (84%)0.0II - Cricetulus griseus (Chinese hamster),1 . . . 458422/482 (86%)474 aa.Q9Z1X2PHOSPHATIDYLSERINE SYNTHASE-1 . . . 470409/481 (85%)0.02 - Mus musculus (Mouse), 473 aa.1 . . . 457419/481 (87%)Q922A1SIMILAR TO95 . . . 470 345/387 (89%)0.0PHOSPHATIDYLSERINE SYNTHASE1 . . . 384354/387 (91%)2 - Mus musculus (Mouse), 400 aa(fragment).Q9CY687 DAYS EMBRYO CDNA, RIKEN1 . . . 273239/273 (87%)e−144FULL-LENGTH ENRICHED1 . . . 252243/273 (88%)LIBRARY, CLONE: C430041K09,FULL INSERT SEQUENCE - Musmusculus (Mouse), 300 aa.


[0394] PFam analysis that the NOV14a protein contains the domains shown in the Table 14E.
79TABLE 14EDomain Analysis of NOV14aIdentities/SimilaritiesNOV14a Matchfor the MatchedExpectPfam DomainRegionRegionValuePeptidase_C20: domain302 . . . 327  8/28 (29%)21 of 1 19/28 (68%)PSS: domain 1 of 1119 . . . 390151/310 (49%)3e−201269/310 (87%)



Example 15

[0395] The NOV15 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 15A.
80TABLE 15ANOV15 Sequence AnalysisSEQ ID NO:771210 bpNOV15a,TCGCTCACCCACCCGGACTCATTCTCCCCAGACGCCAAGGATGGTGGTCATGGCACCCCG59256-01 DNACGAACCCTCTTCCTGCTACTCTCGGGGGCCCTGACCCTGACCGAGACCTGCGCGGGCTSequenceCCCACTCCATGAGGTATTTCAGCGCCGCCGTGTCCCGGCCCGGCCGCGGGGAGCCCCGCTTCATCGCCATGGGCTACGTGGACGACACGCAGTTCGTGCGGTTCGACAGCGACTCGGCGTGTCCGAGGATGGAGCCGCGGGCGCCGTGGGTGGAGCAGGAGGGGCCAGAGTATTGGGAAGAGGAGACACGGAACACCAAGGCCCACGCACAGACTGACAGAATGAACCTGCAGACCCTGCGCGGCTACTACAACCAGAGCGAGGGGGTGGGGCCAGGTTCTCATACCCTCCAGTGGATGATTCGCTGCGACCTGGGGTCCGACGGACGCCTCCTCCGCGGGTATGAACAGTATGCCTACGATGGCAACGATTACCTCCCCCTGAACGAGGACCTGCGCTCCTGGACCGCAGCGGACACTGCGGCTCAGATCTCCAAGCCCAAGTGTGAGGCGGCCAATGTGGCTGAACAAAGGAGAGCCTACCTGGAGGGCACGTGCGTGGAGTGGCTCCACAGATACCTCGAGAACGGGAAGGAGATGCTGCAGCGCGCGGACCCCCCCAAGACACACGTGACCCACCACCCTGTCTTTGACTATCAGGCCACCCTGAGGTGCTGGGCCCTGGGCTTCTACCCTGCGGAGATCATACTGACCTGGCAGCGGGATGGGGAGGACCAGACCCAGGACGTGGAGCTCGTGGAGACCAGGCCTGCAGGGGATGGAACCTTCCAGAAGTGGGCAGCTGTGGTGGTGCCTTCTGGAGAGGAGCAGAGATACACGTGCCATGTGCAGCATGACGGGCTGCCGGAGCCCCTCATGCTGAGATGGGAGCAGTCTTCCCTGCCCACCATCCCCATCATGGGTATCGTTGCTCGTCTGGTTGTCCTTGCAGCTGTAGTCACTGGAGCTGCGGTCGCTGCTGTGCTGTGGAGGAAGAAGAGCTCAGGTAAGAAAGGAGGGAGCTACTCTCAGGCTGCAAGTAGTGACAGTGCCCAGGGCTCTAATGTGTCTCTCACGGCTTGTAAATGTGACACCCCGGGGGGCCTGATGTGTGTGGGTTGTTGAGGGAAACAGTGGACATAGCTGTGCTATGAGORF Start: ATG at 41ORF Stop: TGA at 1178SEQ ID NO:78379 aa MW at 42027.9 kDNOV15a,MVVMAPRTLFLLLSCALTLTETWAGSHSMRYFSAAVSRPGRGEPRFIAMGYVDDTQFVCG59256-01 ProteinRFDSDSACPRMEPRAPWVEQEGPEYWEEETRNTKAHAQTDRMNLQTLRGYYNQSEGVGSequencePGSHTLQWMIGCDLGSDGRLLRGYEQYAYDGKDYLALNEDLRSWTAADTAAQISKRKCEAANVAEQRRAYLEGTCVEWLHRYLENGKEMLQRADPPKTHVTHHPVFDYEATLRCWALGFYPAEIILTWQRDGEDQTQDVELVETRPAGDGTFQKWAAVVVPSGEEQRYTCHVQHEGLPEPLMLRWEQSSLPTIPIMGIVAGLVVLAAVVTGAAVAAVLWRKKSSGKKGGSYSQAASSDSAQGSNVSLTACKCDTPGGLMCVGC


[0396] Further analysis of the NOV15a protein yielded the following properties shown in Table 15B.
81TABLE 15BProtein Sequence Properties NOV15aPSort0.4600 probability located in plasma membrane; 0.1000analysis:probability located in endoplasmic reticulum (membrane);0.1000 probability located in endoplasmic reticulum (lumen);0.1000 probability located in outsideSignalPCleavage site between residues 25 and 26analysis:


[0397] A search of the NOV15a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 15C.
82TABLE 15CGeneseq Results for NOV15aNOV15aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAB36874MHC class I protein - Unidentified, 3651 . . . 367299/367 (81%)e−179aa. [US6140305-A, 31-OCT-2000]1 . . . 364324/367 (87%)AAB58683HLA-A2/A28 protein #4 - Unidentified,1 . . . 367298/367 (81%)e−179365 aa. [US6153408-A, 28-NOV-2000]1 . . . 364324/367 (88%)AAY52922HLA-A2/A28 family peptide A2 (Lee)1 . . . 367298/367 (81%)e−179SEQ ID NO: 100 - Mammalia, 365 aa.1 . . . 364324/367 (88%)[US5976551-A, 02-NOV-1999]AAY68268Human leukocyte antigen A2/A281 . . . 367298/367 (81%)e−179family protein SEQ ID NO: 100 - Homo1 . . . 364324/367 (88%)sapiens, 365 aa. [US6011146-A,04-JAN-2000]AAB58681HLA-A2/A28 protein #2 - Unidentified,1 . . . 367297/367 (80%)e−178365 aa. [US6153408-A, 28-NOV-2000]1 . . . 364323/367 (87%)


[0398] In a BLAST search of public sequence databases, the NOV15a protein was found to have homology to the proteins shown in the BLASTP data in Table 15D.
83TABLE 15DPublic BLASTP Results for NOV15aNOV15aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueP17693HLA class I histocompatibility antigen,1 . . . 340334/340 (98%)0.0alpha chain G precursor (HLA G1 . . . 337335/340 (98%)antigen) - Homo sapiens (Human), 338aa.Q9MYA2MHC CLASS I ANTIGEN - Homo1 . . . 340332/340 (97%)0.0sapiens (Human), 338 aa.1 . . . 337335/340 (97%)Q30182LYMPHOCYTE ANTIGEN - Homo1 . . . 340334/341 (97%)0.0sapiens (Human), 339 aa.1 . . . 338335/341 (97%)AAH21708HYPOTHETICAL 38.3 KDA1 . . . 340331/340 (97%)0.0PROTEIN - Homo sapiens (Human),1 . . . 337334/340 (97%)338 aa.Q9TP69DJ377H14.1 (MAJOR4 . . . 340331/337 (98%)0.0HISTOCOMPATIBILITY1 . . . 334332/337 (98%)COMPLEX, CLASS I, G (HLA 6.0)) -Homo sapiens (Human), 335 aa.


[0399] PFam analysis indicates that the NOV15a protein contains the domains shown in the Table 15E.
84TABLE 15EDomain Analysis of NOV15aIdentities/NOV15aSimilarities for thePfam DomainMatch RegionMatched RegionExpect ValueMHC_1: domain 25 . . . 206145/183 (79%)  2e−1391 of 1179/183 (98%)ig: domain 1 of 1223 . . . 288 15/67 (22%)4.4e−08 45/67 (67%)



Example 16

[0400] The NOV16 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 16A.
85TABLE 16ANOV16 Sequence AnalysisSEQ ID NO:791175 bpNOV16a,ATTCTCCCCAAACGCCAAGGATGGGGGTCATGGCTCCCCGAACCCTCCTCCTGCTGCTCG59239-01 DNACTTGGGGGCCCTGGCCCTGACCGAGACCTGGGCCGGCTCCCACTCCTTGAGGTATTTCSequenceAGCACCGCAGTGTCCCAGCCCGGCCGCGGGGAGCCCCGGTTCATCGCCGTGGGCTACGTGGACGACACAGAGTTCGTGCGGTTCGACAGCGACTCCGTGAGTCCGAGCATCCACCGGCGGGCGCCGTGGGTGGAGCAGGAGCGGCTGGAGTATTGGGACCAGGAGACACGGAACGCCAAGGGCCACGCGCAGATTTACCGAGTGAACCTGCGGACCCTGCTCCGCTATTACAACCAGAGCGAGCATGGTTCTCACACCATCCAGAGGAAGCATGGCTGCGACGTGGGCCCGGACAGGCGCCTCCTCCGCAGGTATGAACAGTTCGCCTACGATGGCAAGGATTACATCGCCCTGAACGACGACCTGCACTCCTGGACCCCCGCGAACACAGCGGCTCAGATCTCCCAGCACAAGTGGGAAGCGGACAAATACTCAGAGCAGGTCAGGGCCTACCTGCAGCGCAAGTGCATGGAGTGGCTCCGCAGACACCTGGAGAACGGGAAGGAGACGCTGCAGCACGCGGATCCCCCAAAGGCACATGTGACCCAGCACCCCATCTCTGACCATGAGGCCACCCTGAGGTGCTGGGCCCTGGGCCTCTACCCTGCGGAGATCACACTGACCTGGCAGCAGGATGGGGAGGACCAGACCCACGACACGGAGCTTGTGGAGACCAGGCCTGCAGGGGACGGAACCGCCCACCATCCCCATCGTGGGCATCGTTGCTGGCCTGTTTCTCCTTGGAGCTGTGGTCACTGCAGCTGTGGTTGCTGCTGCOATOTGGAGCAAGAAAAGCTCAGGTAGGGAAGGCGTGAGAGGTTCTACCCCAGGCAGCAATTGTGCTCAGTACTCTGATGCATCTCATGATACTTGTAAAGCTTGAGACAACTGCCTTGAGTGGGACTGAGAGATACAAAATTTCTTCAGGTCCTTCCTCTGACACORF Start: ATG at 21ORF Stop: TGA at 1113SEQ ID NO:80364 aa MW at 40983.6 kDNOV16a,MGVMAPRTLLLLLLGALALTETWAGSHSLRYFSTAVSQPGRGEPRFIAVGYVDDTEFVCG59239-01 ProteinRFDSDSVSPRMERRAPWVEQEGLEYWDQETRNAKGHAQIYRVNLRTLLRYYNQSEHGSSequenceHTIQRKHGCDVGPDRRLLRRYEQFAYDGKDYIALNEDLHSWTAANTAAQISQHKWEADKYSEQVRAYLEGKCMEWLRRHLENGKETLQHADPPKAHVTQHPISDHEATLRCWALGLYPAEITLTWQQDGEDQTQDTELVETRPAGDGTFQKWVAVVVPSGEEQRYMCHVQHEGLPEPLTLRWGPSSQPTIPIVGIVAGLFLLGAVVTGAVVAAAMWRKKSSGREGVRGSTPGSNCAQYSDASHDTCKA


[0401] Further analysis of the NOV16a protein yielded the following properties shown in Table 16B.
86TABLE 16BProtein Sequence Properties NOV16aPSort0.4600 probability located in plasma membrane; 0.1357analysis:probability located in microbody (peroxisome); 0.1000probability located in endoplasmic reticulum (membrane);0.1000 probability located in endoplasmic reticulum (lumen)SignalPCleavage site between residues 25 and 26analysis:


[0402] A search of the NOV16a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 16C.
87TABLE 16CGeneseq Results for NOV16aNOV16aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAM24017Human EST encoded protein SEQ ID4 . . . 363276/367 (75%)e−165NO: 1542 - Homo sapiens, 368 aa.1 . . . 367307/367 (83%)[WO200154477-A2, 02-AUG-2001]AAB58681HLA-A2/A28 protein #2 -1 . . . 363274/364 (75%)e−164Unidentified, 365 aa. [US6153408-A,1 . . . 364305/364 (83%)28-NOV-2000]AAB58680HLA-A2/A28 protein #1 -1 . . . 363274/364 (75%)e−164Unidentified, 365 aa. [US6153408-A,1 . . . 364305/364 (83%)28-NOV-2000]AAY52920HLA-A2/A28 family peptide A2.4a1 . . . 363274/364 (75%)e−164SEQ ID NO: 98 - Mammalia, 365 aa.1 . . . 364305/364 (83%)[US5976551-A, 02-NOV-1999]AAY52919HLA-A2/A28 family peptide HLA-1 . . . 363274/364 (75%)e−164A2.1 SEQ ID NO: 97 - Mammalia,1 . . . 364305/364 (83%)365 aa. [US5976551-A,02-NOV-1999]


[0403] In a BLAST search of public sequence databases, the NOV16a protein was found to have homology to the proteins shown in the BLASTP data in Table 16D.
88TABLE 16DPublic BLASTP Results for NOV16aNOV16aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ9TQP7MHC CLASS I ANTIGEN - Homo1 . . . 363286/370 (77%)e−168sapiens (Human), 371 aa.1 . . . 370312/370 (84%)Q30718MHC CLASS I ANTIGEN1 . . . 363282/364 (77%)e−167MAMUA*07 - Macaca mulatta1 . . . 364312/364 (85%)(Rhesus macaque), 365 aa.Q95J07MHC CLASS I ANTIGEN HEAVY1 . . . 363286/366 (78%)e−167CHAIN - Homo sapiens (Human),1 . . . 364310/366 (84%)365 aa.Q9MYI5HLA CLASS I ANTIGEN - Homo1 . . . 363286/366 (78%)e−167sapiens (Human), 365 aa.1 . . . 364311/366 (84%)Q9TQP6sapiens (Human), 365 aa.1 . . . 364311/366 (84%)e−167


[0404] PFam analysis indicates that the NOV16a protein contains the domains shown in the Table 16E.
89TABLE 16EDomain Analysis of NOV16aNOV16aIdentities/MatchSimilarities forExpectPfam DomainRegionthe Matched RegionValueMHC_I: domain 1 of 1 25 . . . 203139/180 (77%)5.6e−131165/180 (92%)ig: domain 1 of 1220 . . . 285 12/67 (18%)9.9e−08  47/67 (70%)



Example 17

[0405] The NOV17 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 17A.
90TABLE 17ANOV17 Sequence AnalysisSEQ ID NO:818838 bpNOV17a,AGCAGAGCCCTGGGCCAGGCTCTCTGATTGCCTGGCACCCTGATGGGAGCCCGCATGCCG59295-01 DNACCAGACGATGCTTGCTTCTTCTCTCTTGCTTTTGTCTACTTAGGGTTGAGTCCACTGCSequenceAGAGGTGCAGCACCAGGCCTCAGCACTCACATGGAAAATCAGTGCAGAGCTGCAACAGGAGCCTGCTCCTGAGCCCAGCCACACATACCAGGAGATGTCCCTTGCAGTGGAGGATGTCACAACAGTTATGGAAGGCAAGCAGGCTGAAGCCCCAGACTCCGTGGCCATGTCTTCCTGGGAAAGGCGGCTCCATCGGGCCAAGTGTGCACCATCCTACTTGTTCTCCTGCTTCAATCGAGGCGAGTGTGTGCACCCAGCCTTCTGTCACTGCAGACGCTTCAATCCCACTGGACCGCGCTGCCAGATGGTGTACAATGCCGGCCCTGAGAGGGACAGCATTTGCCGGGCGTGGGGGCAGCACCACGTGGAGACATTTGATGGGCTCTACTACTACCTCTCCGGAAAGGGCAGCTACACCCTGGTGGGTCGCCATGAGCCCGAGGGACAGAGCTTCTCCATCCAGGTACACAATGACCCGCAGTGTGGCTCTTCACCCTACACCTGCTCCAGGGCTGTCAGCCTCTTCTTTGTGGGTGAGCAGGAGATCCATCTGGCCAAGGAGGTCACCCATGGAGGCATGAGGGTCCAACTGCCACATGTCATGGGCAGCGCGCGTCTGCAGCAGCTTGCCGGCTATGTCATCGTGCGGCATCAGTCAGCCTTCACACTGGCCTGGGATGGTGCCTCGGCTGTCTACATCAAGATGAGTCCAGAGCTTCTGGGCTGGACCCATGGGCTGTGTGGGAACAACAATGCTGACCCCAAGGATGATCTGGTGACCAGCTCTGGTGAGGGGAAGCTGACTGACGACGTGGTTGAGTTTGTGCACAGCTGGCAGGAGCAGGCCCCTAACCAGCCTCCAGGGCCCACAACTTCCTCCCTGCCTCGCCCACCGTGCCTACAGCAGAACCCAGGAACCATGCAGGGCGTGTACGAGCACTGTGACGCTCTACTGCGGCCCCCCTTTGACCCCTGCCACGCCTACGTCAGCCCTCTGCCCTTCACAGCCAGTTGTACCAGTGATCTCTGCCAATCAATGGGTGATGTAGCCACCTGGTGCCGGGCACTGGCGGAGTATGCCCGGGCGTGTGCCCAGGCAGGGCGGCCCTTGCAAGGCTGGAGGACCCAGCTCCGGCAATGCACTGTGCACTGCAAGGAGAAGGCCTTTACCTACAATGAGTGCATCGCCTGCTGCCCTGCCTCCTGCCATCCCCGGGCATCCTGTGTGGACAGTGAGATCGCCTGTGTGGACGGCTGCTATTGCCCCAATGGGCTCATCTTCGAGGATGGGGGCTGCGTGGCACCAGCTGAGTGTCCCTGTGAGTTTCACGGGACTCTGTACCCACCTGGCTCTGTGGTGAAGGAAGACTGCAATACTTGCACATGCACCTCAGGCAAGTGGGACTGCAGCACACCTGTCTGCCCAGCTGAGTGCTCAGTGACTGGTGACATTCACTTCACAACCTTTGATGGCCGCCGGTACACGTTCCCCGCCACATGTCAGTACATCCTGGCCAAGAGCCGCTCTTCGGCCACCTTCACCGTGACATTGCAGAATGCCCCATGTGGCCTGAACCAAGATGGAGCCTGTGTCCAGTCAGTGTCAGTGATTCTGCACCAGGACCCTCGGAGGCAGGTGACCCTGACCCAGGCAGGGGATGTCCTTCTGTTTCACCAGTACAAGATCATCCCGCCATACACAGATGATGCCTTTGAGATCCGTAGGCTGTCCTCCGTGTTCCTGCGGGTGAGGACGAACGTGGGCGTGCGGGTGCTCTACGACCGTGAAGGGCTCCGACTGTACCTGCAAGTGGACCAGCGATGGGTGGAGGATACCGTGGGCCTCTGCCGCACCTTCAATGGCAACACGCAGGATGACTTCCTGTCTCCAGTGGGTGTACCTGAGAGCACCCCACAACTTTTTGGCAATTCCTGGAAAACACTTTCTGCTTGCTCCCCGCTGGTCTCTGGCTCCCCTCTGGACCCCTGCGATCTGCACCTGCAAGCCGCCTCCTACTCAGTGCAGGCCTGCAGCGTGCTCACGGGGGAGATGTTTGCGCCCTGCTCTGCGTTCCTGAGCCCCGTGCCCTACTTTCAGCAGTGCCGCAGCGATGCCTGCCGCTGCGGGCAGCCCTGCCTGTGCGCCACACTGGCCCACTACGCCCACCTGTGCCGGCGCCATGGGCTCCCCGTTGATTTCCGCGCCCGCCTGCCAGCCTGTGCACTGTCCTGTGAGGCCTCCAAGGAGTATAGCCCCTGCCTGGCCCCGTGTGGACGTACCTGCCAGGACCTGGCCAGCCCTGAGGCCTGTGGGGTTGATGGTGGCGATGACCTGAGCAGAGACGAGTGTGTGGAGGGCTGTGCCTGCCCACCGGACACCTATCTGGACACCCAGGCTGACCTCTGTGTCCCCCGGAACCAGTGCTCCTGCCACTTCCAGGGAGTGGACTATCCCCCCGGAGACAGTGACATCCCATCCCTGGGCCACTGCCACGCCAGGTCTTCGTGAACTGCAGCGACCTGCACACGGACCTGGAGCTGAGCAGGGAGAGGACGTGTGAGCAGCAACTGCTGAACCTGAGCGTGTCAGCCCGTGGCCCCTGCCTCTCGGGCTGCGCCTGTCCCCAGGGTCTGCTCAGACACGGGGATCCATGTTTCCTGCCAGAGGAGTGCCCCTGCACTTGGAAGGGGAAGGAGTATTTCCCTGGGGACCAGGTGATGTCTCCTTGCCATACCTGTGTGTGCCAGCGGGGCTCATTCCAGTGCACCCTGCACCCTTGCGCCTCCACCTGCACTGCCTATGGGGACCGGCATTACCGCACGTTTGATGGGCTCCCGTTTGACTTCGTGGGGGCATGCAAAGTGCACCTGGTCAAGAGCACATCAGATGTCAGCTTCTCTGTGATTGTAGAGAATGTGAACTGCTACAGCTCTGGCATGATCTGCAGGAAATTTATTTCCATCAACGTTGGGAACTCACTCATTGTCTTTGATGATGACTCCGCAAATCCTAGTCCAGAGAGCTTCCTGGATGACAAGCAGGAGGTCCACACATGGCGAGTGGGATTTTTCACACTGGTGCATTTCCCACAGGAGCACATCACCCTCTTGTGGGACCAGAGAACCACAGTGCACGTCCAGGCTGGGCCTCAGTGGCAGGGCCACCTGGCCGGCCTCTGTCGGAACTTTGACTTAAAAACCATCAATGAGATGAGGACCCCGGAGAACCTAGAGCTAACTAACCCCCAGGAGTTTGGCAGCAGTTGGGCTGCAGTTGAGTGCCCAGACACCCTCGATCCTCGGGATATGTGTGTCCTGAATCCTCTCCCACAACCATTTGCCAAGAAGGAGTGCAGCATCCTGCTCAGTGAGGTGTTTGAGATCTGCCACCCTGTGGTTGATGTCACTTGGTTTTACTCAAACTGCCTGACAGACACATGTGGCTGCAGCCAGGGTGGTGACTGTGAGTGCTTCTGTGCCAGCGTCTCCGCTTATGCCCACCAGTGTTGCCAGCATGGGGTGGCTGTTGACTGGCGAACCCCCCGCCTCTGCCCGTATGACTGTGACTTCTTTAACAAAGTGCTAGGTAAGGGCCCCTATCAGCTATCCAGCTTGGCAGCCGGTGGTGCTCTGGTGGGCATGAAGGCGGTGGGCGATCACATAGTCCTAGTGAGGACAGAGGATGTGGCGCCAGCAGACATTGTGAGCTTCCTCCTGACAGCTGCTCTGTACAAGGCCAAGGCCCATGACCCAGATGTGGTGTCCCTGCAGGCAGCAGACAGACCCAACTTCTTCCTTCACGTCACAGCCAACGGGTCTCTGGAGCTGGCTAAGTGGCAGGGCCGTGACACCTTCCAACAGCATGCCTCCTTCTTGCTGCACCGGGGGACACCGCAGGCAGGCCTCGTGGCCCTGGAGTCCCTGGCCAAGCCCAGCTCCTTCCTCTATGTGTCGGGCGCCGTGCTGGCCCTGCGGCTGTACGAACACACAGAGGTGTTCCGCCGGGGCACACTCTTCCGCCTTCTGGATGCCAAGCCCTCGGGGGCTGCCTACCCCATCTGCGAGTGGCGCTACGATGCCTGTGCCAGCCCCTGCTTCCAAACCTGCCGGGACCCACGGGCAGCCAGCTGCCGGGACGTACCCAGGGTAGAAGGCTGTGTCCCTGTGTGCCCCACCCCCCAGGTCCTGGATGAAGTCACACAGAGATGTGTCTACTTGGAGGACTGTGTGGAGCCAGCACTTTCGGTTCCCACAGAGGCCCTTGGCAATGAGACCCTCCCTCCCAGTCAAGGGTTGCCCACTCCCAGTGATGAGGAGCCACAGCTGTCACAGGAAAGCCCCAGGACCCCCACCCACAGGCCAGCCCTCACCCCAGCTGCCCCACTCACCACAGCCCTGAACCCACCAGTGACAGCCACTGAGGAGCCAGTGGTGTCTCCAGGCCCCACCCAGACCACCCTGCAGCAGCCACTGGAGCTCACTGCATCTCAACTCCCCGCCGGCCCCACGGAGTCCCCAGCCAGCAAGGGAGTGACTGCCAGCCTCCTGGCCATCCCCCATACACCAGAGTCCTCATCCCTCCCTGTTGCACTGCAGACACCCACACCTGGCATGGTGTCAGGTGCCATGGAGACAACAAGGGTGACTGTGATCTTTGCAGGAAGCCCTAACATCACAGTCTCCTCCCGGTCGCCCCCTGCCCCTCGCTTCCCGCTCATGACCAAGGCTGTGACAGTCCGAGGCCATGGCTCCTTGCCTGTTAGGACGACACCCCCACAGCCCTCCTTGACAGCAAGTCCCTCCTCCAGACCTGTGGCTTCCCCTGGAGCCATCTCCAGGTCCCCCACCTCCTCGGGATCCCACAAGGCTGTGCTGACACCTGCAGTAACTAAGGTCATAAGCAGGACAGGGGTCCCCCAGCCCACCCAGGCCCAGAGTGCTTCAAGTCCCAGCACCCCTCTAACTGTGGCTGGAACAGCAGCAGAACAGGTTCCTGTCAGTCCCCTTGCAACCAGGAGCTTGGAGATAGTGCTATCCACAGAGAAGGGCGAAGCCGGGCACAGCCAGCCCATGGGCTCGCCTGCCTCCCCACAGCCACACCCACTCCCCTCTGCACCACCCCCCCCAGCCCAGCATACCACCATGGCCACCAGGTCTCCAGCTCTGCCCCCACACACCCCAGCTGCCGCCAGCCTGTCAACAGCCACTGATGGGCTGGCAGCCACACCCTTCATGTCCCTTGAGTCAACTCGTCCCTCCCAGCTCCTCTCTGGCCTGCCTCCCGACACCAGCCTGCCCCTGGCCAAGGTGGGCACATCTGCCCCAGTGGCCACACCCGGCCCCAAAGCCTCTGTCATCACCACTCCACTCCACCCACAGGCCACCACTCTGCCTGCTCAGACACTTAGCCCAGTACTGCCTTTCACTCCAGCAGCAATGACCCAGGCGCACCCACCCACTCACATAGCACCCCCAGCAGCAGGCACAGCTCCAGGCCTGCTGCTGGGAGCCACATTGCCAACCTCTGGAGTCCTGCCTGTGGCTGAGGGCACGGCCTCCATGGTATCTGTTGTCCCACGAAAGAGCACCACAGGGAAGGTGGCCATCCTATCCAAGCAAGTGTCTCTGCCCACTTCCATGTATGGTTCTGCAGAGGGTGGGCCCACAGAGCTCACCCCTGCTACGAGCCACCCTCTCACGCCCTTGGTGGCTGAGCCCGAGGGAGCCCAGGCAGGCACAGCTCTGCCAGTGCCCACATCCTATGCCCTGAGCCGTGTCTCAGCCAGGACGGCCCCCCAAGACAGCATGCTGGTTCTGTTGCCTCAGCTGGCTGAGGCCCATGGAACCTCGGCAGGGCCTCACCTGGCAGCAGACCCGGTGGACGAGGCCACCACAGAACCATCTGGGCGCTCAGCCCCAGCCCTGAGCATCGTAGAGGGTTTGGCGGAGGCTTTGGCAACTACCACTGAGGCCAATACATCCACCACCTGTGTTCCAATCGCCGAGCAGGACTGCGTCCGCCACATCTGCCTGGAGGGCCAGCTGATTCGCGTGAATCAGTCCCAGCACTGTCCCCAGGGTGCTGCTCCCCCTCGCTGTGGGATCCTGGGCCTCGCCCTGCGGGTGGGTGGGGACCGCTGCTGCCCACTCTGGGAGTGTGCCTGCCGGTGCTCAATCTTCCCTGACCTGAGCTTCGTGACCTTCGATGGGAGCCACGTAGCTCTGTTCAAGGAGGCCATCTACATCCTCAGCCAGAGCCCAGATGAAATGCTCACCGTCCATGTACTGGACTGCAAAAGTGCCAACCTCGGGCACCTGAACTGGCCCCCGTTCTGTCTGGTGATGTTGAACATGACTCACTTGGCCCATCAGGTCACTATTGATCGCTTCAACCGAAAGGTGACTGTGGACTTGCAGCCTGTGTGGCCACCGGTGAGCAGGTATGCATTCAGAATTGAGGACACAGGCCACATGTACATGATCCTGACTCCCTCAGACATCCAGATCCAGTGGCTCCACAGCTCAGGACTCATGATCGTGGAGGCCAGCAAAACCAGCAAGGCCCAGGGCCATGGCCTGTGCGGTATCTGTGATGGAGATGCAGCCAATGACCTTACCCTGAAGGATGGCTCAGTGGTGCGTGCGGCTGAGGACCCTGCTCCCTTTCTGGACAGCTGGCAGGTGCCCAGCTCCCTGACCTCAGTGGGCCAGACCCGCTTCCGCCCAGACAGCTGCGCCACAACTGACTGCTCGCCCTGCCTTCGCATGGTGTCCAACCGCACCTTCAGTGCCTGCCACCGCTTTGTGCCTCCGGAGTCATTCTGTGAGCTGTGGATCCGGGACACCAAGTACGTGCAGCAGCCCTGCGTGGCCCTGACTGTGTACGTGGCCATGTGCCACAAATTTCATGTGTGCATCGAGTGGCGGCGCTCTGACTACTGCCCCTTCCTGTGCTCCAGCGACTCCACATACCAGGCATGTGTGACAGCCTGTGAGCCACCCAAGACATGCCAGGATGGGATACTAGGGCCTCTGGACCCAGAGCACTGCCAGGTGCTGGGCGAGGGCTGCGTCTGCTCCGAGGGCACCATCTTACACCGGCGCCACTCTGCACTCTGCATCCCGGAGGCCAAGTGCGCCTGCACTGACAGCATGGGGGTGCCGAGGGCCCTGGGGGAGACCTGGAACAGCTCCCTCAGCGGCTGCTGCCAGCACCAGTGCCAAGCCCCAGACACCATTGTCCCGGTGGATCTGGGCTGCCCCAGTCCCCGCCCTGAGAGCTGCCTGCGATTCGGCGAGGTGGCCTTGCTCCTACCCACCAAGGACCCCTGCTGCCTGGGGACTGTCTGTGTGTGTAACCAGACTCTGTGTGAGGGTCTCGCCCCCACATGCCGCCCAGGCCACCGCCTCCTCACCCACTTCCAGGAGGACTCCTGCTGCCCCAGCTACAGCTGTGAGTGTGACCCAGATCTCTGTGAGGCAGAGCTGGTCCCCAGCTGCCGACAGGACCAGATCCTGATCACGGGCCGCCTGGGGGACTCCTGCTGCACCTCCTACTTCTGCGCCTGTGGTGACTGTCCAGACTCCATCCCCGAATGTCAAGAAGGGGAGGCGCTCACTGTGCACAGGAATACCACGGAACTCTGCTCCCCTCTGTACCAGTGTGTGTGTGAGAACTTCCGCTGTCCCCAAGTGCAGTGTGCCCTGGGCACTGCCCTGGTCGAGGTGTGGAGCCCCGACCGCTGCTGCCCCTACAAATCCTGTGAATGTGACTGTGACACAATCCCGGTGCCCCGGTGCCATCTGTGGGAGAAATCCCAGCTGGATGAGGAGTTCATGCACAGCGTGGAGAATGTGTGTGGCTGCGCCAAGTACGAGTGTGTGAAGGCCCCGGTGTGTCTGAGCCGCGAGCTGGGTGTGATGCAGCCCGGCCAGACAGTGGTGCAGCTCTCAGCAGATGGCCTGTGCCACACCTCCCGCTGCACCACCGTGCTCGACCCTCTCACCAACTTCTACCAGATCAACACCACCTCCGTGCTCTGTGACATCCACTGTGAGGCGAACCAGGAGTACGAGCACCCGCGGGACCTCGCTGCCTGCTGCGGCTCCTGCAGGAACGTGTCCTGTCTCTTCACCTTCCCCAATGGCACCACCTCCCTGTTCTTGCCCGGGCCATCCTGGATCGCAGACTGCGCCCGCCACCACTGCAGCAGCACGCCCCTGGGTGCCGTGCTGGTCCGCTCTCCCATAAGCTGCCCACCGCTCAATGAGACTGAGTGTGCCAAGGTTGGGGGTTCCGTGGTACCTTCCTTGGAAGGATGCTGCAGGACCTGTAAGGAGGATGGGCGCTCCTGCAAGAAGGTGACCATCCGCATGACCATCCGCAAGAATGAATGCAGGAGCAGCACCCCTGTGAACCTAGTGTCCTGCGATGGGAGGTGCCCATCCGCCAGCATCTACAACTACAACATCAACACCTATGCCCGATTCTGCAAGTGCTGCCGTGAGGTGGGCCTGCAGCGGCGCTCTGTGCAGCTCTTCTGTGCCACCAATGCCACCTGGGTGCCCTATACAGTGCACGAGCCCACCGACTGTGCCTGCCAGTGGTCCTGAGGCCTGGGGCCCCCGGCTAGCTGGACCACCTCTGCCAGCCCCACTTTCTGTORF Start: ATG at 43ORF Stop: TGA at 8785SEQ ID NO:822914 aa MW at 314011.9 kDNOV17a,MGARMPRRCLLLLSCFCLLRVESTAEVQHQASALTWKTSAELQQEPAPEPSHTYQEMSCG59295-01 ProteinLAVEDVTTVMEGKQAEAPDSVAMSSWERRLHRAKCAPSYLFSCFNGGECVHPAFCDCRSequenceRFNATGPRCQMVYNAGPERDSICRAWGQHHVETFDGLYYYLSGKGSYTLVGRHEPEGQSFSIQVHNDPQCGSSPYTCSRAVSLFFVGEQEIHLAKEVTHGGMRVQLPHVNGSARLQQLAGYVIVRHQSAFTLAWDGASAVYIKMSPELLGWTHGLCGNNNADPKDDLVTSSGEGKLTDDVVEFVHSWQEQAPNQPPGPTTSSLPRPPCLQQNPGTMQGVYEQCEALLRPPFDACHAYVSPLPFTASCTSDLCQSMGDVATWCRALAEYARACAQAGRPLQGWRTQLRQCTVHCKEKAFTYNECIACCPASCHPRASCVDSEIACVDGCYCPNGLIFEDGGCVAPAECPCEFHGTLYPPGSVVKEDCNTCTCTSGKWECSTAVCPAECSVTGDIHFTTFDGRRYTFPATCQYILAKSRSSGTFTVTLQNAPCGLNQDGACVQSVSVILHQDPRRQVTLTQAGDVLLFDQYKIIPPYTDDAFEIRRLSSVFLRVRTNVGVRVLYDREGLRLYLQVDQRWVEDTVGLCCTFNGNTQDDFLSPVGVPESTPQLFGNSWKTLSACSPLVSGSPLDPCDVHLQAASYSVQACSVLTGEMFAPCSAFLSPVPYFEQCRRDACRCGQPCLCATLAHYAHLCRRHGLPVDFRARLPACALSCEASKEYSPCVAPCGRTCQDLASPEACGVDGGDDLSRDECVEGCACPPDTYLDTQADLCVPRNQCSCHFQGVDYPPGDSDIPSLCHCHCKDGVMSCDSRAPAAACPAGQVFVNCSDLHTDLELSRERTCEQQLLNLSVSARGPCLSGCACPQGLLRHCDACFLPEECPCTWKGKEYFPGDQVMSPCHTCVCQRGSFQCTLHPCASTCTAYGDRHYRTFDGLPFDFVGACKVHLVKSTSDVSFSVIVENVNCYSSGMICRKFISINVGNSLIVFDDDSGNPSPESFLDDKQEVHTWRVGFFTLVHFPQEHITLLWDQRTTVHVQAGPQWQGQLAGLCGNFDLKTINEMRTPENLELTNPQEFGSSWAAVECPDTLDPRDMCVLNPLREPFAKKECSILLSEVFEICHPVVDVTWFYSNCLTDTCGCSQGGDCECFCASVSAYAHQCCQHGVAVDWRTPRLCPYDCDFFNKVLGKGPYQLSSLIAAGGALVGMKAVGDDIVLVRTEDVAPADIVSFLLTAALYKAKAHDPDVVSLEAADRPNFFLHVTANIGSLELAKWQGRDTFQQHASFLLHRGTRQAGLVALESLAKPSSFLYVSCAVLALRLYEHTEVFRRGTLFRLLDAKPSGAAYPICEWRYDACASPCFQTCRDPRAASCRDVPRVEGCVPVCPTPQVLDEVTQRCVYLEDCVEPAVWVPTEALGNETLPPSQGLPTPSDEEPQLSQESPRTPTHRPALTPAAPLTTALNPPVTATEEPVVSPGPTQTTLQQPLELTASQLPAGPTESPASKGVTASLLAIPHTPESSSLPVALQTPTPGMVSGAMETTRVTVIFAGSPNITVSSRSPPAPRFPLMTKAVTVRGHGSLPVRTTPPQPSLTASPSSRPVASPGAISRSPTSSGSHKAVLTPAVTKVISRTGVPQPTQAQSASSPSTPLTVAGTAAEQVPVSPLATRSLEIVLSTEKGEAGHSQPMGSPASPQPHPLPSAPPRPAQHTTMATRSPALPPETPAAASLSTATDGLAATPFMSLESTRPSQLLSGLPPDTSLPLAKVGTSAPVATPGPKASVITTPLQPQATTLPAQTLSPVLPFTPAAMTQAHPPTHIAPPAAGTAPGLLLGATLPTSGVLPVAEGTASMVSVVPRKSTTGKVAILSKQVSLPTSMYGSAEGGPTELTPATSHPLTPLVAEPEGAQAGTALPVPTSYALSRVSARTAPQDSMLVLLPQLAEAHGTSAGPHLAAEPVDEATTEPSGRSAPALSIVEGLAEALATTTEANTSTTCVPIAEQDCVRHICLEGQLIRVNQSQHCPQGAAPPRCGILGLAVRVGGDRCCPLWECACRCSIFPDLSFVTFDGSHVALFKEAIYILSQSPDEMLTVHVLDCKSANLGHLNWPPFCLVMLNNTHLAHQVTIDRFNRKVTVDLQPVWPPVSRYGFRIEDTGHMYMILTPSDIQIQWLHSSGLMIVEASKTSKAQGHGLCGICDGDAANDLTLKDGSVVGGAEDPAPFLDSWQVPSSLTSVGQTRFRPDSCATTDCSPCLRMVSNRTFSACHRFVPPESFCELWIRDTKYVQQPCVALTVYVANCHKFHVCIEWRRSDYCPFLCSSDSTYQACVTACEPPKTCQDGILGPLDPEHCQVLGEGCVCSEGTILHRRHSALCIPEAKCACTDSMGVPRALGETWNSSLSGCCQHQCQAPDTIVPVDLGCPSPRPESCLRFGEVALLLPTKDPCCLGTVCVCNQTLCEGLAPTCRPGHRLLTHFQEDSCCPSYSCECDPDLCEAELVPSCRQDQILITGRLGDSCCTSYFCACGDCPDSIPECQEGEALTVHRNTTELCCPLYQCVCENFRCPQVQCGLGTALVEVWSPDRCCPYKSCECDCDTIPVPRCHLWEKSQLDEEFMHSVENVCGCAKYECVKAPVCLSRELGVMQPGQTVVELSADGVCHTSRCTTVLDPLTNFYQINTTSVLCDIHCEANQEYEHPRDLAACCGSCRNVSCLFTFPNGTTSLFLPGASWIADCARHHCSSTPLGAVLVRSPISCPPLNETECAKVCGSVVPSLEGCCRTCKEDGRSCKKVTIRMTIRKNECRSSTPVNLVSCDGRCPSASIYNYNINTYARFCKCCREVGLQRRSVQLFCATNATWVPYTVQEPTDCACQWS


[0406] Further analysis of the NOV17a protein yielded the following properties shown in Table 17B.
91TABLE 17BProtein Sequence Properties NOV17aPSort0.4610 probability located in outside; 0.1900analysis:probability located in lysosome (lumen); 0.1000probability located in endoplasmic reticulum (membrane);0.1000 probability located in endoplasmic reticulum(lumen)SignalPCleavage site between residues 24 and 25analysis:


[0407] A search of the NOV17a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 17C.
92TABLE 17CGeneseq Results for NOV17aNOV17aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAU29530Novel human secreted protein #21 -139 . . . 1233392/1136 (34%)0.0Homo sapiens, 2814 aa. 35 . . . 1131561/1136 (48%)[WO200179449-A2, 25-OCT-2001]AAP60053Sequence of von Willebrand factor139 . . . 1233392/1136 (34%)0.0(vWF) - Homo sapiens, 2813 aa. 35 . . . 1131561/1136 (48%)[EP197592-A, 15-OCT-1986]AAP60462Sequence of human von Willebrand139 . . . 1233393/1137 (34%)0.0Factor (VWF) precursor - Homo 35 . . . 1131559/1137 (48%)sapiens, 2813 aa. [WO8606096-A,23-OCT-1986]AAY70557Canine von Willebrand factor - Canis139 . . . 1233386/1137 (33%)e−179familiaris, 2813 aa. [WO200009533-A1, 35 . . . 1131550/1137 (47%)24-FEB-2000]AAW54347Canine von Willebrand Factor (vWF)139 . . . 1233386/1137 (33%)e−179sequence - Canis sp, 2813 aa. 35 . . . 1131550/1137 (47%)[WO9803683-A1, 29-JAN-1998]


[0408] In a BLAST search of public sequence databases, the NOV17a protein was found to have homology to the proteins shown in the BLASTP data in Table 17D.
93TABLE 17DPublic BLASTP Results for NOV17aNOV17aIdentities/ProteinResidues/SimilaritiesAccessionMatchfor theExpectNumberProtein/Organism/LengthResiduesMatched PortionValueO55225OTOGELIN - Mus musculus 1 . . . 29142421/2923 (82%) 0.0(Mouse), 2910 aa. 1 . . . 29102553/2923 (86%) CAA00831VON WILLEBRAND FACTOR -139 . . . 1233392/1136 (34%)0.0synthetic construct, 2324 aa 35 . . . 1131561/1136 (48%)(fragment).P04275Von Willebrand factor precursor139 . . . 1233394/1137 (34%)0.0(vWF) - Homo sapiens (Human), 35 . . . 1131561/1137 (48%)2813 aa.Q28295Von Willebrand factor precursor139 . . . 1233390/1138 (34%)0.0(vWF) - Canis familiaris (Dog), 35 . . . 1131554/1138 (48%)2813 aa.A43932mucin 2 precursor, intestinal -137 . . . 1236365/1126 (32%)e−175human, 3020 aa (fragment). 35 . . . 1125554/1126 (48%)


[0409] PFam analysis indicates that the NOV17a protein contains the domains shown in the Table 17E.
94TABLE 17EDomain Analysis of NOV17aIdentities/NOV17aSimilaritiesMatchfor the MatchedPfam DomainRegionRegionExpect ValueArthro_defensin: 87 . . . 11610/36(28%)7.9domain 1 of 117/36(47%)vwd:139 . . . 28958/165(35%)1.9e−38domain 1 of 4117/165(71%)IBR:357 . . . 4196/78(8%)7domain 1 of 141/78(53%)EB:409 . . . 45715/56(27%)9.7domain 1 of 128/56(50%)TIL:409 . . . 46319/70(27%)0.096domain 1 of 537/70(53%)TILa:462 . . . 51415/57(26%)2.8domain 1 of 130/57(53%)vwc:465 . . . 52518/91(20%)0.0087domain 1 of 145/91(49%)vwd:503 . . . 65862/168(37%)6.1e−45domain 2 of 4130/168(77%)TIL:769 . . . 83319/76(25%)2.7e−06domain 2 of 540/76(67%)TIL:873 . . . 93518/74(24%)0.011domain 3 of 542/74(57%)vwd:975 . . . 112145/166(27%)1.1e−32domain 3 of 4111/166(67%)TIL:1398 . . . 1453 16/69(23%)0.05domain 4 of 540/69(58%)vwd:2101 . . . 2255 38/166(23%)3.9e−21domain 4 of 4111/166(67%)Chitin_bind_2:2333 . . . 2381 10/61(16%)7domain 1 of 127/61(44%)TIL:2362 . . . 2423 20/71(28%)0.0095domain 5 of 548/71(68%)Cys_knot:2822 . . . 2880 12/63(19%)0.06domain 1 of 144/63(70%)



Example 18

[0410] The NOV18 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 18A.
95TABLE 18ANOV18 Sequence AnalysisSEQ ID NO:831882 bpNOV18a,CCCTCCCACGGCCCCTCCCGGCCTCTCTACATAAAGCCGGGGGTACTGGGCCTCAGGTC059293-01 DNACAGGCCTATGGCCATGGCCTTCACACACCTGCTCGATGCTCTGGGCAGCATGGGCCGCSequenceTTCCAGCTCAACCACACAGCCCTGCTGCTGCTGCCCTGCGGCCTGCTGGCCTCCCACAACTTCCTGCAGAACTTCACCCCCGCTGTCCCCCCCCACCACTGCCGGGCCCCTGCCAACCACACTGAGGCCTCCACCAACGACTCCGGCGCCTGGCTGAGGGCCACCATACCCCTGGACCAGCTTGGGGCCCCTGAGCCCTGCCGGCGCTTCACCAAGCCTCAGTGGGCCCTGCTGAGCCCCAACTCCTCCATCCCGGGCGCGGCCACGGAGGGCTGCAAGGACGGCTGGGTCTATAACCGCAGTGTTTTCCCGTCCACCATCGTGATGGAGTGGGATCTGGTGTGTGAGGCCCGCACTCTCCGAGACCTGGCGCAGTCCGTCTACATTGCCGGGGTGCTGGTGGGGGCTGCCGTGTTTGGCAGCTTGGCAGACAGGCTGGGCTGCAAGGGCCCCCTGGTCTGGTCCTACCTGCAGCTGGCAGCTTCGGGGGCCGCCACAGCGTATTTCAGCTCCTTCAGTGCCTATTGCGTCTTCCGGTTCCTGATGGGCATGACCTTCTCTGGCATCATCCTCAACTCCGTCTCCCTGGTGATTGTGGAGTGGATGCCCACACGGGGCCGGACTGTGGCGGGTATTTTGCTGGGGTATTCCTTCACCCTGGGCCAGCTCATCCTGGCTGGGGTAGCCTACCTGATTCGCCCCTGGCGGTGCCTGCAGTTTGCCATCTCTGCTCCTTTCCTGATCTTTTTCCTCTATTCTTGGTGGCTTCCAGAGTCATCCCGCTGGCTCCTCCTGCATGGCAAGTCCCAGTTAGCTGTACAGAATCTGCAGAAGGTGGCTGCAATGAACGGGAGGAAGCAGGAAGGGGAAAGGCTGACCAAGGAGGTGATGAGCTCCTACATCCAAAGCGAGTTTGCAAGTGTCTGCACCTCCAACTCAATCTTGGACCTCTTCCGAACCCCGGCCATCCGCAAGGTCACATGCTGTCTCATGGTGATTTGGTTCTCCAACTCTGTGGCTTACTATGGCCTGGCCATGGACCTGCAGAAGTTTGGGCTCAGCCTATACCTGGTGCAGGCCCTGTTTGGAATCATCAACATCCCGGCCATGCTGGTGGCCACCGCCACCATGATTTACGTGGGCCGCCGTGCCACGGTGGCCTCCTTCCTCATCCTGGCCGGGCTCATGGTGATCCCCAACATGTTTGTGCCAGAAGGCTCCACCCCCTCTCCACTACACCCTGGGCCTCCCTCTCCTCCCCTCCTCCTCAGCTGCACCCTACTCCCCTGTCTAGGCACGCAGATCCTGTGCACAGCCCAGGCAGCGCTGGGCAAAGGCTGCCTGGCCAGCTCCTTCATCTGTGTGTACCTGTTTACCGGCGAGCTGTACCCCACGGAGATCAGGCAGATGGGGATGGGCTTTGCCTCTGTCCACGCCCGCCTCGGGGGCCTGACGGCGCCCCTGGTTACCACACTTGGGGAATACAGCACCATCCTGCCACCCGTGAGCTTTCGGGCCACCGCAATCCTGGCTGGGCTGGCCGTCTGCTTCCTGACTGAGACCCGCAACATGCCCCTGGTCGAGACCATCGCAGCCATGGAGAGGAGGGTCAAAGAAGGCTCTTCCAAGAAACATGTAGAAGAGAAGAGTGAAGAAATTTCTCTTCAGCAGCTGAGAGCATCTCCCCTCAAAGAGACCATCTAAGCTGCCTGGAACCTGGTGCTTGCTAGCAGCACCTGAGCCGATGTCCAGACGGCCCCCTGGCGORF Start: ATG at 66ORF Stop: TAA at 1818SEQ ID NO:84584 aa MW at 63391.5 kDNOV18a,MAMAFTDLLDALGSMGRFQLNHTALLLLPCGLLACHNFLQNFTAAVPPHHCRGPANHTCG59293-01 ProteinEASTNDSGAWLRATIPLDQLGAPEPCRRFTKPQWALLSPNSSIPGAATEGCKDGWVYNSequenceRSVFPSTIVMEWDLVCEARTLRDLAQSVYIAGVLVGAAVFGSLADRLGCKGPLVWSYLQLAASGAATAYFSSFSAYCVFRFLMGMTFSGIILNSVSLVIVEWMPTRGRTVAGILLGYSFTLGQLILAGVAYLIRPWRCLQFAISAPFLIFFLYSWWLPESSRWLLLHGKSQLAVQNLQKVAAMNGRKQEGERLTKEVMSSYIQSEFASVCTSNSILDLFRTPAIRKVTCCLMVIWFSNSVAYYGLAMDLQKFGLSLYLVQALFGIINIPANLVATATMIYVGRRATVASFLILAGLMVIANMFVPEGSTPSPLHPGPPSPPLLLSCTLLPCLGTQILCTAQAALGKGCLASSFICVYLFTGELYPTEIRQMGMGFASVHARLGGLTAPLVTTLGEYSTILPPVSFGATAILAGLAVCFLTETRNMPLVETIAAMERRVKEGSSKKHVEEKSEEISLQQLRASPLKETI


[0411] Further analysis of the NOV18a protein yielded the following properties shown in Table 18B.
96TABLE 18BProtein Sequence Properties NOV18aPSort0.6000 probability located in plasma membrane; 0.4000analysis:probability located in Golgi body; 0.3142 probability located in mitochondrial inner membrane; 0.3000probability located in endoplasmic reticulum (membrane)SignalPCleavage site between residues 35 and 36analysis:


[0412] A search of the NOV18a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 18C.
97TABLE 18CGeneseq Results for NOV18aNOV18aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAW88488Rat organic anion transporter3 . . . 573249/573 (43%)e−137OAT-1 - Rattus sp, 551 aa.1 . . . 542346/573 (59%)[WO9853064-A1, 26-NOV-1998]AAB47271hOAT1 - Homo sapiens, 550 aa.3 . . . 573254/573 (44%)e−137[WO200104283-A2, 18-JAN-2001]1 . . . 541345/573 (59%)AAY44278Human organic anion transporter -3 . . . 573254/573 (44%)e−137Homo sapiens, 550 aa. [WO9964459-1 . . . 541345/573 (59%)A2, 16-DEC-1999]AAW88489Human organic anion transporter3 . . . 553250/553 (45%)e−137OAT-1 - Homo sapiens, 563 aa.1 . . . 522336/553 (60%)[WO9853064-A1, 26-NOV-1998]AAY92903Rat cerebral organic anion transporter3 . . . 573256/577 (44%)e−135OAT3 protein - Rattus sp, 536 aa.1 . . . 533352/577 (60%)[WO200017237-A1, 30-MAR-2000]


[0413] In a BLAST search of public sequence databases, the NOV18a protein was found to have homology to the proteins shown in the BLASTP data in Table 18D.
98TABLE 18DPublic BLASTP Results for NOV18aNOV18aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueO57379RENAL ORGANIC ANION3 . . . 583262/592 (44%)e−139TRANSPORTER - Pseudopleuronecta1 . . . 561362/592 (60%)americanus (Winter flounder), 562 aa.O35956RENAL ORGANIC ANION3 . . . 573250/573 (43%)e−137TRANSPORT PROTEIN 1 - Rattus1 . . . 542348/573 (60%)norvegicus (Rat), 551 aa.Q9TSY7RENAL ORGANIC ANION3 . . . 573253/573 (44%)e−136Oryctolagus cuniculus (Rabbit), 5511 . . . 542344/573 (59%)aa.O95742RENAL ORGANIC ANION3 . . . 553250/553 (45%)e−136TRANSPORT PROTEIN 1 - Homo1 . . . 522336/553 (60%)sapiens (Human), 563 aa.Q9R1U7ORGANIC ANION TRANSPORTER3 . . . 573256/577 (44%)e−1343 - Rattus norvegicus (Rat), 536 aa.1 . . . 533352/577 (60%)


[0414] PFam analysis indicates that the NOV18a protein contains the domains shown in the Table 18E.
99TABLE 18EDomain Analysis of NOV18aIdentities/NOV18aSimilaritiesMatchfor the MatchedExpectPfam DomainRegionRegionValueChal_stil_syntC: domain200 . . . 2125/13(38%)9.81 of 111/13(85%)sugar_tr: domain 1 of 1100 . . . 548102/528(19%)5.9e−07307/528(58%)



Example 19

[0415] The NOV19 was analyzed, and the nucleotide and polypeptide sequences are shown in Table 19A.
100TABLE 19ANOV19 Sequence AnalysisSEQ ID NO:851802 bpNOV19a,TGGGGGAAACAGGCCCGTTGCCCTGGCCTCTTTCCCCTGGGCCAGCCTTTGTGAAGTGC059284-01 DNAGGCCCCTCTTCTGGGCCCCTTGAGTAGGTTCCATGGCATTTTCTGAACTCCTGGACCTSequenceCGTGGGTGGCCTGGGCAGGTTCCAGGTTCTCCAGACGATGGCTCTGATGGTCTCCATCATGTGGCTGTGTACCCAGAGCATGCTGGAGAACTTCTCGGCCGCCGTGCCCAGCCACCGCTGCTGGGCACCCCTCCTGGACAACAGCACGGCTCAGGCCAGCATCCTAGGGAGCTTGAGTCCTGAGGCCCTCCTGCCTATTTCCATCCCGCCGGGCCCCAACCAGAGGCCCCACCAGTGCCGCCGCTTCCGCCAGCCACAGTGGCAGCTCTTGGACCCCAATGCCACGGCCACCAGCTGGAGCGAGGCCGACACGGAGCCGTGTGTGGATGGCTGGGTCTATGACCGCAGCATCTTCACCTCCACAATCGTGGCCAAGTGGAACCTCGTGTGTGACTCTCATGCTCTGAAGCCCATGGCCCAGTCCATCTACCTGGCTGGCATTCTGGTGGGAGCTGCTGCGTGCGGCCCTGCCTCAGACAGGTTTGGGCGCAGGCTGGTGCTAACCTGCAGCTACCTTCAGATGGCTGTGATGGGTACGGCAGCTGCCTTCGCCCCTGCCTTCCCCGTGTACTGCCTGTTCCCCTTCCTGTTGGCCTTTGCCGTGGCAGGCGTCATGATGAACACGGGCACTCTCCTGATGGAGTGCACGCCGGCACGGGCCCGACCCTTGGTGATGACCTTOAACTCTCTGGGCTTCAGCTTCGGCCATGGCCTGACAGCTGCAGTGGCCTACGGTGTGCGGGACTCCACACTGCTGCAGCTGGTGGTCTCGGTCCCCTTCTTCCTCTGCTTTTTGTACTCCTCGTGGCTCGCAGAGTCGGCACGATGGCTCCTCACCACAGGCAGGCTGGATTGGGGCCTGCAGGAGCTGTGGAGGGTCGCTGCCATCAACGGAAAGGGGCCAGTGCAGGACACCCTGACCCCTGAGGTCTTGCTTTCAGCCATGCGGGAGGAGCTGAGCATGGGCCAGCCTCCTGCCAGCCTGGGCACCCTGCTCCGCATGCCCGGACTGCGCTTCCGGACCTGTATCTCCACGTTGTGCTGGTTCGCCTTTGGCTTCACCTTCTTCGGCCTGGCCCTGGACCTGCAGGCCCTGGGCAGCAACATCTTCCTGCTCCAAATGTTCATTGGTGTCGTGGACATCCCAGCCAAGATGGGCGCCCTGCTGCTGCTGACCCACCTGGGCCGCCGCCCCACGCTGGCCGCATCCCTGTTGCTGGCGGGGCTCTGCATTCTGGCCAACACGCTGGTGCCCCACGAAATGGGGGCTCTGCGCTCAGCCTTGGCCGTGCTGGGGCTGGGCGGGGTGGGGGCTGCCTTCACCTGCATCACCATCTACAGCAGCGAGCTCTTCCCCACTGTGCTCAGGATGACGGCAGTGGGCTTGGGCCAGATGGCAGCCCGTCGAGGAGCCATCCTGGGGCCTCTGGTCCGGCTGCTGGGTGTCCATGGCCCCTGGCTGCCCTTGCTGGTGTATGGGACGGTGCCAGTGCTGAGTGGCCTGGCCGCACTGCTTCTGCCCGAGACCCAGAGCTTGCCGCTGCCCGACACCATCCAAGATGTGCAGAACCAGGCAGTAAAGAAGGCAACACATGGCACGCTGGGGAACTCTGTCCTAAAATCCACACAGTTTTAGCCTCCTCGGGAACCTGCGATGGGACGGTCAGAGGAAGAGACTTCTTCTGTORF Start: ATG at 91ORF Stop: TAG at 1750SEQ ID NO:86553 aa MW at 59629.4 kDNOV19a,MAFSELLDLVGGLGRFQVLQTMALMVSIMWLCTQSMLENFSAAVPSHRCWAPLLDNSTCG59284-01 ProteinAQASILGSLSPEALLAISIPPGPNQRPHQCRRFRQPQWQLLDPNATATSWSEADTEPCSequenceVDGWVYDRSIFTSTIVAKWNLVCDSHALKPMAQSIYLAGILVGAAACGPASDRFGRRLVLTWSYLQMAVMGTAAAFAPAFPVYCLFRFLLAFAVAGVMMNTGTLLMEWTAARARPLVNTLNSLGFSFGHGLTAAVAYGVRDWTLLQLVVSVPFFLCFLYSWWLAESARWLLTTGRLDWGLQELWRVAAINGKGAVQDTLTPEVLLSAMREELSMGQPPASLGTLLRMPGLRFRTCISTLCWFAFGFTFFGLALDLQALGSNIFLLQMFIGVVDIPAKMGALLLLSHLGRRPTLAASLLLAGLCILANTLVPHEMGALRSALAVLGLGGVGAAFTCITIYSSELFPTVLRMTAVGLGQMAARGGAILGPLVRLLGVHGPWLPLLVYGTVPVLSGLAALLLPETQSLPLPDTIQDVQNQAVKKATHGTLGNSVLKSTQF


[0416] Further analysis of the NOV19a protein yielded the following properties shown in Table 19B.
101TABLE 19BProtein Sequence Properties NOV19aPSort0.6000 probability located in plasma membrane; 0.4000analysis:probability located in Golgi body; 0.3000 probabilitylocated in endoplasmic reticulum (membrane);0.3000 probability located in microbody (peroxisome)SignalPCleavage site between residues 44 and 45analysis:


[0417] A search of the NOV19a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 19C.
102TABLE 19CGeneseq Results for NOV19aNOV19aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAE10332(TRICH-9) protein - Homo sapiens,1 . . . 553 553/553 (100%)0.0553 aa. [WO200162923-A2,30-AUG-2001]AAE06571Human protein having hydrophobic1 . . . 553552/578 (95%)0.0domain, HP03613 - Homo sapiens,1 . . . 578553/578 (95%)578 aa. [WO200149728-A2,12-JUL-2001]AAE06612Human protein having hydrophobic1 . . . 533284/534 (53%)e−161domain, HP03882 - Homo sapiens,1 . . . 530372/534 (69%)550 aa. [WO200149728-A2,12-JUL-2001]AAB69091Human organic anion transporter OAT41 . . . 533284/534 (53%)e−161protein sequence SEQ ID NO:2 - Homo1 . . . 530372/534 (69%)sapiens, 550 aa. [WO200102562-A1,11-JAN-2001]AAE10336Human transporter and ion channel-131 . . . 533282/549 (51%)e−157(TRICH-13) protein - Homo sapiens,1 . . . 546370/549 (67%)566 aa. [WO200162923-A2,30-AUG-2001]


[0418] In a BLAST search of public sequence databases, the NOV19a protein was found to have homology to the proteins shown in the BLASTP data in Table 19D.
103TABLE 19DPublic BLASTP Results for NOV19aNOV19aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ96S37RST - Homo sapiens (Human),1 . . . 553 553/553 (100%)0.0553 aa.1 . . . 553 553/553 (100%)CAC51145SEQUENCE 21 FROM PATENT1 . . . 553552/578 (95%)0.0WO0149728 - Homo sapiens1 . . . 578553/578 (95%)(Human), 578 aa.Q96DT2ORGANIC ANION TRANSPORTER1 . . . 553507/561 (90%)0.04 LIKE PROTEIN - Homo sapiens1 . . . 552513/561 (91%)(Human), 552 aa.O54778RST - Mus musculus (Mouse),1 . . . 552409/552 (74%)0.0553 aa.1 . . . 552462/552 (83%)Q9NSA0ORGANIC ANION1 . . . 533284/534 (53%)e−160TRANSPORTER 4 (OAT4) - Homo1 . . . 530372/534 (69%)sapiens (Human), 550 aa.


[0419] PFam analysis indicates that the NOV19a protein contains the domains shown in the Table 19E.
104TABLE 19EDomain Analysis of NOV19aNOV19aIdentities/MatchSimilarities forExpectPfam DomainRegionthe Matched RegionValuezf-RanBP: domain 1 of 1 26 . . . 55 7/32(22%)5.817/32(53%)sugar_tr: domain 1 of 1106 . . . 53089/493(18%)4.2e−07277/493(56%)



Example 20

[0420] The NOV20 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 20A.
105TABLE 20ANOV20 Sequence AnalysisSEQ ID NO:871050 bpNOV20a,CTTGAAGTAATTTATATTCTATCTTTATCGCTTGTTCCTAGGAATCATGGATCACGTCCG59278-01 DNAAGTCATAACTGGACTCAGAGTTTTATCCTTGCTGGTTTCACCACCACTGGGACCCTACSequenceAACCTCTTGCCTTCTTGGGGACCCTATGCATCTATCTCCTCACACTTGCAGGGAACATTCTCATCATTGTCCTGGTACAGTTAGATTCTGGACTGTTCACGCCCATGTACTTATTTATCAGTGTCCTCTCCTTTGTAGAGGTGTGGTATGTCAGCACCACAGTGCCCATGCTGCTGCACACCTTGCTCCAAGGGTGTTCACCCGTCTCATCAGCTGTATGCTTTATTCAGCTATCCTTTCATTCCTTAGGGATGACTGAGTGCTACCTGCTGGGTGTCATGGCACTGGATAGCTACCTTATCATCTGCCACCCACTCCACTACCACGCACTCATGAGCAGACAGGTACAGTTACGACTAGCTGGGGCCAGTTGGGTGGCTGGCTTCTCAGCTGCACTTGTGCCAGCCACCCTCACTGCCACTCTGCCCTTCTGCTTGAAAGAGGTGGCCCATTACTTTTGTGACTTGGCACCACTAATGCGGTTGGCATGTGTGGACACAAGCTGGCATGCTAGGGCCCATGGCACAGTGATTGGTGTGGCCACTGGTTGCAACTTTGTGCTCATTTTGGGACTCTATGGAGGTATCCTGAATGCTGTGCTGAAGCTACCCTCAGCTGCCAGTAGTGCCAAGGCCTTCTCTACCTGTTCCTCCCACGTAACTGTGGTGGCACTATTCTATGCTTCTGCCTTCACAGTATATGTGGGCTCACCTGGGAGTCGACCTGAGAGCACAGACAAGCTTGTTGCCTTGGTTTATGCCCTTATTACCCCTTTCCTCAATCCTATCATCTATAGCCTTCGCAACAAGGAGGTGAAGAGGCTTTAAGGAGAGTCATGGCTGGGCGCGGTGGCTCACGCCTGTAACCCAGCACTCTGGGAGGCCGAGGCGGGTGGATCACGAGGTCAGGAGATCGAGACCACGGTGAAACCCORE Start: ATG at 47ORF Stop: TAA at 980SEQ ID NO:88311 aa MW at 33602.3 kDNOV20a,MDHVSHNWTQSFILAGFTTTGTLQPLAFLGTLCIYLLTLAGNILIIVLVQLDSGLFTPCG59278-01 ProteinMYLFISVLSFVEVWYVSTTVPMLLHTLLQGCSPVSSAVCFIQLCFHSLGMTECYLLGVSequenceMALDSYLIICHPLHYHALMSRQVQLRLAGASWVAGFSAALVPATLTATLPFCLKEVAHYFCDLAPLMRLACVDTSWHARAHGTVIGVATGCNFVLILGLYGGILNAVLKLPSAASSAKAFSTCSSHVTVVALFYASAFTVYVGSPGSRPESTDKLVALVYALITPFLNPIIYSLRNKEVKKALRRVMAGRGGSRL


[0421] Further analysis of the NOV20a protein yielded the following properties shown in Table 20B.
106TABLE 20BProtein Sequence Properties NOV20aPSort0.6400 probability located in plasma membrane; 0.5000analysis:probability located in microbody (peroxisome); 0.4600probability located in Golgi body; 0.3700probability located in endoplasmic reticulum (membrane)SignalPCleavage site between residues 41 and 42analysis:


[0422] A search of the NOV20a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 20C.
107TABLE 20CGeneseq Results for NOV20aNOV20aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAG71821Human olfactory receptor polypeptide, 1 . . . 302300/303 (99%) e−172SEQ ID NO: 1502 - Homo sapiens, 1 . . . 303301/303 (99%)303 aa. [WO200127158-A2,19-APR-2001]AAG72628Murine OR-like polypeptide query 1 . . . 302254/303 (83%) e−148sequence, SEQ ID NO: 2309 - Mus 6 . . . 308277/303 (90%)musculus, 333 aa. [WO200127158-A2,19-APR-2001]AAG72627Murine OR-like polypeptide query 1 . . . 266204/267 (76%) e−117sequence, SEQ ID NO: 2308 - Mus14 . . . 280227/267 (84%)musculus, 282 aa. [WO200127158-A2,19-APR-2001]AAG71814Human olfactory receptor polypeptide, 1 . . . 307131/309 (42%)6e−69 SEQ ID NO: 1495 - Homo sapiens, 1 . . . 309188/309 (60%)317 aa. [WO200127158-A2,19-APR-2001]AAG72355Human OR-like polypeptide query12 . . . 303138/294 (46%)5e−68 sequence, SEQ ID NO: 2036 - Homo11 . . . 304181/294 (60%)sapiens, 312 aa. [WO200127158-A2,19-APR-2001]


[0423] In a BLAST search of public sequence databases, the NOV20a protein was found to have homology to the proteins shown in the BLASTP data in Table 20D.
108TABLE 20DPublic BLASTP Results for NOV20aResidues/Similarities forAccessionMatchthe MatchedNumberProtein/Organism/LengthResiduesPortionValueQ96KK4DJ994E9.5 (OLFACTORY12 . . . 303138/294 (46%)2e−67RECEPTOR, FAMILY 10, 5 . . . 298181/294 (60%)SUBFAMILY C, MEMBER 1(HS6M1-17)) - Homo sapiens (Human),306 aa. Q96KK4Olfactory receptor 10C112 . . . 303138/294 (46%)2e−67(Hs6M1-17) - Homo sapiens (Human),11 . . . 304181/294 (60%)312 aa.Q63394OL1 RECEPTOR - Rattus norvegicus 1 . . . 303129/305 (42%)1e−62(Rat), 313 aa. 1 . . . 305192/305 (62%)Q9JKA6OLFACTORY RECEPTOR P2 - Mus 7 . . . 303135/302 (44%)2e−61musculus (Mouse), 315 aa. 5 . . . 306178/302 (58%)Q9H207Olfactory receptor 10A5 (HP3) 7 . . . 301135/302 (44%)3e−61(Putative taste receptor JCG6) - 5 . . . 304181/302 (59%)Homo sapiens (Human), 317 aa.


[0424] PFam analysis indicates that the NOV20a protein contains the domains shown in the Table 20E.
109TABLE 20EDomain Analysis of NOV20aNOV20aIdentities/MatchSimilarities forExpectPfam domainRegionthe Matched RegionValue7tm_1: domain 1 of 141 . . . 288 54/268 (20%)2.7e−18170/268 (63%)



Example 21

[0425] The NOV21 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 21A.
110TABLE 21ANOV21 Sequence AnalysisSEQ ID NO:89793 bpNOV21a,ACTTACTGCATTTGGTGCTGTGATCCAACTCATCTCCCCATCCCTGCAGAGAAACCTGCG59274-01 DNATGACCATGAGGAGCAGCCTGACCATGGTGGGAACCCTCTCAGGCCTTCCTGTCCCTTGTSequenceTACTGCTGTGACCAGTTCTACCAGTTACTTCCTACCTTACTGGCTCTTTGGATCCCAGATGGGGAAGCCAGTGTCATTCAGCACATTCCGGAGGTGCAACTACCCTGTGCGGGGAGAGGGACACAGTCTGATCATGGTGGAAGAATGTGGGCGCTATGCCAGCTTCAATGCCATCCCAAGCCTGGCCTGGCAGATGTGCACAGTGGTGACAGGTGCCGGCTGTGCTCTCCTGCTCCTGGTGGCACTAGCTGCTGTCCTGGGTTGCTGCATGGAGGAGCTCATCTCCAGAATGATGGGACGTTGCATGGGAGCAGCGCAGTTTGTTGGAGGGCTGCTGATAAGCTCAGGCTGTGCCTTATACCCTTTAGGATGGAATAGCCCGGAGATAATGCAAACATGTGGGAATGTCTCCAATCAATTTCAGTTAGGTACCTGTCGGCTTGGCTGGGCCTATTACTGTGCTGGAGGTGGAGCAGCTGCAGCCATGTTGATCTGCACCTGGCTCTCTTCCTTTGCTGGAAGAAACCCCAAGCCTGTCATATTGGTGGAGAGCATCATGAGGAATACCAATTCTTATGCTATGGAGCTTGACCATTGCCTCAAACCTTGAGCTTTGAAAGAAGATTGGAGAGGGTGGGAAAGGGGAGGAGGGAGCCCTGAAAAGAGGTACTAAGGATORF Start: ATG at 64ORF Stop: TGA at 724SEQ ID NO:90220 aa MW at 23776.7 kDNOV21a,MRSSLTMVGTLWAFLSLVTAVTSSTSYFLPYWLFGSQMGKPVSFSTFRRCNYPVRGEGC059274-01 ProteinHSLIMVEECGRYASFNAIPSLAWQMCTVVTGAGCALLLLVALAAVLGCCMEELISRMMSequenceGRCMGAAQFVGGLLISSGCALYPLGWNSPEIMQTCGNVSNQFQLGTCRLGWAYYCAGGGAAAAMLICTWLSCFAGRNPKPVILVESIMRNTNSYAMELDHCLKPSEQ ID NO:91793 bpNOV21b,ACTTACTGCATTTGGTGCTGTGATCCAACTCATCTCCCCATCCCTGCAGAGAAACCTGCG59274-02 DNATGACCATGAGGACCAGCCTGACCATGGTGGGAACCCTCTGGGCCTTCCTGTCCCTTGTSequenceTACTGCTGTGACCAGTTCTACCAGTTACTTCCTACCTTACTGGCTCTTTGGATCCCAGATGGGGAAGCCAGTGTCATTCAGCACATTCCGGAGGTGCAACTACCCTGTGCGGGGAGAGGGACACAGTCTGATCATGGTGGAAGAATGTGGGCGCTATGCCAGCTTCAATGCCATCCCAAGCCTGGCCTGGCAGATGTGCACAGTGGTGACAGGTGCCGGCTGTGCTCTGCTGCTCCTGGTGGCACTAGCTGCTGTCCTGGGTTGCTGCATGGAGGAGCTCATCTCCAGAATGATGGGACGTTGCATGGGAGCAGCGCAGTTCGTTGGAGGGCTGCTGATAAGCTCAGGCTGTGCCTTATACCCTTTAGCATGGAATAGCCCGGAGATAATGCAAACATGTGGGAATGTCTCCAATCAATTTCAGTTAGGTACCTGTCGGCTTGGCTGGGCCTATTACTGTCCTGGAGGTGGAGCAGCTCCAGCCATGTTGATCTGCACCTCCCTCTCTTGCTTTGCTGGAAGAAACCCCAAGCCTGTCATATTGGTGGAGAGCATCATGAGGAATACCAATTCTTATGCTATGGAGCTTGACCATTGCCTCAAACCTTGAGCTTTGAAAGAAGATTGGAGAGGGTGGGAAAGGGGAGGAGGGAGCCCTGAAAAGAGGTACTAGGATORF Start: ATG at 64ORF Stop: TGA at 724SEQ ID NO:92220 aa MW at 23776.7 kDNOV21b,MRSSLTMVGTLWAFLSLVTAVTSSTSYFLPYWLFGSQMGKPVSFSTFRRCNYPVRGEGCG59274-02 ProteinHSLIMVEECCRYASFNAIPSLAWQMCTVVTGAGCALLLLVALAAVLGCCMEELISRMMSequenceGRCMGAAQFVGGLLISSGCALYPLGWNSPEIMQTCGNVSNQFQLGTCRLGWAYYCAGGGAAAAMLICTWLSCFAGRNPKPVILVESIMRNTNSYAMELDHCLKP


[0426] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 21B.
111TABLE 21BComparison of NOV21a against NOV21b and NOV21c.NOV21a Residues/MatchIdentities/SimilaritiesProtein SequenceResiduesfor the Matched RegionNOV21b1 . . . 220181/220 (82%)1 . . . 220181/220 (82%)


[0427] Further analysis of the NOV21 a protein yielded the following properties shown in Table 21C.
112TABLE 21CProtein Sequence Properties NOV21aPSort0.4600 probability located in plasma membrane; 0.1000analysis:probability located in endoplasmicreticulum (membrane); 0.1000 probabilitylocated in endoplasmic reticulum (lumen);0.1000 probability located in outsideSignalPLikely cleavage site between residues 21 and 22analysis:


[0428] A search of the NOV21 a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 21D.
113TABLE 21DGeneseq Results for NOV21aNOV21aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAU14297Human novel protein #168 - Homo1 . . . 220216/261 (82%) e−123sapiens, 261 aa. [WO200155437-A2,1 . . . 261219/261 (83%) 02-AUG-2001]AAU14533Human novel protein #404 - Homo1 . . . 199199/199 (100%)e−117sapiens, 239 aa. [WO200155437-A2,1 . . . 199199/199 (100%)02-AUG-2001]AAU14532Human novel protein #403 - Homo1 . . . 199199/199 (100%)e−117sapiens, 239 aa. [WO200155437-A2,1 . . . 199199/199 (100%)02-AUG-2001]AAU14296Human novel protein #167 - Homo1 . . . 199195/199 (97%) e−115sapiens, 269 aa. [WO200155437-A2,1 . . . 199196/199 (97%) 02-AUG-2001]AAB80378Secreted protein encoded by gene #8 - 1 . . . 195125/196 (63%) 5e−77 Homo sapiens, 200 aa.1 . . . 196151/196 (76%) [WO200107459-A1, 01-FEB-2001]


[0429] In a BLAST search of public sequence databases, the NOV21a protein was found to have homology to the proteins shown in the BLASTP data in Table 21E.
114TABLE 21EPublic BLASTP Results for NOV21aNOV21aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ9Y693PARTNER - Homo sapiens (Human), 1 . . . 196151/196 (76%) 2e−76200 aa.Q96SH5BA183L8.1 (LIPOMA HMGIC 1 . . . 12779/128 (61%)3e−43FUSION PARTNER) - Homo sapiens 1 . . . 12897/128 (75%)(Human), 128 aa (fragment).Q92605KIAA0206 PROTEIN - Homo sapiens67 . . . 19043/125 (34%)3e−15(Human), 193 aa (fragment).47 . . . 17063/125 (50%)Q9W068CG12026 PROTEIN (LP10272P) -  8 . . . 19749/195 (25%)2e−12Drosophila melanogaster (Fruit fly),25 . . . 20885/195 (43%)265 aa.Q955W9SD01285P - Drosophila melanogaster 5 . . . 17141/175 (23%)1e−11(Fruit fly), 219 aa. 6 . . . 17877/175 (43%)


[0430] PFam analysis indicates that the NOV21 a protein contains the domains shown in the Table 21F.
115TABLE 21FDomain Analysis of NOV21aIdentities/Similarities forExpectPfam DomainNOV21a Match Regionthe Matched RegionValueNo Significant Matches Found



Example 22

[0431] The NOV22 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 22A.
116TABLE 22ANOV22 Sequence AnalysisSEQ ID NO:931228 bpNOV22a,AGATCTGTGACCAGTTCTACCAGTTACTTCCTACCTTACTGGCTCTTTGGATCCCAGA172885510 DNATGGGGAAGCCAGTGTCATTCAGCACATTCCGGAGGTGCAACTACCCTGTGCGGGGAGASequenceGGGACACAGTCTGATCATGGTGGAAGAATGTGGGCGCTATGCCAGCTTCAATGCCATCCCAAGCCTGGCCTGGCAGATGTGCACAGTGGTGACAGGTGCCGGCTGTCTCGAGORF Start: ATC at 3ORF Stop: G r at 228SEQ ID NO:9475 aa MW at 8305.5 kDNOV22a,ICDQFYQLLPTLLALWIPDGEASVIQHIPEVQLPCAGRGTQSDHGCRMWALCQLQCHP172885510 ProteinKPGLADVHSGDRCRLSRSequence


[0432] Further analysis of the NOV22a protein yielded the following properties shown in Table 22B.
117TABLE 22BProtein Sequence Properties NOV22aPSort0.3000 probability located in microbody (peroxisome);analysis:0.3000 probability located in nucleus; 0.1000probability located in mitochondrial matrix space; 0.1000probability located in lysosome (lumen)SignalPNo Known Signal Sequence Indicatedanalysis:


[0433] A search of the NOV22a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 22C.
118TABLE 22CGeneseq Results for NOV22aNOV22aIdentities/Protein/Organism/Residues/SimilaritiesGeneseqLengthMatchfor theExpectIdentifier[Patent #, Date]ResiduesMatched RegionValueNo Significant Matches Found


[0434] In a BLAST search of public sequence databases, the NOV22a protein was found to have homology to the proteins shown in the BLASTP data in Table 22D.
119TABLE 22DPublic BLASTP Results for NOV22aNOV22aIdentities/ProteinResidues/SimilaritiesAccessionProtein/Organism/Matchfor theExpectNumberLengthResiduesMatched PortionValueNo Significant Matches Found


[0435] PFam analysis indicates that the NOV22a protein contains the domains shown in the Table 22E.
120TABLE 22EDomain Analysis of NOV22aIdentities/NOV22aSimilaritiesMatchfor the MatchedExpectPfam DomainRegionRegionValueMan-6-P_recep:156 . . . 1689/13(69%)0.7domain 1 of 19/13(69%)perilipin: domain 1 of 1 10 . . . 369139/411(34%)1.4e−76240/411(58%)



Example 23

[0436] The NOV23 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 23A.
121TABLE 23ANOV23 Sequence AnalysisSEQ ID NO:951916 bpNOV23a,GCCGCTGCCGTCGCCCCTAGCCCCAGCAGCCCTGGTCTCGCAGCCTCCTGCGGCTCTGCG57734-01 DNAGTCGCCCGACCAGCCATGTCTCTCGGCGGAGCCTCCGAGCGCAGCGTCCCGGCCACCASequenceAGATTGAAATTACCGTGTCCTGCCGGACCTTGATACCTTCTCCAAGTCCGACCCCAGTAGGCGGCTCCAGGACCGGGAGGGCGAACTTGGGGTCTGGGCGCGACTCAGGGGCGGGTGGAGTCGGGGCCAGGGGTGGGAGCCGACCTGACGTCCTTCCCTCCCCGCCCCCACCTGCAGTGGTGGTGCTTTACACGCAGAGCCGGGCCAGCCAGGAGTGGCGGGAGTTCGGACGGACCGAGGTGATTGATAACACGCTGAACCCAGACTTCGTGCGCAAATTCGTCCTCGACTATTTCTTTGAGGAAAAGCAAAATCTGCGCTTCGATGTGTACAACGTGGACTCCAAAACCAACATCTCCAAACCGAAGGATTTCCTGGGACAAGCGTTCCTGGCCCTGGGAGAGGTGATTGGAGGCCAGGGCAGCCGAGTAGAGCGAACCCTCACGGGTGTACCAGGCAAGAAGTGTGGGACCATATTGCTGACTGCAGAAGAGCTTAGCAATTGTCGGGACATTGCCACCATGCAGCTGTGTGCAAACAAGCTGGACAAGAAGGACTTCTTTGGGAAATCAGACCCCTTCCTTGTGTTCTACAGGAGCAATGAGGATGGCACGTTCACCATCTGCCACAAGACAGAGGTTGTGAAAAACACGCTGAATCCTGTGTGGCAGCCCTTCAGCATCCCTGTGCGGGCTCTGTGCAATGGACACTATGACAGAACGGTGAAGATTGATGTGTACGACTGGGACCGGGATGGAAGCCACGATTTCATTGGTGAGTTCACCACCAGCTACCGGGAGCTGAGCAAGGCCCAGAACCAGTTCACAGTATATGAGGTGCTTAACCCTCGGAAGAAATGTAAGAAGAAGAAATATGTCAACTCAGGAACTGTGACGCTGCTCTCCTTCTCTGTGGACTCTGAATTCACTTTTGTTGATTACATCAAGGGAGGGACACAGCTGAACTTCACAGTAGCCATTGACTTCACGGCTTCCAATGGTAATCCTCTGCAGCCTACCTCCCTGCACTACATGAGTCCCTACCAGCTCAGCGCCTATGCCATGGCCCTCAAGGCAGTGGGAGAGATCATCCAGGACTATGACAGTGATAAGCTCTTCCCAGCTTATGGCTTTGGGGCCAAGCTGCCCCCAGAGGGACGGATCTCCCACCAGTTCCCCCTGAACAACAATGATGAGGACCCCAACTGTGCGCGCATCGAGGGTGTGCTGGAGAGCTATTTCCAGAGCCTGCGCACAGTGCAGCTCTATGGGCCCACCTACTTTGCTCCTGTCATCAACCAAGTGGCCAGGGCTGCAGCCAAGATCTCTGATGGCTCCCAGTACTATGTTCTGCTCATCATCACTGATGGGGTCATCTCTGACATGACGCAGACCAAGGAGGCCATCGTCAGCGCCTCCTCATTGCCCATGTCTATCATTATCGTCGGTGTAGGACCAGCCATGTTTGAGGCAATGGAAGAGTTGGACGGTGATGATGTGCGCGTGTCCTCTAGGGGACGCTACGCAGAGCGGGACATCGTTCAGTTCGTCCCATTCCGAGACTATGTTGACCGGTCGGGGAACCAGGTGTTGAGCATGGCCCGACTGGCCAAGGATGTGCTGGCCGAGATCCCGGACCAGCTGCTGTCCTATATGCGCACCAGAGACATCCAGCCTCCGCCCCCACCCCCTGCCAACCCCAGCCCGATCCCAGCTCCAGAGCAGCCCTGAGCATTCCACATATCCAATGCCTCACAGTCTGCAAGCCTGCTCACCCACTGCTTCTGCTTTAAGCCAGAGGORF Start: ATG at 74ORE Stop: TGA at 1844SEQ ID NO:96590 aa MW at 65041.9 kDNOV23a,MSLGGASERSVPATKIEITVSCRTLIPSPSPTPVGGSRTGRGNLGSGRDSGAGGVGARCG57734-01 ProteinGGSRPDVLPSPPPPAVVVLYTQSRASQEWREFGRTEVIDNTLNPDFVRKFVLDYFFEESequenceKQNLRFDVYNVDSKTNISKPKDFLGQAFLALGEVIGGQGSRVERTLTGVPGKKCGTILLTAEELSNCRDIATMQLCANKLDKKDFFGKSDPFLVFYRSNEDGTFTICHKTEVVKNTLNPVWQPFSIPVRALCNGDYDRTVKIDVYDWDRDGSHDFIGEFTTSYRELSKAQNQFTVYEVLNPRKKCKKKKYVNSGTVTLLSFSVDSEFTFVDYIKGGTQLNFTVAIDFTASNGNPLQPTSLHYMSPYQLSAYAMALKAVGEIIQDYDSDKLFPAYGFGAKLPPEGRISHQFPLHNMDEDPNCAGIEGVLESYFQSLRTVQLYGPTYFAPVINQVARAAAKTSDGSQYYVLLIITDGVTSDMTQTKEAIVSASSLPMSIIIVGVGPAMFEAMEELDGDDVRVSSRGRYAERDIVQFVPFRDYVDRSGNQVLSMARLAKDVLAEIPEQLLSYMRTRDIQPRPPPPANPSPIPAPEQPSEQ ID NO:9711742 bpNOV23b,CCGACCAGCCATGTCTCTCGGCGGAGCCTCCGAGCGCAGCGTCCCGCCCACCAAGATTCG5 7734-02 DNAGAAATTACCGTGTCCTGCCGGAACCTGCTAGACCTCGATACCTTCTCCAAGTCCGACCSequenceCCATGGTGGTGCTTTACACGCAGAGCCGGGCCAGCCAGGAGTGGCGGGAGTTCGGACGGACCGACGTGATTGATAACACGCTGAACCCAGACTTCGTGCGCAAATTCGTCCTCCACTATTTCTTTGAGGAAAAGCAAAATCTGCGCTTCGATGTGTACAACGTGGACTCCAAAACCAACATCTCCAAACCGAAGGATTTCCTGGGACAAGCGTTCCTGGCCCTGGGAGAGGTGATTGGAGGCCAGGGCAGCCGAGTAGAGCGAACCCTCACGGGTGTACCAGGCAAGAAGTGTCGCACCATATTGCTGACTGCAGAAGAGCTTAGCAATTGTCGGGACATTGCCACCATGCAGCTGTGTGCAAACAAGCTGGACAAGAAGGACTTCTTTGGGAAATCAGACCCCTTCCTTGTGTTCTACAGGAGCAATGAGCATCGCACGTTCACCATCTGCCACAAGACAGAGGTTGTGAAAAACACGCTGAATCCTGTGTGGCAGCCCTTCAGCATCCCTGTGCGGGCTCTGTGCAATGGAGACTATGACAGAACGGTGAAGATTGATGTGTACGACTGGGACCGGGATGGAAGCCACGATTTCATTGGTGAGTTCACCACCAGCTACCGGGAGCTGAGCAAGGCCCAGAACCAGTTCACAGTATATGAGGTTCTTAACCCTCGGAAGAAATGTAAGAAGAAGAAATATGTCAACTCAGGAACTGTGACGCTGCTCTCCTTCTCTGTGGACTCTGAATTCACTTTTGTTGATTACATCAAGGGAGGGACACAGCTCAACTTCACACTAGCCATTCACTTCACGGCTTCCAATGGGAATCCTCTGCAGCCTACCTCCCTGCACTACATGAGTCCCTACCAGCTCAGCGCCTATGCCATGGCCCTCAAGGCAGTGGGAGAGATCATCCAGGACTATGACAGTGATAAGCTCTTCCCAGCTTATGGCTTTGGGGCCAAGCTGCCCCCAGAGGGACGGATCTCCCACCAGTTCCCCCTGAACAACAATGATGAGGACCCCAACTGTGCGGGCATCGAGGGTGTGCTGGAGAGCTATTTCCAGAGCCTGCGCACAGTGCAGCTCTATGGGCCCACCTACTTTGCTCCTGTCATCAACCAAGCGGCCAGGGCTGCAGCCAAGATCTCTGATGGCTCCCAGTACTATGTTCTGCTCATCATCACTGATGGGGTCATCTCTGACATGACGCAGACCAAGGAGGCCATCGTCAGCGCCTCCTCATTGCCCATGTCTATCATTATCGTCGGTGTAGGACCAGCCATGTTTGAGGCAATGGAAGAGTTGGACGGTGATGATGTGCGCGTGTCCTCTAGCGCACGCTACGCAGAGCGGGACATCGTTCAGTTCGTCCCATTCCGAGACTATGTTGACCGGTCGGGGAACCAGCTGTTGAGCATGGCCCGACTGGCCAAGGATGTGCTGGCCGAGATCCCGGAGCAGCTGCTGTCCTATATGCGCACCAGAGACATCCACCCTCGGCCCCCACCCCCTGCCAACCCCAGCCCGATCCCAGCTCCAGAGCAGCCCTGAGGATTCCACATATCCAATGCCTCACAGTCTGCAAGCCTGCTCACCCACTGCTTCTGCTTTAAGCCAGAGGORF Start: ATG at 11ORF Stop: TGA at 1670SEQ ID NO:98553 aa MW at 61835.3 kDNOV23b,MSLGGASERSVPATKIEITVSCRNLLDLDTFSKSDPMVVLYTQSRASQEWREFGRTEVCG57734-02 ProteinIDNTLNPDFVRKFVLDYFFEEKQNLRFDVYNvDSKTNISKPKDFLGQAFLALGEVIGGSequenceQGSRVERTLTGVPGKKCGTILLTAEELSNCRDIATMQLCANKLDKKDFFGKSDPFLVFYRSNEDGTFTICHKTEVVKNTLNPVWQPFSIPVRALCNGDYDRTVKIDVYDWDRDGSHDFIGEFTTSYRELSKAQNQFTVYEVLNPRKKCKKKKYVNSGTVTLLSFSVDSEFTFVDYIKGGTQLNFTVAIDFTASNGNPLQPTSLHYMSPYQLSAYAMALKAVGEIIQDYDSDKLFPAYGFGAKLPPEGRISHQFPLNNDEDPNCAGIEGVLESYFQSLRTVQLYGPTYYFAPVINQAARAAAKISDGSQYYVLLIITDCVISDMTQTKEAIVSASSLPMSIIIVGVGPAMFEAMEELDGDDVRVSSRGRYAERDIVQFVPFRDYVDRSGNQVLSMARLAKDVLAEIPEQLLSYMRTRDIQPRPPPPANPSPIPAPEQPSEQ ID NO:991368 bpNOV23c,GGATCCATGTCTGTCGGCCGAGCCTCCGAGCGCAGCGTCCCGGCCACCAAGATTGAAA198363601 DNATTACCGTGTCCTGCCGGAACCTGCTAGACCTTGATACCTTCTCCAAGTCCGACCCCATSequenceGGTGGTGCTTTACGCGCAGAGCCGGGCCAGCCAGGAGTGGCGGGAGTTCGGACGGACCGAGGTGATTGATAACACGCTGAACCCAGACTTCGTGCGCAAATTCGTCCTCGACTATTTCTTTGAGGAAAAGCAAAATCTGCGCTTCGATGTGTACAACGTCGACTCCAAAACCAACATCTCCAAACCGAAGGATTTCCTGGGACAAGCGTTCCTGGCCCTGGGAGAGGTGATTGGAGGCCAGGGCAGCCGAGTAGAGCGAACCCTCACGGGTGTACCAGGCAAGAAGTGTGGGACCATATTGCTGACTGCAGAAGAGCTTAGCAATTGTCGGGACATTGCCACCATCCAGCTGTGTGCAAACAAGCTGGACAAGAAGGACTTCTTTGGGAAATCAGACCCCTTCCTTGTGTTCTACAGGAGTAATGAGGATGGCACGTTCACCATCTGCCACAAGACAGAGGTTGTGAAAAACACGCTGAATCCTGTGTGGCAGCCCTTCAGCATCCCTGTGCGGGCTCTGTGCAATGGAGACTATGACAGAACGGTGAAGATTGATGTGTACGACTGGGACCGCGATGGAAGCCACGATTTCATTGGTGAGTTCACCACCAGCTACCGGGAGCTGAGCAAGGCCCAGAACCAGTTCACAGTATATGAGGTTCTTAACCCTCGGAAGAAATGTAAGAAGGAGAAATATGTCAACTCAGGAACTGTGACGCTGCTCTCCTTCTCTGTGGACTCTGAATTCACTTTTGTTGATTACATCAAGGGACGGACACAGCTGAACTTCACAGTAGCCATTGACTTCACGGCTTCCAATGGGAATCCTCTGCAGCCTACCTCCCTGCACTACATGAGTCCCTACCAGCTCAGCGCCTATGCCATGGCCCTCAAGGCAGTGGGAGAGATCATCCAGGACTATGACAGTGATAAGCTCTTCCCAGCTTATGGCTTTGGCGCCAAGCTGCCCCCAGAGGGACGGATCTCCCACCAGTTCCCCCTGAACAACAATGATGAGGACCCCAACTGTGCGGGCATCGAGGGTGTGCTGGAGAGCTATTTCCAGAGCCTGCGCACAGTGCAGCTCTATGGGCCCACCTACTTTGCTCCTGTCATCAACCAAGTGCCCAGGGCTGCAGCCAACATCTCTGATGGCTCCCAGTACTATGTTCTGCTCATCATCACTdATGGGGTCATCTCTGACATGACGCAGACCAAGGAGGCCATCGTCAGCGCCTCCTCATTGCTCGAGORF Start: GGA at 1ORF Stop: SD at 1369SEQ ID NO:100456 aa MW at 50948.9 kDNOV23c,GSMSVGGASERSVPATKIEITVSCRNLLDLDTFSKSDPMVVLYAQSRASQEWREFGRT198363601ProteinEVIDNTLNPDFVRKFVLDYFFEEKQNLRFDVYNVDSKTNISKPKDFLGQAFLALGEVISequenceGGQGSRVERTLTGVPGKKCGTILLTAEELSNCRDIATMQLCANKLDKKDFFGKSDPFLVFYRSNEDGTFTICHKTEVVKNTLNPVWQPFSIPVRALCNGDYDRTVKIDVYDWDRDGSHDFIGEFTTSYRELSKAQNQFTVYEVLNPRKKCKKEKYVNSGTVTLLSFSVDSEFTFVDYIKGGTQLNFTVAIDFTASNGNPLQPTSLHYMSPYQLSAYAMALKAVGEIIQDYDSDKLFPAYGFGAKLPPEGRISHQFPLNNNDEDPNCAGIEGVLESYFQSLRTVQLYGPTYFAPVINQVARAAAKISDGSQYYVLLIITDGVISDMTQTKEAIVSASSLLE


[0437] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 23B.
122TABLE 23BComparison of NOV23a against NOV23b through NOV23c.NOV23a Residues/MatchIdentities/SimilaritiesProtein SequenceResiduesfor the Matched RegionNOV23b1 . . . 572523/572 (91%)1 . . . 535525/572 (91%)NOV23c1 . . . 489438/489 (89%)3 . . . 454442/489 (89%)


[0438] Further analysis of the NOV23a protein yielded the following properties shown in Table 23C.
123TABLE 23CProtein Sequence Properties NOV23aPSort0.8500 probability located in endoplasmic reticulumanalysis:(membrane); 0.4400 probability located in plasma membrane;0.3388 probability located in microbody(peroxisome); 0.3000 probability located in nucleusSignalPNo Known Signal Sequence Indicatedanalysis:


[0439] A search of the NOV23a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 23D.
124TABLE 23DGeneseq Results for NOV23aNOV23aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAY97293Lipid associated protin (LIPAP)10 . . . 583412/575 (71%)0.03335404CD1 - Homo sapiens, 564 aa.20 . . . 556475/575 (81%)[WO200049043-A2, 24-AUG-2000]AAM39997Human polypeptide SEQ ID NO 3142 - 76 . . . 579248/511 (48%)e−138Homo sapiens, 548 aa.49 . . . 548353/511 (68%)[WO2001533 12-A1, 26-JUL-2001]AAB24231Human vesicle associated protein 1076 . . . 579248/511 (48%)e−138SEQ ID NO: 10 - Homo sapiens, 53233 . . . 532353/511 (68%)aa. [WO200060082-A2, 12-OCT-2000]AAU19736Human novel extracellular matrix64 . . . 582257/527 (48%)e−137protein, Seq ID No 386 - Homo25 . . . 534351/527 (65%)sapiens, 540 aa. [WO200155368-A1,02-AUG-2001]AAU19664Human novel extracellular matrix286 . . . 590 234/308 (75%)e−133protein, Seq ID No 314 - Homo20 . . . 327268/308 (86%)sapiens, 335 aa. [WO200155368-A1,02-AUG-2001]


[0440] In a BLAST search of public sequence databases, the NOV23a protein was found to have homology to the proteins shown in the BLASTP data in Table 23E.
125TABLE 23EPublic BLASTP Results for NOV23aNOV23aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ9HCH3Copine-like protein KIAA 1599 - Homo10 . . . 590422/604 (69%)0.0sapiens (Human), 593 aa.19 . . . 585484/604 (79%)Q9DC531200003E11RIK PROTEIN - Mus10 . . . 583411/575 (71%)0.0musculus (Mouse), 577 aa.33 . . . 569477/575 (82%)O75131Copine III - Homo sapiens (Human),64 . . . 582257/527 (48%)e−137537 aa.22 . . . 531352/527 (66%)Q96A23CDNA FLJ31613 FIS,CLONE55 . . . 574258/528 (48%)e−135NT2R12002958, MODERATELY30 . . . 543347/528 (64%)SIMILAR TO HOMO SAPIENSCOPINE VI PROTEIN (SIMILARTO RIKENCDNA 3632411M23 GENE) - Homosapiens (Human), 557 aa.Q99829Copine I - Homo sapiens (Human),68 . . . 588250/528 (47%)e−133537 aa.24 . . . 536352/528 (66%)


[0441] PFam analysis indicates that the NOV23a protein contains the domains shown in the Table 23F.
126TABLE 23FDomain Analysis of NOV23aNOV23aIdentities/MatchSimilaritiesExpectPfam DomainRegionfor the Matched RegionValueC2: domain 1 of 1191 . . . 27632/99 (32%)6.5e−0759/99 (60%)



Example 24

[0442] The NOV24 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 24A.
127TABLE 24ANOV24 Sequence AnalysisSEQ ID NO: 1011904 bpNOV24a,TTTTTTTTTGACACTGTAAAAGAAGTTTATTTCTTGTTCACATAACTGTCCAAGGCTGCG59389-01 DNAGTGTTCCTGGGCAACTTCCAGTTCTCTTCCATGCAATGATTCAAGGACACACAGTTCTSequenceTCCATCCTGTGACTCTACCATCCCCTAGAGCCCTCTACTGTAAGAGTTACCTAAAGCATCTGTGATGGTCCAGGAGGCTTCTCAGGTGATCGGGCAGTGTCAGTCTTCAGCCACTAAGCCCAGAAGATCTGGGAAGAAGTCAATCAGAGAGCCTTGGGCCAGAGTTCCAGGGGCTCTGGGAGTGGCTGCCAGGTGAGCTGGACAGTCTGATTTTCAGTGGGGTCCACACAGATGGGACGCGGCTTAGGAGGAATCCTGGGCTGCAGGCATTCCTTGGCCTGGTAGTCAGATTTCTGGCACTTGTAGCAAGCTCCTGGCGGAGAAGGTTCTGGAGTAACGCCTGGCCGCTGCGGTTCAGGCATTTGGAAGTTCTTGTGTGCTGGACATCTGCCTGGGGTTTGTCTCACAGTGGAGGTTACCTAACCAAACTCCTGTAAAACCACACCACCTATGCCTGTGATGGGGACTATTTGAATCTACAGTGCCCTCGGCATTCTACGATAAGTGTCCAATCGGCATTTTATGGGCAAGATTACCAAATGTGTAGTTCCCAGAAGCCTGCCTCCCAGAGGGAAGACAGCTTAACCTGTGTGGCAGCCACCACCTTCCAGAAGGTGCTGGACGAATGCCAGAACCAGCGGGCCTGCCACCTCCTGGTCAATAGCCGTGTTTTTGGACCTGACCTTTGTCCAGGAAGCAGTAAATACCTCCTGGTCTCCTTTAAATGCCAACCTAATGAATTAAAAAACAAAACCGTGTGTGAAGACCAGGAGCTGAAACTGCACTGCCATGAATCCAAGTTCCTCAACATCTACTCTGCGACCTACGGCAGGAGGACCCAGGAAAGGCACATCTGCTCCTCCAACGCAGAGCGGCTCCCCCCTTTCGATTGCTTGTCTTACTCAGCTTTGCAAGTCCTATCCCGAAGGTGCTATGGGAAGCAGAGATGCAAAATCATCGTCAACAATCACCATTTTGGAAGCCCCTGTTTGCCAGGCATGAAAAAATACCTCACTGTGACCTACGCATGTGTTCCCAAGAACATACTCACACCGATTGATCCAGCCATTGCTAATCTAAAACCTTCTTTGAAGCAGAAAGATGGTGAATATGGTATAAACTTTGACCCAAGCGGATCGAAGGTTCTGAGGAAAGATGGAATTCTTGTTAGCAACTCTCTGGCAGCCTTTGCTTACATTAGAGCCCACCCGGAGAGAGCTGCCCTGCTGTTCGTCTCCAGTGTCTGCATCGGCCTGGCCCTCACACTGTGCGCCCTGGTCATCAGAGAGTCCTGTGCCAAGGACTTCCCCGACTTGCAGCTGGGGAGGGAGCAGCTGGTGCCAGGAAGTGACAAGGTCGAGCAGGACAGCGAGGATGAAGAAGACGAGGAGGACCCCTCTGAGTCTGATTTCCCAGGGGAACTGTCGGGGTTCTGTAGGACTTCATATCCTATATACAGTTCCATAGAAGCTGCAGAGCTCGCAGAAAGGATTGAGCGCAGGGAGCAAATCATTCAGGAAATATGGATGAACAGTGGTTTGGACACCTCGCTCCCAAGAAACATGGGCCAGTTCTACTGAAAACCACATGCATCTTGATGCGATCGCACTTTCTGAAGAAGGAAGGATCCCAAATGCCCCTCCAGTTCTGGTTCACCTGTACCTTCTATGAAGGAGAATTCGTCATGTCATTCAACACTCGTGAGGCCAGGAAGCTATTAAAGGGATGTTTCAAGCTGTTTCTAGCACATTCCAAATAAATGAGGAGGGAAGAAAAAAAAAAAAAAAORF Start: ATG at 656ORF Stop: TGA at 1694SEQ ID NO: 102346 aaMW at 38793.6kDNOV24a,MCSSQKPASQREDSLTCVAATTFQKVLDECQNQRACHLLVNSRVFGPDLCPGSSKYLLCG59389-01 ProteinVSFKCQPNELKNKTVCEDQELKLHCHESKFLNIYSATYGRRTQERDICSSKAERLPPFSequenceDCLSYSALQVLSRRCYGKQRCKIIVNNHHFGSPCLPGMKKYLTVTYACVPKNILTAIDPAIANLKPSLKQKDGEYGINFDPSGSKVLRKDGILVSNSLAAFAYIRAHPERAALLFVSSVCIGLALTLCALVIRESCAKDFRDLQLGREQLVPGSDKVEEDSEDEEEEEDPSESDFPGELSGFCRTSYPIYSSIEAAELAERIERREQIIQEIWMNSGLDTSLPRNMGQFYSEQ ID NO: 1031802 bpNOV24b,TTTTTTTTTGACACTCTAAAAGAAGTTTATTTCTTGTTCACATAACTGTCCAAGGCTGCG59389-02 DNAGTGTTCCTGGGCAACTTCCAGTTCTCTTCCATGCAATGATTCAAGGACACAGAGTTCTSequenceTCCATCCTGTGACTCTACCATCCCCTAGAGCCCTCTACTGTAAGAGTTACCTAAAGCATCTGTGATGGTCCAGGAGGCTTCTCAGGTGATCGGGCAGTGTCAGTCTTCAGCCACTAAGCCCAGAAGATCTGGGAAGAAGTCAATCAGAGAGCCTTGGGCCAGAGTTCCAGGGGCTCTGGGAGTCGCTGCCAGGTGAGCTGGACAGTCTGATTTTCAGTGGGGTCCACACACATGGGACGCGGCTTAGGAGGAATCCTGGGCTGCAGGCATTCCTTGCCCTGCTAGTCAGATTTCTGGCACTTGTAGCAAGCTCCTGGGGGAGAAGGTTCTGGAGTAACGCCTGGCCGCTGCGCTTCAGGCATTTGGAAGTTCTTGTGTGCTGGAGATGTGGCTGGGGTTTGTCTCACAGTGGAGGTTACCTAACCAAACTCCTGTAAAACCACACCACCTATGCCTGTGATGGGGACTATTTGAATCTACAGTGCCCTCGGCATTCTACGATAAGTGTCCAATCGGCATTTTATGGGCAAGATTACCAAATGTGTAGTTCCCAGAAGCCTGCCTCCCAGAGGGAAGACAGCTTAACCTGTGTGGCAGCCACCACCTTCCAGAAGGTGCTGGACGAATGCCAGAACCAGCGGGCCTGCCACCTCCTGGTCAATAGCCGTGTTTTTGGACCTGACCTTTGTCCAGGAAGCAGTAAATACCTCCTGGTCTCCTTTAAATGCCAACCTAATGAATTAAAAAACAAAACCGTGTGTGAAGACCAGGAGCTGAAACTGCACTGCCATGAATCCAAGTTCCTCAACATCTACTCTGCGACCTACGGCAGGAGGACCCAGGAAAGGGACATCTGCTCCTCCAAGGCAGAGCGGCTCCCCCCTTTCGATTGCTTGTCTTACTCAGCTTTGCAAGTCCTATCCCGAAGGTGCTATGGGAAGCAGAGATGCAAAATCATCGTCAACAATCACCATTTTGGAAGCCCCTGTTTGCCAGGCGTGAAAAAATACCTCACTCTGACCTACGCATGTCGTATAAACTTCGACCCAAGCGGATCGAAGGTTCTGAGGAAAGATGGAATTCTTGTTAGCAACTCTCTGGCAGCCTTTGCTTACATTAGAGCCCACCCGGAGAGAGCTGCCCTGCTGTTCGTGTCCAGTGTCTGCATCGGCCTGGCCCTCACACTGTGCGCCCTGGTCATCAGAGAGTCCTGTGCCAAGGACTTCCGCGACTTGCAGCTGGGGAGGGAGCAGCTGGTGCCAGGAAGTGACAAGGTCGAGGAGGACACCGAGCATGAAGAAGAGGAGGAGGACCCCTCTGAGTCTGATTTCCCAGGGGAACTGTCGCGGTTCTGTAGGACTTCATATCCTATATACAGTTCCATAGAAGCTGCAGAGCTCGCAGAAAGGATTCAGCGCAGGGAGCAAATCATTCAGGAAATATGGATGAACAGTGGTTTGGACACCTCGCTCCCAAGAAACATGGGCCAGTTCTACTGAAAACCACATGCATCTTGATGCGATCGCACTTTCTGAAGAAGCAAGGATCCCAAATGCCCCTCCAGTTCTGGTTCACCTGTACCTTCTATGAAGGAGAATTCGTCATGTCATTCAACACTCGTGAGGCCAGGAAGCTATTAAAGGGATGTTTCAAGCTGTTTCTAGCACAGGGGCTTCCAGCATCCTGORF Start: ATG at 656ORF Stop: TGA at 1613SEQ ID NO: 104319 aaMW at 35842.2 kDNOV24b,MCSSQKPASQREDSLTCVAATTFQKVLDECQNQRACHLLVNSRVFGPDLCPGSSKYLLCG59389-02 ProteinVSFKCQPNELKNKTVCEDQELKLHCHESKFLNIYSATYGRRTQERDICSSKAERLPPFSequenceDCLSYSALQVLSRRCYGKQRCKIIVNNHHFGSPCLPGVKKYLTVTYACGINFDPSGSKVLRKDGILVSNSLAAFAYIRAHPERAALLFVSSVCIGLALTLCALVIRESCAKDFRDLQLGREQLVPGSDKVEEDSEDEEEEEDPSESDFPGELSGFCRTSYPIYSSIEAAELAERIERREQIIQEIWMNSGLDTSLPRNMGQFYSEQ ID NO: 1051326 bpNOV24c,TCCCCGCCATGTGACGCCGTCCTTAGCCCTGCGACCCCCAGCGCGTCCCGGGCCTGCGCG59389-04 DNACCTCCGCCCCGCCGCGCAGCACGATGCTTCTGCCGGGACGCGCACGCCAACCGCCGACSequenceGCCCCAGCCCGTGCAGCATCCCGGCCTCCGCCGGCAGGTAGAGCCGCCGGGGCAGCTCCTGCGCCTCTTCTACTGCACTGTCCTGGTCTGCTCCAAAGAGATCTCAGCGCTCACCGACTTCTCTGGTTACCTAACCAAACTCCTGCAAAACCACACCACCTATGCCTGTGATGGGGACTATTTGAATCTACAGTGCCCTCGGCATTCTACGATAAGTGTCCAATCGGCATTTTATGGGCAAGATTACCAAATGTGTAGTTCCCAGAAGCCTGCCTCCCAGAGGGAAGACAGCTTAACCTGTGTGGCAGCCACCACCTTCCAGAAGGTGCTGGACGAATGCCAGAACCAGCGGGCCTGCCACCTCCTGGTCAATAGCCGTGTTTTTGGACCTGACCTTTGTCCAGGAAGCAGTAAATACCTCCTGGTCTCCTTTAAATGCCAACCTAATGAATTAAAAAACAAAACCGTGTGTGAAGACCAGGAGCTGAAACTGCACTGCCATGAATCCAAGTTCCTCAACATCTACTCTGCGACCTACGGCAGGAGGACCCAGGAAAGGGACATCTGCTCCTCCAAGGCAGAGCCGCTCCCCCCTTTCGATTGCTTGTCTTACTCAGCTTTGCAAGTCCTATCCCGAAGGTGCTATGGGAAGCAGAGATGCAAAATCATCGTCAACAATCACCATTTTGGAAGCCCCTGTTTGCCAGGCGTGAAAAAATACCTCACTGTGACCTACGCATGTGGTATAAACTTCGACCCAAGCGGATCGAAGGTTCTGAGGAAAGATGGAATTCTTGTTAGCAACTCTCTGGCAGCCTTTGCTTACATTAGAGCCCACCCGGAGAGAGCTGCCCTGCTGTTCGTGTCCAGTGTCTGCATCGGCCTGGCCCTCACACTGTGCGCCCTGGTCATCAGAGAGTCCTGTGCCAAGGACTTCCGCGACTTGCAGCTGGGGAGGGAGCAGCTGGTGCCAGGAAGTGACAAGGTCGAGGAGGACAGCGAGGATGAAGAAGAGGAGGAGCACCCCTCTGAGTCTGATTTCCCAGGGGAACTGTCGGGGTTCTGTAGGACTTCATATCCTATATACAGTTCCATAGAAGCTGCAGACCTCGCAGAAAGGATTGAGCGCAGGGAGCAAATCATTCAGGAAATATGGATGAACAGTGGTTTGGACACCTCGCTCCCAAGAAACATGGGCCAGTTCTACTGAORF Start: ATG at 82ORF Stop: TGA at 1324SEQ ID NO: 106414 aaMW at 46563.4 kDNOV24c,MLLPGRARQPPTPQPVQHPGLRRQVEPPCQLLRLFYCTVLVCSKEISALTDFSGYLTKCG59389-04 ProteinLLQNHTTYACDGDYLNLQCPRHSTISVQSAFYGQDYQMCSSQKPASQREDSLTCVAATSequenceTFQKVLDECQNQRACHLLVNSRVFGPDLCPGSSKYLLVSFKCQPNELKNKTVCEDQELKLHCHESKFLNIYSATYGRRTQERDICSSKAERLPPFDCLSYSALQVLSRRCYGKQRCKIIVNNHHFGSPCLPGVKKYLTVTYACGINFDPSGSKVLRKDGILVSNSLAAFAYIRAHPERAALLFVSSVCIGLALTLCALVIRESCAKDFRDLQLGREQLVPGSDKVEEDSEDEEEEEDPSESDFPGELSGFCRTSYPIYSSIEAAELAERIERREQIIQEIWMNSGLDTSLPRNMGQFYSEQ ID NO: 107693 bpNOV24d,AAGCTTACCATGTGTAGTTCCCAGAGCCTGCCTCCCAGAGGGAAGACAGCTTAACCT174308481 DNAGTGTGGCAGCCACCACCTTCCAGAAGGTGCTGGACGAATGCCAGAACCAGCGGGCCTGSequenceCCACCTCCTGGTCAATAGCCGTGTTTTTGGACCTGACCTTTGTCCAGGAAGCAGTAAATACCTCCTGGTCTCCTTTAAATGCCAACCTAATGAATTAAAAAACAAAACCGTGTGTGAAGACCAGGAGCTGAAACTGCACTGCCATGAATCCAAGTTCCTCAACATCTACTCTGCGACCTACGGCAGGAGGACCCAGGAAAGGGACATCTGCTCCTCCAAGGCAGGGCGGCTCCCCCCTTTCGATTGCTTGTCTTACTCAGCTTTGCAAGTCCTATCCCGAAGGTGCTATGGGAAGCAGAGATGCAAAATCATCGTCAACAATCACCATTTTGGAAGCCCCTGTTTGCCAGGCGTGAAAAAATACCTCACTGTGACCTACGCATGTGTTCCCAAGAACATACTCACAGCGATTGATCCAGCCATTGCTAATCTAAAACCTTCTTTGAAGCAGAAAGATGGTGAATATGGTATAAACTTCCACCCAAGCGGATCGAAGGTTCTGAGGAAAGATGGAATTCTTGTTAGCAACTCTCTGGCAGCCTTTGCTTACATTAGAGCCCACCCGGAGAGACTCGAGORF Start: AAG at 1ORF Stop: 37 at 694SEQ ID NO: 108231 aaMW at 25807.5 kDNOV24d,KLTMCSSQKPASQREDSLTCVAATTFQKVLDECQNQRACHLLVNSRVFGPDLCPCSSK174308481 ProteinYLLVSFKCQPNELKNKTVCEDQELKLHCHESKFLNIYSATYGRRTQERDICSSKAGRLSequencePPFDCLSYSALQVLSRRCYCKQRCKIIVNNHHFGSPCLPGVKKYLTVTYACVPKNILTAIDPAIANLKPSLKQKDGEYGINFDPSGSKVLRKDGILVSNSLAAFAYIRAHPERLESEQ ID NO: 109693 bpNOV24e,AAGCTTACCATGTGTAGTTCCCAGAAGCCTGCCTCCCAGAGGCAAGACAGCTTAACCT174308497 DNAGTGTGGCAGCCACCACCTTCCAGAAGGTGCTGGACGAATGCCTGAACCAGCGGGCCTGSequenceCCACCTCCTGGTCAATAGCCGTGTTTTTGGACCTGACCTTTGTCCAGGAACCAGTAAATACCTCCTGGTCTCCTTTAAATGCCAACCTAATGAATTAAAAAACAAAACCGTGTGTGAAGACCAGGAGCTGAAACTCCACTGCCATGAATCCAAGTTCCTCAACATCTACTCTGCGACCTACGGCAGGAGGACCCAGGAAAGGGACATCTGCTCCTCCAAGGCAGAGCGGCTCCCCCCTTTCGATTGCTTGTCTTACTCAGCTTTGCAAGTCCTATCCCCAAGGTGCTATGGGAAGCAGAGATGCAAAATCATCGTCAACAATCACCATTTTGGAAGCCCCTGTTTGCCAGGCGTGAAAAAATACCTCACTGTCACCTACGCATGTGTTCCCAAGAACATACTCACAGCGATTGATCCAGCCATTGCTAATCTAAAACCTTCTTTGAAGCAGAAAGATGGTGAATATGGTATAAACTTCGACCCAAGCCGATCGAAGGTTCTGAGGAAAGATGGAATTCTTGTTAGCAACTCTCTGGCAGCCTTTGCTTACATTAGAGCCCACCCGGAGACACTCGAGORF Start: AAG at 1ORF Stop: 37 at 694SEQ ID NO: 110231 aaMW at 25864.5 kDNOV24e,KLTMCSSQKPASQREDSLTCVAATTFQKVLDECLNQRACHLLVNSRVFGPDLCPGSSK174308497 ProteinYLLVSFKCQPNELKNKTVCEDQELKLHCHESKFLNIYSATYGRRTQERDICSSKAERLSequencePPFDCLSYSALQVLSRRCYGKQRCKIIVNNHHFGSPCLPGVKKYLTVTYACVPKNILTAIDPAIANLKPSLKQKDCEYGINFDPSGSKVLRKDGILVSNSLAAFAYIRAHPERLESEQ ID NO: 111693 bpNOV24f,AAGCTTACCATGTGTAGTTCCCAGAAGCCTGCCTCCCAGAGGGAAGACAGCTTAACCT174308507 DNAGTCTGGCAGCCACCACCTTCCAGAAGGTGCTGGACGAATGCCAGAACCAGCGGGCCTGSequenceCCACCTCCTGGTCAATAGCCGTGTTTTTGGACCTGACCTTTGTCCAGGAAGCAGTAAATACCTCCTGGTCTCCTTTAAATGCCAACCTAATGAATTAAAAAACAAAACCGTGTGTGAAGACCAGGAGCTGAAACTGCACTGCCATGAATCCAAGTTCCTCAACATCTACTCTGCGACCTACGGCAGGAGGACCCAGGAAAGGGACATCTGCTCCTCCAAGCCAGACCGGCTCCCCCCTTTCGATTGCTTGTCTTACTCAGCTTTGCAAGTCCTATCCCGAAGGTGCTATGGGAAGCAGAGATGCAAAATCATCGTCAACAATCACCATTTTGGAAGCCCCTGTTTGCCAGGCGTGAAAAAATACCTCACTGTGACCTACGCATGTGTTCCCAAGAACATACTCACAGCGATTGATCCAGCCATTGCTAATCTAAAACCTTCTTTGAAGCAGAAAGATGGTGAATATGGTATAAACTTCGACCCAAGCGGATCGAAGGTTCTGAGGAAAGATGGAATTCTTGTTAGCAACTCTCTGGCAGCCTTTGCTTACATTAGAGCCCACCCGGACAGACTCGAGORF Start: AAG at 1ORF Stop: 38 at 694SEQ ID NO: 112231 aaMW at 25879.5 kDNOV24f,KLTMCSSQKPASQREDSLTCVAATTFQKVLDECQNQRACHLLVNSRVFGPDLCPGSSK174308507 ProteinYLLVSFKCQPNELKNKTVCEDQELKLHCHESKFLNIYSATYGRRTQERDICSSKAERLSequencePPFDCLSYSALQVLSRRCYGKQRCKIIVNNHHFGSPCLPGVKKYLTVTYACVPKNILTAIDPAIANLKPSLKQKDGEYGINFDPSGSKVLRKDGILVSNSLAAFAYIRAHPERLESEQ ID NO: 113690 bpNOV24g,AAGCTTACCATGTGTAGTTCCCAGAAGCCTGCCTCCCAGAGGGAAGACACCTTAACCT174308517 DNAGTGTGGCAGCCACCACCTTCCAGAAGGTGCTGGACGAATGCCAGAACCAGCGGGCCTGSequenceCCACCTCCTGGTCAATAGCCGTGTTTTTGGACCTGACCTTTGTCCAGGAAGCAGTAAATACCTCCTCGTCTCCTTTAAATGCCAACCTAAATTAAAAAACAAAACCGTGTGTGAAGACCAGGAGCTGAAACTGCACTGCCATGAATCCAAGTTCCTCAACATCTACTCTGCGACCTACGGCAGGAGGACCCAGGAAAGGCACATCTGCTCCTCCAAGGCAGAGCGGCTCCCCCCTTTCGATTGCTTGTCTTACTCAGCTTTGCAAGTCCTATCCCGAACGTGCTATGGGAAGCAGAGATGCAAAATCATCGTCAACAATCACCATTTTGGAAGCCCCTGTTTCCCAGGCGTGAAAAAATACCTCACTGTGACCTACGCATGTGTTCCCAAGAACATACTCACAGCGATTGATCCAGCCATTGCTAATCTAAAACCTTCTTTGAAGCAGAAAGATGGTGAATATGGTATAAACTTCGACCCAAGCGGATCGAAGGTTCTGAGCAAAGATGGAATTCTTGTTACCAACTCTCTGGCAGCCTTTGCTTACATTAGAGCCCACCCGGAGAGACTCGAGORF Start: AAG at 1ORF Stop: e− at 691SEQ ID NO: 114230 aaMW at 25764.5 kDNOV24g,KLTMCSSQKPASQREDSLTCVAATTFQKVLDECQNQRACHLLVNSRVFCPDLCPGSSK174308517 ProteinYLLVSFKCQPKLKNKTVCEDQELKLHCRESKFLNIYSATYGRRTQERDICSSKAERLPSequencePFDCLSYSALQVLSRRCYGKQRCKIIVNNHHFGSPCLPGVKKYLTVTYACVPKNILTAIDPAIANLKPSLKQKDGEYGINFDPSGSKVLRKDGILVSNSLAAFAYIRAHPERLESEQ ID NO: 115693 bpNOV24h,AAGCTTACCATGTGTAGTTCCCAGAAGCCTGCCTCCCAGAGCGAAGACAGCTTAACCT174308525 DNAGTGTGGCACCCACCACCCTCCAGAAGGTGCTGGACGAATGCCAGAACCAGCGGGCCTGSequenceCCACCTCCTGGTCAATAGCCGTGTTTTTGGACCTGACCTTTGTCCAGGAAGCAGTAAATACCTCCTGGTCTCCTTTAAATGCCAACCTAATGAATTAAAAAACAAAACCGTGTGTGAAGACCAGGAGCTGAAACTGCACTGCCATGAATCCAAGTTCCTCAACATCTACTCTGCGACCTACGGCAGGAGGACCCAGGAAAGCGACGTCTGCTCCTCCAAGGCAGAGCGGCTCCCCCCTTTCGATTGCTTGTCTTACTCAGCTTTGCAAGTCCTATCCCGAAGGTGCTATGGGAAGCAGAGATGCAAAATCATCGTCAACAATCACCATTTTGGAAGCCCCTGTTTGCCAGGCGTGAAAAAATACCTCACTGTGACCTACGCATGTGTTCCCAAGAACATACTCACAGCCATTGATCCAGCCATTGCTAATCTAAAACCTTCTTTGAAGCAGAAAGATGGTGAATATGGTATAAACTTCGACCCAAGCGGATCGAAGGTTCTGAGGAAAGATGGAATTCTTGTTAGCAACTCTCTGGCAGCCTTTGCTTACATTAGAGCCCACCCGGAGAGACTCGAGORF Start: AAG at 1ORF Stop: 37 at 694SEQ ID NO: 116231 aaMW at 25831.5 kDNOV24h,KLTMCSSQKPASQREDSLTCVAATTLQKVLDECQNQRACHLLVNSRVFGPDLCPGSSK174308525 ProteinYLLVSFKCQPNELKNKTVCEDQELKLHCHESKFLNIYSATYGRRTQERDVCSSKAERLSequencePPFDCLSYSALQVLSRRCYGKQRCKIIVNNHHFGSPCLPGVKKYLTVTYACVPKNILTAIDPAIANLKPSLKQKDGEYGINFDPSGSKVLRKDGILVSNSLAAFAYIRAHPERLE


[0443] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 24B.
128TABLE 24BComparison of NOV24a against NOV24b through NOV24h.NOV24a Residues/Identities/SimilaritiesProtein SequenceMatch Residuesfor the Matched RegionNOV24b1 . . . 346281/346 (81%)1 . . . 319282/346 (81%)NOV24c1 . . . 346281/346 (81%)96 . . . 414 282/346 (81%)NOV24d1 . . . 226224/226 (99%)4 . . . 229225/226 (99%)NOV24e1 . . . 226224/226 (99%)4 . . . 229225/226 (99%)NOV24f1 . . . 226225/226 (99%)4 . . . 229226/226 (99%)NOV24g1 . . . 226223/226 (98%)4 . . . 228225/226 (98%)NOV24h1 . . . 226223/226 (98%)4 . . . 229225/226 (98%)


[0444] Further analysis of the NOV24a protein yielded the following properties shown in Table 24C.
129TABLE 24CProtein Sequence Properties NOV24aPSort0.7419 probability located in mitochondrial inner membrane;analysis:0.4400 probability located in plasma membrane; 0.2000probability located in endoplasmic reticulum(membrane); 0.1072 probability located in mitochondrialmatrix spaceSignalPNo Known Signal Sequence Indicatedanalysis:


[0445] A search of the NOV24a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 24D.
130TABLE 24DGeneseq Results for NOV24aNOV24aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAU12284Human PRO5993 polypeptide 1 . . . 346345/346(99%)0.0sequence - Homo sapiens, 441 aa. 96 . . . 441346/346(99%)[WO200140466-A2, 07-JUN-2001]AAB68888Human RECAP polypeptide, SEQ ID 1 . . . 346345/346(99%)0.0[WO200107612-A2, 01-FEB-2001] 96 . . . 441346/346(99%)AAB82854Human P2Y-like GPCR polypeptide -  50 . . . 95 46/46(100%)2e−21Homo sapiens, 158 aa. 10 . . . 55 46/46(100%)[WO200168842-A2, 20-SEP-2001]AAB95410Human protein sequence SEQ ID209 . . . 34664/144(44%)9e−20NO: 17796 - Homo sapiens, 152 aa. 16 . . . 15289/144(61%)[EP1074617-A2, 07-FEB-2001]AAB93029Human protein sequence SEQ ID204 . . . 32954/133(40%)7e−16NO: 11799 - Homo sapiens, 165 aa. 5 . . . 13678/133(58%)[EP1074617-A2, 07-FEB-2001]


[0446] In a BLAST search of public sequence databases, the NOV24a protein was found to have homology to the proteins shown in the BLASTP data in Table 24E.
131TABLE 24EPublic BLASTP Results for NOV24aNOV24aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueP58658Protein C21 orf63 precursor (Protein 1 . . . 346345/346 (99%)0.0PRED34) (SUE21) - Homo sapiens 96 . . . 441346/346 (99%)(Human), 441 aa.Q9D4L34931408A02RIK PROTEIN - Mus 1 . . . 346294/346 (84%) e−175musculus (Mouse), 345 aa. 1 . . . 345322/346 (92%)P58659Protein C21 orf63 homolog precursor -  1 . . . 346294/346 (84%) e−175Mus musculus (Mouse), 440 aa. 96 . . . 440322/346 (92%)Q9H8M9CDNA FLJ13391 FIS, CLONE209 . . . 346 64/144 (44%)3e−19 PLACE1001241 (HYPOTHETICAL 16 . . . 152 89/144 (61%)17.5 KDA PROTEIN) - Homo sapiens(Human), 152 aa.Q9HC41HYPOTHETICAL 17.4 KDA209 . . . 346 64/144 (44%)3e−19 PROTEIN - Homo sapiens (Human), 16 . . . 152 89/144 (61%)152 aa.


[0447] PFam analysis indicates that the NOV24a protein contains the domains shown in the Table 24F.
132TABLE 24FDomain Analysis of NOV24aNOV24aIdentities/Matchfor the MatchedExpectPfam DomainRegionRegionValueGal_Lectin: domain 1 of 2 2 . . . 63 23/93 (25%)0.0142/93 (45%)Gal_Lectin: domain 2 of 281 . . . 16428/94 (30%)4.6e−1352/94 (55%)



Example 25

[0448] The NOV25 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 25A.
133TABLE 25ANOV25 Sequence AnalysisSEQ ID NO: 1174517 bpNOV25a,GGCCCTCGCCGCCCGCGGCGCCCCGAGCGCTTTGTGAGCAGATGCGGAGCCGAGTGGACG59885-01 DNAGGGCGCGAGCCAGATGCGGGGCGACAGCTGACTTGCTGAGAGGAGGCGGGGAGGCGCGSequenceGAGCGCGCGTGTGGTCCTTGCGCCGCTGACTTCTCCACTGGTTCCTGGGCACCGAAAGATAAACCTCTCATAATGAAGGCCCCCGCTGTGCTTGCACCTGGCATCCTCCTGCTCCTGTTTACCTTGGTGCAGAGGAGCAATGGGGAGTGTAAAGAGGCACTAGCAAAGTCCGAGATGAATGTGAATATGAAGTATCAGCTTCCCAACTTCACCGCGGAAACACCCATCCAGAATGTCATTCTACATGAGCATCACATTTTCCTTGGTGCCACTAACTACATTTATGTTTTAAATGAGGAAGACCTTCAGAAGGTTGCTGAGTACAAGACTGGGCCTGTGCTGGAACACCCAGATTGTTTCCCATGTCAGGACTGCAGCAGCAAAGCCAATTTATCAGGAGGTGTTTGGAAAGATAACATCAACATGGCTCTAGTTGTCGACACCTACTATGATGATCAACTCATTAGCTGTGGCAGCGTCAACAGAGGGACCTGCCAGCGACATGTCTTTCCCCACAATCATACTGCTGACATACAGTCGGAGGTTCACTGCATATTCTCCCCACAGATAGAAGAGCCCAGCCAGTGTCCTGACTGTGTGGTGAGCGCCCTGGGAGCCAAAGTCCTTTCATCTGTAAAGGACCGGTTCATCAACTTCTTTGTAGGCAATACCATAAATTCTTCTTATTTCCCAGATCATCCATTGCATTCGATATCAGTGAGAACGCTAAAGGAAACGAAAGATGGTTTTATGTTTTTGACGGACCAGTCCTACATTGATGTTTTACCTGAGTTCAGAGATTCTTACCCCATTAAGTATGTCCATGCCTTTGAAAGCAACAATTTTATTTACTTCTTGACGGTCCAAAGGGAAACTCTAGATGCTCAGACTTTTCACACAAGAATAATCAGGTTCTGTTCCATAAACTCTGGATTGCATTCCTACATGGAAATGCCTCTGGAGTGTATTCTCACAGAAAAGAGAAAAAAGAGATCCACAAAGAAGGAAGTGTTTAATATACTTCAGGCTGCGTATGTCAGCAAGCCTGGGGCCCAGCTTGCTAGACAAATAGGAGCCAGCCTGAATGATGACATTCTTTTCGGGGTGTTCGCACAAAGCAAGCCAGATTCTGCCGAACCAATGGATCGATCTGCCATGTGTGCATTCCCTATCAAATATGTCAACGACTTCTTCAACAAGATCGTCAACAAAAACAATGTGAGATGTCTCCAGCATTTTTACGGACCCAATCATGAGCACTGCTTTAATAGGACACTTCTGAGAAATTCATCAGGCTGTGAAGCGCGCCGTGATGAATATCGAACAGAGTTTACCACAGCTTTGCAGCGCGTTGACTTATTCATCGCTCAATTCAGCGAAGTCCTCTTAACATCTATATCCACCTTCATTAAAGGAGACCTCACCATAGCTAATCTTGGGACATCAGAGGGTCGCTTCATGCAGGTTGTGGTTTCTCGATCAGGACCATCAACCCCTCATGTGAATTTTCTCCTGGACTCCCATCCAGTGTCTCCAGAAGTGATTGTGGAGCATACATTAAACCAAAATGGCTACACACTGGTTATCACTGGGAAGAAGATCACGAAGATCCCATTGAATGGCTTGGGCTGCAGACATTTCCAGTCCTGCAGTCAATGCCTCTCTGCCCCACCCTTTGTTCAGTGTGGCTGGTGCCACGACAAATGTGTOCGATCGCAGGAATGCCTGAGCGGGACATGGACTCAACAGATCTGTCTGCCTGCAATCTACAAGGTTTTCCCAAATAGTGCACCCCTTGAAGGACGGACAAGGCTGACCATATGTGGCTGGGACTTTGGATTTCGGAGGAATAATAAATTTGATTTAAAGAAAACTAGAGTTCTCCTTGGAAATGAGAGCTGCACCTTGACTTTAAGTGAGAGCACGATGAATACATTGAAATGCACAGTTGGTCCTGCCATGAATAACCATTTCAATATGTCCATAATTATTTCAAATGGCCACGGGACAACACAATACAGTACATTCTCCTATGTGGATCCTGTAATAACAAGTATTTCGCCGAAATACGGTCCTATGGCTGGTGGCACTTTACTTACTTTAACTGGAAATTACCTAAACAGTGGGAATTCTAGACACATTTCAATTGGTGGAAAAACATGTACTTTAAAAAGTGTGTCAAACAGTATTCTTGAATGTTATACCCCAGCCCAAACCATTTCAACTGAGTTTGCTGTTAAATTGAAAATTGACTTAGCCAACCGACAGACAAGCATCTTCAGTTACCGTGAAGATCCCATTGTCTATGAAATTCATCCAACCAAATCTTTTATTAGTACTTGGTGGAAAGAACCTCTCAACATTGTCAGTTTTCTATTTTGCTTTGCCAGTGGTGGGAGCACAATAACAGGTGTTGGGAAAAACCTGAATTCAGTTAGTGTCCCGAGAATGGTCATAAATGTGCATGAAGCAGGAACGAACTTTACAGTGGCATGTCAACATCGCTCTAATTCAGAGATAATCTGTTGTACCACTCCTTCCCTGCAACAGCTGAATCTGCAACTCCCCCTGAAAACCAAAGCCTTTTTCATGTTAGATGGGATCCTTTCCAAATACTTTGATCTCATTTATGTACATAATCCTGTGTTTAAGCCTTTTGAAAAGCCAGTGATGATCTCAATGGGCAATGAAAATGTACTGGAAATTAAGGGAAATGATATTGACCCTGAAGCAGTTAAAGGTGAAGTGTTAAAAGTTGGAAATAAGAGCTGTGAGAATATACACTTACATTCTGAAGCCGTTTTATGCACGGTCCCCAATGACCTGCTGAAATTGAACAGCGAGCTAAATATAGAGTGGAAGCAAGCAATTTCTTCAACCGTCCTTGGAAAAGTAATAGTTCAACCAGATCAGAATTTCACAGGATTGATTGCTGGTGTTGTCTCAATATCAACAGCACTGTTATTACTACTTGGGTTTTTCCTGTGGCTGAAAAAGAGAAAGCAAATTAAAGATCTGGGCAGTGAATTAGTTCGCTACGATGCAAGAGTACACACTCCTCATTTGGATAGGCTTGTAAGTGCCCGAAGTGTAAGCCCAACTACAGAAATGGTTTCAAATGAATCTGTAGACTACCGAGCTACTTTTCCAGAAGATCAGTTTCCTAATTCATCTCAGAACGGTTCATGCCGACAAGTGCAGTATCCTCTGACAGACATGTCCCCCATCCTAACTAGTGGGGACTCTGATATATCCAGTCCATTACTGCAAAATACTGTCCACATTGACCTCAGTGCTCTAAATCCAGAGCTGGTCCAGGCAGTGCAGCATGTAGTGATTGGGCCCAGTAGCCTGATTGTGCATTTCAATCAAGTCATAGGAAGAGGGCATTTTGGTTGTGTATATCATGGGACTTTGTTGGACAATGATGGCAAGAAAATTCACTGTGCTGTGAAATCCTTGAACAGAATCACTGACATAGGAGAAGTTTCCCAATTTCTGACCGAGGGAATCATCATGAAAGATTTTAGTCATCCCAATGTCCTCTCGCTCCTGGGAATCTGCCTGCGAAGTGAAGGGTCTCCGCTGGTGGTCCTACCATACATGAAACATGGAGATCTTCGAAATTTCATTCGAAATGAGACTCATAATCCAACTGTAAAAGATCTTATTGGCTTTGGTCTTCAAGTAGCCAAAGGCATGAAATATCTTGCAAGCAAAAAGTTTGTCCACAGAGACTTGGCTGCAAGAAACTGTATGCTGGATGAAAAATTCACAGTCAAGGTTGCTGATTTTGGTCTTGCCAGAGACATGTATGATAAAGAATACTATAGTGTACACAACAAAACAGGTGCAAAGCTGCCAGTGAAGTGGATGGCTTTGGAAAGTCTGCAAACTCAAAAGTTTACCACCAAGTCAGATGTGTGGTCCTTTGGCGTGCTCCTCTGGGAGCTGATGACAAGAGGAGCCCCACCTTATCCTGACGTAAACACCTTTGATATAACTGTTTACTTGTTGCAAGGGAGAAGACTCCTACAACCCGAATACTGCCCAGACCCCTTATATGAAGTAATGCTAAAATGCTGGCACCCTAAAGCCGAAATGCGCCCATCCTTTTCTGAACTGGTGTCCCGGATATCAGCGATCTTCTCTACTTTCATTGGGGAGCACTATGTCCATGTGAACGCTACTTATGTGAACGTAAAATGTGTCGCTCCGTATCCTTCTCTGTTGTCATCAGAAGATAACGCTGATGATGAGGTGGACACACGACCAGCCTCCTTCTGGGAGACATCATAGTGCTAGTACTATGTCAAAGCAACAGTCCACACTTTGTCCAATGGTTTTTTCACTGCCTGACCTTTAAAAGGCCATCGATATTCTTTGCTCTTGCCAAAATTGORF Start: ATG at 189ORF Stop: TAG at 4413SEQ ID NO: 1181408 aaMW at 157710.2 kDNOV25a,MKAPAVLAPGILVLLFTLVQRSNGECKEALAKSEMNVNMKYQLPNFTAETPIQNVILHCG59885-01 ProteinEHHIFLGATNYIYVLNEEDLQKVAEYKTGPVLEHPDCFPCQDCSSKANLSGGVWKDNISequenceNMALVVDTYYDDQLISCGSVNRGTCQRHVFPHNHTADIQSEVHCIFSPQIEEPSQCPDCVVSALGAKVLSSVKDRFINFFVGNTINSSYFPDHPLHSISVRRLKETKDGFMFLTDQSYIDVLPEFRDSYPIKYVHAFESNNFIYFLTVQRETLDAQTFHTRIIRFCSINSGLHSYMEMPLECILTEKRKKRSTKKEVFNILQAAYVSKPGAQLARQIGASLNDDILFGVFAQSKPDSAEPMDRSAMCAFPIKYVNDFFNKIVNKNNVRCLQHFYGPNHEHCFNRTLLRNSSGCEARRDEYRTEFTTALQRVDLFMGQFSEVLLTSISTFIKGDLTIANLGTSEGRFMQVVVSRSGPSTPHVNFLLDSHPVSPEVIVEHTLNQNGYTLVITGKKITKIPLNGLGCRHFQSCSQCLSAPPFVQCGWCHDKCVRSEECLSGTWTQQICLPAIYKVFPNSAPLBGGTRLTICGWDFGFRRNNKFDLKKTRVLLGNESCTLTLSESTMNTLKCTVGPAMNKHFNMSIIISNGHGTTQYSTFSYVDPVITSISPKYGPMAGGTLLTLTGNYLNSGNSRHISIGGKTCTLKSVSNSILECYTPAQTISTEFAVKLKIDLANRETSIFSYREDPIVYEIHPTKSFISTWWKEPLNIVSFLFCFASGGSTITGVGKNLNSVSVPRMVINVHEAGRNFTVACQHRSNSEIICCTTPSLQQLNLQLPLKTKAFFMLDGILSKYFDLIYVHNPVFKPFEKPVMISMGNENVLEIKGNDIDPEAVKGEVLKVGNKSCENIHLHSEAVLCTVPNDLLKLNSELNIEWKQAISSTVLGKVIVQPDQNFTGLIAGVVSISTALLLLLGFFLWLKKRKQIKDLGSELVRYDAPVHTPHLDRLVSARSVSPTTEMVSNESVDYRATFPEDQFPNSSQNGSCRQVQYPLTDMSPILTSGDSDISSPLLQNTVHIDLSALNPELVQAVQHVVIGPSSLIVHFNEVIGRGHFGCVYHGTLLDNDGKKIHCAVKSLNRITDIGEVSQFLTEGIIMKDFSHPNVLSLLGICLRSEGSPLVVLPYMKHGDLRNFIRNETHNPTVKDLIGFGLQVAKGMKYLASKKFVHRDLAARNCMLDEKFTVKVADFGLARDMYDKEYYSVHNKTGAKLPVKWMALESLQTQKFTTKSDVWSFGVLLWELMTRGAPPYPDVNTFDITVYLLQGRRLLQPEYCPDPLYEVMLKCWHPKAEMRPSFSELVSRISAIFSTFIGEHYVHVNATYVNVKCVAPYPSLLSSEDNADDEVDTRPASFWETS


[0449] Further analysis of the NOV25a protein yielded the following properties shown in Table 25B.
134TABLE 25BProtein Sequence Properties NOV25aPSort0.4600 probability located in plasma membrane;analysis:0.1226 probability located in microbody (peroxisome); 0.1000probability located in endoplasmic reticulum(membrane); 0.1000 probability located in endoplasmicreticulum (lumen)SignalPCleavage site between residues 25 and 26analysis:


[0450] A search of the NOV25a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 25C.
135TABLE 25CGeneseq Results for NOV25aNOV25aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAW82791Human RON receptor protein - Homo  7 . . . 1377483/1424(33%)0.0sapiens, 1400 aa. [WO9855141-A1,  7 . . . 1363710/1424(48%)10-DEC-1998]AAW94409Human Met proto-oncogene protein 501 . . . 817 300/317(94%)e−175501-850 - Homo sapiens, 300 aa.  1 . . . 300 300/317(94%)[US5871959-A, 16-FEB-1999]AAY43976Human protein kinase #25 - Homo1094 . . . 1362264/269(98%)e−154sapiens, 266 aa. [US5958784-A,  1 . . . 266 265/269(98%)28-SEP-1999]AAW94410Mouse Met proto-oncogene protein 501 . . . 817 256/317(80%)e−152501-850 - Mus sp, 299 aa.  1 . . . 299 279/317(87%)[US5871959-A, 16-FEB-1999]AAR50089Sequence of human Met between the 501 . . . 817 254/317(80%)e−143Ndel - PvuII sites, residues 501-850 -   1 . . . 300 255/317(80%)Homo sapiens, 300 aa. [WO9406909-A, 31-MAR-1994]


[0451] In a BLAST search of public sequence databases, the NOV25a protein was found to have homology to the proteins shown in the BLASTP data in Table 25D.
136TABLE 25DPublic BLASTP Results for NOV25aNOV25aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueP08581Hepatocyte growth factor receptor1 . . . 14081389/1408 (98%)0.0precursor (EC 2.7.1.112) (Met proto-1 . . . 13901390/1408 (98%)oncogene tyrosine kinase) (c-met) (HGFreceptor) (HGF-SF receptor) - Homosapiens (Human), 1390 aa.P16056Hepatocyte growth factor receptor1 . . . 13991237/1399 (88%)0.0precursor (EC 2.7.1.112) (Met proto-1 . . . 13791315/1399 (93%)oncogene tyrosine kinase) (c-met) (HGFreceptor) (HGF-SF receptor) - Musmusculus (Mouse), 1379 aa.P97523Hepatocyte growth factor receptor1 . . . 13991220/1401 (87%)0.0precursor (EC 2.7.1.112) (Met proto-1 . . . 13821302/1401 (92%)oncogene tyrosine kinase) (c-met) (HGFreceptor) (HGF-SF receptor) - Rattusnorvegicus (Rat), 1382 aa.Q90975TYROSINE KINASE - Gallus gallus1 . . . 13991010/1401 (72%)0.0(Chicken), 1382 aa.1 . . . 13821172/1401 (83%)Q9W650C-MET/HEPATOCYTE GROWTH6 . . . 1399 869/1397 (62%)0.0FACTOR RECEPTOR - Xenopus laevis2 . . . 13751083/1397 (77%)(African clawed frog), 1375 aa.


[0452] PFam analysis indicates that the NOV25a protein contains the domains shown in the Table 25E.
137TABLE 25EDomain Analysis of NOV25aIdentities/SimilaritiesNOV25a Matchfor the MatchedExpectPfam Domain/RegionRegionValueSema: domain 1 of 1 55 . . . 500117/493(24%)  5e−172419/493(85%)integrin_B:525 . . . 5437/19(37%)0.39domain 1 of 114/19(74%)Plexin_repeat:519 . . . 56222/67(33%)1.6e−14 domain 1 of 141/67(61%)TIG: domain 1 of 3563 . . . 65528/106(26%)2.7e−21 80/106(75%)TIG: domain 2 of 3657 . . . 73931/104(30%)  8e−21 71/104(68%)TIG: domain 3 of 3762 . . . 85428/113(25%)5.8e−07 67/113(59%)pkinase: domain 1 of 11096 . . . 135585/297(29%)2.1e−91 218/297(73%)



Example 26

[0453] The NOV26 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 26A.
138TABLE 26ANOV26 Sequence AnalysisSEQ ID NO: 1192317 bpNOV26a,AAAACTCCAGGACGCGGAGGAGGCTAGTGGCAGTACCTGGGCACCCTGACCCTCCCCACG93443-01 DNACAGGCCAGAGCCCACCCTCCTGCTCATGAGGGCAGACAGGCCTTTCCAGGGACACAGTSequenceCCCTCTTCTCCCCAGGACCCCAGGGCCAACTCCCCCTGCCGGCCCTCTGCCATCAAATTGGCAGTGGCTCCAGGGGAGTCCCCTGGGGATGGGGCACCACTGTTGGGGACCCCTCTGCGTGCACCCCTGTAGTTGGGGAAGCAGGACAGGGGCCTGGGGAGACGGAAGGGCGCCAGGGGTTGAGAGAGGATGGTGGACGTTGTTGGACTTCAAAGGGAAACAGGCCCTCGGGGAAGCCCCTGGCCAGGCCTGCCTCTCCCCTCCCTGGTGGGCCCAGCGCCCCTGCTCACTTGTCTCTGCCCACAGTGCCTGTCTGTGGAGGACGCCCTGGGCCTGGGCGAGCCTGAGGGGTCAGGGCTGCCCCCGGCCCCGGTCCTGGAGGCCAGGTACGTCGCCCCCCTCAGTGCCGCCGCCGTCCTGTACCTCAGCAACCCCGAGGGCACCTGTGAGGACGCTCGGGCTGGCCTCTCGGCCTCTCATGCAGACCACCTCCTGGCCCTGCTCGAGAGCCCCAAGGCCCTGACCCCGGGCCTGAGCTGGCTGCTGCAGAGGATGCAGGCCCGGGCTGCCGGCCAGACCCCCAAGACGGCCTGCGTAGATATCCCTCAGCTGCTGGAGGAGCCGGTGGGGGCGGGGGCTCCGGGCAGTGCTGGCGGCGTCCTGGCTGCCCTGCTGGACCATGTCAGGAGCGGGTCTTGCTTCCACGCCTTGCCGAGCCCTCAGTACTTCGTGGACTTTGTGTTCCAGCAGCACAGCAGCGAGGTCCCTATGACGCTGGCCGAGCTGTCAGCCTTGATGCAGCGCCTGGGGGTGGGCACCGAGGCCCACAGTGACCACAGTCATCGGCACAGGGGAGCCAGCAGCCGGGACCCTGTGCCCCTCATCAGCTCCAGCAACAGCTCCAGTGTGTGGGACACGGTATGCCTGAGTGCCAGGGACGTGATGGCTGCATATGGACTGTCGGAACAGGCTCGGGTGACCCCGGAGGCCTGGGCCCAACTGAGCCCTGCCCTGCTCCAACAGCAGCTGAGTGGAGCCTACACCTCCCAGTCCAGGCCCCCCGTCCAGGACCAGCTCAGCCAGTCACAGAGATATCTGTACGGCTCCCTGGCCACGCTGCTCATCTGCCTCTGCGCGGTCTTTGGCCTCCTGCTGCTGACCTGCACTGGCTGCAGGGGGGTCGCCCACTACATCCTGCAGACCTTCCTGAGCCTGGCAGTGGGTGCACTCACTGGGGACGCTGTCCTGCATCTGACGCCCAAGGTGCTGGGGCTGCATACACACAGCGAACAGGGCCTCAGCCCACAGCCCACCTGGCGCCTCCTGGCTATGCTGGCCGGGCTCTACGCCTTCTTCCTGTTTGAGAACCTCTTCAATCTCCTCCTGCCCAGGGACCCGGAGGACCTGGAGGACGCGCCCTGCGGCCACAGCAGCCATAGCCACGGCGGCCACAGCCACGGTGTGTCCCTGCAGCTGGCACCCAGCGAGCTCCGGCAGCCCAAGCCCCCCCACGAGGGCTCCCCCCCAGACCTGGTGGCGGAGGAGAGCCCGGAGCTGCTGAACCCTGAGCCCAGGAGACTCAGCCCAGAGTTGAGGCTACTGCCCTATATGATCACTCTGGGCGACGCCGTGCACAACTTCGCCGACGGGCTGGCCGTGGGCGCCGCCTTCGCGTCCTCCTGGAAGACCGGGCTGGCCACCTCGCTGGCCGTGTTCTGCCACGAGTTGCCACACGAGCTGGGGGACTTCGCCGCCTTGCTGCACGCGGGGCTGTCCGTGCGCCAAGCACTGCTGCTGAACCTGGCCTCCGCGCTCACGGCCTTCGCTGGTCTTACGTGGCACTCGCGGTTGGAGTCAGCGAGGAGAGCGAGGCCTGGATCCTGGCAGTGGCCACCGGCCTGTTCCTTACGTAGCACTCTGCGACATGCTCCCGGCGATGTTGAAAGTACGGGACCCGCGGCCCCTGGCTCCTCTTCCTGCTGCACAACGTGGGCCTGCTGGGCGGCTGGACCGTCCTGCTGCTGCTGTCCCTGTACGAGGATGACATCACCTTCTGATACCCTGCCCTAGTCCCCCACCTTTGACTTAAGATCCCACACCTCACAAACCTACAGCCCAGAAACCCAGAAGCCCCTATAGAGCCCCCAGTCCCAACTCCAGTAAAGACACTCTTGTCCCTTGGAAAAAAAAAAAAAAAAAAAORF Start: ATG at 306ORF Stop: TAG at 2184SEQ ID NO: 120626 aaMW at 66248.5 kDNOV26a,MVDVVGLERETGPRGSPWPGLPLPSLVGPAPLLTCLCPQCLSVEDALGLGEPEGSGLPCG93443-01 ProteinPGPVLEARYVARLSAAAVLYLSNPEGTCEDARAGLWASHADHLLALLESPKALTPGLSSequenceWLLQRMQARAAGQTPKTACVDIPQLLEEAVGAGAPGSAGGVLAALLDHVRSGSCFHALPSPQYFVDFVFQQHSSEVPMTLAELSALMQRLGVGREAHSDHSHRHRGASSRDPVPLISSSNSSSVWDTVCLSARDVMAAYGLSEQAGVTPEAWAQLSPALLQQQLSGAYTSQSRPPVQDQLSQSERYLYGSLATLLICLCAVFGLLLLTCTGCRGVAHYILQTFLSLAVGALTGDAVLHLTPKVLGLHTHSEEGLSPQPTWRLLAMLAGLYAFFLFENLFNLLLPRDPEDLEDGPCGHSSHSHGGHSHGVSLQLAPSELRQPKPPHEGSRADLVAEESPELLNPEPRRLSPELRLLPYMITLGDAVHNFADGLAVGAAFASSWKTGLATSLAVFCHELPHELGDFAALLHAGLSVRQALLLNLASALTAFAGLTWHSRLESARRARPGSWQWPPACSLRSTLRHAPGDVESTGPAAPGSSSCCTTWACWAAGPSCCCCPCTRMTSPSDTLP


[0454] Further analysis of the NOV26a protein yielded the following properties shown in Table 26B.
139TABLE 26BProtein Sequence Properties NOV26aPSort0.7000 probability located in plasma membrane;analysis:0.3048 probability located in microbody (peroxisome); 0.2000probability located in endoplasmic reticulum(membrane); 0.1000 probability located in mitochondrialinner membraneSignalPCleavage site between residues 43 and 44analysis:


[0455] A search of the NOV26a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 26C.
140TABLE 26CGeneseq Results for NOV26aNOV26aIdentities/GeneseqProtein/Organism/LengthResidues/Similarities forExpectIdentifier[Patent #, Date]ResiduesRegionValueAAE06574Human protein having hydrophobic 37 . . . 548508/512 (99%)0.0domain, HP10755 - Homo sapiens, 62 . . . 573509/512 (99%)647 aa. [WO200149728-A2,12-JUL-2001]AAE01677Human gene 6 encoded secreted protein 37 . . . 548508/512 (99%)0.0HWLHM66, SEQ ID NO: 89 - Homo 62 . . . 573509/512 (99%)sapiens, 647 aa. [WO200134767-A2,17-MAY-2001]AAB74710Human membrane associated protein 37 . . . 548507/512 (99%)0.0MEMAP-16 - Homo sapiens, 647 aa. 62 . . . 573508/512 (99%)[WO200112662-A2, 22-FEB-2001]AAE01709Human gene 6 encoded secreted protein 37 . . . 410365/374 (97%)0.0HWLHM66, SEQ ID NO: 121 - Homo 62 . . . 435366/374 (97%)sapiens, 440 aa. [WO200134767-A2,17-MAY-2001]AAB59035Breast and ovarian cancer associated436 . . . 548107/113 (94%)2e−54antigen protein sequence SEQ ID 743 - 18 . . . 130108/113 (94%)Homo sapiens, 204 aa. [WO200055173-A1, 21-SEP-2000]


[0456] In a BLAST search of public sequence databases, the NOV26a protein was found to have homology to the proteins shown in the BLASTP data in Table 26D.
141TABLE 26DPublic BLASTP Results for NOV26aNOV26aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ9NXC4CDNA FLJ20327 FIS, CLONE 1 . . . 626 626/626 (100%)0.0HEP10012 - Homo sapiens (Human), 1 . . . 626 626/626 (100%)626 aa.Q9H6T8CDNA: FLJ21884 FIS, CLONE 37 . . . 548508/512 (99%)0.0HEP02863 - Homo sapiens (Human), 62 . . . 573509/512 (99%)647 aa.Q9DAT91600025H15RIK PROTEIN - Mus 37 . . . 548365/531 (68%)0.0musculus (Mouse), 660 aa. 61 . . . 586415/531 (77%)Q95KA5HYPOTHETICAL 72.8 KDA PROTEIN -130 . . . 548141/444 (31%)2e−51Macaca fascicularis (Crab eating177 . . . 580217/444 (48%)macaque) (Cynomolgus monkey), 654 aa.Q96NN4CDNA FLJ30499 FIS, CLONE174 . . . 548127/393 (32%)7e−49BRAWH2000443, WEAKLY SIMILAR227 . . . 580197/393 (49%)TO HUMAN BREAST CANCER,ESTROGEN REGULATED LIV-1PROTEIN (LIV-1) MRNA - Homosapiens (Human), 654 aa.


[0457] PFam analysis indicates that the NOV26a protein contains the domains shown in the Table 26E.
142TABLE 26EDomain Analysis of NOV26aNOV26aIdentities/MatchSimilaritiesExpectPfam DomainRegionfor the Matched RegionValueZip: domain 1 of 1467 . . . 618 37/184 (20%)0.00025108/184 (59%)



Example 27

[0458] The NOV27 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 27A.
143TABLE 27ANOV27 Sequence AnalysisSEQ ID NO: 1212852 bpNOV27a,GTGTGCAGTAAACTGGAATGCTCTCCCTCGCTCACTCCTCAGTGTAGCAGTGATCTGACG50838-01 DNAAGCAGGACAAGCTCAGCCTGCAGCTGCCGTGGGCTTTGTGTGGACTGGACGCAGAGCTSequenceTGGGAGACGGGGGAGGGCTATTACTCCAATTCACTGTCAATGGAATTACAGCTATAGCGGCAGTGTATATAGGATTGCTTTTTCTCGTCTTCCTGGAGATGCTCAGTCCCAGTATATTTTAAGGAAGAGAAATATAAAGGAAATTTAGTATGCCTCCTTTTCTTTAAATGAAGAATTTAGTTTCCTTTACTTCTTAAAAGAGAATACCTGTTCTTGTATAACGTGACTGCACCAGACATTCTGAAAAATCAGCAAGAAGCAAAAGCTGGAAATAGCTATTTCACAGCAGGGTTCTGAAGTAACGGAAGCTACCTTGTATAAAGACCTCAACACTGCTGACCATGATCAGCGCAGCCTGGAGCATCTTCCTCATCGGGACTAAAATTGGGCTGTTCCTTCAAGTAGCACCTCTATCAGTTATGGCTAAATCCTGTCCATCTGTGTGTCGCTGCGATGCGGGTTTCATTTACTGTAATGATCGCTTTCTGACATCCATTCCAACAGGAATACCAGAGGATGCTACAACTCTCTACCTTCAGAACAACCAAATAAATAATGCTGGGATTCCTTCAGATTTGAAAAACTTGCTGAAAGTAGAAAGAATATACCTATACCACAACAGTTTACATGAATTTCCTACCAACCTCCCAAAGTATGTAAAAGAGTTACATTTGCAAGAAAATAACATAAGGACTATCACTTATGATTCACTTTCAAAAATTCCCTATCTGGAAGAATTACATTTAGATGACAACTCTGTCTCTGCAGTTAGCATAGAAGAGGGAGCATTCCCAGACAGCAACTATCTCCGACTGCTTTTCCTGTCCCGTAATCACCTTAGCACAATTCCCTGGGGTTTCCCCAGGACTATAGAACAACTACGCTTGGATGATAATCGCATATCCACTATTTCATCACCATCTCTTCAAGGTCTCACTAGTCTAAAACGCCTGGTTCTAGATGGAAACCTGTTGAACAATCATGGTTTAGGTGACAAAGTTTTCTTCAACCTAGTTAATTTGACAGAGCTGTCCCTGGTGCGGAATTCCCTGACTGCTGCACCAGTAAACCTTCCACGCACAAACCTGAGGAAGCTTTATCTTCAAGATAACCACATCAATCGGGTGCCCCCAAATGCTTTTTCTTATCTAAGGCAGCTCTATCGACTGGATATGTCCAATAATAACCTAAGTAATTTACCTCAGGGTATCTTTGATGATTTGGACAATATAACACAACTGATTCTTCGCAACAATCCCTGGTATTGCGGGTGCAAGATGAAATGCGTACGTGACTGGTTACAATCACTACCTGTGAAGGTCAACGTGCGTGGGCTCATGTGCCAAGCCCCAGAAAAGGTTCGTGGGATGGCTATTAAGGATCTCAATGCAGAACTGTTTGATTGTAAGGACAGTGGGATTGTAAGCACCATTCAGATAACCACTGCAATACCCAACACAGTCTATCCTGCCCAAGGACAGTGGCCAGCTCCAGTGACCAAACAGCCAGATATTAAGAACCCCAAGCTCACTAAGGATCAACAAACCACAGGGAGTCCCTCAAGAAAAACAATTACAATTACTGTGAAGTCTGTCACCTCTGATACCATTCATATCTCTTGGAAACTTGCTCTACCTATGACTGCTTTGAGACTCAGCTGGCTTAAACTGGGCCATAGCCCGGCATTTGGATCTATAACAGAAACAATTGTAACAGGCGAACGCAGTGAGTACTTGGTCACAGCCCTGGAGCCTGATTCACCCTATAAAGTATGCATGGTTCCCATGGAAACCAGCAACCTCTACCTATTTGATGAAACTCCTGTTTGTATTGAGACTGAAACTGCACCCCTTCGAATGTACAACCCTACAACCACCCTCAATCGAGAGCAAGAGAAAGAACCTTACAAAAACCCCAATTTACCTTTGGCTGCCATCATTGGTGGGGCTGTGGCCCTGGTTACCATTGCCCTTCTTGCTTTAGTGTGTTGGTATGTTCATAGGAATGGATCGCTCTTCTCAAGGAACTGTGCATATAGCAAAGGGAGGAGAAGAAAGGATGACTATGCAGPAGCTGGCACTAAGAAGGACAACTCTATCCTGGAAATCAGGGAAACTTCTTTTCAGATGTTACCPATAAGCAATGAACCCATCTCGAAGGAGGAGTTTGTAATACACACCATATTTCCTCCTAATGGAATGAATCTGTACAAAAACAATCACAGTGAAAGCAGTAGTAACCGAAGCTACAGAGACAGTGGTATTCCAGACTCAGATCACTCACACTCATGATGCTGAAGGACTCACAGCAGACTTGTGTTTTGGGTTTTTTAAACCTAAGGGAGGTGATGGTAGGAACCCTGTTCTACTGCAAAACACTGGAAAAAGAGACTGAAAAAAAGCAATGTACTGTACATTTGCCATATAATTTATATTTAAGAACTTTTTATTAAAAGTTTCAAATTTCAGGTTACTGCTGCGATTGATGTAGTGGACATGCCTGAACACAATTCTATATTTTAGTATTTTTTAGTAATTTGTACTGTATTTTCCTTGCAAATATTGGAGTTATAAACCATTTACTTTGTGTTCTACTGAGTAAGATGACTTGTTGACTGTGAAAGTGAATTTTCTTGCTGTGTCGAACAATCAGGACTGCATTCATATGAGATCCTTGTAGTATAAGCACAGGCCATTTTTCACTTTGGTATTAATAAAATGTAAAAAAAAAATTGGTORF Start: ATG at 458ORF Stop: TGA at 2405SEQ ID NO: 122649 aaMW at 72993.5 kDNOV27a,MISAAWSIFLIGTKIGLFLQVAPLSVMAKSCPSVCRCDAGFIYCNDRFLTSIPTGIPECG50838-01 ProteinDATTLYLQNNQINNAGIPSDLKNLLKVERIYLYHNSLDEFPTNLPKYVKELHLQENNISequenceRTITYDSLSKIPYLEELHLDDNSVSAVSIEEGAFRDSNYLRLLFLSRNHLSTIPWGLPRTIEELRLDDNRISTTSSPSLQGLTSLKRLVLDGNLLNNHGLGDKVFFNLVNLTELSLVRNSLTAAPVNLPGTNLRKLYLQDNHINRVPPNAFSYLRQLYRLDMSNNNLSNLPQGIFDDLDNITQLILRNNPWYCGCKMKWVRDWLQSLPVKVNVRGLMCQAPEKVRGMAIKDLNAELFDCKDSGIVSTIQITTAIPNTVYPAQGQWPAPVTKQPDIKNPKLTKDQQTTGSPSRKTITITVKSVTSDTIHISWKLALPMTALRLSWLKLGHSPAFGSITETIVTGERSEYLVTALEPDSPYKVCMVPMETSNLYLFDETPVCIETETAPLRMYNPTTTLNREQEKEPYKNPNLPLAAIICGAVALVTIALLALVCWYVHRNGSLFSRNCAYSKGRRRKDDYAEAGTKKDNSILEIRETSFQMLPISNEPISKEEFVIHTIFPPNGMNLYKNNHSESSSNRSYRDSGIPDSDHSHS


[0459] Further analysis of the NOV27a protein yielded the following properties shown in Table 27B.
144TABLE 27BProtein Sequence Properties NOV27aPSort0.6976 probability located in plasma membrane; 0.6400analysis:probability located in endoplasmic reticulum (membrane);0.1900 probability located in Golgi body;0.1000 probability located in endoplasmic reticulum (lumen)SignalPCleavage site between residues 29 and 30analysis:


[0460] A search of the NOV27a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 27C.
145TABLE 27CGeneseq Results for NOV27aNOV27aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAU29215Human PRO polypeptide sequence1 . . . 649649/649 (100%)0.0#192 - Homo sapiens, 649 aa.1 . . . 649649/649 (100%)[WO200168848-A2, 20-SEP-2001]AAB87591Human PRO1865 - Homo sapiens,1 . . . 649649/649 (100%)0.0649 aa. [WO200116318-A2,1 . . . 649649/649 (100%)08-MAR-2001]AAB70533Human PRO3 protein sequence SEQ1 . . . 649649/649 (100%)0.0ID NO: 6 - Homo sapiens, 649 aa.1 . . . 649649/649 (100%)[WO200110902-A2, 15-FEB-2001]AAB93758Human protein sequence SEQ ID1 . . . 649648/649 (99%) 0.0NO: 13435 - Homo sapiens, 649 aa.1 . . . 649649/649 (99%) [EP1074617-A2, 07-FEB-2001]AAM93408Human polypeptide, SEQ ID NO:1 . . . 649648/649 (99%) 0.03016 - Homo sapiens, 649 aa.1 . . . 649648/649 (99%) [EP1130094-A2, 05-SEP-2001]


[0461] In a BLAST search of public sequence databases, the NOV27a protein was found to have homology to the proteins shown in the BLASTP data in Table 27D.
146TABLE 27DPublic BLASTP Results for NOV27aNOV27aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueCAC33411SEQUENCE 5 FROM PATENT1 . . . 649 649/649 (100%)0.0WO0110902 - Homo sapiens (Human),1 . . . 649 649/649 (100%)649 aa.Q96KB1CDNA FLJ14391 FIS, CLONE1 . . . 649648/649 (99%)0.0HEMBA1003077, WEAKLY1 . . . 649649/649 (99%)SIMILAR TO SLIT PROTEIN(Human), 649 aa.Q9P259KIAA1469 PROTEIN - Homo sapiens1 . . . 649648/649 (99%)0.0(Human), 662 aa (fragment).14 . . . 662 648/649 (99%)Q9NZU0LEUCINE-RICH REPEAT1 . . . 649648/649 (99%)0.0TRANSMEMBRANE PROTEIN1 . . . 649648/649 (99%)FLRT3 (DJ581I13.1) - Homo sapiens(Human), 649 aa.Q96K39CDNA FLJ14788 FIS, CLONE27 . . . 649 622/623 (99%)0.0NT2RP4000925, WEAKLY SIMILAR1 . . . 623622/623 (99%)TO FIBROMODULIN PRECURSOR -Homo sapiens (Human), 623 aa.


[0462] PFam analysis indicates that the NOV27a protein contains the domains shown in the Table 27E.
147TABLE 27EDomain Analysis of NOV27aIdentities/Similarities for NOV27atheExpectPfam DomainMatch RegionMatched RegionValueLRRNT: domain 1 of 1 30 . . . 57 10/31 (32%)0.0003419/31 (61%)LRR: domain 1 of 10 59 . . . 83  7/26 (27%)4420/26 (77%)LRR: domain 2 of 10 84 . . . 103 8/25 (32%)7516/25 (64%)LRR: domain 3 of 10105 . . . 128 7/25 (28%)1218/25 (72%)LRR: domain 4 of 10129 . . . 154 9/26 (35%)7620/26 (77%)LRR: domain 5 of 10155 . . . 17410/25 (40%)5.416/25 (64%)LRR: domain 6 of 10176 . . . 199 8/25 (32%)0.120/25 (80%)LRR: domain 7 of 10200 . . . 225 9/26 (35%)6218/26 (69%)LRR: domain 8 of 10226 . . . 24511/25 (44%)6316/25 (64%)LRR: domain 9 of 10248 . . . 271 9/25 (36%)0.0003320/25 (80%)LRR: domain 10 of 10272 . . . 29513/25 (52%)0.01119/25 (76%)LRRCT: domain 1 of 1305 . . . 35617/54 (31%)9.4e−1342/54 (78%)fn3: domain 1 of 1405 . . . 48518/90 (20%)0.2254/90 (60%)



Example 28

[0463] The NOV28 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 28A.
148TABLE 28ANOV28 Sequence AnalysisSEQ ID NO: 1233373 bpNOV28a,TTGGATTGTCCAAGCCACAGATAAAGGGATGCCCAGGCTTTCTAATACGACTGTAATCACG58567-01 DNAAGGTACAGGTGACTGATATAAATGACAATGCCCCAGCTTTTCTCCCCTCTGAAGCAGTSequenceGGAAATTACAGAAGTCATGACTATTTCAGAAGATTCTTTGCCTGGTGTAATTGTGACTCATGTGTCAGTTCATGATGTGGATTTGAATTCAGCTTTCATATTCAGTTTTGCCAAAGAGAGTAATCCTGGAACCAAGTTTGCTATTGATCACAACACTGGAGTGGTGGTGTTCGTGAAAACATTGGATTTTGAAGAAATGACTGAATATGAGCTGCTCATCCAAATTTCTGATTCAGTGCACTACACAGAGGGAGCACTTGTAGTCCGTGTGCTGGATGTCPATGATAATCCACCAGTGTTTTCTCAACATTTCTATCAGCTCACAGTTCCTGAATCAATACCTGTGGGGTATTCAGTGCTGACTCTGTCAGCCACAGACTTAGAAAGCAATGAGAACATTTCTTACAGAATTCTATCCTCTTCTAAGGAATTCTCCATTGATCCTAAGAATGGCACAATATTTACTATCAGTCCCGTATTACTTCTGGATACAATATCAACAACTCGATTTCTTGTGGAAGCCAGTGATGGTGGAAATCCTGACCCGAGAGCTCTTACTTTAGTGGAGATAGGAATAGAAGATATGAACAATTATGCCCCTGAATTCACAGTCAAATCCTATAATCTTAGCCTAAGTGAGGATGCTCTGGTTGGAAGCACGCTTGTTACATTTTCAAACATCGACCATGACTGGACCCGTGAAAACACATATGTTGAATATTCCATCATCAGTGGTAATTCACAGAACAATTTTCATGTGGAAACTAAGTTCTTTCATTCAGAATATCCTTATAAGCAAGTCGGTTATCTTGTGTTGCTTCACAGTCTGGACAGAGAAGCAAGTGCTAGCCATGAGCTTGTCATTCTGGCATCTGACAGTGGCTGCCCTCCATTGAGTTCCACAGCTGTCATATCAATACAAGTACTTGATGTCAATGACAATCCCCCAAACTTCAGCAGCCTGAGCTATCACACCCATGTCAAGGAAAGCACCCCTCTAGGGAGTCACATCACTGTGGTCTCAGCAAATGACCGTGACACAGGGTCACATGCAGAAATCATCTACAACATCATCTCTGGAAATGAGAAGGGACATTTTTACTTAGAAGAAAACACTGGAGTTCTTTATTTGATTAAACCTCTGGATTATGAAAAAATGACAAAATTCACCTTAACTGTCCAAGCTTCAGATGCAGAAAAGAAACATTTTTCTTTTGCAGTTGTGTTTGTCAGTGTCCTCGATGATAACGACCATGCACCTCAGTTTATCTTCTCAAGCTTCAGCTGTATTGTTCCAGAAAATCTGCCTATTTCCTCTACCATATGCTCTATAAATGCTCTGGATTTTGATGCTGGTCCGTATGGAGAATTGACCTATTCTATTGTATCACCCTGTTTTCTCACTCATGGAATGTCTTATGATCATGATCTCTTCCTCATTGACCCTTTGACAGGCGATATTCATGCTAAGCAAATCCTTGACTATGAAAATGGCAATAAATACTGCCTCACAGTCCAAGCCAAAGACAAAGGTGATGCAACTGCCTCCTTAGTGGTCTGGGTGGATATTGAAGGGATAGATGAATTTGAGCCCATTTTCACTCAAGATCAGTATTTTTTCACCCTCCCAGAAAAGAATAAAGACAGACAGTTGATTGGCAGAGTGGAAGCCTCAGATGCAGATGCTGGTATTGATGGAGTCATTCTTTACTCCCTTGGAACCTCATCTCCTTTCTTTTCAGTAAATAGAACCAATGGAAATATTTATTTCATTACAGCCCTTCCCCTAATAAAAAGTCAACTCAACAAAGAAGACACCTTGGAAATGAAAATAATCGCTCATAGTCCCAAATCAGATTCCAAGTTTGCATCTTGCACTGTTTTTGTGAATGTGTCTTTCTCCTCTGAAGGAACACCCTTGGCAGTGTTCGCCAGCAGCTTTTCAATCAGCCTGGTGGTCTCCTTTTTAGTGTTTCTGATACTCATCTGCATTCTAATTGTAATGATTTTAAGACATAAACAAAAAGACACAATAAACAATTATGAGGAGAAGAAAACCTCATCTTTAGATGCGGACTTGAGAGTGACCCGGGATGCCAGTGTGCTCAAAGCCTTCCAGAAAACTGACGACTGCAGTAACGAGGTGGTCCCTGTGGATGCCACTCCGGAATCGTTGAGTTTAATAAGTATCATGGAGAAGGATATTGTCAATCTGTACAGATACTCAAACTCCAGTGGCCACTGTTCTGTGGAAGGAGAAACTGCAGAAGATAAGGAAATCCAGAGGATAAATGAGCATCCCTACAGAAAGTGCTCAGACTCAGCTCTGAGTGACCACGAGTCCAGGGTGCCAGACTCGGGTATCCCGAGGGACTCAGACCAGCTCTCCTGCCTATCTGGGGAAACTGATGTGATGCTGACTGCCGAAACAGCAGAAGCCAGCCAAACATTTGGGGAAGGAGATCAACGGGAAGGCTCCAGCACCACCTGTGCTCAAAATAATGTGTTACCCCAGACAGTTCAGAAGAGAGAGGCAAAAGAGAGCATCCTGGCTGACGTTAGAAAAGAGTCTGTCTTTATTTCAGGTGATCAGGAAGTAAGGTGTGCAGCTCTTTCAACTCAGACGACCTCTGATCATGATGGAAAAGACAACTATCACTGGAATTATCTTCTTAGTTGGGAGCCCAAATTCCAACCTCTTGCCTCACTATTTAATGATATTGCAAAACTAAAGGATGAACATTTGCATATGCCTGGCATTCCAAAAGAGAAGAAATCTTTTGTTTTTCCACCCCCTTTGATAACAGCAGTAGCCCAGCCTGGGATTAAAGCAGTCCCACCAAGAATGCCGGCAGTAAACCTGGCGCAGGTGCCTCCGAAACACCCACGCTCTCCCATCCCCTACCATCTTGGTTCTCTGCCAGAAGGCATGACTCCCAATTTTTCTCCATCTCTTTCCCTATTGACGATGCAGCCTCCTGCCTTGTCTCCACTGTTGAGAGAAGGAGAATTATTAGGAACACACATCAGTGGTACATGCCATGAACTTAAAGCAGAAGATGAAGTTCAAATATGAAACCACTGGGATGCCAAGTACCTGCTCACCATTGGTCATGAATGAATGAACAAAATTTTAGTTAGAGTTTTTAAAACTTCCCCATTAAAGTTTCTCCAATTTCAAAAAAAAAAAAAAAAAAAAORF Start: TTG at 1ORF Stop: TGA at 3190SEQ ID NO: 1241063 aaMW at 117200.4 kDNOV28a,LIVQATDKGMPRLSNTTVIKVQVTDINDNAPAFLPSEAVEITEVMTISEDSLPGVIVTCG58567-01 ProteinHVSVHDVDLNSAFIFSFAKESNPGTKFAIDQNTGVVVLVKTLDFEEMTEYELLIQISDSequenceSVHYTEGALVVRVLDVNDNPPVFSQDFYQVTVPESIPVGYSVLTLSATDLESNENISYRILSSSKEFSIDPKNGTIFTISPVLLLDTISTTRFLVEASDGGNPDPRALTLVEIGIEDMNNYAPEFTVKSYNLSLSEDALVGSTLVTFSNIDHDWTRENTYVEYSIISGNSQNNFHVETKFFHSEYPYKQVGYLVLLHSLDREASASHELVILASDSGCPPLSSTAVISIQVLDVNDNPPNFSSLSYHTHVKESTPLGSHITVVSANDRDTGSHAEIIYNIISGNEKGHFYLEENTGVLYLIKPLDYEKNTKFTLTVQASDAEKKHFSFAVVFVSVLDDNDHAPQFMFSSFSCIVPENLPISSTICSINALDFDAGPYGELTYSIVSPCFLTHGMSYDHDLFLIDPLTGDIHAKQILDYENGNKYCLTVQAKDKGDATASLVVWVDIEGIDEFEPIFTQDQYFFTLPEKNKDRQLIGRVEASDADAGIDGVILYSLGTSSPFFSVNRTNGNIYLIRALPLIKSQLNKEDTLEMKIIAHSPKSDSKFASCTVFVNVSFSSEGTPLAVFASSFSISLVVSFLVFLILICILIVMILRHKQKDTINNYEEKKTSSLDADLRVTRDASVLKAFQKTDDCSNEVVPVDATPEWLSLISIMEKDIVNLYRYSNSSGHCSVEGETAEDKEIQRINEHPYRKCSDSALSDHESRVPDSGIPRDSDQLSCLSGETDVMVTAETAEASQTFGEGDQGEGCSTTCAQNNVLPQTVQKREAKESILADVRKESVFISGDQEVRCAALSTQTTSDHDGKDNYHWNYLLSWEPKFQPLASVFNDIAKLKDEHLHMPGIPKEKKSFVFPPPLITAVAQPGIKAVPPRMPAVNLGQVPPKHPRSPIPYHLGSLPECMTPNFSPSLSLLTMQPPALSPLLREGELLGTHISGTCHELKAEDEVQISEQ ID NO: 1259193 bpNOV28b,ATGGAGAAATGTGGGCTTAAAGAGGAAGGCAGTTACGCGGACATAGATCCAGTTGCCCCG58567-05 DNAACGATCCGGACGCCGGACTGTTCAGCACTCAGGGCTACACCCTGGTGCAACCGTCCGASequenceCCTGCCCAAGGACCCCGCAGGCCCGTTCTTCCAGTTGCGCTACCGGACTCCGGGGCCACTACCGTCACCGCTTTTGCCAGGCTCCTCGTCACCCCTGGAGCCTCTAGATCTGGTGCTGCTGCGGCGCTTGGACCGAGAGGAGGCGGCGGCGCACCGGCTGCAGATCGAGGCATGGGACGGCGGCCGACCCCGGCGCACCGGCCTCCTGAGCGTGGAGCTGCGCGTGCTGGATGAGAACGACAACCCGCCGGTCTTTGAGCAGGACGAGTACCGCGCCGCGGTGCGCGAGCACGCCCAGCCGGGCGCCGAGGTCTGTCGCGTGCGCGCCACCGACCGCGACCTGGGGCCCAATGGCTTCGTGCGCTACAGCGTCCGCGCCCGGCAAGTGCCTGGGGCGGGTAGCGGCGGCGGGGCACTGGGCGACGCGGCCTACTTCGCGGTGGAGGAGCTGAGCGGCGTGGTGCGAGTGTGGAGACCTCTGGACCGCGAGGCACAGGCCTGGCACCAGTTGGTGGTGGAGGCCCGCGATGGAGGCGCCGAGCCTGAGGTTGCCACGGTCCGCGTGTCCATCGCCGTGCTGGACGTGAATGACAACCGGCCAGCAATTCACGTGCTCTTTCTCACAGAGGGAGGCGTCGCCCGTGTCTCTGAAGCCGCCCGACCGGGCGACTACGTGGCTCGCGTCTCGGTGTCTGACGCGGACGGGGTAATAGGCAAAATTACAGCTATTGACATGGACTCTGGAAAGAATGGACAGCTATTATATTTCCTTTTGTCTGATGGAAAATTCTTCAAGATGAATCCTAATACAGGAGAGTTAATCAATTGGGTGGCACTGGATCGTGAGCACCGGGCGCACCATGAGATGACTGTGCTAGTGACAGACCGCGGCTCCCCACCACGAAACGCCACCATGGCGGTTTACGTCTCAGTTACTGACATCAATGATAACAGGCCCTTCTTCCCCCAGTGTCTCCCTGGAAAGGAGTTACACGTGAAGGTTCTGGAACGTCAACCAGTAAATATGTTGGTTACAACTGTGTTTGCAAAGGATCCTGATGAAGGAAATAATGCAGAAGTTACATACTCAGTATCTTCAGAAGATAGTTCTGATCACTTTAAGATTGACGCCAACAATGGTGAAATAAGAACAACCACAATACTTTCGTATGATTATAGACCTTCCTACAGAATGAGTGTCATTCCCACTGACCAGGGAGTGCCTCCTCTTCAAGGACAGGCAGTTGTTAATATTCAGGAACTTGATTATGAGACGACATCTCATTATCTTTTCAGAGTGATTACTACAGACCATAGCAAAAACCTTTCCCTGAGTAGCACAGTCTTCCTTAGTATCGATGTGGAAGATCAGAATGACCATTCCCCATCTTTCCAGGATGAGCTCATTGTGATCAGTGTAGAGGAGAATGTTCCCATAGGAACCCTGGTGTATGTCTTCAATGCCAAAGATGATGACGGCAGTTTTTTGAACAGTAGAATACAATACTACATTGAATCCCACAACCCTGGCACGAATCCATTTCTCATCCACCCCTCATTTGGCACACTAGTCACTGTGTCCCGTCTTGACAGAGAAAGCATTCCAACTGTCATCCTGACAGTAACAGCATCTGATCAGGCTGTGAATGTGACAGACCGGCGACTGAGATCACTGACAGCACAAATAGTGATTTTGGATGTAAATGACCACAACCCCACTTTTATTTCTTTCCCCAATGCCCATGTCAAAGAGGATGTCACAGTGCGCTCCTTGGTCCACCACATAACTGCTCACGATCCAGACGAAGGAAGGAATGGAAAAGTAACATACACCATCCTCTCAGGAAATGAAAACATGACGTTTATGCTAGATGAGTCATCAGGCTTACTAACCACAACCTGTCCTTTGGATTATGAAATGAAAACTCAGCATATTCTCACTGTTCTGGCACTGGATGATGGCACACCAGCACTTTCTTCATCCCAGACTTTGACAGTTACTGTTCTTCATGTAAATGATGAAGCTCCAGTATTTAAGCAGCACCTGTATGAAGCCTCAGTGAAAGAAAACCAAAATCCAGGGGAGTTTGTTACCAGGGTTGAAGCTCTGGACAGAGATTCAGTGTTCCTTAATACTAGAGAGCTTAACATGTGTTTTCTAGCATTCTACGATGCAGTTTTTAAAAATGGTGGGCTAAGTGCCCAAGCCTTTGTTCGTGTGGACCTGGAGGACGTGAATGATAATCATCCTGTGTTTAACCCATCAACCTATGTGACGAGCATCAGTGATGAGACCCAGCCAGGCACCGAGATCATCPATGTTCTTGCCACTGACCAGGACTCTGGGATATATGGGACAGTCGCTTATGAGCTTATTCCAGGAAACGTGTCGTCCCTTTTTACCATTGACTCCACCACAGGAATTATTTACTTAACATTACCTCTTAGTCATTTGGAATCTACCACACTTTCGTTGATGGTCTCTGCTCAAGACGGTGGTGGGCTCACAGCTGTCATTAATGCCGATGTCACCATACACATTTTCCAGACAACTCTGGCACCTGCTGAGTTTGAAAGGCCTAAGTACACTTTCTTACTTTATGAAGATGTGCCTGAAGATAGTCCCATTGGAACAGTGAAAGCAAGAGAGCCCTTGAATCCACCTAGGAGCTCTGTAATACACCTGCAAGTTAGAGTTTTGGATGCCPATGACCACAGTCCTTCTTTTCCCACACTTTATTACCAGTCCTCTGTGAGAGAAGATGCTGAAGTGGGAACAGTGGTTCTTGTGCTTTCAGCTCTGGACAAGGATGAAGGCCTGAATGGGCAAACTGAGTATTTTCTGACTGATGAGGCTTGTGGTGCATTCACCATTGATCCTATGTCAGCCACATTGAAAACCAGCAACACCCTCGACCGTGAAGCCAGATCTCACCATACATTTAGTGCTGTGGCCAGAGACTGTAGCATCCAGGGTTCACGAAGCACCACTGTAATTATAAAAGTATATGTCACTGATGTTAATGACAATGATCCAGTTTTGGAACAGAACCCTTTTCATGTGTTTCTTTCCCCCGAGTCGCCTACAAACCAGACAACTGTCATTGTGAGAGCTGATCACCTGGACTTGGGCCCCAATGGAACTGTGGACTCCGATGACTCCCCGCTGCTGGACGACTTCCACGTGCACCCGGACACCGGCATCATCCGCACTGCCCGGCGCCTGGACCGCGAGCGCCGGGACCACTACAGCTTCGTCGCCGCCACGCTGCTGGGCGCTGTGGTGCAGGTGGAGATTCGCCTCPACGACGTGAATGACCACTCGCCCCGCTTTCCCCTCGACTCCCTGCAACTCGACGTCTCCGAGCTCAGCCCGCCAGGGACCGCCTTCCGCCTGCCAGTTGCCCACGATCCGGACGCCGGACTGTTCAGCACTCAGGGCTACACCCTGGTGCAACCGTCCGACCTGCCCAAGGACCCCGCAGGCCCGTTCTTCCAGTTGCGCTACCGGACTCCGGGGCCACTACCGTCACCGCTTTTGCCAGGCTCCTCGTCACCCCTGGAGCCTCTAGATCTGGTGCTGCTGCGGCGCTTGGACCGAGAGGAGGCGGCGGCGCACCGGCTGCAGATCGAGGCATGGGACGCCGGCCGACCCCGGCGCACCGGCCTCCTGAGCGTGGAGCTGCGCGTGCTGGATGAGAACGACPACCCGCCGGTCTTTGAGCAGGACGAGTCCCGCGCCGCGGTGCGAGAGCACGCCCAGCCGGGCGCCGAGGTCTGTCGCGTGCGCGCCACCCCCCGCGACGTGGGGCCCAATGGCTTCGTGCGCTACAGCGTCCGCGCCCGGCAAGTGCCTGGGGCGGGTAGCGGCGGCGGGGCACTGGCCGACGCGGCCTACTTCGCGTTGGTGGTGGAGGCCCGCGATGGAGGCGCCGAGCATGAGGTTGCCGCGGTGCGTGTGTCCATCGCCGTGCTGGACGTGAATCACAACCGGCCAGCAATTCACGTGCTCTTTCTCACACAGGGAGGTGTCGCCCGTGTCTCTGAAGGCGCCCCCCCGGGCGACTACGTGGCTCGCGTCTCGGTGTCTCACGCGGGCGGTGACTGGGAGAAGGAAGATGAGGCCACAGGGGAGCTTGGTGTGACAGCCTCTGATGCAGATTCAGGACTCTATGGCTTTATTGAATATTCTCTTTATGATGGATTCCTGAGCTATCAAGCACCTCAGGCATTCCGGATCGACCCTCATGATGGGCAAATCTGTGTTTCTCAAGATATCGACAGGGAAAGGGATCCAGCTACCTATGATCTCCTGGTGGAAGCTAAGGATGGGTTTGAAATCATGCCAGGTGCTTCATTTGAATTATTCGAGATAAATTCTGACACTGGAGAGGTAGTGACAACCACCATACTTGACAGAGAAATTCAAGAAGTCTTCACCCTTCGAGTACTAGTACGAGATGGGGGATTCCCTTCATTGTCCAGCACCACAACAATCCTCTGCACTGTTGAAGATGAAAACGATCACGCACCAGAGTTTATTGTTTCCAGTTATGACATTGAGGTTCTGGAAAACCAGGAACCAGAGGTTGTCTATACGGTTTTACCCTCTGATATGGATGCTGGCAATAACAGAGCTGTTGAATATCACATAATTGACTCCTCAGAACCAATCTTTTACAGGATTTCTTCTGGTGATCTCGGCGGAAAGTTCTCCATTCACCCGCGGCTGGGCACTATTCGCACCCGGAAGCCCCTGGATCACGAGACGCAGCCCGTGGTTGTGCTCACGGTGCAGGCGCAGCTCGGCAGCGCCCCAGCCTGCAGCAGCACCGAGGTCAACATAACAGTCATCGATGTCAATGACAACCACCCACCGTTCCTCAGGACCTCGGATGAGATTAGAATATCCCAGACCACGCCCCCTGGCACAGCCTTGTACCTCGCACGTGCGGAAGACAGAGACAGTGGGCGGAACGGACTCATCCGGTACTCCATCGCCAGCCCGCAGCCAGGCGTCTTTGCCATCGACAGAGCCCTGGGGGTGCTGTTCCTCAACGGCAGCCTGGGCGCGGGCGAGCAGCGGGAGCTCACGCTGACTCTCAGGGCCGAGGACCAAGGCGTGCATCCTCAGGCAGCCCTGCTGGTGCTGACAGTCGTTATCGAGAAACGCGAACACAGCCCATCCTGGACTTTCGAACATTTGGTCTATCAAGTGGAAGTCAGTACTTCTATTGTGACTGTTAAAGCTTTTGCTCCTGACTCAATTCAGGACAGCATGAAATATTCAATTTTTAGTGGAAATGAAGATGGAGTTCTTTCCCTGTGCTCTAAGTCAGGTGTGGTGAACTGCCTTGCTTCTCTCAGTCACACAGACTTTCTCTCCCTGAAATTTGAATCTTCGGTGAAGGGACACCAAGACAGAGACAAATTACAGCCAATTCATCTTGATGACAACAACTCAAAGAAGCTGTGCTTTACATTCCCTAGAGCCACTCAGGCTCTTGTATTCACTGGGCACTGTCTTTCTGATACATCTCTCCCCGGTTGGGTTTTTCCTACCGACTTGGACAGTGGTTTGAACGGCCTGATTGAGTATTCTATTCTGTCTGGCAACCAAGAAGAAGCATTCCAGATTGATGCACTGAGTGGTGTGATAACAACAAAAGCGATTCTAGATTACGAGCTCACCAGCTCCTACAGCTTGATTGTCCAAGCCACAGATAAAGGGATGCCCAGGCTTTCTAATACGACTGTAATCAAGGTACAGGTGACTGATATAAATGACAATGCCCCAGCTTTTCTCCCCTCTGAAGCAGTGGAAATTACAGAAGTCATGACTATTTCAGAAGATTCTTTGCCTGGTGTAATTGTGACTCATGTGTCAGTTCATGATGTGGATTTGAATTCAGCTTTCATATTCAGTTTTGCCAAAGAGAGTAATCCTGGAACCAAGTTTGCTATTGATCAGAACACTGGAGTGGTGGTGTTGGTGAAAACATTGGATTTTGAAGAAATGACTGAATATGAGCTGCTCATCCAAATTTCTGATTCAGTGCACTACACAGAGGGAGCACTTGTAGTCCGTGTGCTGGATGTCAATGATAATCCACCAGTGTTTTCTCAAGATTTCTATCAGGTCACAGTTCCTGAATCAATACCTGTGGCGTATTCAGTGCTGACTCTGTCAGCCACAGACTTAGAAAGCAATGAGAACATTTCTTACAGAATTCTATCCTCTTCTAAGGAATTCTCCATTGATCCTAAGAATGGCACAATATTTACTATCAGTCCCGTATTACTTCTGGATACAATATCAACAACTCGATTTCTTGTGCAAGCCAGTGATGGTGGAAATCCTGACCCGAGAGCTCTTACTTTAGTGGAGATAGGAATAGAAGATATGAACAATTATGCCCCTGAATTCACAGTCAAATCCTATAATCTTAGCCTAAGTGAGCATGCTCTGGTTGGAAGCACGCTTGTTACATTTTCAAACATCOACCATGACTGGACCCGTGAAAACACATATGTTGAATATTCCATCATCAGTGGTAATTCACAGAACAATTTTCATGTGGAAACTAAGTTCTTTCATTCAGAATATCCTTATAAGCAAGTCCGTTATCTTGTGTTGCTTCACAGTCTGGACAGAGAAGCAAGTGCTAGCCATGAGCTTGTCATTCTGGCATCTGACAGTGGCTGCCCTCCATTGAGTTCCACAGCTGTCATATCAATACAAGTACTTGATGTCAATGACAATCCCCCAAACTTCAGCAGCCTGAGCTATCACACCCATGTCAAGGAAAGCACCCCTCTAGGGAGTCACATCACTGTGGTCTCAGCAAATGACCGTGACACAGGGTCACATGCAGAAATCATCTACAACATCATCTCTGGAAATGAGAAGGGACATTTTTACTTAGAAGAAAACACTGGAGTTCTTTATTTGATTAAACCTCTGGATTATGAAAAAATGACAAAATTCACCTTAACTGTCCAAGCTTCAGATGCAGAAAAGAAACATTTTTCTTTTGCAGTTGTGTTTGTCAGTGTCCTGGATGATAACGACCATGCACCTCAGTTTATGTTCTCAAGCTTCAGCTGTATTGTTCCAGAAAATCTGCCTATTTCCTCTACCATATGCTCTATAAATGCTCTGGATTTTGATGCTGGTCCGTATGGAGAATTGACCTATTCTATTGTATCACCCTGTTTTCTCACTCATGGAATGTCTTATGATCATGATCTCTTCCTCATTGACCCTTTGACAGGGGATATTCATGCTAAGCAAATCCTTGACTATGAAAATGGCAATAAATACTGCCTCACAGTCCAAGCCAAAGACAAAGGTGATGCAACTGCCTCCTTAGTGGTCTGGCTGGATATTGAAGGGATAGATGAATTTGAGCCCATTTTCACTCAAGATCAGTATTTTTTCACCCTCCCAGAAAAGAATAAAGACAGACAGTTGATTGGCAGAGTGGAAGCCTCAGATGCAGATGCTGGTATTGATGGAGTCATTCTTTACTCCCTTGGAACCTCATCTCCTTTCTTTTCAGTAAATAGAACCAATGGAAATATTTATTTGATTAGAGCCCTTCCCCTAATAAAAAGTCAACTCAACAAAGAAGACACCTTGGAAATGAAAATAATCGCTCATAGTCCCAAATCAGATTCCAAGTTTGCATCTTGCACTGTTTTTGTGAATGTGTCTTTCTCCTCTGAAGGAACACCCTTGGCAGTGTTCGCCAGCAGCTTTTCAATCAGCCTGGTGGTCTCCTTTTTAGTGTTTCTGATACTCATCTGCATTCTAATTGTAATGATTTTAAGACATAAACAAAAAGACACAATAAACAATTATGAGGAGAAGAAAACCTCATCTTTAGATGCGGACTTGAGAGTGACCCGGGATGCCAGTGTGCTCAAAGCCTTCCAGPAAACTGACGACTGCAGTAACGAGGTGGTCCCTGTGGATGCCACTCCCCAATCCTTCACTTTAATAAGTATCATGGAGAAGGATATTGTCAATCTGTACAGATACTCAAACTCCAGTGGCCACTGTTCTGTGGAAGGAGAAACTGCAGAAGATAAGGAAATCCAGAGGATAAATGAGCATCCCTACAGAAAGTGCTCAGACTCAGCTCTGAGTGACCACGAGTCCAGGGTGCCAGACTCGGGTATCCCGAGGGACTCACACCAGCTCTCCTGCCTATCTGGGGAAACTGATGTGATGGTGACTGCCGAAACAGCAGAAGCCAGCCAAACATTTGGGGAAGCAGATCAAGGGGAAGGCTGCAGCACCACCTGTGCTCAAAATAATGTGTTACCCCAGACAGTTCAGAAGAGAGAGGCAAAAGAGAGCATCCTGGCTGACGTTAGAAAAGAGTCTGTCTTTATTTCAGGTGATCAGGAAGTAAGGTGTGCAGCTCTTTCAACTCAGACGACCTCTCATCATGATGGAAAAGACAACTATCACTGGAATTATCTTCTTAGTTCGGAGCCCAAATTCCAACCTCTTGCCTCAGTATTTAATGATATTGCAAAACTAAAGGATGAACATTTGCATATGCCTGGCATTCCAAAAGAGAAGAAATCTTTTGTTTTTCCACCCCCTTTGATAACAGCAGTAGCCCAGCCTGGGATTAAAGCAGTCCCACCAAGAATGCCGCCAGTAAACCTGGGGCAGGTGCCTCCGAAACACCCACGCTCTCCCATCCCCTACCATCTTGGTTCTCTGCCAGAAGGCATGACTCCCAATTTTTCTCCATCTCTTTCCCTATTGACGATGCAGCCTCCTGCCTTGTCTCCACTGTTGAGAGAAGGAGAATTATTAGGAACACACATCAGTGGTACATGCCATGAACTTAAAGCAGAAGATGAAGTTCAAATATGAAACCACTGGGATGCCAAGTACCTGCTCACCATTGGTCATGAATGAATGAACAAAATGTTTTCAAGCCGGCAACTCGAGATTGGGCTCATTTTTATCTAAAAGCAAGTGATGTAATTTAGTTAGAGTTTTTAAAACTTCCCCATTAAAGTTTCTCCAATTTCAAAAAAAAAAAAAAAAAAAAORF Start: ATG at 1ORF Stop: TGA at 9010SEQ ID NO: 1263003 aaMW at 329184.0 kDNOV28b,MEKCGLKEEGSYADIDPVAHDPDAGLFSTQGYTLVQPSDLPKDPAGPFFQLRYRTPGPCG58567-05 ProteinLPSPLLPGSSSPLEPLDLVLLRRLDREEAAAHRLQIEAWDGGRPRRTGLLSVELRVLDSequenceENDNPPVFEQDEYRAAVREDAQPGAEVCRVRATDRDLGPNGFVRYSVRARQVPGAGSGGGALGDAAYFAVEELSGVVRVWRPLDREAQAWHQLVVEARDGGAEPEVATVRVSIAVLDVNDNRPAIHVLFLTEGGVARVSEGARPGDYVARVSVSDADGVIGKITAIDMDSGKNGQLLYFLLSDGKFFKMNPNTGELINWVALDREHRGHHEMTVLVTDRGSPPRNATMAVYVSVTDINDNRPFFPQCLPGKELHVKVLEGQPVNMLVTTVFAKDPDEGNNAEVTYSVSSEDSSDHFKIDANNGEIRTTTILSYDYRPSYRMSVIATDQGVPPLQGQAVVNIQELDYETTSHYLFRVITTDHSKNLSLSSTVFLSIDVEDQNDHSPSFQDELIVISVEENVPIGTLVYVFNAKDDDCSFLNSRIQYYIESHNPGTNPFLIHPSFGTLVTVSRLDRESIPTVILTVTASDQAVNVTDRRLRSLTAQIVILDVNDHNPTFISFPNAHVKEDVTVGSLVHHITAHDPDEGRNGKVTYSILSGNENMTFMLDESSGLLTTTCPLDYEMKTQHILTVLALDDGTPALSSSQTLTVTVLDVNDEAPVFKQHLYEASVKENQNPGEFVTRVEALDRDSVFLNTRELNMCFLAFYDAVFKNGGLSAQAFVRVDLEDVNDNHPVFNPSTYVTSISDETQPGTEIINVLATDQDSGIYGTVAYELIPGNVSSLFTIDSTTGIIYLTLPLSHLESTTLSLMVSAQDGGGLTAVINADVTIHIFQTTLAPAEFERPKYTFLVYEDVPEDSPIGTVKAREPLNPPRSSVIHLQVRVLDANDHSPSFPTLYYQSSVREDAEVGTVVLVLSAVDKDECLNGQTEYFLTDEACGAFTIDPMSGTLKTSNTLDREARSQHTFSAVARDCSIQGSRSTTVIIKVYVTDVNDNDPVLEQNPFDVFLSPESPTNQTTVIVRADDLDLGPNGTVDSDDSPLLDDFHVHPDTGIIRTARRLDRERRDHYSFVAATLLGAVVQVEIRVNDVNDHSPRFPLDSLQLDVSELSPPGTAFRLPVAHDPDAGLFSTQGYTLVQPSDLPKDPAGPFFQLRYRTPGPLPSPLLPGSSSPLEPLDLVLLRRLDREEAAAHRLQIEAWDGGRPRRTGLLSVELRVLDENDNPPVFEQDESRAAVREHAQPGAEVCRVRATARDVGPNGFVRYSVRARQVPGAGSGGGALGDAAYFALVVEARDGGAEHEVAAVRVSIAVLDVNDNRPAIHVLFLTEGGVARVSEGARPGDYVARVSVSDAGGDWEKEDEATGELGVTASDADSGLYGFIEYSLYDGFLSYEAPQAFRIDPHDGQTCVSQDIDRERDPATYDLLVEAKDGFEIMPGASFELFEINSDTGEVVTTTILDREIQEVFTLRVLVRDGGFPSLSSTTTILCTVEDENDHAPEFIVSSYDIEVLENQEPEVVYTVLASDMDAGNNRAVEYHIIDSSEPIFYRISSGDLCGKFSIHPRLGTIRTRKPLDHETQPVVVLTVQAQLGSAPACSSTEVNITVMDVNDNHPAFLRTSDEIRISQTTPPGTALYLAPAEDRDSGRNGLIRYSIASPQPGVFAIDRALGVLFLNGSLGAGEQRELTLTLRAEDQGVHPQAALLVLTVVIEKREHSPSWTFEHLVYQVEVSTSIVTVKAFAPDSIQDSMKYSIFSGNEDGVLSLCSKSGVVNCLASLSHTDFLSLKFESSvKGHQDRDKLQPIHLDDNNSKKLCFTFPRATQALVFTGHCLSDTSLPGWVFATDLDSGLNGLIEYSILSGNQEEAFQIDALSGVITTKAILDYELTSSYSLIVQATDKGMPRLSNTTVIKVQVTDINDNAPAFLPSEAVEITEVMTISEDSLPGVIVTHVSVHDVDLNSAFIFSFAKESNPGTKFAIDQNTGVVVLVKTLDFEEMTEYELLIQISDSVHYTEGALVVRVLDVNDNPPVFSQDFYQVTVPESIPVGYSVLTLSATDLESNENISYRILSSSKEFSIDPKNGTIFTISPVLLLDTISTTRFLVEASDGGNPDPRALTLVEIGIEDMNNYAPEFTVKSYNLSLSEDALVGSTLVTFSNIDHDWTRENTYVEYSIISGNSQNNFHVETKFFHSEYPYKQVGYLVLLHSLDREASASHELVILASDSGCPPLSSTAVISIQVLDVNDNPPNFSSLSYHTHVKESTPLGSHITVVSANDRDTGSHAEIIYNIISGNEKGHFYLEENTGVLYLIKPLDYEKMTKFTLTVQASDAEKKHFSFAVVFVSVLDDNDHAPQFMFSSFSCIVPENLPISSTICSINALDFDAGPYGELTYSIVSPCFLTHGMSYDHDLFLIDPLTGDIHAKQILDYENGNKYCLTVQAKDKGDATASLVVWVDIEGIDEFEPIFTQDQYFFTLPEKNKDRQLIGRVEASDADAGIDGVILYSLGTSSPFFSVNRTNGNIYLIRALPLIKSQLNKEDTLEMKIIAHSPKSDSKFASCTVFVNVSFSSEGTPLAVFASSFSISLVVSFLVFLILICILIVMILRHKQKDTINNYEEKKTSSLDADLRVTRDASVLKAFQKTDDCSNEVVPVDATPEWLSLISIMEKDIVNLYRYSNSSGHCSVEGETAEDKEIQRINEHPYRKCSDSALSDHESRVPDSGIPRDSDQLSCLSGETDVMVTAETAEASQTFGEGDQGEGCSTTCAQNNVLPQTVQKREAKESILADVRKESVFISGDQEVRCAALSTQTTSDHDGKDNYHWNYLLSWEPKPQPLASVFNDIAKLKDEHLHMPGIPKEKKSFVFPPPLITAVAQPGIKAVPPRMPAVNLGQVPPKHPRSPIPYHLGSLPEGMTPNFSPSLSLLTMQPPALSPLLREGELLGTHISGTCHELKAEDEVQISEQ ID NO: 12710267 bpNOV28c,ATGGAGAAATGTGGGCTTAAAGAGGAAGGCAGTTACGCGGACATAGATCCAGTTGCCCCG58567-06 DNAACGATCCGGACGCCCCACTCTTCAGCACTCAGGGCTACACCCTGGTGCAACCGTCCGASequenceCCTGCCCAAGGACCCCGCAGGCCCGTTCTTCCAGTTGCGCTACCGGACTCCGGGGCCACTACCGTCACCGCTTTTGCCAGGCTCCTCGTCACCCCTGGAGCCTCTAGATCTGGTGCTGCTGCGGCGCTTGGACCGAGAGGAGGCGGCGGCGCACCGGCTGCAGATCGAGGCATGGGACGGCGGCCGACCCCGGCGCACCGGCCTCCTGAGCGTGGAGCTGCGCGTGCTGGATGAGAACGACAACCCGCCGGTCTTTGAGCAGGACGAGTACCGCGCCGCGGTGCGCGAGGACGCCCAGCCGGGCGCCGAGGTCTGTCGCGTGCGCGCCACCGACCGCGACCTGGGGCCCAATGGCTTCGTGCGCTACAGCGTCCGCGCCCGGCAAGTGCCTGGGGCGGGTAGCGGCGGCGGGGCACTGGGCGACGCGGCCTACTTCGCGGTGGAGGAGCTGAGCGGCGTGGTGCGAGTGTGGAGACCTCTGGACCGCGAGGCACAGCCCTGGCACCAGTTGGTGGTGGAGGCCCGCGATGGAGGCGCCGAGCCTGAGGTTGCCACGGTGCGCGTGTCCATCGCCCTGCTGGACGTGAATGACAACCCGCCAGCAATTCACGTGCTCTTTCTCACAGAGGGAGGCGTCGCCCGTGTCTCTGAAGGCGCCCGACCGGGCGACTACGTGGCTCGCGTCTCGGTGTCTGACGCGGACGGTGACTGGGAGAAGGAAGATGAGGCCACAGGGGAGCTTCGTGTGGGTCTTGGAGACGGGAGCATCTCTCTGTCCTTGCAAGGCGGAGAGGGAGACTTCGCGTTGCTACCCGGCGGCCCCCCAGGGGTATTTTTCCTTTGCCTGGAGGGGCCCCTGGACAGAGAGAGCCGCGATCTGTATGAGTTACTACTGGTGGCCACGCACGCGGGGTCCCCGCCGCTGAGCACGGAGGAGACGCTGCTACTCCGGGTCGCTGACCTCAATGACCAACCACCTCTCTTCAGCCAACAGCATTACAAGGCCTCAGTGTCCGAGGCCGCCGCCCCTGGCACTGTAGTCATGTGGGTCAGCGCCTCCGATGCCGACGAGGCAGGCAGTGATCACGCCTGGCTCCGCTACACTGTAGTCCAACTCTCGGCTCCCTGCAATCTCGGCTCCCTGCAATCAAAGATGGTCCACACCGCAGAGTGTGGACCATCTTTTGCCATTGATTCCGAAAGCGGTGCGATCAGCACTATCCGGACTCTAGACCGAGAGGTCCAGGAGGCGGTGGAGCTGAAAGTGCTGGCCCAGGACCTCGGAGAGCCCCCACTCTCTGCCACCTGCCTGGTGAGCATCACCGTAGATGATGTGAATGACAATGAGCCCATCTTCTGGAGGCAGGTGTACAATGCCACCATTGCAGAGCATGCCCCGGTTGGACACTGCTTTCTGCAGCTTATATCTGCTCAAGTTGCCTCTGTCAAAATCAAACACAAACACAAGGAGATACACGAGAAACACAATCTTGCCTATATTTCCTGTCCAGCACGCACCATCTATGTCATAACCTGGGCAGATGGTGCTGCTGCCTTTACTGGGACAGACTTTGCATTCAGTTCTGATGAACTTCAAGCCTTTGTTCTCAAGTCTCTGTTCTGTGAATTAGGAGAAGGAGAGTTAATCAATTGGGTGGCACTGGATCGTGAGCACCGGGGGCACCATGAGATGACTGTGCTAGTGACAGACCGCGGCTCCCCACCACGAAACGCCACCATCGCGCTTTACGTCTCAGTTACTCACATCAATGATAACAGGCCCTTCTTCCCCCAGTGTCTCCCTGGAAAGGAGTTACACGTGAAGGTTCTGGAAGGTCAACCAGTAAATATGTTGGTTACAACTGTGTTTGCAAAGGATCCTGATGAAGGAAATAATGCAGAAGTTACATACTCAGTATCTTCAGAAGATAGTTCTGATCACTTTAAGATTGACGCCAACAATGGTGAAATAAGAACAACCACAATACTTTCGTATGATTATAGACCTTCCTACAGAATGAGTGTCATTGCCACTGACCAGGGAGTGCCTCCTCTTCAAGGACAGGCAGTTGTTAATATTCAGGTGATCCCACTATCCAAAGGGAGAGCAATCATGTCTCAGAATATTAGACATTTAATTATACCAGAAAATTTGAAGCCCACAAAAATAATGAGCTTGATAAAGTCATCTGATCACCTTCAACAACATTATAATGGAAAGTTACATTTTAGTATTGTTGCAGATGATAAGGATGGACACTTTGAAATAGACAGCTCAACCGGAGACTTGTTTCTTTCTAACGAACTTCATTATGAGACGACATCTCATTATCTTTTCAGAGTGATTACTACAGACCATAGCAAAAACCTTTCCCTGAGTAGCACAGTCTTCCTTAGTATCGATGTGGAAGATCAGAATGACCATTCCCCATCTTTCCAGGATGAGCTCATTGTGATCAGTGTAGAGGAGAATGTTCCCATAGGAACCCTGGTGTATGTCTTCAATGCCAAAGATGATGACGGCAGTTTTTTGAACAGTAGAATACAATACTACATTGAATCCCACAACCCTCGCACGAATCCATTTCTCATCCACCCCTCATTTGGCACACTAGTCACTGTCTCCCGTCTTGACAGAGAAAGCATTCCAACTGTCATCCTGACAGTAACAGCATCTGATCAGGCTGTGAATGTGACAGACCGGCGACTGAGATCACTGACAGCACAAATAGTGATTTTGGATGTAAATGACCACAACCCCACTTTTATTTCTTTCCCCAATGCCCATGTCAAAGAGGATGTCACAGTGGGCTCCTTGGTCCACCACATAACTGCTCACGATCCAGACGAAGGAAGGAATGGAAAAGTAACATACAGCATCCTCTCAGGAAATGAAAACATGACGTTTATGCTACATGAGTCATCAGGCTTACTAACCACAACCTGTCCTTTGGATTATGAAATGAAAACTCAGCATATTCTGACTGTTCTGGCACTGGATGATGGCACACCAGCACTTTCTTCATCCCAGACTTTGACAGTTACTGTTCTTGATGTAAATGATGAAGCTCCAGTATTTAAGCAGCACCTGTATGAAGCCTCAGTGAAAGAAAACCAAAATCCAGGGGAGTTTGTTACCAGGGTTGAAGCTCTGGACAGAGATTCAGGTATGAGGCTGAATGGAGATCCAGACAGGGAGCTGTGTGCAGGAGGGAACCCTCTTGGAAGCAGGGCCCCTCCTGGAAGCAGGACCCCTCCTGAAGGTGGGCTAAGTGCCCAAGCCTTTGTTCGTGTGGACCTGGAGGACGTGAATGATAATCATCCTGTGTTTAACCCATCAACCTATGTGACGAGCATCAGTGATGAGACCCAGCCAGGCACCGAGATCATCAATGTTCTTGCCACTGACCAGGACTCTGGGATATATGGGACAGTGGCTTATGAGCTTATTCCAGCAAACGTGTCGTCCCTTTTTACCATTGACTCCACCACAGGAATTATTTACTTAACATTACCTCTTAGTCATTTGGAATCTACCACACTTTCGTTGATGGTCTCTGCTCAAGACGGTGGTGGGCTCACAGCTGTCATTAATGCCGATCTCACCATACACATTTTCCAGACAACTCTGGCACCTGCTGAGTTTGAAAGGCCTAAGTACACTTTCTTAGTTTATGAAGATGTGCCTGAAGATAGTCCCATTGGAACAGTGAAAGCAAGAGAGCCCTTGAATCCACCTAGGAGCTCTGTAATACACCTCCAAGTTAGAGTTTTGGATGCCAATGACCACAGTCCTTCTTTTCCCACACTTTATTACCAGTCCTCTGTGAGAGAAGATGCTGAAGTGGGAACAGTGGTTCTTGTGCTTTCAGCTGTGGACAAGGATGAAGGCCTGAATGGGCAAACTGAGTATTTTCTGACTGATGAGGCTTGTGGTGCATTCACCATTGATCCTATGTCAGGCACATTGAAAACCAGCAACACCCTCGACCGTGAAGCCAGATCTCAGCATACATTTAGTGCTGTGGCCAGAGACTGTAGCATCCAGGGTTCACGAAGCACCACTGTAATTATAAAAGTATATGTCACTGATGTTAATGACAATGATCCAGTTTTGGAACAGAACCCTTTTGATGTGTTTCTTTCCCCCCAGTCGCCTACAAACCAGACAACTGTCATTGTGAGAGCTGATGACCTGGACTTGGGGCCCAATGGAACTGTGGACTCCGATGACTCCCCGCTGCTGGACGACTTCCACGTGCACCCGGACACCGCCATCATCCGCACTGCGCGGCGCCTGGACCGCGAGCGGCGGGACCACTACAGCTTCGTCGCCGCCACGCTGCTGGGCGCTGTGCTGCAGGTGGAGATTCGCGTCAACGACGTGAATGACCACTCCCCCCGCTTTCCCCTCGACTCCCTGCAACTCGACGTCTCCGAGCTCAGCCCGCCAGGGACCCCCTTCCGCCTGCCAGTTGCCCACGATCCGGACGCCGGACTGTTCAGCACTCAGGGCTACACCCTGGTGCAACCGTCCGACCTGCCCAAGGACCCCGCAGGCCCGTTCTTCCAGTTGCGCTACCGGACTCCGCGGCCACTACCGTCACCGCTTTTGCCAGGCTCCTCGTCACCCCTGGAGCCTCTAGATCTGGTGCTGCTGCGGCCCTTGGACCCAGAGGAGGCGGCGCCCCACCGGCTGCAGATCGAGGCATGGGACGGCGGCCGACCCCGGCCCACCGGCCTCCTGAGCGTGGAGCTGCGCGTGCTGGATGAGAACGACAACCCGCCGGTCTTTGAGCACGACGAGTCCCGCGCCGCGGTGCGAGAGCACGCCCAGCCGGGCGCCGAGGTCTGTCGCGTCCCCGCCACCGCCCGCGACGTGGGGCCCAATGGCTTCGTGCGCTACAGCGTCCGCGCCCGGCAAGTGCCTGGGGCGGGTAGCGGCGGCGGGGCACTGGGCGACGCGGCCTACTTCGCGTTGGTGGTGGAGGCCCGCGATGGAGGCGCCGAGCATGAGGTTGCCGCGGTGCGTGTGTCCATCGCCGTGCTGGACGTGAATGACAACCGGCCAGCAATTCACGTGCTCTTTCTCACAGAGGGAGGTGTCGCCCGTGTCTCTGAAGGCGCCCGCCCGGGCGACTACGTGGCTCGCGTCTCGGTGTCTGACGCGGGCGGTGACTGGGAGAAGGAAGATGAGGCCACAGGGGACCTTCCTCTCACAGCCTCTGATGCAGATTCAGGACTCTATGGCTTTATTGAATATTCTCTTTATGATGGATTCCTGAGCTATGAAGCACCTCAGGCATTCCGGATCGACCCTCATGATGGGCAAATCTGTGTTTCTCAACATATCGACAGGGAAAGGGATCCAGCTACCTATGATCTCCTGGTGGAAGCTAAGGATGGGTTTGAAATCATCCCACGTGCTTCATTTGAATTATTCGAGATAAATTCTGACACTGGAGAGGTAGTGACAACCACCATACTTGACAGAGAAATTCAAGAAGTCTTCACCCTTCGAGTACTAGTACGAGATGGGGGATTCCCTTCATTGTCCAGCACCACAACAATCCTCTGCACTCTTGAAGATGAAAACGATCACGCACCAGAGTTTATTGTTTCCAGTTATGACATTGAGGTTCTGGAAAACCAGGAACCAGAGGTTGTCTATACGGTTTTAGCCTCTGATATGGATGCTGGCAATAACAGAGCTGTTGAATATCACATAATTCACTCCTCAGAACCAATCTTTTACAGGATTTCTTCTGGTGATCTCGGCGGAAAGTTCTCCATTCACCCGCGGCTGGGCACTATTCGCACCCGGAAGCGCCTCGATCACGAGACGCAGCCCGTGGTTGTGCTCACGGTGCAGGCGCAGCTCGGCAGCGCCCCAGCCTGCAGCAGCACCGAGGTCAACATAACAGTCATGGATGTCAATGACAACCACCCAGCGTTCCTCAGGACCTCGGATGAGATTAGAATATCCCAGACCACGCCCCCTGGCACAGCCTTGTACCTCGCACGTGCGGAAGACAOAGACAGTGGGCGGAACGGACTCATCCGGTACTCCATCGCCAGCCCGCAGCCAGGCGTCTTTGCCATCGACAGAGCCCTGGGGGTGCTGTTCCTCAACGGCAGCCTGGCCGCGGGCGAGCAGCGGGAGCTCACGCTGACTCTCAGCGCCGAGGACCAAGGCGTGCATCCTCAGGCAGCCCTGCTGGTGCTGACAGTCGTTATCGAGAAACGCGAACACAGCCCATCCTGGACTTTCGAACATTTGGTCTATCAAGTGGAAGTCAGTACTTCTATTGTGACTGTTAAAGCTTTTGCTCCTGACTCAATTCAGCACAGCATGAAATATTCAATTTTTAGTGGAAATGAAGATGGAGTTCTTTCCCTGTGCTCTAAGTCAGGTGTGGTGAACTGCCTTGCTTCTCTCAGTCACACAGACTTTCTCTCCCTGAAATTTGAATCTTCGGTGAAGCGACACCAAGACAGAGACAAATTACAGCCAATTCATCTTGATGACAACAACTCAAAGAAGCTGTGCTTTACATTCCCTAGAGCCACTCAGGCTCTTGTATTCACTGCGCACTGTCTTTCTGATACATCTCTCCCCGGTTGGGTTTTTGCTACCGACTTGGACAGTGGTTTGAACGGCCTGATTGAGTATTCTATTCTGTCTOGCAACCAAGAAGAAGCATTCCAGATTGATGCACTGAGTGGTGTGATAACAACAAAACCGATTCTAGATTACGAGCTCACCAGCTCCTACAGCTTGATTGTCCAAGCCACAGATAAAGGGATGCCCAGGCTTTCTAATACGACTGTAATCAAGGTACAGGTGACTGATATAAATGACAATGCCCCAGCTTTTCTCCCCTCTGAAGCAGTGGAAATTACAGAACTCATGACTATTTCAGAAGATTCTTTGCCTGGTGTAATTGTGACTCATCTGTCAGTTCATGATGTGGATTTGAATTCAGCTTTCATATTCAGTTTTGCCAAAGAGAGTAATCCTGGAACCAAGTTTGCTATTGATCAGAACACTGGAGTGGTGGTGTTGGTGAAAACATTGGATTTTGAAGAAATGACTGAATATGAGCTGCTCATCCAAATTTCTGATTCAGTGCACTACACAGAGGGAGCACTTGTAGTCCGTGTGCTGGATGTCAATGATAATCCACCAGTGTTTTCTCAAGATTTCTATCAGGTCACAGTTCCTGAATCAATACCTGTGGGGTATTCAGTGCTGACTCTGTCAGCCACAGACTTAGAAAGCAATGAGAACATTTCTTACAGAATTCTATCCTCTTCTAAGGAATTCTCCATTGATCCTAAGAATGGCACAATATTTACTATCAGTCCCGTATTACTTCTGGATACAATATCAACAACTCGATTTCTTGTGGAAGCCAGTGATGGTGGAAATCCTGACCCGAGAGCTCTTACTTTAGTGGAGATAGGAATAGAAGATATGAACAATTATCCCCCTGAATTCACAGTCAAATCCTATAATCTTAGCCTAAGTGAGGATGCTCTGGTTGGAAGCACGCTTGTTACATTTTCAAACATCGACCATGACTGGACCCGTGAAAACACATATGTTGAATATTCCATCATCAGTGGTAATTCACAGAACAATTTTCATGTGGAAACTAAGTTCTTTCATTCAGAATATCCTTATAAGCAAGTCGGTTATCTTGTGTTCCTTCACAGTCTGGACAGAGAAGCAAGTGCTAGCCATGAGCTTGTCATTCTGGCATCTGACAGTCGCTGCCCTCCATTGAGTTCCACAGCTGTCATATCAATACAAGTACTTGATGTCAATGACAATCCCCCAAACTTCAGCAGCCTGAGCTATCACACCCATGTCAAGGAAAGCACCCCTCTAGGGAGTCACATCACTGTGGTCTCAGCAAATGACCGTGACACAGGGTCACATGCAGAAATCATCTACAACATCATCTCTGGAAATGAGAAGGGACATTTTTACTTAGAAGAAAACACTGGAGTTCTTTATTTGATTAAACCTCTGGATTATGAAAAAATGACAAAATTCACCTTAACTGTCCAAGCTTCAGATGCAGAAAAGAAACATTTTTCTTTTGCAGTTGTGTTTGTCAGTGTCCTGGATGATAACGACCATGCACCTCAGTTTATGTTCTCAAGCTTCAGCTGTATTGTTCCAGAAAATCTGCCTATTTCCTCTACCATATGCTCTATAAATGCTCTGGATTTTGATGCTGGTCCGTATGGAGAATTGACCTATTCTATTGTATCACCCTGTTTTCTCACTCATGCAATGTCTTATGATCATGATCTCTTCCTCATTGACCCTTTGACAGGGGATATTCATGCTAAGCAAATCCTTGACTATGAAAATGGCAATAAATACTGCCTCACAGTCCAAGCCAAAGACAAACCTGATCCAACTCCCTCCTTACTCCTCTCCCTCCATATTGAAGGGATAGATGAATTTGAGCCCATTTTCACTCAAGATCAGTATTTTTTCACCCTCCCAGAAAAGAATAAAGACAGACAGTTGATTGGCAGAGTGGAAGCCTCAGATGCAGATGCTGGTATTGATGCAGTCATTCTTTACTCCCTTGGAACCTCATCTCCTTTCTTTTCAGTAAATAGAACCAATGGAAATATTTATTTGATTAGAGCCCTTCCCCTAATAAAAAGTCAACTCAACAAAGAAGACACCTTGGAAATGAAAATAATCGCTCATACTCCCAAATCAGATTCCAAGTTTGCATCTTGCACTGTTTTTGTGAATGTGTCTTTCTCCTCTGAAGGAACACCCTTGGCAGTGTTCGCCAGCAGCTTTTCAATCAGCCTGGTGGTCTCCTTTTTAGTGTTTCTCATACTCATCTGCATTCTAATTGTAATGATTTTAAGACATAAACAAAAAGACACAATAAACAATTATGAGGAGAAGAAAACCTCATCTTTAGATGCGGACTTGAGAGTGACCCGGGATGCCAGTGTGCTCAAAGCCTTCCAGAAAACTGACGACTGCAGTAACGAGGTGGTCCCTGTGGATGCCACTCCGGAATGGTTGAGTTTAATAAGTATCATGGAGAAGGATATTGTCAATCTGTACAGATACTCAAACTCCAGTGGCCACTGTTCTGTGGAAGGAGAAACTGCAGAAGATAAGGAAATCCAGAGGATAAATGAGCATCCCTACAGAAAGTGCTCAGACTCAGCTCTGAGTGACCACGAGTCCAGGGTGCCAGACTCGGGTATCCCGAGGCACTCAGACCAGCTCTCCTGCCTATCTGCGGAAACTGATGTGATGGTGACTGCCGAAACAGCAGAACCCAGCCAAACATTTGGGGAAGGAGATCAAGGGGAAGGCTGCAGCACCACCTGTGCTCAAAATAATGTGTTACCCCAGACAGTTCAGAAGAGAGAGGCAAAAGAGAGCATCCTGGCTGACGTTAGAAAAGAGTCTGTCTTTATTTCAGGTGATCAGGAAGTAAGGTGTGCAGCTCTTTCAACTCAGACGACCTCTGATCATGATGGAAAAGACAACTATCACTGGAATTATCTTCTTAGTTGGGAGCCCAAATTCCAACCTCTTGCCTCAGTATTTAATGATATTGCAAAACTAAAGGATGAACATTTGCATATGCCTGGCATTCCAAAAGAGAAGAAATCTTTTGTTTTTCCACCCCCTTTGATAACAGCAGTAGCCCAGCCTGGGATTAAAGCAGTCCCACCAAGAATGCCGGCAGTAAACCTGGGGCAGGTGCCTCCGAAACACCCACGCTCTCCCATCCCCTACCATCTTGGTTCTCTGCCAGAAGGCATGACTCCCAATTTTTCTCCATCTCTTTCCCTATTGACCATGCAGCCTCCTGCCTTGTCTCCACTGTTGAGAGAAGGAGAATTATTAGGAACACACATCAGTGGTACATGCCATGAACTTAAAGCAGAAGATGAAGTTCAAATATGAAACCACTGGGATGCCAAGTACCTGCTCACCATTGGTCATGAATGAATGAACAAAATGTTTTCAAGCCGGCAACTCGAGATTGGGCTCATTTTTATCTAAAAGCAAGTGATGTAATTTAGTTAGAGTTTTTAAAACTTCCCCATTAAAGTTTCTCCAATTTCAAAAAAAAAAAAAAAAAAAAORF Start: ATG at 1ORF Stop: TGA at 10084SEQ ID NO: 1283361 aaMW at 367309.1 kDNOV28c, MEKCGLKEEGSYADIDPVAHDPDAGLFSTQGYTLVQPSDLPKDPAGPFFQLRYRTPGPCG58567-06 ProteinLPSPLLPGSSSPLEPLDLVLLRRLDREEAAAHRLQIEAWDGGRPRRTGLLSVELRVLDSequenceENDNPPVFEQDEYRAAVREDAQPGAEVCRVRATDRDLGPNGFVRYSVRARQVPGACSGGGALGDAAYFAVEELSGVVRVWRPLDREAQAWHQLVVEARDGGAEPEVATVRVSIAVLDVNDNRPAIHVLFLTEGGVARVSEGARPGDYVARVSVSDADGDWEKEDEATGELGVGLGDGSISLSLEGGEGDFALLPGGPPGVFFLCVEGPLDRESRDLYELLLVATDAGSPPLSTEETLLLRVADLNDQPPLFSQQHYKASVSEAAAPGTVVMWVSASDADEAGSDHAWLRYTVVQLSAPCNLGSLQSKMVHTAECGPSFAIDSESGAISTIRTLDPEVQEAVELKVVAQDLGEPPLSATCLVSITVDDVNDNEPIFWRQVYNATIAEHAPVGHCFLQLISAQVASVKIKHKHKEIHEKHNLAYISCPAGTIYVITWADGAAAFSGTDFAFSSDELQAFVLKSLFCELGEGELINWVALDREHRGHHEMTVLVTDRGSPPRNATMAVYVSVTDINDNRPFFPQCLPGKELHVKVLEGQPVNMLVTTVFAKDPDEGNNAEVTYSVSSEDSSDHFKIDANNGEIRTTTILSYDYRPSYRMSVIATDQGVPPLQGQAVVNIQVIPLSKGRAIMSQNIRHLIIPENLKPTKIMSLIKSSDHLQQHYNGKLHFSIVADDKDGHFEIDSSTGDLFLSKELDYETTSHYLFRVITTDHSKNLSLSSTVFLSIDVEDQNDHSPSFQDELIVISVEENVPIGTLVYVFNAKDDDGSFLNSRIQYYIESHNPGTNPFLIHPSFGTLVTVSRLDRESIPTVILTVTASDQAVNVTDRRLRSLTAQIVILDVNDHNPTFISFPNAHVKEDVTVGSLVHHITAHDPDEGRNGKVTYSILSGNENMTFMLDESSGLLTTTCPLDYEMKTQHILTVLALDDGTPALSSSQTLTVTVLDVNDEAPVFKQHLYEASVKENQNPGEFVTRVEALDRDSGMRLNGDPDRELCAGGNPLGSRAPPGSRTPPEGGLSAQAFVRVDLEDVNDNHPVFNPSTYVTSISDETQPGTEIINVLATDQDSGIYGTVAYELIPGNVSSLFTIDSTTGIIYLTLPLSHLESTTLSLMVSAQDGGGLTAVINADVTIHIFQTTLAPAEFERPKYTFLVYEDVPEDSPIGTVKAREPLNPPRSSVIHLQVRVLDANDHSPSFPTLYYQSSVREDAEVGTVVLVLSAVDKDEGLNGQTEYFLTDEACGAFTIDPMSGTLKTSNTLDREARSQHTFSAVARDCSIQGSRSTTVIIKVYVTDVNDNDPVLEQNPEDVELSPESPTNQTTVIVRADDLDLGPNGTVDSDDSPLLDDFHVHPDTGIIRTARRLDRERRDHYSFVAATLLGAVVQVEIRVNDVNDHSPRFPLDSLQLDVSELSPPGTAFRLPVAHDPDAGLFSTQGYTLVQPSDLPKDPAGPFFQLRYRTPGPLPSPLLPGSSSPLEPLDLVLLRRLDREEAAAHRLQIEAWDGGRPRRTGLLSVELRVLDENDNPPVFEQDESRAAVREHAQPGAEVCRVRATARDVGPNGFVRYSVRARQVPGAGSGGGALGDAAYFALVVEARDGGAEHEVAAVRVSIAVLDVNDNRPAIHVLFLTEGGVARVSEGARPGDYVARVSVSDAGGDWEKEDEATGELGVTASDADSGLYGFIEYSLYDGFLSYEAPQAFRIDPHDGQICVSQDIDRERDPATYDLLVEAKDGFEIMPGASFELFEINSDTGEVVTTTILDREIQEVFTLRVLVRDGGFPSLSSTTTILCTVEDENDHAPEFIVSSYDIEVLENQEPEVVYTVLASDMDAGNNRAVEYHIIDSSEPIFYRISSGDLGGKFSIHPRLGTIRTRKPLDHETQPVVVLTVQAQLGSAPACSSTEVNITVMDVNDNHPAFLRTSDEIRISQTTPPGTALYLARAEDRDSGRNGLIRYSIASPQPGVFAIDRALGVLFLNGSLGAGEQRELTLTLRAEDQGVHPQAALLVLTVVIEKREHSPSWTFEHLVYQVEVSTSIVTVKAFAPDSIQDSMKYSIFSGNEDGVLSLCSKSGVVNCLASLSHTDFLSLKFESSVKGHQDRDKLQPIHLDDNNSKKLCFTFPRATQALVFTGHCLSDTSLPGWVFATDLDSGLNGLIEYSILSGNQEEAFQIDALSGVITTKAILDYELTSSYSLIVQATDKGMPRLSNTTVIKVQVTDINDNAPAFLPSEAVEITEVMTISEDSLPGVIVTHVSVHDVDLNSAFIFSFAKESNPGTKFAIDQNTGVVVLVKTLDFEEMTEYELLIQISDSVHYTEGALVVRVLDVNDNPPVFSQDFYQVTVPESIPVGYSVLTLSATDLESNENISYRILSSSKEFSIDPKNGTIFTISPVLLLDTISTTRFLVEASDGGNPDPRALTLVEIGIEDMNNYAPEFTVKSYNLSLSEDALVGSTLVTFSNIDHDWTRENTYVEYSIISGNSQNNFHVETKFFHSEYPYKQVGYLVLLHSLDREASASHELVILASDSGCPPLSSTAVISIQVLDVNDNPPNFSSLSYHTHVKESTPLGSHITVVSANDRDTGSHAEIIYNIISGNEKGHFYLEENTGVLYLIKPLDYEKMTKFTLTVQASDAEKKHFSFAVVFVSVLDDNDHAPQFMFSSFSCIVPENLPISSTICSINALDFDAGPYGELTYSIVSPCFLTHGMSYDHDLFLIDPLTGDIHAKQILDYENGNKYCLTVQAKDKGDATASLVVNVDIEGIDEFEPIFTQDQYFFTLPEKNKDRQLIGRVEASDADAGIDGVILYSLGTSSPFFSVNRTNGNIYLIRALPLIKSQLNKEDTLEMKIIAHSPKSDSKFASCTVFVNVSFSSEGTPLAVFASSFSISLVVSFLVFLILICILIVMILRHKQKDTINNYEEKKTSSLDADLRVTRDASVLKAFQKTDDCSNEVVPVDATPEWLSLISIMEKDIVNLYRYSNSSGHCSVEGETAEDKEIQRINEHPYRKCSDSALSDHESRVPDSGIPRDSDQLSCLSGETDVMVTAETAEASQTFGEGDQGEGCSTTCAQNNVLPQTVQKREAKESILADVRKESVFISGDQEVRCAALSTQTTSDHDGKDNYHWNYLLSWEPKFQPLASVFNDIAKLKDEHLHMPGIPKEKKSFVFPPPLITAVAQPGIKAVPPRMPAVNLGQVPPKHPRSPIPYHLGSLPEGMTPNFSPSLSLLTMQPPALSPLLREGELLGTHISGTCHELKAEDEVQI


[0464] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 28B.
149TABLE 28BComparison of NOV28a against NOV28b through NOV28c.Identities/NOV28a Residues/SimilaritiesProtein SequenceMatch Residuesfor the Matched RegionNOV28b  1 . . . 10631037/1063 (97%)1941 . . . 30031037/1063 (97%)NOV28c  1 . . . 10631037/1063 (97%)2299 . . . 33611037/1063 (97%)


[0465] Further analysis of the NOV28a protein yielded the following properties shown in Table 28C.
150TABLE 28CProtein Sequence Properties NOV28aPSort:0.8000 probability located in mitochondrial inner membrane;analysis:0.7000 probability-located in plasma membrane;0.3000 probability located in microbody(peroxisome); 0.2000 probability locatedin endoplasmic reticulum (membrane)SignalPNo Known Signal Sequence Indicatedanalysis:


[0466] A search of the NOV28a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 28D.
151TABLE 28DGeneseq Results for NOV28aNOV28aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAU68533Human novel cytokine encoded by 1 . . . 646212/680(31%)2e−76cDNA 790CIP2C_4 #1 - 425 . . . 1072338/680(49%)Homo sapiens, 3014 aa.[WO200175093-A1,11-OCT-2001]AAE08586Human NOV7 protein - Homo sapiens, 1 . . . 646212/680(31%)2e−763028 aa. [WO200161009-A2, 425 . . . 1072338/680(49%)23-AUG-2001]AAU02196Seven-pass transmembrane receptor- 1 . . . 646212/680(31%)2e−76like protein, MEM1 - Homo sapiens, 425 . . . 1072338/680(49%)3014 aa. [WO200144473-A2,21-JUN-2001]AAU07054Human Flamingo protein encoded by 1 . . . 611198/627(31%)1e−732923 aa. [WO20016003-A1,365 . . . 960312/627(49%)23-AUG-2001]AAU07053Human Flamingo polypeptide - Homo 1 . . . 611198/627(31%)1e−73sapiens, 2956 aa. [WO200161003-A1,365 . . . 960312/627(49%)23-AUG-2001]


[0467] In a BLAST search of public sequence databases, the NOV28a protein was found to have homology to the proteins shown in the BLASTP data in Table 28E.
152TABLE 28EPublic BLASTP Results for NOV28aNOV28aIdentitiesProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ9NXU8CDNA FLJ20047 FIS, CLONE 105 . . . 1063959/959(100%)0.0COL00577 - Homo sapiens (Human),  1 . . . 959 959/959(100%)959 aa.Q9NRU0CADHERIN-LIKE PROTEIN VR8 - 189 . . . 582 391/394(99%)0.0Homo sapiens (Human), 398 aa  5 . . . 398 393/394(99%)(fragment).Q96JQ0KIAA1773 PROTEIN - Homo  1 . . . 1036366/1073(34%) e−148sapiens (Human), 3298 aa.2245 . . . 3270543/1073(50%)Q24292DACHSOUS PROTEIN  1 . . . 1037327/1165(28%) e−100PRECURSOR (ADHERIN) -2343 . . . 3471528/1165(45%)Drosophila melanogaster (Fruit fly),3503 aa.Q9Y526DJ439F8.2 (SUPPORTED BY  1 . . . 646 212/680(31%)7e−76 GENSCAN AND GENEWISE) - 425 . . . 1072338/680(49%)Homo sapiens (Human), 1181 aa(fragment).


[0468] PFam analysis indicates that the NOV28a protein contains the domains shown in the Table 28F.
153TABLE 28FDomain Analysis of NOV28aNOV28aIdentities/MatchSimilarities forExpectPfam DomainRegionthe Matched RegionValuecadherin: domain 1 of 6 43 . . . 13026/108 (24%)4.5e−1563/108 (58%)cadherin: domain 2 of 6144 . . . 23236/108 (33%)3.4e−1265/108 (60%)cadherin: domain 3 of 6246 . . . 34835/113 (31%)5.1e−1579/113 (70%)cadherin: domain 4 of 6362 . . . 45234/107 (32%)  4e−2373/107 (68%)cadherin: domain 5 of 6466 . . . 56333/115 (29%)1.3e−1166/115 (57%)cadherin: domain 6 of 6577 . . . 67127/110 (25%)0.1160/110 (55%)



Example 29

[0469] The NOV29 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 29A.
154TABLE 29ANOV29 Sequence AnalysisSEQ ID NO: 129924 bpNOV29a,ATGGGGGAGCAGAACCACTCTCCCGGGAAGGAGCTTCAGCACAGGACGCGAGCAGAGGCG59243-01 DNACTCCAGGAAAGAAAAGCTGGCATTCCCAGGCCTATGCCCTTGGGGCCGTTTCCAACTTSequenceTATGTCTACTTTTCTGACCTTTCCTATCTATAAGGTTGTGTTCCGGCAACAGATCCATGCCATGGCAGTGTCAGAGGCTGTGAGACAGCTTTGGCATGAAGGTCCTCAATACTTCTACCGGGGAATCTACCCTCCTCTTCTCTCCAAGACGTTGCAAGGGACTCTTCTGTTTGGGACTTATGATAGCCTGCTGTGCTTTCTCTCTCCTGTTGGGCCACACACCCTGGGACACCGCTGGGCTGCCGGGCTCATGTCTGGCGTGGTGGAGGCCGTGGCACTCACCCCCTTTGAAAGGGTGCAAAATGTGCTCCAGGATGGTCGCAAGCAAGCTCGCTTCCCCAGCACCTTCAGCATTCTCAAGGAATTCAATTCTTATGGGCTTTGGGGGCGGCTGTCACTGGGCTACTATCGTGGTTTCTGGCCTGTCCTGGCCAGGAACAGCCTGGGGAGTGCTCTATATTTTTCTTTCAAGGACCCCATCCAGGATGGCCTGGCAGAGCAAGGCCTGCCCCACTGGGTTCCTGCCTTGGTGTCTGGTAGTGTCAATGGAACAATCACCTGCCTAGTTCTGTATCCTCTGATTGTGCTGGTTGCTAATATGCAGTCCCATATTGGATGGCAGAACATGCCAAGCCTGTGGCCCTCTGCCCAGGATGTATGGAACACTCGGGGCCGAAAGCTGCTCCTGATCTACCGTGGAGGCTCCCTAGTCATCCTAAGGTCCAGTGTGACATGGGGCCTCACTACGGCAATCCATGACTTCCTGCAGACGAAGTCGCACTCCAGGAAAGAGCTCAAGACTGACTAGORF Start: ATG at 1ORF Stop: TAG at 922SEQ ID NO: 130307 aaMW AT 34480.4 kDNOV29a,MGEQNHSPGKELQHRTRAEAPGKKSWHSQAYALGAVSNFMSTFLTFPIYKVVFRQQIHCG59243-01 ProteinAMAVSEAVRQLWHEGPQYFYRGIYPPLLSKTLQGTLLFGTYDSLLCFLSPVGPHTLGHSequenceRWAAGLMSGVVEAVALSPFERVQNVLQDGRKQARFPSTFSILKEFNSYGLWGRLSLGYYRGFWPVLARNSLGSALYFSFKDPIQDGLAEQCLPHWVPALVSGSVNGTITCLVLYPLIVLVANNQSHIGWQNNPSLWASAQDVWNTRGRKLLLIYRGCSLVILRSSVTWGLTTAIHDFLQRKSHSRKELKTDSEQ ID NO: 131669 bpNOV29b,GGATCCATGGGGGAGCAGAACCACTCTCCCGGGAAGGAGCTTCAGCACAGGACGCGAG188822080 DNACAGAGGCTCCAGGAAAGAAAAGCTGGCATTCCCAGGCCCATGCCCTTGGGGCCGTTTCSequenceCAACTTTATGTCTACTTTTCTGACCTTTCCTATCTATAAGGTTGTGTTCCGGCAACAGATCCATGCCATGGCAGTGTCAGAGGCTGTGAGACAGCTTTGGCATGAAGGTCCTCAATACTTCTACCGGGGAATCTACCCTCCTCTTCTCTCCAAGACGTTGCAAGGGACTCTTCTGTTTGCGACTTATGATAGCCTGCTGTGCTTTCTCTCTCCTGTTGGGCCACACACCCTGGGACACCGCTGGGCTGCCGGGCTCATGTCTGGCGTGGTGGAGGCCGTGGCACTCAGCCCCTTTGAAAGGGTGCAAAATGTGCTCCAGGATGGTCGCAAGCAAGCTCGCTTCCCCAGCACCTTCAGCATTCTCAAGGAATTCAATTCTTATGGGCTTTGGGGGCGGCTGTCACTGGGCTACTATCGTGGTTTCTGGCCTGTCCTGGCCAGGAACAGCCTGGGGAGTGCTCTATATTTTTCTTTCAAGGACCCCATCCAGGATGGCCTGGCAGAGCAAGGCCTGCCCCACTGGGTTCCTGCCTTGGTGTCTGGTAGTCTCGAGORF Start: GGA at 1ORF Stop: at 670SEQ ID NO: 132223 aaMW at 24883.2 kDNOV29b,GSMGEQNHSPGKELQHRTRAEAPGKKSWHSQAHALGAVSNFMSTFLTFPIYKVVFRQQ188822080 ProteinIHAMAVSEAVRQLWHEGPQYFYRGIYPPLLSKTLQGTLLFGTYDSLLCFLSPVGPHTLSequenceCHRWAAGLMSGVVEAVALSPFERVQNVLQDGRKQARFPSTFSILKEFNSYGLWGRLSLGYYRGFWPVLARNSLGSALYFSFKDPIQDGLAEQGLPHWVPALVSGSLESEQ ID NO: 133924 bpNOV29c,ATGGGGGAGCAGAACCACTCTCCCGGGAAGGAGCTTCAGCACAGGACGCCAGCAGAGGCG59243-02 DNACTCCAGGAAAGAAAAGCTGGCATTCCCAGGCCTATGCCCTTGGGGCCGTTTCCAACTTSequenceTATGTCTACTTTTCTGACCTTTCCTATCTATAAGCTTGTGTTCCGGCAACAGATCCATGCCATGGCAGTGTCACAGGCTGTCAGACAGCTTTGGCATGAAGGTCCTCAATACTTCTACCGGGGAATCTACCCTCCTCTTCTCTCCAAGACGTTGCAAGGGACTCTTCTGTTTGGGACTTATGATAGCCTGCTGTGCTTTCTCTCTCCTGTTGGGCCACACACCCTGGGACACCGCTGGGCTCCCGGGCTCATGTCTGGCGTGGTGGAGGCCGTGGCACTCAGCCCCTTTGAAAGGGTGCAAAATGTGCTCCAGGATGGTCGCAAGCAAGCTCGCTTCCCCAGCACCTTCACCATTCTCAAGGAATTCAATTCTTATGGGCTTTGGGGGCGGCTGTCACTGGGCTACTATCGTGGTTTCTGGCCTGTCCTGGCCAGGAACAGCCTGGGCAGTGCTCTATATTTTTCTTTCAAGGACCCCATCCAGGATGGCCTGGCAGAGCAAGGCCTGCCCCACTGGGTTCCTGCCTTGGTGTCTGGTAGTGTCAATGGAACAATCACCTGCCTAGTTCTGTATCCTCTGATTGTGCTGGTTGCTAATATGCAGTCCCATATTGGATGGCAGAACATGCCAAGCCTGTGGGCCTCTGCCCAGGATGTATGGAACACTCGGGGCCGAAAGCTGCTCCTGATCTACCGTGGAGGCTCCCTAGTCATCCTAAGGTCCAGTGTGACATGGGGCCTCACTACGGCAATCCATGACTTCCTGCAGAGGAAGTCGCACTCCAGGAAAGAGCTGAAGACTGACTAGORF Start: ATG at 1ORF Stop: TAG at 922SEQ ID NO: 134307 aaMW at 34480.4 kDNOV29c,MGEQNHSPGKELQHRTRAEAPGKKSWHSQAYALGAVSNFMSTFLTFPIYKVVFRQQIHCG59243-02 ProteinAMAVSEAVRQLWHEGPQYFYRGIYPPLLSKTLQGTLLFGTYDSLLCFLSPVGPHTLGHSequenceRWAAGLMSGVVEAVALSPFERVQNVLQDGRKQARFPSTFSILKEFNSYGLWGRLSLGYYRGFWPVLARNSLGSALYFSFKDPIQDGLAEQGLPHWVPALVSGSVNGTITCLVLYPLIVLVANMQSHIGWQNMPSLWASAQDVWNTRGRKLLLIYRGGSLVILRSSVTWGLTTAIHDFLQRKSHSRKELKTD


[0470] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 29B.
155TABLE 29BComparison of NOV29a against NOV29b through NOV29c.NOV29a Residues/Identities/SimilaritiesProtein SequenceMatch Residuesfor the Matched RegionNOV29b3 . . . 222220/220 (99%) NOV29c1 . . . 307307/307 (100%)1 . . . 307307/307 (100%)


[0471] Further analysis of the NOV29a protein yielded the following properties shown in Table 29C.
156TABLE 29CProtein Sequence Properties NOV29aPSort0.7000 probability located in plasma membrane;analysis:0.6400 probability located in microbody (peroxisome);0.2000 probability located in endoplasmic reticulum(membrane); 0.1000 probability located in mitochondrialinner membraneSignalPNo Known Signal Sequence Indicatedanalysis:


[0472] A search of the NOV29a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 29D.
157TABLE 29DGeneseq Results for NOV29aNOV29aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAM40554Human polypeptide SEQ ID NO 5485 -31 . . . 29493/269(34%)3e−39Homo sapiens, 304 aa.41 . . . 300146/269(53%)[WO200153312-A1, 26-JUL-2001]AAM38768Human polypeptide SEQ ID NO 1913 -31 . . . 29493/269(34%)3e−39Homo sapiens, 297 aa.34 . . . 293146/269(53%)[WO200153312-A1, 26-JUL-2001]AAB60090Human transport protein TPPT-10 -31 . . . 29493/269(34%)3e−39Homo sapiens, 297 aa.34 . . . 293146/269(53%)[WO200078953-A2, 28-DEC-2000]AAY97294Lipid associated protein (LIPAP)31 . . . 29493/269(34%)3e−393735780CD1 - Homo sapiens, 297 aa.34 . . . 293146/269(53%)[WO200049043-A2, 24-AUG-2000]AAG03236Human secreted protein, SEQ ID NO:46 . . . 10626/61(42%)4e−087317 - Homo sapiens, 95 aa.19 . . . 79 38/61(61%)[EP1033401-A2, 06-SEP-2000]


[0473] In a BLAST search of public sequence databases, the NOV29a protein was found to have homology to the proteins shown in the BLASTP data in Table 29E.
158TABLE 29EPublic BLASTP Results for NOV29aNOV29aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ9H1U9BA3J10.3 (CG7943 PROTEIN)31 . . . 294 93/269 (34%)1e−38(UNKNOWN) (PROTEIN FOR34 . . . 293146/269 (53%)MGC: 14836) - Homo sapiens(Human), 297 aa.Q960B8SD08549P -Drosophila melanogaster25 . . . 296 83/275 (30%)2e−31(Fruit fly), 332 aa.51 . . . 319146/275 (52%)Q9VAB1CG7943 PROTEIN - Drosophila25 . . . 296 83/275 (30%)2e−31melanogaster (Fruit fly), 349 aa.68 . . . 336146/275 (52%)O01256T20D3.5 PROTEIN - Caenorhabditis88 . . . 296 71/221 (32%)3e−19elegans, 221 aa. 2 . . . 215103/221 (46%)Q9V3T2CG5254 PROTEIN - Drosophila56 . . . 240 55/195 (28%)5e−11melanogaster (Fruit fly), 306 aa.57 . . . 242 99/195 (50%)


[0474] PFam analysis indicates that the NOV29a protein contains the domains shown in the Table 29F.
159TABLE 29FDomain Analysis of NOV29aNOV29aIdentities/MatchSimilarities forExpectPfam DomainRegionthe Matched RegionValuemito_carr: domain 1 of 3 26 . . . 11219/125 (15%)0.005762/125 (50%)mito_carr: domain 2 of 3113 . . . 20923/130 (18%)5.6e−0770/130 (54%)mito_carr: domain 3 of 3210 . . . 30418/126 (14%)0.03761/126 (48%)



Example 30

[0475] The NOV30 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 30A.
160TABLE 30ANOV30 Sequence AnalysisSEQ ID NO: 1355101 bpNOV3Oa,ATCCTCCTACCTCAGTCTACTGAGTAGCTAGGACTACAGGCATGTGCCACCACACCTGCG59534-01 DNAGCTAGTTTTTATTTTTTGATGAGATGGGATCTTGCTGTGTTGCCCAGACTGGTCTTGASequenceTCTCCTGGGCTCAAGTGATCCTCCTGCCTTCGCCTGCGGCCGCCTGCACTTGCGCTGGGGACTCGCTGGACTGCGGTGGGCGCCGGCTGGCTGCGTTGCCCGGGGACCTCCCCTCCTCGACGCGGAGCCTAAACCTGAGTTACAACAAACTCTCTGACATTGACCCTGCTCGTTTTGAGGACTTGCCGAACCTACAGGAAGTGTACCTCAATAATAATGAGTTGACAGCGGTACCATCCCTGGGCGCTGCTTCATCACATGTCGTCTCTCTCTTTCTGCAGCACAACAAGATTCGCAGCGTGGAGGGGAGCCAGCTGAAGGCCTACCTTTCCTTAGAAGTGTTAGATCTGAGTTTGAACAACATCACGGAAGTGCGGAACACCTGCTTTCCACACGGACCGCCTATAAAGGAGCTGAACCTGGCAGCCAATCGGATTGGCACCCTGGAGTTGGGAGCATTTGATGGTCTGTCACGGTCGCTGCTAACTCTTCGCCTGAGCAAAAACAGGATCACCCAGCTTCCTGTAAGAGCATTCAAGCTACCCAGGCTGACACAACTGGACCTCAATCGGAACAGGATTCGGCTGATAGAGGGCCTCACCTTCCAGGGGCTCAACACCTTGGAGGTGCTGAAGCTTCAGCGAAACAACATCACCAAACTGACAGATGGGGCCTTCTGGGGACTGTCCAAGATGCATGTGCTGCACCTGGAGTACAACAGCCTGGTAGAAGTGAACAGCGGCTCGCTCTACGCCCTCACGGCCCTGCATCAGCTCCACCTCAGCAACAATTCCATCGCTCGCATTCACCGCAAGGGCTGGAGCTTCTGCCAGAAGCTGCATGAGTTGGTCCTGTCCTTCAACAACCTGACACGGCTGGACGAGGAGAGCCTGGCCGAGCTGAGCAGCCTGAGTGTCCTGCGTCTCAGCCACAATTCCATCAGCCACATTGCGGAGGGTGCCTTCAAGGCACTCACCACCCTGCGAGTCTTGGATCTGGACCATAACGAGATTTCGGGCACAATAGAGGACACGAGCGGCGCCTTCTCAGCGCTCGACAGCCTCAGCAAGCTGACTCTGTTTGGAAACAAGATCAAGTCTGTGGCTAAGAGAGCATTCTCGGGGCTGGAAGGCCTGGAGCACCTGAACCTTGGAGGGAATGCGATCAGATCTGTCCAGTTTGATGCCTTTGTGAAGATGAAGAATCTTAAAGAGCTCCATATCAGCAGCGACAGCTTCCTGTGTGACTGCCAGCTGAAGTGGCTGCCCCCGTGGCTAATTGGCAGGATGCTGCAGGCCTTTGTGACAGCCACCTGTGCCCACCCAGAATCACTGAAGGGTCAGAGCATTTTCTCTGTGCCACCAGAGAGTTTCGTGTGCGATGACTTCCTGAAGCCACAGATCATCACCCAGCCAGAAACCACCATGCCTATGGTGGGCAAGGACATCCGGTTTACATGCTCAGCAGCCAGCAGCAGCAGCTCCCCCATGACCTTTGCCTGGAAGAAAGACAATGAAGTCCTGACCAATGCAGACATGGAGAACTTTGTCCACGTCCACCCGCAGGACGGGGAAGTGATGGAGTACACCACCATCCTGCACCTCCGTCAGGTCACTTTCGGGCACGAGGGCCGCTACCAATGTGTCATCACCAACCACTTTGGCTCCACCTATTCACATAAGGCCAGGCTCACCGTGAATGTGTTGCCATCATTCACCAAAACGCCCCACGACATAACCATCCGGACCACCACCATGGCCCGCCTCGAATGTGCTGCCACAGGTCACCCAAACCCTCAGATTGCCTGGCAGAAGGATGGAGGCACGGATTTCCCCGCTGCCCGTGAGCGACGCATGCATGTCATGCCGGATGACGACGTGTTTTTCATCACTGATGTGAAAATAGATGACGCAGGGGTTTACAGCTGTACTGCTCAGAACTCAGCCGGTTCTATTTCAGCTAATGCCACCCTGACTGTCCTAGAGACCCCATCCTTGGTGGTCCCCTTGGAAGACCGTGTCGTATCTGTGGGAGAAACAGTGGCCCTCCAATGCAAAGCCACGGGGAACCCTCCGCCCCGCATCACCTGGTTCAAGGGGGACCGCCCGCTGAGCCTCACTGAGCGGCACCACCTGACCCCTGACAACCAGCTCCTGGTGGTTCAGAACGTGGTGGCAGAGGATGCCGGCCGATATACCTGTGAGATGTCCAACACCCTGGGCACGGAGCGAGCTCACAGCCAGCTGAGCGTCCTGCCCGCAGCAGGCTGCAGGAAGGATGGCACCACGGTAGGCATCTTCACCATTGCTGTCGTGAGCAGCATCGTCCTGACGTCACTGGTCTGCGTGTGCATCATCTACCAGACCAGGAAGAAGAGTGAAGAGTACAGTGTCACCAACACAGATGAAACCGTCGTGCCACCAGATGTTCCAAGCTACCTCTCTTCTCAGGGGACCCTTTCTGACCGACAAGAAACCGTGGTCAGGACCGAGGGTGGCCCTCAGGCCAATGGGCACATTGAGAGCAATGGTGTGTGTCCAAGAGATGCAAGCCACTTTCCAGAGCCCGACACTCACAGCGTTGCCTGCAGGCAGCCAAAGCTCTGTGCTGGGTCTGCGTATCACAAAGAGCCGTGGAAAGCGATGGAGAAAGCTGAACGGACACCTGGGCCACATAAGATGGAACACGGTGGCCGGGTCGTATGCAGTGACTGCAACACCGAAGTGGACTGTTACTCCAGGGGACAAGCCTTCCACCCCCAGCCTCTGTCCAGAGACAGCGCACAGCCAAGTGCGCCAAATGGCCCGGAGCCGGGTGGGAGTGACCAAGAGCATTCTCCACATCACCAGTGCAGCAGGACTGCCGCTGGCTCCTGCCCCGAGTGCCAAGGGTCGCTCTACCCCAGTAACCACGATAGAATGCTGACGGCTGTGAAGAAAAAGCCAATGGCATCTCTAGATGGGAAAGGGGATTCTTCCTGGACTTTAGCAAGGTTGTATCACCCGGACTCCACAGAGCTACAGCCTGCATCTTCATTAACTTCAGGCAGTCCAGAGCGCGCGGAAGCCCAGTACTTGCTTGTTTCCAATGGCCACCTCCCCAAAGCATGTGACGCCAGTCCCGAGTCCACGCCACTGACAGGACAGCTCCCCGGGAAACAGAGGGTGCCACTGCTGTTGGCACCAAAAAGCTAGGTTTTGTCTACCTCAGTTCTTGTCATACCAATCTCTACGGGAAAGAGAGGTAGGAGAGGCTGCGAGGAAGCTTGGGTTCAAGCGTCACTCATCTGTACATAGTTGTAACTCCCATGTGGAGTATCAGTCGCTCACAGGACTTGGATCTGAAGCACAGTAAACGCAAGAGGGGATTTGTGTACAAAAGGCAAAAAAAAGTATTTGATATCATTGTACATAAGAGTTTTCAGAGATTTCATATATATCTTTTACAGAGGCTATTTTAATCTTTAGTGCATGGTTAACAGAAAAAAATTATACAATTTTGACAATATTATTTTTCGTATCAGGTTGCTGTTTAATTTTGGAGGGGGTGGGGAAATAGTTCTGGTGCCTTAACGCATGGCTGGAATTTATAGAGGCTACAACCACATTTGTTCACAGGAGTTTTTGGTGCGGGGTGGGAAGGATGGAAGGCCTTGGATTTATATTGCACTTCATAGACCCCTAGGCTGCTGTGCGGTGGGACTCCACATGCGCCGGAAGGAGCTTCAGGTGAGCACTGCTCATGTGTGGATGCCCCTGCAACAGGCTTCCCTGTCTGTAGAGCCAGGGGTGCAAGTGCCATCCACACTTGCAGTGAATGGCTTTTCCTTTTAGGTTTAAGTCCTGTCTGTCTGTAAGGCGTAGAATCTGTCCGTCTGTAAGGCGTAGAATGAGGGTTGTTAATCCATCACAAGCAAAAGGTCAGAACAGTTAAACACTGCCTTTCCTCCTCCTCTTATTTTATGATAAAAGCAAATGTGGCCTTCTCAGTATCATTCGATTGCTATTTGAGACTTTTAAATTAAGGTAAAGGCTGCTGGTGTTGGTACCTGTGGATTTTTCTATACTGATGTTTTCGTTTTGCCAATATAATGAGTATTACATTGGCCTTGGGGGACAGAAAGGAGGAAGTTCTGACTTTTCAGGGCTACCTTATTTCTACTAAGGACCCAGAGCAGGCCTGTCCATGCCATTCCTTCGCACAGATGAAACTGAGCTCCCACTCGAAAGGACAGCCCTTGACCTGGGTTCTGGGTATAATTTGCACTTTTGAGACTGGTAGCTAACCATCTTATGAGTGCCAATGTGTCATTTAGTAAAACTTAAATAGAAACAAGGTCCTTCAAATGTTCCTTTGGCCAAAAGCTGAAGGGAGTTACTGAGAAAATAGTTAACAATTACTGTCAGGTGTCATCACTGTTCAAAAGGTAAGCACATTTAGAATTTTGTTCTTGACAGTTAACTGACTAATCTTACTTCCACAAAATATGTGAATTTGCTGCTTCTGAGAGGCAATGTGAAAGAGGGAGTATTACTTTTATGTACAAAGTTATTTATTTATAGAAATTTTGGTACAGTGTACATTGAAAACCATGTAAAATATTGAAGTGTCTAACAAATGGCATTGAAGTGTCTTTAATAAAGGTTCATTTATAAATGTCAGTATAGTTGGTGGTCCTTCTTTTACAAACGCAGTCATTCTGCCTTTAATTATCTTCCCCCAAAAAAGAAAAAAAAAATAGGCGAAGCAAAATCACATACTGTTTGTTTGCTCCAGGGCAGACAACACTGCTAGATTCCTCACATTTTGTTTTGAATTTTTCTACACCTGGAGCTTGTTAGTCAAGGTCTAAAATCCCTAAGTGTGGTGACCTTTCCATTTCATCCTGCCTTTTCAAAGCTGGCCCAGGCCCTCCTTTCAGTCTGACATGAGAATGGCGAGAATGGCTCACCCACCGTGCCCTCCTGCACGAAGCCAGCTGGGCCORF Start: ATG at 77ORF Stop: TAG at 3308SEQ ID NO: 1361077 aaMW at 117735.2 kDNOV3Oa,MRWDLAVLPRLVLISWAQVILLPWPAAACTCAGDSLDCGGRGLAALPCDLPSWTRSLNCG59534-01 ProteinLSYNKLSEIDPAGFEDLPNLQEVYLNNNELTAVPSLGAASSHVVSLFLQHNKIRSVEGSequenceSQLKAYLSLEVLDLSLNNITEVRNTCFPHGPPIKELNLAGNRIGTLELGAFDGLSRSLLTLRLSKNRITQLPVRAFKLPRLTQLDLNRNRIRLIEGLTFQGLNSLEVLKLQRNNISKLTDGAFWGLSKMHVLHLEYNSLVEVNSGSLYGLTALHQLHLSNNSIARIHRKGWSFCQKLHELVLSFNNLTRLDEESLAELSSLSVLRLSHNSISHIAEGAFKGLRSLRVLDLDHNEISGTIEDTSGAFSGLDSLSKLTLFGNKIKSVAKRAFSGLEGLEHLNLGGNAIRSVQFDAFVKMKNLKELHISSDSFLCDCQLKWLPPWLIGRMLQAFVTATCAHPESLKGQSIFSVPPESFVCDDFLKPQIITQPETTMAMVGKDIRFTCSAASSSSSPMTFAWKKDNEVLTNADMENFVHVHAQDGEVMEYTTILHLRQVTFGHEGRYQCVITNHFGSTYSHKARLTVNVLPSFTKTPHDITIRTTTMARLECAATGHPNPQIAWQKDGGTDFPPARERRMHVMPDDDVFFITDVKIDDACVYSCTAQNSAGSISANATLTVLETPSLVVPLEDRVVSVGETVALQCKATGNPPPRITWFKGDRPLSLTERHHLTPDNQLLVVQNVVAEDAGRYTCEMSNTLGTERHSQLSVLPAAGCRKDGTTVGIFTIAVXJSSIVLTSLVWVCIIYQTRKKSEEYSVTNTDETVVPPDVPSYLSSQGTLSDRQETVVRTEGGPQANGHIESNGVCPRDASHFPEPDTHSVACRQPKLCAGSAYHKEPWKAMEKAEGTPGPHKMEHGGRVVCSDCNTEVDCYSRGQAFHPQPVSRDSAQPSAPNGPEPGGSDQEHSPHHQCSRTAAGSCPECQGSLYPSNHDRMLTAVKKKPMASLDGKGDSSWTLARLYHPDSTELQPASSLTSGSPERAEAQYLLVSNGHLPKACDASPESTPLTGQLPGKQRVPLLLAPKS


[0476] Further analysis of the NOV30a protein yielded the following properties shown in Table 30B.
161TABLE 30BProtein Sequence Properties NOV30aPSort0.4600 probability located in plasma membrane; 0.1000analysis:probability located in endoplasmic reticulum (membrane);0.1000 probability located in endoplasmic reticulum (lumen);0.1000 probability located in outsideSignalPCleavage site between residues 29 and 30analysis:


[0477] A search of the NOV30a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 30C.
162TABLE 30CGeneseq Results for NOV30aNOV30aResidues/Identities/GeneseqProtein/Organism/Length [Patent #,MatchSimilarities for theExpectIdentifierDate]ResiduesMatched RegionValueAAY08008Human HLIG-1 protein - Homo sapiens,29 . . . 10771030/1050 (98%)0.01101 aa. [EP913472-A2,52 . . . 11011040/1050 (98%)06-MAY-1999]AAY97833Murine LIG-1 protein - Mus sp, 1091 9 . . . 1077 890/1088 (81%)0.0aa. [JP2000093043-A, 04-APR-2000]16 . . . 1091 950/1088 (86%)AAY08010Mouse LIG-1 protein - Mus sp, 1091 9 . . . 1077 890/1088 (81%)0.0aa. [EP913472-A2, 06-MAY-1999]16 . . . 1091 950/1088 (86%)AAY08099Murine glial cell membrane 9 . . . 1077 890/1088 (81%)0.0glycoprotein LIG-1 - Mus sp, 109116 . . . 1091 950/1088 (86%)aa. [WO9914241-A2, 25-MAR-1999]AAW41641Sequence used in detection method -  9 . . . 1077 890/1088 (81%)0.0Mus sp, 1091 aa. [JP09107971-A,16 . . . 1091 950/1088 (86%)28-APR-1997]


[0478] In a BLAST search of public sequence databases, the NOV30a protein was found to have homology to the proteins shown in the BLASTP data in Table 30D.
163TABLE 30DPublic BLASTP Results for NOV30aNOV30aProteinResidues/Identities/AccessionMatchSimilarities for theExpectNumberProtein/Organism/LengthResiduesMatched PortionValueQ96JA1MEMBRANE GLYCOPROTEIN 26 . . . 10771051/1052 (99%)0.0LIG-1 - Homo sapiens (Human), 42 . . . 10931052/1052 (99%)1093 aa.Q9BYB8MEMBRANE GLYCOPROTEIN 26 . . . 10771051/1053 (99%)0.0LIG-1 - Homo sapiens (Human), 42 . . . 10941052/1053 (99%)1094 aa.P70193MEMBRANE GLYCOPROTEIN -  9 . . . 1077 890/1088 (81%)0.0Mus musculus (Mouse), 1091 aa. 16 . . . 1091 950/1088 (86%)Q9UFI4HYPOTHETICAL 51.9 KDA 595 . . . 1077 480/483 (99%)0.0PROTEIN - Homo sapiens 1 . . . 483  481/483 (99%)(Human), 483 aa (fragment).O94898KIAA0806 PROTEIN - Homo 7 . . . 1002 507/1026 (49%)0.0sapiens (Human), 1065 aa. 20 . . . 991  648/1026 (62%)


[0479] PFam analysis indicates that the NOV30a protein contains the domains shown in the Table 30E.
164TABLE 30EDomain Analysis of NOV30aIdentities/SimilaritiesNOV30a Matchfor the MatchedExpectPfam DomainRegionRegionValueLRRNT: domain 1 of 126 . . . 5114/31 (45%)0.3419/31 (61%)LRR: domain 1 of 1553 . . . 7610/25 (40%)0.8819/25 (76%)LRR: domain 2 of 1577 . . . 98 9/25 (36%)0.7117/25 (68%)LRR: domain 3 of 15100 . . . 120 5/25 (20%)1.1e+0217/25 (68%)LRR: domain 4 of 15124 . . . 14710/25 (40%)4.418/25 (72%)LRR: domain 5 of 15148 . . . 171 7/25 (28%)3.918/25 (72%)LRR: domain 6 of 15173 . . . 19510/25 (40%)0.2218/25 (72%)LRR: domain 7 of 15196 . . . 219 7/25 (28%)0.619/25 (76%)LRR: domain 8 of 15220 . . . 24321/25 (84%)0.0044LRR: domain 9 of 15244 . . . 267 6/25 (24%)1.818/25 (72%)LRR: domain 10 of 15268 . . . 291 6/25 (24%)3414/25 (56%)LRR: domain 11 of 15292 . . . 31512/25 (48%)0.0119/25 (76%)LRR: domain 12 of 15316 . . . 339 8/25 (32%)0.0003721/25 (84%)IGPD: domain 1 of 1329 . . . 34210/15 (67%)1.112/15 (80%)LRR: domain 13 of 15340 . . . 363 8/25 (32%)0.120/25 (80%)LRR: domain 14 of 15367 . . . 390 7/25 (28%)2.516/25 (64%)LRR: domain 15 of 15391 . . . 414 7/25 (28%)0.4918/25 (72%)LRRCT: domain 1 of 1424 . . . 47422/54 (41%)2.1e−1343/54 (80%)ig: domain 1 of 3493 . . . 56312/72 (17%)1.4e−0649/72 (68%)ig: domain 2 of 3597 . . . 65813/65 (20%)1.3e−0746/65 (71%)ig: domain 3 of 3691 . . . 74918/62 (29%)2.9e−1147/62 (76%)Adeno_E3_CR1:687 . . . 76423/89 (26%)1.3domain 1 of 145/89 (51%)



Example 31

[0480] The NOV31 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 31A.
165TABLE 31ANOV31 Sequence AnalysisSEQ ID NO:1374200 bpNOV31a,TAACGAGGTCTAATTTAATTCTCCCAACACCCTATGAAGTCAGCTCTGATACCCCTAGCG59289-01 DNATTTACAGAGGAGCTAAACGAGGCCCAGAGATGGCCAGTCCCAGAGCCAGGAAGCCCCASequenceGAGCCAGTGCTGGGATTTCACAGTACACTGTGCTACTTCCCTAGGCAAAGTCACGTCTCTTCTCTGTCTCTACAAAACGAGGACAGACTGGCTTACTCCGAGCGCTGGTATAAGGATTGGAAGAGAATGCAGTGAGCGGTTCCCCACCCCAGGAGGTAACTCCCTGGAACTGTGCTCTGAGCCCAAACTCTCAAGGGTTGGTCAGTGCCAGGCACAGGGTAGGTGCTCCGTCCCTGACAGCTATTGTTGCAATCGAGGTAACTCCCTGGAACTGTGCTCTGAGCCCPAACTCTCAAGGGTTCGTCAGTGCCACCCACAGGGGACGCTGCCTTCAGAGCCCCCCAGTGCCTGTGCCTCAGACCCGTGCGCTCCAGGGACCGAGTGCCAGGCTACCGAGAGTGGTGGCTATACCTGTGGGCCCATGGAGCCCCGGGGCTGTGCCACCCAGCCATGCCACCACGGCGCTCTGTGTGTGCCCCAGGGTCCAGATCCCACCGGCTTCCGCTGCTACTCCGTGCCGGGTTTCCAGGGCCCACGCTGCGAGCTGGACATCGATGAGTGTGCATCCCGGCCGTGCCACCATGGGGCCACCTGCCGCAACCTGGCCGATCGCTACGAGTGCCATTGCCCCCTTGGCTATGCAGGCGTGACCTGCGAGATGGAGGTGGACGAGTGCGCCTCAGCGCCCTGCCTOCACCGGGGCTCGTGCCTGGACGGCGTGGGCTCCTTCCGCTCTGTGTGCGCGCCAGGCTACGGGGGCACCCGTTGCCAGCTGGACCTCGACGAGTGCCAGAGCCAGCCGTGCGCACATGGGGGCACGTGCCACGACCTCGTCAACGGGTTCCGGTGCGACTGCGCGGGCACCGGCTACGAGGGCACGCACTGCGAGCGGGAGGTGCTGGAGTGCCCATCGGCGCCCTGCGAGCACAACGCGTCCTGCCTCGAGGGCCTCGGGAGCTTCCGCTGCCTCTGTTGGCCAGGCTACAGCGGCCAGCTGTGCGAGGTGGACGAGGACGAGTGTGCATCGAGCCCCTGCCAGCATGGGGGCCGATGCCTGCAGCGCTCTGACCCGGCCCTCTACGGGGGTGTCCAGGCCGCCTTCCCTGGCGCCTTCAGCTTCCGCCATGCTGCGGGTTTCCTGTGCCACTGCCCTCCTGGCTTTGAGGGAGCCGACTGCGGTGTGGAGGTGGACGAGTGTGCCTCACGGCCATGCCTCAACCCAGGCCACTGCCAGGACCTGCCCAATGGCTTCCAGTGTCACTGCCCAGATGGCTACGCAGGGCCGACATGTGAGGAAGATGTGGATGAATGCCTGTCGGATCCCTGCCTGCACGGCGGAACCTGCAGTGACACTGTGGCAGGCTATATCTGCAGGTGCCCAGAGACCTGGGGTGGGCGCGACTGTTCTGTGCAGCTCACTGGCTGCCAGGGCCACACCTGCCCGCTGGCTGCCACCTGCATCCCTATCTTCGAGTCTGGGGTCCACAGTTACGTCTGCCACTGCCCACCTGGTACCCATGGACCGTTCTGTGGCCAGAATACCACCTTCTCTGTGATGGCTGCGAGCCCCATTCAGGCATCAGTGCCAGCTGGTGGCCCCCTGGGTCTGGCACTGAGGTTTCGCACCACACTGCCCGCTGGGACCTTGGCCACTCGCAATGACACCAAGGAAAGCTTGGAGCTGGCATTGGTGGCAGCCACACTTCAGGCCACACTCTGGAGCTACAGCACCACTGTGCTTGTCCTGAGACTGCCGGACCTGGCCCTAAACCATGGCCATTCGCACCAGGTGGAGGTTGTGCTCCATCTAGCGACCCTGGAGCTACGGCTCTGGCATGAGGGCTGCCCTGCCCGGCTCTGTGTGGCCTCTGGTCCTGTCGCCCTGCCTTCCACGGCTTCGGCAACTCCGCTGCCTGCCGGCATCTCCTCTGCCCAGCTGGGGGACGCGACCTTTGCAGGCTGCCTCCAGGACGTGCGTGTGGATGGCCACCTCCTGCTGCCTGAGGATCTCGGTGAGAACGTCCTCCTGGGCTGTGAGCGCCGAGAGCAGTGCCGGCCTCTGCCTTGTGTCCACGGAGGGTCCTGTGTGGATCTGTGGACTCATTTCCGTTGCGACTGTGCCCGGCCCCATAGAGGTCCCACGTGCGCTGATGAGATTCCTGCTGCCACCTTTGGCTTGGGAGGCGCCCCAAGCTCTGCCTCCTTTCTGCTCCAAGAGCTGCCAGGTCCCAACCTCACACTGTCTTTCCTTCTCCCCACTCGGGAGTCCGCTGGCCTGTTGCTCCAGTTTGCCAATGACTCCGCAGCTGGCCTAACAGTATTCCTGAGTGAGGGTCGGATCCGGGCTGAGGTGCCGGGCAGTCCTCCTGTAGTGCTCCCTGGGCGCTGGGATGATGGGCTCCGTCACCTGGTGATGCTCAGCTTCGGCCCTGACCAGCTGCAGGACCTGGGGCAGCACGTGCACGTGGGTGGGAGGCTCCTTGCTGCCGACAGCCAGCCCTGGGGTGGGCCCTTCCGAGGCTGCCTCCAGGACCTGCGACTCGATGGCTGCCACCTCCCCTTCTTTCCTCTGCCACTGGATAACTCAAGCCAGCCCAGCGAGCTCGGCGGCAGGCAGTCCTGGAACCTCACTGCCGGCTGCGTCTCCGAGGACATGTGCAGTCCTGACCCCTGTTTCAATGGTGGGACTTGCCTCGTCACCTGGAATGACTTCCACTGTACCTGCCCTGCCAATTTCACGGGGCCTACGTGTGCCCACCAGCTGTCGTGTCCCGGCCACCCCTGTCTCCCACCTGCCACGTGTGAGGAGGTCCCTGATGCCTTTGTGTGTGTGGCGGAGGCCACGTTCCGCGAGGGTCCCCCCGCCGCGTTCAGCGGGCACAACGCGTCGTCAGGGCGCTTGCTCGGCGGCCTGTCGCTGGCCTTTCGCACGCGCGACTCCGAGGCCTGGCTGCTGCGTGCCGCGGCGGGCGCCCTGGAAGGCGTGTGGCTGGCGGTGCGCAATGGCTCGCTGGCGGGGGGCGTGCGCGGAGGCCATGGCCTCCCCGGCGCTGTGCTGCCCATACCCGGCCCGCGCGTGGCCGATGGTGCCTGGCACCGCGTGCGTCTCGCCATGGAGCGCCCGGCCGCCACCACCTCGCGCTGGCTGCTGTGGCTGGATGGTGCCGCCACCCCGGTGGCGCTGCGCGGCCTGGCCAGTCACCTGGGCTTCCTGCAGGGCCCGGGTGCTGTGCGCATCCTGCTGGCTGAGAACTTCACCGGCTGCTTGGGCCGCGTGGCGCTGGGCGGCCTGCCCCTGCCCTTGGCGCGGCCCCGGCCCGGCGCGGCCCCTGGCGCCCGAGAGCACTTCGCGTCTTGGCCTGGGACGCCGGCCCCGATCCTCGGCTGCCGCGCCCCGCCCGTGTGTGCGCCCTCGCCCTGTCTGCACGACGGTGCCTGCCGTGACCTCTTCGACGCCTTTGCCTGCGCCTGCGGCCCCGGGTGGGAAGGCCCGCGCTGCGAAGCCCACGTCGACCCCTGTCACTCCGCCCCCTGCGCCCGTGGCCGCTGTCACACGCACCCCGACGGCCGCTTCGAGTGCCGCTGCCCGCCTGGCTTCGGGGGCCCGCGCTGCAGGTTGCCTGTCCCATCCAAGGAGTGCAGCCTGAATGTCACCTGCCTCGATGGCAGCCCATGTGAGCGTGGCTCTCCCGCTGCCAACTGCAGCTGCCTGGAGGGTCTTGCTGGCCAGAGGTGTCAGGTCCCCACTCTCCCCTGTGAAGCCAACCCCTGCTTGAATGGGGGCACCTGCCGGGCAGCTGGAGGGGTGTCTGAATGTATCTGCAATGCCAGATTCTCCGGCCAGTTCTGTGAAGTGGCGAAGGGCCTGCCCCTGCCGCTGCCATTCCCACTGCTGGAGGTGGCCGTACCTGCAGCCTGTGCCTGCCTCCTCCTCCTCCTCCTGGGCCTCCTTTCAGGGATCCTGGCAGCCCGAAAGCGCCGCCAGTCTGAGGGCACCTACAGCCCAAGCCAGCAGGAGGTGGCTGGGGCCCGGCTGGAGATCGACAGTGTCCTCAAGGTGCCACCGGAGGAGAGACTCATCTAGORF Start: TTC at 19ORF Stop: GAG at 4183SEQ ID NO:1381388 aa MW at 145607.6 kDNOV31a.MKSALIPLVYRGGKRGPEMASPRARKPQSQCWDFTVHCATCLGKVTSLLCLYKTRTDWCG59289-01 ProteinLTPSAGIRIGRECSERFPTPGGNSLELCSEPKLSRVGQCQAQGRCSVPDSYCCNXGNSSequenceLELCSEPKLSRVGQCQAQGTVPSEPPSACASDPCAPGTECQATESGGYTCGPMEPRGCATQPCHHGALCVPQGPDPTGFRCYCVPGFQGPRCELDIDECASRPCHHGATCRNLADRYECHCPLGYAGVTCEMEVDECASAPCLHGGSCLDGVGSFRCVCAPGYGGTRCQLDLDECQSQPCAHGGTCHDLVNGFRCDCAGTGYEGTHCEREVLECASAPCEHNASCLEGLGSFRCLCWPGYSGELCEVDEDECASSPCQHGGRCLQRSDPALYGGVQAAFPGAFSFRHAAGFLCHCPPGFEGADCGVEVDECASRPCLNGGHCQDLPNGFQCHCPDGYAGPTCEEDVDECLSDPCLHGGTCSDTVAGYICRCPETwGGRDCSVQLTGCQGHTCPLAATCIPIFESGVHSYVCHCPPGTHCPFCGQNTTFSVMAGSPIQASVPAGGPLGLALRFRTTLPAGTLATRNDTKESLELALVAATLQATLWSYSTTVLVLRLPDLALNDGHWHQVEVVLHLATLELRLWHEGCPARLCVASGPVALASTASATPLPAGISSAQLGDATFAGCLQDVRVDGHLLLPEDLGENVLLGCERREQCRPLPCVHGGSCVDLWTHFRCDCARPHRGPTCADEIPAATFGLGGAPSSASFLLQELPGPNLTVSFLLRTRESAGLLLQFANDSAAGLTVFLSEGRIRAEVPGSPAVVLPGRWDDGLRHLVMLSFGPDQLQDLGQHVHVGGRLLAADSQPWGGPFRGCLQDLRLDGCHLPFFPLPLDNSSQPSELGGRQSWNLTAGCVSEDMCSPDPCFNGGTCLVTWNDFHCTCPANFTGPTCAQQLWCPGQPCLPPATCEEVPDGFVCVAEATFREGPPAAFSGHNASSGRLLGGLSLAFRTRDSEAWLLRAAAGALEGVWLAVRNGSLAGGVRGGHGLPGAVLPIPGPRVADGAWHRVRLANERPAATTSRWLLWLDGAATPVALRGLASDLGFLQGPGAVRILLAENFTGCLGRVALGGLPLPLARPRPGAAPGAREHFASWPGTPAPILGCRGAPVCAPSPCLHDGACRDLFDAFACACGPGWEGPRCEAHVDPCHSAPCARGRCHTHPDGRFECRCPPGFGGPRCRLPVPSKECSLNVTCLDGSPCEGGSPAANCSCLEGLAGQRCQVPTLPCEANPCLNGGTCRAAGGVSECICNARFSGQFCEVAKGLPLPLPFPLLEVAVPAACACLLLLLLCLLSGILAARKRRQSEGTYSPSQQEVAGARLEMDSVLKVPPEERLISEQ ID NO:1394200 bpNOV31b,TAACGAGGTCTAATTTAATTCTCCCAACAGCCTATGAAGTCAGCTCTGATACCCCTAGCG59289-02 DNATTTACAGAGGAGGTAAACGAGGCCCAGAGATGGCCAGTCCCAGAGCCAGGAAGCCCCASequenceGAGCCAGTGCTCGGATTTCACAGTACACTGTGCTACTTGCCTAGGCAAAGTCACGTCTCTTCTCTGTCTCTACAAAACGAGGACAGACTGGCTTACTCCGAGCGCTGGTATAAGGATTGGAAGAGAATGCAGTGAGCGGTTCCCCACCCCAGGAGGTAACTCCCTGGAACTGTGCTCTGAGCCCAAACTCTCAAGCGTTGGTCAGTGCCAGGCACAGGGTAGGTGCTCCGTCCCTGACAGCTATTGTTGCAATCGAOCTAACTCCCTGGAACTGTGCTCTGAGCCCAAACTCTCAAGGGTTGGTCAGTGCCAGGCACAGCGGACGGTGCCTTCAGAGCCCCCCACTGCCTGTGCCTCAGACCCGTGCGCTCCAGGGACCGAGTGCCAGGCTACCGAGAGTGGTGGCTATACCTGTCCGCCCATGGAGCCCCGGGGCTGTGCCACCCAGCCATGCCACCACGGCGCTCTGTGTGTGCCCCAGGGTCCAGATCCCACCGGCTTCCGCTGCTACTGCGTGCCGGGTTTCCAGGGCCCACGCTGCGAGCTGGACATCGATGAGTGTGCATCCCGGCCGTGCCACCATGGGGCCACCTGCCGCAACCTGGCCGATCGCTACGAGTGCCATCGCCCCCTTGGCTATGCAGGCGTGACCTGCGAGACGGAGGTGGACGAGTGCGCCTCAGCGCCCTGCCTGCACGGGGCCTCGTGCCTGGACGGCGTGGGCTCCTTCCGCTGTGTGTGCGCGCCAGGCTACGGGGGCACCCGTTGCCAGCTCGACCTCGACCAGTGCCAGAGCCAGCCGTGCGCACATGGGGGCACGTGCCACGACCTGGTCAACGGGTTCCCCTGCGACTGCGCGGGCACCGGCTACGAGGGCACGCACTGCGAGCGGGAGGTGCTGGAGTGCGCATCGGCGCCCTGCGAGCACAACGCGTCCTGCCTCGAGGGCCTCGGGAGCTTCCGCTGCCTCTGTTGGCCAGGCTACAGCGGCGAGCTGTGCGAGGTGCACGAGGACGAGTGTGCATCGAGCCCCTGCCAGCATGGGGGCCGATGCCTGCAGCGCTCTGACCCGGCCCTCTACGGGGGTGTCCAGGCCGCCTTCCCTCGCGCCTTCAGCTTCCGCCATGCTGCGGGTTTCCTGTGCCACTGCCCTCCTGGCTTTGAGGGAGCCGACTGCGGTGTGGAGGTGGACGAGTGTGCCTCACGGCCATGCCTCAACGGAGGCCACTGCCAGGACCTGCCCAATGGCTTCCAGTGTCACTGCCCAGATGGCTACGCAGGGCCGACATGTGACCAAGATGTGGATGAATGCCTGTCGGATCCCTGCCTGCACGGCGGAACCTGCAGTGACACTGTGGCAGGCTATATCTGCAGGTGCCCAGAGACCTGGGGTGGGCGCGACTGTTCTGTGCAGCTCACTGGCTGCCAGGGCCACACCTGCCCGCTGGCTGCCACCTGCATCCCTATCTTCGAGTCTGGGGTCCACAGTTACGTCTGCCACTGCCCACCTGGTACCCATGGACCGTTCTGTGGCCAGAATACCACCTTCTCTGTGATGGCTGGGAGCCCCATTCAGGCATCAGTGCCAGCTGGTGGCCCCCTGGGTCTGGCACTGAGGTTTCGCACCACACTGCCCGCTGGGACCTTGGCCACTCGCAATGACACCAAGGAAAGCTTGGAGCTGGCATTGGTGGCAGCCACACTTCAGGCCACACTCTGGAGCTACAGCACCACTGTGCTTGTCCTGAGACTGCCGGACCTGGCCCTAAACGATGGCCATTGGCACCAGGTGGAGGTTGTGCTCCATCTAGCGACCCTGGAGCTACGGCTCTGGCATGAGGGTGCCCTGCCCGGCTCTGTGTGGCCTCTGGTCCTGTGGCCCTGGCTTCCACGGCTTCGGCAACTCCGCTGCCTGCCGGGATCTCCTCTGCCCAGCTGGGGGACGCGACCTTTGCAGGCTGCCTCCAGGACGTGCGTGTGGATGGCCACCTCCTGCTGCCTGAGGATCTCGGTGAGAACGTCCTCCTGGGCTGTGAGCGCCGAGAGCAGTGCCGGCCTCTGCCTTGTGTCCACGGAGGGTCCTGTGTGGATCTGTGGACTCATTTCCGTTGCGACTGTGCCCGGCCCCATAGAGGTCCCACGTGCGCTGATGAGATTCCTGCTGCCACCTTTGGCTTGGGAGGCGCCCCAAGCTCTGCCTCCTTTCTGCTCCAAGAGCTGCCAGGTCCCAACCTCACAGTGTCTTTCCTTCTCCGCACTCGGGAGTCCGCTGGCCTGTTGCTCCAGTTTGCCAATGACTCCGCAGCTGGCCTIACAGTATTCCTGAGTCACCGTCGGATCCGGGCTGAGGTGCCGGGCAGTCCTGCTGTAGTGCTCCCTGGGCGCTGGGATGATGGGCTCCGTCACCTGGTGATGCTCAGCTTCGGGCCTGACCAGCTGCAGGACCTGGGGCAGCACGTGCACGTGGGTGGGAGGCTCCTTGCTGCCGACAGCCAGCCCTGGGGTGGGCCCTTCCGAGGCTGCCTCCAGGACCTGCGACTCGATGGCTGCCACCTCCCCTTCTTTCCTCTGCCACTGGATAACTCAAGCCAGCCCAGCGAGCTCGGCGGCACGCAGTCCTGGAACCTCACTGCGGGCTGCGTCTCCGAGCACATGTGCAGTCCTGACCCCTGTTTCAATGGTGGGACTTGCCTCGTCACCTGGAATGACTTCCACTGTACCTGCCCTGCCAATTTCACGGGGCCTACGTGTGCCCAGCAGCTGTGGTGTCCCGCCCAGCCCTGTCTCCCACCTGCCACGTGTGAGGAGGTCCCTGATGGCTTTGTGTGTGTGGCGGAGGCCACGTTCCGCGACCGTCCCCCCGCCGCGTTCAGCGGGCACAACGCGTCGTCAGGGCGCTTGCTCGGCGGCCTGTCGCTGGCCTTTCGCACGCGCGACTCCGAGGCCTGGCTGCTGCGTGCCGCGGCGGGCGCCCTGGAAGGCGTGTGGCTGGCGGTGCGCAATGGCTCGCTGGCGGGGGGCGTGCGCGGAGGCCATGGCCTGCCCGGCGCTGTGCTGCCCATACCGGGGCCGCGCGTGGCCGATGGTGCCTGGCACCGCGTGCGTCTGGCCATGGACCGCCCGGCGGCCACCACCTCGCGCTGGCTGCTGTGCCTCGATGGTGCCGCCACCCCGGTGGCGCTGCGCGGCCTGGCCAGTGACCTGGGCTTCCTGCAGGGCCCGGCTGCTGTGCGCATCCTGCTGGCTGAGAACTTCACCGGCTGCTTGGGCCGCGTGGCGCTGGGCGGCCTGCCCCTGCCCTTGGCGCGGCCCCGGCCCGGCGCGGCCCCTGGCGCCCGAGAGCACTTCGCGTCTTGGCCTGGGACGCCGGCCCCGATCCTCGGCTCCCGCGGCGCGCCCGTGTGTGCGCCCTCGCCCTGTCTGCACGACGGTGCCTGCCGTGACCTCTTCGACGCCTTTGCCTGCGCCTGCGGCCCGGGGTGGGAAGGCCCGCGCTGCGAAGCCCACGTCGACCCCTGTCACTCCGCCCCCTGCGCCCGTGGCCGCTGTCACACGCACCCCGACGGCCGCTTCGAGTGCCGCTGCCCGCCTGGCTTCGCGGCCCCGCGCTGCAGGTTGCCTGTCCCATCCAAGGAGTGCAGCCTGAATGTCACCTCCCTCGATGGCAGCCCATGTGAGGGTGGCTCTCCCGCTGCCAACTGCAGCTGCCTGGAGGGTCTTGCTGGCCAGAGGTGTCAGGTCCCCACTCTCCCCTGTGAAGCCAACCCCTGCTTGAATGGGGGCACCTGCCGGGCAGCTGGAGGGGTGTCTGAATGTATCTGCAATGCCAGATTCTCCGGCCAGTTCTGTGAAGTGGCGAAGGGCCTGCCCCTGCCGCTGCCATTCCCACTGCTGGAGGTGGCCGTACCTGCAGCCTGTGCCTGCCTCCTCCTCCTCCTCCTGGGCCTCCTTTCAGGGATCCTCGCAGCCCGAAAGCGCCGCCAGTCTGAGGGCACCTACAGCCCAAGCCACCAGGACCTCGCTGGGGCCCGGCTGGAGATGGACAGTGTCCTCAAGGTGCCACCGGAGGAGAGACTCATCTAGORF Start: ATG at 34ORF Stop: TAG at 4198SEQ ID NO:1401388 aa MW at 145800.8 kDNOV31b,MKSALIPLVYRGGKRGPEMASPRARKPQSQCWDFTVHCATCLGKVTSLLCLYKTRTDWCG59289-02 ProteinLTPSAGIRIGRECSERFPTPGGNSLELCSEPKLSRVGQCQAQGRCSVPDSYCCNRGNSSequenceLELCSEPKLSRVGQCQAQGTVPSEPPSACASDPCAPGTECQATESGGYTCGPMEPRGCATQPCHHGALCVPQGPDPTGFRCYCVPCFQGPRCELDIDECASRPCHHGATCRNLADRYECHRPLGYAGVTCETEVDECASAPCLHCASCLDGVGSFRCVCAPGYGGTRCQLDLDECQSQPCAHGGTCHDLVNGFRCDCAGTGYEGTHCEREVLECASAPCEHNASCLEOLGSFRCLCWPGYSGELCEVDEDECASSPCQHGGRCLQRSDPALYGGVQAAFPGAFSFRHAAGFLCHCPPGFEGADCGVEVDECASRPCLNGGHCQDLPNGFQCHCPDGYAGPTCEEDVDECLSDPCLHGGTCSDTVAGYICRCPETWGGRDCSVQLTGCQGHTCPLAATCIPIFESGVHSYVCHCPPGTHGPFCGQNTTFSVMAGSPIQASVPAGGPLGLALRFRTTLPAGTLATRNDTKESLELALVAATLQATLWSYSTTVLVLRLPDLALNDGHWHQVEVVLHLATLELRLWHEGCPARLCVASGPVALASTASATPLPAGISSAQLGDATFAGCLQDVRVDGHLLLPEDLGENVLLGCERREQCRPLPCVHGGSCVDLWTHFRCDCARPHRGPTCAEEIPAATFGLGGAPSSASFLLQELPGPNLTVSFLLRTRESAGLLLQFANDSAAGLTVFLSEGRIRAEVPGSPAVVLPGRWDDGLRHLVMLSFGPDQLQDLGQHVHVGGRLLAADSQPWGGPFRGCLQDLRLDGCHLPFFPLPLDNSSQPSELGGRQSWNLTAGCVSEDMCSPDPCFNGGTCLVTWNDFHCTCPANFTGPTCAQQLWCPGQPCLPPATCEEVPDGFVCVAEATFREGPPAAFSGHNASSGRLLGGLSLAFRTRDSEAWLLRAAAGALEGVWLAVRNGSLAGGVRGGHGLPGAVLPIPGPRVADGAWHRVRLAMERPAATTSRWLLWLDGAATPVALRGLASDLGFLQGPGAVRILLAENFTGCLGRVALGGLPLPLARPRPGAAPGAREHFASWPGTPAPILGCRGAPVCAPSPCLHDGACRDLFDAFACACGPGWEGPRCEAHVDPCHSAPCARGRCHTHPDGRFECRCPPGFCGPRCRLPVPSKECSLNVTCLDGSPCEGGSPAANCSCLEGLAGQRCQVPTLPCEANPCLNGGTCRAAGGVSECICNARFSGQFCEVAKGLPLPLPFPLLEVAVPAACACLLLLLLGLLSGILAARKRRQSEGTYSPSQQEVAGARLEMDSVLKVPPEERLI


[0481] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 31B.
166TABLE 31BComparison of NOV31a against NOV31b and NOV31c.NOV31a Residues/Identities/SimilaritiesProtein SequenceMatch Residuesfor the Matched RegionNOV31b1 . . . 13881284/1388 (92%)1 . . . 13881284/1388 (92%)


[0482] Further analysis of the NOV31 a protein yielded the following properties shown in Table 31C.
167TABLE 31CProtein Sequence Properties NOV31aPSort0.7000 probability located in plasma membrane; 0.3000analysis:probability located in microbody (peroxisome); 0.2000probability located in endoplasmic reticulum (membrane);0.1000 probability located in mitochondrial inner membraneNo Known Signal Sequence Indicatedanalysis:


[0483] A search of the NOV31a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 31D.
168TABLE 31DGeneseq Results for NOV31aNOV31aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAB40530Human ORFX ORF294 polypeptide339 . . . 586248/248 (100%)  e−160sequence SEQ ID NO: 588 - Homo 1 . . . 248248/248 (100%) sapiens, 248 aa. [WO200058473-A2,05-OCT-2000]AAU16970Human novel secreted protein, SEQ ID194 . . . 743214/581 (36%) e−118211 - Homo sapiens, 604 aa. 19 . . . 557308/581 (52%)[WO200155441-A2, 02-AUG-2001]AAY06816Human Notch2 (humN2) protein145 . . . 541166/434 (38%)2e−94 sequence - Homo sapiens, 2471 aa. 799 . . . 1225229/434 (52%)[WO9904746-A2, 04-FEB-1999]AAB40789Human ORFX ORF553 polypeptide842 . . . 990147/149 (98%)2e−92 sequence SEQ ID NO: 1106 - Homo 1 . . . 149148/149 (98%)sapiens, 149 aa. [WO200058473-A2,05-OCT-2000]AAW49698Human Notch3 protein - Homo144 . . . 747201/618 (32%)3e−92 sapiens, 2321 aa. [FR2751986-A1,354 . . . 888260/618 (41%)06-FEB-1998]


[0484] In a BLAST search of public sequence databases, the NOV31a protein was found to have homology to the proteins shown in the BLASTP data in Table 31E.
169TABLE 31EPublic BLASTP Results for NOV31aNOV31aProteinResidues/Identities/AccessionMatchSimilarities for theExpectNumberProtein/Organism/LengthResiduesMatched PortionValueAAL10682CRB1 ISOFORM II PRECURSOR - 111 . . . 1388448/1375 (32%)0.0Homo sapiens (Human), 1406 aa. 98 . . . 1406664/1375 (47%)AAL65131PRECURSOR - Mus musculus 37 . . . 1405656/1434 (45%)0.0(Mouse), 1405 aa.P82279Crumbs protein homolog 1 111 . . . 1313421/1300 (32%)0.0precursor - Homo sapiens (Human), 98 . . . 1334621/1300 (47%)1376 aa.Q9VC97CRB PROTEIN - Drosophila 95 . . . 1312430/1432 (30%)e−174melanogaster (Fruit fly), 2146 aa. 552 . . . 1948610/1432 (42%)P10040Crumbs protein precursor (95F) - 95 . . . 1312430/1444 (29%)e−172Drosophila melanogaster (Fruit fly), 554 . . . 1951613/1444 (41%)2139 aa.


[0485] PFam analysis indicates that the NOV31a protein contains the domains shown in the Table 31F.
170TABLE 31FDomain Analysis of NOV31aIdentities/SimilaritiesPfam DomainNOV31a Match Regionfor the Matched RegionExpect ValueEGF: domain 1 of 16 86 . . . 120 8/50 (16%)5220/50 (40%)EGF: domain 2 of 16174 . . . 20815/47 (32%)3.5e−0527/47 (57%)EGF: domain 3 of 16215 . . . 24616/47 (34%)2.2e−0927/47 (57%)EGF: domain 4 of 16253 . . . 28416/47 (34%)6.5e−0827/47 (57%)EGF: domain 5 of 16291 . . . 32313/47 (28%)0.0001427/47 (57%)EGF: domain 6 of 16330 . . . 36113/47 (28%)5.3e−0725/47 (53%)EGF: domain 7 of 16368 . . . 42015/61 (25%)1.833/61 (54%)EGF: domain 8 of 16427 . . . 45817/47 (36%)5.1e−0929/47 (62%)EGF: domain 9 of 16465 . . . 49615/47 (32%)2.9e−0825/47 (53%)EGF: domain 10 of 16503 . . . 53812/47 (26%)0.1925/47 (53%)laminin_G: domain 1 of 5568 . . . 62824/76 (32%)0.01239/76 (51%)laminin_G: domain 2 of 5679 . . . 694 7/16 (44%)0.215/16 (94%)EGF: domain 11 of 16712 . . . 74312/47 (26%)0.0001525/47 (53%)laminin_G: domain 3 of 5865 . . . 881 6/17 (35%)4.414/17 (82%)EGF: domain 12 of 16914 . . . 94516/47 (34%)6.1e−0928/47 (60%)laminin_G: domain 4 of 51003 . . . 106821/79 (27%)0.0003145/79 (57%)laminin_G: domain 5 of 51113 . . . 1128 7/16 (44%)0.8612/16 (75%)EGF: domain 13 of 161163 . . . 119414/47 (30%)1.8e−0724/47 (51%)EGF: domain 14 of 161201 . . . 123215/47 (32%)0.00125/47 (53%)metalthio: domain 1 of 11198 . . . 126620/75 (27%)6.941/75 (55%)EGF: domain 15 of 161241 . . . 127311/47 (23%)4.517/47 (36%)EB: domain 1 of 11223 . . . 127315/60 (25%)4.833/60 (55%)EGF: domain 16 of 161280 . . . 131115/47 (32%)0.0004523/47 (49%)



Example 32

[0486] The NOV32 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 32A.
171TABLE 32ANOV32 Sequence AnalysisSEQ ID NO:1412855 bpNOV32aGAGGGAATGCGCGCACCTCACAGGCCCTGGGAGTGAGCTGGTGCCCGGCGACCTGGCACG57111-01 DNACCCGCGCCTGGATATGGGGCGTCTACATCGTCCCAGGAGCAGCACCAGCTACACGAACSequenceCTGCCGCATCTGTTTCTGTTTTTCCTCTTCGTGGGACCCTTCAGCTGCCTCGGGAGTTACAGCCGGGCCACCGAGCTTCTGTACAGCCTAAACGAGGGACTACCCGCGGGGGTGCTCATCGGCAGCCTGGCCGAGGACCTGCGGCTGCTGCCCAGGTCTGCAGGGAGGCCGGACCCGCAGTCGCAGCTGCCAGAGCGCACCGGTGCTCAGTGGAACCCCCCTCTCTCCTTCAGCCTGGCCTCCCGGGGACTGAGTGGCCAGTACGTGACCCTAGACAACCGCTCTGGGGAGCTGCACACTTCACCTCAGGAGATCGACAGGCAGGCCCTGTGTGTTCAAGGGGGTGGAGGGACTGCGTGGAGCGGCAGCGTTTCCATCTCCTCCTCTCCTTCTGACTCTTGTCTTTTGCTGCTGGATGTGCTTGTCCTGCCTCAGGAATACTTCAGGTTTGTGAAGGTGAAGATCGCCATCAGAGACATCAATGACAACGCCCCGCAGTTCCCTGTTTCCCAGATCTCGGTGTCGGTCCCGGAAAATGCACCTGTAAACACCCGACTGGCCATAGAGCATCCTGCTGTGGACCCAGATGTTGGCATTAATGGCGTTCAGACCTATCGCTTACTGGACTACCATGGTATGTTCACCCTGGACGTGGAGGAGAATGAGAATGGGGAGCGCACCCCCTACCTAATTCTCATGCGTGCTTTGGACAGGGAAACCCAGGACCAGTATGTGAGCATCATCACAGCTGAGGATGGTGGCTCTCCACCACTTTTGGGCAGTGCCACTCTCACCATTGGCATCAGTGACATTAATGACAATTGCCCTCTCTTCACAGACTCACAAATCAATGTCACTGTGTATGGGAATGCTACAGTGGGCACCCCAATTGCAGCTGTCCAGGCTGTGGATAAAGACTTGGGGACCAATGCTCAAATTACTTATTCTTACAGTCAGAAAGTTCCACAAGCATCTAAGGATTTATTTCACCTGGATGAAAACACTGGAGTCATTAAACTTTTCAGTAAGATTGGAGGAAGTGTTCTGGAGTCCCACAAGCTCACCATCCTTGCTAATGGACCAGGCTGCATCCCTGCTGTPATCACTGCTCTTGTGTCCATTATTAAAGTTATTTTCAGACCCCCTGAAATTGTCCCTCGTTACATAGCAAACGAGATAGATGGTGTTGTTTATCTGAAAGAACTGGAACCCGTTAACACTCCCATTGCGTTTTTCACCATAAGAGATCCAGAAGGTAAATACAAGGTTAACTGCTACCTGGATGGTGAAGGGCCGTTTAGGTTATCACCTTACAAACCATACAATAATGAATATTTACTAGAGACCACAAAACCTATGGACTATGAGCTACAGCAGTTCTATGAAGTAGCTGTGGTGGCTTGGAACTCTGAGGGATTTCATGTCAAAAGGGTCATTAAAGTGCAACTTTTAGATGACAATGATAATGCTCCAATTTTCCTTCAACCCTTAATAGAACTAACCATCGAAGAGAACAACTCACCCAATGCCTTTTTGACTAAGCTGTATGCTACAGATGCCGACAGCGAGGAGAGAGGCCAAGTTTCATATTTTCTGGGACCTGATGCTCCATCATATTTTTCCTTAGACAGTGTCACAGGAATTCTGACAGTTTCTACTCACCTGGACCGAGAAGAGAAAGAAAAGTACAGATACACTGTCAGAGCTGTTGACTGTGGGAAGCCACCCAGAGAATCAGTAGCCACTGTGGCCCTCACAGTGTTGGATAAAAATGACAACAGTCCTCGGTTTATCAACAAGGACTTCAGCTTTTTTGTGCCTGAAAACTTTCCAGGCTATGGTGAGATTGGAGTAATTAGTGTAACAGATGCTGACGCTGGACGAAATGGATGGGTCGCCCTCTCTGTGGTGAACCAGAGTGATATTTTTGTCATAGATACAGGAAAGGGTATGCTGAGGGCTAAAGTCTCTTTGGACAGAGAGCAGCAAAGCTCCTATACTTTGTGCGTTGAAGCTGTTGATGGGGGTGAGCCTGCCCTCTCCTCTACAGCAAAAATCACAATTCTCCTTCTAGATATCAATGACAACCCTCCTCTTGTTTTGTTTCCTCAGTCTAATATGTCTTATCTGTTAGTACTGCCTTCTACTCTGCCAGGCTCCCCGGTTACAGAAGTCTATGCTGTCGACAAAGACACACGCATGAATCCTGTCATAGCTTACAGCATCATAGGGAGAAGAGGTCCTAGGCCTGAGTCCTTCAGGATTGACCCTAAAACTGGCAACATTACTTTGGAAGAGGCATTGCTGCAGACAGATTATGGGCTCCATCGCTTACTGGTGAAAGTGAGTGATCATGGTTATCCCCAGCCTCTCCACTCCACACTCATGGTGAACCTATTTGTCAATGACACTGTCAGTAATGAGAGTTACATTGAGAGTCTTTTAAGAAAAGAACCAGAGATTAATATAGAGGAGAAAGAACCACAAATCTCAATAGAACCGACTCATAGGAAGGTACAATCTCTGTCTTGTATGCCCACCTTAGTAGCTCTGTCTGTAATAAGCTTGGGTTCCATCACACTGGTCACAGGGATCGGCATATACATCTGTTTAAGGAAAGGGGAAAAGCATCCCAGGGAAGATGAAAATTTGGAAGTACAGATTCCACTGAAAGGAAAAATTGACTTGCATATGCGAGAGAGAAAGCCAATGGATATTTCTAATATTTGATATTTCATGORF Start: GGG at 3ORF Stop: TGA at 2844SEQ ID NO:142947 aa MW at 104405.1 kDNOV32a,GNARSSQALGVSWCPATWHPRLDMGRLHRPRSSTSYRNLPHLFLFFLPVGPFSCLGSYCG57111-01ProteinSRATELLYSLNEGLPAGVLIGSLAEDLRLLPRSAGRPDPQSQLPERTGAEWNPPLSFSSequenceLASRGLSGQYVTLDNRSGELHTSAQEIDREALCVEGGCGTAWSGSVSISSSPSDSCLLLLDVLVLPQEYFRFVKVKIAIRDINDNAPQFPVSQISVWVPENAPVNTRLAIEHPAVDPDVGILNGVQTYRLLDYHGMFTLDVEENENGERTPYLIVMGALDRETQDQYVSIITAEDGGSPPLLGSATLTIGISDINIJNCPLFTDSQINVTVYGNATVGTPIAAVQAVDKDLGTNAQITYSYSQKVPQASKDLFHLDENTGVIKLFSKIGGSVLESHIKLTILANGPCCIPAVITALVSIIKVIFRPPEIVPRYIANEIDGVVYLKELEPVNTPIAFFTIRDPEGKYKVNCYLDGEGPFRLSPYKPYNNEYLLETTKPMDYELQQFYEVAVVAWNSEGFHVKRVIKVQLLDDNDNAPIFLQPLIELTIEENNSPNAFLTKLYATDADSEERGQVSYFLGPDAPSYFSLDSVTGILTVSTQLDREEKEKYRYTVRAVDCGKPPRESVATVALTVLDKNDNSPRFINKDFSFFVPENFPGYGEIGVISVTDADAGRNGWVALSVVNQSDIFVIDTGKGMLRAKVSLDREQQSSYTLWVEAVDGGEPALSSTAKITILLLDINDNPPLVLFPQSNMSYLLVLPSTLPGSPVTEVYAVDKDTGMNAVIAYSIIGRRGPRPESFRIDPKTGNITLEEALLQTDYGLHRLLVKVSDHGYPEPLHSTVMVNLFVNDTVSNESYIESLLRKEPEINIEEKEPQISIEPTHRKVESVSCMPTLVALSVISLGSITLVTGMGIYICLRKGEKHPREDENLEVQIPLKGKIDLHMRERKPMDISNI


[0487] Further analysis of the NOV32a protein yielded the following properties shown in Table 32B.
172TABLE 32BProtein Sequence Properties NOV32aPSort0.6400 probability located in plasma membrane; 0.4000analysis:probability located in Golgi body; 0.3000probability located in endoplasmic reticulum (membrane);0.0300 probability located in mitochondrial inner membraneSignalPCleavage site between residues 57 and 58analysis:


[0488] A search of the NOV32a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 32C.
173TABLE 32CGeneseq Results for NOV32aNOV32aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAU19645Human novel extracellular matrix551 . . . 947396/397 (99%)0.0protein, Seq ID No 295 - Homo 1 . . . 397397/397 (99%)sapiens, 397 aa. [WO200155368-A1,02-AUG-2001]AAM79103Human protein SEQ ID NO 1765 -  46 . . . 858347/820 (42%)0.0Homo sapiens, 1021 aa. 8 . . . 791506/820 (61%)[WO200157190-A2, 09-AUG-2001]AAM80087Human protein SEQ ID NO 3733 - 127 . . . 868325/747 (43%)e−175Homo sapiens, 1090 aa. 5 . . . 728475/747 (63%)[WO200157190-A2, 09-AUG-2001]AAU19807Human novel extracellular matrix553 . . . 839 287/287 (100%)e−164protein, Seq ID No 457 - Homo 1 . . . 287 287/287 (100%)sapiens, 288 aa. [WO200155368-A1,02-AUG-2001]AAM31106measuring placental gene expression -  4 . . . 611398/612 (64%)e−148Homo sapiens, 831 aa.[WO200157272-A2, 09-AUG-2001]


[0489] In a BLAST search of public sequence databases, the NOV32a protein was found to have homology to the proteins shown in the BLASTP data in Table 32D.
174TABLE 32DPublic BLASTP Results for NOV32aNOV32aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ9NRT9PROTOCADHERIN 13 - Homo 1 . . . 947 947/947 (100%)0.0sapiens (Human), 947 aa (fragment). 1 . . . 947 947/947 (100%)Q9HC56ROTOCADHERIN-9 - Homo sapiens 45 . . . 862364/823 (44%)0.0(Human), 1203 aa. 6 . . . 797507/823 (61%)Q95KD8HYPOTHETICAL 113.7 KDA 45 . . . 862363/823 (44%)0.0PROTEIN - Macaca fascicularis (Crab 6 . . . 797507/823 (61%)eating macaque) (Cynomolgusmonkey), 1032 aa.Q9H4E0PROTOCADHERIN - Homo sapiens 46 . . . 858347/820 (42%)0.0(Human), 1025 aa. 8 . . . 791506/820 (61%)Q9BZA6PROTOCADHERIN 11 - Homo 46 . . . 858347/820 (42%)0.0sapiens (Human), 1337 aa. 8 . . . 791506/820 (61%)


[0490] PFam analysis indicates that the NOV32a protein contains the domains shown in Table 32E.
175TABLE 32EDomain Analysis of NOV32aldentities/SimilaritiesPfam DomainNOV32a Match Regionfor the Matched RegionExpect Valuecadherin: domain 1 of 5210 . . . 30738/111 (34%)1.5e−0872/111 (65%)cadherin: domain 2 of 5321 . . . 41327/110 (25%)0.0002867/110 (61%)cadherin: domain 3 of 5536 . . . 62632/107 (30%)1.1e−1868/107 (64%)cadherin: domain 4 of 5640 . . . 72970/107 (65%)9.1e−20cadherin: domain 5 of 5747 . . . 84037/112 (33%)6.6e−1169/112 (62%)



Example 33

[0491] The NOV33 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 33A.
176TABLE 33ANOV33 Sequence AnalysisSEQ ID NO:1431289 bpNOV33a,TCCCAGCCTCGCAGCCGGCCTGAGCCGCCATGCGCGGGAAGTTGCTGCCGCTGGCCGGCG59363-01 DNACCTCTACCTGGTGCAGGGCCTGCCCTACGGGCTCCAGTCCGGCCTCCTGCCAGTCCTGSequenceCTGCGTGCCGGCGGCCTCTCGCTGACGCGCGTGGGGCTGGCCAAGGTTCTGTACGCTCCGTGCCTGCTCAAGCTGGCTTGGGCCCCGCTGGTGGACGCGCAGGGCTCGGCGAGGGCCTGCGTCACCCGCAGCACCGCGGGCCTCGGCCTGGTCTGTGGCCTGCTTGCCGGGCTGCCCCCTCCTGGAGCTGGCCAGGCCCGGCTGCCCGCCGCTGTGGCGGGGTTGCTGCTGTTGTTGAACCTGGGTGCCGCCATGCAGGATGTGGCCCTGGACGCGCTGGCTGTGCAGCTGCTGGAGCCGCCCGAACTGCGGCCGGGCAATACCGTGCAGGTGGTCGCGTACAAGCTGGGGGCCGCGCTAGCTGGGGGCGCGCTCCTGGCGCTGCTGCCCACCTTCTCGTGGCCGCAACTCTTTCTGCTCCTGGCTGCCACCTACTGGCTGGCCGCGGCCCTGGCCTGGGCTGCACCAGCCCTGCCGCGGCTCCCACAGCAGCCCCCTTCCGAGCAGCGTCCCCACACCGCGCACCTTCTGCGGGACGTGCTAGCCGTGCCGGGCACCGTGTGGACGGCAGGCTTTGTGCTCACCTACAAGCTGGGTGAGCAGGGTGCCAGCAGCCTGTTTCCTCTTCTCCTGCTGGACCACGGCGTTTCTGCTCCCGAGTTGGGACTGTGGAATGGTGTGGGTGCTGTGGTCTGCTCCATCGCTGGCTCCTCCCTGGGTGGGACCTTGCTGGCCAAGCACTGGAAACTGCTGCCTCTGTTGAGGTCGGTGCTGCGCTTCCGCCTCGGGGGCCTAGCCTGTCAGACTGCCTTGGTCTTCCACCTGGACACCCTGGGGGCCAGCATGGACGCTGGCACAATCTTGAGAGGTTCAGCCTTGCTGAGCCTATGTCTGCACCACTTCTTGGCAGGCCTGGTCACCACAGTCACCTTCACTGGGATGATGCGCTGCAGCCAGCTGGCCCCCAGGGCCCTGCAGGCCACACACTACAGCCTTCTCGCCACGCTGGAGCTGCTGGGGAAGCTGCTGCTGGGCACTCTGGCCGGAGGCCTGGCTGATGGGTTGGGGCCACATCCCTGCTTCTTGCTCCTGCTCATCCTCTCTGCCTTTCCCGTTCTCTACCTGGACCTAGCACCCAGCACCTTTCTCTGAGCTGAGTGGCTGGAGTGGTCAORF Start: ATG at 30ORF Stop: TGA at 1266SEQ ID NO:144412 aa MW at 42695.2 kDNOV33a,MRGKLLPLAGLYLVQGLPYCLQSGLLPVLLRAGGLSLTRVGLAKVLYAPWLLKLAWAPCG59363-01 ProteinLVDAQGSARAWVTRSTAGLGLVCGLLAGLPPPGACQAGLPAAVAGLLLLLNLGAAMQDSequenceVALDALAVQLLEPAELGPGNTVQVVAYKLGAALAGGALLALLPTFSWPQLFLLLAATYWLAAALAWAAPALRRLPQQPPSEQRPHTAHLLRDVLAVPGTVWTAGFVLTYKLGEQCASSLFPLLLLDHGVSAPELGLWNGVGAVVCSIAGSSLGGTLLAKHWKLLPLLRSVLRFRLGGLACQTALVFHLDTLGASMDAGTILRGSALLSLCLQHFLGGLVTTVTFTGMMRCSQLAPRALQATHYSLLATLELLGKLLLGTLAGGLADGLGPHPCFLLLLILSAFPVLYLDLAPSTFLSEQ ID NO:1451256 bpNOV33b,CATGCGCGGGAAGTTGCTGCCGCTGGCCGGCCTCTACCTGGTGCAGGGCCCGCCCTACCG59363-02 DNAGGGCTCCAGTCCGGCCTCCTGCCAGTGCTGCTGCGTGCCGGCGGCCTCTCGCTGACGCSequenceCCGTGGGGCTGGCCAAGGTTCTGTACGCTCCGTGGCTGCTCAAGCTGGCTTGGGCCCCGCTGGTGGACGCGCAGGGCTCGGCGAGGGCCTGGGTGACGCGCAGCACGGCGGGCCTCGGCCTGGTGTGTGGGCTGCTTGCCGGGCTGCCCCCTCCTGGAGCTGGCCAGGCCGCGCTGCCCGCCGCTGTGGCGGGGTTGCTGCTGTTGTTGAACCTGGGTGCCGCCATGCAGGATGTGGCCCTGGACGCGCTGGCTGTGCAGCTGCTGGAGCCGGCCGAACTGGGGCCGGGCAATACCGTGCAGGTGGTCGCGTACAAGCTCGGGGCCGCGCTAGCTGGGGGCGCGCTGCTGGCGCTGCTGCCCACCTTCTCGTGGCCGCAACTCTTTCTGCTCCTGGCTGCCACCTACTGGCTGGCCGCGGCCCTGGCCTGGGCTGCACCAGCCCTGCGGCGGCTCCCACAGCAGCCCCCTTCCGAGCAGCGTCCCCACACCGCGCACCTTCTGCGGGACGTGCTAGCCGTGCCGGGGACCGTGTGGACGGCAGGCTTTGTGCTCACCTACAAGCTGGGTGAGCAGGGTGCCAGCAGCCTGTTTCCTCTTCTCCTGCTGCACCACGGCGTTTCTGCTCCCCAGTTGGGACTGTGGAATGGTGTGGGTGCTGTGGTCTCCTCCATCGCTGGCTCCTCCCTGGGTCGCACCTTGCTGGCCAAGCACTGGAAACTGCTGCCTCTGTTGAGGTCGGTGCTGCGCTTCCGCCTCGGGCGCCTAGCCTGTCAGACTGCCTTGGTCTTCCACCTGGACACCCTGGGGGCCAGCATGGACGCTGGCACAATCTTGAGAGGGTCAGCCTTGCTGAGCCTATGTCTGCAGCACTTCTTGGGAGCCCTGGTCACCACAGTCACCTTCACTGGGATGATGCGCTGCAGCCAGCTGGCCCCCAGGGCCCTGCAGGCCACACACTACAGCCTTCTGGCCACGCTGGAGTTGCTGGGGAAGCTGCTGCTGGGCACTCTGGCCGGAGGCCTGGCTGATGGGTTGGGGCCACATCCCTGCTTCTTGCTCCTGCTCATCCTCTCTGCCTTTCCCGTTCTGTACCTGGACCTAGCACCCAGCACCTTTCTCTGAGCTGAGTGGCTGGAGTORF Start: ATG at 2ORF Stop: TGA at 1238SEQ ID NO:146412 aa MW at 42679.2 kDNOV33b,MRGKLLPLAGLYLVQGPPYGLQSGLLPVLLRAGGLSLTRVGLAKVLYAPWLLKLAWAPCG59363-02 ProteinLVDAQGSARAWVTRSTAGLGLVCGLLAGLPPPGAGQAGLPAAVAGLLLLLNLGAAMQDSequenceVALDALAVQLLEPAELGPGNTVQVVAYKLGAALAGGALLALLPTFSWPQLFLLLAATYWLAAALAWAAPALRRLPQQPPSEQRPHTAHLLRDVLAVPGTVWTAGFVLTYKLGEQGASSLFPLLLLDHGVSAPELGLWNGVGAVVCSIAGSSLGGTLLAKHWKLLPLLRSVLRFRLGGLACQTALVFHLDTLGASMDAGTILRGSALLSLCLQHFLGGLVTTVTFTGMMRCSQLAPRALQATHYSLLATLELLGKLLLGTLACGLADCLGPHPCFLLLLILSAFPVLYLDLAPSTFLSEQ ID NO:1471186 bpNOV33C,TCCCAGCCTCGCAGCCGGCCTGAGCCGCCATGCGCGGGAAGTTGCTGCCGCTGGCCGGCG59363-03 DNACCTCTACCTGGTGCAGGGCCTGCCCTACGGGCTCCAGTCCGGCCTCCTGCCAGTGCTGSequenceCTCCGTGCCGGCGGCCTCTCGCTGACGCCCGTGGGGCTGGCCAAGGTTCTGTACGCTCCGTGGCTGCTCAAGCTGGCTTGCGCCCCGCTGGTGGACGCGCAGGGCTCGGCGAGGGCCTGGGTGACGCGCAGCACGGCGGGCCTGGGCCTGGTGTGTGGGCTGCTTGCCGGGCTGCCCCCTCCTGGAGCTGCCCAGGCCGGGCTGCCCGCCGCTGTGGCGGGGTTGCTGCTGTTGTTGAACCTGGGTGCCGCCATGCAGGATGTGGCCCTGCACGCCCTGGCTGTGCAGCTGCTGGAGCCGGCCGAACTGGGGCCGGGCAATACCGTGCAGGTGGTCGCGTACAAGCTGGGGGCCGCGCTAGCTGGGGGCGCGCTGCTGGCGCTGCTGCCCACCTTCTCGTGGCCGCAACTCTTTCTGCTCCTGGCTGCCACCTACTGGCTGGCCGCGGCCCTGGCCTGGGCTGCACCAGCCCTGCGGCGGCTCCCACAGCAGCCCCCTTCCGAGCAGCGTCCCCACACCGCGCACCTTCTGCGGGACGTGCTAGCCGTGCCGGGGACCGTGTGGACGGCAGGCTTTGTGCTCACCTACAAGCTGGGTGAGCAGGGTGCCAGCAGCCTGTTTCCTCTTCTCCTGCTGGACCACGGCGTTTCTGCTCCCGAGTTGGGACTGTGGAATGGTGTGGGTGCTGTGGTCTGCTCCATCGCTGCCTCCTCCCTGGGTCGGACCTTGCTGGCCAAGCACTGGAAACTGCTGCCTCTGTTGAGGTCGGTGCTGCGCTTCCGCCTCGGGGGCCTAGCCTGTCAGACTGCCTTGGTCTTCCCCAGGGCCCTGCAGGCCACACACTACAGCCTTCTGGCCACGCTCGAGCTGCTGGGGAAGCTGCTGCTGGGCACTCTGCCCGGAGGCCTGGCTGATGGCTTGCGGCCACATCCCTGCTTCTTGCTCCTGCTCATCCTCTCTGCCTTTCCCGTTCTGTACCTGGACCTAGCACCCAGCACCTTTCTCTGAGCTGAGTGGCTGGAGTGGTCAATAAAGCCACATGTCCTGTGGCCCAGATGTCTCTGTGCCTGORF Start: ATG at 30ORF Stop: TGA at 1122SEQ ID NO:148364 aa MW at 37703.4 kDNOV33C,MRGKLLPLAGLYLVQGLPYGLQSGLLPVLLRAGGLSLTRVGLAKVLYAPWLLKLAWAPCG59363-03 ProteinLVDAQCSARAWVTRSTAGLGLVCGLLAGLPPPGAGQAGLPAAVAGLLLLLNLGAAMQDSequenceVALDALAVQLLEPAELGPGNTVQVVAYKLGAALAGGALLALLPTFSWPQLFLLLAATYWLAAALAWAAPALRRLPQQPPSEQRPHTAHLLRDVLAVPGTVWTAGFVLTYKLGEQGASSLFPLLLLDHGVSAPELGLWNGVGAVVCSIAGSSLGGTLLAKHWKLLPLLRSVLRFRLGGLACQTALVFPRALQATHYSLLATLELLGKLLLGTLAGGLADGLGPHPCFLLLLILSAFPVLYLDLAPSTFL


[0492] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 33B.
177TABLE 33BComparison of NOV33a against NOV33b through NOV33c.NOV33a Residues/Identities/SimilaritiesProtein SequenceMatch Residuesfor the Matched RegionNOV33b1 . . . 412253/412 (61%)1 . . . 412253/412 (61%)NOV33c1 . . . 412221/412 (53%)1 . . . 364221/412 (53%)


[0493] Further analysis of the NOV33a protein yielded the following properties shown in Table 33C.
178TABLE 33CProtein Sequence Properties NOV33aPSort0.6400 probability located in plasma membrane; 0.4600analysis:probability located in Golgi body; 0.3700 probability locatedin endoplasmic reticulum (membrane); 0.1000probability located in endoplasmic reticulum (lumen)SignalPCleavage site between residues 63 and 64analysis:


[0494] A search of the NOV33a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 33D.
179TABLE 33DGeneseq Results for NOV33aNOV33aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAW70898Acetyl-coenzyme A transporter (AT) 5 . . . 252 72/280 (25%)2e−10protein - Homo sapiens, 549 aa.75 . . . 347116/280 (40%)[US5851788-A, 22-DEC-1998]AAW69948(AT-1) protein - Homo sapiens, 549 aa.75 . . . 347116/280 (40%)2e−10[WO9833816-A1, 06-AUG-1998]


[0495] In a BLAST search of public sequences databases, the NOV33a protein was found to have homology to the proteins shown in the BLASTP data in Table 33E.
180TABLE 33EPublic BLASTP Results for NOV33aNOV33aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ96ES6SIMILAR TO RIKEN CDNA 1 . . . 412 412/412 (100%)0.02310010G13 GENE - Homo sapiens 1 . . . 412 412/412 (100%)(Human), 412 aa.AAH19171SIMILAR TO RIKEN CDNA 1 . . . 409321/409 (78%)0.02310010G13 GENE - Mus musculus 1 . . . 409351/409 (85%)(Mouse), 412 aa.Q9D7F82310010G13RIK PROTEIN - Mus 1 . . . 409317/409 (77%) e−180musculus (Mouse), 412 aa. 1 . . . 409351/409 (85%)CAD13682TRANSPORT TRANSMEMBRANE11 . . . 404120/403 (29%)8e−33 PROTEIN - Ralstonia solanacearum21 . . . 399187/403 (45%)(Pseudomonas solanacearum), 426 aa.Q92SY4PUTATIVE TRANSPORT PROTEIN - 8 . . . 399115/400 (28%)2e−25 Rhizobium meliloti (Sinorhizobium20 . . . 386172/400 (42%)meliloti), 421 aa.


[0496] PFam analysis indicates that the NOV33a protein contains the domains shown in the Table 33F.
181TABLE 33FDomain Analysis of NOV33aIdentities/SimilaritiesNOV33a Matchfor the MatchedExpectPfam DomainRegionRegionValueBac_Ubq_Cox: domain24 . . . 55 16/32 (50%)3.41 of 1 26/32 (81%)BT1: domain 1 of 1 15 . . . 411 99/602 (16%)8.7251/602 (42%)sugar_tr: domain 1 of 1 3 . . . 411 81/522 (16%)8.5243/522 (47%)



Example 34

[0497] The NOV34 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 34A.
182TABLE 34ANOV34 Sequence AnalysisSEQ ID NO:1491020 bpNOV34a,ATGGCGGGGCAGTGGGAGGCGGGGCCCAGTCGGAGAGCGGGGCGGATTTGGGCGGGTGCG59301-01 DNAAGGGGAAATCGGCCTGCCCCTACGGAAATCCCGTTTCTTTATACACCCCGTCCTGGCTSequenceGGGCGGTGTCTTCCCCGTGGAAGAGAGGGTCCGGGAGGTCCGTGGGGCGGAACAGTCCGAGGGCTTCGGGAGTCAGCCCGGGTGGATTTGTTTCGTGGCTCTCGTTGCTGGCTGGGACGGCCGTGTCCCCGTGTTGTTCCGGAGATCGAGGCCAACGGATGCCGTACTCTGTCCTCGCCGGGTGCTCAGTGAGGACCCACAGCTGGGCAGGGACCCTGGGAGGCCCCTGAGCAAGACTTGGAGGGACGCCCTTGTGCCCCCTGAGCACGTGGGGAAGGCCCTGTCCTGGGCCCTGCACCGCTCTGTGTGTTCATTGCACGAGTGTGGAAGCCTCAGAGACGCTGCATGGTGTTCCCGGGCCATCCTGGCCAAGGTGGGAGAACGCAGCCTCCGTGAGGACCCGCGGGATGCCCTCCCGCCCCCCCTCCTCCTTCTCCTCTCCTCTCAAGTGCAGACGACGCTGGCCCACATCCTTGTCGGGCAGAGGGGCTGCCGACTGGCCCCTGGCCATGCCTCTTGCTGGGAGCCGTGTGGCCTGGGCTTGGACCCACATCCACCTCTTGCTGGCTGCCTGCTCTTGCCAGTGGCTGAGCCTGGCTTCTCCCATGACAGTGGCCGCAGACAGAGGGGACCCGTGCCACCAGCCAAGGATGTGATCATTGGCAGGGATGAGATTGACGGGGACGGTGTCTGGGGGCGAGGTGAGAGTTCTGCCAAAGCCGGAGCCAGGGTTGGACCCCCCGAGCTCGTTGGTCCGCCCCTGCACGGAGAGTGGTGTGTTCACACCACGGCCCTGGTGGCCCAGCTCTGCCCATCTTCATCCCAGGTGGCAGCTGCTGCCCAGCTCTCTGGCCAGTGCCTCTTAGATGGTGTCACCACCTGCAGAAGAAAACAGAAGTGCTGAORF Start: ATG at 1ORF Stop: TGA at 1018SEQ ID NO:150339 aa MW at 36292.0 kDNOV34a,MAGQWEAGPSRRAGRIWAGEGKSACPYGNPVSLYTRSWLGGVFPVEERVREVRGAEQSCG59301-01 ProteinEGFGSQPGWICFVALVAGWDGRVPVLFRRSRPTDAVLCPRRVLSEDPQLGRDPGRPLSSequenceKTWRDALVPPEHVGKALSWALHRSVCSLHECGSLRDAAWCSRGILAKVGERSLREDPRDALGGRLLVLVSSEVQTTLAHILVGQRCCRLAPGHGSCWEPCGLGLDPHPPLAGCLLLPVAEPGFSHDSGRRQRGPVPPGKDVIIGRDEIDGDGVWGRGESSAKACARVGPPELVGRPLEGEWCVHTTALVAQLCPSSSQVAAAAQLSGQCLLDGVTTCRRKQKC


[0498] Further analysis of the NOV34a protein yielded the following properties shown in Table 34B.
183TABLE 34BProtein Sequence Properties NOV34aPSort0.4500 probability located in cytoplasm; 0.1626 probabilityanalysis:located in lysosome (lumen); 0.1139 probability located inmicrobody (peroxisome); 0.1000 probabilitylocated in mitochondrial matrix spaceSignalPNo Known Signal Sequence Indicatedanalysis:


[0499] A search of the NOV34a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 34C.
184TABLE 34CGeneseq Results for NOV34aNOV34aIdentities/Protein/Organism/Residues/Similarities forGeneseqLength [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueNo Significant Matches Found


[0500] In a BLAST search of public sequence databases, the NOV34a protein was found to have homology to the proteins shown in the BLASTP data in Table 34D.
185TABLE 34DPublic BLASTP Results for NOV34aNOV34aProteinResidues/Identities/AccessionProtein/Organism/MatchSimilarities for theExpectNumberLengthResiduesMatched PortionValueNo Significant Matches Found


[0501] PFam analysis indicates that the NOV34a protein contains the domains shown in the Table 34E.
186TABLE 34EDomain Analysis of NOV34aNOV34a MatchIdentities/SimilaritiesExpectPfam DomainRegionfor the Matched RegionValueAndrogen_recep:107 . . . 12210/17 (59%)7.2domain 1 of 111/17 (65%)EB: domain298 . . . 33910/56 (18%)9.31 of 126/56 (46%)



Example 35

[0502] The NOV35 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 35A.
187TABLE 35ANOV35 Sequence AnalysisSEQ ID NO:151781 bpNOV35a,CAAACAGCCCCTACCCTCAATGATCTCCATACAAAGAGCTCCAAAGAGTGCCTCTCCCCG59525-01 DNACCTCCCTGCAGAGGGCGCATCCCCTGGCAGCGGTTCCTTCTCACAGCCTCAGTTTTAASequenceCTTTCTGGAACCCACCCACTACTGCCATGCTCACTGTTGAAGCCATGCTGTCCAATGCCACAAAGGGGAAGGAGGTTCTTCTACTCACTCACAATCTGCCCCATGATCTTATTGGCTATAACTGGTACAAAGGGGAAAGGGTGGAGGCCAACCACCATATTACAGGATATGTAATAGGAACTCTAATAACTACCCCAGGGCCTGCCCACAGCATTCAAGGGACAATATACCCCAATCCATCCCTGCTGATTCAGAATGTCACCCAGGACACAGGATTCTACACCCTACACGCCATAAAGATAAACCCTGAGAAAGAAGAAGTATCTGGCCAGTTCCATGTATACGAAAAAAATGCCCCAGGCCTTCCTGTGGGGGCCTTCACTGGCATCGTGACCAGGGTTCTGGTCGGGGTGGCACCGGTGGCCACCCTGGCATGTTTCCTGCTCCTCGTCAGGACTGGAAGGGCCAGTCGCCAGCATGACTTTAGAGAGCAGCTCCCAGGCCATGGTCCCTCAAACAACTCCACCTACCCTACATCCCCTCTCTCCCCTGCCCAGGCCCCGCTACCCGACCCCAGGACAGCCGCTCCCATCTATGAGGAATTGCTAAACCATGACACAAACATTTACTGCTGGGTCAACCACAAAGCAGATGTGCTTTCTTAGORF Start: ATG at 20ORF Stop: TAG at 779SEQ ID NO:152253 aa MW at 27528.2 kDNOV35a,MISIQRAPKSASPPPCRGRIPWQGFLLTASVLTFWNPPTTAMLTVEAMLSNATKGKEVCG59525-01 ProteinLLLTHNLPHDLIGYNWYKGERVEANHHITGYVIGTLITTPGPAHSIQGTIYPNASLLISequenceQNVTQDTGFYTLHAIKINPEKEEVSGQFHVYEKNAPGLPVGAFTGIVTRVLVGVAPVATLACFLLLVRTGRASGQHDFREQLPGHGPSNNSTYPTSPLSPAQAPLPDPRTAAPIYEELLNHDTNIYCWVNHKADVVS


[0503] Further analysis of the NOV35a protein yielded the following properties shown in Table 35B.
188TABLE 35BProtein Sequence Properties NOV35aPSort0.8500 probability located in endoplasmic reticulumanalysis:(membrane); 0.4400 probability located in plasma membrane;0.1358 probability located in microbody (peroxisome); 0.1000probability located in mitochondrial inner membraneSignalPCleavage site between residues 42 and 43analysis:


[0504] A search of the NOV35a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 35C.
189TABLE 35CGeneseq Results for NOV35aNOV35aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAR22042Carcino embryonic antigen-related 8 . . . 253166/252 (65%)7e−87antigen encoded by clone W264 -  3 . . . 252188/252 (73%)Homo sapiens, 252 aa. [JP04045788-A,14-FEB-1992]AAR22041Carcino embryonic antigen-related 8 . . . 253134/252 (53%)4e−68antigen encoding clone W236 - Homo 3 . . . 244165/252 (65%)sapiens, 244 aa. [JP04045788-A,14-FEB-1992]AAW83138FL-CEA protein - Homo sapiens, 52612 . . . 155 97/145 (66%)2e−48aa. [US5843761-A, 01-DEC-1998] 5 . . . 145107/145 (72%)AAW06873Carcinoembryonic antigen CEA-c - 12 . . . 155 97/145 (66%)2e−48Homo sapiens, 526 aa. [US5571710-A, 5 . . . 145107/145 (72%)05-NOV-1996]AAR65166Biliary glycoprotein - Homo sapiens,12 . . . 155 97/145 (66%)2e−48464 aa. [WO9506067-A1, 5 . . . 145107/145 (72%)02-MAR-1995]


[0505] In a BLAST search of public sequence databases, the NOV35a protein was found to have homology to the proteins shown in the BLASTP data in Table 35D.
190TABLE 35DPublic BLASTP Results for NOV35aNOV35aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueP40198Carcinoembryonic antigen-related cell 8 . . . 253167/252 (66%)7e−87adhesion molecule 3 precursor 3 . . . 252189/252 (74%)(Carcinoembryonic antigen CGM1)(CD66d antigen) - Homo sapiens(Human), 252 aa.O75871NONSPECIFIC CROSS-REACTING 8 . . . 253137/252 (54%)2e−69ANTIGEN W236 - Homo sapiens 3 . . . 244168/252 (66%)(Human), 244 aa.Q03715CGM7 NONSPECIFIC CROSS- 8 . . . 253134/252 (53%)2e−67REACTING ANTIGEN (NCA) - Homo 3 . . . 244165/252 (65%)sapiens (Human), 244 aa.S33324carcinoembryonic antigen - human, 21212 . . . 187121/177 (68%)7e−62aa. 5 . . . 181135/177 (75%)Q13858BILIARY GLYCOPROTEIN - Homo12 . . . 199120/193 (62%)1e−57sapiens (Human), 252 aa. 5 . . . 197133/193 (68%)


[0506] PFam analysis indicates that the NOV35a protein contains the domains shown in the Table 35E.
191TABLE 35EDomain Analysis of NOV35aNOV35aIdentities/SimilaritiesExpectPfam DomainMatch Regionfor the Matched RegionValueNo Significant Matches Found



Example 36

[0507] The NOV36 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 36A.
192TABLE 36ANOV36 Sequence AnalysisSEQ ID NO:1534517 bpNOV36a,GTTTGAAAACACAAACACAATGGCAGGAAACAGCCTTGTTCTACCCATTGTTCTTTGGCG59484-01 DNAGGTCGAAAAGCGCCCACACATTGCATCTCAGCCGTACTTTTAACAGATGATGGGCCCASequenceCGATCGTAACAGGATGTCACGACGGACAAATATGTCTCTGGGATCTTTCAGTAGAACTGCAAGTGAATCCTCGAGCACTGTTGTTTGGTCATACAGCATCAATCACTTGTTTGTCTAAAGCTTGTGCTTCCAGTGACAAACAGTATATTGTGAGTGCATCTGAAAGTGGGGAGATGTGCCTCTGGGATGTGAGTGATGGCAGATGTATTGAATTTACAAAATTAGCTTGCACACATACTGGCATACAGTTCTACCAGTTCTCTGTTGGGAATCAGCGAGAAGGAAGGCTTTTATGCCACGGACATTACCCTGAAATCCTTGTTGTGGATCCTACCAGCCTTGAAGTATTATACTCCTTAGTATCAAAGATATCACCAGACTGGATTAGCTCCATGAGTATTATTCGATCCCACCGAACACAAGAGGACACAGTGGTAGCACTCTCGGTGACTGGCATCCTGAAGGTCTGGATTGTTACCTCGGAAATAAGTGACATGCAGGATACTGAGCCAATATTTCAGGAGGAATCCAAACCAATTTATTGTCAGAATTGCCAAAGCATCTCTTTTTGTGCATTTACACAAAGGTCACTTTTGGTTGTGTGTTCCAAATATTCGAGGGTATTCGATGCCGGAGACTATTCCTTGTTGTGTTCAGGTCCTAGTGAAAATGGACAGACATGGACCGGGGGGGACTTTGTCTCATCAGATAAAGTCATCATTTGGACAGAAAATGGGCAAAGTTATATTTACAAACTACCTGCCAGTTGCCTTCCAGCTAGTGATTCATTCCGCAGTGATGTGGGGAAGGCAGTTGAAAATTTAATTCCTCCTCTACAACATATCCTCTTGGATCGAAAAGATAAAGAGTTGCTAATTTGTCCTCCTGTTACTCGGTTCTTCTATGGATGCAGAGAATATTTCCATAAACTGTTAATTCAGGGTGATTCTTCTGGAAGGTTGAATATTTGGAACATATCAGACACAGCTGATAAACAGGGAAGTGAAGAAGGGCTGGCAATGACAACTTCTATTAGTTTGCAAGAGGCATTTGATAAACTGAATCCTTGTCCTGCTGGAATTATAGATCAGCTGAGTGTGATTCCCAATAGTAATGAACCTCTTAAAGTAACTGCAAGTGTGTACATACCAGCACATGGACGACTTGTTTGTGGTCGTGAAGATGGAAGCATAGTTATTGTACCTGCCACACAGACGGCCATAGTACAGCTGTTGCAAGGGGAACACATGCTCAGAAGAGGTTGGCCACCTCACAGAACACTCCGTGGTCATCGGAACAAAGTCACATGTTTGCTATATCCTCATCAGGTCTCAGCTCGGTATGATCAAAGATACCTGATATCTGGAGGTGTGGATTTTTCAGTCATAATTTGGGACATATTTTCTGGAGAAATGAAACATATCTTCTGTGTTCATGGTGGTGAGATTACTCAACTTCTAGTTCCACCTGAAAACTGTAGTGCAAGAGTACAGCACTGCATCTGCTCTGTAGCCAGTGACCACTCAGTAGGACTTCTAAGTTTGCGAGAGAAAAAATGCATAATGTTGGCATCTCGTCACCTTTTTCCTATTCAAGTAATCAAATGGAGGCCTTCTGATGATTACCTGGTGGTGGGGTGTTCAGATGGTTCTGTGTACGTCTGGCAAATGGATACTGGTGCATTGGATCGTTGTGTGATGGGGATAACAGCAGTTGAGATTCTAAACGCTTGTGATGAAGCTGTTCCTGCTGCTGTTGATTCACTTAGTCATCCAGCAGTCAACCTAAAACAAGCTATGACGAGACGTAGTCTTGCTGCTCTTAAAAATATGGCCCATCATAAGCTACAAACCCTTGCAACTAACCTCTTGGCTTCTGAGGCATCTGACAAGGGAAATTTACCTAAATATTCTCATAACTCCCTGATGGTTCAAGCAATAAAGACAAACCTAACAGACCCGGACATACATGTGCTATTCTTTGATGTGGAAGCGTTGATTATTCAACTCCTGACTGAAGAAGCCTCTAGGCCGAATACTGCTCTTATTTCCCCAGAGAATTTGCAAAAAGCATCTGCCAGTTCAGACAAAGGGGGCTCTTTTTTAACTGGAAAACGAGCAGCAGTTCTCTTCCAACAAGTGAAAGAAACGATCAAAGAGAACATCAAGGAACACCTCCTTGATGATGAACAGGAGGATGAGGAGATAATGAGGCAGAGAAGGGAAGAAAGTGATCCTGAATATCGGTCCAGCAAATCAAAGCCATTGACCCTATTAGAATATAATTTAACTATGGACACTGCAAAGCTGTTTATGTCCTGCCTTCACGCCTGGGGTTTGAATGAAGTACTGGATGAAGTTTGCCTGGATCGCCTTGGAATGCTGAAACCCCACTGCACCGTATCGTTTGGCCTCTTGTCAAGAGGAGGCCATATGTCACTGATGCTGCCGGGTTATAATCAGCCTGCTTGTAAACTGTCACATGGGAAAACAGAAGTAGGAAGGAAGCTGCCAGCGTCTGAGGGAGTAGGAAAGGCAACTTACGCAGTGTCCCGTGCCGTCACCACACAGCATCTCCTGTCTATCATTTCTTTGGCAAATACTTTAATGAGTATGACCAATGCAACTTTTATTGGTGATCATATGAAGAAGGGTCCTACCAGGCCACCTAGACCAAGCACCCCAGACCTTTCTAAGGCAAGGGGTTCCCCTCCAACTTCCAGTAATATTGTGCAAGGACAGATTAAACAAGTTGCTGCACCTGTCGTTTCCGCTCGGTCTGATGCTGATCACTCTGGCTCTGACCCTCCTTCTGCTCCTGCTTTACATACCTGTTTCTTAGTAAATGAAGGTTCGAGTCAGTTAGCTGCTATGCACTGTGTTATGCTGCCAGACCTACTGGGATTGGATAAATTTAGCCCTCCCCTTCTGCAGATGCTCGCCCGAAGATGGCAAGATCGATGCTTGGAGGTAAGAGAAGCCGCGCAGGCCCTGCTTCTGGCGGAACTGAGAAGAATTGAGCAGGCAGGCAGGAAGGAAGCCATTGATGCCTCGGCTCCTTACTTACCTCAGTACATAGACCACGTCATATCACGTGGAGTCACATCAGAAGCCGCGCAGACTATCACCACGGCTCCTGATGCCTCAGGGCCTGAAGCAAAAGTCCAGGAGGAAGAGCATGACCTTGTTGACGATGACATCACCACTGGTTGCTTATCAAGTGTCCCACAAATGAAAAAAATTTCTACATCTTACGAGGAAAGACGGAAGCAAGCTACCGCTATTGTTTTACTTGCAGTAATAGGAGCTGAATTTGGTGCTGAAATTGAACCTCCTAAACTATTGACCAGACCTCGAAGCTCTAGCCAAATTCCTGAGGGATTCGGGTTGACTAGTGGTGGATCCAACTACTCGCTGGCCAGACATACTTCCAAGGCACTGACGTTTCTTCTGCTACAGCCTCCAAGCCCCAAACTTCCTCCACACAGCACTATCCGAAGAACAGCCATTGATCTGATTGGACGTGGGTTCACTGTTTGGGAGCCTTACATGGATGTGTCCGCTGTTCTGATGGGGCTTCTCGAACTTTCTGCCGATGCCGAGAAACAACTTGCCAACATCACAATGGGGTTGCCTCTGAGCCCAGCAGCTGACTCGGCCCGCTCTGCGAGCCATGCCCTCTCGCTCATTGCCACCCCCAGACCACCCGCCTTCATCACCACCATAGCCAAAGAGGTACACAGACATACGGCTCTTGCAGCAAATACCCAATCACAGCAGAATATGCACACAACAACTCTTGCACGAGCTAAAGGGGAAATTTTGAGAGTCATTGAAATTCTTATTGAAAAGATGCCCACAGATGTTGTGGATCTTCTCGTGGAGGTTATGGACATCATTATGTACTGCCTTGAACGATCTTTAGTTAAAAAGAAAGGTCTTCAAGAATGTTTCCCAGCCATCTGCAGGTTCTACATGGTCAGCTATTATGAGCGGAATCACAGAATAGCAGTTCGAGCTCGCCATGGTTCAGTGGCCCTGTACGACATCCGGACTGGAAAATGTCAGACAATCCATGGACACAAGGGACCAATCACTGCAGTGCCTTTTGCTCCTGATGGAAGATATCTTGCCACCTACTCAAACACTGACAGCCACATTTCTTTTTGGCAGATGAACACGTCACTGCTGGGAACCATCGGCATGCTGAACTCGGCACCTCAGCTGCGCTGCATTAAAACCTACCAGGTGCCCCCTGTGCAGCCCGCGTCCCCCGGCTCCCACAATGCCCTCAAGCTGGCCCGGCTCATCTGGACTTCCAACCGCAACGTCATCCTCATGGCCCATGACGGGAAGGAGCACCGCTTCATGGTCTAATGCTGCTGCCTGCCGCCGTGACTGCORF Start: ATG at 20ORF Stop: TAA at 4490SEQ ID NO:1541490 aa MW at 163853.2 kDNOV36a,MAGNSLVLPIVLWGRKAPTHCISAVLLTDDGATIVTCCHDGQICLWDLSVELQVNPRACG59484-01 ProteinLLFGHTASITCLSKACASSDKQYIVSASESGEMCLWDVSDGRCIEFTKLACTHTGIQFSequenceYQFSVGNQREGRLLCHGHYPEILVVDATSLEVLYSLVSKISPDWISSMSIIRSHRTQEDTVVALSVTGILKVWIVTSEISDMQDTEPIFEEESKPIYCQNCQSISFCAFTQRSLLVVCSKYWRVFDAGDYSLLCSGPSENGQTWTGGDFVSSDKVIIWTENGQSYIYKLPASCLPASDSFRSDVGKAVENLIPPVQHILLDRKDKELLICPPVTRFFYGCREYFHKLLIQGDSSGRLNIWNISDTADKQGSEEGLAMTTSISLQEAFDKLNPCPAGIIDQLSVIPNSNEPLKVTASVYIPAHGRLVCGREDGSIVIVPATQTAIVQLLQGEHMLRRGWPPHRTLRGHRNKVTCLLYPHQVSARYDQRYLISGGVDFSVIIWDIFSGEMKHIFCVHGGEITQLLVPPENCSARVQHCICSVASDHSVGLLSLREKKCIMLASRHLFPIQVIKWRPSDDYLVVGCSDGSVYVWQMDTGALDRCVMGITAVEILNACDEAVPAAVDSLSHPAVNLKQAMTRRSLAALKNMAHHKLQTLATNLLASEASDKGNLPKYSHNSLMVQAIKTNLTDPDIHVLFFDVEALlIQLLTEEASRPNTALISPENLQKASGSSDKGGSFLTGKPAAVLFQQVKETIKENIKEHLLDDEEEDEEIMRQRREESDPEYRSSKSKPLTLLEYNLTMDTAKLFMSCLHAWGLNEVLDEVCLDRLGMLKPHCTVSFGLLSRGGHMSLMLPGYNQPACKLSHGKTEVGRKLPASEGVGKGTYGVSRAVTTQHLLSIISLANTLMSMTNATFIGDHMKKGPTRPPRPSTPDLSKARGSPPTSSNIVQGQIKQVAAPVVSARSDADHSGSDPPSAPALHTCFLVNEGWSQLAAMHCVMLPDLLGLDKFRPPLLEMLARRWQDRCLEVREAAQALLLAELRRIEQAGRKEAIDAWAPYLPQYIDHVISRGVTSEAAQTITTAPDASGPEAKVQEEEHDLVDDDITTGCLSSVPQMKKISTSYEERRKQATAIVLLGVIGAEFGAEIEPPKLLTRPRSSSQIPEGFGLTSGGSNYSLARHTCKALTFLLLQPPSPKLPPHSTIRRTAIDLIGRGFTVWEPYMDVSAVLMGLLELCADAEKQLANITMGLPLSPAALSARSARHALSLIATARPPAFITTIAKEVHRHTALAANTQSQQNMHTTTLARAKGEILRVIEILIEKMPTDVVDLLVEVMDIIMYCLEGSLVKKKGLQECFPAICRFYMVSYYERNHRIAVGARHGSVALYDIRTGKCQTIHGHKGPITAVAFAPDGRYLATYSNTDSHISFWQMNTSLLGSIGMLNSAPQLRCIKTYQVPPVQPASPGSHNALKLARLIWTSNRNVILMAHDGKEHRFMV


[0508] Further analysis of the NOV36a protein yielded the following properties shown in Table 36B.
193TABLE 36BProtein Sequence Properties NOV36aPSort0.8110 probability located in plasma membrane; 0.6400analysis:probability located in endoplasmic reticulum (membrane);0.3700 probability located in Golgi body;0.1000 probability located in endoplasmic reticulum (lumen)SignalPCleavage site between residues 22 and 23analysis:


[0509] A search of the NOV36a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 36C.
194TABLE 36CGeneseq Results for NOV36aNOV36aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAE10802Human TGF-beta Resistance 1 . . . 14901489/1490 (99%)0.0Associated Gene (TRAG) protein -  1 . . . 14901489/1490 (99%)Homo sapiens, 1490 aa.[WO200166739-A1, 13-SEP-2001]AAE10803Mouse TGF-beta Resistance 1 . . . 14901415/1490 (94%)0.0Associated Gene (TRAG) protein -  1 . . . 14891450/1490 (96%)Mus sp, 1489 aa. [WO200166739-A1,13-SEP-2001]AAE10801Rat TGF-beta Resistance Associated 1 . . . 14901408/1490 (94%)0.0Gene (TRAG) protein - Rattus sp, 1 . . . 14881446/1490 (96%)1488 aa. [WO200166739-A1,13-SEP-2001]AAM40548Human polypeptide SEQ ID NO 5479 -454 . . . 594  38/146 (26%)2e−07Homo sapiens, 277 aa. 48 . . . 181  63/146 (43%)[WO200153312-A1, 26-JUL-2001]AAM40547Homo sapiens, 277 aa. 48 . . . 181  63/146 (43%)2e−07[WO200153312-A1, 26-JUL-2001]


[0510] In a BLAST search of public sequence databases, the NOV36a protein was found to have homology to the proteins shown in the BLASTP data in Table 36D.
195TABLE 36DPublic BLASTP Results for NOV36aNOV36aProteinResidues/Identities/AccessionMatchSimilarities for theExpectNumberProtein/Organism/LengthResiduesMatched PortionValueCAC88575SEQUENCE 3 FROM PATENT1 . . . 14901489/1490 (99%)0.0WO0166739 - Homo sapiens1 . . . 14901489/1490 (99%)(Human), 1490 aa.Q96PS7TGF-BETA RESISTANCE-1 . . . 14901456/1490 (97%)0.0ASSOCIATED PROTEIN TRAG - 1 . . . 14571456/1490 (97%)Homo sapiens (Human), 1457 aa(fragment).CAC88576SEQUENCES 5 FROM PATENT1 . . . 14901415/1490 (94%)0.0WO0166739 - unidentified, 1489 aa.1 . . . 14891450/1490 (96%)Q92019TGF-BETA RESISTANCE-1 . . . 14901414/1490 (94%)0.0ASSOCIATED PROTEIN TRAG - 1 . . . 14891449/1490 (96%)Mus musculus (Mouse), 1489 aa(fragment).Q9ERH3TGF-BETA RESISTANCE-1 . . . 14901408/1490 (94%)0.0ASSOCIATED PROTEIN - Rattus1 . . . 14881446/1490 (96%)norvegicus (Rat), 1488 aa.


[0511] PFam analysis indicates that the NOV36a protein contains the domains shown in Table 36E.
196TABLE 36EDomain Analysis of NOV36aIdentities/SimilaritiesNOV36a Matchfor the MatchedExpectPfam DomainRegionRegionValueWD40: domain 1 of 811 . . . 47 9/37 (24%)0.02229/37 (78%)WD40: domain 2 of 856 . . . 9510/40 (25%)1430/40 (75%)WD40: domain 3 of 8151 . . . 190 5/41 (12%)1.5e+0327/41 (66%)WD40: domain 4 of 8209 . . . 242 6/37 (16%)5.7e+0223/37 (62%)HSF_DNA-bind:267 . . . 282 7/16 (44%)3.1domain 1 of 114/16 (88%)WD40: domain 5 of 8456 . . . 49815/43 (35%)0.004830/43 (70%)WD40: domain 6 of 8504 . . . 546 6/43 (14%)2.7e+0227/43 (63%)WD40: domain 7 of 8552 . . . 588 8/37 (22%)0.2226/37 (70%)WD40: domain 8 of 81386 . . . 142311/38 (29%)429/38 (76%)



Example 37

[0512] The NOV37 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 37A.
197TABLE 37ANOV37 Sequence AnalysisSEQ ID NO:155848 bpNOV37a,GCCTCGCTCGGGCGCCCAGTGGTCCTGCCGCCTGGTCTCACCTCGCCATGGTTCGTCTCG57245-02 DNAGCCTCTGCAGTGCGTCCTCTGGGGCTGCTTGCTGACCGCTGTCCATCCAGAACCACCCSequenceACTGCATGCAGAGAAAAACAGTACCTAATAAACAGTCAGTGCTGTTCTTTGTCCCAGCCAGGACAGAAACTGGTGAGTGACTGCACAGAGTTCACTGAAACGGPATGCCTTCCTTGCGGTGAAAGCGAATTCCTAGACACCTGGAACAGAGAGACACACTGCCACCAGCACAAATACTGCGACCCCAACCTAGGGCTTCGGGTCCAGCAGAAGGGCACCTCAGAAACAGACACCATCTGCACCTGTGAAGAAGGCTGGCACTGTACGAGTGAGGCCTGTGAGAGCTGTGTCCTGCACCGCTCATGCTCGCCCGGCTTTGGGGTCAAGCAGATTGGTCCCCAGGATCGGCTGAGAGCCCTGGTCGTGATCCCCATCATCTTCGGGATCCTGTTTGCCATCCTCTTGGTGCTGGTCTTTATCAAAAAGGTGGCCAAGAAGCCAACCAATAAGGCCCCCCACCCCAAGCAGGAACCCCAGGAGATCAATTTTCCCGACGATCTTCCTGGCTCCAACACTGCTGCTCCAGTGCAGGACACTTTACATGGATGCCAACCGGTCACCCAGGAGGATGGCAAAGAGAGTCGCATCTCAGTGCAGGAGAGACAGTGAGGCTGCACCCACCCAGGAGTGTGGCCACGTGGCCAAACAGGCAGTTGGCCAGAGAGCCTGGTGCTGCTGCTGCAGGGGTGCAGGCAGAAGCGGGGAGCTATGCCCAGTCAGTGCCAGCCCCTCORF Start: ATG at 48ORF Stop: TGA at 723SEQ ID NO:156225 aa MW at 25098.5 kDNOV37a,MVRLPLQCVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECG57245-02 ProteinCLPCCESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACSequenceESCVLHRSCSPGFGVKQIGPQDRLRALVVIPIIFGILFAILLVLVFIKKVAKKPTNKAPHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDCKESRISVQERQSEQ ID NO:1571016 bpNOV37b,GCCTCGCTCGGGCGCCCAGTGGTCCTGCCGCCTGGTCTCACCTCGCCATGGTTCGTCTCG57245-04 DNAGCCTCTGCAGTGCGTCCTCTGGGGCTGCTTGCTGACCGCTGTCCATCCAGAACCACCCSequenceACTGCATGCAGAGAAAAACAGTACCTAATAAACAGTCAGTGCTGTTCTTTGTGCCAGCCAGGACACAAACTGGTGAGTGACTGCACAGAGTTCACTGAAGCGGAATGCCTTCCTTGCGGTGAAACCGAATTCCTAGACACCTGGAACAGAGAGACACACTGCCACCAGCACAAATACTGCGACCCCAACCTAGGGCTTCGGGTCCAGCAGAAGGGCACCTCAGAAACAGACACCATCTGCACCTGTGAAGAAGGCTGGCACTGTACGAGTGAGGCCTGTGAGAGCTGTGTCCTGCACCGCTCATGCTCGCCCGGCTTTGGGGTCAAGCAGATTGCTACAGGGGTTTCTGATACCATCTGCGAGCCCTGCCCAGTCGGCTTCTTCTCCAATGTGTCATCTGCTTTCGAAAAATGCCACCCTTGCACAAGCTGTGAGACCAAACACCTGGTTGTGCAACAGGCAGGCACAAACAAGACTGATGTTGTCCGTGGTCCCCAGGATCGGCTGAGAGCCCTGGTGGTGATCCCCATCATCTTCGGGATCCTGTTTGCCATCCTCCTGGTGCTGGTCTTTATCAGTGAGTCCTCAGAAAAGGTGGCCAAGAAGCCAACCAATAAGGCCCCCCACCCCAAGCAGGAACCCCAGGAGATCAATTTTCCCGACGATCTTCCTGGCTCCAACACTGCTGCTCCAGTGCAGGAGACTTTACATGGATGCCAACCGGTCACCCAGGAGGATGGCAAAGAGAGTCGCATCTCAGTGCAGGAGAGACAGTGAGGCTGCACCCACCCAGGAGTGTGGCCACGTGGGCAAACAGGCAGTTGGCCAGAGAGCCTGGTGCTGCTGCTGCAGGGGTGCAGGCAGAAGCCGGGAGCTATGCCCAGTCAGTGCCAGCCCCTCORF Start: ATG at 48ORF Stop: TGA at 891SEQ ID NO:1581281 aa MW at 31033.0 kDNOV37b,MVRLPLQCVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTEAECG57245-04 ProteinCLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACSequenceESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVVRCPQDRLRALVVIPIIFGILFAILLVLVFISESSEKVAKKPTNKAPHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQSEQ ID NO:159375 bpNOV37c,AGATCTGAACCACCCACTGCATGCAGAGAAAAACAGTACCTAATAAACAGTCAGTCCT174308232 DNAGTTCTTTGTGCCAGCCAGGACAGAAACTGGTGAGTGACTGCACAGAGTTCACTGAAACSequenceGCAATGCCTTCCTTGCGGTGAAAGCGAATTCCTAGACACCTGGAACAGAGAGACACACTGCCACCAGCACAAATACTGCGACCCCAACCTAGGGCTTCGGGTCCAGCAGAAGGGCACCTCAGAAACAGACACCATCTGCACCTGTGAAGAAGGCTGGCACTGTACGAGTGAGGCCTGTGAGAGCTGTGTCCTGCACCGCTCATGCTCGCCCGGCTTTGGGGTCAAGCAGATTGGTCCCCAGGATCGGCTGAGACTCGAGORF Start: AGA at 1ORF Stop: at 376SEQ ID NO:160125 aa MW at 14132.6 kDNOV37c,RSEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETH174308232 ProteinCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACESCVLHRSCSPGFGVKQISequenceCPQDRLRLE


[0513] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 37B.
198TABLE 37BComparison of NOV37a against NOV37b through NOV37c.NOV37a Residues/Identities/SimilaritiesProtein SequenceMatch Residuesfor the Matched RegionNOV37b1 . . . 225204/281 (72%)1 . . . 281205/281 (72%)NOV37c21 . . . 141 121/121 (100%)3 . . . 123 121/121 (100%)


[0514] Further analysis of the NOV37a protein yielded the following properties shown in Table 37C.
199TABLE 37CProtein Sequence Properties NOV37aPSort0.4600 probability located in plasma membrane;analysis:0.1000 probability located inendoplasmic reticulum (membrane);0.1000 probability located in endoplasmicreticulum (lumen); 0.1000 probability located in outsideSignalPCleavage site between residues 21 and 22analysis:


[0515] A search of the NOV37a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 37D.
200TABLE 37DGeneseq Results for NOV37aNOV37aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAB20170Human CD40 receptor splice variant -1 . . . 225225/246 (91%)e−134Homo sapiens, 246 aa. [WO200105967-1 . . . 246225/246 (91%)A1, 25-JAN-2001]AAB84892Human CD40 antigen - Homo sapiens,1 . . . 225225/277 (81%)e−130277 aa. [WO200130974-A2, 03-MAY-2001]1 . . . 277225/277 (81%)AAB37807Human CD40 - Homo sapiens, 277 aa.1 . . . 225225/277 (81%)e−130[WO200066155-A1, 09-NOV-2000]1 . . . 277225/277 (81%)AAB50520Human tumour necrosis factor receptor1 . . . 225225/277 (81%)e−130CD40 protein SEQ ID NO: 10 - Homo1 . . . 277225/277 (81%)sapiens, 277 aa. [WO200071150-A1,30-NOV-2000]AAY52701Human CD40 protein - Homo sapiens,1 . . . 225225/277 (81%)e−130277 aa. [WO9953101-A1, 21-OCT-1999]1 . . . 277225/277 (81%)


[0516] In a BLAST search of public sequence databases, the NOV37a protein was found to have homology to the proteins shown in the BLASTP data in Table 37E.
201TABLE 37EPublic BLASTP Results for NOV37aNOV37aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueP25942Tumor necrosis factor receptor1 . . . 225225/277 (81%) e−130superfamily member 5 precursor1 . . . 277225/277 (81%)(CD40L receptor) (B-cell surfaceantigen CD40) (Bp50) (CDw40) - Homosapiens (Human), 277 aa.Q9BYU0CD40 TYPE II ISOFORM - Homo1 . . . 134 134/134 (100%)1e−82sapiens (Human), 203 aa.1 . . . 134 134/134 (100%)A46476B cell-associated surface molecule1 . . . 225137/281 (48%)3e−73CD40, long splice form - mouse, 305 aa.1 . . . 278168/281 (59%)P27512Tumor necrosis factor receptor1 . . . 225137/281 (48%)3e−73superfamily member 5 precursor1 . . . 278168/281 (59%)(CD40L receptor) (B-cell surfaceantigen CD40) (BP50) (CDw40) - Musmusculus (Mouse), 289 aa.Q99NE0CD40 TYPE V ISOFORM - Mus1 . . . 225130/252 (51%)7e−67musculus (Mouse), 260 aa.1 . . . 249157/252 (61%)


[0517] PFam analysis indicates that the NOV37a protein contains the domains shown in the Table 37F.
202TABLE 37FDomain Analysis of NOV37aIdentities/SimilaritiesNOV37afor theExpectPfam DomainMatch RegionMatched RegionValueTNFR_c6: domain26 . . . 5919/42 (45%)2.7e−091 of 230/42 (71%)EB: domain26 . . . 7710/60 (17%)8.31 of 133/60 (55%)TNFR_c6: domain 62 . . . 10311/44 (25%)0.92 of 229/44 (66%)ATP-synt_B: domain 148 . . . 174   5/27 (19%)6.81 of 123/27 (85%)



Example 38

[0518] The NOV38 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 38A.
203TABLE 38ANOV38 Sequence AnalysisSEQ ID NO:1611080 bpNOV38a,GATTTAATTGGCATTATTGTGTTCCCGACCATGACTGCAGAGACCATGGAGCTGAAGTCG59454-01 DNAGGGTGAGTTTCCTGGCCTTCCTTCTGCTCAACTTTCGTGTCTGCCTCCTTTTGCTTCASequenceGCTGCTCATGCCTCACTCAGCTCAGTTTTCTCTCCTTGGACCCTCTGGGCCCATCCTGGCCATGGTGGGTGAAGACGCTGATCTGCCCTGTCACCTGTTCCCGACCATGAGTGCAGAGACCATGGAGCTGAAGTGGGTAAGTTCCAGCCTAAGGCAGGTGGTGAACGTGTATGCAGATGGAAZGGAAGTGGAAGACAGGCAGAGTGCACCGTATCGAGGGAGAACTTCGATTCTGCGGGATGGCATCACTGCGGGGAAGGCTGCTCTCCGAATACACAACGTCACAGCCTCTGACAGTGGAAAGTACTTGTCTTATTTCCAAGATGGTGACTTCTATCAAAAACCCCTGGTGGAGCTGAAGGTTGCAGCACTGGGTTCTAATCTTCACGTCGAAGTGAAGGGTTATGAAGATGGAGGCATCCATCTGCAGTGCAGGTCCACCCCCTGGTACCCCCAACCCCAAATACAGTGGGGCAACGCCAAGGGAGAGAACATCCCAGCTGTGGAAGCACCTGTGGTTGCAGATGGAGTGGGCCTATATGAAGTAGCAGCATCTGTGATCATGAAAAGCCGCTCCGGGGAAGGTGTATCCTGCATCATCAGAAATTCCCTCCTCGGCCTGGAAAAGACAGCCAGCATTTCCATCGCAGACCCCTTCTTCAGGAGCGCCCAGCCCTGGATCGCAGCCCTGGCAGGGACCCTGCCTATCTTGCTGCTGCTTCTCGCCGGAGCCAGTTACTTCTTGTCGAGACAACAGAAGGAAATAACTGCTCTGTCCAGTGAGATAGAAAGTGAGCAAGAGATGAAAGAAATGGGATATGCTGCAACAGAGCGGGAAATAAGCCTAAGAGAGAGCCTCCAGGAGGAACTCAAGAGGAAAAAAATCCAGTACTTGACTCGTGGAGAGGAGTCTTCGTCCGATACCAATAAGTCAGCCTGATGCTCTAATGGAAAAATGGCCCTCORF Start: ATG at 31ORF Stop: TGA at 1054SEQ ID NO:162341 aa MW at 37417.4 kDNOV38a,MSAETMELKWVSFLAFLLLNFRVCLLLLQLLMPHSAQFSVLGPSGPILAMVGEDADLPCG59454-01 ProteinCHLFPTMSAETMELKWVSSSLRQVVNVYADCKEVEDRQSAPYRGRTSILRDGITAGKASequenceALRIHNVTASDSGKYLCYFQDGDFYEKALVELKVAALGSNLHVEVKGYEDGGIHLECRSTGWYPQPQIQWGNAKGENIPAVEAPVVADGVGLYEVAASVIMKSCSGEGVSCIIRNSLLCLEKTASISIADPFFRSAQPWIAALAGTLPILLLLLAGASYFLWRQQKEITALSSEIESEQEMKEMGYAATEREISLRESLQEELKRKKIQYLTRGEESSSDTNKSASEQ ID NO:163935 bpNOV38b,ATTTGCTTTCTCTTTTTCCTTTCTTCCGGATGAGAGGCTAAGCCATAATAGAAAGAATCG 59454-03 DNAGGAGAATTATTGATTGACCGTCTTTATTCTGTGGGCTCTCATTCTCCAATGGGAATACSequenceCAAGCCATGGTTTTCCATACTGGAACCCAAAGGTAAAGACACTCAAGGACAGACATTTTTGGCAGAGCATAGATGAAAATGGCAAGTTCCCTCGCTTTCCTTCTGCTCAACTTTCATGTCTCCCTCCTCTTGGTCCAGCTGCTCACTCCTTGCTCAGCTCAGTTTTCTGTGCTTGGACCCTCTGGGCCCATCCTGGCCATGGTGGGTGAAGACGCTGATCTGCCCTGTCACCTGTTCCCGACCATCAGTGCAGAGACCATCGAGCTGAAGTGGGTAAGTTCCAGCCTAAGGCAGGTGGTGAATGTGTATGCAGATGGAAAGGAAGTGGAAGACAGGCAGACTGCACCGTATCGAGGGAGAACTTCGATTCTGCGGGATGGCATCACTGCAGGGAAGGCTGCTCTCCGAATACACAACGTCACAGCCTCTGACAGTGGAAAGTACTTGTGTTATTTCCAAGATGGTGACTTCTATGAAAAAGCCCTGGTGGAGCTGAAGGTTGCAGACCCCTTCTTCAGGAGCGCCCAGCCCTGGATCGCAGCCCTGGCAGGGACCCTGCCTATCTTGCTGCTGCTTCTCGCCGGAGCCAGTTACTTCTTGTGGAGACAACACAAGGAAATAACTGCTCTGTCCAGTGAGATAGAAAGTGAGCAAGAGATGAAAGAAATGGGATATGCTGCAACAGAGCGGGAAATAAGCCTAAGAGAGACCCTCCAGGAGGAACTCAACAGGAAAAAAATCCAGTACTTGACTCGTGGAGAGGAGTCTTCGTCCGATACCAATAAGTCAGCCTGATGCTCTAATGGAAAAATGGCCCTCORF Start: ATG at 189ORF Stop: TGA at 909SEQ ID NO:164240 aa MW at 26651.2 kDNOV38b,MKMASSLAFLLLNFHVSLLLVQLLTPCSAQFSVLGPSGPILAIVIVGEDADLPCHLFPTMCG59454-03 ProteinSAETMELKWVSSSLRQVVNVYADGKEVEDRQSAPYRGRTSILRDGITAGKAALRIHNVSequenceTASDSGKYLCYFQDGDFYEKALVELKVADPFFRSAQPWIAALAGTLPILLLLLAGASYFLWRQQKEITALSSEIESEQEMKEMGYAATEREISLRESLQEELKRKKIQYLTRGEESSSDTNKSASEQ ID NO:1651689 bpNOV38c,ATTTGCTTTCTCTTTTTCCTTTCTTCCGGATGAGAGGCTAAGCCATAATAGAAAGAATCG59454-04 DNAGGAGAATTATTCATTGACCGTCTTTATTCTGTGGGCTCTGATTCTCCAATGGGAATACSequenceCAAGCGATGGTTTTCCATACTGGAACCCAAAGGTAAAGACACTCAAGGACAGACATTTTTGGCAGAGCATAGATGAAAATCGCAAGTTCCCTGGCTTTCCTTCTGCTCAACTTTCATGTCTCCCTCCTCTTGGTCCAGCTGCTCACTCCTTGCTCAGCTCAGTTTTCTGTGCTTGGACCCTCTGGGCCCATCCTGGCCATGGTGGGTGAAGACGCTGATCTGCCCTGTCACCCGTTCCCGACCATGAGTGCAGAGACCATGGAGCTGAAGTGGGTAAGTTCCAGCCTAAGTATCGAGGGAGAACTTCGATTCTGCGGGATGCCATCACTGCACGGAAGGCTGCTCTCCGAATACACAACGTCACAGCCTCTGACAGTGGAAAGTACTTGTGTTATTTCCAAGATGGTGACTTCTATGAAAAAGCCCTGGTGGAGCTGAAGGTTGCAGCACTGGGTTCTAATCTTCACGTCGAAGTGAAGGGTTATGAGGATGGAGGGATCCATCTGGAGTGCAGGTCCACCGGCTGGTACCCCCAACCCCAAATACAGTGGAGCAACGCCAAGGGAGAGAACATCCCAGCTGTGGAAGCACCTCTGGTTGCAGATGGAGTGGGCCTATATGAAGTAGCAGCATCTGTGATCATGAGAGGCGGCTCCGGGGAGGGTGTATCCTGCATCATCAGAAATTCCCTCCTCGGCCTGGAAAAGACAGCCAGCATTTCCATCGCAGAGAGCCTCCAGGAGGAACTCAAGAGGAAAAAATCCAGTACTTGACTCGTGGAGAGGAGTCTTCGTCCGATACCAATAAGTCAGCCTGATGCTCTAATGGAAAAATGGCCCTCTTCAAGCCTGCAGATGTAATTCTGTATCCAGACATGGCAAATGCCATCCTCCTTGTTTCTGAGGACCAGAGGAGTGTACAGCGTGCTGAGGAGCCCCATGACCTACCAGACAACCCTGAGAGATTTGAATGGCGTTACTGTGTGCTTGGCTGTGAAAGCTTCATGTCAGAGAGACACTACTCGGAGGTGGAAGTGGCGGACAGAAAAGAGTGGCATATTGGGCTATGTAGTAAGAACGTGGAGAGGAAAAAAGTTTGGGTCAAAATGACACCGGAGAACGGATACTGGACTATGGGCCTGACTGATGGGAATAAGTATCGGGCTCTCACTGAGCCCAGAACCAACCTGAAACTTCCTGAGCCTCCTAGGAAAGTGGGGGTCATCCTGGACTATGAGACTGGACATATCTCGTTCTACAATGCCACGGATGGATCTCATATCTACACATTTCTGCACGCCTCTTCCTCTGAGCCTCTGTATCCTGTATTCAGAATTTTGACCTTGGAGCCCACTGCCCTGACCGTTTGCCCAATACCAAAAGTAGAGAGTTCCCCCGATCCCGACCTAGTGCCTGATCATTCCCTGGAGATACCACTGACCCCAGGCTTAGCTAATGAAAGTGGGCACCCTCAGGCTGAAGTAACATCTCTGCTTCTCCCTGCCCAGCCTGGAGCORF Start: ATG at 189ORF Stop: TGA at 945SEQ ID NO:166252 aa MW at 27148.7 kDNOV38c,MKMASSLAFLLLNFHVSLLLVQLLTPCSAQFSVLGPSGPILANVGEDADLPCHPFPTMCG59454-04 ProteinSAETMELKWVSSSLRQVVNVYADGKEVEDRQSAPYRGRTSILRDGITAGKAALRIHNVSequenceTASDSGKYLCYFQDGDFYEKALVELKVAALGSNLHVEVKGYEDGGIHLECRSTGWYPQPQIQWSNAKGENIPAVEAPVVADGVGLYEVAASVIMRGGSGEGVSCIIRNSLLGLEKTASISIAESLQEELKRKKSST


[0519] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 38B.
204TABLE 38BComparison of NOV38a against NOV38b through NOV38c.NOV38a Residues/Identities/Similarities forProtein SequenceMatch Residuesthe Matched RegionNOV38b33 . . . 151118/119 (99%)26 . . . 144118/119 (99%)NOV38c33 . . . 246208/214 (97%)26 . . . 239210/214 (97%)


[0520] Further analysis of the NOV38a protein yielded the following properties shown in Table 38C.
205TABLE 38CProtein Sequence Properties NOV38aPSort0.6850 probability located in endoplasmic reticulumanalysis:(membrane); 0.6400 probability located in plasma membrane;0.4600 probability located in Golgi body;0.1000 probability located in endoplasmic reticulum (lumen)SignalP Cleavage site between residues 37 and 38analysis:


[0521] A search of the NOV38a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 38D.
206TABLE 38DGeneseq Results for NOV38aNOV38aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAW99661Human secreted protein clone cc 130_18 . . . 341323/334 (96%)0.0protein - Homo sapiens, 334 aa.1 . . . 334325/334 (96%)[WO9907840-A1, 18-FEB-1999]AAW71592Human myelin oligodendrocyte8 . . . 334315/327 (96%)e−178glycoprotein-like protein - Homo1 . . . 327318/327 (96%)sapiens, 331 aa. [WO9833912-A1, 06-AUG-1998]AAW78917Bovine butyrophilin protein BTF4 -8 . . . 323304/316 (96%)e−172Bos sp, 319 aa. [WO9814466-A1, 09-1 . . . 316307/316 (96%)APR-1998]AAW78916Bovine butyrophilin protein BTF3 -8 . . . 333290/326 (88%)e−165Bos sp, 584 aa. [WO9814466-A1, 09-1 . . . 326303/326 (91%)APR-1998]AAW78918Bovine butyrophilin protein BTF5 -8 . . . 335273/328 (83%)e−156Bos sp, 513 aa. [WO9814466-A1, 09-1 . . . 328294/328 (89%)APR-1998]


[0522] In a BLAST search of public sequence databases, the NOV38a protein was found to have homology to the proteins shown in the BLASTP data in Table 38E.
207TABLE 38EPublic BLASTP Results for NOV38aNOV38aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ9NR44BUTYROPHILIN, SUBFAMILY 3,8 . . . 341325/334 (97%)0.0MEMBER A2 - Homo sapiens1 . . . 334327/334 (97%)(Human), 334 aa.Q9BU81SIMILAR TO BUTYROPHILIN,8 . . . 341322/334 (96%)0.0SUBFAMILY 3, MEMBER A21 . . . 334325/334 (96%)(DJ45P21.5) - Homo sapiens (Human),334 aa.P78410HYPOTHETICAL 39.4 KDA8 . . . 341322/334 (96%)0.0PROTEIN - Homo sapiens (Human),1 . . . 334325/334 (96%)359 aa.O15338BUTYROPHILIN - Homo sapiens12 . . . 341 320/330 (96%)e−180(Human), 357 aa.3 . . . 332322/330 (96%)O00477BUTYROPHILIN - Homo sapiens8 . . . 323304/316 (96%)e−171(Human), 319 aa.1 . . . 316307/316 (96%)


[0523] PFam analysis indicates that the NOV38a protein contains the domains shown in Table 38F.
208TABLE 38FDomain Analysis of NOV38aIdentities/Nov38aSimilaritiesExpectPfam DomainMatch Regionfor the Matched RegionValueig: domain 1 of 152 . . . 13514/85 (16%)0.0006955/85 (65%)



Example 39

[0524] The NOV39 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 39A.
209TABLE 39ANOV39 Sequence AnalysisSEQ ID NO:1679705 bpNOV39a,ATGGACCCTGCTCAGCGCCCGGCCCCTGGGGCTGCTATTGTCGAGGGCCTGCCCTCTCCG59307-01 DNACCTCAGACGCCTCCCTGGAGAGCCAAGCTGGTGTTCGAGGGTCCACCCTGCTGCCCAASequenceCAGCCCCGCGGCCACCAGAGGGCCGTCCCTGGCCCGGCTGTGTGCCCTGGTGGACCTGTGTCTGGGCTGCTCCCGCTGCACCCAGCGGCTCAATGAAAGCACCTACGTCCTCCGTAGGGTGGAGCATGACTGCTCCCGCGAGATCCTGCTGGCCCGCTTTAAGCAGGCCACCAAGAGCAACGTCTGGCCCGTGGTGGGCTGCCGGCCCACCTTCCCAAGCCCCCTGTCCTACCAAGTCTGCCACTACTACAGCCCTGGGCTCGGCTGCCGGCGCCACCGAAACCGGTGCACCTTTGCCCGCAGTCGCCAGGAGGCCCTGGTCTGGACCTTCGAGCGTCAGCACAACCTCCAGCGCCTATGGCTGAAGGCGGAGGTGCAGCGCAGCGGGGCCCAGGGAGGGGCAGGCCGGGCGGCCGACGCCATCCTTACGGAGTTTGGCGGCCGCTTCGAGCTGCTTTGCTCCCTCTGCTTCAGGCGCTGTCCCCCATGCATCTGTCGCGTGGACCCCCAGGGGCAGTGCCCTGAGCACGGAGCCTGCCCCTCCCTCCTCCCCACGTGAGCCCCGAGGGCCGCCGCAAAGCAACAGTTTGTGGTGGTGAGGCCGCGGCCCCGGGCCGGCCAGCCTCCTGCCTACTGCAGGTTTGTGGGGCGTGGGCAGCCGTGCTGGCGTGGGGAGTCCCGCTGCCAGTTTGCACACAGCCCCGTGGAGATGGCTGTGTGGGAGGCCGAGCAGCTGGGTGGCCTCCAGCGCGGGGACCTGCTCACACCCCCTGCCCCTGATGGCGACGGGCCCACGGCCCCCCTTGGCCAGCCCCCTGGGGCCCAGCTGTACTGCCCGGCCTGCTTGGTCACCTGCCACTCTCAGGAGGCCTTCGAGAACCACTGCGCATCCTCGGAGCACGCACAGATGGTGGCCTTCGACCAGCCCCTGCCCTGGGACCACCGTTCCCCACCCCCGGGACTCTCCAAGTTCGAGCTCTGCCCAAAGCCTGACCTCTGTGAGTATGGGGACGCCTGCACCAAGGCACACTCAGCACAGGAGCTGCAGGAGTGGGTCCGGCGCACGCAGGCTGTGGAGCTGCGGGGGCAGGCGGCCTCGCAGGACGGGCTGGTGCCCTACCAGGAGCGGCTGCTGGCCGAGTACCAGCGCAGCACCAGTGAGGTCCTTGTGCTGGCAGAGACCCTTGATGGAGTGCGTGTCACCTGCAACCAGCCCCTGATGTACCAGGCCCAGGAGAGGAAGACCCAGTACAGCTGGACGTTTGCCGTCCACTCTGAGGAGCCCCTGCTACACGTGGCCCTGCTGAAGCAGGAGCCAGGAGCCGACTTCTCTCTGGTGGCTCCCGGCCTCCCGCCAGGCCGGCTCTACGCACGGGGTGAGCGCTTCCGTGTGCCCAGCTCCACTGCCCACTTCCAGGTGGGAGTGCGTGTGCAGGCTGCCTCGTTCGGCACCTTTGAGCAATGGGTGGTCTTCGACTTTGGCCGCCGGCCGGTGCTGCTACAAAAGCTGGGGCTGCAGCTGGGCCAGGGGCGTCCCCCAGGACCCTGCAGGAATCTGGCGCTCGGCCACCCTGAGGAGATGGAGCGCTGGCACACTGGCAACCGCCACGTGGTGCCTGGCGTCGAGCGGACGGCCGAGCAGACGGCCCTGATGGCCAAGTACAAGGGCCCTGCCCTGGCCCTGGAGTTCAACCGCAGCAGCGTGGCCTCGGGCCCCATCTCACCAACCAACTATCGGCAGAGGATGCACCAGTTTCTCTATGAGGAGGAGGCGGCTCAGCAGCAGCTGGTGGCCAAGCTGACCCTGCGGGCCCAGGTGTTCCTGAAGACGGCATTGCAGACGCCAGCGCTGAACATGCTCTTCGCGCCTCCGGGAGCACTGTACGCAGAGGTCCCCGTCCCCTCCTCCCTGATGCCAGACACAGACCAGGGCTTCCTGCTGGCCCGGGCGGTCAGCACAGCCCTGGTGGCCCCTGTACCTGCACCCGACAATACGGTGTTCGAGGTGCGGCTGGAGAGGCGGGCCAGCTCAGAGCAGGCGCTGTGGCTGCTGCTTCCGGCCCGCTGCTGCTTGGCCCTCGGGCTGCAGCCTGAGGCCCGCCTGGTCCTGGAGGTGCAGTTCCAGATTGACCCGATGACCTTCCGCCTCTGGCACCAGGCAGTGGACACACTGCCTGACGAGCAGCTGGTGGTGCCCGACTTGCCCACCTGCGCCCTGCCCAGACCTTGGTCTGTCCCACCCTTGCGGCGTGGCAACCGCAAGCAGGAGCTGGCCGTGGCGCTCATCGCGGGCTGGGGCCCTGGGGATGGGAGGCGTGTCCCCCCGCTACTCATCTATGGCCCCTTTGGCACCGGCAAGACCTACACGCTGGCCATGGCCTCCCTGGAGGTCATCCGGAGGCCTGAAACCAAGGTGCTCATCTGCACACACACCAACAGTCTACACCGGGCAGGCGGTCACCCCCTGGATGTGCTCCACTCCTCTGATTCTGCACTCCCTGTAGCCGACCAGCTTTGGGCTTTGGCTTTATCAGGCCCAGCTCAGGCCACCGAGGGTGGCCGGGTCTGCTGTCAGGAGGGACACCAGTGTTTGCTGCTCACCTCTGACAGCCAGACAAGGGCTGTGCTCAGGGGCAGCTCGGCTGGGCACACAGTAGGTGCTTTAGCGGACAGCACTGAGGCCCCCAGCAAGAACCCCATGAGCTCCTCCCCCTCCCGCAGTGCCGCCGACATCTACATCCGGGAGTATTTCCACAGCCACGTCAGCGGCGGCCACCCCGAGGCCACTCCTCTCCGTGTGATGTACACGGACCCGCCGCTGAGCCAGACGGACCCAGTCACGCTGCAGTACTGTTGCCTGACCCACGACCGCCAGGCTTTCCGCCCGCCCACACGGGCAGAGCTGGCGCGGCACCGCGTGGTGGTCACCACCACCTCCCAGGCCCGTGAGCTCAGCCTGCCGGTCGGCTTCTTCTCCCACATTCTCATCGATGAGGCGGCCCAGATGCTGGAGTGCGAGGCCCTCACCCCGCTGGCCTATGCCTCGCACGGCACCCGCCTCGTGCTGGCGGGCGACCACATGCAGGTCACACCCCGGCTGTTCAGTGTGGCCAGGGCCCGGCCGGCCGAGCACACGCTGCTGCACCGCCTCTTCCTGTGCTACCAGCAGGAGACTCACGAGGTGGCGCGGCAGAGCCGCCTGGTCTTCCACGAGAACTACCGCTGCACGGACGCCATTGTCAGCTTCATCTCGCGGCACTTCTACGTGGCCAAGGGCAACCCCATCCACGCCAGCGGCAAGGTTCCGCCCCACCCCCGCCACTACCCGCTCATGTTCTGCCACGTGGCGGGCAGCCCAGACCGGGACATGTCCATGGCGTCCTGGCTGAATCTGGCTGAGATTGCGCAGGTCGTCGAGAAGGTGCAGGAGGCCTACAACACCTGGCCCAGCTGCTGGGGCGGCCGCGAGCAGAGGTGCATCTGTGTCGTTTCCCACGGTGCCCAGGTCAGTGCACTGAGGCAGGAGCTGAGGAGGCGGGACCTAGGCCAGGTGTCTGTCGGCAGTTTTGAGATCCTGCCAGGGCGGCAGTTCCGGGTCGTGGTGCTCAGCACTGTGCACACCTGCCAGAGCCTGCTCAGCCCTGGCGCACTCGCCCCTGAGTTCTTCACCGACGCCCGCGTGCTCAACACCGTCCTGACCCGCGCCCAGTCCCAGCTGGTGGTAGTGGGGGACGCCGTGGCCCTCTGCTCCTTCGGGGCCTGCGGCAAGCTCTGGGAGAGCTTCATCCGTGAGTGCGTGGAGCGGCACAGTGTCTGCCCCGAGGGCCTGTCCATGGAGCAGGTCGAGCAGGGTGTGGCGCAGAGACGGCGCTGGCCTCCCCGAGGCACACAGGCTGGGCCACCGGGCAACTGGGAGGCTGCCCCAGACCCAGTAGGGGACCTGGCCGAGGAGCAGGCGGCTGTGGTGACGGCCATGGTGAAGGCAGAGCCGGGAGATGAGGCTCTGAGCCCAGCATCCCGTGACATCACGGCAACCACAGCGCAGACGGAGGCTGCGGCAGCACCAGCAGGAGACCCAGTGAAGGAAGACGTGGTGCCCGGGCCCTGTGCGGCAGGAGCGGCTGCTGCAGCGGGCGTGGAGTCCACGGAGGCTGAGGATGCAGAGGCTGACTTCTGGCCGTGGGACGGGGAGCTCAACGCTGACGACGCCATCCTACGGGAGCTTCTGGACGAGAGCCAGAAGGTGATGGTGACCGTCGGGGAGGACGGGCTGCTGGACACTGTCGCCAGGCCCGAGTCCCTGCAGCAGGCCCGGCTGTACGAGAACCTGCCCCCGGCTGCGCTACGGAAGCTGCTGCACGCGGAGCCCGAGCGGTACCGCCACTGCTCTTTCGTGCCAGAGACCTTCGACCGGGCGTCAGCCATCCCGCTGGACGATGCCTCCTCCGGCCCCATCCACGTCAGGGGCCGCCTGGACTGTGGGATGGCCTTCGCCGGGGATGAGGTGCTGGTGCAGCTCCTTTCGGGAGACAAGGCGCCCGAGGGGCGGCTTCGGGGCCGCGTGCTGGGCGTGCTGAAGAGGAAGAGGCACGAGCTGGCGTTTGTGTGCCGCATGGACACGTGGGACCCGCGCATCATGCTCCCCATCAATGGCTCCGTGACCAAGATCTTCGTGGCCGAGCTGAAGGACCCATCGCAGGTCCCCATCTACAGCCTCCGGAAGGGCCGCCTGCAGCGTGTGGGGCTTGAGAGGCTCACCCCCGAGGCCCGGCACAGCCGGCTCTTCTGGGTCCAAATTGTCCTGTGGCGGCAAGGCTTCTACTACCCGCTGGGCATCGTCCGGGAGGTGCTGCCTGAGGCCAGCACCTGGGAGCAGGGCCTCCGCATCCTCGGCCTGCAGTACAGCTTGAGGGTGCCCCCGTCGGACCAGGCCACCATCACCAAGGTGCTGCAGAAATACCACACGGAGCTTGGCCGCGTTGCCCGCCGCCGAGAGGACTGCCGCGCCTTCTTGACCTTCACTGTGGACCCCCAGGGCGCCTGCAACCTCGATGATGCCCTCAGTGTCCGAGACCTGGGTCCCAGGTGCGAGGTGGCTGTGCACATCACTGATGTGGCCAGCTTCGTGCCCAGGGACGGCGTGCTGGACGTGGAGGCGCGAAGGCAGGGCGCTGCGTTCTATGCCCCCGGCAGGGAGCCAGTGCCCATGCTGCCGGCCAGCCTCTGCCAGCACGTCCTCAGCCTCCTGCCTGGCCGGGACCGCCTGGCCATCTCCCTGTTCCTCACCATGGAGAAGGCCAGTGGCCAGCTGAAGAGCCTGCGCTTTGCACCCTCCGTGGTCCAGTCTGACCGCCAGCTGTCCTACGAGGAGGCGGAGGAGGTGATCAGGCAGCACCCGGGTGCCGGCCGTGAGCTGCCGGCCCGCCTGGACTCCGTGGACGCCTGCGTCGTGGCCGCGTCCTACTTCTCTCCGCTGCTGCGCCGGCACCGCCTGCGGTCCGACTGCTTCTATGAGCAGCCGGACGAGGACGGCACCCTGGGCTTCCGCGCGGCCCACATCATGGTGAAGGAGTACATGATTCAGTTTAATAGGCTCGTGGCTGAGTTCCTGGTGGGCAGCGAGTGCACGCGGACGGTCACGCCTCTGCGGTGGCAGCCAGCACCCCGCAGCCAGCAGCTCAAGGCCCTGTGTGAGAAGCATGGGGACCGGGTGCCCCTGTCACTGCACCTCGGCCACCACCTGCACGGCGGCGGGGGCAGTCCCCCCGACACGCGGCTGCACCTCCTGGCCTCCCTCTGGAAGCAGGTCCAGTTTGCTGCCCGCACCCACCACTACCAACAGATGGTGGACTTGGTCACCACCGACGACATGCACCCATTCCTGGCTCCTGCAGGCCGCGACCTCCGCAAGGCCCTGGAGCGCTCGGCGTTCGGCCGCTGCGCCCGGGGCCACCAGCAGCAGCGCGGCCACTACTCGCTGCAGGTGGACTGGTACACGTGGGCCACCTCGCCCATCCGCAGGTACCTGGACGTGGTGTTGCAGCGGCAGATCCTGCTGGCGCTGGGCCATGCGGGCTCTGCCTACTCTGCCAGGGACATCGATGGGCTCTGCCAGGCCTTCAGCCTCCAGCACGCACTTGCCCAGAGCTATCAGCGGCGGGCGCGCAGCCTGCACCTGGCCGTGCAGCTCAAGGCCCAGCCTCTGGACAAGCTGGGCTTCGTGGTGGACCTGGAGGCGGGCTCCCGCTGCTTCCGGCTGCTCTTCCCCAGCAACCGCGAGACGCTGCCTGACCCCTGCCCCGTCCCCTACGGCTCCCTGCAGCTGGCCGAGCACCCCCACGCCCTGGCAGGCCGGCCGGGCCTGCGGCTCCTGTGGCGGCGCCGTGTCTACTCAGCGCAGGGATCCAGCCCGCCCCTGCCACTGCCTGGCACTGTGCCGGACCCACACACCCTGGCCGTGGAGACGGCCCTGTGGAAGCAGCTGCTGGAGCTGGTGGAGCTGCAGCGCTGGCCGGAGGCGGCTGCTCTCATCCAGGAGAAGGGCGAGGCGTCCCAGCGGCGGGAGCTGGTGCAGGTGCAGCGGAGCCACTGTGGCCATTTCCTGGAGGTGGCCCGGGAGCTGGGCAGTGGGGACACCCTGCAGGTGCAGCTCGGCACCAGCCTCCAGCACGCTTCCTGGTACCGAGCCCTCAGCTCTGGACGGTGGCACCGGGCTTCAGCCTCTGCCTGGAGCACGTGGAGCGGCCCGGAGACTGCTTCTCAGGCCGTGTGTACCGGGCCCCGAGGGACCGGTACCGCGACCTGGATGAGTACGCCTGCGTGTGGGAACCATTCTGCGCCCTGGAGTCGGCCACCGGCGCGGTTGCCGAGAATGACTCCGTCACACTTCAGCACCTGAGTGTCTCCTGGGAGGCGTCACGGACGCCGCAGGGGCAGCTGCAGGGCGCCTTCCGCCTGGAGGCCGCCTTCCTCGAGGAGAACTGTGCCGACATCAACTTCAGCTGCTGCTACCTCTGCATCCCCCTCGAGCCGCTGCCGGCTCCCACCGCCAGCCCACGCCCTGCGCCCAGCACCCTCGGCCCTGGCCTGAATCTTGACCCCGGCACCTATACCTCGGTGGCCCACGGGCAGACCTCTTCGTCCACCACATGGGCATGGAGAAGGTTCCGGAAGAGGTGCTGAGGCCGGGCACCCTGTTCACCGTTGAGCTGCTGCCCAAGCAGCTTCCTGATCTCCGCAAGGAGGAAGCCGTGCGTGGACTAGAGGAGGCGTCCCCGCTGGTCACCAGCATCGCACTGGGCCGGCCTGTCCCGCAGCCCCTCTGCAGAGCCCCACCCTGCATGAGTGCTCAGGGAGGCTGCCCCCTCTCAGTGATCCCCAGCAGGTTCCTGGAGCGGCAGACCTACAACATCCCCGGAGGCCGCCACAAGCTGAACCCCAGCCACAACGTGGCGGTCAGGCACGCTCTGGAGAAGCCTTTCACGGTCATTCAGGGCCCACCAGGTACAGGGAAGACGATCGTGGGCCTCCACATCGTATTCTGGTTTCATAAATCAAACCAGGAGCAGGTGCAGCCCGGAGGCCCCCCCCGTGGGCAGAAGCGGCTGGGGGGTCCCTCCATCTTGTACTGCGGCCCCTCCAACAAGTCGGTGGATGTCCTGGCAGGACTGCTCCTGAGAAGGATGGAGCTGAAGCCCCTCCGTGTGTACAGTGAGCAGGCTGAGCCCAGCGACTTCCCAGTGCCGCGTGTGGGCAGCAGGAAGCTGCTCAGGAAGAGCCCCCGGGAGGGGAGGCCGAACCAGAGCCTCAGGAGCATCACCCTGCACCACCGGATCCGCCAGGCCCCCAACCCTTACTCGTCGGAAATCAAGGCCTTTGACACCCGGCTGCAGAGAGGGGAGCTCTTCTCCAGCGAGGACCTGGTCTGGTACAAGAAGGTCTTGTGGGAGGCTCGGAAGTTCGAGCTGGACCGGCATGAGGTCATCCTCTGCACCTGCTCCTGTGCAGCCTCTGCCAGCCTCAAAATCCTGGACGTGAGGCAGATCCTTCTTGACGAGGCAGGCATGGCCACGCAACCTGAAACCCTCATCCCCCTGGTGCAGTTCCCACAGGCCGAGAAGGTGGTTCTTCTCGGAGACCACAAGCAGCTGCGGCCTGTGGTCAAGAATGAGCGGCTGCAAAACCTGGGTCTGGACCGGTCTCTGTTCGAGCGGTACCACGAGGACGCACATATGCTGGACACTCAGTACCGCATGCATGAGGGCATCTGTGCCTTCCCCTCTGTCGCGTTCTACAAGAGCAACCTGAAGACGTGGCACGGCCTGAGGAGGCCGCCCAGTGTCCTGGGCCACGCTGGCAAGGAGAGCTGCCCTGTCATCTTTGGCCACGTGCAGCGCCACGAGCGGAGCCTGCTGGTGTCCACGGACGAAGGGAATGAGAACTCCAAGGCCAACCTGGACGAGGTGGCTGAGGTGGTCCGTATCACCAAGCAGCTGACCCTGGGGAGGACCGTAGAGCCCCAGGACATCGCCGTCCTCACGCCCTACAACGCGCAGGCCTCTGAGATCAGCAAGGCCCTTCGGCGAGAGGGCATCGCCCCGGTGGCCCTGTCCTCCATCACCAAGAGCCAGGGGAGCGAGTGGCGCTATGTGCTGGTGAGCACCGTCCGCACCTGTCCCAAGAGCGACCTGGACCAGCGGCCCACCAAGAGCTGGCTCAAGAAGTTTCTGGGCTTCGTTGTGGACCCCAACCAAGTGAATGTGGCTGTCACGCGGGCCCAGGAGGGGCTCTGCCTGATCGGTGAGGGCGGGGCTGGGCTCTTCCAGGGTGGGAACACAGGAGACCACCTCCTTCTGCGCTGCTCCCCCCTCTGGCGTAGCCTCCTGGACTTCTGCGAGGCTCAGCAGACCCTCGTGCCTGCCGGCCAGGCCCGGTGTCTCCGGCTGCCTGTGTGGGCAGGGGAGGGCCGTGCCTGGTGTGGTGGGGACAAGCCACAGCTCCAGAGCTGCTCCGGTGTCACCAGGCTGGCCAAGTCCAAAGTCCCTGAGGCCACCAGCCTTGACTGTCCTGCTGGTCCCACTTTTAAAGCTGCTCCCCAGGACCCCCTGGCCGCTGTGGACTGGGGTCCCTCCGCACCTGGCCCATTTGTGGCTGCGTCCACAGGGGCTCCTGTGGCCTCCCAGAGCCAGCTCGGGGGTCAGATGGTCGCGGGGGCTATGGTCACTGTGGGAAAAGAGGTTCTGGGCATCTGTGGAGGGAGGGGTGGAGCATGGAGTCTCCAGGACTGTGGCCCCGTTGGTGTGCTGGACGGGCCCTGCCTTGAAGACCATGTCTATTCTTGGACCGTCATGAAATAAORF Start: ATG at 1ORF Stop: TAA at 9703SEQ ID NO:1683234 aa MW at 355870.4 kDNOV39a,MDPAQRPAPGAAIVEGLPSPRSSNVIGLRRGSLVVDGPPSRPPEVADTATAKASTWASCG59307-01 ProteinGLRTVANSSSGLRCPVSSGASDASLESQAGVRGSTLLPNSPAATRGPSLARLCALVDLSequenceCLGCSRCTQRLNESTYVLRRVEHDCSREILLARFKQATKSKVWRVVGCRPTFPRPLCYQVCHYYSPGLGCRRHRNRCTFARSREEALVWTFERQHNLQRLWLKAEVQGSGAQGGAGRAADAILTEFGGRFELLCSLCFRRCPPCICRVDPQGQCPEHGACPSLLAHVSAEGRRKQQFVVVRPRPRACQPPAYCRFVGRGQPCWRGESRCQFAHSAVEMAVWEAEQLGGLQRGDLLTPPAPDGDGRTAPLGQPPGAQLYCPACLVTCHSQEAFENHCASSEHAQMVAFDQALPWEHRSPPPGLSKFELCPKPDLCEYGDACTKAHSAQELQEWVRRTQAVELRGQAAWQDGLVPYQERLLAEYQRSSSEVLVLAETLDGVRVTCNQPLMYQAQERKTQYSWTFAVHSEEPLLHVALLKQEPGADFSLVAPGLPPGRLYARGERFRVPSSTADFQVGVRVQAASFGTFEQWVVFDFGRRPVLLQKLGLQLGQGRRPGPCRNLALGHPEEMERWHTCNRHVVPGVERTAEQTALMAKYKGPALALEFNRSSVASGPISPTNYRQRMHQFLYEEEAAQQQLVAKLTLRGQVFLKTALQTPALNMLFAPPGALYAEVPVPSSLMPDTDQGFLLGRAVSTALVAPVPAPDNTVFEVRLERRASSEQALWLLLPARCCLALGLQPEARLVLEVQFQIDPMTFRLWHQAVDTLPEEQLVVPDLPTCALPRPWSVPPLRRGNRKQELAVALIAGWGPGDGRRVPPLLIYGPFGTGKTYTLAMASLEVIRRPETKVLICTHTNSLHRACGHPLDVLQSSDSALPVADQLWALALSGPAQGTEGGRVCCQEGHQCLLLTSDSQTRAVLRGSSAGHTVGALADSTEAPSKKPMSSSPSRSAADIYIREYFHSHVSGGHPEATPLRVMYTDRPLSQTDPVTLQYCCLTDDRQAFRPPTRAELARHRVVVTTTSQARELRVPVGFFSHILIDEAAQMLECEALTPLAYASHGTRLVLAGDHMQVTPRLFSVARARAAEHTLLHRLFLCYQQETHEVARQSRLVFHENYRCTDAIVSFISRHFYVAKGNPIHARGKVPPHPRHYPLMFCHVAGSPDRDMSMASWLNLAEIAQVVEKVQEAYNTWPSCWGGREQRCICVVSHGAQVSALRQELRRRDLGQVSVGSFEILPGRQFRVVVLSTVHTCQSLLSPGALAPEFFTDARVLNTVLTRAQSQLVVVGDAVALCSFGACGKLWESFIRECVERHSVCPEGLSMEQVEQGVAQRRRWPPRGTQAGAAGNWEAAPEPVGDLAEEQAAVVTAMVKAEPGDEALSPASRDITATTAQTEAAAAPAGDAVKEDVVPGACAAGAAAAAGVESTEAEDAEADFWPWDGELNADDAILRELLDESQKVMVTVGEDGLLDTVARPESLQQARLYENLPPAALRKLLHAEPERYRHCSFVPETFERASAIPLDDASSGPIQVRGRLDCGMAFAGDEVLVQLLSGDKAPEGRLRGRVLGVLKRKRHELAFVCRMDTWDPRIMVPINGSVTKIFVAELKDPSQVPIYSLRKGRLQRVGLERLTAEARHSRLFWVQIVLWRQGFYYPLCIVREVLPEASTWEQGLRILGLEYSLRVPPSDQATITKVLQKYHTELGRVAGRREDCRAFLTFTVDPQGACNLDDALSVRDLGPRCEVAVHITDVASFVPRDGVLDVEARRQGAAFYAPGREPVPMLPASLCQDVLSLLPGRDRLAISLFLTMEKASGQLKSLRFAPSVVQSDRQLSYEEAEEVIRQHPGAGRELPARLDSVDACVVAACYFSRLLRRHRLRSDCFYEQPDEDGTLGFRAAHIMVKEYMIQFNRLVAEFLVGSECTRTVTPLRWQPAPRSQQLKALCEKHGDRVPLSLHLGHHLHGGGGSPPDTRLHLLASLWKQVQFAARTQDYEQMVDLVTTDDMHPFLAPAGRDLRKALERSAFGRCARGHQQQGGHYSLQVDWYTWATSPIRRYLDVVLQRQILLALGHGGSAYSARDIDGLCQAFSLQHALAQSYQRRARSLHLAVQLKAQPLDKLGFVVDVEAGSRCFRLLFPSNRETLPDPCPVPYGSLQLAEHPHALAGRPGLRLLWRRRVYSAQGSSPPLPLPGTVPDPHTLAVETALWKQLLELVELQRWPEAAALIQEKGEASQRRELVQVQRSHCGHFLEVARELGSGDTLQVQLGTSLQHGFLVPSPQLWTVAPGFSLCLEHVERPGDCFSGRVYRAPRDRYRDVDEYACVWEPFCALESATGAVAENDSVTLQHLSVSWEASRTPQGQLQGAFRLEAAFLEENCADINFSCCYLCIRLEGLPAPTASPRPGPSSLGPGLNVDPGTYTWVAHGQTQDWDQERRADRQEAPRRVHLFVHHMCMEKVPEEVLRPGTLFTVELLPKQLPDLRKEEAVRGLEEASPLVTSIALGRPVPQPLCRAPPCMSAQGGCPLSVIPSRFLERQTYNIPGGRHKLNPSQNVAVREALEKPFTVIQGPPGTGKTIVGLHIVFWFHKSNQEQVQPGGPPRGEKRLGGPCILYCGPSNKSVDVLAGLLLRRMELKPLRVYSEQAEASEFPVPRVGSRKLLRKSPREGRPNQSLRSITLHHRIRQAPNPYSSEIKAFDTRLQRGELFSREDLVWYKKVLWEARKFELDRHEVILCTCSCAASASLKILDVRQILVDEAGMATEPETLIPLVQFPQAEKVVLLGDHKQLRPVVKNERLQNLGLDRSLFERYHEDAHMLDTQYRMHEGICAFPSVAFYKSKLKTWQGLRRPPSVLGHAGKESCPVIFGHVQGHERSLLVSTDEGNENSKANLEEVAEVVRITKQLTLGRTVEPQDIAVLTPYNAQASEISKALRREGIAGVAVSSITKSQGSEWRYVLVSTVRTCAKSDLDQRPTKSWLKKFLGFVVDPNQVNVAVTRAQEGLCLIGEGGAGLFQGGNTGDHLLLRCCPLWRSLLDFCEAQQTLVPAGQGRCLRLPVWGGEGRAWCGGDKPQLQSCSGVTRLAKSKVPEATSLDCPAGPTFKAAPQDPLAAVDWGPSAPGPFVAASTGAPVASQSQLGGQMVAGAMVTVGKEVLGICGGRGGAWSLQDCGPVGVLDGPCLEDHVYSWTVMK


[0525] Further analysis of the NOV39a protein yielded the following properties shown in Table 39B.
210TABLE 39BProtein Sequence Properties NOV39aPSort0.7000 probability located in plasma membrane;analysis:0.3500 probability located in nucleus;0.3000 probability located in microbody (peroxisome);0.2000 probability located in endoplasmicreticulum (membrane)SignalPNo Known Signal Sequence Indicatedanalysis:


[0526] A search of the NOV39a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 39C.
211TABLE 39CGeneseq Results for NOV39aNOV39aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAB94712Human protein sequence SEQ ID334 . . . 523190/190 (100%)  e−112NO: 15712 - Homo sapiens, 293 aa. 1 . . . 190190/190 (100%) [EP 1074617-A2, 07-FEB-2001]AAU23357Novel human enzyme polypeptide1759 . . . 1901141/143 (98%) 5e−75#443 - Homo sapiens, 143 aa. 1 . . . 143141/143 (98%) [WO200155301-A2, 02-AUG-2001]ABB25190Protein #7189 encoded by probe for817 . . . 909 93/93 (100%)4e−49measuring heart cell gene expression - 1 . . . 93 93/93 (100%)Homo sapiens, 93 aa. [WO200157274-A2, 09-AUG-2001]AAM74813Human bone marrow expressed probe817 . . . 909 93/93 (100%)4e−49encoded protein SEQ ID NO: 35119 - 1 . . . 93 93/93 (100%)Homo sapiens, 93 aa. [WO200157276-A2, 09-AUG-2001]AAM62011Human brain expressed single exon817 . . . 909 93/93 (100%)4e−4934116 - Homo sapiens, 93 aa. 1 . . . 93 93/93 (100%)[WO200157275-A2, 09-AUG-2001]


[0527] In a BLAST search of public sequence databases, the NOV39a protein was found to have homology to the proteins shown in the BLASTP data in Table 39D.
212TABLE 39DPublic BLASTP Results for NOV39aNOV39aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ9C094KIAA1769 PROTEIN - Homo sapiens963 . . . 30992102/2137 (98%)0.0(Human), 2114 aa (fragment). 1 . . . 21102104/2137 (98%)Q9BYK8DJ697K14.6 (NOVEL PROTEIN,992 . . . 30991985/2108 (94%)0.0KIAA1769) - Homo sapiens (Human),565 . . . 25631988/2108 (94%)2567 aa.Q9BGV5HYPOTHETICAL 60.5 KDA2244 . . . 2754  460/511 (90%)0.0PROTEIN - Macaca fascicularis 3 . . . 499 475/511 (92%)(Crab eating macaque) (Cynomolgusmonkey), 545 aa.Q922U3UNKNOWN (PROTEIN FOR2453 . . . 3090  463/694 (66%)0.0IMAGE: 3589116) - Mus musculus 1 . . . 681 529/694 (75%)(Mouse), 717 aa (fragment).Q96ND3CDNA FLJ31049 FIS, CLONE2678 . . . 3099  405/422 (95%)0.0HSYRA2000510, WEAKLY 1 . . . 409 405/422 (95%)SIMILAR TO NAM7 PROTEIN -Homo sapiens (Human), 413 aa.


[0528] PFam analysis indicates that the NOV39a protein contains the domains shown in Table 39E.
213TABLE 39EDomain Analysis of NOV39aIdentities/SimilaritiesNOV39a Matchfor the MatchedExpectPfam DomainRegionRegionValuezf-CCCH: domain304 . . . 331 11/28 (39%)1.11 of 2 19/28 (68%)zf-CCCH: domain419 . . . 442 11/27 (41%)2.32 of 2 16/27 (59%)Runt: domain1734 . . . 1756 6/23 (26%)0.71 of 1 18/23 (78%)RNB: domain1682 . . . 203698/414 (24%)2.1e−291 of 1240/414 (58%) UvrD-helicase: domain2594 . . . 2622 14/29 (48%)2.41 of 2 23/29 (79%)UPF0066: domain2591 . . . 269225/138 (18%)5.31 of 162/138 (45%)UvrD-helicase: domain2951 . . . 2981 15/32 (47%)1.72 of 2 25/32 (78%)



Example 40

[0529] The NOV40 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 40A.
214TABLE 40ANOV40 Sequence AnalysisSEQ ID NO:16911603 bpNOV40a,CCCTCCATTGCTATGGATACCGAATCCACTTATTCTGGATATTCTTACTATTCAAGTCCG59713-01 DNAATTCGAAAAAATCTCACAGACAAAGGGAAAGAACTAGAGAGAGACACAAGTCACCCCGSequenceGAATAAAGACGGCAGAGGGTCAGAAAAGTCTGTCACCATTCAACCTCCCACTGGAGAGCCCCTGTTGGGAAATGATTCTACTCGGACAGAGGAACAGGATGACAACTGGGGAGAGACCACCACGGCCATCACAGGCACCTCGGAGCACAGCATATCCCAAGAGGACATTGCCAGGATCAGCAAGGACATGGAGGACAGCGTGGGGCTGGATTGCAAACGCTACCTGGGCCTCACCGTCGCCTCTTTTCTTGGACTTCTAGTTTTCCTCACCCCTATTGCCTTCATCCTTTTACCTCCCATCCTGTGGAGGGATGAGCTGGAGCCTTGTGGCACAATTTGTGAGGGGCTCTTTATCTCCATGGCATTCAAACTCCTCATTCTGCTCATAGCGACCTGCGCACTTTTTTTCCGCAAGCGGAGAGCTGACATGCCACGGGTGTTTGTGTTTCGTGCCCTTTTGTTGGTCCTCATCTTTCTCTTTGTGGTTTCCTATTGGCTTTTTTACGGGGTCCGCATTTTGGACTCTCGGGACCGGAATTACCAGGGCATTGTGCAATATGCAGTCTCCCTTGTGGATGCCCTCCTCTTCATCCATTACCTGGCCATCGTCCTGCTCGAGCTCAGGCAGCTGCAGCCCATGTTCACGCTGCAGGTGGTCCGCTCCACCGATGGCGAGTCCCGCTTCTACAGCCTGGGACACCTCAGTATCCAGCGAGCAGCATTGGTGGTCCTAGAAAATTACTACAAAGATTTCACCATCTATAACCCAAACCTCCTAACAGCCTCCAAATTCCGAGCAGCCAAGCATATGGCCGGGCTGAAAGTCTACAATGTATTCCCCAAAGGCCCCAGTAACAATGCCACTGGCCAGTCCCGGGCCATGATTGCTGCAGCTGCTCGGCGCAGGGACTCAAGCCACAACGAGTTGTATTATCAAGAGGCCGAACATGAACGGCGAGTAAAGAAGCGGAAAGCAAGGCTGGTGGTTGCAGTGGAAGAGGCCTTCATCCACATTCAGCGTCTCCAGGCTGAGCAGCAGCAGAAAGCCCCAGGGGAGGTGATGGACCCTAGGGAGGCCGCCCACGCCATTTTCCCCTCCATGGCCAGGGCTCTCCAGAAGTACCTGCGCATCACCCGGCAGCAGAACTACCACAGCATGGAGAGCATCCTGCAGCACCTGGCCTTCTGCATCACCAACGCCATGACCCCCAAGGCCTTCCTAGAACGGTACCTCAGTGCGGGCCCCACCCTGCAATATGACAAGGACCGCTGGCTCTCTACACAGTGGAGGCTTGTCAGTGATGAGGCTGTGACTAATGGATTACGGGATGGAATTGTGTTCGTCCTTAAGTGCTTGGACTTCAGCCTCGTAGTCAATGTGAAGAAAATTCCATTCATCATACTCTCTGAAGAGTTCATAGACCCCAAATCTCACAAATTTGTCCTTCGCTTACAGTCTGAGACATCCGTTTAAAAGTTCTATATTTORF Start: ATG at 13ORF Stop: TAA at 1588SEQ ID NO:170525aa MW at 60231.6 kDNOV40a,MDTESTYSGYSYYSSHSKKSHRQRERTRERHKSPRNKDGRGSEKSVTIQPPTGEPLLGCG59713-01 ProteinNDSTRTEEQDDNWGETTTAITGTSEHSISQEDIARISKDMEDSVGLDCKRYLGLTVASSequenceFLGLLVFLTPIAFILLPPILWRDELEPCGTICEGLFISMAFKLLILLIGTWALFFRKRRADMPRVFVFRALLLVLIFLFVVSYWLFYGVRILDSRDRNYQGIVQYAVSLVDALLFIHYLAIVLLELRQLQPMFTLQVVRSTDGESRFYSLGHLSIQRAALVVLENYYKDFTIYNPNLLTASKFRAAKHMAGLKVYNVFPKGPSNNATGQSRAMIAAAARRRDSSHNELYYEEAEHERRVKKRKARLVVAVEEAFIHIQRLQAEEQQKAPGEVMDPREAAQAIFPSMARALQKYLRITRQQNYHSMESILQHLAFCITNGMTPKAFLERYLSAGPTLQYDKDRWLSTQWRLVSDEAVTNGLRDGIVFVLKCLDFSLVVNVKKIPFIILSEEFIDPKSHKFVLRLQSETSVSEQ ID NO:171342 bpNOV40b,GGATCCATGGATACCGAATCCACTTATTCTGGATATTCTTACTATTCAAGTCATTCGA170645777 DNAAAAAATCTCACAGACAAGGGGAAAGAACTAGAGAGAGACACAAGTCACCCCGGAATAASequence AGACGGCAGAGGGTCAGAAAAGTCTGTCACCATTCAACCTCCCACTGGAGGGCCCCTGTTGGGAAATGATTCTACTCGGACAGAGGAAGTTCAGGATGACAACTGGGGAGAGACCACCACGGCCATCACAGGCACCTCGGAGCACAGCATATCCCAAGAGGACATTGCCAGGATCAGCAAGGACATGGAGGACAGCGTGGGGCTGGATTGCAAACGCTACCTCGAG ORF Start: GGA at 1ORF Stop: b at 343SEQ ID NO:172114aa MW at 12715.5 kDNOV40b,GSMDTESTYSGYSYYSSHSKKSHRQGERTRERHKSPRNKDGRGSEKSVTIQPPTGGPL170645777 ProteinLGNDSTRTEEVQDDNWGETTTAITGTSEHSISQEDIARISKDMEDSVGLDCKRYLESequence


[0530] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 40B.
215TABLE 40BComparison of NOV40a against NOV40b and NOV40c.NOV40a Residues/Identities/Similarities for theProtein SequenceMatch ResiduesMatched RegionNOV40b1 . . . 11091/111 (81%)3 . . . 11391/111 (81%)


[0531] Further analysis of the NOV40a protein yielded the following properties shown in Table 40C.
216TABLE 40CProtein Sequence Properties NOV40aPSort0.6000 probability located in plasma membrane;analysis:0.4000 probability located in Golgi body;0.3000 probability located in endoplasmic reticulum(membrane); 0.3000 probability located inmicrobody (peroxisome)SignalPNo Known Signal Sequence Indicatedanalysis:


[0532] A search of the NOV40a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 40D.
217TABLE 40DGeneseq Results for NOV40aNOV40aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAY73493Human secreted protein clone yk224_1 98 . . . 525425/428 (99%)0.0protein sequence SEQ ID NO: 208 - 1 . . . 426425/428 (99%)Homo sapiens, 426 aa. [WO9958642-A2, 18-NOV-1999]AAG81268Human AFP protein sequence SEQ ID178 . . . 525343/348 (98%)0.0NO: 54 - Homo sapiens, 346 aa. 1 . . . 346343/348 (98%)[WO200129221-A2, 26-APR-2001]AAY86275Human secreted protein HSRGW16,269 . . . 525254/257 (98%) e−141SEQ ID NO: 190 - Homo sapiens, 295 41 . . . 295254/257 (98%)aa. [WO9966041-A1, 23-DEC-1999]AAB45189Human secreted protein sequence359 . . . 525166/167 (99%)2e−90encoded by gene 18 SEQ ID NO: 130 - 1 . . . 167166/167 (99%)Homo sapiens, 167 aa. [WO200058467-A1, 05-OCT-2000]AAY86492Human gene 61-encoded protein258 . . . 426160/169 (94%)3e−83fragment, SEQ ID NO: 407 - Homo 42 . . . 208161/169 (94%)sapiens, 236 aa. [WO9966041-A1, 23-DEC-1999]


[0533] In a BLAST search of public sequence databases, the NOV40a protein was found to have homology to the proteins shown in the BLASTP data in Table 40E.
218TABLE 40EPublic BLASTP Results for NOV40aNOV40aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ923Z8LTAP - Mus musculus (Mouse), 1 . . . 525382/525 (72%)0.0521 aa. 1 . . . 521455/525 (85%)Q9ULK5KIAA1215 PROTEIN - Homo 1 . . . 525384/525 (73%)0.0(fragment).55 . . . 575453/525 (86%)AAK63188LPP1 - Mus musculus (Mouse), 1 . . . 525380/525 (72%)0.0521 aa. 1 . . . 521454/525 (86%)Q90X64STRABISMUS - Xenopus laevis 1 . . . 525383/525 (72%)0.0(African clawed frog), 521 aa. 1 . . . 521448/525 (84%)Q91ZD4LPPI - Mus musculus (Mouse), 1 . . . 525380/526 (72%)0.0522 aa. 1 . . . 522454/526 (86%)


[0534] PFam analysis indicates that the NOV40a protein contains the domains shown in the Table 40F.
219TABLE 40FDomain Analysis of NOV40aIdentities/NOV40aSimilarities for thePfam DomainMatch RegionMatched RegionExpect ValueNo Significant Matches Found



Example 41

[0535] The NOV41 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 41A.
220TABLE 41ANOV41 Sequence AnalysisSEQ ID NO:1731066 bpNOV41a,GACAAAACATGGTTCAAGCATCTGGGCACAGGCGGTCCACCCGTGGCTCCAAAATGGTCG59570-01 DNACTCCTGGTCCGTGATAGCAAAGATCCAGGAAATATCGTGCGAGGAAGATGAGAGGAAGSequenceATGGTGCGAGAGTTCTTGGCCGAGTTCATGAGCACATATGTCATGATGGTATTCGGCCTTGGTTCTGTGGCCCATATGGTTCTAAATAAAACATATGGGAGCTACCTTGGTGTCAACTTGGGTTTTGGCTTCGGGGTCACCATGGGAGTCCACGTGGCAGGCCGCATCTCTGGAGCCCACATGAATGCAGCTGTGACCTTCACTAACTGTGCGCTGGGCCGCGTGCCCTGGAGGAAGTTTCCAGTCCATGTGCTGGGGCAGTTCCTGGGCTCCTTCCTGGCAGCTGCCACCATCTACAGTCTCTTCTACAGCGCCATTCTCCACTTTTCGGGTGGAGAGCTGATGGTGACCGGTCCCTTTGCTACAGCTGGCATTTTTGCCACCTACCTTCCTGATCACATGACATTGTGGCGGGGCTTCCTGAATGAGGAGTGGCTGACCAGGATGCTCCAGCTGTGTCTCTTCACCATCACGGACCAGGAGAACAACCCAGCACTGCCAGGAACACACGCGCTGGTGATAAGCATCCTCGTGGTCATCATCAGGGTGTCCCATGGCATAAACACAGGATATGCCATCAATCCATCCCGGGACCCGCCCCCCAGCATCTTCACCTTCATTGCTGGCTGGGGCAAACAGGTCTTCAGCGATGGGGAGAACTGGTGGTGGGTGCCAGTGGTGGCACCACTTCTGGGTGCCTCTCTAGGTGGCATCATCTACCTGGTCTTCATTGGCTCCACCATCCCACGGGAGCCCCTGAAATTGGAGGACTCTGTGGCGTATGAAGACCACGGGATAACCGTATTGCCCAAGATGGGATCTCATGAACCCATGATCTCTCCCCTCACCCTCATCTCCGTGAGCCTTGCCAACAGATCTTCAGTCCACTCTGCCCCACCCTTACATGAATCCATGGCCCTAGAGCACTTCTAAGCAGAGATTATTTGTGAORF Start: ATG at 9ORF Stop: TAA at 1047SEQ ID NO:174346 aa MW at38029.9 kDNOV41a,MVQASGHRRSTRGSKMVSWSVIAKIQEIWCEEDERKMVREFLAEFMSTYVMMVFGLGSCG59570-01 ProteinVAHMVLNKTYGSYLGVNLGFGFGVTMGVHVAGRISGAHMNAAVTFTNCALGRVPWRKFSequencePVHVLGQFLGSFLAAATIYSLFYSAILHFSGGELMVTGPFATAGIFATYLPDHMTLWRGFLNEEWLTRMLQLCLFTITDQENNPALPGTHALVISILVVIIRVSHGINTGYAINPSRDPPPSIFTFIAGWGKQVFSDGENWWWVPVVAPLLGASLGGIIYLVFIGSTIPREPLKLEDSVAYEDHGITVLPKNGSHEPMISPLTLISVSLANRSSVHSAPPLHESMALEHF


[0536] Further analysis of the NOV41a protein yielded the following properties shown in Table 41B.
221TABLE 41BProtein Sequence Properties NOV41aPSort0.8586 probability located in mitochondrial inner membrane;analysis:0.6000 probability located in plasma membrane;0.4000 probability located in Golgi body;0.3568 probability located in mitochondrialintermembrane spaceSignalPNo Known Signal Sequence Indicatedanalysis:


[0537] A search of the NOV41 a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 41C.
222TABLE 41CGeneseq Results for NOV41aNOV41aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAW87644A protein with water channel activity - 1 . . . 346316/346 (91%)0.0Homo sapiens, 342 aa. [WO9843997-1 . . . 342323/346 (93%)A1, 08-OCT-1998]AAY70455Human membrane channel protein-55 . . . 346312/343 (90%) e−179(MECHP-5) - Homo sapiens, 341 aa.3 . . . 341319/343 (92%)[WO200012711-A2, 09-MAR-2000]AAY70468Human membrane channel protein-1837 . . . 296 104/261 (39%)7e−56(MECHP-18) - Homo sapiens, 301 aa.20 . . . 280 162/261 (61%)[WO200012711-A2, 09-MAR-2000]AAB65991Human secreted protein BLAST search133 . . . 280  62/148 (41%)9e−33protein SEQ ID NO: 131 - Homo1 . . . 148 99/148 (66%)sapiens, 177 aa. [WO200077023-A1,21-DEC-2000]AAB65992Human secreted protein BLAST search133 . . . 280  62/148 (41%)4e−31protein SEQ ID NO: 132 - Homo1 . . . 148 96/148 (63%)21-DEC-2000]


[0538] In a BLAST search of public sequence databases, the NOV41a protein was found to have homology to the proteins shown in the BLASTP data in Table 41D.
223TABLE 41DPublic BLASTP Results for NOV41aNOV41aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueCAD13298BA251O17.3 (SIMILAR TO1 . . . 346345/346 (99%)0.0AQUAPORIN 7) - Homo sapiens1 . . . 346346/346 (99%)(Human), 346 aa.O14520Aquaporin 7 (Aquaporin-7 like)1 . . . 346317/346 (91%)0.0(Aquaporin adipose) (AQPap) - 1 . . . 342324/346 (93%)Homo sapiens (Human), 342 aa.O54794Aquaporin 7 - Mus musculus16 . . . 296 201/281 (71%)e−114(Mouse), 303 aa.1 . . . 277233/281 (82%)P56403Aquaporin 7 - Rattus norvegicus20 . . . 285 188/266 (70%)e−107(Rat), 269 aa.4 . . . 265220/266 (82%)P47862Aquaporin 3 (31.4 kDa water channel36 . . . 292 120/258 (46%)2e−68 protein) - Rattus norvegicus (Rat),20 . . . 277 175/258 (67%)292 aa.


[0539] PFam analysis indicates that the NOV41a protein contains the domains shown in the Table 41E.
224TABLE 41EDomain Analysis of NOV41aIdentities/SimilaritiesNOV41a for theExpectPfam DomainMatch RegionMatched RegionValueMIP: domain 1 of 131 . . . 276 78/268 (29%)5.2e−56180/268 (67%)



Example 42

[0540] The NOV42 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 42A.
225TABLE 42ANOV42 Sequence AnalysisSEQ ID NO:175895 bpNOV42a,CTGTCGTGGTTGTGGAATGCAAACGCCAGCACATAATGGAAACAGGACCTGAAGACCCCG56162-02 DNATTCCAGCATGCCAGAGGAAAGTTCCCCCAGGCGGACCCCGCAGAGCATTCCCTACCAGSequenceGACCTCCCTCACCTGGTCAATGCAGACGGACAGTACCTCTTCTGCAGGTACTGGAAACCCACAGGCACACCCAAGGCCCTCATCTTTGTGTCCCATGGAGCCGGAGAGCACAGTGGCCGCTATGAAGAGCTGGCTCGGATGCTGATGGGGCTGGACCTGCTGGTGTTCGCCCACGACCATGTTGGCCACGGACAGAGCGAAGGGGAGAGGATGGTAGTGTCTGACTTCCACGTTTTCGTCAGGGATGTGTTGCAGCATGTGCATTCCATGCAGAAAGACTACCCTGGGCTTCCTGTCTTCCTTCTGGGCCACTCCATGGGAGGCGCCATCGCCATCCTCACGGCCGCAGAGAGGCCGGGCCACTTCGCCGGCATGGTACTCATTTCGCCTCTGGTTCTTGCCAATCCTGAATCTGCAACAACTTTCAAGGTCGACATTTATAACTCAGACCCCCTGATCTGCCGGGCAGGGCTGAAGGTGTGCTTCGGCATCCAACTGCTGAATGCCGTCTCACGGGTGGAGCGCGCCCTCCCCAAGCTGACTGTGCCCTTCCTGCTGCTCCAGGGCTCCGCCGATCGCCTATGTGACAGCAAAGGGGCCCACCTGCTCATGGAGTTAGCCAACAGCCAGGACAAGACTCTCAAGATTTATGAAGGTGCCTACCATGTTCTCCACAAGGAGCTTCCTGAAGTCACCAACTCCGTCTTCCATGAAATAAACATGTGGGTCTCTCAAAGGACAGCCACGGCAGGAACTGCGTCCCCACCCTGAATGCATTGORF Start: ATG at 36ORF Stop: TGA at 885SEQ ID NO:176283 aa MW at 31122.4 kDNOV42a,METGPEDPSSMPEESSPRRTPQSIPYQDLPHLVNADGQYLFCRYWKPTGTPKALIFVSCG56162-02 ProteinHGAGEHSGRYEELARMLMGLDLLVFAHDHVGHGQSEGERMVVSDFHVFVRDVLQHVDSSequenceMQKDYPGLPVFLLGHSMGGAIAILTAAERPGHFAGMVLISPLVLANPESATTFKVDIYNSDPLICRAGLKVCFGIQLLNAVSRVERALPKLTVPFLLLQGSADRLCDSKGAHLLMELAKSQDKTLKIYEGAYHVLHKELPEVTNSVFHEINMWVSQRTATAGTASPPSEQ ID NO:177861 bpNOV42b,AGATCTATGGAACAGGACCTGAAGACCCTTCCAGCATGCCAGAGGAAAGTTCCCCCA174228465 DNAGGCGGACCCCGCAGAGCATTCCCTACCAGGACCTCCCTCACCTGGTCAATGCAGACGGSequenceACAGTACCTCTTCTGCAGGTACTGGAAACCCACAGGCACACCCAAGGCCCTCATCTTTGTGTCCCATGGAGCCGGAGAGCACAGTGGCCGCTATGAAGAGCTGGCTCGGATGCTGATGGGGCTGGACCTGCTGGTGTTCGCCCACGACCATGTTGGCCACGGACAGAGCGAAGGGGAGAGGATGGTAGTGTCTGACTTCCACGTTTTCGTCAGGGATGTGTTGCAGCATGTGGATTCCATGCAGAAAGACTACCCTGGGCTTCCTGTCTTCCTTCTGGGCCACTCCATGGGAGGCGCCATCGCCATCCTCACGGCCGCAGAGAGGCCGGGCCACTTCGCCGGCATGGTACTCATTTCGCCTCTGGTTCTTGCCAATCCTGAATCTGCAACAACTTTCAAGGTCGACATTTATAACTCAGACCCCCTGATCTGCCGGGCAGGGCTGAAGGTGTGCTTCGGCATCCAACTGCTGAATGCCGTCTCACGGGTGGAGCGCGCCCTCCCCAAGCTGACTGTGCCCTTCCTGCTGCTCCAGGGCTCTGCCGATCGCCTATGTGACAGCAAAGGGGCCTACCTGCTCATGGAGTTAGCCAAGAGCCAGGACAAGACTCTCAAGATTTATGAAGGTGCCTACCATGTTCTCCACAAGGAGCTTCCTGAAGTCACCAACTCCGTCTTCCATGAAATAAACATGTGGGTCTCTCAAAGGACAGCCACGGCAGGAACTGCGTCCCCACCCCTCGAGORF Start: AGA at 1ORF Stop: 8 at 862SEQ ID NO:178287 aa MW at 31634.0 kDNOV42b,RSMETGPEDPSSMPEESSPRRTPQSIPYQDLPHLVNADGQYLFCRYWKPTGTPKALIF174228465 ProteinVSHGAGEHSGRYEELARMLMGLDLLVFAHDHVGHGQSEGERMVVSDFHVFVRDVLQHVSequenceDSMQKDYPGLPVFLLGHSMGGAIAILTAAERPGHFAGMVLISPLVLANPESATTFKVDIYNSDPLICRAGLKVCFGIQLLNAVSRVERALPKLTVPFLLLQGSADRLCDSKGAYLLMELAKSQDKTLKIYEGAYHVLHKELPEVTNSVFHEINMWVSQRTATAGTASPPLE


[0541] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 42B.
226TABLE 42BComparison of NOV42a against NOV42b and NOV42c.NOV42a Residues/Identities/SimilaritiesProtein SequenceMatch Residuesfor the Matched RegionNOV42b1 . . . 283269/283 (95%)3 . . . 285270/283 (95%)


[0542] Further analysis of the NOV42a protein yielded the following properties shown in Table 42C.
227TABLE 42CProtein Sequence Properties NOV42aPSort0.4500 probability located in cytoplasm;analysis:0.4273 probability located in microbody (peroxisome);0.2034 probability located in lysosome (lumen);0.1000 probability located in mitochondrial matrix spaceSignalPNo Known Signal Sequence Indicatedanalysis:


[0543] A search of the NOV42a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 42D.
228TABLE 42DGeneseq Results for NOV42aNOV42aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAG10770Arabidopsis thaliana protein fragment 37 . . . 273 86/271 (31%)9e−27SEQ ID NO: 9224 - Arabidopsis104 . . . 371126/271 (45%)thaliana, 383 aa. [EP1033405-A2, 06-SEP-2000]AAG10769Arabidopsis thaliana protein fragment 37 . . . 273 86/271 (31%)9e−27SEQ ID NO: 9223 - Arabidopsis111 . . . 378126/271 (45%)thaliana, 390 aa. [EP1033405-A2, 06-SEP-2000]AAG10768Arabidopsis thaliana protein fragment 37 . . . 273 86/271 (31%)9e−27SEQ ID NO: 9222 - Arabidopsis140 . . . 407126/271 (45%)thaliana, 419 aa. [EP1033405-A2, 06-SEP-2000]AAG16436Arabidopsis thaliana protein fragment 31 . . . 279 80/286 (27%)6e−24SEQ ID NO: 17083 - Arabidopsis 11 . . . 296133/286 (45%)thaliana, 301 aa. [EP1033405-A2, 06-SEP-2000]AAG46122Arabidopsis thaliana protein fragment 34 . . . 275 83/281 (29%)2e−23SEQ ID NO: 57993 - Arabidopsis 15 . . . 295132/281 (46%)thaliana, 351 aa. [EP1033405-A2, 06-SEP-2000]


[0544] In a BLAST search of public sequence databases, the NOV42a protein was found to have homology to the proteins shown in the BLASTP data in Table 42E.
229TABLE 42EPublic BLASTP Results for NOV42aNOV42aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ99685LYSOPHOSPHOLIPASE HOMOLOG 1 . . . 283282/313 (90%) e−160(LYSOPHOSPHOLIPASE-LIKE) -  1 . . . 313283/313 (90%)Homo sapiens (Human), 313 aa.Q96AA5MONOGLYCERIDE LIPASE (EC11 . . . 283272/303 (89%) e−1543.1.1.23) - Homo sapiens (Human), 1 . . . 303273/303 (89%)303 aa.O35678MONOGLYCERIDE LIPASE (EC11 . . . 283230/303 (75%) e−1333.1.1.23) - Mus musculus (Mouse), 303 1 . . . 303255/303 (83%)aa.O11456H14-E - Ectromelia virus, 277 aa.32 . . . 273122/270 (45%)6e−64 6 . . . 274168/270 (62%)P8762741KBP FRAGMENT FROM LEFT32 . . . 273121/270 (44%)5e−63END OF GENOME - Cowpox virus 6 . . . 274167/270 (61%)(CPV), 276 aa.


[0545] PFam analysis indicates that the NOV42a protein contains the domains shown in the Table 42F.
230TABLE 42FDomain Analysis of NOV42aIdentities/NOV42a MatchSimilarities forExpectPfam DomainRegionthe Matched RegionValueabhydrolase: domain80 . . . 270 46/247 (19%)0.0331 of 1134/247 (54%)Thioesterase: domain53 . . . 270 47/271 (17%)1.71 of 1139/271 (51%)



Example 43

[0546] The NOV43 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 43A.
231TABLE 43ANOV43 Sequence AnalysisSEQ ID NO:1792018 bpNOV43a,GCGCCCCCCACCCTTCCGGCCCCCCAGAACCCGCGCCATCCCCCGGAGCCTCCCCAGACG59681-01 DNAGCTGGCCGCGCAGGATGGGGCGCCCTCAGGCCCACGCTGCTGCCGCCTTCGCTGCCGCTSequenceGCTGCTGCTCCTAATGCTAGGAATGGGATGCTGGGCCCGGGAGGTGCTGGTCCCCGAGGGGCCCTTGTACCGCGTGGCTGGCACAGCTGTCTCCATCTCCTGCAATGTGACCGGCTATGAGGGCCCTGCCCAGCAGAACTTCCAGTGGTTCCTCTATAGGCCCGAGGCCCCAGATACTGCACTGGGCATTGTCAGTACCAAGGATACCCAGTTCTCCTATGCTGTCTTCAAGTCCCCAGTGGTGGCCCGTGAGGTGCAGGTGCAGCGCCTACAAGGTGATGCCGTGGTGCTCAAGATTGCCCCCCTGCAGGCCCAGGATGCCGGCATTTATGAGTGCCACACCCCCTCCACTGATACCCGCTACCTGGGCAGCTACAGCGGCAAGGTGGAGCTGAGAGTTCTTCCAGATGTCCTCCAGGTGTCTGCTGCCCCCCCAGGGCCCCGAGGCCGCCAGGCCCCAACCTCACCCCCACGCATGACGGTGCATCAGGGGCAGGAGCTGGCACTGGGCTGCCTGGCGAGGACAAGCACACAGAAGCACACACACCTGGCAGTGTCCTTTGGGCGATCTGTGCCCGAGGCACCAGTTGGGCGGTCAACTCTGCAGGAAGTGGTGGGAATCCGGTCAGACTTGGCCGTGGAGGCTGGAGCTCCCTATGCTGAGCGATTCGCTGCAGGGGAGCTTCGTCTGGGCAAGGAAGGGACCGATCGGTACCGCATGGTAGTAGGGGGTGCCCAGGCAGGGGACGCAGGCACCTACCACTGCACTGCCGCTGAGTGGATTCAGGATCCTGATGGCAGCTGGGCCCAGATTGCAGAGAAAAGGGCCGTCCTGGCCCACGTGGATGTGCAGGCACTGTCCAGCCAGCTGGCAGTGACAGTGGGGCCTGGTGAACGTCGGATCGGCCCAGGGGAGCCCTTGGAACTGCTGTGCAATGTGTCAGGGGCACTTCCCCCAGCAGGCCGTCATGCTGCATACTCTGTAGGTTGGGAGATGGCACCTGCCGGGGCACCTGGGCCCGGCCGCCTGGTAGCCCAGCTGGACACAGAGGGTGTGGGCAGCCTGGGCCCTGGCTATGAGGGCCGACACATTGCCATGGAGAAGGTGGCATCCAGAACATACCGGCTACGGCTAGAGGCTCCCACGCCTGGTGATGCGGGCACCTACCGCTGCCTCGCCAAAGCCTATGTTCGAGGGTCTGGGACCCGGCTTCGTGAAGCAGCCAGTGCCCGTTCCCGGCCTCTCCCTGTACATGTGCGGGAGGAAGGTGTGGTGCTGGAGGCTGTGGCATGGCTAGCAGGAGGCACAGTGTACCGCGGGGAGACTGCCTCCCTGCTGTGCAACATCTCTGTGCGGGGTGGCCCCCCAGGACTGCGGCTGGCCGCCAGCTGGTGGGTGGAGCGACCAGAGGACGGAGAGCTCAGCTCTGTCCCTGCCCAGCTGGTGGGTGGCGTAGGCCAGGATGGTGTGGCAGAGCTGGGAGTCCGGCCTGGAGGAGGCCCTGTCAGCGTAGAGCTGGTGGGGCCCCGAAGCCATCGGCTGAGACTACACAGCTTGGGGCCCGAGGATGAAGGCGTGTACCACTGTGCCCCCAGCGCCTGGGTGCAGCATGCCGACTACAGCTGCTACCAGGCGGGCAGTGCCCGCTCAGGGCCTGTTACAGTCTACCCCTACATGCATGGTGAGTGACACCCCCTCCACCCTCCTCACTCTGCCTTCCTCCTGGCCTCTGCCACTGGCCTTCCCTTCCCATCTTCTGACCCTCCTGCTACTATCTCTCTCCTCCACATTATGTCACATCAACTCTCAAAAAATCCAACTTCCAGCCCTGCAGTGCCCACCTGCACGGGGTCCTCTGTGGTTGATGCTGACTTGCATGCTGAGGGTGCATGGTGGGCAGCORF Start: ATG at 73ORF Stop: TGA at 1804SEQ ID NO:180577 aa MW at 61171.8 kDNOV43a,MCALRPTLLPPSLPLLLLLMLGMCCWAREVLVPEGPLYRVAGTAVSISCNVTGYEGPACG59681-01 ProteinQQNFEWFLYRPEAPDTALGIVSTKDTQFSYAVFKSRVVAGEVQVQRLQGDAVVLKIARSequenceLQAQDAGIYECHTPSTDTRYLGSYSGKVELRVLPDVLQVSAAPPGPRGRQAPTSPPRMTVHEGQELALGCLARTSTQKHTHLAVSFGRSVPEAPVGRSTLQEVVGIRSDLAVEAGAPYAERLAAGELRLGKEGTDRYRMVVGGAQAGDAGTYHCTAAEWIQDPDGSWAQIAEKRAVLAHVDVQALSSQLAVTVGPGERRIGPGEPLELLCNVSGALPPAGRHAAYSVGWEMAPAGAPGPGRLVAQLDTEGVGSLGPGYEGRHIAMEKVASRTYRLRLEAARPGDAGTYRCLAKAYVRGSGTRLREAASARSRPLPVHVREEGVVLEAVAWLAGGTVYRGETASLLCNISVRGGPPGLRLAASWWVERPEDGELSSVPAQLVGGVGQDGVAELGVRPGGGPVSVELVGPRSHRLRLHSLCPEDEGVYHCAPSAWVQHADYSWYQACSARSGPVTVYPYMHGESEQ ID NO:1811662 bpNOV43b,AGATCTCGGGAGGTGCTGGTCCCCGAGGGGCCCTTGTACCGCGTCGCTGGCACAGCTG174308213 DNATCTCCATCTCCTGCAATGTGACCGGCTATGAGGGCCCTGCCCAGCAGAACTTCGAGTGSequenceGTTCCTGTATAGGCCCGAGGCCCCAGATACTGCACTGGGCATTGTCAGTACCAAGGATACCCAGTTCTCCTATGCTGTCTTCAAGTCCCGAGTGGTGGCGGGTGAGGTGCAGGTGCAGCGCCTACAAGGTGATGCCGTGGTGCTCAAGATTGCCCGCCTGCAGGCCCAGGATGCCGGCATTTATGAGTGCCACACCCCCTCCACTGATACCCGCTACCTGGGCAGCTACAGCGGCAAGGTGCAGCTGAGAGTTCTTCCAGATCTCCTCCAGGTGTCTGCTCCCCCCCCAGGGCCCCGAGGCCGCCAGGCCCCAACCTCACCCCCACGCATGACGGTGCATGAGGGGCAGGAGCTGGCACTGGGCTGCCTGGCGAGGACAAGCACACAGAAGCACACACACCTGGCAGTGTCCTTTGGGCGATCTCTGCCCGAGGCACCAGTTGGGCGGTCAACTCTGCAGGAAGTGGTGGGAATCCGGTCAGACTTGGCCGTGGAGGCTGGAGCTCCCTATGCTGAGCGATTGGCTGCAGGGGAGCTTCGTCTGGGCAAGGAAGGGACCGATCCGTACCCCATGGTAGTAGGGGGTCCCCAGGCAGGGCACGCAGGCACCTACCACTGCACTGCCGCTGAGTGGATTCAGGATCCTGATGGCAGCTGGGCCCAGATTGCAGAGAAAAGGGCCGTCCTGGCCCACGTGGATGTGCAGACGCTGTCCAGCCAGCTGGCAGTGACAGTGGGGCCTGGTGAACGTCGGCAGGCCGTCATGCTGCATACTCTGTAGGTTGGGAGATGGCACCTGCGGGGGCACCTGGGCCCGGCCGCCTGGTAGCCCAGCTGGACACAGAGGGTGTGGGCAGCCTGGGCCCTGGCTATGAGGGCCGACACATTGCCATGGAGAAGGTGGCATCCAGAACATACCGGCTACGGCTAGAGGCTGCCAGGCCTGGTGATGCGGGCACCTACCGCTGCCTCCCCAAAGCCTATGTTCGAGGGTCTGGGACCCGGCTTCGTGAAGCAGCCAGTGCCCGTTCCCGGCCTCTCCCTGTACATGTGCGGGAGGAAGGTGTGGTGCTGGAGGCTGTGGCATGGCTAGCAGGAGGCACAGTGTACCGCGGGGAGACTGCCTCCCTGCTGTGCAACATCTCTGTGCGGGGTGGCCCCCCAGGACTGCGGCTGGCCGCCAGCTGGTGGGTGGAGCGACCAGAGGACGGAGAGCTCAGCTCTGTCCCTGCCCAGCTGGTGGGTGGCGTAGGCCAGGATGGTGTGGCAGAGCTGGGAGTCCGGCCTGCAGGAGGCCCTGTCAGCGTAGAGCTGGTGGGGCCCCGAAGCCATCGGCTGAGACTACACAGCTTGGGGCCCGAGGATGAAGGCGTGTACCACTGTGCCCCCAGCGCCTGGGTGCAGCATGCCGACTACAGCTGGTACCAGGCGGGCAGTGCCCGCTCAGGGCCTGTTACAGTCTACCCCTATATGCATGGTGAGCTCGAGORF Start: AGA at 1ORF Stop: A at 1663SEQ ID NO:182554 aa MW at 58826.7 kDNOV43b,RSREVLVPEGPLYRVAGTAVSISCNVTGYEGPAQQNFEWFLYRPEAPDTALGIVSTKD174308213 ProteinTQFSYAVFKSRVVAGEVQVQRLQGDAVVLKIARLQAQDAGIYECHTPSTDTRYLGSYSSequenceGKVELRVLPDVLQVSAAPPGPRGRQAPTSPPRMTVHEGQELALGCLARTSTQKHTHLAVSFGRSVPEAPVGRSTLQEVVGIRSDLAVEAGAPYAERLAAGELRLGKEGTDRYRMVVGGAQAGDAGTYHCTAAEWIQDPDGSWAQIAEKRAVLAHVDVQTLSSQLAVTVGPGERRIGPGEPLELLCNVSGALPPAGRHAAYSVGWEMAPAGAPGPGRLVAQLDTEGVGSLGPGYEGRHIAMEKVASRTYRLRLEAARPGDAGTYRCLAKAYVRGSGTRLREAASARSRPLPVHVREEGVVLEAVAWLAGGTVYRGETASLLCNISVRGGPPCLRLAASWWVERPEDGELSSVPAQLVGGVGQDGVAELGVRPGGGPVSVELVGPRSHRLRLHSLGPEDEGVYHCAPSAWVQHADYSWYQAGSARSGPVTVYPYMHGELESEQ ID NO:1831662 bpNOV43c,AGATCTCCGGAGGTGCTGGTCCCCGAGGGGCCCTTGTACCGCGTGGCTGGCACAGCTG174308218 DNATCTCCATCTCCTGCAATGTGACCGGCTATGAGGGCCCTGCCCAGCAGAACTTCGAGTGSequenceCTTCCTGTATAGGCCCGAGGCCCCACATACTCCACTGCGCATTGTCACTACCAAGGATACCCAGTTCTCCTATGCTGTCTTCAAGTCCCGAGTGGTGGCGGGTGAGGTGCAGGTGCAGCGCCTACAAGGTGATGCCGTGGTGCTCAAGATTGCCCGCCTGCAGGCCCAGGATGCCGGCATTTATGAGTGCCACACCCCCTCCACTGATACCCGCTACCTGGGCAGCTACAGCGGCAAGGTGGAGCTGAGAGTTCTTCCAGATGTCCTCCAGGTGTCTGCTGCCCCCCCAGGGCCCCGAGGCCGCCAGGCCCCAACCTCACCCCCACGCATGACGGTGCATGAGGGGCAGGAGCTGGCACTGGGCTGCCTGGCGAGGACAAGCACACAGAAGCACACACACCTGGCAGTGTCCTTTGGGCGATCTGTGCCCGAGGCACCAGTTGGGCGGTCAACTCTGCAGGAAGTGGTGGGAATCCGGTCAGACTTGGCCGTGCAGGCTGGAGCTCCCTATGCTGAGCGATTGGCTGCAGGGGAGCTTCGTCTGCGCAAGGAAGGCACCGATCGGTACCGCATGGTAGTAGGGGGTGCCCAGGCAGGGGACGCAGGCACCTACCACTGCACTGCCGCTGAGTGGATTCAGGATCCTGATGGCAGCTGGGCCCAGATTGCAGAGAAAAGGGCCGTCCTGGCCCACGTGGATGTGCAGACGCTGTCCAGCCAGCTGGCAGTGACAGTGGGGCCTGGTGAACGTCGGATCGGCCCAGGGGACCCCTTGGAACTGCTGTGCAATGTGTCAGGGGCACTTCCCCCAGCAGGCCGTCATGCTGCATACTCTGTAGGTTGGGAGATGGCACCTGCGGGGGCACCTGGGCCCGGCCGCCTGGTAGCCCAGCTGGACACAGAGGGTGTGGGCAGCCTGGGCCCTGGCTATGAGGCCCGACACATTCCCATGGAGAAGGTGGCATCCAGAACATACCGGCTACGGCTAGAGGCTGCCAGGCCTGGTGATGCGGGCACCTACCGCTGCCTCGCCAAAGCCTATGTTCGAGGGTCTGGGACCCGGCTTCGTGAAGCAGCCAGTGCCTGTTCCCGCCCTCTCCCTGTACATGTGCGGGAGGAAGGTGTGGTGCTGGAGGCTGTGGCATGGCTAGCAGGAGGCACAGTGTACCGCGGGGAGACTGCCTCCCTGCTGTGCAACATCTCTGTGCGGGGTGCCCCCCCAGGACTGCGGCTGGCCOCCAGCTGGTGGGTGGAGCGACCAGAGGACGGAGAGCTCAGCTCTGTCCCTGCCCAGCTGGTGGGTGGCGTAGGCCAGGATGGTGTGGCAGAGCTGGGAGTCCGGCCTGGAGGAGGCCCTGTCAGCGTAGAGCTGGTGGGGCCCCGAAGCCATCGGCTGAGACTACACAGCTTGGGGCCCGAGGATGAAGGCGTGTACCACTGTCCCCCCAGCGCCTGGGTGCAGCATGCCGACTACAGCTGGTACCAGGCGGGCAGTGCCCGCTCAGGGCCTGTTACAGTCTACCCCTACATGCATCGTGAGCTCGAGORF Start: AGA at 1ORF Stop: A at 1663SEQ ID NO:184554 aa MW at 58773.7 kDNOV43c,RSREVLVPEGPLYRVAGTAVSISCNVTGYEGPAQQNFEWFLYRPEAPDTALGIVSTKD1743082 18 ProteinTQFSYAVFKSRVVAGEVQVQRLQGDAVVLKIARLQAQDAGIYECHTPSTDTRYLGSYSSequenceGKVELRVLPDVLQVSAAPPGPRGRQAPTSPPRMTVHEGQELALGCLARTSTQKHTHLAVSFGRSVPEAPVGRSTLQEVVGIRSDLAVEAGAPYAERLAAGELRLGKEGTDRYRMVVGGAQAGDAGTYHCTAAEWIQDPDGSWAQIAEKRAVLAHVDVQTLSSQLAVTVGPGERRIGPGEPLELLCNVSGALPPAGRHAAYSVGWEMAPAGAPGPGRLVAQLDTEGVGSLGPGYEGRHIAMEKVASRTYRLRLEAARPGDAGTYRCLAKAYVRGSGTRLREAASACSRPLPVHVREEGVVLEAVAWLAGGTVYRGETASLLCNISVRGGPPGLRLAASWWVERPEDGELSSVPAQLVGGVGQDGVAELGVRPGGGPVSVELVGPRSHRLRLHSLGPEDEGVYHCAPSAWVQHADYSWYQAGSARSGPVTVYPYMHGELESEQ ID NO:18511662 bpNOV43d,AGATCTCGGGAGGTGCTGGTCCCCGAGGGGCCCTTGTACCGCGTGGCTGGCACAGCTG174308224 DNATCTCCATCTCCTGCAATGTGACCGGCTATGAGGGCCCTGCCCACCAGAACTTCGAGTGSequenceGTTCCTGTATAGGCCCGAGGCCCCAGATACTGCACTGGGCATTGTCAGTACCAAGGATACCCAGTTCTCCTATGCTGTCTTCAAGTCCCGAGTGGTGGCGGGTGAGGTGCAGGTGCAGCGCCTACAAGGTGATGCCGTGGTCCTCAAGATTGCCCGCCTGCAGGCCCAGGATGCCGGCATTTATGAGTGCCACACCCCCTCCACTGATACCCGCTACCTGGGCAGCTACAGCGGCAAGGTGGAGCTGAGAGTTCTTCCAGATGTCCTCCAGGTGTCTGCTGCCCCCCCAGGGCCCCGAGGCCGCCAGOCCCCAACCTCACCCCCACGCATGACGGTGCATGAGGCGCAGGAGTTGGCACTGGGCTGCCTGCCGAGGACAAGCACACAGAAGCACACACACCTGGCAGTGTCCTTTGGGCGATCTGTGCCCGAGCCACCAGTTGGGCGGTCAACTCTGCAGGAAGTGGTGGGAATCCGGTCAGACTTGGCCGTGGAGGCTGGAGCTCCCTATGCTGAGCGATTGGCTGCAGGGGAGCTTCGTCTGGGCAAGGAAGGGACCGATCGGTACCGCATGGTAGTAGGGGGTGCCCAGGCAGGGGACGCAGGCACCTACCACTGCACTGCCGCTGAOTGGATTCAGGATCCTGATGGCAGCTGGGCCCAGATTGCAGAGAAAAGGGCCGTCCTCGCCCACGTGGATGTGCAGACGCTGTCCAGCCAGCTGGCAGTGACAGTGGGGCCTGGTGAACGTCGGATCGGCCCAGGGGAGCCCTTGGAACTGCTGTGCAATGTGTCAGGGGCACTTCCCCCAGCAGGCCGTCATGCTGCATACTCTCTAGGTTGGGAGATGGCACCTGCGGGGGCACCTGGGCCCGGCCGCCTGGTAGCCCAGCTGGACACAGAGGGTGTGCGCAGCCTGGGCCCTGGCTATGAGGGCCGACACATTGCCATGGAGAAGGTGGCATCCAGAACATACCGGCTACGGCTAGAGGCTGCCAGGCCTGGTGATGCGGGCACCTACCGCTGCCTCGCCAAACCCTATGTTCGAGGGTCTGGGACCCGGCTTCGTGAAGCAGCCAGTGCCCGTTCCCGGCCTCTCCCTGTACATGTGCGGGAGGAAGGTGTGGTGCTGGAGGCTGTGGCATGGCTAGCAGGAGGCACAGTGTACCGCGGGGAGACTGCCTCCCTGCTGTGCAACATCTCTGTGCGGGGTGGCCCCCCAGGACTGCGGCTGGCCGCCAGCTGGTGGGTGGAGCGACCAGAGGACCGAGAGCTCAGCTCTGTCCCTGCCCAGCTGGTGGGTGGCGTAGGCCAGGATGGTGTGGCAGAGCTGGGAGTCCGGCCTGGAGGAGGCCCTGTCAGCGTAGAGCTGGTGGGGCCCCGAAGCCATCGGCTGAGACTACACAGCTTGGGACCCGAGGATGAAGGCGTGTACCACTGTGCCCCCAGCGCCTGGGTGCAGCATGCCGACTACAGCTGGTACCAGGCGGGCAGTGCCCGCTCAGGGCCTGTTACAGTCTACCCCTACATGCATGGTGAGCTCGAGORF Start: AGA at 1ORF Stop: A at 1663SEQ ID NO:186554 aa MW at 58826.7 kDNOV43d,RSREVLVPEGPLYRVAGTAVSISCNVTGYEGPAQQNFEWFLYRPEAPDTALGIVSTKD174308224 ProteinTQFSYAVFKSRVVAGEVQVQRLQGDAVVLKIARLQAQDAGIYECHTPSTDTRYLGSYSSequenceGKVELRVLPDVLQVSAAPPGPRGRQAPTSPPRMTVHEGQELALGCLARTSTQKHTHLAVSFGRSVPEAPVGRSTLQEVVGIRSDLAVEAGAPYAERLAAGELRLCKEGTDRYRMVVGGAQAGDAGTYHCTAAEWIQDPDGSWAQIAEKRAVLAHVDVQTLSSQLAVTVGPGERRIGPGEPLELLCNVSGALPPAGRHAAYSVGWEMAPAGAPGPGRLVAQLDTEGVGSLGPGYEGRHIANEKVASRTYRLRLEAARPGDACTYRCLAKAYVRGSGTRLREAASARSRPLPVHVREEGVVLEAVAWLAGGTVYRGETASLLCNISVRGGPPGLRLAASWWVERPEDGELSSVPAQLVGGVGQDGVAELGVRPGGGPVSVELVGPRSHRLRLHSLGPEDEGVYHCAPSAWVQHADYSWYQAGSARSGPVTVYPYMHGELE


[0547] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 43B.
232TABLE 43BComparison of NOV43a against NOV43b through NOV43d.NOV43a Residues/Identities/SimilaritiesProtein SequenceMatch Residuesfor the Matched RegionNOV43b27 . . . 577525/551 (95%) 2 . . . 552526/551 (95%)NOV43c27 . . . 577524/551 (95%) 2 . . . 552525/551 (95%)NOV43d27 . . . 577525/551 (95%) 2 . . . 552526/551 (95%)


[0548] Further analysis of the NOV43a protein yielded the following properties shown in Table 43C.
233TABLE 43CProtein Sequence Properties NOV43aPSort0.8497 probability located in lysosome (lumen);analysis:0.5947 probability located in outside;0.1197 probability located in microbody (peroxisome);0.1000 probabilitylocated in endoplasmicreticulum (membrane)SignalPCleavage site between residues 28 and 29analysis:


[0549] A search of the NOV43a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 43D.
234TABLE 43DGeneseq Results for NOV43aNOV43aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAM24248Human EST encoded protein SEQ ID1 . . . 575574/575 (99%)0.0NO: 1773 - Homo sapiens, 613 aa.1 . . . 575574/575 (99%)[WO200154477-A2, 02-AUG-2001]AAB90544Human secreted protein, SEQ ID NO:1 . . . 575574/575 (99%)0.082 - Homo sapiens, 613 aa.1 . . . 575574/575 (99%)[WO200121658-A1, 29-MAR-2001]AAB15536Human immune system molecule from1 . . . 575574/575 (99%)0.0Incyte clone 2705028 - Homo sapiens,1 . . . 575574/575 (99%)613 aa. [WO200060080-A2,12-OCT-2000]AAB90560Human secreted protein, SEQ ID NO:1 . . . 575573/575 (99%)0.098 - Homo sapiens, 613 aa.1 . . . 575573/575 (99%)[WO200121658-A1, 29-MAR-2001]AAB81411Partial human IgSF protein, SEQ ID136 . . . 575 437/440 (99%)0.0NO: 5 - Homo sapiens, 478 aa.1 . . . 440439/440 (99%)[WO200127278-A2, 19-APR-2001]


[0550] In a BLAST search of public sequence databases, the NOV43a protein was found to have homology to the proteins shown in the BLASTP data in Table 43E.
235TABLE 43EPublic BLASTP Results for NOV43aNOV43aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ969P0EWI2 (CD81 PARTNER 3) -1 . . . 575574/575 (99%)0.0Homo sapiens (Human), 613 aa.1 . . . 575574/575 (99%)AAL02217IMMUNOGLOBULIN1 . . . 575508/575 (88%)0.0SUPERFAMILY RECEPTOR PGRL -1 . . . 573542/575 (93%)Mus musculus (Mouse), 611 aa.Q9BTG9PROTEIN - Homo sapiens (Human),4 . . . 449445/446 (99%)0.0487 aa (fragment).CAC37841SEQUENCE 4 FROM PATENT136 . . . 575 437/440 (99%)0.0WO0127278 - Homo sapiens1 . . . 440439/440 (99%)(Human), 478 aa (fragment).CAC37842SEQUENCE 6 FROM PATENT174 . . . 575 401/402 (99%)0.0WO0127278 - Homo sapiens1 . . . 402401/402 (99%)(Human), 440 aa.


[0551] PFam analysis indicates that the NOV43a protein contains the domains shown in the Table 43F.
236TABLE 43FDomain Analysis of NOV43aIdentities/SimilaritiesNOV43afor thePfam DomainMatch RegionMatched RegionExpect Valueig: domain 1 of 4 42 . . . 12913/89 (15%)0.001155/89 (62%)ig: domain 2 of 4179 . . . 2728/97 (8%)0.7458/97 (60%)ig: domain 3 of 4319 . . . 40815/91 (16%)0.0001260/91 (66%)ig: domain 4 of 4455 . . . 54615/93 (16%)3.7e−0561/93 (66%)



Example 44

[0552] The NOV44 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 44A.
237TABLE 44ANOV44 Sequence AnalysisSEQ ID NO:1873201 bpNOV44a,AGAGTCCTCAGCAGGGTAGCCGAGCCCAGGCCACTTCTGCTGAGGATGGGGCAGGCTGCG59869-01 DNAGGGTCTGGGTGTGGCCTGGGGTGGCTCAGGGCTGGAACTGCTGCCTGATTCCTGTGTGSequenceGGGAGAAGCTCAGTGGCCGTTTCCTGCCACTGACAAGGATTTCACATGCAGAAGAGAAAAGGCCCCCCTCCACCCCCCGCATTCCCTGCCGACTGAGAGCCAGTGTTTGCTGCCCTTGCTGGGGGCGGGTAGGAAACCCTGAGCTTCCTGATGCGGAGTCATGAAGCAGAGTCCTCGGGAAGGCATCTCCCCAACCTTCCCTCATCTCTGGCGGCCCTCTTGGGCCTCTGACCCAGCCCCTCCCCGGGCCAGGCTCACAGAAGCTGGCTTCTGGGACTGTCCTGGGCCCAAGTGGGCACCTGCGCCAGCCCCACCTGTGCCTGGGCTGTGGCCCCTTCCTACAGGGCGCTCACCATGGCCCCGCCGCTCCTGCTGCTGCTGCTGGCCAGTGGAGCGGCCGCCTGCCCGCTGCCCTGCGTCTGCCAGAACCTGTCCGAGTCGCTCAGCACCCTCTGTGCCCACCGAGGCCTGCTGTTTGTGCCGCCCAACGTGGACCGGCGCACAGTGGAGCTGCGGCTGGCTGACAACTTCATCCAGGCCCTGGGGCCCCCTGACTTCCGCAACATGACGGGACTGGTGGACCTGACACTGTCTCGCAATGCCATCACCCGCATTGGGGCCCGCGCCTTTGGGGACCTCGAGAGCCTGCGTTCCCTCCACCTTGACGGCAACAGGCTGGTGGAGCTGGGCACCGGGACCCTCCGGGGCCCCGTCAATCTGCAGCACCTCATCCTCAGCGGCAACCAGCTGGGCCGCATCGCGCCGGGAGCCTTCCACGACTTCCTAGAGAGCCTGGAGGACCTGGACCTGTCCTACAACAACCTCCGGCAGGTGCCCTGGGCCGGCATCGGCGCCATGCCTGCCCTGCACACCCTCAACCTGGACCATAACCTTATTGACGCACTGCCCCCAGGCGCCTTCGCCCAGCTCGGTCAGCTCTCCCGCCTGGACCTCACCTCCAACCGCCTGGCCACGCTGGCTCCGGACCCGCTTTTCTCTCGTGCGCGTCATGCAGAGGCCTCTCCCGCCCCCCTGGTGCTGAGCTTTAGCGGGAACCCCCTGCACTGCAACTGTGAGCTGCTGTGGCTGCGGCGGCTGGCGCGGCCGGACGACCTGGAAACGTGCGCCTCCCCGCCCCGCCTGGCCCGCCGCTACTTCTGGGCAGTGCCCGAGGGCGAGTTCTCCTGTGAGCCGCCCCTCATTGCCCGCCACACGCAGCGCCTCTGGGTGCTGGAAGGCCAGCGGGCCACGCTGCGGTGCCGGGCCCTGGGTGACCCCGCGCCTACCATGCACTGGGTCGGTCCTGACGACCGGTTGGTTGGCAACTCCTCCCGAGCCCGGGCTTTCCCCAACGCGACCTTAGAGATTGGGCTGACCGGCGCTCGGGACGCTGGGGGCTACACCTGCATCGCCACCAACCCTGCTGGTGAGGCCACAGCCCGAGTAGAACTGCOGGTGCTGGCCTTGCCCCATGGTGGGAACAGCAGTGCCGAGGGGGGCCGCCCCGGGCCCTCGGACATCGCCGCCTCCGCTCGCACTGCTCCCGAGGGTGAGGGGACGCTGGAGTCTGAGCCAGCCGTGCAGGTGACGGAGGTGACCGCCACCTCAGGGCTGGTGAGCTGGGGTCCCGGGCGGCCAGCCGACCCAGTGTGGATGTTCCAAATCCAGTACAACAGCACCGACACCTCGTCCCCGGCGCTGACTATGACCTCTGCCTGCTGGCCTTGTCACCGGCCGCTGGGCCCTCTGACCTCACGGCCACCAGGCTGCTGGGCTGTGCCCATTTCTCCACGCTGCCGGCCTCGCCCCTGTGCCACGCCCTGCAGGCCCACGTGCTGGGCGGGACCCTGACCGTGGCCGTGGGGGGTGTGCTGGTGGCTGCCTTACTGGTCTTCACTGTGGCCTTGCTGGTTCGGGGCCGGGGGGCCCGAAATGGCCGCCTCCCCCTCAAGCTCAGCCACGTCCAGTCCCAGACCAATGGAGGCCCCAGCCCCACACCCAAGGCCCACCCGCCGCGGGAGCCCCCCGCCCCGGCCGCAGCGCAGCTGCTCTCTGGACCTGGGAGATGCCGGGTGCTACGGTTATGCCAGGCGCCTGGGAGGAGCTTCGGCCCGACCGAGCCACTCTGTGCATGGGGGGCTGCTCGGGGCAGGGTGCCGGGGGGTAGGAGGCAGCGCCGAGCGGCTGGAAGAGAGTGTGGTGTGATGGACGGGCAGCTTCCTGTGTGCTCCAAGGGATGAGCCTCGTGGGGCAGAGGGCCCGGGGCCGCCGCCTCGCCTGGGAGTCCCTCCCTGGTTTTTATTCTCAGTACCTCAGGCTCCCCTGTGTACTTGGAGGGGCAGGGAGCCCTTTCCTCGGTTCTGGCCTCCAGACCAGGGTAAGGGCAGGCCCCTCCAACAGGTGCTCACAGCCACCGAGGCAGGGGCTGCAGCCACCCACTGGGAGTCTTGTTTTTATTTATAATAAAATTGTTGGGGACACCTCAAAAAAAAAAAAGCCCACAAATTCCCCGAGGGACAATTACGGTACAGCGTCATGACAAAGGCCCACAGAGTCAAAACCCAAACCGCGCCCTTACAAGCCAGACGGCACAGTCTCGGTCACGAGACACTCTGGATCATCCACACAAGTACCCAGACAAACGAGCGCACCATCGCTCTACCCCCCCACCGGGCCCGCGGCCCCACCCACCCACAGGACGCACCCGCGCAGCGCCAGCACCCACACCACGCGGCCACCAACGACGACACGCACCACCGACAAGCGACACGCACAGCACCGCCACGAACAAGACGCTGGAGCTCCTCCGGCACGCGCCCGCAGGCCCCCCGCCCACACGACCGCCTCCAACACCCCCGCGCGCGCCCTCCACACGAGGACAACGAAACACAAACCAGGCGGCACCCCGACGCGCAGCCACCCAGCGCCACCGCACGCACACCCCCCAGCGAGCGACGCCCCAACGCGCGCAGCACGGCCACAGGAGCGCGCACCCCCACCGAACCTAGTTGGTAGATAGCAGGTTGCORF Start: ATG at 471ORF Stop: TGA at 2412SEQ ID NO:188647 aa MW at 68097.9 kDNOV44a,MAPPLLLLLLASGAAACPLPCVCQNLSESLSTLCAHRGLLFVPPNVDRRTVELRLADNCG59869-01 ProteinFIQALGPPDFRNNTGLVDLTLSRNAITRIGARAFGDLESLRSLHLDGNRLVELGTGSLSequenceRGPVNLQHLILSGNQLGRIAPGAFDDFLESLEDLDLSYNNLRQVPWAGIGANPALHTLNLDHNLIDALPPGAFAQLGQLSRLDLTSNRLATLAPDPLFSRGRDAEASPAPLVLSFSGNPLHCNCELLWLRRLARPDDLETCASPPGLAGRYFWAVPEGEFSCEPPLIARHTQRLWVLEGQRATLRCRALGDPAPTMHWVGPDDRLVGNSSRARAFPNGTLEIGVTGAGDAGGYTCIATNPAGEATARVELRVLALPHGGNSSAEGGRPGPSDIAASARTAAEGEGTLESEPAVQVTEVTATSGLVSWGPGRPADPVWMFQIQYNSSEDETLIYRIVPASSHHFLLKHLVPGADYDLCLLALSPAAGPSDLTATRLLGCAHFSTLPASPLCHALQAHVLGGTLTVAVGGVLVAALLVFTVALLVRGRGAGNGRLPLKLSHVQSQTNGGPSPTPKAHPPREPPAPAAAQLLSCPGRCRVLRLCQAPGRSLGPTEPLCAWGAARGRVPGGRRQRRAAGRECGVMDGQLPVCSKGSEQ ID NO:1892451 bpNOV44b,AGAGTCCTCAGCAGGGTAGCCGAGGCCAGGCCACTTCTGCTGAGGATCGGGCAGGCTGCG59869-02 DNAGGGTGTGGGTGTGGCCTGGGGTGGCTCAGGGCTGGAACTGCTGCCTGATTCCTGTGTGSequenceCGGAGAAGCTCAGTGGCCGTTTGCTGCCACTGACAAGGATTTCACATGCAGAAGAGAAAAGGCCCCCCTCCACCCCCCGCATTCCCTGCCGAGTGAGAGCCAGTGTTTGCTGCCCTTGCTGGGGGCGGGTAGGAAACCCTGACCTTCCTCATGCGGAGTCATGAAGCAGAGTCCTCGGGAAGGCATCTCCCCAACCTTCCCTCATCTCTGGCGCCCCTCTTGGGCCTCTGACCCAGCCCCTCCCCGGGCCAGGCTCACAGAAGCTGGCTTCTGGGACTGTCCTGGGCCCAAGTCGGCACCTGCGCCAGCCCCACCTGTGCCTGGGCTGTGGCCCCTTCCTACAGGGCGCTCACCATGGCCCCGCCGCTCCTCCTGCTGCTGCTGGCCAGTGGAGCGGCCGCCTGCCCGCTGCCCTGCGTCTGCCAGAACCTGTCCGAGTCGCTCAGCACCCTCTGTGCCCACCGAGGCCTGCTGTTTGTGCCGCCCAACGTGGACCGGCGCACAGTGGAGCTCCGGCTGGCTGACAACTTCATCCAGGCCCTGGGGCCCCCTGACTTCCGCAACATGACGGGACTGGTGGACCTGACACTGTCTCGCAATGCCATCACCCGCATTGGGGCCCGCGCCTTTGGGGACCTCGAGAGCCTGCGTTCCCTCCACCTTGACGGCAACAGGCTGGTGGAGCTGGGCACCGGGAGCCTCCGGGGCCCCGTCAATCTGCAGCACCTCATCCTCAGCCGCAACCAGCTGGGCCGCATCGCGCCGGGAGCCTTCGACGACTTCCTAGAGAGCCTGGAGGACCTGGACCTGTCCTACAACAACCTCCGGCAGGTGCCCTGGGCCGGCATCGGCGCCATGCCTGCCCTGCACACCCTCAACCTGGACCATAACCTTATTGACGCACTGCCCCCAGGCGCCTTCGCCCAGCTCGGTCAGCTCTCCCGCCTGGACCTCACCTCCAACCGCCTGGCCACGCTGGCTCCGGACCCGCTTTTCTCTCGTGGGCGTGATGCAGAGGCCTCTCCCGCCCCCCTGGTGCTGAGCTTTAGCGGGAACCCCCTGCACTCCAACTGTGAGCTGCTGTGGCTGCGGCGGCTGGCGCGGCCGGACGACCTGGAAACGTGCGCCTCCCCGCCCGGCCTGGCCGCCCGCTACTTCTGGCCAGTCCCCGAGGGCGAGTTCTCCTGTGAGCCGCCCCTCATTGCCCGCCACACGCAGCGCCTCTGGGTGCTGGAAGGCCAGCGGGCCACGCTGCGGTGCCGGGCCCTGGGTGACCCCGCGCCTACCATGCACTGGGTCGGTCCTGACGACCGGTTGGTTGGCAACTCCTCCCGAGCCCGGGCTTTCCCCAACGGGACCTTAGAGATTGGGGTGACCGGCGCTGGGGACGCTGGGGGCTACACCTGCATCGCCACCAACCCTGCTGGTGAGGCCACAGCCCGAGTAGAACTGCGGGTGCTGGCCTTGCCCCATGGTGGGAACAGCAGTGCCGAGGGGGGCCGCCCCGGGCCCTCCGACATCGCCGCCTCCGCTCGCACTGCTGCCGAGGGTGAGGGGACGCTGGAGTCTGACCCAGCCGTGCAGGTGACGGAGGTGACCGCCACCTCAGGGCTGGTGAGCTGGGGTCCCGGGCGGCCAGCCGACCCAGTGTGGATGTTCCAAATCCAGTACAACAGCAGCGAAGATGAGACCCTCATCTACCGGATTGTCCCAGCCTCCAGCCACCACTTCCTGCTGAAGCACCCCGTCCCCGGCGCTGACTATGACCTCTGCCTGCTGGCCTTGTCACCGGCCGCTGGGCCCTCTGACCTCACGGCCACCAGGCTGCTGGGCTGTGCCCATTTCTCCACGCTGCCGGCCTCGCCCCTGTGCCACGCCCTGCAGGCCCACGTGCTGGGCGGGACCCTGACCGTGGCCGTGGGGCGTGTGCTGGTGGCTGCAGCCCCTGCCTCGGTGGCTGTGAGCACCTGTTGGAGGGGCCTGCCCTTACCCTGGTCTGGAGGCCAGAACCGAGGAAAGGGCTCCCTGCCCCTCCAAGTACACAGGGGAGCCTGAGGTACTGAGAATAAAAACCAGGCAGGGACTCCCAGGCCAGGCGGCGGCCCCGGGCCCTCTGCCCCACGAGGCTCATCCCTTGGAGCACACAGGAAGCTGCCCGTCCATCACACCACACTCTCTTCCAGCCGCTCGGCGCTGCCTCCTACCCCCCGGCACCCTGCCCCGAGCAGCCCCCCATGCACAGAGTGGCTCCGTCGGGCCTACGCTCCTCCCAGGCGCCTGGCATAACCGTAGCACCCGGCATCTCCCAGGTCCAGAGACCAGCTGCGCTGCGGCCORF Start: ATG at 471ORF Stop: TGA at 2169SEQ ID NO:190566 aa MW at 59683.1 kDNOV44b,MAPPLLLLLLASGAAACPLPCVCQNLSESLSTLCAHRGLLFVPPNVDRRTVELRLADNCG59869-02 ProteinFIQALGPPDFRNMTGLVDLTLSRNAITRIGARAFGDLESLRSLHLDGNRLVELGTGSLSequenceRGPVNLQHLILSGNQLGRIAPGAFDDFLESLEDLDLSYNNLRQVPWAGIGAMPALHTLNLDHNLIDALPPGAFAQLGQLSRLDLTSNRLATLAPDPLFSRGRDAEASPAPLVLSFSGNPLHCNCELLWLRRLARPDDLETCASPPGLAGRYFWAVPEGEFSCEPPLIARHTQRLWVLEGQPATLRCRALGDPAPTMHWVGPDDRLVGNSSRARAFPNGTLEIGVTGAGDAGGYTCIATNPAGEATARVELRVLALPHGGNSSAEGGRPGPSDIAASARTAAEGEGTLESEPAVQVTEVTATSGLVSWGPGRPADPVWMFQIQYNSSEDETLIYRIVPASSHHFLLKHPVPGADYDLCLLALSPAAGPSDLTATRLLGCAHFSTLPASPLCHALQAHVLGGTLTVAVGGVLVAAAPASVAVSTCWRGLPLPWSGGQNRGKGSLPLQVHRGASEQ ID NO:1912563 bpNOV44c,TCCCAATCTGGAGGGGAACGTTGCACCCCAGCCCCAGGAGGCCCTGCCCGTGTGAAGACG59869-03 DNAGCCAGCCAAGTGGGCACCTGCGCCAGCCCCACCTGTGCCTGCCTGTGGCCCCTTCCTASequenceCAGGGCGCTCACCATGCCCCCCGCGCTCCTGCTGCTGCTGCTGGCCAGTGGAGCGGCCGCCTGCCCCCTGCCCTGCGTCTGCCAGAACCTGTCCGAGTCGCTCAGCACCCTCTGTGCCCACCGACGCCTGCTGTTTCTGCCGCCCAACGTGGACCGGCGCACAGTGGAGCTGCGGCTGGCTGACAACTTCATCCAGGCCCTCGGGCCCCCCGACTTCCGCAACATGACGGGACTGGTGGACCTGACACTGTCTCGCAATGCCATCACCCGCATTGCGGCCCGCGCCTTTGGGGACCTCGAGAGCCTACGTTCCCTCCACCTTGACGGCAACAGGCTGGTGGAGCTGGGCACCGCGAGCCTCCGGGGCCCCGTCAATCTGCAGCACCTCATCCTCAGCGGCAACCAGCTGGGCCGCATCGCGCCGGGAGCCTTCGACGACTTCCTAGAGAGCCTGGAGGACCTGGACCTGTCCTACAACAACCTCCGGCAGGTGCCCTGGGCCGGCATCGGCGCCATGCCTGCCCTGCACACCCTCAACCTGGACCATAACCTTATTGACGCACTGCCCCCAGGCGCCTTCGCCCAGCTCGGTCAGCTCTCCCGCCTGGACCTCACCTCCAACCGCCTGGCCACGCTGGCTCCGGACCCGCTTTTCTCTCGTGGGCGTGATGCAGAGGCCTCTCCCGCCCCCCTGGTGCTGAGCTTTAGCGGGAACCCCCTGCACTGCAACTGTGAGCTGCTCTGGCTGCGGCGGCTGGCGCGGCCGGACGACCTGGAAACGTGCGCCTCCCCGCCCGGCCTGGCCGGCCGCTACTTCTGGGCAGTGCCCGAGGGCGAGTTCTCCTGTGAGCCGCCCCTCATTGCCCGCCACACGCAGCGCCTCTGGGTGCTGGAAGGCCAGCGGGCCACGCTGCGGTGCCGGGCCCTGGGTGACCCCGCGCCTACCATGCACTGGGTCGGTCCTGACGACCGGTTGGTTGGCAACTCCTCCCGAGCCCGGGCTTTCCCCAACGGGACCTTAGAGATTGGGGTGACCGGCGCTGGGGACGCTGGGGGCTACACCTGCATCGCCACCAACCCTGCTGGTGAGGCCACAGCCCGAGTAGAACTGCGGGTGCTGGCCTTGCCCCATGGTGGGAACAGCAGTCCCGAGGGGGGCCGCCCGGGCCCTCGGACATCGGCCCCATGGTGGGAACAGCAGTGCCGAGGGGGGCCGCCCGGGCCCTCGGACATCGCCGCCTCCGCTCGCACTGCTGCCGAGGGTGAGGGGACGCTGGAGTCTGAGCCAGCCGTGCAGGTGACGGAGGTGACCGCCACCTCAGGGCTGGTGAACTGGGGTCCCCGGCAGCCAGCGACCCACGTGTGGATGTTCCAAATCCAGTACAACAGCAGCGAAGATGAGACCCTCATCTGCCGGATTGTCCCAGCCTCCAGCCACCACTTCCTGCTGAAGCACCTCGTCCCCGGCGCTGACTATGACCTCTGCCTGCTCGCCTTGTCACCGGCCGCTGGGCCCTCTGACCTCACGGCCACCAGGCTGCTGGGCTGTGCCCATTTCTCCACGCTGCCGGCCTCGCCCCTGTGCCACGCCCTGCAGGCCCACGTGCTGGGCGGGACCCTGACCGTGGCCGTGGGGGGTGTGCTGGTGGCTGCCTTACTGGTCTTCACTGTGGCCTTGCTCGTTCGGGGCCGGGGGGCCGGAAATGGCCGCCTCCCCCTCAAGCTCAGCCACGTCCAGTCCCACACCAATGGAGGCCCCAGCCCCACACCCAAGGCCCACCCGCCGCGGAGCCCCCCGCCCCGGCCGCAGCGCAGCTGCTCTCTGGACCTGGGAGATGCCGGGTGCTACGGTTATGCCAGGCGCCTGGGAGGAGCTTGGGCCCGACGGAGCCACTCTGTCCATGGGGGGCTGCTCGGGGCAGGGTGCCGGGGGGTAGGAAGGGAGCCCTCCTGGAGAAGGCGCGAGTCTTGCTGTGCTGAGGAGCCTGCCGTGGACCGCCTCAGCGCCCCCTACACCACTCTCGCCCTGAGGACCAGCACCCTGAGGAAGCTCCAGGGAGGCAGGTATCAGCTCGGCAGACACAAGAGCTTGCATGGCCAGGGCCCCCACAGTGAAAATGACCCCGAGTTGGGGCAAGCTCCCCATCAAGGGAGACCGCCGCGGAGCCCCCCGCCCCGGCCGCAGCGCAGCTGCTCTCTGGACCTGGGAGATGCCGGGTGCTACGGTTATGCCAGGCGCCTGGGAGGAGCTTGGGCCCGACGGAGCCACTCTGTGCATGGGGGGCTGCTCGGGGCAGGGTGCCGGGGGGTAGGAGGCAGCGCCGAGCGGCTGGAAGAGAGTGTGGTGTGATGGACGGGCAGCTTCCTGTGTGCTCCAAGGGATGAGCCTCGTGCGGCAGAGGGCCCGGGGCCGCCGCCTGGCCTGGGAGTCCCTCCCTGGTTTTTATORF Start: ATG at 130ORF Stop: TGA at 2464SEQ ID NO:192778 aa MW at 82472.5 kDNOV44c,MAPALLLLLLASGAAACPLPCVCQNLSESLSTLCAHRGLLFVPPNVDRRTVELRLADNCG59869-03 ProteinFIQALGPPDFRNMTGLVDLTLSRNAITRIGARAFGDLESLRSLHLDGNRLVELGTGSLSequenceRGPVNLQHLILSGNQLGRIAPGAFDDFLESLEDLDLSYNNLRQVPWAGIGAMPALHTLNLDHNLIDALPPGAFAQLGQLSRLDLTSNRLATLAPDPLFSRGRDAEASPAPLVLSFSGNPLHCNCELLWLRRLARPDDLETCASPPGLAGRYFWAVPEGEFSCEPPLIARHTQRLWVLEGQRATLRCRALGDPAPTMHWVGPDDRLVGNSSRARAFPNGTLEIGVTGAGDAGGYTCIATNPAGEATARVELRVLALPHGGNSSAEGGRPGPRTSAPWWEQQCRGGPPGPSDIAASARTAAEGEGTLESEPAVQVTEVTATSGLVNWGPRQPATHVWMFQIQYNSSEDETLICRIVPASSHHFLLKHLVPGADYDLCLLALSPAAGPSDLTATRLLGCAHFSTLPASPLCHALQAHVLGGTLTVAVGGVLVAALLVFTVALLVRGRGAGNGRLPLKLSHVQSQTNGGPSPTPKAHPPRSPPPRPQRSCSLDLGDAGCYGYARRLGGAWARRSHSVHCGLLGAGCRGVGREPSWRRRESCCAEEPAVDRLSAPYTTLALRTSTLRKLQGGRYQLGRHKSLHGQGPHSENDPELGQAPHQGRPPRSPPPRPQRSCSLDLGDAGCYGYARRLGGAWARRSHSVHGGLLGAGCRGVGGSAERLEESVV


[0553] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 44B.
238TABLE 44BComparison of NOV44a against NOV44b through NOV44c.NOV44a Residues/Identities/SimilaritiesProtein SequenceMatch Residuesfor the Matched RegionNOV44b21 . . . 512477/492 (96%)21 . . . 512477/492 (96%)NOV44c21 . . . 563496/561 (88%)21 . . . 581498/561 (88%)


[0554] Further analysis of the NOV44a protein yielded the following properties shown in Table 44C.
239TABLE 44CProtein Sequence Properties NOV44aPSort0.4600 probability located in plasma membrane; 0.1000analysis:probability located in endoplasmic reticulum (membrane);0.1000 probability located in endoplasmic reticulum (lumen);0.1000 probability located in outsideSignalPCleavage site between residues 17 and 18analysis:


[0555] A search of the NOV44a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 44D.
240TABLE 44DGeneseq Results for NOV44aNOV44aIdentities/GeneseqProtein/Organism/Length [Patent #,Residues/Similarities forExpectIdentifierDate]ResiduesRegionValueAAB70072Human secreted protein #11 -168 . . . 577 408/410 (99%)0.0Homo sapiens, 468 aa. [WO200112776-A2,1 . . . 410408/410 (99%)22-FEB-2001]AAB12448Human hh00149 protein SEQ ID NO: 4 -9 . . . 577330/590 (55%)e−180Homo sapiens, 785 aa.4 . . . 592408/590 (68%)[WO200031255-A1, 02-JUN-2000]AAB09968Human brain-specific transmembrane9 . . . 577330/590 (55%)e−180glycoprotein - Homo sapiens, 789 aa.8 . . . 596408/590 (68%)[WO200031256-A1, 02-JUN-2000]AAU28092Novel human secretory protein, Seq ID9 . . . 577329/590 (55%)e−179No 261 - Homo sapiens, 789 aa.8 . . . 596407/590 (68%)[WO200166689-A2, 13-SEP-2001]AAM39059Human polypeptide SEQ ID NO 2204 -9 . . . 577329/590 (55%)e−179Homo sapiens, 789 aa.8 . . . 596407/590 (68%)[WO200153312-a1, 26-JUL-2001]


[0556] In a BLAST search of public sequence databases, the NOV44a protein was found to have homology to the proteins shown in the BLASTP data in Table 44E.
241TABLE 44EPublic BLASTP Results for NOV44aNOV44aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueQ9ULH4KIAA1246 PROTEIN - Homo sapiens9 . . . 577330/590 (55%)e−179(Human), 832 aa (fragment).51 . . . 639 408/590 (68%)Q9BE71HYPHOTHETICAL 84.7 KDA9 . . . 577328/590 (55%)e−178PROTEIN - Macaca fascicularis (Crab8 . . . 596406/590 (68%)eating macaque) (Cynomolgusmonkey), 789 aa.Q9CYK35730420O05RIK PROTEIN -9 . . . 577327/595 (54%)e−174Mus musculus (Mouse), 788 aa.8 . . . 601407/595 (67%)CAD10239SEQUENCE 1 FROM PATENT4 . . . 582329/608 (54%)e−171WO0172827 - Homo sapiens (Human),5 . . . 608398/608 (65%)628 aa.Q9BTN0HYPOTHETICAL 66.3 KDA4 . . . 582329/608 (54%)e−171PROTEIN - Homo sapiens (Human),5 . . . 608398/608 (65%)628 aa.


[0557] PFam analysis indicates that the NOV44a protein contains the domains shown in the Table 44F.
242TABLE 44FDomain Analysis of NOV44aIdentities/SimilaritiesPfam DomainNOV44a Match Regionfor the Matched RegionExpect ValueLRRNT: domain 1 of 116 . . . 4712/33 (36%)120/33 (61%)LRR: domain 1 of 749 . . . 72 8/25 (32%)7515/25 (60%)LRR: domain 2 of 773 . . . 96 8/25 (32%)1.415/25 (60%)LRR: domain 3 of 7 97 . . . 120 7/25 (28%)0.8219/25 (76%)LRR: domain 4 of 7121 . . . 144 9/25 (36%)0.02217/25 (68%)LRR: domain 5 of 7146 . . . 16912/25 (48%)0.04919/25 (76%)LRR: domain 6 of 7170 . . . 193 9/25 (36%)0.009618/25 (72%)LRR: domain 7 of 7194 . . . 214 9/25 (36%)8615/25 (60%)LRRCT: domain 1 of 1234 . . . 27921/54 (39%)1.1e−0537/54 (69%)ig: domain 1 of 1295 . . . 35315/62 (24%)  9e−1043/62 (69%)fn3: domain 1 of 1404 . . . 48721/86 (24%)2.7e−0858/86 (67%)



Example 45

[0558] The NOV45 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 45A.
243TABLE 45ANOV45 Sequence AnalysisSEQ ID NO:193704 bpNOV45a,GAAGCGCQGAGGCCCGTCCCGGTGGCCGGGGAGCGGGCGGGTGGGGGCGCCATGTGGTCG59859-01 DNATCATGTACCTGCTGAGCTGGCTGTCGCTCTTCATCCAGGTGGCCTTCATCACGCTGGCSequenceTGTCGCGGCTGGACTCTATTACCTGGCAGAACTGATAGAAGAATACACAGTGGCCACCAGCAGGATCATAAAATACATGATCTGGTTCTCCACCGCTGTACTGATTGGCCTCTACGTCTTTGAGCGCTTCCCCACCAGCATGATTGGAGTGGGCCTATTCACCAACCTCGTCTACTTTGGCCTCCTCCAGACCTTCCCCTTCATCATGCTCACCTCGCCTAACTTCATCCTGTCGTGTGGACTAGTGGTGGTGAATCATTACCTAGCATTTCAGTTTTTTGCAGAAGAATATTATCCCTTCTCAGAGGTCCTGGCCTATTTCACTTTCTGCCTGTGGATAATTCCGTTTGCGTTTTTTGTGTCACTTTCGGCCGGGGAGAACGTCCTGCCCTCTACCATGCAGCCAGGAGATGATGTCGTCTCCAATTATTTCACCAAAGGCAAGCGGGGCAAACGCTTAGGGATCCTGGTTGTCTTCTCCTTCATCAAAGAGGCCATTCTACCCAGTCGTCAGAAGATATACTGACCCCCATGCAGGCAGGATGTGGGGGGCAAGATCAGGAGAGTCAGGCCCCTGGGCCTCTATGCORF Start: ATG at 52ORF Stop: TGA at 640SEQ ID NO:194196 aa MW at 22537.4 kDNOV45a,MWFMYLLSWLSLFIQVAFITLAVAAGLYYLAELIEEYTVATSRIIKYMIWFSTAVLIGCG59859-01 ProteinLYVFERFPTSMIGVGLFTNLVYFGLLQTFPFIMLTSPNFILSCGLVVVNHYLAFQFFASequenceEEYYPFSEVLAYFTFCLWIIPFAFFVSLSAGENVLPSTMQPGDDVVSNYFTKGKRGKRLGILVVFSFIKEAILPSRQKIYSEQ ID NO:195619 bpNOV45b,CATGTGGTTCATGTACCTGCTGAGCTGGCTGTCGCTCTTCATCCAGGTGGCCTTCATCCG59859-02 DNAACGCTGGCTGTCGCGGCTGGACTCTATTACCTGGCAGAACTGATAGAAGAATACACAGSequence TGGCCACCAGCAGGATCATAAAATACATGATCTGGTTCTCCACCGCTGTACTGATTGGCCTCTACGTCTTTGAGCGCTTCCCCACCAGCATGATTGGAGTGGGCCTATTCACCAACCTCGTCTACTTTGGCCTCCTCCAGACCTTCCCCTTCATCATGCTGACCTCGCCTAACTTCATCCTGTCGTGTGGACTAGTGGTGGTGAATCATTACCTAGCATTTCAGTTTTTTGCAGAAGAATATTATCCCTTCTCAGAGGTCCTGGCCTATTTCACTTTCTGCCTGTGGATAATTCCGTTTGCGTTTTTTGTGTCACTTTCGGCCGGGGAGAACGTCCTGCCCTCTACCATGCAGCCAGGAGATGATGTCGTCTCCAATTATTTCACCAAAGGCAAGCGGGGCAAACGCTTAGGGATCCTGGTTGTCTTCTCCTTCATCAAAGAGGCCATTCTACCCAGTCGTCAGAAGATATACTGACCCCCATGCAGGTACATGAACCACATGORF Start: ATG at 2ORF Stop: TGA at 590SEQ ID NO:196196 aa MW at 22537.4 kDNOV45b,MWFMYLLSWLSLFIQVAFITLAVAAGLYYLAELIEEYTVATSRIIKYMIWFSTAVLIGCG59859-02 ProteinLYVFERFPTSMIGVGLFTNLVYFGLLQTFPFIMLTSPNFILSCGLVVVNHYLAFQFFASequence EEYYPFSEVLAYFTFCLWIIPFAFFVSLSAGENVLPSTMQPGDDVVSNYFTKGKRGKRLGILVVFSFIKEAILPSRQKIY


[0559] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 45B.
244TABLE 45BComparison of NOV45a against NOV45b and NOV45c.NOV45a Residues/Identities/SimilaritiesProtein SequenceMatch Residuesfor the Matched RegionNOV45b1 . . . 196196/196 (100%)1 . . . 196196/196 (100%)


[0560] Further analysis of the NOV45a protein yielded the following properties shown in Table 45C.
245TABLE 45CProtein Sequence Properties NOV45aPSort0.6400 probability located in plasma membrane; 0.4600analysis:probability located in Golgi body; 0.3700 probability locatedin endoplasmic reticulum (membrane); 0.1000 probabilitylocated in endoplasmic reticulum (lumen)SignalPCleavage site between residues 25 and 26analysis:


[0561] A search of the NOV45a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 45D.
246TABLE 45DGeneseq Results for NOV45aNOV45aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAU12255Human PRO4325 polypeptide1 . . . 196196/196 (100%) e−111sequence - Homo sapiens, 196 aa.1 . . . 196196/196 (100%)[WO200140466-A2, 07-JUN-2001]AAM40045Human polypeptide SEQ ID NO 3190 -1 . . . 196196/196 (100%) e−111Homo sapiens, 196 aa.1 . . . 196196/196 (100%)[WO200153312-A1, 26-JUL-2001]AAM41831Human polypeptide SEQ ID NO 6762 -1 . . . 173173/173 (100%)5e−98 Homo sapiens, 203 aa.31 . . . 203 173/173 (100%)[WO200153312-A1, 26-JUL-2001]AAM93368Human polypeptide, SEQ ID NO: 2935 -91 . . . 196 106/106 (100%)6e−57 Homo sapiens, 106 aa. [EP1130094-1 . . . 106106/106 (100%)A2, 05-SEP-2001]ABB18676Protein #675 encoded by probe for51 . . . 101  51/51 (100%)8e−23 measuring heart cell gene expression -1 . . . 51  51/51 (100%)Homo sapiens, 51 aa. [WO200157274-A2, 09-AUG-2001]


[0562] In a BLAST search of public sequence databases, the NOV45a protein was found to have homology to the proteins shown in the BLASTP data in Table 45E.
247TABLE 45EPublic BLASTP Results for NOV45aProteinNOV45aIdentities/AccessionResidues/Similarities forExpectNumberProtein/Organism/LengthResiduesPortionValueQ62302TESTIS EXPRESSED PROTEIN 2611 . . . 196195/196 (99%)  e−110(TEG-261) (TESTIS EXPRESSED1 . . . 196196/196 (99%) GENE 261) - Mus musculus (Mouse),196 aa.AAH20251HYPOTHETICAL 17.0 KDA48 . . . 196 149/149 (100%)1e−82PROTEIN - Homo sapiens (Human),1 . . . 149149/149 (100%)149 aa.Q96FM0UNKNOWN (PROTEIN FOR84 . . . 196 113/113 (100%)1e−60IMAGE: 3855224) - Homo sapiens1 . . . 113113/113 (100%)(Human), 113 aa (fragment).Q9W1R8CG3500 PROTEIN - Drosophila1 . . . 19499/198 (50%)9e−49melanogaster (Fruit fly), 198 aa.1 . . . 195135/198 (68%) JC5386steroidogenic acute regulatory protein -48 . . . 133  86/86 (100%)7e−45rat, 362 aa.1 . . . 86  86/86 (100%)


[0563] PFam analysis predicts that the NOV45a protein contains the domains shown in the Table 45F.
248TABLE 45FDomain Analysis of NOV45aIdentities/NOV45aSimilaritiesExpectPfam DomainMatch Regionfor the Matched RegionValueNo Significant Matches Found



Example 46

[0564] The NOV46 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 46A.
249TABLE 46ANOV46 Sequence AnalysisSEQ ID NO:1974798 bpNOV46a,GAAACAGGTCAAAATGAGCAAGAGACGCATGAGCGTGGGTCAGCAAACATGGGCTCTTCG59913-01 DNACTCTGCAAGAACTGTCTCAAAAAATGGAGAATGAAAAGACAGACCTTGTTGGAATGGCSequenceTCTTTTCATTTCTTCTGGTACTGTTTCTGTACCTATTTTTCTCCAATTTACATCAAGTTCATGACACTCCTCAAATGTCTTCAATGGATCTGGGACGTGTAGATAGTTTTAATGATACTAATTATGTTATTGCATTTGCACCTGAATCCAAAACTACCCAAGAGATAATGAACAAAGTGGCTTCAGCCCCATTCCTAGCAGGAAGAACAATCATGGGGTGGCCTGATGAAAAAAGCATGGATGAATTGGATTTGAACTATTCAATAGACGCACTGAGAGTCATCTTTACTGATACCTTCTCCTACCATTTGAAGTTTTCTTGGGGACATAGAATCCCCATGATGAAAGAGCACAGAGACCATTCAGCTCACTGTCAAGCAGTGAATGAAAAAATGAAGTGTGAAGGTTCAGAGTTCTGGGAGAAAGGCTTTGTACCTTTTCAAGCTGCCATTAATGCTGCTATCATAGAAGTGAGTACAAATCATTCAGTGATGGAACAGCTGATGTCAGTTACTGGTGTACATATGAAGATATTACCTTTTGTTGCCCAAGGAGGAGTTGCAACTGATTTTTTCATTTTCTTTTGCATTATTTCTTTTTCTACATTTATATACTATGTATCAGTCAATGTTACACAAGAAAGACAATACATTACGTCATTGATGACAATGATGGGACTCCGAGAGTCAGCATTCTGGCTTTCCTGGGGTTTGATGTATGCTGGCTTCATCCTTATCATGGCCACTTTAATGGCTCTTATTGTAAAATCTGCACAAATTGTCGTCCTGACTGGTTTTGTGATGGTCTTCACCCTCTTTCTCCTCTATGGCCTGTCTTTGGTGAGTTTAGCTTTCCTGATGAGTGTGTTGATAAAGAAACCTTTCCTTACGGGCTTGGTTGTGTTTCTCCTTATTGTCTTTTGGGGGATCCTGGGATTCCCAGCATTGTATACACGTCTTCCTGCATTTTTGGAATGGACTTTGTGTCTTCTTAGCCCCTTTGCCTTCACTGTTGGGATGGCCCAGCTTATACATTTGGACTATGATGTGAATTCTAATGCCCACTTGCATTCTTCACAAAATCCATACCTCATAATAGCTACTCTTTTCATGTTGGTTTTTGACACCCTTCTGTATTTGGTATTGACATTATATTTTGACAAAATTTTGCCCGGTGAATATGGACATCGATGTTCTCCCTTGTTTTTCCTGAAATCCTGTTTTTGGTTTCAACACGGAAGGGCTAATCATGTGGTCCTTGAGAATGAAACAGATTCTGATCCTACACCTAATGACTGTTTTGAACCAGTGTCTCCAGAATTCTGTGGGAAAGAAGCCATCAGAATCAAAAATCTTAAAAAAGAATATGCAGGGAAGTGTGAGAGAGTAGAAGCTTTGAAAGGTGTGGTGTTTOACATATATGAAGGCCAGATCACTGCCCTCCTTGGTCACAGTGGAGCTGGAAAAACTACCCTGTTAAACATACTTAGTGGGTTGTCAGTTCCAACATCAGGTTCAGTCACTGTCTATAATCACACACTTTCAAGAATGGCTCATATAGAAAATATCAGCAAGTTCACTGGATTTTGTCCACAATCCAATGTGCAATTTGGATTTCTCACTGTGAAAGAAAACCTCAGGCTGTTTGCTAAAATAAAAGGGATTTTGCCACATGAAGTGGAGAAAGAGGTATTGCTATTGGATGAACCGACTCCTGCATTGCATCCTCTTTCAAGGCACCGAATATGGAATCTCCTGAAAGAGGGGAAATCAGACAGAGTAATTCTCTTCAGCACCCAGTTTATAGATGAGGCTGACATTCTGGCGGACAGGAAGGTGTTCATATCCAATGGGAAGCTGAAGTGTGCAGGCTCTTCTCTGTTCCTTAAGAAGAAATGGGGCATAGGCTACCATTTAAGTTTGCATCTGAATGAAAGGTGTGATCCAGAGAGTATAACATCACTGGTTAAGCAGCACATCTCTGATGCCAAATTGACAGCACAAAGTGAAGAAAAACTTGTATATATTTTGCCTTTGGAAACGACAAACAAATTTCCAGAACTTTACAGGGATCTTGATAGATGTTCTAACCAAGGCATTGAGGATTATGGTGTTTCCATAACAACTTTGAATGAGGTGTTTCTGAAATTAGAAGGAAAATCAACTATTGATGAATCAGATATTGGAATTTGGGGACAATTACAAACTGATGGGGCAAAAGATATAGGAAGCCTTGTTGAGCTGGAACAAGTTTTGTCTTCCTTCCACGAAACAAGGAAAACAATCAGTGGCGTGGCGCTCTGGAGGCAGCAGGTCTGTGCAATAGCAAAAGTTCGCTTCCTAAAGTTAAAGAAAGAAAGAAAAAGCCTGCTGCATAGATTATTGCTTTTTGGTATTAGCTTTATCCCTCAACTTTTGGAACATCTATTCTACGAGTCATATCAGAAAAGTTACCCGTGGGAACTGTCTCCAAATACATACTTCCTCTCACCAGGACAACAACCACAGGATCCTCTGACCCATTTACTGGTCATCAATAAGACAGGTTCAACCATTGATAACTTTTTACATTCACTGAGGCGACAGAACATAGCTATAGAAGTGGATGCCTTTGGAACTAGAAATGGCACAGATGACCCATCTTACAATGGTGCTATCATTGTGTCAGGTGATGAAAAGGATCACAGATTTTCAATAGCATGTAATACAAAACGGCTGAATTGCTTTCCTGTCCTCCTGGATGTCATTAGCAATGGACTACTTGGAATTTTTAATTCGTCAGAACACATTCAGACTGACAGAAGCACATTTTTTGAAGAGCATATGGATTATGAGTATGGGTACCGAAGTAACACCTTCTTCTGGATACCGATGGCAGCCTCTTTCACTCCATACATTGCAATGAGCAGCATTGGTCACTACAAAGTAAGAGCTCATTCCCAGCTACGGATTTCAGGCCTCTACCCTTCTGCATACTGGTTTGCCCAAGCACTGGTGGATGTTTCCCTGTACTTTTTGATCCTCCTGCTAATGCAAATAATGGATTATATTTTTAGCCCAGAGGAGATTATATTTATAATTCAAAACCTGTTAATTCAAGTAAGTGGCAGCAATTTTGAAATGGTTTTATTAGACTATTTTTTCATGAATGCAGTAATATCATTAATCTTAAACCAAAGAACTTCAAATTACCTGTGCTATTGCATAGTTTTGGTGGTCATCTTCTCGATAGTTGCTACTGATCTAAATGAATATGGATTTCTAGGGCTATTTTTTGGCACCATGTTAATACCTCCCTTCACATTGATTGGCTCTCTATTCATTTTTTCTGAGGTAAGTAGTTCCACTTATAGCTCAAGAAACAAAATTGTCCTTTTACCTTTTATTTGCAAAAGAGTGGGGTACCTTCATTTTCTCATTTTTCTTTTCATTCTGCGATGCCTAGAAATGAACTGCAGGAAGAAACTAATGAGAAAGGATCCTGTGTTCAGAATTTCTCCAAGAAGCAACGCTATTTTTCCAAACCCAGAAGAGCCTGAAGGAGAGGAGGAAGATATCCAGATGGAAAGAATGAGAACAGTGAATGCTATGGCTGTGCGAGACTTTGATGAGACACCCGTCATCATTGCCAGCTGTCTACGGAAGGAATATGCAGGCAAAAAGAAAAATTGCTTTTCTAAAAGGAAGAAAAAAATTGCCACAAGAAATGTCTCTTTTTGTGTTAAAAAAGGTGAAGTTATAGGACTGTTAGGACACAATGGAGCTGGTAAAAGTACAACTATTAAGATGATAACTGGAGACACAAAACCAACTGCAGGACAGGTCATTTTGAAAGGGAGCGGTGGAGGGGAACCCCTGGGCTTCCTGGGGTACTGCCCTCAGGAGAATGCGCTGTGGCCCAACCTGACAGTGAGGCAGCACCTGGAGGTGTACGCTGCCGTGAAAGGTCTCAGGAAAGGGGACGCAATGATCGCCATCACACGGTTAGTGGATGCGCTCAAGCTGCAGGACCAGCTGAAGGCTCCCGTGAAGACCTTGTCAGAGGGAATAAAGCGAAAGCTGTGCTTTGTGCTGAGCATCCTGGGGAACCCGTCAGTGGTGCTTCTGGATGAGCCGTCGACCGGGATGGACCCCGAGGGGCAGCAGCAAATGTGGCAGGTGATTCGGGCCACCTTTAGAAACACGGAGAGGGGCGCCCTCCTGACCACCCACTACATGGCAGAGGCTGAGGCGGTGTGTGACCGAGTGGCCATCATGGTGTCAGGAAGCCTGAGGTGTATTGGTTCCATCCAACACCTGAAAAGCAAATTTGGCAAAGACTACCTGCTGGAGATGAAGCTGAAGAACCTGGCACAAATGGAGCCCCTCCATGCAGAGATCCTGAGGCTTTTCCCCCAGGCTGCTCAGCAGGAAAGGTTCTCCTCCCTGATGGTCTATAAGTTGCCTGTTGAGGATGTGCGACCTTTATCACAGGCTTTCTTCAAATTAGAGATAGTTAAACAGAGTTTCGACCTGGAGGAGTACAGCCTCTCACAGTCTACCCTGGAGCAGGTTTTCCTGGAGCTCTCCAAGGAGCAGGAGCTGGGTGATCTTGAAGAGGACTTTGATCCCTCGGTGAAGTGGAAACTCCTCCTGCAGGAAGAGCCTTAAAGCTCCAAATACCCTATATCTTTCTTTAATCCTORF Start: ATG at 14ORF Stop: TAA at 4763SEQ ID NO:1981583 aa MW at 179792.1 kDNOV46a,MSKRRMSVGQQTWALLCKNCLKKWRMKRQTLLEWLFSFLLVLFLYLFFSNLHQVHDTPCG59913-01 ProteinQMSSMDLGRVDSFNDTNYVIAFAPESKTTQEIMNKVASAPFLAGRTIMGWPDEKSMDESequenceLDLNYSIDAVRVIFTDTFSYHLKFSWGHRIPMMKEHRDHSAHCQAVNEKMKCEGSEFWEKGFVAFQAAINAAIIEVSTNHSVMEQLMSVTGVHMKILPFVAQGGVATDFFIFFCIISFSTFIYYVSVNVTQERQYITSLMTMMGLRESAFWLSWGLMYAGFILIMATLMALIVKSAQIVVLTGFVMVFTLFLLYGLSLVSLAFLMSVLIKKPFLTGLVVFLLIVFWGILGFPALYTRLPAFLEWTLCLLSPFAFTVGMAQLIHLDYDVNSNAHLDSSQNPYLIIATLFMLVFDTLLYLVLTLYFDKILPGEYGHRCSPLFFLKSCPWFQHGRANHVVLENETDSDPTPNDCFEPVSPEFCGKEAIRIKNLKKEYAGKCERVEALKGVVFDIYEGQITALLGHSGAGKTTLLNILSGLSVPTSGSVTVYNHTLSRMADIENISKFTGFCPQSNVQFGFLTVKENLRLFAKIKGILPHEVEKEVLLLDEPTAGLDPLSRHRIWNLLKEGKSDRVILFSTQFIDEADILADRKVFISNGKLKCAGSSLFLKKKWGIGYHLSLHLNERCDPESITSLVKQHISDAKLTAQSEEKLVYILPLERTNKFPELYRDLDRCSNQGIEDYGVSITTLNEVFLKLEGKSTIDESDIGIWGQLQTDGAKDIGSLVELEQVLSSFHETRKTISGVALWRQQVCAIAKVRFLKLKKERKSLLHRLLLFGISFIPQLLEHLFYESYQKSYPWELSPNTYFLSPGQQPQDPLTHLLVINKTGSTIDNFLHSLRRQNIAIEVDAFGTRNGTDDPSYNGAIIVSGDEKDHRFSIACNTKRLNCFPVLLDVISNGLLGIFNSSEHIQTDRSTFFEEHMDYEYGYRSNTFFWIPMAASFTPYIAMSSIGDYKVPAHSQLRISGLYPSAYWFGQALVDVSLYFLILLLMQIMDYIFSPEEIIFIIQNLLIQVSGSNFEMVLLDYFFMNAVISLILNQRTSNYLCYCIVLVVIFSIVATDLNEYGFLGLFFGTMLIPPFTLIGSLFIFSEVSSSTYSSRNKIVLLPFICKRVGYLHFLIFLFILRCLEMNCRKKLMRKDPVFRISPRSNAIFPNPEEPEGEEEDIQMERMRTVNAMAVRDFDETPVIIASCLRKEYAGKKKNCFSKRKKKIATRNVSFCVKKGEVIGLLGHNGAGKSTTIKMITGDTKPTAGQVILKGSGGOEPLGFLCYCPQENALWPNLTVRQHLEVYAAVKGLRKGDAMIAITRLVDALKLQDQLKAPVKTLSEGIKRKLCFVLSILGNPSVVLLDEPSTGMDPEGQQQMWQVIRATFRNTERGALLTTHYMAEAEAVCDRVAIMVSGRLRCIGSIQHLKSKFGKDYLLEMKLKNLAQMEPLHAEILRLFPQAAQQERFSSLMVYKLPVEDVRPLSQAFFKLEIVKQSFDLEEYSLSQSTLEQVFLELSKEQELGDLEEDFDPSVKWKLLLQEEP


[0565] Further analysis of the NOV46a protein yielded the following properties shown in Table 46B.
250TABLE 46BProtein Sequence Properties NOV46aPSort0.8000 probability located in plasma membrane; 0.6281analysis:probability located in mitochondrial inner membrane;0.4410 probability located in mitochondrial intermembranespace; 0.4000 probability located in Golgi bodySignalPCleavage site between residues 54 and 55analysis:


[0566] A search of the NOV46a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 46C.
251TABLE 46CGeneseq Results for NOV46aNOV46aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAM93187Human polypeptide, SEQ ID NO: 2559 -374 . . . 816442/483 (91%)0.0Homo sapiens, 483 aa. [EP1130094- 1 . . . 483442/483 (91%)A2, 05-SEP-2001]AAB67309ABC transport related protein #3 -1222 . . . 1583330/362 (91%)0.0Homo sapiens, 362 aa. 1 . . . 362348/362 (95%)[WO200107658-A1, 01-FEB-2001]AAU18484Human endocrine polypeptide SEQ ID1232 . . . 1534216/303 (71%)e−122No 439 - Homo sapiens, 310 aa. 9 . . . 309253/303 (83%)[WO200155364-A2, 02-AUG-2001]AAE09582Human gene 2 encoded ABC1232 . . . 1534216/303 (71%)e−122transporter protein HDPVY34, SEQ ID 9 . . . 309253/303 (83%)NO: 24 - Homo sapiens, 310 aa.[WO200155208-A1, 02-AUG-2001]AAM42360Human polypeptide SEQ ID NO 93 -1232 . . . 1534216/303 (71%)e−122Homo sapiens, 310 aa. 9 . . . 309253/303 (83%)[WO200155449-A1, 02-AUG-2001]


[0567] In a BLAST search of public sequence databases, the NOV46a protein was found to have homology to the proteins shown in the BLASTP data in Table 46D.
252TABLE 46DPublic BLASTP Results for NOV46aNOV46aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueAAK30024ATP-BINDING CASSETTE A9 -1 . . . 15831521/1629 (93%)0.0Homo sapiens (Human), 1624 aa.1 . . . 16241541/1629 (94%)O94911(Human), 1581 aa.1 . . . 15811313/1588 (82%)0.0AAK30025ATP-BINDING CASSETTE A10 -91 . . . 1583  920/1557 (59%)0.0Homo sapiens (Human), 1543 aa.1 . . . 15431159/1557 (74%)AAK30023ATP-BINDING CASSETTE A6 -1 . . . 1578 906/1630 (55%)0.0Homo sapiens (Human), 1617 aa.1 . . . 16111153/1630 (70%)Q96MD8CDNA FLJ32506 FIS, CLONE1 . . . 816  809/856 (94%)0.0SMINT1000042, WEAKLY SIMILAR1 . . . 856  813/856 (94%)TO ATP-BINDING CASSETTE, SUB-FAMILY A, MEMBER 3 - Homosapiens (Human), 856 aa (fragment).


[0568] PFam analysis indicates that the NOV46a protein contains the domains shown in the Table 46E.
253TABLE 46EDomain Analysis of NOV46aIdentities/SimilaritiesPfam DomainNOV46a Match Regionfor the Matched RegionExpect ValueCyto_ox_2: domain 1 of 1136 . . . 42454/408 (13%)7190/408 (47%) PRK: domain 1 of 2512 . . . 525 8/14 (57%)14 11/14 (79%)ABC_tran: domain 1 of 2510 . . . 65256/199 (28%)3.2e−25120/199 (60%) biopterin_H: domain 1 of 1719 . . . 732 7/16 (44%)9.1 10/16 (62%)PRK: domain 2 of 21280 . . . 1299 10/20 (50%)2.1 15/20 (75%)ABC_tran: domain 2 of 21278 . . . 145660/200 (30%)1.6e−44139/200 (70%) 



Example 47

[0569] The NOV47 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 47A.
254TABLE 47ANOV47 Sequence AnalysisSEQ ID NO:1994766 bpNOV47a,CGAATAGGCTAAATGAATATGAAACAGAAAAGCGTGTATCAGCAAACCAAAGCACTTCCG59909-01 DNATGTGCAAGAATTTTCTTAAGAAATGGAGGATGAAAAGAGAGAGCTTATTGGAATGGGGSequenceCCTCTCAATACTTCTAGGACTGTGTATTGCTCTGTTTTCCAGTTCCATGAGAAATGTCCAGTTTCCTGGAATGGCTCCTCAGAATCTGCGAAGGGTAGATAAATTTAATAGCTCTTCTTTAATGGTTGTGTATACACCAATATCTAATTTAACCCAGCACATAATGAATAAAACAGCACTTGCTCCTCTTTTGAAAGGTAGGAGTGTCATTGGGGCACCAAATAAAACACACATGGACGAAATACTTCTGGAAAATTTACCATATGCTATGGGAATCATCTTTAATGAAACTTTCTCTTATAAGTTAATATTTTTCCAGGGATATAACAGTCCACTTTGGAAAGAAGATTTCTCAGGTACAGCTCATTGCTGGGATGGATATGGTGAGTTTTCATGTACATTGACCAAATACTGGAATAGAGGATTTGTGGCTTTACAAACAGCTATTAATACTGCCATTATAGAAATCACAACCAATCACCCTGTGATGGAGGAGTTGATGTCAGTTACTGCTATAACTATGAAGACATTACCTTTCATAACTAAAAATCTTCTTCACAATGAGATGTTTATTTTATTCTTCTTGCTTCATTTCTCCCCACTTGTATATTTTATATCACTCAATGTAACAAAAGAGAGAAAAAAGTCTAAGAATTTGATGAAAATGATGGGTCTCCAAGATTCAGCATTCTGGCTCTCCTGGGGTCTAATCTATGCTGGCTTCATCTTTATTATTTCCATATTCGTTACAATTATCATAACATTCACCCAAATTATAGTCATGACTGGCTTCATGGTCATATTTATACTCTTTTTTTTATATGGCTTATCTTTGGTAGCTTTGGTGTTCCTGATGAGTGTGCTGTTAAAGAAAGCTGTCCTCACCAATTTGGTTGTGTTTCTCCTTACCCTCTTTTGGGGATCTCTGGGATTCACTGTATTTTATGAACAACTTCCTTCATCTCTGGAGTGGATTTTGAATATTTGTAGCCCTTTTGCCTTTACTACTGGAATGATTCAGGTAATCAAACTGGATTATAACTTGAATGGTGTAATTTTTCCTGACCCTTCAGGAGACTCATATACAATGATAGCAACTTTTTCTATGTTGCTTTTGGATGGTCTCATCTACTTGCTATTGGCATTATACTTTGACAAAATTGTTTCCAACACCAAAGGACTAATGCTAAGGTTATTGAGAAAGAAATCGATGCTGAGCATCCCTCTGATGATTATTTTGAACCAGTAGCTCCTGAATTCCAACGAAAAGPAGCCATCAGAATCAGAAATGTTAAGAAGGAATATAAAGGAAAATCTGGAAAAGTGGAAGCATTGAAAGGTTTGCTCTTTGACATATATGAAGGTCAAATCACGGCAATCCTGGGTCACAGTGGAGCTGGCAAATCTTCACTGCTAAATATTCTTAATGGATTGTCTGTTCCAACAGAAGGTTCAGTTACCATCTATAATAAAAATCTCTCTGAAATGCAAGACTTGGAGGAAATCAGAAAGATAACTGGCGTCTGTCCTCAATTCAATGTTCAATTTGACATACTCACCGTGAAGGAAAACCTCAGCCTGTTTGCTAAAATAAAAGGGATTCATCTAAAGGAAGTGGAACAAGAGATTTTGCTTTTAGATGAACCAACTACTGGATTGGATCCCTTTTCCAGAGATCAAGTGTGGACCCTCCTGAGAGAGCGTAGAGCAGATCATGTGATCCTTTTCAGTACCCAGTCCATGGATGAGGCTGACATCCTGGCTGATAGAAAAGTGATCATGTCCAATGGGAGACTGAAGTGTGCAGGTTCTTCTATGTTTTTGAAAAGAAGGTGGGGTCTTGGATATCACCTAAGTTTACATAGGAATGAAATATGTAACCCAGAACAAATAACATCCTTCATTACTCATCACATCCCCGATGCTAAATTAAAAACAGAAAACAAAGAAAAGCTTGTATATACTTTGCCACTGGAAAGGACAAATACATTTCCAGATCTTTTCAGTGATCTGGATAAGTGTTCTGACCAGGGAGTGACAGGTTATGACATTTCCATGTCAACTCTAAATGAAGTCTTTATGAAACTGGAAGGACAGTCAACTATCGAACAAGGTAAAGCCATTTGTATAATTCACAGACAAGTGGAGATGATAAGAGACTCAGAAAGCCTCAATGAAATGGAGCTGGCTCACTCTTCCTTCTCTGAAATGCAGACAGCTGTGAGTGACATGGGCCTCTGGAGAATGCAAGTCTTTGCCATGGCACGGCTCCGTTTCTTAAAGTTAAAACGTCAAACTAAAGTGTTATTGACCCTGTTATTGGTATTTGGAATCGCAATATTCCCTTTGATTGTTGAAAATATAATGTATGCTATGTTAAATGAAAAGATCGATTGGGAATTTAAAAACGAATTGTATTTTCTCTCTCCTGGACAACTTCCCCAGGAACCCCGTACCAGCCTGTTGATCATCAATAACACAGGTTCAAATATTGAAGATTTTATAAAATCACTGAAGCATCAAAATATACTTTTGGAAGTAGATGACTTTGAAAACAGAAATGGTACTGATGGCCTCTCATACAATGGAGCTATCATAGTTTGTTTCTGTTTTAAGGATTATAGATTTTCAGTTGTGTGTAATACCAAGAGATTGCACTGTTTTCCAATTCTTATGAATATTATCAGCAATGGGCTACTTCAAATGTTTAATCACACACAACATATTCGAATTGAGTCAAGCCCATTTAGCCACATAGCACTCTGGACTGGGTTGCCGGATGGTTCCTTTTTCTTATTTTTGGTTCTATGTAGCATTTCTCCTTATATCACCATGGGCAGCATCAGTCATTACAAGGTAAGAGCTAAGTCCCAGCTATGGATTTCAGGCCTCTACACTTCTGCTTACTGGTGTGGGCAGGCACTAGTGGACGTCACCTTCTTCATTTTAATTCTCCTTTTAATGTATTTAATTTTCTACATAGAAAACATGCAGTACCTTCTTATTACATATTTCTTTTATGCTCACGTTATAGTTACTCCTGGTTATGCAGCTTCTCTTGTCTTCTTCATATATATGATATCATTTATTTTTCGCAAAAGGAGAAAAAACAGTGGCCTTTGGTCATTTTACTTCTTTTTTGCCTCCACCATCATGTTTTCCATCACTTTAATCAATCATTTTGACCTAAGTATATTGATTACCACCATGGTATTGGTTCCTTCATATACCTTGCTTGGATTTAAAACTTTTTTGGAAGTGAGAGACCAGGAGCACTACAGAGAATTGAGTGCCACTGATTTTCTAGTCTGCTTCATACCCTACTTTCAGACTTTGCTATTCGTTTTTGTTCTAAGATGCATGGAACTAAAATGTGGAAAGAAAAGAATGCGAAAAGATCCTGTTTTCAGGATTTCCCCCCAAAGTAGAGATGCTAAGCCAAATCCAGAAGAACCCATAGATGAAGATGAAGATATTCAAACAGAAAGAATAAGAACAGCCACTGCTCTGACCACTTCAATCTTAGATGAGAAACCTGTTATAATTGCCAGCTGTCTACACAAAGAATATGCAGGCCAGAAGAAAAGTTGCTTTTCAAAGAGGAAGAAGAAAATAGCAGCAAGAAATATCTCTTTCTGTGTTCAAGAAGGTGAAATTTTGGGATTGCTAGGACCCAATGGTGCTGGAAAAAGTTCATCTATTAGAATCATATCTGGGATCACAAAGCCAACTGCTGGAGAGGTAGTGCTGAAAGGCTGCAGTTCAGTTTTGGGCCACCTGGGGTACTGCCCTCAAGAGAACGTGCTGTGGCCCATGCTGACGTTGAGGGAACACCTGGAGGTGTATGCTGCCGTCAAGGGGCTCAGGAAAGCGCACGCGAGGCTCGCCATCGCAAGGAGATTAGTGAGTGCTTTCAAACTGCATGAGCAGCTGAATGTTCCTGTGCAGAAATTAACAGCAGGAATCACGAGAAAGTTGTGTTTTGTGCTGAGCCTCCTGGGAAACTCACCTGTCTTGCTCCTGGATGAACCATCTACGGGCATAGACCCCACAGGGCAGCAGCAAATGTGGCAGGCAATCCAGGCAGTCGTTAAAAACACAGAGACAGGTGTCCTCCTGACCACCCATAACCTGGCTGAGGCGGAAGCCTTGTGTGACCGTGTGGCCATCATGGTGTCTGGAAGGCTTAGATGCATTGGCTCCATCCAACACCTGAAAAACAAACTTGGCAAGGATTACATTCTAGAGCTAAAAGTGAAGGAAACGTCTCAAGTGACTTTGGTCCACACTGAGATTCTGAAGCTTTTCCCACAGGCTGCAGGGCAGGAAAGGTATTCCTCTTTGTTAACCTATAAGCTGCCCGTGGCAGACGTTTACCCTCTATCACAGACCTTTCACAAATTAGAAGCAGTGAAGCATAACTTTAACCTGGAAGAATACAGCCTTTCTCAGTGCACACTGGAGAAGGTATTCTTAGAGCTTTCTAAAGAACAGGAAGTAGGAAATTTTGATGAAGAAATTGATACAACAATGAGATGGAAACTCCTCCCTCATTCAGATGAACCTTAAAACCTCAAACCTAGTAATTTTTTORF Start: ATG at 13ORF Stop: TAA at 4741SEQ ID NO:2001576 aa MW at 179721.1 kDNOV47a,MNMKQKSVYQQTKALLCKNFLKKWRMKRESLLEWGLSILLGLCIALFSSSMRNVQFPGCG59909-01 ProteinMAPQNLGRTDKFNSSSLMVVYTPISNLTQQIMNKTALAPLLKGRSVIGAPNKTHMDEISequenceLLENLPYAMGIIFNETFSYKLIFFQGYNSPLWKEDFSGTAHCWDGYGEFSCTLTKYWNRGFVALQTAINTAIIEITTNHPVMEELMSVTAITMKTLPFITKNLLHNEMFILFFLLHFSPLVYFISLNVTKERKKSKNLMKMMGLQDSAFWLSWGLIYAGFIFIISIFVTIIITFTQIIVMTGFMVIFILFFLYGLSLVALVFLMSVLLKKAVLTNLVVFLLTLFWGCLGFTVFYEQLPSSLEWILNICSPFAFTTGMIQVIKLDYNLNGVIFPDPSGDSYTMIATFSMLLLDGLIYLLLALYFDKILPCKDERHYSPLFFLNSSSCFQHQRTNAKVIEKEIDAEHPSDDYFEPVAPEFQCKEAIRIRNVKKEYKGKSGKVEALKGLLFDIYEGQITAILGHSGAGKSSLLNILNGLSVPTEGSVTIYNKNLSEMQDLEEIRKITGVCPQFNVQFDILTVKENLSLFAKIKGIHLKEVEQEILLLDEPTTGLDPFSRDQVWSLLRERRADHVILFSTQSMDEADILADRKVIMSNGRLKCAGSSMFLKRRWGLGYHLSLHRNEICNPEQITSFITHHIPDAKLKTENKEKLVYTLPLERTNTFPDLFSDLDKCSDQCVTGYDISMSTLNEVFMKLEGQSTIEQGKAICIIHRQVEMIRDSESLNEMELAHSSFSEMQTAVSDMGLWRMQVFAMARLRFLKLKRQTKVLLTLLLVFGIAIFPLIVENIMYAMLNEKIDWEFKNELYFLSPGQLPQEPRTSLLIINNTGSNIEDFIKSLKHQNILLEVDDFENRNGTDGLSYNGAIIVCFCFKDYRFSVVCNTKRLHCFPILMNIISNGLLQMFNHTQHIRIESSPFSHIGLWTGLPDGSFFLFLVLCSISPYITMCSISDYKVRAKSQLWISGLYTSAYWCGQALVDVSFFILILLLMYLIFYIENMQYLLITYFFYAQVIVTPGYAASLVFFIYMISFIFRKRRKNSGLWSFYFFFASTIMFSITLINHFDLSILITTMVLVPSYTLLGFKTFLEVRDQEHYRELSATDFLVCFIPYFQTLLFVFVLRCMELKCGKKRMRKDPVFRISPQSRDAKPNPEEPIDEDEDIQTERIRTATALTTSILDEKPVIIASCLHKEYAGQKKSCFSKRKKKIAARNISFCVQEGEILGLLGPNGAGKSSSIRMISGITKPTAGEVVLKGCSSVLGHLGYCPQENVLWPMLTLREHLEVYAAVKGLRKADARLAIARRLVSAFKLHEQLNVPVQKLTAGITRKLCFVLSLLGNSPVLLLDEPSTGIDPTCQQQMWQAIQAVVKNTERGVLLTTHNLAEAEALCDRVAIMVSGRLRCIGSIQHLKNKLGKDYILELKVKETSQVTLVHTEILKLFPQAAGQERYSSLLTYKLPVADVYPLSQTFHKLEAVKHNFNLEEYSLSQCTLEKVFLELSKEQEVGNFDEEIDTTMRWKLLPHSDEP


[0570] Further analysis of the NOV47a protein yielded the following properties shown in Table 47B.
255TABLE 47BProtein Sequence Properties NOV47aPSort0.8000 probability located in plasma membrane; 0.4000analysis:probability located in Golgi body; 0.3000 probability locatedin endoplasmic reticulum (membrane); 0.3000 probabilitylocated in microbody (peroxisome)SignalPCleavage site between residues 51 and 52analysis:


[0571] A search of the NOV47a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 47C.
256TABLE 47CGeneseq Results for NOV47aNOV47aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAU18484Human endocrine polypeptide SEQ ID1229 . . . 1526294/298 (98%)e−164No 439 - Homo sapiens, 310 aa. 13 . . . 309294/298 (98%)[WO200155364-A2, 02-AUG-2001]AAE09582Human gene 2 encoded ABC1229 . . . 1526294/298 (98%)e−164transporter protein HDPVY34, SEQ ID 13 . . . 309294/298 (98%)NO: 24 - Homo sapiens, 310 aa.[WO200155208-A1, 02-AUG-2001]AAM42360Human polypeptide SEQ ID NO 93 -1229 . . . 1526294/298 (98%)e−164Homo sapiens, 310 aa. 13 . . . 309294/298 (98%)[WO200155449-A1, 02-AUG-2001)AAM93187Human polypeptide, SEQ ID NO: 2559 -373 . . . 815273/483 (56%)e−149Homo sapiens, 483 aa. [EP1130094- 1 . . . 483339/483 (69%)A2, 05-SEP-2001]AAB67309ABC transport related protein #3 -1216 . . . 1574256/361 (70%)e−146Homo sapiens, 362 aa. 2 . . . 361303/361 (83%)[WO200107658-A1, 01-FEB-2001]


[0572] In a BLAST search of public sequence databases, the NOV47a protein was found to have homology to the proteins shown in the BLASTP data in Table 47D.
257TABLE 47DPublic BLASTP Results for NOV47aResidues/AccessionMatchSimilarities for theNumberProtein/Organism/LengthResiduesMatched PortionValueAAK30023ATP-BINDING CASSETTE A6 -1 . . . 15761544/1626 (94%)0.0Homo sapiens (Human), 1617 aa.1 . . . 16171549/1626 (94%)O94911KIAA0822 PROTEIN - Homo1 . . . 1574 929/1581 (58%)0.0sapiens (Human), 1581 aa.1 . . . 15801149/1581 (71%)AAK30025ATP-BINDING CASSETTE A10 -90 . . . 1574  922/1543 (59%)0.0Homo sapiens (Human), 15431 . . . 15421126/1543 (72%)aa.AAK30024ATP-BINDING CASSETTE A9 -1 . . . 1570 917/1620 (56%)0.0Homo sapiens (Human), 1624 aa.1 . . . 16191162/1620 (71%)AAK30022ATP-BINDING CASSETTE A5 -3 . . . 1568 653/1651 (39%)0.0Homo sapiens (Human), 1642 aa.5 . . . 1633 969/1651 (58%)


[0573] PFam analysis indicates that the NOV47a protein contains the domains shown in the Table 47E.
258TABLE 47EDomain Analysis of NOV47aIdentities/NOV47aSimilaritiesMatchfor the MatchedExpectPfam DomainRegionRegionValuePeptidase_S26: domain 1 1 . . . 46 14/47 (30%)7.9of 1 35/47 (74%)Virus_HS: domain 1 of 1169 . . . 174  4/6 (67%)2.1   6/6 (100%)ABC_tran: domain 1 of 2509 . . . 651 58/199 (29%)4.7e−26117/199 (59%)7tm_1: domain 1 of 11053 . . . 1085  6/34 (18%) 0.46 25/34 (74%)ABC_tran: domain 2 of 21271 . . . 1448 59/199 (30%)8.7e−44137/199 (69%)



Example 48

[0574] The NOV48 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 48A.
259TABLE 48ANOV48 Sequence AnalysisSEQ ID NO:2011599 bpNOV48a,CGCAGCAGTTTGTGTTCCCTGATGGAAAATGAAGCCTCATCTACTGACTCTCCCATCCCG59945-01 DNAAAAAAGACTTGAGGGCAAACGAGGACAAAAGTTCCCACGAGGTGGGCACTGCGGGAAGSequenceGAGGCCCACGACCCCGAGATTCTCCGGCGACCCCGGCGGGCCACCCCGGGCCGGTGAGGGTTCCCGCGGCACGTGTGCGGCGGCGCCCGCCGCTTCCCCCGCCGCCCGGGAAGGTCACGCCGCCCGGACGCCGAGGCTCTCCCCGTGCCCCGCTCCCTCCGCCCCGCACACTCCCGTGACCAGCCCCATCTCCAGCCAGGTGGTGGGCAGTGAGCCACTACAGTACATCATGGCAGAGCCGGCCAGGCCTGACAGTCCAAAGGGCTCCTCGGAGACAGAGACCGAGCCTCCTGTGGCCCTGGCCCCTGGTCCAGCTCCCACCCACTGCCTCCCAGGCCACAAGGAAGAGGAGGATGGGGAGGGGGCTGGGCCTGGCGAGCAGGGCGGTGGGAAGCTGGTGCTCAGCTCCCTGTCCAAGCGCCTCTGCCTGGTCTGTGGGGACGTGGCCTCCGGCTACCACTGCGGTGTGTCATCCTGTGAGGACTGCAAAGCCTTCTTCAAGAGGACCATCCAGCCCAGTATGGAGTACAGCTGTCTGGCCTCCAACGAGTGTGAGATCACCAAGCGGAGACGCAACCCCTGTCAGGCCTGCCGCTTCACCAAGAGCCTGCGGCTTCACCAAGAGCCTGCGGGAGCCCGCCTGGACCGCGTCCGGGGTGGGCGGGAGTACAAGCCGTGCCCAGAGGTGGACCCGCTGCCCTTCCCGGGCGCCTTCCCTGCTGGGCCCCTGGCAGTCGCTGGAGGCCCCCAGACGACAGGCCCAGTGAATGCACTGGTGTCTCATCTAATGGTGGTTGAGCCTGAGAAGCTCTATGCCTTGCCCGACCCTGCTGGCCCTGATGGGCACCTTCCAGCCGTGGCTACCCTCTGTGACCTCTTTGACCGAGAGATCGTGGTCACCATCAGCTGGGCCAAGAGCATCCCACGCTTCTCATCGCTGTCGCTGTCTGACCAGATGTCAGTACTGCAGAGAGTATGGATGGAGGTGCTGGTGCCGGGTGTGGCCCAGCGCTCACTGCCACTGCAGGATGAGTTGGCCTTCGCTGAGGACTTAGTCCTGGATGAACAGGGGGCACGGGCAGCTGGCCTGGGGGAACTGGGGGCTGCCCTGCTGCAACTGGTGCGGCGGCTGCAGTCCCTGCGGCTGGAGCGAGGGGAGTACGTTCTACTGAAGGCCCTGGCCCTTGCCAATTCAGACTCTGTGCCCATCGAAGATGCCGAGGCTGTGGAGCAGCTGCCAGAAGCTCCGCACGAGGCCCTGCTGGAGTATGAAGCCGGCCGAGCTGGCACCGGAGGGGGTGCTGAGCGGCGGCGGCCACGCAGGCTGCTGTTCACGCTACCGCTCCTCCACCAGACAGCGGGCAAAGTGCTGGCCCATTTCTATGGGGTGAAGCTGGAGGGCAAGGTGCCCATGCACAAGCTGTTCTTGGAGATGCTCGAGGCCATGATGGACTGA+E, UNS GGCGAGGGGTGGGACTGGTGGGGGTTCORF Start: ATG at 22ORF Stop: TGA at 1570SEQ ID NO:202516 aa MW at 54706.5 kDNOV48a,MENEASSTDSPIQKDLRAKEDKSSHEVGTAGRRPTTPRFSGDPGGPPRGGEGSRGTCACG59945-01 ProteinAAPAASPAAREGHAARTPRLSPCPAPSAPHTPVTSAMSSQVVGSEPLQYIMAEPARPDSequenceSPKGSSETETEPPVALAPGPAPTHCLPGHKEEEDGEGAGPGEQGGGKLVLSSLSKRLCLVCGDVASCYHCCVSSCEDCKAFFKRTIQGSMEYSCLASNECEITKRRRKACQACRFTKSLRLHQEPAGARLDRVRGGREYKRCPEVDPLPFPGAFPAGPLAVAGGPQTTGPVNALVSHLMVVEPEKLYALPDPAGPDGHLPAVATLCDLFDREIVVTISWAKSIPGFSSLSLSDQMSVLQRVWMEVLVPGVAQRSLPLQDELAFAEDLVLDEEGARAAGLGELGAALLQLVRRLQSLRLERGEYVLLKALALANSDSVPTEDAEAVEQLPEAPHEALLEYEAGRAGTGGGAERRRPGRLLFTLPLLHQTAGKVLAHFYGVKLEGKVPMHKLFLEMLEAMMD


[0575] Further analysis of the NOV48a protein yielded the following properties shown in Table 48B.
260TABLE 48BProtein Sequence Properties NOV48aPSort0.7000 probability located in nucleus; 0.3000 probabilityanalysis:located in microbody (peroxisome); 0.1000 probability locatedin mitochondrial matrix space; 0.1000 probability located inlysosome (lumen)SignalPNo Known Signal Sequence Indicatedanalysis:


[0576] A search of the NOV48a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 48C.
261TABLE 48CGeneseq Results for NOV48aNOV48aIdentities/Residues/Similarities forGeneseqProtein/Organism/Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAM39411Human polypeptide SEQ ID NO 2556 - 4 . . . 516418/520 (80%)0.0Homo sapiens, 552 aa. 36 . . . 552432/520 (82%)[WO200153312-A1, 26-JUL-2001]AAP80930Sequence of human estrogen-related 4 . . . 516409/521 (78%)0.0receptor protein (hERR1) - Homo 4 . . . 521425/521 (81%)sapiens, 521 aa. [WO8803168-A, 05-MAY-1988]AAM41197Human polypeptide SEQ ID NO 6128 - 4 . . . 516406/521 (77%)0.0Homo sapiens, 556 aa. 39 . . . 556422/521 (80%)[WO200153312-A1, 26-JUL-2001]AAY83822Human nuclear receptor nNR1 - Homo100 . . . 513227/438 (51%)e−115sapiens, 500 aa. [US6054295-A, 25- 8 . . . 431287/438 (64%)APR-2000]AAB12970Human oestrogen related receptor 4100 . . . 513227/438 (51%)e−115(ERR4) protein sequence - Homo 8 . . . 431287/438 (64%)sapiens, 433 aa. [WO200042180-A1,20-JUL-2000]


[0577] In a BLAST search of public sequence databases, the NOV48a protein was found to have homology to the proteins shown in the BLASTP data in Table 48D.
262TABLE 48DPublic BLASTP Results for NOV48aNOV48aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueP11474Steroid hormone receptor ERR14 . . . 516418/519 (80%)0.0(Estrogen-related receptor, alpha) (ERR-4 . . . 519432/519 (82%)alpha) (Estrogen receptor-like 1) - Homosapiens (Human), 519 aa.A29345precursor - human, 521 aa.4 . . . 521425/521 (81%)0.0E1262508SEQUENCE 18 FROM PATENT4 . . . 513404/518 (77%)0.0WO9709348 - Homo sapiens (Human),4 . . . 518421/518 (80%)518 aa.O08580Steroid hormone receptor ERR166 . . . 516 393/463 (84%)0.0(Estrogen-related receptor, alpha) (ERR-2 . . . 462404/463 (86%)alpha) (Estrogen receptor-like 1) - Musmusculus (Mouse), 462 aa (fragment).Q96102UNKNOWN (PROTEIN FOR199 . . . 516 289/320 (90%)e−158IMAGE: 4301880) - Homo sapiens4 . . . 323296/320 (92%)(Human), 323 aa (fragment).


[0578] PFam analysis indicates that the NOV48a protein contains the domains shown in the Table 48E.
263TABLE 48EDomain Analysis of NOV48aIdentities/SimilaritiesNOV48a Matchfor the MatchedExpectPfam DomainRegionRegionValuezf-C4: domain 1 of 1172 . . . 233 35/63 (56%)9.3e−36 58/63 (92%)hormone_rec: domain 1326 . . . 511 58/209 (28%)2.2e−30of 1136/209 (65%)



Example B

[0579] Identification of NOVX Clones


[0580] The novel NOVX target sequences identified in the present invention may have been subjected to the exon linking process to confirm the sequence. PCR primers were designed by starting at the most upstream sequence available, for the forward primer, and at the most downstream sequence available for the reverse primer. In each case, the sequence was examined, walking inward from the respective termini toward the coding sequence, until a suitable sequence that is either unique or highly selective was encountered, or, in the case of the reverse primer, until the stop codon was reached. Such primers were designed based on in silico predictions for the full length cDNA, part (one or more exons) of the DNA or protein sequence of the target sequence, or by translated homology of the predicted exons to closely related human sequences from other species. These primers were then employed in PCR amplification based on the following pool of human cDNAs: adrenal gland, bone marrow, brain—amygdala, brain—cerebellum, brain—hippocampus, brain—substantia nigra, brain—thalamus, brain—whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma—Raji, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea, uterus.


[0581] Usually the resulting amplicons were gel purified, cloned and sequenced to high redundancy. The PCR product derived from exon linking was cloned into the pCR2.1 vector from Invitrogen. The resulting bacterial clone has an insert covering the entire open reading frame cloned into the pCR2. 1 vector. The resulting sequences from all clones were assembled with themselves, with other fragments in CuraGen Corporation's database and with public ESTs. Fragments and ESTs were included as components for an assembly when the extent of their identity with another component of the assembly was at least 95% over 50 bp. In addition, sequence traces were evaluated manually and edited for corrections if appropriate. These procedures provide the sequence reported herein.



Example C


Quantitative Expression Analysis of Clones in Various Cells and Tissues

[0582] The quantitative expression of various clones was assessed using microtiter plates containing RNA samples from a variety of normal and pathology-derived cells, cell lines and tissues using real time quantitative PCR (RTQ PCR). RTQ PCR was performed on an Applied Biosystems ABI PRISM® 7700 or an ABI PRISM® 7900 HT Sequence Detection System. Various collections of samples are assembled on the plates, and referred to as Panel 1 (containing normal tissues and cancer cell lines), Panel 2 (containing samples derived from tissues from normal and cancer sources), Panel 3 (containing cancer cell lines), Panel 4 (containing cells and cell lines from normal tissues and cells related to inflammatory conditions), Panel 5D/5I (containing human tissues and cell lines with an emphasis on metabolic diseases), AI_comprehensive_panel (containing normal tissue and samples from autoimmune diseases), Panel CNSD.01 (containing central nervous system samples from normal and diseased brains) and CNS_neurodegeneration_panel (containing samples from normal and Alzheimer's diseased brains).


[0583] RNA integrity from all samples is controlled for quality by visual assessment of agarose gel electropherograms using 28S and 18S ribosomal RNA staining intensity ratio as a guide (2:1 to 2.5:1 28s:18s) and the absence of low molecular weight RNAs that would be indicative of degradation products. Samples are controlled against genomic DNA contamination by RTQ PCR reactions run in the absence of reverse transcriptase using probe and primer sets designed to amplify across the span of a single exon.


[0584] First, the RNA samples were normalized to reference nucleic acids such as constitutively expressed genes (for example, β-actin and GAPDH). Normalized RNA (5 ul) was converted to cDNA and analyzed by RTQ-PCR using One Step RT-PCR Master Mix Reagents (Applied Biosystems; Catalog No. 4309169) and gene-specific primers according to the manufacturer's instructions.


[0585] In other cases, non-normalized RNA samples were converted to single strand cDNA (sscDNA) using Superscript II (Invitrogen Corporation; Catalog No. 18064-147) and random hexamers according to the manufacturer's instructions. Reactions containing up to 10 μg of total RNA were performed in a volume of 20 μl and incubated for 60 minutes at 42° C. This reaction can be scaled up to 50 μg of total RNA in a final volume of 100 μl . sscDNA samples are then normalized to reference nucleic acids as described previously, using 1× TaqMan® Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions.


[0586] Probes and primers were designed for each assay according to Applied Biosystems Primer Express Software package (version I for Apple Computer's Macintosh Power PC) or a similar algorithm using the target sequence as input. Default settings were used for reaction conditions and the following parameters were set before selecting primers: primer concentration=250 nM, primer melting temperature (Tm) range=58°-60° C., primer optimal Tm=59° C., maximum primer difference=2° C., probe does not have 5′G, probe Tm must be 10° C. greater than primer Tm, amplicon size 75 bp to 100 bp. The probes and primers selected (see below) were synthesized by Synthegen (Houston, Tex., USA). Probes were double purified by HPLC to remove uncoupled dye and evaluated by mass spectroscopy to verify coupling of reporter and quencher dyes to the 5′ and 3′ ends of the probe, respectively. Their final concentrations were: forward and reverse primers, 900 nM each, and probe, 200 nM.


[0587] PCR conditions: When working with RNA samples, normalized RNA from each tissue and each cell line was spotted in each well of either a 96 well or a 384-well PCR plate (Applied Biosystems). PCR cocktails included either a single gene specific probe and primers set, or two multiplexed probe and primers sets (a set specific for the target clone and another gene-specific set multiplexed with the target probe). PCR reactions were set up using TaqMan® One-Step RT-PCR Master Mix (Applied Biosystems, Catalog No. 4313803) following manufacturer's instructions. Reverse transcription was performed at 48° C. for 30 minutes followed by amplification/PCR cycles as follows: 95° C. 10 min, then 40 cycles of 95° C. for 15 seconds, 60° C. for 1 minute. Results were recorded as CT values (cycle at which a given sample crosses a threshold level of fluorescence) using a log scale, with the difference in RNA concentration between a given sample and the sample with the lowest CT value being represented as 2 to the power of delta CT. The percent relative expression is then obtained by taking the reciprocal of this RNA difference and multiplying by 100.


[0588] When working with sscDNA samples, normalized sscDNA was used as described previously for RNA samples. PCR reactions containing one or two sets of probe and primers were set up as described previously, using 1× TaqMan® Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions. PCR amplification was performed as follows: 95° C. 10 min, then 40 cycles of 95° C. for 15 seconds, 60° C. for 1 minute. Results were analyzed and processed as described previously.


[0589] Panels 1, 1.1, 1.2, and 1.3D


[0590] The plates for Panels 1, 1.1, 1.2 and 1.3D include 2 control wells (genomic DNA control and chemistry control) and 94 wells containing cDNA from various samples. The samples in these panels are broken into 2 classes: samples derived from cultured cell lines and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in these panels are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on these panels are comprised of samples derived from all major organ systems from single adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, adult lung, fetal lung, various regions of the brain, the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose.


[0591] In the results for Panels 1, 1.1, 1.2 and 1.3D, the following abbreviations are used:


[0592] ca.=carcinoma,


[0593] *=established from metastasis,


[0594] met=metastasis,


[0595] s cell var=small cell variant,


[0596] non-s=non-sm=non-small,


[0597] squam=squamous,


[0598] pl. eff pl effusion=pleural effusion,


[0599] glio=glioma,


[0600] astro=astrocytoma, and


[0601] neuro=neuroblastoma.


[0602] General_Screening_Panel_v1.4


[0603] The plates for Panel 1.4 include 2 control wells (genomic DNA control and chemistry control) and 94 wells containing cDNA from various samples. The samples in Panel 1.4 are broken into 2 classes: samples derived from cultured cell lines and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in Panel 1.4 are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on Panel 1.4 are comprised of pools of samples derived from all major organ systems from 2 to 5 different adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, adult lung, fetal lung, various regions of the brain, the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose. Abbreviations are as described for Panels 1, 1.1, 1.2, and 1.3D.


[0604] Panels 2D and 2.2


[0605] The plates for Panels 2D and 2.2 generally include 2 control wells and 94 test samples composed of RNA or cDNA isolated from human tissue procured by surgeons working in close cooperation with the National Cancer Institute's Cooperative Human Tissue Network (CHTN) or the National Disease Research Initiative (NDRI). The tissues are derived from human malignancies and in cases where indicated many malignant tissues have “matched margins” obtained from noncancerous tissue just adjacent to the tumor. These are termed normal adjacent tissues and are denoted “NAT” in the results below. The tumor tissue and the “matched margins” are evaluated by two independent pathologists (the surgical pathologists and again by a pathologist at NDRI or CHTN). This analysis provides a gross histopathological assessment of tumor differentiation grade. Moreover, most samples include the original surgical pathology report that provides information regarding the clinical stage of the patient. These matched margins are taken from the tissue surrounding (i.e. immediately proximal) to the zone of surgery (designated “NAT”, for normal adjacent tissue, in Table RR). In addition, RNA and cDNA samples were obtained from various human tissues derived from autopsies performed on elderly people or sudden death victims (accidents, etc.). These tissues were ascertained to be free of disease and were purchased from various commercial sources such as Clontech (Palo Alto, Calif.), Research Genetics, and Invitrogen.


[0606] Panel 3D


[0607] The plates of Panel 3D are comprised of 94 cDNA samples and two control samples. Specifically, 92 of these samples are derived from cultured human cancer cell lines, 2 samples of human primary cerebellar tissue and 2 controls. The human cell lines are generally obtained from ATCC (American Type Culture Collection), NCI or the German tumor cell bank and fall into the following tissue groups: Squamous cell carcinoma of the tongue, breast cancer, prostate cancer, melanoma, epidermoid carcinoma, sarcomas, bladder carcinomas, pancreatic cancers, kidney cancers, leukemias/lymphomas, ovarian/uterine/cervical, gastric, colon, lung and CNS cancer cell lines. In addition, there are two independent samples of cerebellum. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. The cell lines in panel 3D and 1.3D are of the most common cell lines used in the scientific literature.


[0608] Panels 4D, 4R, and 4.1D


[0609] Panel 4 includes samples on a 96 well plate (2 control wells, 94 test samples) composed of RNA (Panel 4R) or cDNA (Panels 4D)/4.1D) isolated from various human cell lines or tissues related to inflammatory conditions. Total RNA from control normal tissues such as colon and lung (Stratagene, La Jolla, Calif.) and thymus and kidney (Clontech) was employed. Total RNA from liver tissue from cirrhosis patients and kidney from lupus patients was obtained from BioChain (Biochain Institute, Inc., Hayward, Calif.). Intestinal tissue for RNA preparation from patients diagnosed as having Crohn's disease and ulcerative colitis was obtained from the National Disease Research Interchange (NDRI) (Philadelphia, Pa.).


[0610] Astrocytes, lung fibroblasts, dermal fibroblasts, coronary artery smooth muscle cells, small airway epithelium, bronchial epithelium, microvascular dermal endothelial cells, microvascular lung endothelial cells, human pulmonary aortic endothelial cells, human umbilical vein endothelial cells were all purchased from Clonetics (Walkersville, Md.) and grown in the media supplied for these cell types by Clonetics. These primary cell types were activated with various cytokines or combinations of cytokines for 6 and/or 12-14 hours, as indicated. The following cytokines were used; IL-1 beta at approximately 1-5 ng/ml, TNF alpha at approximately 5-10 ng/ml, IFN gamma at approximately 20-50 ng/ml, IL-4 at approximately 5-10 ng/ml, IL-9 at approximately 5-10 ng/ml, IL-13 at approximately 5-10 ng/ml. Endothelial cells were sometimes starved for various times by culture in the basal media from Clonetics with 0.1% serum.


[0611] Mononuclear cells were prepared from blood of employees at CuraGen Corporation, using Ficoll. LAK cells were prepared from these cells by culture in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco/Life Technologies, Rockville, Md.), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco) and Interleukin 2 for 4-6 days. Cells were then either activated with 10-20 ng/ml PMA and 1-2 μg/ml ionomycin, IL-12 at 5-10 ng/ml, IFN gamma at 20-50ng/ml and IL-18 at 5-10 ng/ml for 6 hours. In some cases, mononuclear cells were cultured for 4-5 days in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco) with PHA (phytohemagglutinin) or PWM (pokeweed mitogen) at approximately 5 μg/ml. Samples were taken at 24, 48 and 72 hours for RNA preparation. MLR (mixed lymphocyte reaction) samples were obtained by taking blood from two donors, isolating the mononuclear cells using Ficoll and mixing the isolated mononuclear cells 1:1 at a final concentration of approximately 2×106 cells/ml in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol (5.5×10−5M) (Gibco), and 10 mM Hepes (Gibco). The MLR was cultured and samples taken at various time points ranging from 1-7 days for RNA preparation.


[0612] Monocytes were isolated from mononuclear cells using CD14 Miltenyi Beads, +ve VS selection columns and a Vario Magnet according to the manufacturer's instructions. Monocytes were differentiated into dendritic cells by culture in DMEM 5% fetal calf serum (FCS) (Hyclone, Logan, Utah), 100 μnon essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco), 50 ng/ml GMCSF and 5 ng/ml IL-4 for 5-7 days. Macrophages were prepared by culture of monocytes for 5-7 days in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), 10 mM Hepes (Gibco) and 10% AB Human Serum or MCSF at approximately 50 ng/ml. Monocytes, macrophages and dendritic cells were stimulated for 6 and 12-14 hours with lipopolysaccharide (LPS) at 100 ng/ml. Dendritic cells were also stimulated with anti-CD40 monoclonal antibody (Pharmingen) at 10 μg/ml for 6 and 12-14 hours.


[0613] CD4 lymphocytes, CD8 lymphocytes and NK cells were also isolated from mononuclear cells using CD4, CD8 and CD56 Miltenyi beads, positive VS selection columns and a Vario Magnet according to the manufacturer's instructions. CD45RA and CD45RO CD4 lymphocytes were isolated by depleting mononuclear cells of CD8, CD56, CD14 and CD19 cells using CD8, CD56, CD14 and CD19 Miltenyi beads and positive selection. CD45RO beads were then used to isolate the CD45RO CD4 lymphocytes with the remaining cells being CD45RA CD4 lymphocytes. CD45RA CD4, CD45RO CD4 and CD8 lymphocytes were placed in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco) and plated at 106 cells/ml onto Falcon 6 well tissue culture plates that had been coated overnight with 0.5 μg/ml anti-CD28 (Pharmingen) and 3 ug/ml anti-CD3 (OKT3, ATCC) in PBS. After 6 and 24 hours, the cells were harvested for RNA preparation. To prepare chronically activated CD8 lymphocytes, we activated the isolated CD8 lymphocytes for 4 days on anti-CD28 and anti-CD3 coated plates and then harvested the cells and expanded them in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethaniol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco) and IL-2. The expanded CD8 cells were then activated again with plate bound anti-CD3 and anti-CD28 for 4 days and expanded as before. RNA was isolated 6 and 24 hours after the second activation and after 4 days of the second expansion culture. The isolated NK cells were cultured in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco) and IL-2 for 4-6 days before RNA was prepared.


[0614] To obtain B cells, tonsils were procured from NDRI. The tonsil was cut up with sterile dissecting scissors and then passed through a sieve. Tonsil cells were then spun down and resupended at 106 cells/ml in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco). To activate the cells, we used PWM at 5 μg/ml or anti-CD40 (Pharmingen) at approximately 10 μg/ml and IL-4 at 5-10 ng/ml. Cells were harvested for RNA preparation at 24, 48 and 72 hours.


[0615] To prepare the primary and secondary Th1/Th2 and Tr1 cells, six-well Falcon plates were coated overnight with 10 μg/ml anti-CD28 (Pharmingen) and 2 μg/ml OKT3 (ATCC), and then washed twice with PBS. Umbilical cord blood CD4 lymphocytes (Poietic Systems, German Town, Md.) were cultured at 105-106 cells/ml in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), 10 mM Hepes (Gibco) and IL-2 (4 ng/ml). IL-12 (5 ng/ml) and anti-IL4 (1 μg/ml) were used to direct to Th1, while IL-4 (5 ng/ml) and anti-IFN gamma (1 μg/ml) were used to direct to Th2 and IL-10 at 5 ng/ml was used to direct to Tr1. After 4-5 days, the activated Th1, Th2 and Tr1 lymphocytes were washed once in DMEM and expanded for 4-7 days in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), 10 mM Hepes (Gibco) and IL-2 (1 ng/ml). Following this, the activated Th1, Th2 and Tr1 lymphocytes were re-stimulated for 5 days with anti-CD28/OKT3 and cytokines as described above, but with the addition of anti-CD95L (1 μg/ml) to prevent apoptosis. After 4-5 days, the Th1, Th2 and Tr1 lymphocytes were washed and then expanded again with IL-2 for 4-7 days. Activated Th1 and Th2 lymphocytes were maintained in this way for a maximum of three cycles. RNA was prepared from primary and secondary Th1, Th2 and Tr1 after 6 and 24 hours following the second and third activations with plate bound anti-CD3 and anti-CD28 mAbs and 4 days into the second and third expansion cultures in Interleukin 2.


[0616] The following leukocyte cells lines were obtained from the ATCC: Ramos, EOL-1, KU-812. EOL cells were further differentiated by culture in 0.1 mM dbcAMP at 5×105 cells/ml for 8 days, changing the media every 3 days and adjusting the cell concentration to 5×105 cells/ml. For the culture of these cells, we used DMEM or RPMI (as recommended by the ATCC), with the addition of 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), 10 mM Hepes (Gibco). RNA was either prepared from resting cells or cells activated with PMA at 10 ng/ml and ionomycin at 1 μg/ml for 6 and 14 hours. Keratinocyte line CCD106 and an airway epithelial tumor line NCI-H292 were also obtained from the ATCC. Both were cultured in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco). CCD1106 cells were activated for 6 and 14 hours with approximately 5 ng/ml TNF alpha and 1 ng/ml IL-1 beta, while NCI-H292 cells were activated for 6 and 14 hours with the following cytokines: 5 ng/ml IL-4, 5 ng/ml IL-9, 5 ng/ml IL-13 and 25 ng/ml IFN gamma.


[0617] For these cell lines and blood cells, RNA was prepared by lysing approximately 107 cells/ml using Trizol (Gibco BRL). Briefly, {fraction (1/10)} volume of bromochloropropane (Molecular Research Corporation) was added to the RNA sample, vortexed and after 10 minutes at room temperature, the tubes were spun at 14,000 rpm in a Sorvall SS34 rotor. The aqueous phase was removed and placed in a 15 ml Falcon Tube. An equal volume of isopropanol was added and left at −20° C. overnight. The precipitated RNA was spun down at 9,000 rpm for 15 min in a Sorvall SS34 rotor and washed in 70% ethanol. The pellet was redissolved in 300 μl of RNAse-free water and 35 μl buffer (Promega) 5 μl DTT, 7 μl RNAsin and 8 μl DNAse were added. The tube was incubated at 37° C. for 30 minutes to remove contaminating genomic DNA, extracted once with phenol chloroform and re-precipitated with {fraction (1/10)}volume of 3M sodium acetate and 2 volumes of 100% ethanol. The RNA was spun down and placed in RNAse free water. RNA was stored at −80° C.


[0618] AI_Comprehensive Panel_v1.0


[0619] The plates for AI_comprehensive panel_v1.0 include two control wells and 89 test samples comprised of cDNA isolated from surgical and postmortem human tissues obtained from the Backus Hospital and Clinomics (Frederick, Md). Total RNA was extracted from tissue samples from the Backus Hospital in the Facility at CuraGen. Total RNA from other tissues was obtained from Clinomics.


[0620] Joint tissues including synovial fluid, synovium, bone and cartilage were obtained from patients undergoing total knee or hip replacement surgery at the Backus Hospital. Tissue samples were immediately snap frozen in liquid nitrogen to ensure that isolated RNA was of optimal quality and not degraded. Additional samples of osteoarthritis and rheumatoid arthritis joint tissues were obtained from Clinomics. Normal control tissues were supplied by Clinomics and were obtained during autopsy of trauma victims.


[0621] Surgical specimens of psoriatic tissues and adjacent matched tissues were provided as total RNA by Clinomics. Two male and two female patients were selected between the ages of 25 and 47. None of the patients were taking prescription drugs at the time samples were isolated.


[0622] Surgical specimens of diseased colon from patients with ulcerative colitis and Crohns disease and adjacent matched tissues were obtained from Clinomics. Bowel tissue from three female and three male Crohn's patients between the ages of 41-69 were used. Two patients were not on prescription medication while the others were taking dexamethasone, phenobarbital, or tylenol. Ulcerative colitis tissue was from three male and four female patients. Four of the patients were taking lebvid and two were on phenobarbital.


[0623] Total RNA from post mortem lung tissue from trauma victims with no disease or with emphysema, asthma or COPD was purchased from Clinomics. Emphysema patients ranged in age from 40-70 and all were smokers, this age range was chosen to focus on patients with cigarette-linked emphysema and to avoid those patients with alpha-1anti-trypsin deficiencies. Asthma patients ranged in age from 36-75, and excluded smokers to prevent those patients that could also have COPD. COPD patients ranged in age from 35-80 and included both smokers and non-smokers. Most patients were taking corticosteroids, and bronchodilators.


[0624] In the labels employed to identify tissues in the AI_comprehensive panel_v1.0 panel, the following abbreviations are used:


[0625] AI=Autoimmunity


[0626] Syn=Synovial


[0627] Normal=No apparent disease


[0628] Rep22 /Rep20=individual patients


[0629] RA=Rheumatoid arthritis


[0630] Backus=From Backus Hospital


[0631] OA=Osteoarthritis


[0632] (SS) (BA) (MF)=Individual patients


[0633] Adj=Adjacent tissue


[0634] Match control=adjacent tissues


[0635] -M=Male


[0636] -F=Female


[0637] COPD=Chronic obstructive pulmonary disease


[0638] Panels 5D and 5I


[0639] The plates for Panel 5D and 5I include two control wells and a variety of cDNAs isolated from human tissues and cell lines with an emphasis on metabolic diseases. Metabolic tissues were obtained from patients enrolled in the Gestational Diabetes study. Cells were obtained during different stages in the differentiation of adipocytes from human mesenchymal stem cells. Human pancreatic islets were also obtained.


[0640] In the Gestational Diabetes study subjects are young (18-40 years), otherwise healthy women with and without gestational diabetes undergoing routine (elective) Caesarean section. After delivery of the infant, when the surgical incisions were being repaired/closed, the obstetrician removed a small sample (<1 cc) of the exposed metabolic tissues during the closure of each surgical level. The biopsy material was rinsed in sterile saline, blotted and fast frozen within 5 minutes from the time of removal. The tissue was then flash frozen in liquid nitrogen and stored, individually, in sterile screw-top tubes and kept on dry ice for shipment to or to be picked up by CuraGen. The metabolic tissues of interest include uterine wall (smooth muscle), visceral adipose, skeletal muscle (rectus) and subcutaneous adipose. Patient descriptions are as follows:
264Patient 2Diabetic Hispanic, overweight, not on insulinPatient 7-9Nondiabetic Caucasian and obese (BMI > 30)Patient 10Diabetic Hispanic, overweight, on insulinPatient 11Nondiabetic African American and overweightPatient 12Diabetic Hispanic on insulin


[0641] Adipocyte differentiation was induced in donor progenitor cells obtained from Osirus (a division of Clonetics/BioWhittaker) in triplicate, except for Donor 3U which had only two replicates. Scientists at Clonetics isolated, grew and differentiated human mesenchymal stem cells (HuMSCs) for CuraGen based on the published protocol found in Mark F. Pittenger, et al., Multilineage Potential of Adult Human Mesenchymal Stem Cells Science Apr. 2 1999: 143-147. Clonetics provided Trizol lysates or frozen pellets suitable for mRNA isolation and ds cDNA production. A general description of each donor is as follows:


[0642] Donor 2 and 3 U: Mesenchymal Stem cells, Undifferentiated Adipose


[0643] Donor 2 and 3 AM: Adipose, AdiposeMidway Differentiated


[0644] Donor 2 and 3 AD: Adipose, Adipose Differentiated


[0645] Human cell lines were generally obtained from ATCC (American Type Culture Collection), NCI or the German tumor cell bank and fall into the following tissue groups: kidney proximal convoluted tubule, uterine smooth muscle cells, small intestine, liver HepG2 cancer cells, heart primary stromal cells, and adrenal cortical adenoma cells. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. All samples were processed at CuraGen to produce single stranded cDNA.


[0646] Panel 51 contains all samples previously described with the addition of pancreatic islets from a 58 year old female patient obtained from the Diabetes Research Institute at the University of Miami School of Medicine. Islet tissue was processed to total RNA at an outside source and delivered to CuraGen for addition to panel 51.


[0647] In the labels employed to identify tissues in the 5D and 5I panels, the following abbreviations are used:


[0648] GO Adipose=Greater Omentum Adipose


[0649] SK=Skeletal Muscle


[0650] UT=Uterus


[0651] PL=Placenta


[0652] AD=Adipose Differentiated


[0653] AM=Adipose Midway Differentiated


[0654] U=Undifferentiated Stem Cells


[0655] Panel CNSD.01


[0656] The plates for Panel CNSD.01 include two control wells and 94 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center. Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at −80° C. in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathlology.


[0657] Disease diagnoses are taken from patient records. The panel contains two brains from each of the following diagnoses: Alzheimer's disease, Parkinson's disease, Huntington's disease, Progressive Supernuclear Palsy, Depression, and “Normal controls”. Within each of these brains, the following regions are represented: cingulate gyrus, temporal pole, globus palladus, substantia nigra, Brodman Area 4 (primary motor strip), Brodman Area 7 (parietal cortex), Brodman Area 9 (prefrontal cortex), and Brodman area 17 (occipital cortex). Not all brain regions are represented in all cases; e.g., Huntington's disease is characterized in part by neurodegeneration in the globus palladus, thus this region is impossible to obtain from confirmed Huntington's cases. Likewise Parkinson's disease is characterized by degeneration of the substantia nigra making this region more difficult to obtain. Normal control brains were examined for neuropathology and found to be free of any pathology consistent with neurodegeneration.


[0658] In the labels employed to identify tissues in the CNS panel, the following abbreviations are used:


[0659] PSP=Progressive supranuclear palsy


[0660] Sub Nigra=Substantia nigra


[0661] Glob Palladus=Globus palladus


[0662] Temp Pole=Temporal pole


[0663] Cing Gyr=Cingulate gyrus


[0664] BA 4=Brodman Area 4


[0665] Panel CNS_Neurodegeneration_V1.0


[0666] The plates for Panel CNS_Neurodegeneration_V1.0 include two control wells and 47 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center (McLean Hospital) and the Human Brain and Spinal Fluid Resource Center (VA Greater Los Angeles Healthcare System). Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at −80° C. in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology.


[0667] Disease diagnoses are taken from patient records. The panel contains six brains from Alzheimer's disease (AD) patients, and eight brains from “Normal controls” who showed no evidence of dementia prior to death. The eight normal control brains are divided into two categories: Controls with no dementia and no Alzheimer's like pathology (Controls) and controls with no dementia but evidence of severe Alzheimer's like pathology, (specifically senile plaque load rated as level 3 on a scale of 0-3; 0=no evidence of plaques, 3=severe AD senile plaque load). Within each of these brains, the following regions are represented: hippocampus, temporal cortex (Brodman Area 21), parietal cortex (Brodman area 7), and occipital cortex (Brodman area 17). These regions were chosen to encompass all levels of neurodegeneration in AD. The hippocampus is a region of early and severe neuronal loss in AD; the temporal cortex is known to show neurodegeneration in AD after the hippocampus; the parietal cortex shows moderate neuronal death in the late stages of the disease; the occipital cortex is spared in AD and therefore acts as a “control” region within AD patients. Not all brain regions are represented in all cases.


[0668] In the labels employed to identify tissues in the CNS_Neurodegeneration_V1.0 panel, the following abbreviations are used:


[0669] AD=Alzheimer's disease brain; patient was demented and showed AD-like pathology upon autopsy


[0670] Control=Control brains; patient not demented, showing no neuropathology


[0671] Control (Path)=Control brains; patient not demented but showing sever AD-like pathology


[0672] SupTemporal Ctx=Superior Temporal Cortex


[0673] Inf Temporal Ctx=Inferior Temporal Cortex



A. NOV1a (CC58546-01: ADILICAN)

[0674] Expression of gene CG58546-01 was assessed using the primer-probe sets Ag2933, Ag3370 and Ag3837, described in Tables AA, AB and AC.
265TABLE AAProbe Name Ag2933StartPrimersSequencesLengthPositionForward5′-caccaccactaagccagaac-3′(SEQ ID NO:203)204546ProbeTET-5′-ttctcagtccaagaacatctcaaatatgt-3′-TAMRA(SEQ ID NO:204)Reverse5′-ggattccccatgtaattcaag-3′(SEQ ID NO:205)214618


[0675]

266





TABLE AB










Probe Name Ag3370













Start


Primers
Sequences
Length
Position














Forward
5′-agctggattcttccaaacaga-3′
(SEQ ID NO:206)
21
1844





Probe
TET-5′-tcacatgtatacatgctgccaaatgg-3′-TAMRA
(SEQ ID NO: 207)
26
1892





Reverse
5′-acctttgggatggaaagagtt-3′
(SEQ ID NO:208)
21
1918










[0676]

267





TABLE AC










Probe Name Ag3837













Start


Primers
Sequences
Length
Position














Forward
5′-acgagcttgaggatgtggat-3′
(SEQ ID N0:209)
20
4260





Probe
TET-5′-ttttgtcctctgtgacagtctccaca-3′-TAMRA
(SEQ ID NO:210)
26
4293





Reverse
5′-gcttcttcctggtgaaatgg-3′
(SEQ ID N0:211)
20
4319










[0677] CNS_neurodegeneration_v1.0 Summary: Ag2933/Ag3370 Expression of the CG58546-01 gene is low/undetectable (CTs>35) across all of the samples on this panel.


[0678] General_screening_panel_v1.4 Summary: Ag3370/Ag3837 The amp plots suggest that there were experimental difficulties with these runs.


[0679] Panel 1.3D Summary: Ag2933 Expression of the CG58546-01 gene is low/undetectable (CTs>35) across all of the samples on this panel.



B. NOV2a and NOV2b (CG58598-01 and CG58598-02: BRAIN-SPECIFIC TM PROTEIN)

[0680] Expression of genes CG58598-01 and CG58598-02 was assessed using the primer-probe set Ag3383, described in Table BA. Results of the RTQ-PCR runs are shown in Tables BB, BC, and BD. Please note that CG58598-02 represents a full-length physical clone of the CG58598-01 gene, validating the prediction of the gene sequence.
268TABLE BAProbe Name Ag3383StartPrimersSequencesLengthPositionForward5′-ttcatqggagtgaggatagttg-3′(SEQ ID NO:212)22367ProbeTET-5′-ctgcaataatggcaattaccggcatt-3′-TAMRA(SEQ ID NO:213)26389Reverse5′-cgtggaaattatctgcatatgc-3′(SEQ ID NO:214)22424


[0681]

269





TABLE BB










CNS_neurodegeneration_v1.0











Rel. Exp.(%) Ag3383,

Rel. Exp.(%) Ag3383,


Tissue Name
Run 210154822
Tissue Name
Run 210154822













AD 1 Hippo
0.0
Control (Path) 3
0.0




Temporal Ctx


AD 2 Hippo
15.9
Control (Path) 4
15.2




Temporal Ctx


AD 3 Hippo
1.8
AD 1 Occipital Ctx
8.1


AD 4 Hippo
0.0
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 Hippo
80.7
AD 3 Occipital Ctx
2.2


AD 6 Hippo
3.0
AD 4 Occipital Ctx
11.9


Control 2 Hippo
26.2
AD 5 Occipital Ctx
40.9


Control 4 Hippo
4.4
AD 6 Occipital Ctx
11.9


Control (Path) 3
0.0
Control 1 Occipital
0.0


Hippo

Ctx


AD 1 Temporal Ctx
0.0
Control 2 Occipital
100.0




Ctx


AD 2 Temporal Ctx
8.4
Control 3 Occipital
7.2




Ctx


AD 3 Temporal Ctx
0.0
Control 4 Occipital
0.0




Ctx


AD 4 Temporal Ctx
3.3
Control (Path) 1
45.4




Occipital Ctx


AD 5 Inf Temporal
13.6
Control (Path) 2
3.5


Ctx

Occipital Ctx


AD 5 Sup Temporal
6.5
Control (Path) 3
0.0


Ctx

Occipital Ctx


AD 6 Inf Temporal
8.5
Control (Path) 4
4.4


Ctx

Occipital Ctx


AD 6 Sup Temporal
0.0
Control 1 Parietal
0.0


Ctx

Ctx


Control 1 Temporal
0.0
Control 2 Parietal
7.5


Ctx

Ctx


Control 2 Temporal
24.1
Control 3 Parietal
12.9


Ctx

Ctx


Control 3 Temporal
9.3
Control (Path) 1
28.1


Ctx

Parietal Ctx


Control 3 Temporal
0.0
Control (Path) 2
9.2


Ctx

Parietal Ctx


Control (Path) 1
21.6
Control (Path) 3
0.0


Temporal Ctx

Parietal Ctx


Control (Path) 2
8.5
Control (Path) 4
19.8


Temporal Ctx

Parietal Ctx










[0682]

270





TABLE BC










General_screening_panel_v1.4











Rel. Exp.(%) Ag3383,

Rel. Exp.(%) Ag3383,


Tissue Name
Run 213496699
Tissue Name
Run 213496699













Adipose
0.0
Renal ca. TK-10
0.0


Melanoma*
0.0
Bladder
0.3


Hs688(A).T


Melanoma*
0.0
Gastric ca. (liver met.)
0.0


Hs688(B).T

NCI-N87


Melanoma* M14
0.0
Gastric ca. KATO III
0.0


Melanoma*
0.0
Colon ca. SW-948
0.0


LOXIMVI


Melanoma* SK-
0.0
Colon ca. SW480
0.0


MEL-5


Squamous cell
0.2
Colon ca.* (SW480
0.0


carcinoma SCC-4

met) SW620


Testis Pool
2.8
Colon ca. HT29
0.0


Prostate ca.* (bone
0.3
Colon ca. HCT-116
0.0


met) PC-3


Prostate Pool
5.7
Colon ca. CaCo-2
0.0


Placenta
0.0
Colon cancer tissue
0.0


Uterus Pool
0.3
Colon ca. SW1116
0.0


Ovarian ca. OVCAR-3
0.0
Colon ca. Colo-205
0.0


Ovarian ca. SK-OV-3
0.0
Colon ca. SW-48
0.0


Ovarian ca. OVCAR-4
0.0
Colon Pool
3.8


Ovarian ca. OVCAR-5
0.0
Small Intestine Pool
0.0


Ovarian ca. IGROV-1
0.6
Stomach Pool
0.0


Ovarian ca. OVCAR-8
0.0
Bone Marrow Pool
1.8


Ovary
0.0
Fetal Heart
0.0


Breast ca. MCF-7
0.0
Heart Pool
1.4


Breast ca. MDA-
0.0
Lymph Node Pool
2.7


MB-231


Breast ca. BT 549
0.2
Fetal Skeletal Muscle
0.4


Breast ca. T47D
0.0
Skeletal Muscle Pool
0.0


Breast ca. MDA-N
0.0
Spleen Pool
0.0


Breast Pool
3.3
Thymus Pool
0.7


Trachea
0.6
CNS cancer (glio/astro)
53.6




U87-MG


Lung
0.0
CNS cancer (glio/astro)
0.0




U-118-MG


Fetal Lung
0.0
CNS cancer (neuro; met)
0.0




SK-N-AS


Lung ca. NCI-N417
0.0
CNS cancer (astro) SF-
0.0




539


Lung ca. LX-1
3.4
CNS cancer (astro)
0.0




SNB-75


Lung ca. NCI-H146
0.0
CNS cancer (glio) SNB-
0.0




19


Lung ca. SHP-77
54.0
CNS cancer (glio) SF-
0.3




295


Lung ca. A549
0.0
Brain (Amygdala) Pool
1.6


Lung ca. NCI-H526
79.0
Brain (cerebellum)
100.0


Lung ca. NCI-H23
0.0
Brain (fetal)
9.9


Lung ca. NCI-H460
0.0
Brain (Hippocampus)
6.3




Pool


Lung ca. HOP-62
0.0
Cerebral Cortex Pool
4.6


Lung ca. NCI-H522
0.0
Brain (Substantia nigra)
3.5




Pool


Liver
0.0
Brain (Thalamus) Pool
5.6


Fetal Liver
0.0
Brain (whole)
15.4


Liver ca. HepG2
0.0
Spinal Cord Pool
6.8


Kidney Pool
6.9
Adrenal Gland
0.0


Fetal Kidney
7.7
Pituitary gland Pool
0.4


Renal ca. 786-0
0.0
Salivary Gland
0.0


Renal ca. A498
0.0
Thyroid (female)
11.4


Renal ca. ACHN
26.4
Pancreatic ca. CAPAN2
0.4


Renal ca. UO-31
0.6
Pancreas Pool
2.8










[0683]

271





TABLE BD










Panel CNS_1











Rel. Exp.(%) Ag3383,

Rel. Exp.(%) Ag3383,


Tissue Name
Run 171787529
Tissue Name
Run 171787529













BA4 Control
0.0
BA17 PSP
2.7


BA4 Control2
12.1
BA17 PSP2
0.0


BA4
0.0
Sub Nigra Control
0.0


Alzheimer's2


BA4 Parkinson's
0.0
Sub Nigra Control2
16.5


BA4
15.5
Sub Nigra
4.1


Parkinson's2

Alzheimer's2


BA4
8.2
Sub Nigra
25.5


Huntington's

Parkinson's2


BA4
0.0
Sub Nigra
30.4


Huntington's2

Huntington's


BA4 PSP
0.0
Sub Nigra
0.0




Huntington's2


BA4 PSP2
5.5
Sub Nigra PSP2
0.0


BA4 Depression
0.0
Sub Nigra
0.0




Depression


BA4
0.0
Sub Nigra
9.5


Depression2

Depression2


BA7 Control
4.1
Glob Palladus
0.0




Control


BA7 Control2
4.1
Glob Palladus
5.8




Control2


BA7
0.0
Glob Palladus
5.3


Alzheimer's2

Alzheimer's


BA7 Parkinson's
0.0
Glob Palladus
0.0




Alzheimer's2


BA7
100.0
Glob Palladus
18.3


Parkinson's2

Parkinson's


BA7
0.0
Glob Palladus
0.0


Huntington's

Parkinson's2


BA7
0.0
Glob Palladus PSP
3.7


Huntington's2


BA7 PSP
0.0
Glob Palladus PSP2
0.0


BA7 PSP2
6.2
Glob Palladus
0.0




Depression


BA7 Depression
0.0
Temp Pole Control
0.0


BA9 Control
0.0
Temp Pole Control2
0.0


BA9 Control2
18.4
Temp Pole
0.0




Alzheimer's


BA9 Alzheimer's
0.0
Temp Pole
0.0




Alzheimer's2


BA9
5.4
Temp Pole
0.0


Alzheimer's2

Parkinson's


BA9 Parkinson's
0.0
Temp Pole
0.0




Parkinson's2


BA9
14.2
Temp Pole
5.0


Parkinson's2

Huntington's


BA9
0.0
Temp Pole PSP
0.0


Huntington's


BA9
0.0
Temp Pole PSP2
0.0


Huntington's2


BA9 PSP
0.0
Temp Pole
0.0




Depression2


BA9 PSP2
0.0
Cing Gyr Control
0.0


BA9 Depression
0.0
Cing Gyr Control2
0.0


BA9
0.0
Cing Gyr Alzheimer's
0.0


Depression2


BA17 Control
8.4
Cing Gyr
0.0




Alzheimer's2


BA17 Control2
9.0
Cing Gyr Parkinson's
0.0


BA17
0.0
Cing Gyr
0.0


Alzheimer's2

Parkinson's2


BA17
5.7
Cing Gyr
0.0


Parkinson's

Huntington's


BA17
17.3
Cing Gyr
0.0


Parkinson's2

Huntington's2


BA17
12.0
Cing Gyr PSP
4.5


Huntington's


BA17
0.0
Cing Gyr PSP2
0.0


Huntington's2


BA17
0.0
Cing Gyr Depression
0.0


Depression


BA17
4.1
Cing Gyr
0.0


Depression2

Depression2










[0684] CNS_neurodegeneration_v1.0 Summary: Ag3383 This panel confirms the expression of the CG58598-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. The brain preferential expression of this novel protein in both this panel and panel 1.4 suggests that this protein product may be a drug target for the treatment of neurologic disorders.


[0685] General_screening_panel_v1.4 Summary: Ag3383 Expression of the CG58598-01 gene appears to be preferential to the brain, with the highest level of expression in the cerebellum (CT=30.2). Please see Panel CNS_neurodegeneration_v1.0 for discussion of utility in the central nervous system. There is also expression in the CNS cancer cell line U87-MG (CT=3.1) but no expression in any other CNS cancer cell line. Therefore, expression of this gene can be used to distinguish between the U87-MG cell line and other CNS cancer cell lilies on this panel.


[0686] Additionally, there is low to moderate expression of this gene in renal and lung cancer cell lines. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of cancer. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of these cancers.


[0687] Panel 2.2 Summary: Ag3383—Expression of the CG58598-01 gene is low/undetectable (CTs>35) across all of the samples on this panel.


[0688] Panel 4D Summary: Ag3383—Expression of the CG58598-01 gene is low/undetectable (CTs>35) across all of the samples on this panel.


[0689] Panel CNS1 Summary: Ag3383 Expression in this panel confirms expression of the CG58598-01 gene in the brain. Please see Panel CNS_neurodegeneration_v1.0 for discussion of utility in the central nervous system.



C. NOV3a (CG57833-01: AMINO ACID TRANSPORTER)

[0690] Expression of gene CG57833-01 was assessed using the primer-probe set Ag3341, described in Table CA. Results of the RTRQ-PCR runs are shown in Tables CB and CC.
272TABLE CAProbe Name Ag3341StartPrimersSequencesLengthPositionForward5′-aacactaactgtgcccattgtc-3′(SEQ ID NO:215)221284ProbeTET-5′-tcccaattcgtacatcagtgatcaca-3′-TAMRA(SEQ ID NO:216)261310Reverse5′-gaaatgtcgtatccagctgaag-3′(SEQ ID NO:217)221356


[0691]

273





TABLE CB










Panel 1.3D











Rel. Exp.(%) Ag3341,

Rel. Exp.(%) Ag3341,


Tissue Name
Run 165524268
Tissue Name
Run 165524268













Liver adenocarcinoma
0.2
Kidney (fetal)
6.9


Pancreas
0.8
Renal ca. 786-0
0.1


Pancreatic ca. CAPAN 2
1.6
Renal ca. A498
0.2


Adrenal gland
0.5
Renal ca. RXF 393
0.4


Thyroid
0.1
Renal ca. ACHN
0.0


Salivary gland
0.0
Renal ca. UO-31
0.1


Pituitary gland
0.3
Renal ca. TK-10
0.0


Brain (fetal)
0.4
Liver
100.0


Brain (whole)
0.2
Liver (fetal)
54.3


Brain (amygdala)
0.0
Liver ca.
0.7




(hepatoblast) HepG2


Brain (cerebellum)
0.0
Lung
0.2


Brain (hippocampus)
0.1
Lung (fetal)
0.2


Brain (substantia nigra)
0.0
Lung ca. (small cell)
0.1




LX-1


Brain (thalamus)
0.3
Lung ca. (small cell)
0.0




NCI-H69


Cerebral Cortex
0.0
Lung ca. (s.cell var.)
0.1




SHP-77


Spinal cord
0.2
Lung ca. (large
0.6




cell)NCI-H460


glio/astro U87-MG
0.0
Lung ca. (non-sm.
0.0




cell) A549


glio/astro U-118-MG
1.6
Lung ca. (non-s.cell)
0.0




NCI-H23


astrocytoma SW1783
3.2
Lung ca. (non-s.cell)
0.8




HOP-62


neuro*; met SK-N-AS
0.1
Lung ca. (non-s.cl)
0.1




NCI-H522


astrocytoma SF-539
0.0
Lung ca. (squam.)
0.0




SW 900


astrocytoma SNB-75
0.1
Lung ca. (squam.)
0.2




NCI-H596


glioma SNB-19
0.0
Mammary gland
0.0


glioma U251
0.0
Breast ca.* (pl.ef)
0.0




MCF-7


glioma SF-295
0.5
Breast ca.* (pl.ef)
5.3




MDA-MB-231


Heart (fetal)
0.0
Breast ca.* (pl.ef)
0.0




T47D


Heart
0.0
Breast ca. BT-549
0.0


Skeletal muscle (fetal)
0.3
Breast ca. MDA-N
0.0


Skeletal muscle
31.0
Ovary
0.2


Bone marrow
0.3
Ovarian ca. OVCAR-3
0.5


Thymus
0.1
Ovarian ca. OVCAR-4
0.0


Spleen
0.0
Ovarian ca. OVCAR-5
3.0


Lymph node
0.5
Ovarian ca. OVCAR-8
0.0


Colorectal
0.2
Ovarian ca. IGROV-1
0.1


Stomach
0.0
Ovarian ca.* (ascites)
0.0




SK-OV-3


Small intestine
0.8
Uterus
2.0


Colon ca. SW480
0.0
Placenta
0.0


Colon ca.*
0.1
Prostate
0.3


SW620(SW480 met)


Colon ca. HT29
0.0
Prostate ca.* (bone
0.0




met)PC-3


Colon ca. HCT-116
0.0
Testis
0.0


Colon ca. CaCo-2
10.2
Melanoma
1.1




Hs688(A).T


Colon ca.
0.1
Melanoma* (met)
0.2


tissue(ODO3866)

Hs688(B).T


Colon ca. HCC-2998
0.0
Melanoma UACC-62
0.0


Gastric ca.* (liver met)
0.0
Melanoma M14
0.0


NCI-N87


Bladder
10.2
Melanoma LOX
0.0




IMVI


Trachea
0.3
Melanoma* (met)
0.0




SK-MEL-5


Kidney
0.7
Adipose
0.8










[0692]

274





TABLE CC










Panel 4D











Rel. Exp.(%)

Rel. Exp.(%)



Ag3341, Run

Ag3341, Run


Tissue Name
165222714
Tissue Name
165222714













Secondary Th1 act
1.5
HUVEC IL-1 beta
0.0


Secondary Th2 act
0.0
HUVEC IFN gamma
0.8


Secondary Tr1 act
0.0
HUVEC TNF alpha + IFN
4.2




gamma


Secondary Th1 rest
0.0
HUVEC TNF alpha + IL4
0.8


Secondary Th2 rest
0.0
HUVEC IL-11
0.0


Secondary Tr1 rest
0.0
Lung Microvascular EC
0.0




none


Primary Th1 act
0.6
Lung Microvascular EC
0.7




TNFalpha + IL-1 beta


Primary Th2 act
1.4
Microvascular Dermal EC
9.7




none


Primary Tr1 act
0.0
Microsvasular Dermal EC
0.5




TNFalpha + IL-1 beta


Primary Th1 rest
0.0
Bronchial epithelium
14.5




TNFalpha + IL1 beta


Primary Th2 rest
0.0
Small airway epithelium
1.0




none


Primary Tr1 rest
0.0
Small airway epithelium
23.0




TNFalpha + IL-1 beta


CD45RA CD4
12.6
Coronery artery SMC rest
3.3


lymphocyte act


CD45RO CD4
0.9
Coronery artery SMC
0.0


lymphocyte act

TNFalpha + IL-1 beta


CD8 lymphocyte act
0.0
Astrocytes rest
0.0


Secondary CD8
0.0
Astrocytes TNFalpha + IL-1
0.0


lymphocyte rest

beta


Secondary CD8
0.0
KU-812 (Basophil) rest
0.0


lymphocyte act


CD4 lymphocyte none
0.0
KU-812 (Basophil)
0.0




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
0.0
CCD1106 (Keratinocytes)
3.0


CD95 CH11

none


LAK cells rest
0.0
CCD1106 (Keratinocytes)
5.4




TNFalpha + IL-1 beta


LAK cells IL-2
0.9
Liver cirrhosis
100.0


LAK cells IL-2 + IL-12
0.0
Lupus kidney
1.8


LAK cells IL-2 + IFN
0.0
NCI-H292 none
46.0


gamma


LAK cells IL-2 + IL-18
0.0
NCI-H292 IL-4
72.7


LAK cells
0.0
NCI-H292 IL-9
56.3


PMA/ionomycin


NK Cells IL-2 rest
0.0
NCI-H292 IL-13
39.2


Two Way MLR 3 day
0.0
NCI-H292 IFN gamma
87.1


Two Way MLR 5 day
0.0
HPAEC none
2.0


Two Way MLR 7 day
0.0
HPAEC TNF alpha + IL-1
0.0




beta


PBMC rest
0.0
Lung fibroblast none
14.4


PBMC PWM
0.8
Lung fibroblast TNF
2.5




alpha + IL-1 beta


PBMC PHA-L
0.0
Lung fibroblast IL-4
15.4


Ramos (B cell) none
0.0
Lung fibroblast IL-9
11.3


Ramos (B cell)
0.0
Lung fibroblast IL-13
12.0


ionomycin


B lymphocytes PWM
0.0
Lung fibroblast IFN
21.2




gamma


B lymphocytes CD40L
0.0
Dermal fibroblast
66.9


and IL-4

CCD1070 rest


EOL-1 dbcAMP
0.0
Dermal fibroblast
28.3




CCD1070 TNF alpha


EOL-1 dbcAMP
0.0
Dermal fibroblast
27.0


PMA/ionomycin

CCD1070 IL-1 beta


Dendritic cells none
0.0
Dermal fibroblast IFN
1.1




gamma


Dendritic cells LPS
0.0
Dermal fibroblast IL-4
3.2


Dendritic cells anti-
0.0
IBD Colitis 2
0.0


CD40


Monocytes rest
0.0
IBD Crohn's
0.9


Monocytes LPS
0.0
Colon
6.9


Macrophages rest
0.0
Lung
1.4


Macrophages LPS
0.0
Thymus
40.9


HUVEC none
0.8
Kidney
6.9


HUVEC starved
3.9










[0693] Panel 1.3D Summary: Ag3341 The CG57833-01 gene codes for amino acid transporter HNAT3. Tissue distribution of this gene is similar to the results previously reported (Ref. 1) with highest expression of this gene in liver sample (CT=28.2). High expression of this gene is also detected in fetal liver (CT=29). Therefore, expression of this gene can be used to distinguish liver samples from other samples used in this panel. In addition, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of liver related diseases such as liver cirrhosis.


[0694] Low expression of this gene is also seen in ovarian cancer OVCAR-5, colon cancer CaCo-2, astrocytoma SW1783, glio/astro U-118-MG, and pancreatic cancer CAPAN 2 cell lines (CTs=33-34). Therefore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of lung cancer or ovarian cancer.


[0695] Significant expression of this gene is also detected in skeletal muscle (CT=29.9). Interestingly, this gene is expressed at much higher levels in adult (CT=29.9) when compared to fetal skeletal Muscle (CT=36.6). This observation suggests that expression of this gene can be used to distinguish adult from fetal skeletal muscle. Furthermore, therapeutic modulation of the amino acid transporter encoded by this gene could be useful in treatment of muscle related diseases. More specifically, treatment of weak or dystrophic muscle with the protein encoded by this gene could restore muscle mass or function.


[0696] In addition, moderate expression of this gene is also detected in fetal kidney and bladder (CTs=31-32). Interestingly, this gene is expressed at much higher levels in fetal (CT=32) when compared to adult kidney (CT=35.3). Therefore, expression of this gene can be used to distinguish fetal from adult kidney. Furthermore, therapeutic modulation of the amino acid transporter encoded by this gene could be useful in treatment of renal diseases.


[0697] References.


[0698] 1. Gu S, Adan-Rice D, Leach R J, Jaiang J X. (2001) A novel human amino acid transporter, hNAT3: cDNA cloning, chromosomal mapping, genomic structure, expression, and functional characterization. Genomics 74(3):262-72.


[0699] Panel 4D Summary: Ag3341 Highest expression of CG57833-01 is seen in liver cirrhosis samples (CT=31.3). The amino acid transporter encoded for by this gene could potentially allow cells within the liver to respond to specific microenvironmental signals. Therefore, therapies designed with the protein encoded for by this gene may potentially modulate liver function and play a role in the identification and treatment of inflammatory or autoimmune diseases which affect the liver including liver cirrhosis and fibrosis.


[0700] Significant expression of this gene is also seen in thymus, dermal fibroblast, lung fibroblast, NCI-H292 cell lines, and TNFalpha+IL-1 beta treated bronchial and small airway epithelium samples (CTs=32-34). Interestingly, this gene is expressed at much higher levels in TNFalpha+IL-1 beta treated small airway epithelium (CT=33.4) when compared to untreated cells (CT=37.9). This observation suggests that expression of this gene can be used to distinguish the cytokine treated from untreated small airway epithelium. Furthermore, modulation of the expression or activity of the protein encoded by this gene through the application of small molecule therapeutics may be useful in the treatment of asthma, COPD, psoriasis and emphysema.



D. NOV4a, NOV4b, AND NOV4c (CG57853-01, CG57853-02, and CC57853-03: ILEAL SODIUM/BILE ACID COTRANSPORTER)

[0701] Expression of gene CG57853-01, CG57853-02, and CG57853-03 was assessed using the primer-probe sets Ag3350 and Ag2838, described in Tables DA and DB. Results of the RTQ-PCR runs are shown in Tables DC, DD and DE. Please note that CG57853-03 represents a full-length physical clone of the CG57853-01 gene, validating the prediction of the gene sequence.
275TABLE DAProbe Name Ag3350StartPrimerSequencesLengthPositionForward5′-cttagctcttgccgttattcag-3′(SEQ ID NO:218)22938ProbeTET-5′-aggccaatttagcttctgtggctcct-3′-TAMRASEQ ID NO:219)26979Reverse5′-catttcacatccagaacacatg-3′(SEQ ID NO:220)221016


[0702]

276





TABLE DB










Probe Name Ag2838













Start


Primers
Sequences
Length
Position














Forward
5′-tcttagctcttgccgttattca-3′
(SEQ ID NO:221)
22
937





Probe
TET-5′-aggccaatttagcttctgtggctcct-3′-TAMRA
(SEQ ID NO:222)
26
979





Reverse
5′-acatccagaacacatggctact-3′
(SEQ ID NO:223)
22
1010










[0703]

277





TABLE DC










CNS_neurodegeneration_v1.0











Rel. Exp.(%)

Rel. Exp.(%)



Ag3350, Run

Ag3350, Run


Tissue Name
210141593
Tissue Name
210141593













AD 1 Hippo
5.7
Control (Path) 3
0.4




Temporal Ctx


AD 2 Hippo
12.1
Control (Path) 4
57.8




Temporal Ctx


AD 3 Hippo
3.2
AD 1 Occipital Ctx
18.7


AD 4 Hippo
0.9
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 Hippo
100.0
AD 3 Occipital Ctx
4.7


AD 6 Hippo
78.5
AD 4 Occipital Ctx
6.7


Control 2 Hippo
12.9
AD 5 Occipital Ctx
19.9


Control 4 Hippo
1.4
AD 6 Occipital Ctx
37.4


Control (Path) 3
0.0
Control 1 Occipital
2.1


Hippo

Ctx


AD 1 Temporal
10.2
Control 2 Occipital
45.4


Ctx

Ctx


AD 2 Temporal
59.9
Control 3 Occipital
6.5


Ctx

Ctx


AD 3 Temporal
4.7
Control 4 Occipital
1.4


Ctx

Ctx


AD 4 Temporal
5.9
Control (Path) 1
46.3


Ctx

Occipital Ctx


AD 5 Inf
95.3
Control (Path) 2
8.3


Temporal Ctx

Occipital Ctx


AD 5 Sup
33.9
Control (Path) 3
0.0


Temporal Ctx

Occipital Ctx


AD 6 Inf
66.0
Control (Path) 4
6.6


Temporal Ctx

Occipital Ctx


AD 6 Sup
95.9
Control 1 Parietal
1.0


Temporal Ctx

Ctx


Control 1
1.5
Control 2 Parietal
12.3


Temporal Ctx

Ctx


Control 2
14.8
Control 3 Parietal
7.2


Temporal Ctx

Ctx


Control 3
3.3
Control (Path) 1
29.3


Temporal Ctx

Parietal Ctx


Control 3
55.1
Control (Path) 2
63.3


Temporal Ctx

Parietal Ctx


Control (Path) 1
39.5
Control (Path) 3
1.3


Temporal Ctx

Parietal Ctx


Control (Path) 2
24.0
Control (Path) 4
24.1


Temporal Ctx

Parietal Ctx










[0704]

278





TABLE DD










General_screening_panel_v1.4











Rel. Exp.(%)

Rel. Exp.(%)



Ag3350, Run

Ag3350, Run


Tissue Name
216523465
Tissue Name
216523465













Adipose
1.8
Renal ca. TK-10
28.7


Melanoma*
1.0
Bladder
4.2


Hs688(A).T


Melanoma*
2.1
Gastric ca. (liver
100.0


Hs688(B).T

met.) NCI-N87


Melanoma* M14
3.8
Gastric ca.
11.7




KATO III


Melanoma*
3.1
Colon ca. SW-948
6.4


LOXIMVI


Melanoma* SK-
3.3
Colon ca. SW480
12.3


MEL-5


Squamous cell
4.2
Colon ca.* (SW480
17.0


carcinoma SCC-4

met) SW620


Testis Pool
6.9
Colon ca. HT29
13.7


Prostate ca.*
19.9
Colon ca. HCT-116
10.4


(bone met) PC-3


Prostate Pool
3.4
Colon ca. CaCo-2
48.0


Placenta
0.0
Colon cancer tissue
14.5


Uterus Pool
0.3
Colon ca. SW1116
0.7


Ovarian ca.
14.3
Colon ca. Colo-205
14.0


OVCAR-3


Ovarian ca.
12.4
Colon ca. SW-48
16.0


SK-OV-3


Ovarian ca.
2.1
Colon Pool
2.6


OVCAR-4


Ovarian ca.
62.0
Small Intestine Pool
4.9


OVCAR-5


Ovarian ca.
1.8
Stomach Pool
3.2


IGROV-1


Ovarian ca.
2.7
Bone Marrow Pool
2.9


OVCAR-8


Ovary
3.4
Fetal Heart
2.5


Breast ca. MCF-7
4.6
Heart Pool
0.9


Breast ca. MDA-
10.2
Lymph Node Pool
5.3


MB-231


Breast ca. BT 549
14.1
Fetal Skeletal
4.3




Muscle


Breast ca. T47D
62.4
Skeletal Muscle
2.0




Pool


Breast ca.
1.6
Spleen Pool
1.4


MDA-N


Breast Pool
3.7
Thymus Pool
1.9


Trachea
15.4
CNS cancer
2.0




(glio/astro) U87-MG


Lung
3.4
CNS cancer (glio/
3.6




astro) U-118-MG


Fetal Lung
8.8
CNS cancer (neuro;
2.1




met) SK-N-AS


Lung ca.
0.1
CNS cancer (astro)
3.8


NCI-N417

SF-539


Lung ca. LX-1
17.3
CNS cancer (astro)
2.8




SNB-75


Lung ca.
2.9
CNS cancer (glio)
2.5


NCI-H146

SNB-19


Lung ca. SHP-77
4.7
CNS cancer (glio)
6.0




SF-295


Lung ca. A549
7.2
Brain (Amygdala)
0.8




Pool


Lung ca.
8.2
Brain (cerebellum)
6.0


NCI-H526


Lung ca.
6.9
Brain (fetal)
8.0


NCI-H23


Lung ca.
7.6
Brain
3.5


NCI-H460

(Hippocampus) Pool


Lung ca. HOP-62
3.5
Cerebral Cortex
2.0




Pool


Lung ca.
5.0
Brain (Substantia
0.8


NCI-H522

nigra) Pool


Liver
0.8
Brain (Thalamus)
6.0




Pool


Fetal Liver
45.1
Brain (whole)
2.5


Liver ca. HepG2
20.0
Spinal Cord Pool
1.2


Kidney Pool
8.1
Adrenal Gland
0.6


Fetal Kidney
13.5
Pituitary gland Pool
1.8


Renal ca. 786-0
7.2
Salivary Gland
1.0


Renal ca. A498
4.2
Thyroid (female)
0.2


Renal ca. ACHN
3.8
Pancreatic ca.
6.3




CAPAN2


Renal ca. UO-31
3.0
Pancreas Pool
3.5










[0705]

279





TABLE DE










Panel 4D











Rel. Exp.(%)

Rel. Exp.(%)



Ag3350, Run

Ag3350, Run


Tissue Name
165222880
Tissue Name
165222880













Secondary Th1
3.0
HUVEC IL-1 beta
0.0


act


Secondary Th2
4.1
HUVEC IFN
3.7


act

gamma


Secondary Tr1 act
3.5
HUVEC TNF
1.3




alpha + IFN gamma


Secondary Th1
0.0
HUVEC TNF
2.5


rest

alpha + IL4


Secondary Th2
2.2
HUVEC IL-11
1.1


rest


Secondary Tr1
1.9
Lung Microvascular
4.6


rest

EC none


Primary Th1 act
4.0
Lung Microvascular
4.9




EC TNF alpha +




IL-1 beta


Primary Th2 act
3.2
Microvascular
3.2




Dermal EC none


Primary Tr1 act
3.5
Microvasular
1.7




Dermal EC




TNF alpha +




IL-1 beta


Primary Th1 rest
6.6
Bronchial
7.1




epithelium TNF




alpha + IL1 beta


Primary Th2 rest
3.8
Small airway
2.7




epithelium none


Primary Tr1 rest
4.0
Small airway
25.7




epithelium




TNF alpha +




IL-1 beta


CD45RA CD4
4.0
Coronery artery
1.8


lymphocyte act

SMC rest


CD45RO CD4
3.7
Coronery artery
1.1


lymphocyte act

SMC TNF alpha +




IL-1 beta


CD8 lymphocyte
2.4
Astrocytes rest
3.3


act


Secondary CD8
2.9
Astrocytes
4.4


lymphocyte rest

TNF alpha +




IL-1 beta


Secondary CD8
2.1
KU-812 (Basophil)
12.3


lymphocyte act

rest


CD4 lymphocyte
0.6
KU-812 (Basophil)
26.1


none

PMA/ionomycin


2ry Th1/Th2/
3.7
CCD1106
6.8


Tr1_anti-CD95

(Keratinocytes)


CH11

none


LAK cells rest
1.0
CCD1106
2.9




(Keratinocytes)




TNF alpha +




IL-1 beta


LAK cells IL-2
3.4
Liver cirrhosis
7.4


LAK cells IL-2 +
3.3
Lupus kidney
1.9


IL-12


LAK cells IL-2 +
6.7
NCI-H292 none
7.7


IFN gamma


LAK cells IL-2 +
4.5
NCI-H292 IL-4
11.9


IL-18


LAK cells
1.4
NCI-H292 IL-9
8.1


PMA/ionomycin


NK Cells IL-2
0.8
NCI-H292 IL-13
6.6


rest


Two Way MLR 3
1.7
NCI-H292 IFN
8.7


day

gamma


Two Way MLR 5
3.1
HPAEC none
3.5


day


Two Way MLR 7
1.0
HPAEC TNF
1.8


day

alpha + IL-1 beta


PBMC rest
0.3
Lung fibroblast
2.0




none


PBMC PWM
14.5
Lung fibroblast TNF
1.1




alpha + IL-1 beta


PBMC PHA-L
4.9
Lung fibroblast IL-4
7.6


Ramos (B cell)
3.2
Lung fibroblast IL-9
3.6


none


Ramos (B cell)
13.2
Lung fibroblast
2.0


ionomycin

IL-13


B lymphocytes
15.8
Lung fibroblast
2.9


PWM

IFN gamma


B lymphocytes
4.7
Dermal fibroblast
7.7


CD40L and IL-4

CCD1070 rest


EOL-1 dbcAMP
4.6
Dermal fibroblast
6.6




CCD1070 TNF




alpha


EOL-1 dbcAMP
2.5
Dermal fibroblast
1.7


PMA/ionomycin

CCD1070 IL-1 beta


Dendritic cells
0.2
Dermal fibroblast
0.6


none

IFN gamma


Dendritic cells
0.3
Dermal fibroblast
6.7


LPS

IL-4


Dendritic cells
0.7
IBD Colitis 2
0.7


anti-CD40


Monocytes rest
0.0
IBD Crohn's
4.0


Monocytes LPS
0.0
Colon
86.5


Macrophages rest
0.0
Lung
3.6


Macrophages LPS
0.0
Thymus
100.0


HUVEC none
2.0
Kidney
7.7


HUVEC starved
5.7










[0706] CNS_neurodegeneration_v1.0 Summary: Ag3350 This panel does not show differential expression of the CG57853-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.


[0707] General_screening_panel_v1.4 Summary: Ag3350—The CG157853-01 gene encodes a novel ileal sodium-bile acid cotransporter. Ileal sodium-dependent bile acid transporters play a role in the absorption of bile acids, regulating levels of bile acids in the large intestine and preventing accumulation of cytotoxic secondary bile acids in the colon (Ref. 1). The highest expression of this gene is seen in gastric cancer cell line NCI-N87 (CT=29.5). Significant expression of this gene is also associated with CNS, colon, renal, liver, lung, breast, ovarian and prostate cancers as well as melanomas. Thus, expression of this gene could be used as a diagnostic marker for the presence of these cancers. Furthermore, therapeutic inhibition using antibodies or small molecule drugs might be of use in the treatment of these cancers.


[0708] Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, fetal skeletal muscle, heart, fetal liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as intestinal bile acid malabsorption (IBAM), hypertriglyceridemia, obesity and diabetes.


[0709] Interestingly, this gene is expressed at much higher levels in fetal (CT=30.6) when compared to adult liver (CT=36.5). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver. In addition, modulation of expression of this gene may be useful in the treatment of liver related disease such as liver cirrhosis, and cholestasis.


[0710] This gene is also widely expressed in tissues originating in the central nervous system. These tissues include the hippocampus, thalamus, and cerebellum. This transporter gene most likely plays a role in the uptake of nutrients. Blockade of this transporter may decrease the loss of neurons due to excitotoxicity during ischemic stroke. In addition, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.


[0711] References.


[0712] 1. Small D M. (1997) Point mutations in the ileal bile salt transporter cause leaks in the enterohepatic circulation leading to severe chronic diarrhea and malabsorption. J Clin Invest 99(8):1807-8


[0713] 2. Montagnani M, Love M W, Rossel P, Dawson P A, Qvist P. Absence of dysfunctional ileal sodium-bile acid cotransporter gene mutations in patients with adult-onset idiopathic bile acid malabsorption. Scand J Gastroenterol Octiber 2001;36(10):1077-80.


[0714] 3. Wang W, Xue S, Ingles S A, Chen Q, Diep A T, Frankl H D, Stolz A, Haile R W. An association between genetic polymorphisms in the ileal sodium-dependent bile acid transporter gene and the risk of colorectal adenomas. Cancer Epidemiol Biomarkers Prev 2001 Sep;10(9):931-6.


[0715] 4. Duane W C, Hartich L A, Bartman A E, Flo S B. Diminished gene expression of ileal apical sodium bile acid transporter explains impaired absorption of bile acid in patients with hypertriglyceridemia. J Lipid Res September 2000;41(9):1384-9.


[0716] Panel 1.3D Summary: Ag2838—Results using this primer pair are in very good agreement with the results obtained using Ag3350 on panel 1.4. Please see panel 1.4 for discussion.


[0717] Panel 4D Summary: Ag3350 Moderate to low expression of the CG57853-01 gene is seen in many samples on this panel, with the highest expression in thymus tissue (CT=29.3). This gene is expressed at low to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the A-cell, B-cell, endothelial cell, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_v1.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and ostearthritis.


[0718] Interestingly, high expression of this gene is detected in normal colon (CT=29.5), but expression of this gene is decreased in colon samples from patients with IBD colitis (CT=36.4) and Crohn's disease (CT=34.0). Therefore, therapeutic modulation of the activity of the transporter encoded by this gene may be useful in the treatment of inflammatory bowel disease.


[0719] In addition, expression of this gene is up regulated in PWM/PHA-L-stimulated PBMC (CTs=32-33.6), compared to resting PBMC cells (CT=37.6). Thus, expression of this gene may be used as a marker for activated PBMC cells.



E. NOV5a AND NOV5b (CG57829-01 AND CC57829-05: A DISINTEGRIN AND METALLOPROTEINASE WITH THROMBOSPONDIN MOTIFS 1)

[0720] Expression of gene CG57829-01 and CG57829-05 was assessed using the primer-probe sets Ag3340 and Ag554, described in Tables EA and EB. Results of the RTQ-PCR runs are shown in Tables EC, ED, EE, EF, EG, EH, EI, EJ, EK, EL and EM. Please note that CG57829-05 represents a full-length physical clone.
280TABLE EAProbe Name Ag3340StartPrimersSequencesLengthPositonForward5′-aatggcactggctacttctatg-3′(SEQ ID NO:224)221894ProbeTET-5′-acgctgtgctctcctgactccacct-3′-TAMRA(SEQ ID NO: 225)251942Reverse5′-cacttgccttggacacaga-3′(SEQ ID NO:226)191970


[0721]

281





TABLE EB










Probe Name Ag554













Start


Primers
Sequences
Length
Position














Forward
5′-cctggcagaagaagctgaaca-3′
(SEQ ID NO:227)
21
905





Probe
TET-5′-tgacaagcaccccgagtactgggac-3′-TAMRA
(SEQ ID NO:228)
25
933





Reverse
5′-tgcctggtgaagaggatgg-3′
(SEQ ID NO:229)
19
962







[0722]

282





TABLE EC










AI_comprehensive panel_v1.0











Rel. Exp.(%)

Rel. Exp.(%)



Ag3340, Run

Ag3340, Run


Tissue Name
211063355
Tissue Name
211063355













110967 COPD-F
2.5
112427 Match
1.3




Control Psoriasis-F


110980 COPD-F
1.3
112418 Psoriasis-M
2.5


110968 COPD-M
3.6
112723 Match
0.0




Control Psoriasis-M


110977 COPD-M
2.4
112419 Psoriasis-M
2.4


110989
6.2
112424 Match
1.0


Emphysema-F

Control Psoriasis-M


110992
12.2
112420 Psoriasis-M
11.3


Emphysema-F


110993
5.0
112425 Match
0.0


Emphysema-F

Control Psoriasis-M


110994
2.4
104689 (MF) OA
6.2


Emphysema-F

Bone-Backus


110995
14.2
104690 (MF) Adj
8.1


Emphysema-F

“Normal” Bone-




Backus


110996
13.5
104691 (MF) OA
12.5


Emphysema-F

Synovium-Backus


110997
0.0
104692 (BA) OA
0.0


Asthma-M

Cartilage-Backus


111001
5.5
104694 (BA) OA
6.7


Asthma-M

Bone-Backus


111002
4.1
104695 (BA) Adj
8.0


Asthma-M

“Normal” Bone-




Backus


111003 Atopic
10.6
104696 (BA) OA
25.2


Asthma-F

Synovium-Backus


111004 Atopic
9.2
104700 (SS) OA
1.9


Asthma-F

Bone-Backus


111005 Atopic
6.6
104701 (SS) Adj
11.9


Asthma-F

“Normal” Bone-




Backus


111006 Atopic
1.5
104702 (SS) OA
32.3


Asthma-F

Synovium-Backus


111417
3.3
117093 OA
6.9


Allergy-M

Cartilage Rep7


112347
0.2
112672 OA Bone5
1.5


Allergy-M


112349 Normal
0.1
112673 OA
0.9


Lung-F

Synovium5


112357 Normal
4.1
112674 OA
0.8


Lung-F

Synovial




Fluid cells5


112354 Normal
1.7
117100 OA
1.9


Lung-M

Cartilage Rep14


112374 Crohns-F
5.2
112756 OA Bone9
2.7


112389 Match
1.8
112757 OA
2.1


Control Crohns-F

Synovium9


112375 Crohns-F
3.6
112758 OA
4.6




Synovial




Fluid Cells9


112732 Match
0.4
117125 RA
7.6


Control Crohns-F

Cartilage Rep2


112725 Crohns-M
0.1
113492 Bone2 RA
2.5


112387 Match
2.7
113493 Synovium2
1.1


Control

RA


Crohns-M


112378 Crohns-M
0.1
113494 Syn Fluid
0.9




Cells RA


112390 Match
1.7
113499 Cartilage4
2.9


Control

RA


Crohns-M


112726 Crohns-M
10.2
113500 Bone4 RA
1.6


112731 Match
1.5
113501 Synovium4
2.0


Control

RA


Crohns-M


112380 Ulcer
0.6
113502 Syn Fluid
0.4


Col-F

Cells4 RA


112734 Match
0.6
113495 Cartilage3
1.7


Control Ulcer

RA


Col-F


112384 Ulcer
23.7
113496 Bone3 RA
3.1


Col-F


112737 Match
2.9
113497 Synovium3
1.2


Control Ulcer

RA


Col-F


112386 Ulcer
2.6
113498 Syn Fluid
2.6


Col-F

Cells3 RA


112738 Match
4.9
117106 Normal
7.1


Control Ulcer

Cartilage Rep20


Col-F


112381 Ulcer
0.1
113663 Bone3
0.2


Col-M

Normal


112735 Match
1.2
113664 Synovium3
0.1


Control Ulcer

Normal


Col-M


112382 Ulcer
1.5
113665 Syn Fluid
0.1


Col-M

Cells3 Normal


112394 Match
0.4
117107 Normal
1.0


Control Ulcer

Cartilage Rep22


Col-M


112383 Ulcer
100.0
113667 Bone4
1.1


Col-M

Normal


112736 Match
0.8
113668 Synovium4
1.6


Control Ulcer

Normal


Col-M


112423
0.0
113669 Syn Fluid
2.8


Psoriasis-F

Cells4 Normal










[0723]

283





TABLE ED










CNS_neurodegeneration_v1.0











Rel. Exp.(%)

Rel. Exp.(%)



Ag3340, Run

Ag3340, Run


Tissue Name
210139046
Tissue Name
210139046













AD 1 Hippo
0.0
Control (Path) 3
22.5




Temporal Ctx


AD 2 Hippo
51.4
Control (Path) 4
32.1




Temporal Ctx


AD 3 Hippo
12.7
AD 1 Occipital Ctx
17.8


AD 4 Hippo
14.3
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 hippo
12.9
AD 3 Occipital Ctx
0.0


AD 6 Hippo
40.3
AD 4 Occipital Ctx
23.8


Control 2 Hippo
36.3
AD 5 Occipital Ctx
9.0


Conirol 4 Hippo
40.3
AD 6 Occipital Ctx
100.0


Control (Path) 3
4.3
Control 1 Occipital
15.1


Hippo

Ctx


AD 1 Temporal
0.0
Control 2 Occipital
25.0


Ctx

Ctx


AD 2 Temporal
69.7
Control 3 Occipital
38.4


Ctx

Ctx


AD 3 Temporal
16.4
Control 4 Occipital
8.1


Ctx

Ctx


AD 4 Temporal
47.6
Control (Path) 1
35.6


Ctx

Occipital Ctx


AD 5 Inf
85.9
Control (Path) 2
0.0


Temporal Ctx

Occipital Ctx


AD 5 Sup
44.4
Control (Path) 3
0.0


Temporal Ctx

Occipital Ctx


AD 6 Inf
79.6
Control (Path) 4
11.4


Temporal Ctx

Occipital Ctx


AD 6 Sup
57.0
Control 1 Parietal
29.3


Temporal Ctx

Ctx


Control 1
9.3
Control 2 Parietal
53.6


Temporal Ctx

Ctx


Control 2
32.3
Control 3 Parietal
37.4


Temporal Ctx

Ctx


Control 3
19.6
Control (Path) 1
18.7


Temporal Ctx

Parietal Ctx


Control 4
13.2
Control (Path) 2
29.5


Temporal Ctx

Parietal Ctx


Control (Path) 1
77.4
Control (Path) 3
7.0


Temporal Ctx

Parietal Ctx


Control (Path) 2
39.0
Control (Path) 4
38.7


Temporal Ctx

Parietal Ctx










[0724]

284





TABLE EE










General_screening_panel_v1.4













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag3340, Run
Ag3340, Run

Ag3340, Run
Ag3340, Run


Tissue Name
213333210
217049357
Tissue Name
213333210
217049357















Adipose
9.2
9.1
Renal ca. TK-10
3.5
4.5


Melanoma*
0.0
0.0
Bladder
1.7
2.3


Hs688(A).T


Melanoma*
1.7
1.9
Gastric ca. (liver
3.3
4.0


Hs688(B).T


met.) NCI-N87


Melanoma*
0.0
0.0
Gastric ca. KATO
5.9
7.7


M14


III


Melanoma*
0.0
0.0
Colon ca. SW-
3.9
4.6


LOXIMVI


948


Melanoma*
0.2
0.4
Colon ca. SW480
21.0
24.3


SK-MEL-5


Squamous cell
0.1
0.2
Colon ca.*
1.8
1.6


carcinoma


(SW480 met)


SCC-4


SW620


Testis Pool
2.1
1.1
Colon ca. HT29
0.0
0.0


Prostate ca.*
4.1
3.6
Colon ca. HCT-
1.1
1.0


(bone met)


116


PC-3


Prostate Pool
0.6
0.4
Colon ca. CaCo-2
1.9
2.2


Placenta
6.6
6.7
Colon cancer
2.8
2.6





tissue


Uterus Pool
0.5
0.5
Colon ca.
0.1
0.2





SW1116


Ovarian ca.
50.0
37.1
Colon ca. Colo-
0.1
0.2


OVCAR-3


205


Ovarian ca.
43.2
29.9
Colon ca. SW-48
0.0
0.0


SK-OV-3


Ovarian ca.
31.4
36.6
Colon Pool
2.5
3.1


OVCAR-4


Ovarian ca.
28.1
33.0
Small Intestine
0.4
0.8


OVCAR-5


Pool


Ovarian ca.
8.5
8.5
Stomach Pool
1.8
1.5


IGROV-1


Ovarian ca.
3.6
5.7
Bone Marrow
0.7
0.7


OVCAR-8


Pool


Ovary
1.1
1.2
Fetal Heart
6.7
7.6


Breast ca.
0.8
0.6
Heart Pool
2.5
2.8


MCF-7


Breast ca.
100.0
100.0
Lymph Node
4.0
5.0


MDA-MB-231


Pool


Breast ca. BT
46.0
43.5
Fetal Skeletal
2.4
1.9


549


Muscle


Breast ca.
78.5
72.2
Skeletal Muscle
1.5
1.2


T47D


Pool


Breast ca.
0.0
0.0
Spleen Pool
0.9
1.0


MDA-N


Breast Pool
2.1
1.7
Thymus Pool
2.2
2.1


Trachea
1.0
1.7
CNS cancer
0.0
0.0





(glio/astro) U87-





MG


Lung
0.4
0.3
CNS cancer
46.0
52.5





(glio/astro) U-





118-MG


Fetal Lung
14.4
14.7
CNS cancer
1.4
1.6





(neuro;met) SK-





N-AS


Lung ca. NCI-
0.2
0.0
CNS cancer
3.0
3.1


N417


(astro) SF-539


Lung ca. LX-1
4.5
4.4
CNS cancer
13.2
27.9





(astro) SNB-75


Lung ca. NCI-
0.0
0.0
CNS cancer (glio)
7.2
9.1


H146


SNB-19


Lung ca. SHP-
17.4
17.7
CNS cancer (glio)
1.8
1.7


77


SF-295


Lung ca. A549
8.4
6.6
Brain (Amygdala)
0.2
0.1





Pool


Lung ca. NCI-
0.0
0.0
Brain
0.2
0.3


H526


(cerebellum)


Lung ca. NCI-
0.4
0.3
Brain (fetal)
3.0
1.8


H23


Lung ca. NCI-
0.1
0.1
Brain
0.4
0.4


H460


(Hippocampus)





Pool


Lung ca.
0.7
0.5
Cerebral Cortex
0.5
0.2


HOP-62


Pool


Lung ca. NCI-
0.2
0.1
Brain (Substantia
0.6
0.2


H522


nigra) Pool


Liver
0.0
0.0
Brain (Thalamus)
0.2
0.2





Pool


Fetal Liver
0.8
0.8
Brain (whole)
0.6
0.7


Liver ca.
0.0
0.0
Spinal Cord Pool
1.1
1.0


HepG2


Kidney Pool
2.6
2.5
Adrenal Gland
1.2
0.9


Fetal Kidney
12.4
15.1
Pituitary gland
0.3
0.4





Pool


Renal ca. 786-0
15.8
18.7
Salivary Gland
0.3
0.2


Renal ca.
3.5
4.1
Thyroid (female)
2.9
2.6


A498


Renal ca.
53.6
48.0
Pancreatic ca.
1.7
1.6


ACHN


CAPAN2


Renal ca. UO-
13.1
13.0
Pancreas Pool
7.1
5.3


31










[0725]

285





TABLE EF










Panel 1.1











Rel. Exp.(%)

Rel. Exp.(%)



Ag554, Run

Ag554, Run


Tissue Name
109665128
Tissue Name
109665128













Adrenal gland
0.1
Renal ca. UO-31
6.2


Bladder
4.2
Renal ca. RXF 393
0.2


Brain (amygdala)
0.0
Liver
0.3


Brain
0.0
Liver (fetal)
0.7


(cerebellum)


Brain
0.1
Liver ca.
0.0


(hippocampus)

(hepatoblast) HepG2


Brain (substantia
0.0
Lung
4.3


nigra)


Brain (thalamus)
0.0
Lung (fetal)
13.2


Cerebral Cortex
0.0
Lung ca. (non-s.
0.3




cell) HOP-62


Brain (fetal)
0.5
Lung ca. (large
0.0




cell) NCI-H460


Brain (whole)
0.0
Lung ca. (non-s.)
0.0




cell) NCI-H23


glio/astro
34.9
Lung ca. (non-s.cl)
0.0


U-118-MG

NCI-H522


astrocytoma
1.7
Lung ca. (non-sm.
0.1


SF-539

cell) A549


astrocytoma
13.3
Lung ca. (s.cell
9.9


SNB-75

var.) SHP-77


astrocytoma
1.2
Lung ca. (small
3.2


SW1783

cell) LX-1


glioma U251
24.0
Lung ca. (small
0.1




cell) NCI-H69


glioma SF-295
0.0
Lung ca. (squam.)
0.0




SW 900


glioma SNB-19
27.0
Lung ca. (squam.)
0.6




NCI-H596


glio/astro
0.0
Lymph node
1.9


U87-MG


neuro*; met
0.1
Spleen
0.0


SK-N-AS


Mammary gland
34.9
Thymus
0.1


Breast ca. BT-549
8.4
Ovary
13.0


Breast ca.
0.0
Ovarian ca.
4.6


MDA-N

IGROV-1


Breast ca.*
95.3
Ovarian ca.
100.0


(pl.ef) T47D

OVCAR-3


Breast ca.*
0.0
Ovarian ca.
88.3


(pl.ef) MCF-7

OVCAR-4


Breast ca.*
50.0
Ovarian ca.
44.4


(pl.ef)

OVCAR-5


MDA-MB-231


Small intestine
0.5
Ovarian ca.
0.0




OVCAR-8


Colorectal
1.1
Ovarian ca.*
57.4




(ascites) SK-OV-3


Colon ca. HT29
0.0
Pancreas
0.0


Colon ca.
0.0
Pancreatic ca.
0.0


CaCo-2

CAPAN2


Colon ca.
0.0
Pituitary gland
0.8


HCT-15


Colon ca.
0.0
Placenta
21.6


HCT-116


Colon ca.
0.0
Prostate
0.0


HCC-2998


Colon ca. SW480
7.5
Prostate ca.* (bone
3.0




met) PC-3


Colon ca.*
0.4
Salivary gland
0.0


SW620 (SW480


met)


Stomach
5.4
Trachea
0.6


Gastric ca. (liver
1.1
Spinal cord
1.4


met) NCI-N87


Heart
54.7
Testis
0.0


Skeletal muscle
69.7
Thyroid
6.5


(Fetal)


Skeletal muscle
0.9
Uterus
1.1


Endothelial cells
0.0
Melanoma M14
0.0


Heart (Fetal)
55.9
Melanoma LOX
0.0




IMVI


Kidney
35.6
Melanoma
0.0




UACC-62


Kidney (fetal)
59.9
Melanoma
0.0




SK-MEL-28


Renal ca. 786-0
16.6
Melanoma* (met)
0.0




SK-MEL-5


Renal ca. A498
7.7
Melanoma
0.0




Hs688(A).T


Renal ca. ACHN
94.6
Melanoma* (met)
0.0




Hs688(B).T


Renal ca. TK-10
5.8










[0726]

286





TABLE EG










Panel 1.2













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag554, Run
Ag554, Run

Ag554, Run
Ag554, Run


Tissue Name
121754027
124088899
Tissue Name
121754027
124088899















Endothelial cells
0.0
0.0
Renal ca. 786-0
5.8
0.0


Heart (Fetal)
69.3
56.6
Renal ca. A498
2.3
0.0


Pancreas
0.0
0.0
Renal ca. RXF
0.0
0.0





393


Pancreatic ca.
0.0
0.0
Renal ca.
44.1
9.6


CAPAN 2


ACHN


Adrenal Gland
0.1
0.0
Renal ca. UO-
0.5
0.0





31


Thyroid
0.2
0.0
Renal ca. TK-
0.1
0.0





10


Salivary gland
0.0
0.0
Liver
0.1
0.0


Pituitary gland
0.0
0.0
Liver (fetal)
0.0
0.0


Brain (fetal)
0.0
0.0
Liver ca.
0.0
0.0





(hepatoblast)





HepG2


Brain (whole)
0.0
0.0
Lung
3.2
0.0


Brain (amygdala)
0.0
0.0
Lung (fetal)
6.0
0.4


Brain
0.0
0.0
Lung ca. (small
0.0
0.0


(cerebellum)


cell) LX-1


Brain
0.0
0.0
Lung ca. (small
0.0
0.0


(hippocampus)


cell) NCI-H69


Brain (thalamus)
0.0
0.0
Lung ca. (s.cell
4.2
0.0





var.) SHP-77


Cerebral Cortex
0.0
0.0
Lung ca. (large
0.0
0.0





cell)NCI-H460


Spinal cord
0.0
0.0
Lung ca. (non-
0.0
0.0





sm. cell) A549


glio/astro U87-
0.0
0.0
Lung ca. (non-
0.0
0.0


MG


s.cell) NCI-





H23


glio/astro U-118-
18.0
0.2
Lung ca. (non-
0.0
0.0


MG


s.cell) HOP-62


astrocytoma
0.0
0.0
Lung ca. (non-
0.0
0.0


SW1783


s.cl) NCI-H522


neuro*; met SK-
0.0
0.0
Lung ca.
0.0
0.0


N-AS


(squam.) SW





900


astrocytoma SF-
0.0
0.0
Lung ca.
0.0
0.0


539


(squam.) NCI-





H596


astrocytoma
1.2
0.0
Mammary
24.1
18.0


SNB-75


gland


glioma SNB-19
14.7
2.8
Breast ca.*
0.0
0.0





(pl.ef) MCF-7


glioma U251
6.2
0.0
Breast ca.*
31.0
12.7





(pl.ef) MDA-





MB-231


glioma SF-295
0.0
0.0
Breast ca.* (pl.
39.8
17.6





ef) T47D


Heart
79.0
6.4
Breast ca. BT-
12.2
0.6





549


Skeletal Muscle
0.0
0.0
Breast ca.
0.0
0.0





MDA-N


Bone marrow
0.0
0.0
Ovary
7.4
0.0


Thymus
0.0
0.0
Ovarian ca.
37.1
24.8





OVCAR-3


Spleen
0.0
0.0
Ovarian ca.
54.3
16.7





OVCAR-4


Lymph node
0.0
0.0
Ovarian ca.
16.6
2.9





OVCAR-5


Colorectal Tissue
1.5
0.0
Ovarian ca.
0.0
0.0





OVCAR-8


Stomach
5.3
0.0
Ovarian ca.
2.1
0.0





IGROV-1


Small intestine
0.0
0.0
Ovarian ca.
21.2
4.7





(ascites) SK-





OV-3


Colon ca.
0.0
0.0
Uterus
0.1
0.0


SW480


Colon ca.*
0.0
0.0
Placenta
38.7
2.2


SW620 (SW480


met)


Colon ca. HT29
0.0
0.0
Prostate
0.0
0.0


Colon ca. HCT-
0.0
0.0
Prostate ca.*
5.6
0.0


116


(bone met)





PC-3


Colon ca. CaCo-2
0.0
0.0
Testis
0.0
0.0


Colon ca. Tissue
0.1
0.0
Melanoma
0.0
0.0


(ODO3866)


Hs688(A).T


Colon ca. HCC-
0.0
0.0
Melanoma*
0.0
0.0


2998


(met)





Hs688(B).T


Gastric ca.*
0.7
0.0
Melanoma
0.0
0.0


(liver met) NCI-


UACC-62


N87


Bladder
1.9
0.0
Melanoma
0.0
0.0





M14


Trachea
0.2
0.0
Melanoma
0.0
0.0





LOX IMVI


Kidney
11.0
0.6
Melanoma*
0.0
0.0





(met) SK-





MEL-5


Kidney (fetal)
100.0
100.0










[0727]

287





TABLE EH










Panel 1.3D











Rel. Exp.(%) Ag554,

Rel. Exp.(%) Ag554,


Tissue Name
Run 165702013
Tissue Name
Run 165702013













Liver adenocarcinoma
0.2
Kidney (fetal)
15.7


Pancreas
0.1
Renal ca. 786-0
9.0


Pancreatic ca. CAPAN2
0.6
Renal ca. A498
7.3


Adrenal gland
0.8
Renal ca. RXF 393
4.1


Thyroid
5.0
Renal ca. ACHN
42.9


Salivary gland
0.7
Renal ca. UO-31
33.9


Pituitary gland
0.8
Renal ca. TK-10
2.2


Brain (fetal)
0.3
Liver
0.3


Brain (whole)
0.2
Liver (fetal)
1.3


Brain (amygdala)
1.2
Liver ca.
0.0




(hepatoblast) HepG2


Brain (cerebellum)
0.2
Lung
5.4


Brain (hippocampus)
1.2
Lung (fetal)
10.7


Brain (substantia nigra)
0.5
Lung ca. (small cell)
2.7




LX-1


Brain (thalamus)
0.3
Lung ca. (small cell)
1.1




NCI-H69


Cerebral Cortex
0.7
Lung ca. (s.cell var.)
19.3




SHP-77


Spinal cord
1.9
Lung ca. (large
0.7




cell) NCI-H460


glio/astro U87-MG
0.0
Lung ca. (non-sm.
1 .2




cell) A549


glio/astro U-118-MG
75.8
Lung ca. (non-s.cell)
0.0




NCI-H23


astrocytoma SW1783
5.1
Lung ca. (non-s.cell)
1.0




HOP-62


neuro*; met SK-N-AS
0.7
Lung ca. (non-s.cl)
0.0




NCI-H522


astrocytoma SF-539
3.3
Lung ca. (squam.)
0.8




SW 900


astrocytoma SNB-75
13.5
Lung ca. (squam.)
1.3




NCI-H596


glioma SNB-19
24.0
Mammary gland
15.3


glioma U251
48.0
Breast ca.* (pl.ef)
0.9




MCF-7


glioma SF-295
0.3
Breast ca.* (pl.ef)
100.0




MDA-MB-231


Heart (fetal)
22.2
Breast ca.* (pl.ef)
34.6




T47D


Heart
10.7
Breast ca. BT-549
21.3


Skeletal muscle (fetal)
22.1
Breast ca. MDA-N
0.0


Skeletal muscle
2.4
Ovary
3.1


Bone marrow
0.0
Ovarian ca. OVCAR-3
31.9


Thymus
0.8
Ovarian ca. OVCAR-4
43.2


Spleen
1.2
Ovarian ca. OVCAR-5
19.3


Lymph node
4.3
Ovarian ca. OVCAR-8
0.0


Colorectal
3.0
Ovarian ca. IGROV-1
2.2


Stomach
3.0
Ovarian ca.* (ascites)
22.7




SK-OV-3


Small intestine
2.9
Uterus
4.4


Colon ca. SW480
5.0
Placenta
6.7


Colon ca.*
0.5
Prostate
0.9


SW620(SW480 met)


Colon ca. HT29
0.0
Prostate ca.* (bone
2.2




met) PC-3


Colon ca. HCT-116
0.0
Testis
1.0


Colon ca. CaCo-2
0.5
Melanoma
0.0




Hs688(A).T


Colon ca.
2.3
Melanoma* (met)
1.4


tissue (ODO3866)

Hs688(B).T


Colon ca. HCC-2998
0.0
Melanoma UACC-62
1.0


Gastric ca.* (liver met)
3.5
Melanoma M14
0.0


NCI-N87


Bladder
1.2
Melanoma LOX
0.0




IMVI


Trachea
1.7
Melanoma* (met)
0.3




SK-MEL-5


Kidney
7.9
Adipose
23.2










[0728]

288





TABLE EI










Panel 2.1











Rel. Exp.(%) Ag3340,

Rel. Exp.(%) Ag3340,


Tissue Name
Run 170686167
Tissue Name
Run 170686167













Normal Colon
6.0
Kidney Cancer
7.0




9010320


Colon cancer (OD06064)
0.9
Kidney margin
14.7




9010321


Colon cancer margin
1.4
Kidney Cancer
4.2


(OD06064)

8120607


Colon cancer (OD06159)
0.3
Kidney margin
7.8




8120608


Colon cancer margin
0.3
Normal Uterus
11.1


(OD06159)


Colon cancer (OD06298-
2.6
Uterus Cancer
6.1


08)


Colon cancer margin
1.4
Normal Thyroid
1.4


(OD06298-018)


Colon Cancer Gr.2 ascend
3.0
Thyroid Cancer
18.2


colon (ODO3921)


Colon Cancer margin
2.1
Thyroid Cancer
0.6


(ODO3921)

A302152


Colon cancer metastasis
2.5
Thyroid margin
4.4


(OD06104)

A302153


Lung margin (OD06104)
1.6
Normal Breast
22.1


Colon mets to lung
0.0
Breast Cancer
10.4


(OD04451-01)


Lung margin (OD04451-
3.5
Breast Cancer
6.7


02)


Normal Prostate
0.8
Breast Cancer
24.8




(OD04590-01)


Prostate Cancer
0.4
Breast Cancer Mets
29.3


(OD04410)

(OD04590-03)


Prostate margin
1.9
Breast Cancer
100.0


(OD04410)

Metastasis


Normal Lung
14.4
Breast Cancer
3.4


Invasive poor diff. lung
0.3
Breast Cancer
14.4


adeno 1 (ODO4945-01)

9100266


Lung margin (ODO4945-
11.1
Breast margin
6.8


03)

9100265


Lung Malignant Cancer
2.6
Breast Cancer
4.7


(OD03126)

A209073


Lung margin (OD03126)
1.2
Breast margin
16.8




A2090734


Lung Cancer (OD05014A)
1.0
Normal Liver
0.9


Lung margin (OD05014B)
4.2
Liver Cancer 1026
3.0


Lung Cancer (OD04237-
1.8
Liver Cancer 1025
0.4


01)


Lung margin (OD04237-
5.1
Liver Cancer 6004-T
0.1


02)


Ocular Mel Met to Liver
0.0
Liver Tissue 6004-N
0.0


(ODO4310)


Liver margin (ODO4310)
0.7
Liver Cancer 6005-T
5.9


Melanoma Mets to Lung
1.0
Liver Tissue 6005-N
3.7


(OD04321)


Lung margin (OD04321)
6.4
Liver Cancer
0.3


Normal Kidney
20.9
Normal Bladder
2.2


Kidney Ca, Nuclear grade
23.3
Bladder Cancer
1.7


2 (OD04338)


Kidney margin (OD04338)
1.6
Bladder Cancer
0.9


Kidney Ca Nuclear grade
4.5
Normal Ovary
5.6


1/2 (OD04339)


Kidney margin (OD04339)
5.0
Ovarian Cancer
4.9


Kidney Ca, Clear cell type
1.6
Ovarian cancer
2.7


(OD04340)

(OD06145)


Kidney margin (OD04340)
10.4
Ovarian cancer
3.1




margin (OD06145)


Kidney Ca, Nuclear grade
0.4
Normal Stomach
24.8


3 (OD04348)


Kidney margin (OD04348)
8.5
Gastric Cancer
0.0




9060397


Kidney Cancer (OD04450-
0.5
Stomach margin
16.5


01)

9060396


Kidney margin (OD04450-
12.7
Gastric Cancer
4.9


03)

9060395


Kidney Cancer 8120613
0.0
Stomach margin
11.3




9060394


Kidney margin 8120614
6.2
Gastric Cancer
2.1




064005










[0729]

289





TABLE EJ










Panel 2D













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag554, Run
Ag554, Run

Ag554, Run
Ag554, Run


Tissue Name
145968942
145968960
Tissue Name
145968942
145968960















Normal Colon
12.9
15.4
Kidney Margin
12.2
14.3





8120608


CC Well to Mod
1.9
1.9
Kidney Cancer
0.2
0.2


Diff (ODO3866)


8120613


CC Margin
3.0
3.8
Kidney Margin
8.7
16.2


(ODO3866)


8120614


CC Gr.2
1.4
1.8
Kidney Cancer
17.1
21.3


rectosigmoid


9010320


(ODO3868)


CC Margin
1.2
1.4
Kidney Margin
16.6
18.9


(ODO3868)


9010321


CC Mod Diff
0.5
0.5
Normal Uterus
2.9
4.2


(ODO3920)


CC Margin
0.8
1.5
Uterus Cancer
5.3
4.7


(ODO3920)


064011


CC Gr.2 ascend
7.1
9.9
Normal
5.6
7.0


colon


Thyroid


(ODO3921)


CC Margin
1.2
1.9
Thyroid
20.2
28.7


(ODO3921)


Cancer 064010


CC from Partial
1.6
2.7
Thyroid
1.4
1.4


Hepatectomy


Cancer


(ODO4309) Mets


A302152


Liver Margin
0.7
1.0
Thyroid
7.3
9.0


(ODO4309)


Margin





A302153


Colon mets to
3.1
5.8
Normal Breast
23.0
29.9


lung (OD04451-


01)


Lung Margin
2.7
1.8
Breast Cancer
28.3
34.6


(OD04451-02)


(OD04566)


Normal Prostate
0.7
0.5
Breast Cancer
87.7
80.7


6546-1


(OD04590-01)


Prostate Cancer
1.1
0.9
Breast Cancer
100.0
100.0


(OD04410)


Mets





(OD04590-03)


Prostate Margin
2.5
2.2
Breast Cancer
76.8
81.2


(OD04410)


Metastasis





(OD04655-05)


Prostate Cancer
1.7
1.4
Breast Cancer
10.2
11.1


(OD04720-01)


064006


Prostate Margin
2.1
3.6
Breast Cancer
19.9
20.0


(OD04720-02)


1024


Normal Lung
7.0
11.1
Breast Cancer
26.2
31.6


061010


9100266


Lung Met to
0.4
0.9
Breast Margin
10.1
13.2


Muscle


9100265


(ODO4286)


Muscle Margin
2.9
6.9
Breast Cancer
13.6
21.6


(ODO4286)


A209073


Lung Malignant
2.0
3.2
Breast Margin
10.4
12.3


Cancer


A209073


(OD03126)


Lung Margin
3.6
6.5
Normal Liver
0.5
0.4


(OD03126)


Lung Cancer
4.1
7.8
Liver Cancer
0.5
0.3


(OD04404)


064003


Lung Margin
19.3
20.0
Liver Cancer
0.2
0.3


(OD04404)


1025


Lung Cancer
0.4
0.7
Liver Cancer
1.9
2.7


(OD04565)


1026


Lung Margin
3.9
3.3
Liver Cancer
0.2
0.5


(OD04565)


6004-T


Lung Cancer
3.0
4.8
Liver Tissue
0.2
0.3


(OD04237-01)


6004-N


Lung Margin
8.0
8.1
Liver Cancer
2.0
2.2


(OD04237-02)


6005-T


Ocular Mel Met
0.0
0.2
Liver Tissue
1.2
1.3


to Liver


6005-N


(ODO4310)


Liver Margin
0.6
1.0
Normal
3.1
3.3


(ODO4310)


Bladder


Melanoma Mets
1.5
2.6
Bladder Cancer
1.7
1.5


to Lung


1023


(OD04321)


Lung Margin
6.4
9.8
Bladder Cancer
0.6
0.8


(OD04321)


A302173


Normal Kidney
27.0
54.0
Bladder Cancer
0.8
0.9





(OD04718-01)


Kidney Ca,
2.3
3.1
Bladder
42.6
53.6


Nuclear grade 2


Normal


(OD04338)


Adjacent





(OD04718-03)


Kidney Margin
11.7
16.0
Normal Ovary
3.3
4.0


(OD04338)


Kidney Ca
7.5
7.1
Ovarian
15.0
18.9


Nuclear grade 1/2


Cancer 064008


(OD04339)


Kidney Margin
14.9
16.8
Ovarian
1.3
1.7


(OD04339)


Cancer





(OD04768-07)


Kidney Ca, Clear
1.5
2.3
Ovary Margin
9.8
9.7


cell type


(OD04768-08)


(OD04340)


Kidney Margin
19.8
18.3
Normal
14.8
15.1


(OD04340)


Stomach


Kidney Ca,
0.8
1.2
Gastric Cancer
3.0
3.1


Nuclear grade 3


9060358


(OD04348)


Kidney Margin
13.5
19.3
Stomach
8.0
7.7


(OD04348)


Margin





9060359


Kidney Cancer
1.5
1.9
Gastric Cancer
2.8
3.1


(OD04622-01)


9060395


Kidney Margin
4.7
5.8
Stomach
8.1
8.7


(OD04622-03)


Margin





9060394


Kidney Cancer
0.1
0.2
Gastric Cancer
0.5
0.9


(OD04450-01)


9060397


Kidney Margin
11.1
17.7
Stomach
9.8
9.7


(OD04450-03)


Margin





9060396


Kidney Cancer
2.1
3.1
Gastric Cancer
1.7
2.6


8120607


064005










[0730]

290





TABLE EK










Panel 3D











Rel. Exp.(%) Ag554,

Rel. Exp.(%) Ag554,


Tissue Name
Run 164886640
Tissue Name
Run 164886640













Daoy-Medulloblastoma
18.3
Ca Ski-Cervical epidermoid
6.6




carcinoma (metastasis)


TE671-Medulloblastoma
1.0
ES-2-Ovarian clear cell
0.9




carcinoma


D283 Med-
1.8
Ramos-Stimulated with
0.0


Medulloblastoma

PMA/ionomycin 6h


PFSK-1-Primitive
0.0
Ramos-Stimulated with
0.0


Neuroectodermal

PMA/ionomycin 14h


XF-498-CNS
46.7
MEG-01-Chronic
0.0




myelogenous leukemia




(megokaryoblast)


SNB-78-Glioma
1.2
Raji-Burkitt's lymphoma
0.0


SF-268-Glioblastoma
3.5
Daudi-Burkitt's lymphoma
0.0


T98G-Glioblastoma
3.5
U266-B-cell plasmacytoma
0.0


SK-N-SH-Neuroblastoma
2.1
CA46-Burkitt's lymphoma
0.0


(metastasis)


SF-295-Glioblastoma
2.9
RL-non-Hodgkin's B-cell
0.0




lymphoma


Cerebellum
0.0
JM1-pre-B-cell lymphoma
0.0


Cerebellum
0.1
Jurkat-T cell leukemia
0.0


NCI-H292-
13.8
TF-1-Erythroleukemia
0.0


Mucoepidermoid lung


carcinoma


DMS-114-Small cell lung
1.1
HUT 78-T-cell lymphoma
0.0


cancer


DMS-79-Small cell lung
77.9
U937-Histiocytic lymphoma
0.0


cancer


NCI-H146-Small cell
0.0
KU-812-Myelogenous
0.0


lung cancer

leukemia


NCI-H526-Small cell
0.6
769-P-Clear cell renal
2.8


lung cancer

carcinoma


NCI-N417-Small cell
0.0
Caki-2-Clear cell renal
2.4


lung cancer

carcinoma


NCI-H82-Small cell lung
3.1
SW 839-Clear cell renal
4.8


cancer

carcinoma


NCI-H157-Squamous
18.9
G401-Wilms' tumor
0.0


cell lung cancer


(metastasis)


NCI-H1155-Large cell
3.5
Hs766T-Pancreatic carcinoma
13.5


lung cancer

(LN metastasis)


NCI-H1299-Large cell
0.0
CAPAN-1-Pancreatic
2.2


lung cancer

adenocarcinoma (liver




metastasis)


NCI-H727-Lung
27.9
SU86.86-Pancreatic
8.7


carcinoid

carcinoma (liver metastasis)


NCI-UMC-11-Lung
0.2
BxPC-3-Pancreatic
5.3


carcinoid

adenocarcinoma


LX-1-Small cell lung
2.9
HPAC-Pancreatic
13.9


cancer

adenocarcinoma


Colo-205-Colon cancer
2.0
MIA PaCa-2-Pancreatic
13.6




carcinoma


KM12-Colon cancer
7.0
CFPAC-1-Pancreatic ductal
23.0




adenocarcinoma


KM20L2-Colon cancer
0.0
PANC-1-Pancreatic
100.0




epithelioid ductal carcinoma


NCI-H716-Colon cancer
0.3
T24-Bladder carcinoma
7.5




(transitional cell)


SW-48-Colon
0.0
5637-Bladder carcinoma
2.3


adenocarcinoma


SW1116-Colon
0.7
HT-1197-Bladder carcinoma
0.3


adenocarcinoma


LS 174T-Colon
1.4
UM-UC-3-Bladder carcinma
0.0


adenocarcinoma

(transitional cell)


SW-948-Colon
2.7
A204-Rhabdomyosarcoma
0.0


adenocarcinoma


SW-480-Colon
0.0
HT-1080-Fibrosarcoma
5.7


adenocarcinoma


NCI-SNU-5-Gastric
17.4
MG-63-Osteosarcoma
7.4


carcinoma


KATO III-Gastric
0.2
SK-LMS-1-Leiomyosarcoma
10.8


carcinoma

(vulva)


NCI-SNU-16-Gastric
6.9
SJRH30-Rhabdomyosarcoma
8.2


carcinoma

(met to bone marrow)


NCI-SNU-1-Gastric
0.0
A431-Epidermoid carcinoma
6.3


carcinoma


RF-1-Gastric
0.0
WM266-4-Melanoma
0.0


adenocarcinoma


RF-48-Gastric
0.0
DU 145-Prostate carcinoma
0.0


adenocarcinoma

(brain metastasis)


MKN-45-Gastric
9.3
MDA-MB-468-Breast
0.0


carcinoma

adenocarcinoma


NCI-N87-Gastric
2.2
SCC-4-Squamous cell
0.0


carcinoma

carcinoma of tongue


OVCAR-5-Ovarian
6.5
SCC-9-Squamous cell
0.0


carcinoma

carcinoma of tongue


RL95-2-Uterine
0.2
SCC-15-Squamous cell
0.7


carcinoma

carcinoma of tongue


HelaS3-Cervical
0.9
CAL 27-Squamous cell
0.6


adenocarcinoma

carcinoma of tongue










[0731]

291





TABLE EL










Panel 4.1D













Rel.
Rel.

Rel.
Rel.



Exp.(%)
Exp.(%)

Exp.(%)
Exp.(%)



Ag3340,
Ag3340,

Ag3340,
Ag3340,



Run
Run

Run
Run


Tissue Name
170737060
170766524
Tissue Name
170737060
170766524















Secondary Th1 act
0.2
0.0
HUVEC IL-1 beta
0.0
0.0


Secondary Th2 act
0.0
0.0
HUVEC IFN
0.0
0.0





gamma


Secondary Tr1 act
0.0
0.0
HUVEC TNF
0.0
0.0





alpha + IFN





gamma


SecondaryTh1 rest
0.0
0.0
HUVEC TNF
1.2
1.8





alpha + IL4


Secondary Th2 rest
0.0
0.0
HUVEC IL-11
0.2
0.0


Secondary Tr1 rest
0.0
0.0
Lung
1.7
2.0





Microvascular EC





none


Primary Th1 act
0.0
0.0
Lung
0.0
0.0





Microvascular EC





TNF alpha + IL-





1 beta


Primary Th2 act
0.0
0.0
Microvascular
0.5
1.2





Dermal EC none


Primary Tr1 act
0.0
1.5
Microsvasular
0.0
0.0





Dermal EC





TNF alpha + IL-





1 beta


Primary Th1 rest
0.0
0.0
Bronchial
0.6
0.4





epithelium





TNF alpha +





IL1 beta


Primary Th2 rest
0.0
0.0
Small airway
0.0
1.9





epithelium none


Primary Tr1 rest
0.2
0.0
Small airway
0.4
0.3





epithelium





TNF alpha + IL-





1 beta


CD45RA CD4
1.3
0.4
Coronery artery
2.6
7.6


lymphocyte act


SMC rest


CD45RO CD4
0.0
0.0
Coronery artery
3.1
2.9


lymphocyte act


SMC TNF alpha +





IL-1 beta


CD8 lymphocyte
0.0
0.0
Astrocytes rest
18.4
35.4


act


Secondary CD8
0.0
0.0
Astrocytes
7.0
11.7


lymphocyte rest


TNF alpha + IL-





1 beta


Secondary CD8
0.0
0.0
KU-812 (Basophil)
0.0
0.0


lymphocyte act


rest


CD4 lymphocyte
0.0
0.0
KU-812 (Basophil)
0.4
0.0


none


PMA/ionomycin


2ry
0.0
0.0
CCD1106
10.3
8.5


Th1/Th2/Tr1_anti-


(Keratinocytes)


CD95 CH11


none


LAK cells rest
0.0
0.0
CCD1106
1.2
3.3





(Keratinocytes)





TNF alpha + IL-





1 beta


LAK cells IL-2
0.4
0.0
Liver cirrhosis
0.3
0.9


LAK cells IL-2 +
0.0
0.0
NCI-H292 none
1.1
5.6


IL-12


LAK cells IL-
0.0
0.0
NCI-H292 IL-4
28.1
42.3


2 + IFN gamma


LAK cells IL-2 +
0.0
0.0
NCI-H292 IL-9
4.3
10.1


IL-18


LAK cells
0.0
0.4
NCI-H292 IL-13
46.7
52.1


PMA/ionomycin


NK Cells IL-2 rest
0.2
0.8
NCI-H292 IFN
0.8
8.1





gamma


Two Way MLR 3
0.0
0.0
HPAEC none
0.0
1.5


day


Two Way MLR 5
0.0
0.0
HPAEC TNF
0.0
3.9


day


alpha + IL-1 beta


Two Way MLR 7
0.0
0.0
Lung fibroblast
76.3
74.7


day


none


PBMC rest
0.0
0.0
Lung fibroblast
0.8
2.2





TNF alpha + IL-1





beta


PBMC PWM
0.0
0.0
Lung fibroblast IL-4
100.0
92.7


PBMC PHA-L
0.0
0.3
Lung fibroblast IL-9
48.3
48.0


Ramos (B cell)
0.0
0.0
Lung fibroblast IL-
100.0
100.0


none


13


Ramos (B cell)
0.0
0.0
Lung fibroblast
32.1
51.4


ionomycin


IFN gamma


B lymphocytes
0.0
0.0
Dermal fibroblast
4.5
7.4


PWM


CCD1070 rest


B lymphocytes
0.0
0.0
Dermal fibroblast
3.0
3.1


CD40L and IL-4


CCD1070 TNF





alpha


EOL-1 dbcAMP
0.0
0.0
Dermal fibroblast
1.8
2.2





CCD1070 IL-1





beta


EOL-1 dbcAMP
0.0
0.0
Dermal fibroblast
2.7
6.5


PMA/ionomycin


IFN gamma


Dendritic cells none
0.6
0.0
Dermal fibroblast
40.9
43.2





IL-4


Dendritic cells LPS
0.2
0.5
Dermal Fibroblasts
8.0
9.2





rest


Dendritic cells anti-
4.5
3.4
Neutrophils
1.1
0.9


CD40


TNFa + LPS


Monocytes rest
0.0
0.0
Neutrophils rest
2.2
0.0


Monocytes LPS
0.0
0.0
Colon
3.5
2.3


Macrophages rest
0.9
1.1
Lung
7.0
8.5


Macrophages LPS
0.0
0.0
Thymus
5.0
12.8


HUVEC none
0.1
0.0
Kidney
21.2
36.1


HUVEC starved
0.3
0.0










[0732]

292





TABLE EM










Panel 4D













Rel.
Rel.

Rel.
Rel.



Exp. (%)
Exp. (%)

Exp. (%)
Exp. (%)



Ag3340,
Ag554,

Ag3340,
Ag554,



Run
Run

Run
Run


Tissue Name
165222713
164886924
Tissue Name
165222713
164886924















Secondary Th1 act
0.0
0.1
HUVEC IL-1 beta
0.0
0.0


Secondary Th2 act
0.0
0.1
HUVEC IFN
0.0
0.0





gamma


Secondary Tr1 act
0.0
0.1
HUVEC TNF
0.0
0.0





alpha + IFN





gamma


Secondary Th1 rest
0.0
0.0
HUVEC TNF
0.6
0.5





alpha + IL4


Secondary Th2 rest
0.0
0.0
HUVEC IL-11
0.1
0.0


Secondary Tr1 rest
0.1
0.0
Lung
0.4
0.9





Microvascular EC





none


Primary Th1 act
0.0
0.0
Lung
0.1
0.2





Microvascular EC





TNF alpha + IL-





1 beta


Primary Th2 act
0.0
0.0
Microvascular
0.3
0.6





Dermal EC none


Primary Tr1 act
0.0
0.0
Microsvasular
0.0
0.1





Dermal EC





TNF alpha + IL-





1 beta


Primary Th1 rest
0.0
0.0
Bronchial
0.0
0.4





epithelium





TNF alpha +





IL1 beta


Primary Th2 rest
0.0
0.0
Small airway
0.5
0.2





epithelium none


Primary Tr1 rest
0.3
0.0
Small airway
0.4
1.0





epithelium





TNF alpha + IL-





1 beta


CD45RA CD4
0.1
0.4
Coronery artery
2.7
3.5


lymphocyte act


SMC rest


CD45RO CD4
0.0
0.0
Coronery artery
1.2
0.8


lymphocyte act


SMC TNF alpha +





IL-1 beta


CD8 lymphocyte
0.0
0.0
Astrocytes rest
19.5
21.8


act


Secondary CD8
0.0
0.0
Astrocytes
7.0
6.9


lymphocyte rest


TNF alpha + IL-





1 beta


Secondary CD8
0.0
0.0
KU-812 (Basophil)
0.0
0.0


lymphocyte act


rest


CD4 lymphocyte
0.0
0.0
KU-812 (Basophil)
0.0
0.0


none


PMA/ionomycin


2ry
0.1
0.1
CCD1106
2.8
3.4


Th1/Th2/Tr1_anti-


(Keratinocytes)


CD95 CH11


none


LAK cells rest
0.0
0.0
CCD1106
2.3
1.3





(Keratinocytes)





TNF alpha + IL-





1 beta


LAK cells IL-2
0.0
0.0
Liver cirrhosis
0.6
1.6


LAK cells IL-2 +
0.1
0.0
Lupus kidney
0.5
0.9


IL-12


LAK cells IL-
0.0
0.0
NCI-H292 none
2.7
2.7


2 + IFN gamma


LAK cells IL-2 +
0.1
0.1
NCI-H292 IL-4
33.4
39.5


IL-18


LAK-cells
0.1
0.0
NCI-H292 IL-9
4.6
3.5


PMA/ionomycin


NK Cells IL-2 rest
0.1
0.2
NCI-H292 IL-13
31.0
26.1


Two Way MLR 3
0.0
0.0
NCI-H292 IFN
3.4
3.6


day


gamma


Two Way MLR 5
0.0
0.2
HPAEC none
0.0
0.0


day


Two Way MLR 7
0.0
0.0
HPAEC TNF
0.0
0.0


day


alpha + IL-1 beta


PBMC rest
0.0
0.0
Lung fibroblast
36.9
53.6





none


PBMC PWM
0.0
0.0
Lung fibroblast
0.6
0.8





TNF alpha + IL-1





beta


PBMC PHA-L
0.0
0.0
Lung fibroblast IL-4
100.0
100.0


Ramos (B cell)
0.0
0.0
Lung fibroblast IL-9
26.8
29.7


none


Ramos (B cell)
0.0
0.0
Lung fibroblast IL-
75.8
74.2


ionomycin


13


B lymphocytes
0.0
0.0
Lung fibroblast
32.8
36.6


PWM


IFN gamma


B lymphocytes
0.0
0.0
Dermal fibroblast
2.5
5.6


CD40L and IL-4


CCD1070 rest


EOL-1 dbcAMP
0.0
0.0
Dermal fibroblast
0.9
2.8





CCD1070 TNF





alpha


EOL-1 dbcAMP
0.1
0.0
Dermal fibroblast
0.4
0.4


PMA/ionomycin


CCD1070 IL-1





beta


Dendritic cells none
0.2
0.6
Dermal fibroblast
0.6
2.8





IFN gamma


Dendritic cells LPS
0.0
0.1
Dermal fibroblast
26.6
29.9





IL-4


Dendritic cells anti-
1.2
2.0
IBD Colitis 2
0.4
0.7


CD40


Monocytes rest
0.0
0.0
IBD Crohn's
1.6
1.5


Monocytes LPS
0.0
0.0
Colon
1.8
2.5


Macrophages rest
0.3
0.9
Lung
4.8
8.5


Macrophages LPS
0.0
0.0
Thymus
16.3
24.7


HUVEC none
0.0
0.0
Kidney
3.4
3.8


HUVEC starved
0.0
0.4










[0733] AI_comprehensive panel_v1.0 Summary: Ag3340 The transcript is highly expressed in 3 out of 6 ulcerative colitis samples, but not in the matched control samples. Similarly, it is expressed in OA tissue and not in normal control samples. Asthma and emphysema lung samples express the transcript at higher levels than in normal lung.


[0734] The protein encoded for by CG57829-01 has homology to ADAMTS family of molecules suggesting that it may function as an enzyme. Based on its homology, it may contribute to the tissue destruction and remodeling processes associated with asthma, ulcerative colitis, emphysema and osteoarthritis. Therefore, blocking the function of the protein encoded for by CG57829-01 with antagonistic antibody therapeutics or small molecule therapeutics could reduce or inhibit tissue destruction in the lungs, intestine, or joints due to emphysema, allergy, asthma, colitis, or osteoarthritis.


[0735] CNS_neurodegeneration_v1.0 Summary: Ag3340 This panel does not show differential expression of the CG57829-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.


[0736] General_screening_panel_v1.4 Summary: Ag3340 Two experiments with the same probe and primer set are in excellent agreement. Highest expression of the CG57829-01 gene is seen in breast cancer MDA-MB-231 cell line (CTs=25). As seen in Panel 1.1, 1.2, and 1.3, this gene has high expression in ovarian and breast cancer cell lines which is also confirmed in Panels 2.1 and 2D. Therefore, expression of this gene could be used as a diagnostic marker for the presence of these cancers. Furhtermore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of breast or ovarian cancer.


[0737] Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, fetal liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.


[0738] Interestingly, this gene is expressed at much higher levels in fetal (CT=32) when compared to adult liver (CT=36). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver.


[0739] In addition, this gene is expressed at low to moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.


[0740] This gene encodes a homologue of rat ADAMTS-1. Members belonging to ADAM and ADAMTS family has been found to play a role in various inflammatory processes such as arthritic diseases, as well as, development of cancer cachexia and thrombotic thrombocytopenic purpura (Ref. 1, 2, 3). Therefore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of these diseases.


[0741] References.


[0742] 1. Martel-Pelletier J, Welsch D J, Pelletier J P. (2001) Metalloproteases and inhibitors in arthritic diseases. Best Pract Res Clin Rheumatol 15(5):805-29


[0743] 2. Kuno K, Kanada N, Nakashima E, Fujiki F, Ichimura F, Matsushima K. (1 997) Molecular cloning of a gene encoding a new type of metalloproteinase-disintegrin family protein with thrombosponidin motifs as an inflammation associated gene. J Biol Chem 272(1):556-62.


[0744] 3. Levy G G, Nichols W C, Lian E C, Foroud T, McClintick J N, McGee B M, Yang A Y, Siemieniak D R, Stark K R, Gnippo R, Sarode R, Shurin S B, Chandrasekaran V, Stabler S P, Sabio H, Bouhassira E E, Upshaw J D Jr, Ginsburg D, Tsai H M. (2001) Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 413(6855):488-94


[0745] Panel 1.1 Summary: Ag554 Highest expression of the CG57829-01 gene is seen in ovarian cancer OVCAR-3 cell line (CT=22). Expression pattern of this gene in this panel is similar to that of panel 1.4. Please see panel 1.4 for discussion and potential utility of this gene.


[0746] Panel 1.2 Summary: Ag554 Highest expression of the CG57829-01 gene is seen in fetal kidney (CT=23.8). Interestingly, this gene is expressed at much higher levels in fetal (CT=23.8) when compared to adult kidney (CT=27-31). This observation suggests that expression of this gene can be used to distinguish fetal from adult kidney.


[0747] High expression of this gene is also seen in cluster of ovarian cancer, breat cancer, renal cancer, prostate cancer, CNS cancer cell lines, as well as in placenta, mammary glands, liver, trachea, stomach, colorectal, and heart. Please see panel 1.4 for discussion and potential utility of this gene.


[0748] Panel 1.3D Summary: Ag554 Highest expression of the CG57829-01 gene is seen in breast cancer MDA-MB-231 cell line (CT=27.8). Expression pattern of this gene in this panel is similar to that of panel 1.4. Please see panel 1.4 for discussion and potential utility of this gene.


[0749] Panel 2.1 Summary: Ag3340 Highest expression of the CG57829-01 gene is seen in breast cancer metastasis sample (CT=28). As seen in panel 1.4, expression of this gene is associated with most cancers. Interestingly, expression of this gene seems to be down-regulated in kidney cancers (OD04340, OD04348, OD04450-01, 8120614) and colon metastasis to lung (OD04451-01) (CTs=35-40) compared to the marginal control samples (CTs=31-33). Therefore, expression of this gene can be used as potential marker to distinguishing between these cancer and normal tissues.


[0750] Please see panel 1.4 for discussion and potential utility of this gene.


[0751] Panel 2D Summary: Ag554 Highest expression of the CG57829-01 gene is seen in breast cancer metastasis (OD04590-03) sample (CT=27). As seen in panel 1.4, expression of this gene is associated with most cancers, with high expression in breast cancer samples. Please see panel 1.4 for discussion and potential utility of this gene.


[0752] Panel 3D Summary: Ag554 Highest expression of the CG57829-01 gene is seen in PANC-1-Pancreatic epithelioid ductal carcinoma sample (CT=28). As seen in panel 1.4, expression of this gene is associated with most cancers, with high expression in XF-CNS, small cell lung and pancreatic cancers. Please see panel 1.4 for discussion and potential utility of this gene.


[0753] Panel 4.1D Summary: Ag3340 CG57829-01 is highly induced in the mucoepidermoid cell line NCI-H292 by IL-4 and IL-13 (CTs=29-30). Expression is also high in lung fibroblasts treated with IL-4 or IL-13 and dermal fibroblasts treated with IL-4 (CTs=28-29). These findings are consistent in 3 separate runs with two sets of primers and probes.


[0754] Potential Role(s) of CG57829-01 in Inflammation: The protein encoded for by CG57892-01 has homology to ADAMTS family of molecules suggesting that it may function as an enzyme (see references in panel 1.4). The expression of this transcript by lung fibroblasts, the goblet cell like cell line NCI-H292 and dermal fibroblasts, particularly after exposure to IL-4 and IL-13 is consistent with it participating in diseases such as asthma, psoriasis, emphysema and arthritis (Ref. 1, 2). Based on its homology, it may contribute to the tissue destruction and remodeling processes associated with asthma, psoriasis, emphysema and arthritis.


[0755] Blocking the function of the protein encoded for by CG57892-01 with antagonistic antibody therapeutics could reduce or inhibit tissue destruction in the lungs, skin, or joints due to emphysema, allergy, asthma, psoriasis, or arthritis.


[0756] References.


[0757] 1. Laliberte R, Rouabhia M, Bosse M, Chakir J. Decreased capacity of asthmatic bronchial fibroblasts to degrade collagen. Matrix Biol January 2001;19(8):743-53


[0758] 2. Vankemmelbeke M N, Holen I, Wilson A, Ilic M Z, Handley C J, Kelner G S, Clark M, Liu C, Maki R A, Burnett D, Buttle D J. Expression and activity of ADAMTS-5 in synovium. Eur J Biochem March 2001;268(5):1259-68


[0759] Panel 4D Summary: Ag554/Ag3340 Expression pattern for the CG57829-01 gene is same as seen in panel 4.1D with highest expression in IL-4 Stimulated lung fibroblast (CT=26.7). Please see the panel 4.1D for discussion and potential utility of this gene.



F. NOV6a (CG59197-01: TULIP 2)

[0760] Expression of gene CG59197-01 was assessed using the primier-probe set Ag3391, described in Table FA. Results of the RTQ-PCR runs are shown in Tables FB, FC and FD.
293TABLE FAProbe Name Ag3391StartPrimersSequencesLengthPositionForward5′-cctgaactctttgagagtccaa-3′(SEQ ID NO:230)221146ProbeTET-5′-caaccttagtgtcctgtatccagatca-3′-TAMRA(SEQ ID NO:231)271195Reverse5′-ctccaggcatattctcttctga-3′(SEQ ID NO:232)221224


[0761]

294





TABLE FB










CNS_neurodegeneration_v1.0











Rel. Exp.(%) Ag3391,

Rel. Exp.(%) Ag3391,


Tissue Name
Run 210349173
Tissue Name
Run 210349173













AD 1 Hippo
9.5
Control (Path) 3
5.7




Temporal Ctx


AD 2 Hippo
24.5
Control (Path) 4
33.0




Temporal Ctx


AD 3 Hippo
5.4
AD 1 Occipital Ctx
15.0


AD 4 Hippo
4.3
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 Hippo
85.9
AD 3 Occipital Ctx
5.4


AD 6 Hippo
46.7
AD 4 Occipital Ctx
18.8


Control 2 Hippo
22.5
AD 5 Occipital Ctx
38.2


Control 4 Hippo
8.6
AD 6 Occipital Ctx
34.4


Control (Path) 3
9.4
Control 1 Occipital
6.8


Hippo

Ctx


AD 1 Temporal Ctx
19.3
Control 2 Occipital
60.7




Ctx


AD 2 Temporal Ctx
32.3
Control 3 Occipital
17.9




Ctx


AD 3 Temporal Ctx
5.7
Control 4 Occipital
7.3




Ctx


AD 4 Temporal Ctx
19.9
Control (Path) 1
97.3




Occipital Ctx


AD 5 Inf Temporal
100.0
Control (Path) 2
12.2


Ctx

Occipital Ctx


AD 5 Sup Temporal
43.5
Control (Path) 3
5.1


Ctx

Occipital Ctx


AD 6 Inf Temporal
53.2
Control (Path) 4
16.6


Ctx

Occipital Ctx


AD 6 Sup Temporal
59.9
Control 1 Parietal
8.9


Ctx

Ctx


Control 1 Temporal
7.0
Control 2 Parietal
41.8


Ctx

Ctx


Control 2 Temporal
35.6
Control 3 Parietal
17.6


Ctx

Ctx


Control 3 Temporal
14.6
Control (Path) 1
73.7


Ctx

Parietal Ctx


Control 3 Temporal
8.7
Control (Path) 2
26.2


Ctx

Parietal Ctx


Control (Path) 1
57.0
Control (Path) 3
6.7


Temporal Ctx

Parietal Ctx


Control (Path) 2
36.9
Control (Path) 4
44.4


Temporal Ctx

Parietal Ctx










[0762]

295





TABLE FC










General_screening_panel v1.4











Rel. Exp.(%) Ag3391,

Rel. Exp.(%) Ag3391,


Tissue Name
Run 216822195
Tissue Name
Run 216822195













Adipose
12.9
Renal ca. TK-10
25.9


Melanoma*
14.7
Bladder
30.6


Hs688(A).T


Melanoma*
14.3
Gastric ca. (liver met.)
30.6


Hs688(B).T

NCI-N87


Melanoma* M14
9.0
Gastric ca. KATO III
24.1


Melanoma*
12.0
Colon ca. SW-948
5.9


LOXIMVI


Melanoma* SK-
30.1
Colon ca. SW480
24.1


MEL-5


Squamous cell
6.9
Colon ca.* (SW480
20.9


carcinoma SCC-4

met) SW620


Testis Pool
16.0
Colon ca. HT29
7.2


Prostate ca.* (bone
35.6
Colon ca. HCT-116
39.8


met) PC-3


Prostate Pool
16.5
Colon ca. CaCo-2
24.1


Placenta
3.0
Colon cancer tissue
12.4


Uterus Pool
16.8
Colon ca. SW1116
7.6


Ovarian ca. OVCAR-3
24.5
Colon ca. Colo-205
2.2


Ovarian ca. SK-OV-3
54.3
Colon ca. SW-48
2.1


Ovarian ca. OVCAR-4
2.2
Colon Pool
36.9


Ovarian ca. OVCAR-5
49.0
Small Intestine Pool
44.4


Ovarian ca. IGROV-1
21.9
Stomach Pool
21.5


Ovarian ca. OVCAR-8
10.4
Bone Marrow Pool
18.8


Ovary
13.9
Fetal Heart
13.7


Breast ca. MCF-7
46.3
Heart Pool
18.0


Breast ca. MDA-
22.4
Lymph Node Pool
48.6


MB-231


Breast ca. BT 549
44.8
Fetal Skeletal Muscle
8.7


Breast ca. T47D
100.0
Skeletal Muscle Pool
21.2


Breast ca. MDA-N
9.3
Spleen Pool
17.9


Breast Pool
40.9
Thymus Pool
23.7


Trachea
17.4
CNS cancer (glio/astro)
18.6




U87-MG


Lung
11.3
CNS cancer (glio/astro)
40.6




U-118-MG


Fetal Lung
57.4
CNS cancer (neuro;met)
38.2




SK-N-AS


Lung ca. NCI-N417
6.2
CNS cancer (astro) SF-
7.5




539


Lung ca. LX-1
27.9
CNS cancer (astro)
35.6




SNB-75


Lung ca. NCI-H146
8.7
CNS cancer (glio) SNB-
21.3




19


Lung ca. SHP-77
46.7
CNS cancer (glio) SF-
35.6




295


Lung ca. A549
30.4
Brain (Amygdala) Pool
28.1


Lung ca. NCI-H526
5.8
Brain (cerebellum)
33.7


Lung ca. NCI-H23
50.0
Brain (fetal)
65.5


Lung ca. NCI-H460
25.0
Brain (Hippocampus)
29.3




Pool


Lung ca. HOP-62
10.8
Cerebral Cortex Pool
37.1


Lung ca. NCI-H522
26.2
Brain (Substantia nigra)
33.0




Pool


Liver
0.6
Brain (Thalamus) Pool
49.3


Fetal Liver
15.5
Brain (whole)
21.2


Liver ca. HepG2
45.1
Spinal Cord Pool
23.5


Kidney Pool
70.2
Adrenal Gland
16.3


Fetal Kidney
28.3
Pituitary gland Pool
10.7


Renal ca. 786-0
12.2
Salivary Gland
3.4


Renal ca. A498
3.6
Thyroid (female)
16.2


Renal ca. ACHN
8.4
Pancreatic ca. CAPAN2
18.8


Renal ca. UO-31
14.4
Pancreas Pool
47.6










[0763]

296





TABLE FD










Panel 4D











Rel. Exp.(%) Ag3391,

Rel. Exp.(%) Ag3391,


Tissue Name
Run 165296469
Tissue Name
Run 165296469













Secondary Th1 act
16.2
HUVEC IL-1 beta
8.4


Secondary Th2 act
20.3
HUVEC IFN gamma
17.3


Secondary Tr1 act
17.2
HUVEC TNF alpha + IFN
9.0




gamma


Secondary Th1 rest
8.8
HUVEC TNF alpha + IL4
8.2


Secondary Th2 rest
7.3
HUVEC IL-11
4.4


Secondary Tr1 rest
9.6
Lung Microvascular EC
14.5




none


Primary Th1 act
25.7
Lung Microvascular EC
10.6




TNF alpha + IL-1 beta


Primary Th2 act
24.8
Microvascular Dermal EC
14.9




none


Primary Tr1 act
39.2
Microsvasular Dermal EC
10.3




TNF alpha + IL-1 beta


Primary Th1 rest
54.3
Bronchial epithelium
17.9




TNF alpha + IL1 beta


Primary Th2 rest
31.6
Small airway epithelium
5.7




none


Primary Tr1 rest
29.9
Small airway epithelium
43.5




TNF alpha + IL-1 beta


CD45RA CD4
8.7
Coronery artery SMC rest
11.0


lymphocyte act


CD45RO CD4
16.6
Coronery artery SMC
6.4


lymphocyte act

TNF alpha + IL-1 beta


CD8 lymphocyte act
12.7
Astrocytes rest
8.8


Secondary CD8
13.6
AstrocytesTNF alpha + IL-
7.3


lymphocyte rest

1 beta


Secondary CD8
9.5
KU-812 (Basophil) rest
4.9


lymphocyte act


CD4 lymphocyte none
7.6
KU-812 (Basophil)
26.8




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
12.9
CCD1106 (Keratinocytes)
8.0


CD95 CH11

none


LAK cells rest
14.5
CCD1106 (Keratinocytes)
3.9




TNF alpha + IL-1 beta


LAK cells IL-2
16.4
Liver cirrhosis
4.0


LAK cells IL-2 + IL-12
18.7
Lupus kidney
3.6


LAK cells IL-2 + IFN
36.9
NCI-H292 none
29.9


gamma


LAK cells IL-2 + IL-18
33.4
NCI-H292 1L-4
50.3


LAK cells
18.9
NCI-H292 IL-9
34.2


PMA/ionomycin


NK Cells IL-2 rest
18.4
NCI-H292 IL-13
17.0


Two Way MLR 3 day
24.3
NCI-H292 IFN gamma
17.3


Two Way MLR 5 day
10.3
HPAEC none
8.0


Two Way MLR 7 day
7.5
HPAEC TNF alpha + IL-1
13.2




beta


PBMC rest
8.7
Lung fibroblast none
7.0


PBMC PWM
61.1
Lung fibroblast TNF
5.3




alpha + IL-1 beta


PBMC PHA-L
14.9
Lung fibroblast IL-4
14.6


Ramos (B cell) none
19.1
Lung fibroblast IL-9
15.8


Ramos (B cell)
100.0
Lung fibroblast IL-13
9.7


ionomycin


B lymphocytes PWM
65.1
Lung fibroblast IFN
17.4




gamma


B lymphocytes CD40L
24.7
Dermal fibroblast
21.5


and IL-4

CCD1070 rest


EOL-1 dbcAMP
7.7
Dermal fibroblast
63.7




CCD1070 TNF alpha


EOL-1 dbcAMP
12.4
Dermal fibroblast
8.5


PMA/ionomycin

CCD1070 IL-1 beta


Dendritic cells none
13.1
Dermal fibroblast IFN
6.1




gamma


Dendritic cells LPS
19.2
Dermal fibroblast IL-4
14.8


Dendritic cells anti-
12.3
IBD Colitis 2
2.1


CD40


Monocytes rest
14.8
IBD Crohn's
3.0


Monocytes LPS
29.9
Colon
23.2


Macrophages rest
18.8
Lung
11.0


Macrophages LPS
18.8
Thymus
34.9


HUVEC none
12.5
Kidney
25.2


HUVEC starved
28.9










[0764] CNS_neurodegeneration_v1.0 Summary: Ag3391 This panel confirms the expression of the CG59197-01 gene at significant levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.


[0765] General_screening_panel_v1.4 Summary: Ag3391 The CG59197-01 gene codes for a homologue of rat tuberin like protein, Tulip 2. Expression of this gene is ubiquitous in this panel, with highest expression in a breast cancer T47D cell line (CT=27). Expression of this gene appears to be higher in samples derived from breast, ovarian, prostate and melanoma cancer cell lines than in normal tissues. The widespread expression suggests that this gene product is involved in cell growth and proliferation. Thus, therapeutic modulation of the expression or function of this gene may be useful in the treatment of cancer.


[0766] Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract (CTs=28-34). Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity, and Types 1 and 2 diabetes.


[0767] Interestingly, this gene is expressed at much higher levels in fetal (CT=29.7) when compared to adult liver (CT=34.5). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver.


[0768] In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord (CTs=27-29). Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.


[0769] Panel 4D Summary: Ag3391 Highest expression of the CG59197-01 gene is seen in ionomycin treated Ramos B cells (CT=27.6). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_v1.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.


[0770] In addition, expression of this gene is up-regulated in TNFalpha+IL-1beta-treated small airway epithelium, and PWM-treated PBMC (CTs=28) as compared to the untreated counterparts (CTs=31). Thus, expression of this gene may be used to distinguish between cytokine-treated small airway epithelium and PWM-treated PBMC cells from their untreated counterparts.



G. NOV9a (CC58180-01: PROHIBITION)

[0771] Expression of gene CG58180-01 was assessed using the primer-probe set Ag3515, described in Table GA. Results of the RTQ-PCR runs are shown in Tables GB, GC and GD.
297TABLE GAProbe Name Ag3515StartPrimersSequencesLengthPositionForward5′-gcctttctccaccacgtaa-3′(SEQ ID NO:233)19223ProbeTET-5′-tgtaccaatcatcactggtagcaaaga-3′-TAMRA(SEQ ID NO:234)27242Reverse5′-caacaggctggaagatgatg-3′(SEQ ID NO:235)20296


[0772]

298





TABLE GB










CNS_neurodegeneration_v1.0











Rel. Exp.(%) Ag3515,

Rel. Exp.(%) Ag3515,


Tissue Name
Run 210499747
Tissue Name
Run 210499747













AD 1 Hippo
12.4
Control (Path) 3
6.5




Temporal Ctx


AD 2 Hippo
26.8
Control (Path) 4
40.1




Temporal Ctx


AD 3 Hippo
8.2
AD 1 Occipital Ctx
18.7


AD 4 Hippo
11.0
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 hippo
71.7
AD 3 Occipital Ctx
19.3


AD 6 Hippo
100.0
AD 4 Occipital Ctx
36.6


Control 2 Hippo
15.3
AD 5 Occipital Ctx
15.1


Control 4 Hippo
21.9
AD 6 Occipital Ctx
31.4


Control (Path) 3
12.9
Control 1 Occipital
6.4


Hippo

Ctx


AD 1 Temporal Ctx
26.4
Control 2 Occipital
33.0




Ctx


AD 2 Temporal Ctx
42.6
Control 3 Occipital
45.7




Ctx


AD 3 Temporal Ctx
14.9
Control 4 Occipital
5.0




Ctx


AD 4 Temporal Ctx
48.3
Control (Path) 1
95.3




Occipital Ctx


AD 5 Inf Temporal Ctx
73.7
Control (Path) 2
27.7


Ctx

Occipital Ctx


AD 5 Sup Temporal
55.5
Control (Path) 3
3.5


Ctx

Occipital Ctx


AD 6 Inf Temporal
47.3
Control (Path) 4
36.1


Ctx

Occipital Ctx


AD 6 Sup Temporal
69.7
Control 1 Parietal
19.8


Ctx

Ctx


Control 1 Temporal
12.2
Control 2 Parietal
50.0


Ctx

Ctx


Control 2 Temporal
11.0
Control 3 Parietal
18.4


Ctx

Ctx


Control 3 Temporal
13.8
Control (Path) 1
47.0


Ctx

Parietal Ctx


Control 4 Temporal
11.7
Control (Path) 2
48.0


Ctx

Parietal Ctx


Control (Path) 1
51.4
Control (Path) 3
5.6


Temporal Ctx

Parietal Ctx


Control (Path) 2
55.9
Control (Path) 4
56.3


Temporal Ctx

Parietal Ctx










[0773]

299





TABLE GC










General_screening_panel_v1.4











Rel. Exp.(%) Ag3515,

Rel. Exp.(%) Ag3515,


Tissue Name
Run 216709850
Tissue Name
Run 216709850













Adipose
3.6
Renal ca. TK-10
21.6


Melanoma*
12.5
Bladder
46.3


Hs688(A).T


Melanoma*
12.0
Gastric ca. (liver met.)
57.4


Hs688(B).T

NCI-N87


Melanoma* M14
7.4
Gastric ca. KATO III
25.7


Melanoma*
7.3
Colon ca. SW-948
3.9


LOXIMVI


Melanoma* SK-
18.0
Colon ca. SW480
34.6


MEL-5


Squamous cell
5.2
Colon ca.* (SW480
37.4


carcinoma SCC-4

met) SW620


Testis Pool
6.5
Colon ca. HT29
15.4


Prostate ca.* (bone
6.1
Colon ca. HCT-116
49.7


met) PC-3


Prostate Pool
15.6
Colon ca. CaCo-2
51.1


Placenta
8.8
Colon cancer tissue
20.6


Uterus Pool
6.7
Colon ca. SW1116
6.0


Ovarian ca. OVCAR-3
12.2
Colon ca. Colo-205
3.0


Ovarian ca. SK-OV-3
46.3
Colon ca. SW-48
2.1


Ovarian ca. OVCAR-4
6.0
Colon Pool
30.4


Ovarian ca. OVCAR-5
27.0
Small Intestine Pool
35.1


Ovarian ca. IGROV-1
6.3
Stomach Pool
20.4


Ovarian ca. OVCAR-8
2.8
Bone Marrow Pool
15.4


Ovary
17.9
Fetal Heart
17.7


Breast ca. MCF-7
0.0
Heart Pool
9.3


Breast ca. MDA-
10.3
Lymph Node Pool
40.9


MB-231


Breast ca. BT 549
28.3
Fetal Skeletal Muscle
15.9


Breast ca. T47D
28.1
Skeletal Muscle Pool
13.8


Breast ca. MDA-N
4.9
Spleen Pool
20.9


Breast Pool
43.8
Thymus Pool
40.1


Trachea
25.3
CNS cancer (glio/astro)
29.3




U87-MG


Lung
9.2
CNS cancer (glio/astro)
39.2




U-118-MG


Fetal Lung
50.0
CNS cancer (neuro;met)
30.4




SK-N-AS


Lung ca. NCI-N417
2.0
CNS cancer (astro) SF-
5.1




539


Lung ca. LX-1
44.1
CNS cancer (astro)
3.4




SNB-75


Lung ca. NCI-H146
4.6
CNS cancer (glio) SNB-
8.4




19


Lung ca. SHP-77
27.4
CNS cancer (glio) SF-
41.5




295


Lung ca. A549
26.8
Brain (Amygdala) Pool
5.8


Lung ca. NCI-H526
1.7
Brain (cerebellum)
20.6


Lung ca. NCI-H23
100.0
Brain (fetal)
23.7


Lung ca. NCI-H460
27.5
Brain (Hippocampus)
9.1




Pool


Lung ca. HOP-62
16.5
Cerebral Cortex Pool
12.1


Lung ca. NCI-H522
30.4
Brain (Substantia nigra)
8.1




Pool


Liver
0.4
Brain (Thalamus) Pool
8.5


Fetal Liver
6.6
Brain (whole)
8.9


Liver ca. HepG2
10.3
Spinal Cord Pool
7.2


Kidney Pool
40.1
Adrenal Gland
5.8


Fetal Kidney
60.3
Pituitary gland Pool
3.9


Renal ca. 786-0
0.0
Salivary Gland
6.7


Renal ca. A498
1.8
Thyroid (female)
3.3


Renal ca. ACHN
25.9
Pancreatic ca. CAPAN2
52.5


Renal ca. UO-31
12.5
Pancreas Pool
43.8










[0774]

300





TABLE GD










Panel 4D











Rel. Exp.(%) Ag3515,

Rel. Exp.(%) Ag3515,


Tissue Name
Run 166407127
Tissue Name
Run 166407127













Secondary Th1 act
21.3
HUVEC IL-1 beta
4.8


Secondary Th2 act
32.3
HUVEC IFN gamma
20.2


Secondary Tr1 act
46.7
HUVEC TNF alpha + IFN
5.8




gamma


Secondary Th1 rest
22.2
HUVEC TNF alpha + IL4
9.5


Secondary Th2 rest
20.7
HUVEC IL-11
14.7


Secondary Tr1 rest
28.3
Lung Microvascular EC
13.9




none


Primary Th1 act
15.6
Lung Microvascular EC
15.4




TNF alpha + IL-1 beta


Primary Th2 act
29.5
Microvascular Dermal EC
19.5




none


Primary Tr1 act
38.2
Microsvasular Dermal EC
11.7




TNF alpha + IL-1 beta


Primary Th1 rest
100.0
Bronchial epithelium
6.5




TNF alpha + IL1 beta


Primary Th2 rest
46.7
Small airway epithelium
4.9




none


Primary Tr1 rest
35.4
Small airway epithelium
24.3




TNF alpha + IL-1 beta


CD45RA CD4
13.0
Coronery artery SMC rest
4.4


lymphocyte act


CD45RO CD4
29.9
Coronery artery SMC
3.5


lymphocyte act

TNF alpha + IL-1 beta


CD8 lymphocyte act
24.3
Astrocytes rest
19.6


Secondary CD8
23.0
Astrocytes TNF alpha + IL-
24.3


lymphocyte rest

1 beta


Secondary CD8
19.8
KU-812 (Basophil) rest
15.2


lymphocyte act


CD4 lymphocyte none
14.7
KU-812 (Basophil)
32.8




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
41.5
CCD1106 (Keratinocytes)
16.4


CD95 CH11

none


LAK cells rest
13.9
CCD1106 (Keratinocytes)
62.9




TNF alpha + IL-1 beta


LAK cells IL-2
32.8
Liver cirrhosis
6.4


LAK cells IL-2 + IL-12
32.3
Lupus kidney
18.0


LAK cells IL-2 + IFN
49.0
NCI-H292 none
35.8


gamma


LAK cells IL-2 + IL-18
36.1
NCI-H292 IL-4
29.7


LAK cells
11.7
NCI-H292 IL-9
31.4


PMA/ionomycin


NK Cells IL-2 rest
28.9
NCI-H292 IL-13
26.8


Two Way MLR 3 day
38.2
NCI-H292 IFN gamma
17.2


Two Way MLR 5 day
12.1
HPAEC none
8.3


Two Way MLR 7 day
15.7
HPAEC TNF alpha + IL-1
17.7




beta


PBMC rest
8.5
Lung fibroblast none
22.4


PBMC PWM
25.2
Lung fibroblast TNF
9.9




alpha + IL-1 beta


PBMC PHA-L
10.5
Lung fibroblast IL-4
15.4


Ramos (B cell) none
51.4
Lung fibroblast IL-9
12.0


Ramos (B cell)
17.3
Lung fibroblast IL-13
16.7


ionomycin


B lymphocytes PWM
18.6
Lung fibroblast IFN
11.3




gamma


B lymphocytes CD40L
49.0
Dermal fibroblast
24.5


and IL-4

CCD1070 rest


EOL-1 dbcAMP
28.3
Dermal fibroblast
50.3




CCD1070 TNF alpha


EOL-1 dbcAMP
50.7
Dermal fibroblast
14.6


PMA/ionomycin

CCD1070 IL-1 beta


Dendritic cells none
19.6
Dermal fibroblast IFN
10.6




gamma


Dendritic cells LPS
23.0
Dermal fibroblast IL-4
19.8


Dendritic cells anti-
19.1
IBD Colitis 2
5.8


CD40


Monocytes rest
47.6
IBD Crohn's
3.8


Monocytes LPS
16.8
Colon
61.6


Macrophages rest
20.7
Lung
9.3


Macrophages LPS
7.1
Thymus
32.1


HUVEC none
12.9
Kidney
54.0


HUVEC starved
22.8










[0775] CNS_neurodegeneration_v1.0 Summary: Ag3515 This panel does not show differential expression of the CG58180-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.


[0776] General_screening_panel_v1.4 Summary: Ag3515 - Highest expression of the CG58180-01 gene is detected in lung cancer NCI-H23 cell line (CT=28.3). Expression of this gene is associated with gastric, pancreatic, brain, colon, renal, lung, breast, ovarian and prostate cancers, as well as, melanomas. This gene is a homologue of the human prohibitin (PHB), which has been found to be mutated in hereditary breast cancer (Ref. 1). Thus, expression of this gene could be used as a diagnostic marker for the presence of these cancers. Furthermore, therapeutic modulation of the activity of this gene using antibodies or small molecule drugs might be of use in the treatment of these cancers.


[0777] In addition, this gene is expressed at significant levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.


[0778] This gene product is also expressed in adipose, pancreas, adrenal, thyroid, pituitary, skeletal muscle, heart, and liver. This widespread expression in tissues with metabolic function suggests that this gene product may be important for the pathogenesis, diagnosis, and/or treatment of metabolic and endocrine diseases, including obesity and Types 1 and 2 diabetes.


[0779] References


[0780] 1. Sato T, Saito 1-1, Swenseni J, Olifant A, Wood C, Danner D, Sakamoto Tr, Takita K, Kasumi F, Miki Y, et al. The human prohibitin gene located on chromosome 17q21 is mutated in sporadic breast cancer.: Cancer Res Mar. 15, 1992;52(6):1643-6.


[0781] Panel 4D Summary: Ag3515 - The CG58180-01 gene is expressed at low to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monolytic, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.



H. NOV11a and NOV11b (CG59249-01 and CG59249-02: METALLAPROTEINASE-DISINTEGRIN BETA)

[0782] Expression of gene CG59249-01 and CG59249-02 was assessed using the primer-probe set Ag1930, described in Table HA. Results of the RTQ-PCR runs are shown in Table HB.
301TABLE HAProbe Name Ag1930StartPrimersSequencesLengthPositionForward5′-tatgcagtgtcaagccctttt-3′(SEQ ID NO:236)211558ProbeTET-5′-ctaccaagtgaaagacggttccccag-3′-TAMRA(SEQ ID NO:237)261582Reverse5′-agtttccaaatcggttaccaat-3′(SEQ ID NO:238)221631


[0783]

302





TABLE HB










Panel 4D











Rel. Exp.(%) Ag1930,

Rel. Exp.(%) Ag1930,


Tissue Name
Run 160658070
Tissue Name
Run 160658070













Secondary Th1 act
6.5
HUVEC IL-1 beta
1.1


Secondary Th2 act
4.4
HUVEC IFN gamma
11.6


Secondary Tr1 act
4.6
HUVEC TNF alpha + IFN
5.6




gamma


Secondary Th1 rest
4.1
HUVEC TNF alpha + IL4
12.8


Secondary Th2 rest
4.2
HUVEC IL-11
14.7


Secondary Tr1 rest
2.0
Lung Microvascular EC
14.9




none


Primary Th1 act
3.6
Lung Microvascular EC
12.0




TNF alpha + IL-1 beta


Primary Th2 act
1.2
Microvascular Dermal EC
20.9




none


Primary Tr1 act
3.5
Microsvasular Dermal EC
11.5




TNF alpha + IL-1 beta


Primary Th1 rest
12.1
Bronchial epithelium
5.4




TNF alpha + IL1 beta


Primary Th2 rest
13.9
Small airway epithelium
31.4




none


Primary Tr1 rest
9.4
Small airway epithelium
100.0




TNF alpha + IL-1 beta


CD45RA CD4
3.6
Coronery artery SMC rest
6.1


lymphocyte act


CD45RO CD4
8.9
Coronery artery SMC
10.3


lymphocyte act

TNF alpha + IL-1 beta


CD8 lymphocyte act
1.7
Astrocytes rest
28.7


Secondary CD8
13.5
Astrocytes TNF alpha + IL-
21.8


lymphocyte rest

1 beta


Secondary CD8
3.4
KU-812 (Basophil) rest
36.6


lymphocyte act


CD4 lymphocyte none
16.6
KU-812 (Basophil)
84.7




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
3.6
CCD1106 (Keratinocytes)
10.3


CD95 CH11

none


LAK cells rest
11.9
CCD1106 (Keratinocytes)
1.6




TNF alpha + IL-1 beta


LAK cells IL-2
14.4
Liver cirrhosis
32.5


LAK cells IL-2 + IL-12
17.9
Lupus kidney
20.9


LAK cells IL-2 + IFN
32.3
NCI-H292 none
38.7


gamma


LAK cells IL-2 + IL-18
35.6
NCI-H292 IL-4
16.4


LAK cells
1.4
NCI-H292 IL-9
53.2


PMA/ionomycin


NK Cells IL-2 rest
5.2
NCI-H292 IL-13
8.2


Two Way MLR 3 day
27.9
NCI-H292 IFN gamma
21.3


Two Way MLR 5 day
7.7
HPAEC none
4.1


Two Way MLR 7 day
8.2
HPAEC TNF alpha + IL-1
8.2




beta


PBMC rest
7.0
Lung fibroblast none
21.3


PBMC PWM
47.0
Lung fibroblast TNF
10.7




alpha + IL-1 beta


PBMC PHA-L
10.3
Lung fibroblast IL-4
17.0


Ramos (B cell) none
3.1
Lung fibroblast IL-9
24.0


Ramos (B cell)
20.2
Lung fibroblast IL-13
4.5


ionomycin


B lymphocytes PWM
11.1
Lung fibroblast IFN
11.8




gamma


B lymphocytes CD40L
19.2
Dermal fibroblast
14.0


and IL-4

CCD1070 rest


EOL-1 dbcAMP
36.9
Dermal fibroblast
37.4




CCD1070 TNF alpha


EOL-1 dbcAMP
47.3
Dermal fibroblast
5.6


PMA/ionomycin

CCD1070 IL-1 beta


Dendritic cells none
11.0
Dermal fibroblast IFN
7.1




gamma


Dendritic cells LPS
8.8
Dermal fibroblast IL-4
21.5


Dendritic cells anti-
27.5
IBD Colitis 2
7.9


CD40


Monocytes rest
4.0
IBD Crohn's
2.6


Monocytes LPS
3.3
Colon
25.5


Macrophages rest
6.3
Lung
4.4


Macrophages LPS
8.5
Thymus
29.7


HUVEC none
2.6
Kidney
100.0


HUVEC starved
12.2










[0784] Panel 4D Summary: Ag1930 The CG3CG59249-01 gene is widely expressed among the samples in this panel, with highest expression of this gene in the kidney and small airway epithelium treated with TNF-alpha and IL-1 beta (CTs=32). Low but significant levels of expression are also seen in both treated and untreated samples derived from the basophil cell line KU-812, the pulmonary mucoepidermoid cell line NCI-H292, LAK cells and eosinophils. This pattern of expression in a variety of cell types of significance in the immune response in health and disease suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosis, psoriasis, rheumatoid arthritis, and osteoarthritis.



I. NOV12a (CG58577-01: CASPR4)

[0785] Expression of gene CG58577-01 was assessed using the primer-probe set Ag3377, described in Table IA. Results of the RTQ-PCR runs are shown in Tables IB, IC, ID and IE.
303TABLE IAProbe Name Ag3377StartPrimerSequencesLengthPositionForward5′-cacagcattatccggagtttt-3′(SEQ ID NO:239)212372ProbeTET-5′-tggcattaaagacttcattcgactcga-3′-TAMRA(SEQ ID NO:240)272435Reverse5′-ggtgatctctgaaggagagctt-3′(SEQ ID NO:241)222435


[0786]

304





TABLE IB










CNS_neurodegeneration_v1.0











Rel. Exp.(%) Ag3377,

Rel. Exp.(%) Ag3377,


Tissue Name
Run 210154572
Tissue Name
Run 210154572













AD 1 Hippo
6.9
Control (Path) 3
2.4




Temporal Ctx


AD 2 Hippo
23.3
Control (Path) 4
41.8




Temporal Ctx


AD 3 Hippo
3.2
AD 1 Occipital Ctx
9.9


AD 4 Hippo
2.7
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 Hippo
79.0
AD 3 Occipital Ctx
3.7


AD 6 Hippo
31.0
AD 4 Occipital Ctx
11.2


Control 2 Hippo
28.7
AD 5 Occipital Ctx
47.3


Control 4 Hippo
2.8
AD 6 Occipital Ctx
20.3


Control (Path) 3
2.7
Control 1 Occipital
1.2


Hippo

Ctx


AD 1 Temporal Ctx
7.4
Control 2 Occipital
92.0




Ctx


AD 2 Temporal Ctx
40.6
Control 3 Occipital
14.9




Ctx


AD 3 Temporal Ctx
2.4
Control 4 Occipital
2.4




Ctx


AD 4 Temporal Ctx
11.5
Control (Path) 1
100.0




Occipital Ctx


AD 5 Inf Temporal
68.8
Control (Path) 2
14.7


Ctx

Occipital Ctx


AD 5 Sup Temporal
20.6
Control (Path) 3
1.2


Ctx

Occipital Ctx


AD 6 Inf Temporal
22.4
Control (Path) 4
15.0


Ctx

Occipital Ctx


AD 6 Sup Temporal
21.8
Control 1 Parietal
3.7


Ctx

Ctx


Control 1 Temporal
4.9
Control 2 Parietal
18.3


Ctx

Ctx


Control 2 Temporal
33.9
Control 3 Parietal
11.6


Ctx

Ctx


Control 3 Temporal
9.8
Control (Path) 1
87.1


Ctx

Parietal Ctx


Control 3 Temporal
26.2
Control (Path) 2
37.4


Ctx

Parietal Ctx


Control (Path) 1
61.1
Control (Path) 3
1.8


Temporal Ctx

Parietal Ctx


Control (Path) 2
26.4
Control (Path) 4
24.8


Temporal Ctx

Parietal Ctx










[0787]

305





TABLE IC










Panel 1.3D











Rel. Exp.(%) Ag3377,

Rel. Exp.(%) Ag3377,


Tissue Name
Run 165674254
Tissue Name
Run 165674254













Liver adenocarcinoma
0.0
Kidney (fetal)
0.0


Pancreas
0.0
Renal ca. 786-0
0.0


Pancreatic ca. CAPAN2
0.0
Renal ca. A498
0.0


Adrenal gland
0.0
Renal ca. RXF 393
0.0


Thyroid
0.0
Renal ca. ACHN
0.0


Salivary gland
0.0
Renal ca. UO-31
0.0


Pituitary gland
2.8
Renal ca. TK-10
0.0


Brain (fetal)
40.6
Liver
0.0


Brain (whole)
97.9
Liver (fetal)
0.0


Brain (amygdala)
64.2
Liver ca.
0.0




(hepatoblast) HepG2


Brain (cerebellum)
50.7
Lung
0.0


Brain (hippocampus)
72.2
Lung (fetal)
0.0


Brain (substantia nigra)
22.5
Lung ca. (small cell)
0.0




LX-1


Brain (thalamus)
100.0
Lung ca. (small cell)
0.0




NCI-H69


Cerebral Cortex
91.4
Lung ca. (s.cell var.)
39.8




SHP-77


Spinal cord
4.8
Lung ca. (large
0.0




cell) NCI-H460


glio/astro U87-MG
0.0
Lung ca. (non-sm.
0.0




cell) A549


glio/astro U-118-MG
0.0
Lung ca. (non-s.cell)
0.0




NCI-H23


astrocytoma SW1783
0.0
Lung ca. (non-s.cell)
0.0




HOP-62


neuro*; met SK-N-AS
28.9
Lung ca. (non-s.cl)
0.0




NCI-H522


astrocytoma SF-539
0.0
Lung ca. (squam.)
0.0




SW 900


astrocytoma SNB-75
0.0
Lung ca. (squam.)
0.0




NCI-H596


glioma SNB-19
0.0
Mammary gland
1.7


glioma U251
0.0
Breast ca.* (pl.ef)
0.0




MCF-7


glioma SF-295
0.0
Breast ca.* (pl.ef)
0.0




MDA-MB-231


Heart (fetal)
0.0
Breast ca.* (pl.ef)
0.0




T47D


Heart
0.0
Breast ca. BT-549
0.0


Skeletal muscle (fetal)
4.0
Breast ca. MDA-N
0.0


Skeletal muscle
0.0
Ovary
0.0


Bone marrow
0.0
Ovarian ca. OVCAR-3
0.0


Thymus
0.0
Ovarian ca. OVCAR-4
0.0


Spleen
1.2
Ovarian ca. OVCAR-5
0.0


Lymph node
0.0
Ovarian ca. OVCAR-8
0.0


Colorectal
0.0
Ovarian ca. IGROV-1
0.0


Stomach
0.0
Ovarian ca.* (ascites)
0.0




SK-OV-3


Small intestine
2.0
Uterus
0.0


Colon ca. SW480
0.0
Placenta
0.0


Colon ca.*
0.0
Prostate
0.0


SW620(SW480 met)


Colon ca. HT29
0.0
Prostate ca.* (bone
0.0




met) PC-3


Colon ca. HCT-116
0.0
Testis
0.0


Colon ca. CaCo-2
0.0
Melanoma
0.0




Hs688(A).T


Colon ca.
0.0
Melanoma* (met)
0.0


tissue (ODO3866)

Hs688(B).T


Colon ca. HCC-2998
0.0
Melanoma UACC-62
0.0


Gastric ca.* (liver met)
1.8
Melanoma M14
0.0


NCI-N87


Bladder
0.0
Melanoma LOX
0.0




IMVI


Trachea
0.0
Melanoma* (met)
0.0




SK-MEL-5


Kidney
0.0
Adipose
0.0










[0788]

306





TABLE ID










Panel 4D











Rel. Exp.(%) Ag3377,

Rel. Exp.(%) Ag3377,


Tissue Name
Run 165296551
Tissue Name
Run 165296551













Secondary Th1 act
0.0
HUVEC IL-1 beta
0.0


Secondary Th2 act
0.0
HUVEC IFN gamma
0.0


Secondary Tr1 act
0.0
HUVEC TNF alpha + IFN
0.0




gamma


Secondary Th1 rest
0.0
HUVEC TNF alpha + IL4
0.0


Secondary Th2 rest
0.0
HUVEC IL-11
0.0


Secondary Tr1 rest
0.0
Lung Microvascular EC
0.0




none


Primary Th1 act
0.0
Lung Microvascular EC
0.0




TNF alpha + IL-1 beta


Primary Th2 act
0.0
Microvascular Dermal EC
6.7




none


Primary Tr1 act
0.0
Microsvasular Dermal EC
0.0




TNF alpha + IL-1 beta


Primary Th1 rest
0.0
Bronchial epithelium
0.0




TNF alpha + IL1 beta


Primary Th2 rest
0.0
Small airway epithelium
0.0




none


Primary Tr1 rest
0.0
Small airway epithelium
0.0




TNF alpha + IL-1 beta


CD45RA CD4
0.0
Coronery artery SMC rest
100.0


lymphocyte act


CD45RO CD4
0.0
Coronery artery SMC
70.7


lymphocyte act

TNF alpha + IL-1 beta


CD8 lymphocyte act
0.0
Astrocytes rest
0.0


Secondary CD8
0.0
Astrocytes TNF alpha + IL-
0.0


lymphocyte rest

1 beta


Secondary CD8
0.0
KU-812 (Basophil) rest
0.0


lymphocyte act


CD4 lymphocyte none
0.0
KU-812 (Basophil)
0.0




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
0.0
CCD1106 (Keratinocytes)
0.0


CD95 CH11

none


LAK cells rest
0.0
CCD1106 (Keratinocytes)
0.0




TNF alpha + IL-1 beta


LAK cells IL-2
0.0
Liver cirrhosis
0.0


LAK cells IL-2 + IL-12
0.0
Lupus kidney
0.0


LAK cells IL-2 + IFN
0.0
NCI-H292 none
0.0


gamma


LAK cells IL-2 + IL-18
0.0
NCI-H292 IL-4
0.0


LAK cells
0.0
NCI-H292 IL-9
0.0


PMA/ionomycin


NK Cells IL-2 rest
0.0
NCI-H292 IL-13
0.0


Two Way MLR 3 day
0.0
NCI-H292 IFN gamma
0.0


Two Way MLR 5 day
0.0
HPAEC none
0.0


Two Way MLR 7 day
0.0
HPAEC TNF alpha + IL-1
0.0




beta


PBMC rest
0.0
Lung fibroblast none
0.0


PBMC PWM
0.0
Lung fibroblast TNF
0.0




alpha + IL-1 beta


PBMC PHA-L
0.0
Lung fibroblast IL-4
0.0


Ramos (B cell) none
0.0
Lung fibroblast IL-9
0.0


Ramos (B cell)
0.0
Lung fibroblast IL-13
0.0


ionomycin


B lymphocytes PWM
0.0
Lung fibroblast IFN
0.0




gamma


B lymphocytes CD40L
0.0
Dermal fibroblast
0.0


and IL-4

CCD1070 rest


EOL-1 dbcAMP
0.0
Dermal fibroblast
0.0




CCD1070 TNF alpha


EOL-1 dbcAMP
0.0
Dermal fibroblast
0.0


PMA/ionomycin

CCD1070 IL-1 beta


Dendritic cells none
0.0
Dermal fibroblast IFN
0.0




gamma


Dendritic cells LPS
0.0
Dermal fibroblast IL-4
0.0


Dendritic cells anti-
0.0
IBD Colitis 2
5.3


CD40


Monocytes rest
0.0
IBD Crohn's
0.0


Monocytes LPS
0.0
Colon
9.0


Macrophages rest
0.0
Lung
0.0


Macrophages LPS
0.0
Thymus
81.8


HUVEC none
0.0
Kidney
47.3


HUVEC starved
0.0










[0789]

307





TABLE IE










Panel CNS_1











Rel. Exp.(%) Ag3377,

Rel. Exp.(%) Ag3377,


Tissue Name
Run 171787512
Tissue Name
Run 171787512













BA4 Control
16.7
BA17 PSP
40.3


BA4 Control2
67.4
BA17 PSP2
20.0


BA4
3.4
Sub Nigra Control
38.2


Alzheimer's2


BA4 Parkinson's
29.1
Sub Nigra Control2
54.7


BA4
94.6
Sub Nigra
14.5


Parkinson's2

Alzheimer's2


BA4
42.3
Sub Nigra
34.4


Huntington's

Parkinson's2


BA4
7.1
Sub Nigra
60.3


Huntington's2

Huntington's


BA4 PSP
6.8
Sub Nigra
29.1




Huntington's2


BA4 PSP2
39.8
Sub Nigra PSP2
3.0


BA4 Depression
17.3
Sub Nigra
4.2




Depression


BA4
3.2
Sub Nigra
8.3


Depression2

Depression2


BA7 Control
60.3
Glob Palladus
1.4




Control


BA7 Control2
42.0
Glob Palladus
3.0




Control2


BA7
9.4
Glob Palladus
15.5


Alzheimer's2

Alzheimer's


BA7 Parkinson's
21.5
Glob Palladus
2.9




Alzheimer's2


BA7
80.1
Glob Palladus
54.7


Parkinson's2

Parkinson's


BA7
74.7
Glob Palladus
1.7


Huntington's

Parkinson's2


BA7
42.0
Glob Palladus PSP
0.0


Huntington's2


BA7 PSP
40.1
Glob Palladus PSP2
2.7


BA7 PSP2
24.1
Glob Palladus
3.1




Depression


BA7 Depression
15.7
Temp Pole Control
14.0


BA9 Control
29.5
Temp Pole Control2
87.1


BA9 Control2
100.0
Temp Pole
1.2




Alzheimer's


BA9 Alzheimer's
3.0
Temp Pole
9.7




Alzheimer's2


BA9
21.6
Temp Pole
25.7


Alzheimer's2

Parkinson's


BA9 Parkinson's
39.5
Temp Pole
21.9




Parkinson's2


BA9
74.7
Temp Pole
48.0


Parkinson's2

Huntington's


BA9
62.0
Temp Pole PSP
1.7


Huntington's


BA9
2.6
Temp Pole PSP2
3.6


Huntington's2


BA9 PSP
10.8
Temp Pole
10.3




Depression2


BA9 PSP2
1.6
Cing Gyr Control
99.3


BA9 Depression
8.2
Cing Gyr Control2
57.4


BA9
9.0
Cing Gyr Alzheimer's
18.6


Depression2


BA17 Control
88.9
Cing Gyr
4.3




Alzheimer's2


BA17 Control2
84.1
Cing Gyr Parkinson's
11.0


BA17
6.1
Cing Gyr
24.5


Alzheimer's2

Parkinson's2


BA17
56.3
Cing Gyr
62.9


Parkinson's

Huntington's


BA17
80.1
Cing Gyr
11.1


Parkinson's2

Huntington's2


BA17
89.5
Cing Gyr PSP
17.1


Huntington's


BA17
25.2
Cing Gyr PSP2
1.4


Huntington's2


BA17
7.6
Cing Gyr Depression
4.3


Depression


BA17
18.7
Cing Gyr
9.8


Depression2

Depression2










[0790] CNS_neurodegeneration_v1.0 Summary: Ag3377 This panel confirms the expression of the CG58577-01 gene at low levels in the brain in an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.3D for a discussion of the potential utility of this gene in treatment of central nervous system disorders.


[0791] Panel 1.3D Summary: Ag3377 Expression of the CG58577-01 gene is seen almost exclusively in the brain. The highest level of expression is in the thalamus (CT=3 1.0), with low to moderate expression in amygdala, substanitia nigra, cerebellum, hippocampus and cerebral cortex. This gene encodes a protein homologous to the mouse Caspr4 protein. The Caspr proteins are contactin-associated transmembrane receptors that may function with contactin, in the recruitment and activation of neural intracellular signaling pathways. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.


[0792] There is also low levels of expression in lung cancer cell line SHP-77 and neuroblastoma cancer cell line SK-N-AS (CTs=32). Therefore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of lung cancer or neuroblastoma cancer.


[0793] References


[0794] 1. Peles E, Nativ M, Lustig M, Grumet M, Schilling J, Martinez R, Plowman G D, Schlessinger J. (1997) Identification of a novel contactin-associated transmembrane receptor with multiple domains implicated in protein-protein interactions. EMBO J 16(5):978-88.


[0795] Panel 4D Summary: Ag3377 Significant expression of the CG58577-01 gene is seen only in coronary artery, thymus, and kidney (CTs=33-34.8). Therefore expression of this gene can be used to distinguish between these samples and others on this panel. In addition, therapeutic modulation of the activity of the CASPR protein encoded by this gene may be useful in the treatment of asthma, restenosis, arthritis, systemic lupus erythematosus and kidney disorders.


[0796] Panel CNS1 Summary: Ag3377—This panel confirms the expression of this gene at significant levels in the brain in an independent group of individuals. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.



J. NOV14 (CG58575-01: PHOSPHATIDYLSERINE SYNTHASE-2)

[0797] Expression of gene CG58575-01 was assessed using the primer-probe set Ag3376, described in Table JA. Results of the RTQ-PCR runs are shown in Tables JB, JC, JD and JE.
308TABLE JAProbe Name Ag3376StartPrimerSequencesLengthPositionForward5′-atctacgacccagacaatgaga-3′(SEQ ID NO:242)22592ProbeTET-5′-cccctttcacaacatctgggacaagt-3′-TAMRA(SEQ ID NO:243)26618Reverse5′-tcaggtaccagccaagaaagt-3′(SEQ ID NO:244)21665


[0798]

309





TABLE JB










CNS_neurodegeneration_v1.0











Rel. Exp.(%) Ag3376,

Rel. Exp.(%) Ag3376,


Tissue Name
Run 210154240
Tissue Name
Run 210154240













AD 1 Hippo
18.8
Control (Path) 3
6.1




Temporal Ctx


AD 2 Hippo
48.3
Control (Path) 4
18.8




Temporal Ctx


AD 3 Hippo
7.6
AD 1 Occipital Ctx
14.5


AD 4 Hippo
11.2
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 hippo
60.7
AD 3 Occipital Ctx
6.8


AD 6 Hippo
38.7
AD 4 Occipital Ctx
17.4


Control 2 Hippo
24.1
AD 5 Occipital Ctx
17.7


Control 4 Hippo
13.6
AD 6 Occipital Ctx
34.9


Control (Path) 3
9.4
Control 1 Occipital
3.7


Hippo

Ctx


AD 1 Temporal Ctx
20.0
Control 2 Occipital
52.5




Ctx


AD 2 Temporal Ctx
35.6
Control 3 Occipital
14.8




Ctx


AD 3 Temporal Ctx
8.4
Control 4 Occipital
8.0




Ctx


AD 4 Temporal Ctx
18.4
Control (Path) 1
57.4




Occipital Ctx


AD 5 Inf Temporal
100.0
Control (Path) 2
9.0


Ctx

Occipital Ctx


AD 5 Sup Temporal
59.9
Control (Path) 3
7.2


Ctx

Occipital Ctx


AD 6 Inf Temporal
39.2
Control (Path) 4
17.4


Ctx

Occipital Ctx


AD 6 Sup Temporal
40.1
Control 1 Parietal
7.9


Ctx

Ctx


Control 1 Temporal
8.1
Control 2 Parietal
47.3


Ctx

Ctx


Control 2 Temporal
31.2
Control 3 Parietal
19.1


Ctx

Ctx


Control 3 Temporal
14.8
Control (Path) 1
39.0


Ctx

Parietal Ctx


Control 4 Temporal
14.3
Control (Path) 2
17.4


Ctx

Parietal Ctx


Control (Path) 1
51.1
Control (Path) 3
4.5


Temporal Ctx

Parietal Ctx


Control (Path) 2
19.9
Control (Path) 4
26.8


Temporal Ctx

Parietal Ctx










[0799]

310





TABLE JC










Panel 1.3D











Rel. Exp.(%) Ag3376,

Rel. Exp.(%) Ag3376,


Tissue Name
Run 165674234
Tissue Name
Run 165674234













Liver adenocarcinoma
19.1
Kidney (fetal)
13.8


Pancreas
7.5
Renal ca. 786-0
6.5


Pancreatic ca. CAPAN2
6.5
Renal ca. A498
12.4


Adrenal gland
13.5
Renal ca. RXF 393
21.9


Thyroid
11.7
Renal ca. ACHN
1.7


Salivary gland
10.2
Renal ca. UO-31
8.2


Pituitary gland
8.1
Renal ca. TK-10
8.0


Brain (fetal)
31.9
Liver
2.0


Brain (whole)
82.9
Liver (fetal)
7.0


Brain (amygdala)
50.3
Liver ca.
11.3




(hepatoblast) HepG2


Brain (cerebellum)
57.0
Lung
8.4


Brain (hippocampus)
51.4
Lung (fetal)
3.6


Brain (substantia nigra)
30.4
Lung ca. (small cell)
8.4




LX-1


Brain (thalamus)
51.8
Lung ca. (small cell)
0.7




NCI-H69


Cerebral Cortex
27.5
Lung ca. (s.cell var.)
5.4




SHP-77


Spinal cord
31.6
Lung ca. (large
21.5




cell) NCI-H460


glio/astro U87-MG
6.3
Lung ca. (non-sm.
4.2




cell) A549


glio/astro U-118-MG
7.7
Lung ca. (non-s.cell)
5.8




NCI-H23


astrocytoma SW1783
2.3
Lung ca. (non-s.cell)
9.2




HOP-62


neuro*; met SK-N-AS
6.6
Lung ca. (non-s.cl)
10.5




NCI-H522


astrocytoma SF-539
1.7
Lung ca. (squam.)
1.8




SW 900


astrocytoma SNB-75
4.7
Lung ca. (squam.)
9.7




NCI-H596


glioma SNB-19
5.0
Mammary gland
15.7


glioma U251
17.3
Breast ca.* (pl.ef)
2.0




MCF-7


glioma SF-295
4.2
Breast ca.* (pl.ef)
53.2




MDA-MB-231


Heart (fetal)
29.1
Breast ca.* (pl.ef)
1.9




T47D


Heart
11.6
Breast ca. BT-549
34.2


Skeletal muscle (fetal)
13.1
Breast ca. MDA-N
1.1


Skeletal muscle
44.4
Ovary
10.8


Bone marrow
4.5
Ovarian ca. OVCAR-3
6.5


Thymus
6.6
Ovarian ca. OVCAR-4
7.9


Spleen
12.6
Ovarian ca. OVCAR-5
5.2


Lymph node
14.5
Ovarian ca. OVCAR-8
3.9


Colorectal
2.1
Ovarian ca. IGROV-1
2.5


Stomach
13.7
Ovarian ca.* (ascites)
5.2




SK-OV-3


Small intestine
14.8
Uterus
35.4


Colon ca. SW480
9.2
Placenta
11.6


Colon ca.*
4.9
Prostate
16.0


SW620(SW480 met)


Colon ca. HT29
3.4
Prostate ca.* (bone
11.0




met) PC-3


Colon ca. HCT-116
8.3
Testis
100.0


Colon ca. CaCo-2
5.1
Melanoma
3.6




Hs688(A).T


Colon ca.
8.5
Melanoma* (met)
4.1


tissue (ODO3866)

Hs688(B).T


Colon ca. HCC-2998
4.9
Melanoma UACC-62
20.4


Gastric ca.* (liver met)
11.9
Melanoma M14
10.2


NCI-N87


Bladder
1.9
Melanoma LOX
5.2




IMVI


Trachea
7.2
Melanoma* (met)
4.0




SK-MEL-5


Kidney
14.3
Adipose
2.5










[0800]

311





TABLE JD










Panel 4D











Rel. Exp.(%) Ag3376,

Rel. Exp.(%) Ag3376,


Tissue Name
Run 165296548
Tissue Name
Run 165296548













Secondary Th1 act
41.2
HUVEC IL-1 beta
6.5


Secondary Th2 act
26.2
HUVEC IFN gamma
38.2


Secondary Tr1 act
36.3
HUVEC TNF alpha + IFN
18.4




gamma


Secondary Th1 rest
4.4
HUVEC TNF alpha + IL4
22.5


Secondary Th2 rest
6.8
HUVEC IL-11
30.6


Secondary Tr1 rest
11.6
Lung Microvascular EC
32.1




none


Primary Th1 act
15.5
Lung Microvascular EC
32.8




TNF alpha + IL-1 beta


Primary Th2 act
21.2
Microvascular Dermal EC
40.6




none


Primary Tr1 act
45.1
Microsvasular Dermal EC
28.7




TNF alpha + IL-1 beta


Primary Th1 rest
20.4
Bronchial epithelium
62.9




TNF alpha + IL1 beta


Primary Th2 rest
7.9
Small airway epithelium
19.6




none


Primary Tr1 rest
9.3
Small airway epithelium
55.9




TNF alpha + IL-1 beta


CD45RA CD4
13.4
Coronery artery SMC rest
34.4


lymphocyte act


CD45RO CD4
8.1
Coronery artery SMC
29.7


lymphocyte act

TNF alpha + IL-1 beta


CD8 lymphocyte act
12.5
Astrocytes rest
28.9


Secondary CD8
12.9
Astrocytes TNF alpha + IL-
22.4


lymphocyte rest

1 beta


Secondary CD8
6.7
KU-812 (Basophil) rest
33.7


lymphocyte act


CD4 lymphocyte none
2.5
KU-812 (Basophil)
55.1




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
6.8
CCD1106 (Keratinocytes)
31.6


CD95 CH11

none


LAK cells rest
6.6
CCD1106 (Keratinocytes)
22.5




TNF alpha + IL-1 beta


LAK cells IL-2
9.6
Liver cirrhosis
1.7


LAK cells IL-2 + IL-12
14.1
Lupus kidney
3.2


LAK cells IL-2 + IFN
12.9
NCI-H292 none
40.3


gamma


LAK cells IL-2 + IL-18
8.7
NCI-H292 IL-4
67.8


LAK cells
3.4
NCI-H292 IL-9
70.2


PMA/ionomycin


NK Cells IL-2 rest
4.8
NCI-H292 IL-13
48.3


Two Way MLR 3 day
9.1
NCI-H292 IFN gamma
42.3


Two Way MLR 5 day
14.5
HPAEC none
37.9


Two Way MLR 7 day
8.4
HPAEC TNF alpha + IL-1
23.0




beta


PBMC rest
3.3
Lung fibroblast none
32.1


PBMC PWM
46.3
Lung fibroblast TNF alpha
19.2




+ IL-1 beta


PBMC PHA-L
12.0
Lung fibroblast IL-4
76.3


Ramos (B cell) none
24.5
Lung fibroblast IL-9
49.7


Ramos (B cell)
100.0
Lung fibroblast IL-13
33.2


ionomycin


B lymphocytes PWM
57.8
Lung fibroblast IFN
79.6




gamma


B lymphocytes CD40L
12.5
Dermal fibroblast
29.7


and IL-4

CCD1070 rest


EOL-1 dbcAMP
17.1
Dermal fibroblast
39.5




CCD1070 TNF alpha


EOL-1 dbcAMP
6.7
Dermal fibroblast
21.0


PMA/ionomycin

CCD1070 IL-1 beta


Dendritic cells none
7.5
Dermal fibroblast IFN
16.0




gamma


Dendritic cells LPS
7.7
Dermal fibroblast IL-4
28.7


Dendritic cells anti-
5.4
IBD Colitis 2
0.3


CD40


Monocytes rest
12.5
IBD Crohn's
1.1


Monocytes LPS
3.4
Colon
11.2


Macrophages rest
23.0
Lung
14.6


Macrophages LPS
3.3
Thymus
59.9


HUVEC none
46.3
Kidney
26.8


HUVEC starved
34.9










[0801]

312





TABLE JE










Panel CNS_1











Rel. Exp.(%) Ag3376,

Rel. Exp.(%) Ag3376,


Tissue Name
Run 171787488
Tissue Name
Run 171787488













BA4 Control
29.5
BA17 PSP
22.4


BA4 Control2
49.0
BA17 PSP2
11.3


BA4
3.5
Sub Nigra Control
66.9


Alzheimer's2


BA4 Parkinson's
52.9
Sub Nigra Control2
27.4


BA4
71.2
Sub Nigra
11.0


Parkinson's2

Alzheimer's2


BA4
44.4
Sub Nigra
100.0


Huntington's

Parkinson's2


BA4
24.3
Sub Nigra
77.4


Huntington's2

Huntington's


BA4 PSP
11.0
Sub Nigra
53.2




Huntington's2


BA4 PSP2
20.6
Sub Nigra PSP2
8.7


BA4 Depression
15.6
Sub Nigra
9.9




Depression


BA4
6.7
Sub Nigra
9.1


Depression2

Depression2


BA7 Control
42.3
Glob Palladus
34.4




Control


BA7 Control2
44.8
Glob Palladus
29.9




Control2


BA7
4.5
Glob Palladus
26.4


Alzheimer's2

Alzheimer's


BA7 Parkinson's
33.9
Glob Palladus
1.9




Alzheimer's2


BA7
22.1
Glob Palladus
95.3


Parkinson's2

Parkinson's


BA7
40.1
Glob Palladus
26.6


Huntington's

Parkinson's2


BA7
79.6
Glob Palladus PSP
5.8


Huntington's2


BA7 PSP
22.4
Glob Palladus PSP2
6.4


BA7 PSP2
25.5
Glob Palladus
0.0




Depression


BA7 Depression
19.1
Temp Pole Control
15.6


BA9 Control
24.0
Temp Pole Control2
35.8


BA9 Control2
92.7
Temp Pole
6.7




Alzheimer's


BA9 Alzheimer's
9.9
Temp Pole
5.1




Alzheimer's2


BA9
13.7
Temp Pole
37.1


Alzheimer's2

Parkinson's


BA9 Parkinson's
43.8
Temp Pole
36.9




Parkinson's2


BA9
58.6
Temp Pole
53.6


Parkinson's2

Huntington's


BA9
49.7
Temp Pole PSP
1.4


Huntington's


BA9
19.5
Temp Pole PSP2
3.5


Huntington's2


BA9 PSP
14.1
Temp Pole
7.5




Depression2


BA9 PSP2
2.0
Cing Gyr Control
80.7


BA9 Depression
11.3
Cing Gyr Control2
54.0


BA9
22.5
Cing Gyr Alzheimer's
24.8


Depression2


BA17 Control
65.1
Cing Gyr
6.8




Alzheimer's2


BA17 Control2
67.4
Cing Gyr Parkinson's
70.2


BA17
8.2
Cing Gyr
47.3


Alzheimer's2

Parkinson's2


BA17
57.0
Cing Gyr
72.2


Parkinson's

Huntington's


BA17
46.7
Cing Gyr
23.5


Parkinson's2

Huntington's2


BA17
86.5
Cing Gyr PSP
12.1


Huntington's


BA17
19.3
Cing Gyr PSP2
3.8


Huntington's2


BA17
26.2
Cing Gyr Depression
11.4


Depression


BA17
42.0
Cing Gyr
11.8


Depression2

Depression2










[0802] CNS_neurodegeneration_v1.0 Summary: Ag3376 This panel does not show differential expression of the CG58575-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.3D for discussion of utility of this gene in the central nervous system.


[0803] Panel 1.3D Summary: Ag3376 The CG58575-01 gene encodes a putative phosphatidylserine synthase-2. In agreement with published results on the mouse homologue of this gene, the highest expression of this gene is in testis (CT=29.5).


[0804] Expression of this gene is confirmed in all regions of the brain. Phosphatidylserine synthase activity was found to be reduced in the mnd/mnd mouse, a model for the human degenerative disease neuronal ceroid lipofuscinosis. Therefore, this gene may play a role in neurodegenerative disorders in which there is an abnormal accumulation of lipids and proteins in cellular storage bodies.


[0805] In addition, expression of this gene is higher in breast cancer cell lines when compared to expression in normal breast tissue. Thus, expression of this gene could be used to differentiate between breast cancer cell lines and other samples on this panel and as a marker for breast cancer. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of breast cancer.


[0806] Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.


[0807] References


[0808] 1. Vance J E, Stone S J, Faust J R. Abnormalities in mitochondria-associated membranes and phospholipid biosynthetic enzymes in the mnd/mnd mouse model of neuronal ceroid lipofuscinosis.Biochim Biophys Acta Feb. 18, 1997; 1344(3):286-99.


[0809] 2. Sturbois-Balcerzak B, Stone S J, Sreenivas A, Vance J E. Structure and expression of the murine phosphatidylserine syntilase-1 gene. J Biol Chem Mar. 16, 2001; 276(11):8205-12.


[0810] Panel 4D Summary: Ag3376 Highest expression of the CG58575-01 gene is seen in the B cell line Ramos treated with ionomycin (CT=29.3). Significant levels of expression are seen in activated and untreated NCI-H292 cells, IL-4, 1L-9, IL-13 and IFN gamma activated lung fibroblasts, human pulmonary aortic endothelial cells (treated and untreated), small airway epithelium (treated and untreated), treated bronchial epithelium and lung microvascular endothelial cells (treated and untreated). The expression of this gene in cells derived from or within the lung suggests that this gene may be involved in normal conditions as well as pathological and inflammatory lung disorders that include chronic obstructive pulmonary disease, asthma, allergy and emphysema. Moderate/low expression of this gene is also detected in treated and untreated HUVECs (endothelial cells), coronary artery smooth muscle cells (treated and untreated), treated and untreated astrocytes, treated KU-812 basophils, treated and untreated CCD1106 keratinocytes, IL-4 treated dermal fibroblasts, and normal tissues that include lung, colon, thymus and kidney. Expression in the various immune cell types (as well as in diseased tissue samples) suggests that therapeutic modulation of this gene product may ameliorate symptoms associated with infectious conditions as well as inflammatory and autoimmune disorders that include psoriasis, allergy, asthma, inflammatory bowel disease, rheumatoid arthritis and osteoarthritis.


[0811] Panel CNS1 Summary: AG3376 This panel confirms expression of the CG58575-01 gene in the brain. Please see Panel 1.3D for discussion of utility of this gene in the central nervous system.



K. NOV16a (CG59239-01: MHC CLASS I)

[0812] Expression of gene CG59239-01 was assessed using the primer-probe sets Ag3516 and Ag3517, described in Tables KA and KB. Results of the RTQ-PCR runs are shown in Tables KC, KD and KE.
313TABLE KAProbe Name Ag3516StartPrimerSequencesLengthPositionForward5′-cggagaggagcagagataca-3′(SEQ ID NO:245)20845ProbeTET-5′-cagagcccctcaccctgagatgg-3′-TAMRA(SEQ ID NO:246)23892Reverse5′-gatggtgggctgagaagac-3′(SEQ ID NO:247)19920


[0813]

314





TABLE KB










Probe Name Ag3517













Start


Primers
Sequenecs
Length
Position














Forward
5′-cggagaggagcagagataca-3′
(SEQ ID NO:248)
20
845





Probe
TET-5′-cagagcccctcaccctgagatgg-3′-TAMRA
(SEQ ID NO:249)
23
892





Reverse
5′-gatggtgggctgagaagac-3′
(SEQ ID NO:250)
19
920










[0814]

315





TABLE KC










CNS_neurodegeneration_v1.0













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag3516, Run
Ag3517, Run

Ag3516, Run
Ag3517, Run


Tissue Name
211005124
210629732
Tissue Name
211005124
210629732















AD 1 Hippo
48.6
34.2
Control
20.7
23.0





(Path) 3





Temporal





Ctx


AD 2 Hippo
87.7
88.3
Control
32.8
28.3





(Path) 4





Temporal





Ctx


AD 3 Hippo
10.9
10.7
AD 1
25.3
25.3





Occipital Ctx


AD 4 Hippo
13.4
11.3
AD 2
0.0
0.0





Occipital Ctx





(Missing)


AD 5 Hippo
79.6
85.9
AD 3
9.8
10.3





Occipital Ctx


AD 6 Hippo
59.5
57.0
AD 4
16.6
17.3





Occipital Ctx


Control 2
63.7
71.2
AD 5
73.2
87.7


Hippo


Occipital Ctx


Control 4
33.9
24.7
AD 6
2.8
18.0


Hippo


Occipital Ctx


Control
11.1
11.3
Control 1
6.3
6.0


(Path) 3


Occipital Ctx


Hippo


AD 1
41.8
40.6
Control 2
100.0
100.0


Temporal


Occipital Ctx


Ctx


AD 2
52.9
78.5
Control 3
14.4
11.7


Temporal


Occipital Ctx


Ctx


AD 3
9.7
8.4
Control 4
12.8
12.2


Temporal


Occipital Ctx


Ctx


AD 4
24.1
23.2
Control
85.3
92.7


Temporal


(Path) 1


Ctx


Occipital Ctx


AD 5 Inf
87.1
87.7
Control
22.7
16.7


Temporal


(Path) 2


Ctx


Occipital Ctx


AD 5 Sup
79.0
85.9
Control
21.8
23.3


Temporal


(Path) 3


Ctx


Occipital Ctx


AD 6 Inf
48.3
52.5
Control
29.3
27.4


Temporal


(Path) 4


Ctx


Occipital Ctx


AD 6 Sup
46.3
50.3
Control 1
7.8
8.6


Temporal


Parietal Ctx


Ctx


Control 1
6.8
6.1
Control 2
59.9
70.2


Temporal


Parietal Ctx


Ctx


Control 2
61.6
79.6
Control 3
21.9
16.3


Temporal


Parietal Ctx


Ctx


Control 3
16.4
15.0
Control
69.3
84.1


Temporal


(Path) 1


Ctx


Parietal Ctx


Control 3
16.2
14.0
Control
47.3
51.1


Temporal


(Path) 2


Ctx


Parietal Ctx


Control
75.8
82.4
Control
20.2
23.5


(Path) 1


(Path) 3


Temporal


Parietal Ctx


Ctx


Control
49.7
45.7
Control
40.6
43.8


(Path) 2


(Path) 4


Temporal


Parietal Ctx


Ctx










[0815]

316





TABLE KD










General_screening_panel_v1.4













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag3516, Run
Ag3517, Run

Ag3516, Run
Ag3517, Run


Tissue Name
216861071
216862935
Tissue Name
216861071
216862935















Adipose
5.2
5.7
Renal ca. TK-10
6.4
9.5


Melanoma*
7.1
8.4
Bladder
15.4
18.2


Hs688(A).T


Melanoma*
5.7
6.0
Gastric ca. (liver
13.2
15.4


Hs688(B).T


met.) NCI-N87


Melanoma*
6.0
8.5
Gastric ca. KATO
62.9
52.9


M14


III


Melanoma*
1.5
1.5
Colon ca. SW-
3.4
3.3


LOXIMVI


948


Melanoma*
7.3
8.7
Colon ca. SW480
5.5
5.6


SK-MEL-5


Squamous cell
3.2
3.0
Colon ca.*
5.2
6.4


carcinoma


(SW480 met)


SCC-4


SW620


Testis Pool
1.4
1.3
Colon ca. HT29
4.8
5.3


Prostate ca.*
3.5
3.0
Colon ca. HCT-
3.7
5.7


(bone met)


116


PC-3


Prostate Pool
3.5
2.7
Colon ca. CaCo-2
7.2
9.7


Placenta
2.1
2.3
Colon cancer
30.6
54.0





tissue


Uterus Pool
2.2
1.9
Colon ca.
0.0
0.0





SW1116


Ovarian ca.
1.6
1.7
Colon ca. Colo-
6.2
5.5


OVCAR-3


205


Ovarian ca.
66.4
62.9
Colon ca. SW-48
18.8
19.9


SK-OV-3


Ovarian ca.
1.7
2.0
Colon Pool
3.9
4.9


OVCAR-4


Ovarian ca.
18.7
20.2
Small Intestine
9.1
10.0


OVCAR-5


Pool


Ovarian ca.
32.3
63.3
Stomach Pool
2.9
1.7


IGROV-1


Ovarian ca.
81.8
73.7
Bone Marrow
1.1
0.8


OVCAR-8


Pool


Ovary
5.3
6.2
Fetal Heart
0.9
1.1


Breast ca.
2.0
1.5
Heart Pool
2.9
3.1


MCF-7


Breast ca.
32.3
34.6
Lymph Node
2.9
2.7


MDA-MB-


Pool


231


Breast ca. BT
6.5
7.1
Fetal Skeletal
1.0
1.1


549


Muscle


Breast ca.
53.6
54.0
Skeletal Muscle
2.5
2.6


T47D


Pool


Breast ca.
5.8
5.6
Spleen Pool
16.2
15.2


MDA-N


Breast Pool
4.6
4.9
Thymus Pool
5.4
5.7


Trachea
9.8
8.9
CNS cancer
11.3
13.2





(glio/astro) U87-





MG


Lung
2.0
2.1
CNS cancer
3.1
2.8





(glio/astro) U-





118-MG


Fetal Lung
7.0
6.6
CNS cancer
2.1
2.7





(neuro;net)SK-





N-AS


Lung ca. NCI-
0.7
0.6
CNS cancer
27.4
24.1


N417


(astro) SF-539


Lung ca. LX-1
3.0
4.2
CNS cancer
100.0
100.0





(astro) SNB-75


Lung ca. NCI-
1.2
1.3
CNS cancer (glio)
46.3
41.8


H146


SNB-19


Lung ca. SHP-
1.7
1.4
CNS cancer (glio)
62.4
66.4


77


SF-295


Lung ca. A549
1.6
1.1
Brain (Amygdala)
1.6
1.6





Pool


Lung ca. NCI-
2.7
3.0
Brain
1.3
1.5


H526


(cerebellum)


Lung ca.NCI-
0.2
0.3
Brain (fetal)
0.7
0.8


H23


Lung ca. NCI-
14.7
12.0
Brain
1.5
1.6


H460


(Hippocampus)





Pool


Lung ca.
19.9
21.3
Cerebral Cortex
1.2
1.2


HOP-62


Pool


Lung ca. NCI-
3.8
4.3
Brain (Substantia
2.5
2.6


H522


nigra) Pool


Liver
2.6
2.8
Brain (Thalamus)
1.4
1.5





Pool


Fetal Liver
1.6
1.4
Brain (whole)
0.8
0.7


Liver ca.
4.9
6.4
Spinal Cord Pool
5.3
5.0


HepG2


Kidney Pool
12.0
11.9
Adrenal Gland
4.2
5.1


Fetal Kidney
0.9
1.1
Pituitary gland
2.8
2.5





Pool


Renal ca. 786-0
9.2
8.9
Salivary Gland
1.7
1.6


Renal ca.
5.2
5 0
Thyroid (female)
11.8
12.2


A498


Renal ca.
3.3
3.4
Pancreatic ca.
10.4
9.7


ACHN


CAPAN2


Renal ca. UO-31
6.7
7.8
Pancreas Pool
7.0
7.5










[0816]

317





TABLE KE










Panel 4.1 D













Rel.
Rel.

Rel.
Rel.



Exp.(%)
Exp.(%)

Exp.(%)
Exp.(%)



Ag3516,
Ag3517,

Ag3516,
Ag3517,



Run
Run

Run
Run


Tissue Name
169840392
169840401
Tissue Name
169840392
169840401















Secondary Th1 act
24.5
24.0
HUVEC IL-1 beta
14.0
12.6


Secondary Th2 act
49.3
54.7
HUVEC IFN
2.9
2.8





gamma


Secondary Tr1 act
50.7
51.1
HUVEC TNF
27.2
27.4





alpha + IFN





gamma


Secondary Th1 rest
10.5
10.1
HUVEC TNF
12.3
12.1





alpha + IL4


Secondary Th2 rest
13.6
12.5
HUVEC IL-11
1.6
0.9


Secondary Tr1 rest
12.1
12.0
Lung
7.5
5.7





Microvascular EC





none


Primary Th1 act
11.2
12.2
Lung
11.3
8.0





Microvascular EC





TNF alpha + IL-





1 beta


Primary Th2 act
13.3
15.1
Microvascular
7.4
7.8





Dermal EC none


Primary Tr1 act
14.1
14.3
Microvascular
19.3
22.5





Dermal EC





TNF alpha + IL-





1 beta


Primary Th1 rest
33.4
36.6
Bronchial
3.8
3.5





epithelium





TNF alpha +





IL1 beta


Primary Th2 rest
26.8
26.2
Small airway
3.1
2.7





epithelium none


Primary Tr1 rest
45.7
37.9
Small airway
5.8
5.2





epithelium





TNF alpha + IL-





1 beta


CD45RA CD4
27.0
24.8
Coronery artery
7.0
6.1


lymphocyte act


SMC rest


CD45RO CD4
38.7
37.9
Coronery artery
4.9
5.0


lymphocyte act


SMC TNF alpha +





IL_1 beta


CD8 lymphocyte
47.3
42.3
Astrocytes rest
7.6
6.4


act


Secondary CD8
36.9
27.9
Astrocytes
9.2
7.6


lymphocyte rest


TNF alpha + IL-





1 beta


Secondary CD8
25.7
25.0
KU-812 (Basophil)
0.9
0.6


lymphocyte act


rest


CD4 lymphocyte
14.0
13.1
KU-812 (Basophil)
2.4
2.2


none


PMA/ionomycin


2ry
38.7
40.9
CCD1106
2.4
2.3


Th1/Th2/Tr1_anti-


(Keratinocytes)


CD95 CH11


none


LAK cells rest
43.8
37.1
CCD1106
6.3
4.1





(Kerationcytes)





TNF alpha + IL-





1 beta


LAK cells IL-2
27.9
28.5
Liver cirrhosis
6.5
6.6


LAK cells IL-2 +
51.4
48.0
NCI-H292 none
3.1
3.4


IL-12


LAK cells IL-
50.3
53.6
NCI-H292 IL-4
3.8
3.4


2 + IFN gamma


LAK cells IL-2 +
53.6
46.7
NCI-H292 IL-9
4.2
2.8


IL-18


LAK cells
48.3
41.5
NCI-H292 IL-13
2.5
2.4


PMA/ionomycin


NK Cells IL-2 rest
63.3
58.2
NCI-H292 IFN
10.0
9.4





gamma


Two Way MLR 3
65.5
61.6
HPAEC none
4.9
3.1


day


Two Way MLR 5
49.0
53.6
HPAEC TNF
24.7
21.0


day


alpha + IL-1 beta


Two Way MLR 7
35.4
33.2
Lung fibroblast
8.8
7.1


day


none


PBMC rest
26.8
22.5
Lung fibroblast
42.3
33.9





TNF alpha + IL-1





beta


PBMC PWM
42.0
29.1
Lung fibroblast IL-4
8.7
7.2


PBMC PHA-L
29.3
36.9
Lung fibroblast IL-9
9.9
10.7


Ramos (B cell)
6.9
8.0
Lung fibroblast IL-
8.8
8.2


none


13


Ramos (B cell)
7.1
7.7
Lung fibroblast
23.2
18.8


ionomycin


IFN gamma


B lymphocytes
27.4
20.9
Dermal fibroblast
10.7
11.3


PWM


CCD1070 rest


B lymphocytes
54.7
40.9
Dermal fibroblast
28.5
22.4


CD40L and IL-4


CCD1070 TNF





alpha


EOL-1 dbcAMP
2.6
3.0
Dermal fibroblast
6.7
6.3





CCD1070 IL-1





beta


EOL-1 dbcAMP
2.7
2.8
Dermal fibroblast
25.0
23.2


PMA/ionomycin


IFN gamma


Dendritic cells none
29.7
33.9
Dermal fibroblast
13.4
13.8





IL-4


Dendritic cell LPS
57.4
53.2
Dermal Fibroblasts
5.0
3.5





rest


Dendritic cells anti-
29.7
29.9
Neutrophils
51.8
45.4


CD40


TNFa + LPS


Monocytes rest
23.7
23.8
Neutrophils rest
76.8
75.3


Monocytes LPS
100.0
100.0
Colon
26.8
22.8


Macrophages rest
25.5
23.5
Lung
23.2
27.0


Macrophages LPS
61.1
60.3
Thymus
9.3
11.6


HUVEC none
4.4
6.3
Kidney
3.7
4.2


HUVEC starved
8.0
9.5










[0817] CNS_neurodegeneration_v1.0 Summary: Ag3516/Ag3517 This panel does not show differential expression of the CG59239-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.


[0818] General_screening_panel_v1.4 Summary: Ag3516/Ag3517 Two experiments with the same probe and primer set produce results that are in excellent agreement, with highest expression of the CG59239-01 gene in a brain cancer cell line (CT=24). This gene encodes a major histocompatibility complex (MIJC) class I homologue. MHC Class I genes mediate the recognition of intracellular antigens by cytotoxic T cells and are typically ubiquitously expressed. Significant expression is also seen in clusters of cell lines derived from gastric, colon, lung, breast, ovarian and brain cancers. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of gastric, colon, lung, breast, ovarian and brain cancer.


[0819] Among tissues with metabolic function, this gene is expressed at moderate levels in adipose, adrenal gland, pancreas, pituitary, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal metabolic and neuroendocrine function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.


[0820] In addition, this gene shows moderate expression in all regions of the CNS examined. Inflammation has been implicated in many CNS neurodegenerative disorders, including Alzheimer's disease. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurodegenerative disorders such as Alzheillmer's disease, Parkinson's disease, and multiple sclerosis.


[0821] References:


[0822] 1. Bauer J, Rauschka H, Lassmann H. Inflammation in the nervous system: the human perspective. Glia November 2001;36(2):235-43


[0823] Panel 4.1D Summary: Ag3516/Ag3517 Two experiments with the same probe and primer set produce results that are in excellent agreement, with highest expression of the CG59239-01 gene in LPS-stimulated inonocytes (CT=24). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_v1.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.


[0824] This gene encodes a major histocompatibility complex (MIHC) class I homolog. MHC class I-like molecules may have utility in forensics, such as in genotyping criminal suspects, and in settling paternity disputes. These antigens are ubiquitously expressed on all nucleated human cells except neurons and trophoblasts, and participate in antigen presentation of viral antigens in the adaptive immune response.



L. NOV17a (CG59295-0 1: OTOGELIN)

[0825] Expression of gene CG59295-01 was assessed using the primer-probe set Ag3534, described in Table LA. Results of the RTQ-PCR runs are shown in Tables LB, and LC.
318TABLE LAProbe Name Ag3534StartPrimerSequencesLengthPositionForward5′-agctgagtgtccctgtgagtt-3′(SEQ ID NO:251)211422ProbeTET-5′-actctgtacccacctggctctgtggt-3′-TAMRA(SEQ ID NO:252)261450Reverse5′-tgcaagtattgcagtcttcctt-3′(SEQ ID NO:253)221477


[0826]

319





TABLE LB










General_screening_panel_v1.4











Rel. Exp.(%) Ag3534,

Rel. Exp.(%) Ag3534,


Tissue Name
Run 217044594
Tissue Name
Run 217044594













Adipose
0.0
Renal ca. TK-10
0.0


Melanoma*
0.0
Bladder
10.9


Hs688(A).T


Melanoma*
0.0
Gastric ca. (liver met.)
11.4


Hs688(B).T

NCI-N87


Melanoma* M14
0.0
Gastric ca. KATO III
0.0


Melanoma*
0.0
Colon ca. SW-948
0.0


LOXIMVI


Melanoma* SK-
0.0
Colon ca. SW480
20.3


MEL-5


Squamous cell
0.0
Colon ca.* (SW480
3.7


carcinoma SCC-4

met) SW620


Testis Pool
25.7
Colon ca. HT29
0.0


Prostate ca.* (bone
0.0
Colon ca. HCT-116
2.6


met) PC-3


Prostate Pool
0.0
Colon ca. CaCo-2
100.0


Placenta
0.0
Colon cancer tissue
0.0


Uterus Pool
0.0
Colon ca. SW1116
0.0


Ovarian ca. OVCAR-3
9.2
Colon ca. Colo-205
0.0


Ovarian ca. SK-OV-3
0.0
Colon ca. SW-48
2.7


Ovarian ca. OVCAR-4
2.5
Colon Pool
6.0


Ovarian ca. OVCAR-5
11.7
Small Intestine Pool
3.0


Ovarian ca. IGROV-1
0.0
Stomach Pool
3.1


Ovarian ca. OVCAR-8
0.0
Bone Marrow Pool
0.0


Ovary
0.0
Fetal Heart
2.9


Breast ca. MCF-7
0.0
Heart Pool
2.8


Breast ca. MDA-
0.0
Lymph Node Pool
2.6


MB-231


Breast ca. BT 549
0.0
Fetal Skeletal Muscle
0.0


Breast ca. T47D
23.5
Skeletal Muscle Pool
0.0


Breast ca. MDA-N
0.0
Spleen Pool
0.0


Breast Pool
2.8
Thymus Pool
2.6


Trachea
0.0
CNS cancer (glio/astro)
0.0




U87-MG


Lung
0.0
CNS cancer (glio/astro)
0.0




U-118-MG


Fetal Lung
0.0
CNS cancer (neuro;met)
0.0




SK-N-AS


Lung ca. NCI-N417
0.0
CNS cancer (astro) SF-
0.0




539


Lung ca. LX-1
66.9
CNS cancer (astro)
0.0




SNB-75


Lung ca. NCI-H146
19.1
CNS cancer (glio) SNB-
0.0




19


Lung ca. SHP-77
0.0
CNS cancer (glio) SF-
2.8




295


Lung ca. A549
0.0
Brain (Amygdala) Pool
2.7


Lung ca. NCI-H526
4.8
Brain (cerebellum)
0.0


Lung ca. NCI-H23
3.9
Brain (fetal)
6.3


Lung ca. NCI-H460
2.7
Brain (Hippocampus)
5.2




Pool


Lung ca. HOP-62
0.0
Cerebral Cortex Pool
0.0


Lung ca. NCI-H522
0.0
Brain (Substantia nigra)
2.7




Pool


Liver
0.0
Brain (Thalamus) Pool
0.0


Fetal Liver
0.0
Brain (whole)
0.0


Liver ca. HepG2
1.5
Spinal Cord Pool
5.5


Kidney Pool
0.0
Adrenal Gland
0.0


Fetal Kidney
10.7
Pituitary gland Pool
16.7


Renal ca. 786-0
0.0
Salivary Gland
0.0


Renal ca. A498
6.9
Thyroid (female)
0.0


Renal ca. ACHN
0.0
Pancreatic ca. CAPAN2
0.0


Renal ca. UO-31
0.0
Pancreas Pool
4.3










[0827]

320





TABLE LC










Panel 4D











Rel. Exp.(%) Ag3534,

Rel. Exp.(%) Ag3534,


Tissue Name
Run 166444750
Tissue Name
Run 166444750













Secondary Th1 act
2.4
HUVEC IL-1 beta
0.0


Secondary Th2 act
2.0
HUVEC IFN gamma
0.0


Secondary Tr1 act
2.5
HUVEC TNF alpha + IFN
0.0




gamma


Secondary Th1 rest
0.0
HUVEC TNF alpha + IL4
0.0


Secondary Th2 rest
0.0
HUVEC IL-11
0.0


Secondary Tr1 rest
0.0
Lung Microvascular EC
0.0




none


Primary Th1 act
0.0
Lung Microvascular EC
0.0




TNF alpha + IL-1 beta


Primary Th2 act
0.0
Microvascular Dermal EC
0.0




none


Primary Tr1 act
0.0
Microsvasular Dermal EC
0.0




TNF alpha + IL-1 beta


Primary Th1 rest
0.0
Bronchial epithelium
0.0




TNF alpha + IL1 beta


Primary Th2 rest
0.0
Small airway epithelium
0.0




none


Primary Tr1 rest
0.0
Small airway epithelium
0.0




TNF alpha + IL-1 beta


CD45RA CD4
0.0
Coronery artery SMC rest
0.0


lymphocyte act


CD45RO CD4
0.0
Coronery artery SMC
0.0


lymphocyte act

TNF alpha + IL-1 beta


CD8 lymphocyte act
0.0
Astrocytes rest
0.0


Secondary CD8
0.0
Astrocytes TNF alpha + IL-
0.0


lymphocyte rest

1 beta


Secondary CD8
0.0
KU-812 (Basophil) rest
0.0


lymphocyte act


CD4 lymphocyte none
0.0
KU-812 (Basophil)
0.0




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
0.0
CCD1106 (Keratinocytes)
0.0


CD95 CH11

none


LAK cells rest
0.0
CCD1106 (Keratinocytes)
0.0




TNF alpha + IL-1 beta


LAK cells IL-2
0.0
Liver cirrhosis
100.0


LAK cells IL-2 + IL-12
0.0
Lupus kidney
6.0


LAK cells IL-2 + IFN
0.0
NCI-H292 none
0.0


gamma


LAK cells IL-2 + IL-18
0.0
NCI-H292 IL-4
0.0


LAK cells
0.0
NCI-H292 IL-9
0.0


PMA/ionomycin


NK Cells IL-2 rest
1.5
NCI-H292 IL-13
0.0


Two Way MLR 3 day
0.0
NCI-H292 IFN gamma
0.0


Two Way MLR 5 day
0.0
HPAEC none
0.0


Two Way MLR 7 day
0.0
HPAEC TNF alpha + IL-1
0.0




beta


PBMC rest
0.0
Lung fibroblast none
0.0


PBMC PWM
0.0
Lung fibroblast TNF
0.0




alpha + IL-1 beta


PBMC PHA-L
0.0
Lung fibroblast IL-4
0.0


Ramos (B cell) none
0.0
Lung fibroblast IL-9
0.0


Ramos (B cell)
0.0
Lung fibroblast IL-13
0.0


ionomycin


B lymphocytes PWM
0.0
Lung fibroblast IFN
0.0




gamma


B lymphocytes CD40L
0.0
Dermal fibroblast
0.0


and IL-4

CCD1070 rest


EOL-1 dbcAMP
0.0
Dermal fibroblast
0.0




CCD1070 TNF alpha


EOL-1 dbcAMP
0.0
Dermal fibroblast
0.0


PMA/ionomycin

CCD1070 IL-1 beta


Dendritic cells none
2.7
Dermal fibroblast IFN
0.0




gamma


Dendritic cells LPS
0.0
Dermal fibroblast IL-4
0.0


Dendritic cells anti-
0.0
IBD Colitis 2
4.4


CD40


Monocytes rest
0.0
IBD Crohn's
0.0


Monocytes LPS
0.0
Colon
44.4


Macrophages rest
0.0
Lung
15.9


Macrophages LPS
0.0
Thymus
10.0


HUVEC none
0.0
Kidney
0.0


HUVEC starved
0.0










[0828] CNS_neurodegeneration_v1.0 Summary: Ag3534 Expression of the CG59295-01 gene is low/undetectable in all samples on this panel (CTs>35).


[0829] General_screening_panel_v1.4 Summary: Ag3534 Highest expression of the CG59295-01 gene is seen in a colon cancer cell line (CT=3 1). Low but significant levels of expression are seen in lung and breast cancer cell lines. Therefore, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker for colon cancer. This gene has been linked to deafness. Thus, therapeutic modulation of the expression or function of this gene may be effective in the treatment of deafness.


[0830] References:


[0831] Simmler M C, Cohen-Salmon M, El-Amraoui A, Guillaud L, Benichou J C, Petit C, Panthier J J.


[0832] Panel 4D Summary: Ag3534 Expression of the CG59295-01 gene is restricted to a few samples, with highest expression in liver cirrhosis (CT=32.2). Low but significant level of expression are also seen in lung and colon. In addition, expression is undetectable in colon from patients with IBD colitis and Crohn's and in liver on Panel 1.4. Thus, expression of this gene may be used to differentiate between normal and diseased liver and colon tissue. Also, therapeutic modulation of the activity of the otogelin protein encoded by this gene may be useful in the treatment of inflammatory bowel disease and inflammatory or autoimmune diseases which affect the liver including liver cirrhosis and fibrosis.


[0833] Panel CNS1 Summary: Ag3534 Expression of the CG59295-01 gene is low/undetectable in all samples on this panel (CTs>35).



M. NOV18a (CG59293-01: Renal Organic Anion Transport Protein 1)

[0834] Expression of gene CG59293-01 was assessed using the primer-probe sets Ag3948, Ag3532 and Ag2874, described in Tables MA, MB and MC. Results of the RTQ-PCR runs are shown in Tables MD, ME, MF, MG, MH, MI, MJ and MK.
321TABLE MAProbe Name Ag3948StartPrimerSequencesLengthPositionForward5′-ctctattcttggtggcttcca-3′(SEQ ID NO:254)21867ProbeTET-5′-ctcctgcatggcaagtcccagttag-3′-TAMRA(SEQ ID NO:255)25906Reverse5′-ccaccttctgcagattctgtac-3′(SEQ ID NO:256)22993


[0835]

322





TABLE MB










Probe Name Ag3532













Start


Primer
Sequences
Length
Position














Forward
5′-ccaactcaatcttggacctctt-3′
(SEQ ID NO:257)
22
1048





Probe
TET-5′-atccgcaaggtcacatgctgtctcat-3′-TAMRA
(SEQ ID NO:258)
26
1083





Reverse
5′-cagagttggagaaccaaatcac-3′
(SEQ ID NO:259)
22
1110










[0836]

323








TABLE MC










Probe Name Ag2874





Start


Primers
Sequences
Length
Position














Forward
5′-ccaactcaatcttggacctctt-3′
(SEQ ID NO:260)
22
1048





Probe
TET-5′-atccgcaaggtcacatgctgtctcat-3′-TAMRA
(SEQ ID NO:261)
26
1083
JNO:261)
I





Reverse
5′-cagagttggagaaccaaatcac-3′
(SEQ ID NO:262)
22
1110










[0837]

324





TABLE MD










AI_comprehensive panel_v1.0











Rel. Exp.(%) Ag3948,

Rel. Exp.(%) Ag3948,


Tissue Name
Run 247842315
Tissue Name
Run 247842315













110967 COPD-F
17.8
112427 Match Control
12.1




Psoviasis-F


110980 COPD-F
6.7
112418 Psoriasis-M
11.2


110968 COPD-M
9.2
112723 Match Control
9.6




Psoriasis-M


110977 COPD-M
20.0
112419 Psoriasis-M
30.6


110989 Emphysema-F
34.6
112424 Match Control
18.4




Psoriasis-M


110992 Emphysema-F
0.0
112420 Psoriasis-M
94.6


110993 Emphysema-F
18.6
112425 Match Control
42.6




Psoriasis-M


110994 Emphysema-F
9.2
104689 (MF) OA Bone-
20.2




Backus


110995 Emphysema-F
100.0
104690 (MF) Adj
7.2




“Normal” Bone-Backus


110996 Emphysema-F
5.2
104691 (MF) OA
10.0




Synovium-Backus


110997 Asthma-M
18.0
104692 (BA) OA
0.0




Cartilage-Backus


111001 Asthma-F
0.0
104694 (BA) OA Bone-
14.2




Backus.


111002 Asthma-F
8.8
104695 (BA) Adj
7.5




“Normal” Bone-Backus


111003 Atopic
5.6
104696 (BA) OA
13.9


Asthma-F

Synovium-Backus


111004 Atopic
41.5
104700 (SS) OA Bone-
35.6


Asthma-F

Backus


111005 Atopic
17.6
104701 (SS) Adj
8.7


Asthma-F

“Normal” Bone-Backus


111006 Atopic
0.0
104702 (SS) OA
26.8


Asthma-F

Synovium-Backus


111417 Allergy-M
2.4
117093 OA Cartilage
18.9




Rep7


112347 Allergy-M
0.0
112672 OA Bone5
13.4


112349 Normal Lung-F
10.1
112673 OA Synovium5
0.0


112357 Normal Lung-F
9.2
112674 OA Synovial
5.8




Fluid cells5


112354 Normal Lung-M
19.2
117100 OA Cartilage
14.8




Rep14


112374 Crohns-F
28.3
112756 OA Bone9
21.0


112389 Match Control
15.2
112757 OA Synovium9
20.3


Crohns-F


112375 Crohns-F
14.3
112758 OA Synovial
7.2




Fluid Cells9


112732 Match Control
92.7
117125 RA Cartilage
25.9


Crohns-F

Rep2


112725 Crohns-M
23.5
113492 Bone2 RA
10.9


112387 Match Control
13.6
113493 Synovium2 RA
8.8


Crohns-M


112378 Crohns-M
14.4
113494 Syn Fluid Cells
16.8




RA


112390 Match Control
72.7
113499 Cartilage4 RA
12.9


Crohns-M


112726 Crohns-M
12.8
113500 Bone4 RA
20.7


112731 Match Control
65.5
113501 Synovium4 RA
13.8


Crohns-M


112380 Ulcer Col-F
18.6
113502 Syn Fluid
3.1




Cells4 RA


112734 Match Control
89.5
113495 Cartilage3 RA
6.8


Ulcer Col-F


112384 Ulcer Col-F
57.8
113496 Bone3 RA
20.7


112737 Match Control
15.6
113497 Synovium3 RA
8.7


Ulcer Col-F


112386 Ulcer Col-F
2.7
113498 Syn Fluid
21.6




Cells3 RA


112738 Match Control
4.3
117106 Normal
5.7


Ulcer Col-F

Cartilage Rep20


112381 Ulcer Col-M
0.0
113663 Bone3 Normal
16.2


112735 Match Control
58.2
113664 Synovium3
2.6


Ulcer Col-M

Normal


112382 Ulcer Col-M
8.4
113665 Syn Fluid
5.2




Cells3 Normal


112394 Match Control
17.1
117107 Normal
11.0


Ulcer Col-M

Cartilage Rep22


112383 Ulcer Col-M
47.3
113667 Bone4 Normal
15.4


112736 Match Control
1.9
113668 Synovium4
20.2


Ulcer Col-M

Normal


112423 Psoriasis-F
27.4
113669 Syn Fluid
40.9




Cells4 Normal










[0838]

325





TABLE ME










CNS_neurodegeneration_v1.0











Rel. Exp.(%) Ag3948,

Rel. Exp.(%) Ag3948,


Tissue Name
Run 212345604
Tissue Name
Run 212345604













AD 1 Hippo
0.0
Control (Path) 3
0.0




Temporal Ctx


AD 2 Hippo
57.0
Control (Path) 4
33.4




Temporal Ctx


AD 3 Hippo
32.5
AD 1 Occipital Ctx
67.8


AD 4 Hippo
0.0
AD 2 Occipital Ctx
5.3




(Missing)


AD 5 Hippo
47.0
AD 3 Occipital Ctx
0.0


AD 6 Hippo
20.3
AD 4 Occipital Ctx
0.0


Control 2 Hippo
0.0
AD 5 Occipital Ctx
18.4


Control 4 Hippo
0.0
AD 6 Occipital Ctx
39.2


Control (Path) 3
0.0
Control 1 Occipital
0.0


Hippo

Ctx


AD 1 Temporal Ctx
0.0
Control 2 Occipital
79.6




Ctx


AD 2 Temporal Ctx
16.7
Control 3 Occipital
42.0




Ctx


AD 3 Temporal Ctx
14.9
Control 4 Occipital
0.0




Ctx


AD 4 Temporal Ctx
0.0
Control (Path) 1
46.0




Occipital Ctx


AD 5 Inf Temporal
100.0
Control (Path) 2
0.0


Ctx

Occipital Ctx


AD 5 Sup Temporal
0.0
Control (Path) 3
0.0


Ctx

Occipital Ctx


AD 6 Inf Temporal
65.1
Control (Path) 4
11.7


Ctx

Occipital Ctx


AD 6 Sup Temporal
91.4
Control 1 Parietal
10.3


Ctx

Ctx


Control 1 Temporal
0.0
Control 2 Parietal
49.3


Ctx

Ctx


Control 2 Temporal
0.0
Control 3 Parietal
0.0


Ctx

Ctx


Control 3 Temporal
0.0
Control (Path) 1
67.8


Ctx

Parietal Ctx


Control 3 Temporal
18.0
Control (Path) 2
14.4


Ctx

Parietal Ctx


Control (Path) 1
32.1
Control (Path) 3
0.0


Temporal Ctx

Parietal Ctx


Control (Path) 2
9.7
Control (Path) 4
20.4


Temporal Ctx

Parietal Ctx










[0839]

326





TABLE MF










General_screening_panel_v1.4











Rel. Exp.(%) Ag3948,

Rel. Exp.(%) Ag3948,


Tissue Name
Run 219279808
Tissue Name
Run 219279808













Adipose
0.3
Renal ca. TK-10
2.1


Melanoma*
0.5
Bladder
2.8


Hs688(A).T


Melanoma*
0.2
Gastric ca. (liver met.)
22.2


Hs688(B).T

NCI-N87


Melanoma* M14
0.2
Gastric ca. KATO III
4.0


Melanoma*
0.0
Colon ca. SW-948
0.1


LOXIMVI


Melanoma* SK-
0.1
Colon ca. SW480
10.5


MEL-5


Squamous cell
2.4
Colon ca.* (SW480
1.6


carcinoma SCC-4

met) SW620


Testis Pool
0.3
Colon ca. HT29
1.5


Prostate ca.* (bone
0.9
Colon ca. HCT-116
2.3


met) PC-3


Prostate Pool
0.3
Colon ca. CaCo-2
0.7


Placenta
0.2
Colon cancer tissue
0.2


Uterus Pool
0.1
Colon ca. SW1116
0.1


Ovarian ca. OVCAR-3
11.5
Colon ca. Colo-205
0.6


Ovarian ca. SK-OV-3
1.3
Colon ca. SW-48
0.8


Ovarian ca. OVCAR-4
0.4
Colon Pool
0.6


Ovarian ca. OVCAR-5
8.0
Small Intestine Pool
0.4


Ovarian ca. IGROV-1
1.9
Stomach Pool
0.1


Ovarian ca. OVCAR-8
0.5
Bone Marrow Pool
0.4


Ovary
0.4
Fetal Heart
0.1


Breast ca. MCF-7
3.2
Heart Pool
0.3


Breast ca. MDA-
2.3
Lymph Node Pool
0.7


MB-231


Breast ca. BT 549
0.2
Fetal Skeletal Muscle
0.6


Breast ca. T47D
9.6
Skeletal Muscle Pool
0.4


Breast ca. MDA-N
0.2
Spleen Pool
0.2


Breast Pool
0.7
Thymus Pool
0.3


Trachea
0.6
CNS cancer (glio/astro)
0.5




U87-MG


Lung
0.2
CNS cancer (glio/astro)
0.1




U-118-MG


Fetal Lung
1.7
CNS cancer (neuro;met)
0.4




SK-N-AS


Lung ca. NCI-N417
0.1
CNS cancer (astro) SF-
0.1




539


Lung ca. LX-1
100.0
CNS cancer (astro)
0.1




SNB-75


Lung ca. NCI-H146
1.0
CNS cancer (glio) SNB-
0.9




19


Lung ca. SHP-77
0.1
CNS cancer (glio) SF-
9.3




295


Lung ca. A549
2.2
Brain (Amygdala) Pool
0.1


Lung ca. NCI-H526
0.1
Brain (cerebellum)
5.1


Lung ca. NCI-H23
0.9
Brain (fetal)
2.3


Lung ca. NCI-H460
0.2
Brain (Hippocampus)
0.0




Pool


Lung ca. HOP-62
0.5
Cerebral Cortex Pool
0.0


Lung ca. NCI-H522
1.1
Brain (Substantia nigra)
0.2




Pool


Liver
0.3
Brain (Thalamus) Pool
0.0


Fetal Liver
0.8
Brain (whole)
0.8


Liver ca. HepG2
0.2
Spinal Cord Pool
0.0


Kidney Pool
0.7
Adrenal Gland
0.2


Fetal Kidney
0.7
Pituitary gland Pool
0.0


Renal ca. 786-0
0.2
Salivary Gland
0.1


Renal ca. A498
0.2
Thyroid (female)
0.7


Renal ca. ACHN
0.2
Pancreatic ca. CAPAN2
3.8


Renal ca. UO-31
1.6
Pancreas Pool
0.6










[0840]

327





TABLE MG










Panel 1.3D













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag2874, Run
Ag2874, Run

Ag2874, Run
Ag2874, Run


Tissue Name
161973724
165721687
Tissue Name
161973724
165721687















Liver
4.9
5.6
Kidney (fetal)
0.0
0.0


adenocarcinoma


Pancreas
0.0
0.0
Renal ca. 786-0
0.0
0.0


Pancreatic ca.
0.0
0.0
Renal ca. A498
0.0
0.0


CAPAN 2


Adrenal gland
0.0
0.0
Renal ca RXF
0.0
0.0





393


Thyroid
0.0
6.3
Renal ca.
0.0
0.0





ACHN


Salivary gland
0.0
0.0
Renal ca. UO-
0.0
0.0





31


Pituitary gland
0.0
0.0
Renal ca. TK-
0.0
0.0





10


Brain (fetal)
0.0
3.8
Liver
0.0
3.1


Brain (whole)
3.1
6.1
Liver (fetal)
0.0
0.0


Brain (amygdala)
4.3
0.0
Liver ca.
0.0
0.0





(hepatoblast)





HepG2


Brain (cerebellum)
1.8
7.6
Lung
0.0
0.0


Brain
0.0
0.0
Lung (fetal)
4.5
4.1


(hippocampus)


Brain (substantia
0.0
3.5
Lung ca.
100.0
100.0


nigra)


(small cell)





LX-1


Brain (thalamus)
0.0
0.0
Lung ca.
0.0
3.2





(small cell)





NCI-H69


Cerebral Cortex
2.3
0.0
Lang ca. (s.cell
0.0
0.0





var.) SHP-77


Spinal cord
0.0
0.0
Lung ca. (large
0.0
0.0





cell) NCI-H460


glio/astro U87-MG
0.0
0.0
Lung ca. (non-
0.0
0.0





sm. cell) A549


glio/astro U-118-
0.0
0.0
Lung ca. (non-
0.0
0.0


MG


s.cell) NCI-





H23


astrocytoma
0.0
0.0
Lung ca. (non-
0.0
0.0


SW1783


s.cell) HOP-62


neuro*; met SK-N-
0.0
0.0
Lung ca. (non-
1.7
0.0


AS


s.cl) NCI-H522


astrocytoma SF-
3.8
0.0
Lung ca.
2.1
0.0


539


(squam.) SW





900


astrocytoma SNB-
0.0
0.0
Lung ca.
0.0
0.0


75


(squam.) NCI-





H596


glioma SNB-19
0.0
0.0
Mammary
0.0
0.0





gland


glioma U251
0.0
0.0
Breast ca.*
13.9
0.0





(pl.ef) MCF-7


glioma SF-295
10.7
12.5
Breast ca.*
2.6
0.0





(pl.et) MDA-





MB-231


Heart (fetal)
0.0
0.0
Breast ca.*
3.2
4.7





(pl.ef) T47D


Heart
0.0
0.0
Breast ca. BT-549
0.0
0.0


Skeletal muscle
0.0
5.3
Breast ca.
0.0
0.0


(fetal)


MDA-N


Skeletal muscle
0.0
0.0
Ovary
0.0
0.0


Bone marrow
17.9
6.1
Ovarian ca.
24.1
4.7





OVCAR-3


Thymus
18.7
0.0
Ovarian ca.
4.7
0.0





OVCAR-4


Spleen
0.0
0.0
Ovarian ca.
4.8
4.8





OVCAR-5


Lymph node
10.5
0.0
Ovarian ca.
0.0
0.0





OVCAR-8


Colorectal
4.9
3.1
Ovarian ca.
3.0
0.0





IGROV-1


Stomach
0.0
0.0
Ovarian ca.*
0.0
3.4





(ascites) SK-





OV-3


Small intestine
0.0
0.0
Uterus
0.0
6.5


Colon ca. SW480
2.7
0.0
Placenta
0.0
0.0


Colon ca.*
0.0
0.0
Prostate
10.8
2.7


SW620(SW480


met)


Colon ca. HT29
0.0
0.0
Prostate ca.*
0.0
0.0





(bone met)PC-3


Colon Ca. HCT-
0.0
0.0
Testis
0.0
0.0


116


Colon ca. CaCo-2
0.0
0.0
Melanoma
0.0
0.0





Hs688(A).T


Colon ca.
8.8
0.0
Melanoma*
0.0
0.0


tissue(ODO3866)


(met)





Hs688(B).T


Colon Ca. HCC-
17.1
2.7
Melanoma
0.0
0.0


2998


UACC-62


Gastric ca.* (liver
28.9
13.4
Melanoma
0.0
0.0


met) NCI-N87


M14


Bladder
13.6
0.0
Melanoma
0.0
0.0





LOX IMVI


Trachea
6.7
5.6
Melanoma *
0.0
0.0





(met) SK-





MEL-5


Kidney
2.6
0.0
Adipose
0.0
0.0










[0841]

328





TABLE MH










Panel 2D











Rel. Exp.(%) Ag2874,

Rel. Exp.(%) Ag2874,


Tissue Name
Run 161973958
Tissue Name
Run 161973958













Normal Colon
24.3
Kidney Margin
0.0




8120608


CC Well to Mod Diff
0.0
Kidney Cancer
0.0


(ODO3866)

8120613


CC Margin (ODO3866)
26.2
Kidney Margin
21.3




8120614


CC Gr.2 rectosigmoid
0.0
Kidney Cancer
0.0


(ODO3868)

9010320


CC Margin (ODO3868)
13.8
Kidney Margin
0.0




9010321


CC Mod Diff (ODO3920)
11.7
Normal Uterus
0.0


CC Margin (ODO3920)
0.0
Uterus Cancer 064011
10.8


CC Gr.2 ascend colon
65.1
Normal Thyroid
20.2


(ODO3921)


CC Margin (ODO3921)
0.0
Thyroid Cancer
42.6




064010


CC from Partial
27.9
Thyroid Cancer
24.1


Hepatectomy (ODO4309)

A302152


Mets


Liver Margin (ODO4309)
0.0
Thyroid Margin
0.0




A302153


Colon mets to lung
7.5
Normal Breast
0.0


(OD04451-01)


Lung Margin (OD04451-
0.0
Breast Cancer
0.0


02)

(OD04566)


Normal Prostate 6546-1
13.0
Breast Cancer
49.7




(OD04590-01)


Prostate Cancer
0.0
Breast Cancer Mets
18.8


(OD04410)

(OD04590-03)


Prostate Margin
0.0
Breast Cancer
58.2


(OD04410)

Metastasis (OD04655-




05)


Prostate Cancer
59.5
Breast Cancer 064006
40.9


(OD04720-01)


Prostate Margin
28.7
Breast Cancer 1024
100.0


(OD04720-02)


Normal Lung 061010
0.0
Breast Cancer
9.7




9100266


Lung Met to Muscle
0.0
Breast Margin
43.5


(ODO4286)

9100265


Muscle Margin
0.0
Breast Cancer
32.5


(ODO4286)

A209073


Lung Malignant Cancer
0.0
Breast Margin
13.4


(OD03126)

A209073


Lung Margin (OD03126)
11.3
Normal Liver
0.0


Lung Cancer (OD04404)
0.0
Liver Cancer 064003
0.0


Lung Margin (OD04404)
0.0
Liver Cancer 1025
0.0


Lung Cancer (OD04565)
16.3
Liver Cancer 1026
0.0


Lung Margin (OD04565)
0.0
Liver Cancer 6004-T
0.0


Lung Cancer (OD04237-
0.0
Liver Tissue 6004-N
0.0


01)


Lung Margin (OD04237-
0.0
Liver Cancer 6005-T
0.0


02)


Ocular Mel Met to Liver
0.0
Liver Tissue 6005-N
0.0


(ODO4310)


Liver Margin (ODO4310)
0.0
Normal Bladder
58.2


Melanoma Mets to Lung
0.0
Bladder Cancer 1023
0.0


(OD04321)


Lung Margin (OD04321)
0.0
Bladder Cancer
16.6




A302173


Normal Kidney
16.5
Bladder Cancer
66.0




(OD04718-01)


Kidney Ca, Nuclear grade
16.0
Bladder Normal
0.0


2 (OD04338)

Adjacent (OD04718-




03)


Kidney Margin
14.1
Normal Ovary
0.0


(OD04338)


Kidney Ca Nuclear grade
13.9
Ovarian Cancer
85.9


1/2 (OD04339)

064008


Kidney Margin
13.0
Ovarian Cancer
0.0


(OD04339)

(OD04768-07)


Kidney Ca, Clear cell type
0.0
Ovary Margin
0.0


(OD04340)

(OD04768-08)


Kidney Margin
0.0
Normal Stomach
14.7


(OD04340)


Kidney Ca, Nuclear grade
14.8
Gastric Cancer
0.0


3 (OD04348)

9060358


Kidney Margin
0.0
Stomach Margin
0.0


(OD04348)

9060359


Kidney Cancer
0.0
Gastric Cancer
0.0


(OD04622-01)

9060395


Kidney Margin
0.0
Stomach Margin
14.0


(OD04622-03)

9060394


Kidney Cancer
0.0
Gastric Cancer
17.2


(OD04450-01)

9060397


Kidney Margin
19.2
Stomach Margin
0.0


(OD04450-03)

9060396


Kidney Cancer 8120607
23.5
Gastric Cancer 064005
20.3










[0842]

329





TABLE MI










Panel 3D











Rel. Exp.(%)

Rel. Exp.(%)



Ag2874, Run

Ag2874, Run


Tissue Name
164543575
Tissue Name
164543575













Daoy-Medulloblastoma
0.0
Ca Ski-Cervical epidermoid
0.0




carcinoma (metastasis)


TE671-Medulloblastoma
0.0
ES-2-Ovarian clear cell-
0.0




carcinoma


D283 Med-
0.0
Ramos-Stimulated with
0.0


Medulloblastoma

PMA/ionomycin 6 h


PFSK-1-Primitive
0.0
Ramos-Stimulated with
0.0


Neuroectodermal

PMA/ionomycin 14 h


XF-498-CNS
0.0
MEG-01-Chronic




myelogenous leukemia
0.0




(megokaryoblast)


SNB-78-Glioma
0.0
Raji-Burkitt's lymphoma
3.3


SF-268-Glioblastoma
0.0
Daudi-Burkitt's lymphoma
0.0


T98G-Glioblastoma
0.0
U266-B-cell plasmacytoma
0.0


SK-N-SH-
0.0
CA46-Burkitt's lymphoma
0.0


Neuroblastoma


(metastasis)


SF-295-Glioblastoma
0.0
RL-non-Hodgkin's B-cell
0.0




lymphoma


Cerebellum
0.5
JM1-pre-B-cell lymphoma
0.0


Cerebellum
2.3
Jurkat-T cell leukemia
0.0


NCI-H292-
16.8
TF-1-Erythroleukemia
0.0


Mucoepidermoid lung


carcinoma


DMS-114-Small cell
0.0
HUT 78-T-cell lymphoma
8.2


lung cancer


DMS-79-Small cell lung
4.2
U937-Histiocytic lymphoma
0.0


cancer


NCI-H146-Small cell
0.0
KU-812-Myelogenous
0.0


lung cancer

leukemia


NCI-H526-Small cell
0.0
769-P-Clear cell renal
0.0


lung cancer

carcinoma


NCI-N417-Small cell
0.0
Caki-2-Clear cell renal
0.0


lung cancer

carcinoma


NCI-H82-Small cell lung
0.0
SW 839-Clear cell renal
2.9


cancer

carcinoma


NCI-H157-Squamous
0.0
G401-Wilm's tumor
0.0


cell lung cancer


(metastasis)


NCI-H1155-Large cell
0.0
Hs766GT-Pancreatic carcinoma
3.6


lung cancer

(LN metastasis)


NCI-H1299-Large cell
16.6
CAPAN-1-Pancreatic
4.4


lung cancer

adenocarcinoma (liver




metastasis)


NCI-H727-Lung
0.0
SU86.86-Pancreatic
100.0


carcinoid

carcinoma (liver metastasis)


NCI-UMC-11-Lung
0.0
BxPC-3-Pancreatic
0.0


carcinoid

adenocarcinoma


LX-1-Small cell lung
48.0
HPAC-Pancreatic
3.6


cancer

adenocarcinoma


Colo-205-Colon cancer
9.9
MIA PaCa-2-Pancreatic
0.0




carcinoma


KM12-Colon cancer
0.0
CFPAC-1-Pancreatic ductal
4.4




adenocarcinoma


KM20L2-Colon cancer
0.0
PANC-1-Pancreatic
0.0




epithelioid ductal carcinoma


NCI-H716-Colon cancer
0.0
T24-Bladder carcinoma
3.9




(transitional cell)


SW-48-Colon
0.0
5637-Bladder carcinoma
0.0


adenocarcinoma


SW1116-Colon
0.0
HT-1197-Bladder carcinoma
0.0


adenocarcinoma


LS 174T-Colon
8.3
UM-UC-3-Bladder carcinma
0.0


adenocarcinoma

(transitional cell)


SW-948-Colon
5.1
A204-Rhabdomyosarcoma
0.0


adenocarcinoma


SW-480-Colon
0.0
HT-1080-Fibrosarcoma
0.0


adenocarcinoma


NCI-SNU-5-Gastric
13.5
MG-63-Osteosarcoma
0.0


carcinoma


KATO III-Gastric
0.0
SK-LMS-1-Leiomyosarcoma
4.1


carcinoma

(vulva)


NCI-SNU-16-Gastric
0.0
SJRH30-Rhabdomyosarcoma
0.0


carcinoma

(met to bone marrow)


NCI-SNU-1-Gastric
0.0
A431-Epidermoid carcinoma
0.0


carcinoma


RF-1-Gastric
0.0
WM266-4-Melanoma
0.0


adenocarcinoma


RF-48-Gastric
0.0
DU 145-Prostate carcinoma
0.0


adenocarcinoma

(brain metastasis)


MKN-45-Gastric
0.0
MDA-MB-468-Breast
6.5


carcinoma

adenocarcinoma


NCI-N87-Gastric
0.0
SCC-4-Squamous cell
0.0


carcinoma

carcinoma of tongue


OVCAR-5-Ovarian
10.2
SCC-9-Squamous cell
0.0


carcinoma

carcinoma of tongue


RL95-2-Uterine
0.0
SCC-15-Squamous cell
0.0


carcinoma

carcinoma of tongue


HelaS3-Cervical
0.0
CAL 27-Squamous cell
21.6


adenocarcinoma

carcinoma of tongue










[0843]

330





TABLE MJ










Panel 4.1D











Rel.Exp.(%)

Rel.Exp.(%)



Ag3948, Run

Ag3948, Run


Tissue Name
170684837
Tissue Name
170684837













Secondary Th1 act
1.6
HUVEC IL-1 beta
3.1


Secondary Th2 act
8.6
HUVEC IFN gamma
7.4


Secondary Tr1 act
4.4
HUVEC TNF alpha + IFN
2.7




gamma


Secondary Th1 rest
0.3
HUVEC TNF alpha + IL4
0.9


Secondary Th2 rest
3.9
HUVEC IL-11
6.0


Secondary Tr1 rest
1.6
Lung Microvascular EC
7.3




none


Primary Th1 act
0.3
Lung Microvascular EC
2.7




TNF alpha + IL-1 beta


Primary Th2 act
1.6
1 Microvascular Dermal EC
0.0




none


Primary Tr1 act
0.0
Microsvascular Dermal EC
0.5




TNF alpha + IL-1 beta


Primary Th1 rest
0.0
Bronchial epithelium
15.5




TNF alpha + IL1 beta


Primary Th2 rest
1.6
Small airway epitheliurn
6.3




none


Primary Tr1 rest
0.4
Small airway epithelium
20.4




TNF alpha + IL-1 beta


CD45RA CD4
0.0
Coronery artery SMC rest
6.0


lymphocyte act


CD45RO CD4
1.2
Coronery artery SMC
1.6


lymphocyte act

TNF alpha + IL-1 beta


CD8 lymphocyte act
2.8
Astrocytes rest
0.3


Secondary CD8
2.0
Astrocytes TNF alpha + IL-
1.5


lymphocyte rest

1 beta


Secondary CD8
1.2
KU-812 (Basophil) rest
3.4


lymphocyte act


CD4 lymphocyte none
1.6
KU-812 (Basophil)
6.3




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
4.6
CCD1106 (Keratinocytes)
14.6


CD95 CH11

none


LAK cells rest
1.6
CCD1106 (Keratinocytes)
20.6




TNF alpha + IL-1 beta


LAK cells IL-2
1.7
Liver cirrhosis
0.0


LAK cells IL-2 + IL-12
3.6
NCI-H292 none
49.7


LAK cells IL-2 + IFN
0.0
NCI-H292 IL-4
79.6


gamma


LAK cells IL-2 + IL-18
1.7
NCI-H292 IL-9
92.7


LAK cells
0.0
NCI-H292 IL-13
58.2


PMA/ionomycin


NK Cells IL-2 rest
4.9
NCI-H292 IFN gamma
50.0


Two Way MLR 3 day
3.1
HPAEC none
8.6


Two Way MLR 5 day
1.4
HPAEC TNF alpha + IL-1
3.5




beta


Two Way MLR 7 day
4.1
Lung fibroblast none
2.7


PBMC rest
2.5
Lung fibroblast TNF
2.9




alpha + IL-1 beta


PBMC PWM
2.3
Lung fibroblast IL-4
2.9


PBMC PHA-L
0.4
Lung fibroblast IL-9
4.0


Ramos (B cell) none
0.0
Lung fibroblast IL-13
5.5


Ramos (B cell)
0.0
Lung fibroblast IFN
5.8


ionomycin

gamma


B lymphocytes PWM
0.0
Dermal fibroblast
16.2




CCD1070 rest


B lymphocytes CD40L
7.6
Dermal fibroblast
4.7


and IL-4

CCD1070 TNF alpha


EOL-1 dbcAMP
1.9
Dermal fibroblast
1.8




CCD1070 IL-1 beta


EOL-1 dbcAMP
5.5
Dermal fibroblast IFN
6.7


PMA/ionomycin

gamma


Dendritic cells none
1.6
Dermal fibroblast IL-4
4.1


Dendritic cells LPS
0.0
Dermal fibroblasts rest
12.2


Dendritic cells anti-
0.7
Neutrophils TNFa + LPS
0.7


CD40


Monocytes rest
2.8
Neutrophils rest
1.5


Monocytes LPS
9.3
Colon
5.5


Macrophages rest
0.0
Lung
11.6


Macrophages LPS
0.8
Thymus
40.6


HUVEC none
0.3
Kidney
100.0


HUVEC starved
9.9










[0844]

331





TABLE MK










Panel 4D













Rel.
Rel.

Rel.
Rel.



Exp.(%)
Exp.(%)

Exp.(%)
Exp.(%)



Ag2874,
Ag3532,

Ag2874,
Ag3532,



Run
Run

Run
Run


Tissue Name
159776813
166444749
Tissue Name
159776813
166444749















Secondary Th1 act
0.0
0.0
HUVEC IL- 1 beta
0.0
0.0


Secondary Th2 act
0.0
0.0
HUVEC IFN
4.4
5.5





gamma


Secondary Tr1 act
0.0
7.2
HUVEC TNF
0.0
0.0





alpha + IFN







gamma


Secondary Th1 rest
0.0
0.0
HUVEC TNF
0.0
0.0





alpha + IL4


Secondary Th2 rest
0.0
0.0
HUVEC IL-11
0.0
0.0


Secondary Tr1 rest
0.0
3.3
Lung
0.0
9.0





Microvascular EC





none


Primary Th1 act
0.0
0.0
Lung
0.0
0.0





Microvascular EC





TNF alpha + IL-





1 beta


Primary Th2 act
0.0
0.0
Microvascular
0.0
0.0





Dermal EC none


Primary Tr1 act
0.0
0.0
Microsvascular
0.0
0.0





Dermal EC





TNF alpha + IL-





1 beta


Primary Th1 rest
0.0
6.4
Bronchial
0.0
0.0





epithelium





TNF alpha +





IL1 beta


Primary Th2 rest
5.6
0.0
Small airway
5.2
21.2





epithelium none


Primary Tr1 rest
8.6
0.0
Small airway
25.5
19.6





epithelium





TNF alpha + IL-





1 beta


CD45RA CD4
0.0
0.0
Coronery artery
0.0
2.1


lymphocyte act


SMC rest


CD45RO CD4
0.0
0.0
Coronery artery
0.0
0.0


lymphocyte act


SMC TNF alpha +





IL-1 beta


CD8 lymphocyte
0.0
0.0
Astrocytes rest
0.0
0.0


act


Secondary CD8
0.0
0.0
Astrocytes
0.0
5.8


lymphocyte rest


TNF alpha + IL-





1 beta


Secondary CD8
0.0
0.0
KU-812 (Basophil)
0.0
0.0


lymphocyte act


rest


CD4 lymphocyte
4.1
6.9
KU-812 (Basophil)
0.0
3.0


none


PMA/ionomycin


2ry
0.0
0.0
CCD1106
13.5
6.7


Th1/Th2/Tr1_anti-


(Keratinocytes)


CD95 CH11


none


LAK cells rest
0.0
0.0
CCD1106
0.0
69.3





(Keratinocytes)





TNF alpha + IL-





1 beta


LAK cells IL-2
0.0
0.0
Liver cirrhosis
0.0
0.0


LAK cells IL-2 +
0.0
0.0
Lupus kidney
0.0
4.2


IL-12


LAK cells IL-
0.0
3.5
NCI-H292 none
71.7
85.9


2 + IFN gamma


LAK cells IL-2 +
0.0
0.0
NCI-H292 IL-4
53.6
100.0


IL-18


LAK cells
0.0
0.0
NCI-H292 IL-9
100.0
68.8


PMA/ionomycin


NK Cells IL-2 rest
0.0
3.4
NCI-H292 IL-13
36.9
60.3


Two Way MLR 3
0.0
0.0
NCI-H292 IFN
8.1
64.2


day


gamma


Two Way MLR 5
0.0
7.0
HPAEC none
0.0
0.0


day


Two Way MLR 7
0.0
0.9
HPAEC TNF
0.0
0.0


day


alpha + IL-1 beta


PBMC rest
0.0
0.0
Lung fibroblast
0.0
0.0





none


PBMC PWM
8.2
6.9
Lung fibroblast
4.0
4.9





TNF alpha + IL-1





beta


PBMC PHA-L
0.0
0.0
Lung fibroblast IL-4
0.0
0.0


Ramos (B cell)
0.0
0.0
Lung fibroblast IL-9
4.6
0.0


none


Ramos (B cell)
0.0
0.0
Lung fibroblast IL-
0.0
0.0


ionomycin


13


B lymphocytes
0.0
3.4
Lung fibroblast
5.0
0.0


PWM


IFN gamma


B lymphocytes
0.0
5.0
Dermal fibroblast
4.6
3.0


CD40L and IL-4


CCD1070 rest


EOL-1 dbcAMP
0.0
0.0
Dermal fibroblast
0.0
0.0





CCD1070 TNF





alpha


EOL-1 dbcAMP
3.7
0.0
Dermal fibroblast
0.0
0.0


PMA/ionomycin


CCD1070 IL-1





beta


Dendritic cells none
0.0
0.0
Dermal fibroblast
4.6
6.6





IFN gamma


Dendritic cells LPS
0.0
0.0
Dermal fibroblast
0.0
6.5





IL-4


Dendritic cells anti-
0.0
2.1
IBD Colitis 2
0.0
0.0


CD40


Monocytes rest
4.5
0.0
IBD Crohn's
0.0
0.0


Monocytes LPS
8.6
2.7
Colon
12.0
13.7


Macrophages rest
0.0
0.0
Lung
0.0
0.0


Macrophages LPS
0.0
0.0
Thymus
0.0
7.6


HUVEC none
0.0
0.0
Kidney
4.0
17.6


HUVEC starved
0.0
3.5










[0845] AI_comprehensive panel_v1.0 Summary: Ag3948 This panel confirms expression of the CG59293-01 gene in tissue samples related to the immune and inflammatory response. Please see Panels 4 and 4.1D for discussion of utility of this gene in inflammation.


[0846] CNS_neurodegeneration_v1.0 Summary: Ag3948 This panel does not show differential expression of the CG59293-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel General_screening_panel_v1.4 for discussion of utility of this gene in the central nervous system. Ag3532 Expression of the CG59293-01 gene is low/undetectable in all samples on this panel (CTs>35).


[0847] General_screening_panel_v1.4 Summary: Ag3948 The expression of the CG59293-01 gene, an organic anion transporter homolog, is highest in a small cell lung cancer line LX-1 (CT-28.2). This gene is also expressed in some ovarian, breast, CNS, gastric. pancreatic, renal and colon cancer cell lines. Therefore, expression of this gene may be associated with these forms of cancer and therapeutic modulation of this gene might be of use in the treatment or diagnosis of these cancers.


[0848] This gene is also expressed at low levels in the cerebellum and fetal brain. The organic anion transporters are involved in transport across the blood brain barrier. This gene may therefore be of use in drug delivery to the CNS, specifically for compounds such as nerve growth factors protein therapeutics which are believed to have numerous uses in the CNS, but lack a delivery system.


[0849] References:


[0850] Sugiyama D, Kusuhara H, Shitara Y, Abe T, Meier P J, Sekine T, Endou H, Suzuki H, Sugiyama Y. Characterization of the efflux transport of 17beta-estradiol-D-17beta-glucuronide from the brain across the blood-brain barrier.


[0851] Panel 1.3D Summary: Ag2874 The expression of the CG59293-01 gene was assessed in two independent runs on this panel with reasonable concordance between the runs. The highest expression is seen in a small cell lung cancer line LX-1 (CTs=3 1-32), consistent with expression in Panel 1.3D. This gene is also expressed in some ovarian, breast, CNS, gastric and colon cancer cell lines. Therefore, expression of this gene might be associated with these forms of cancer and therapeutic modulation of this gene might be of use in the treatment or diagnosis of these cancers.


[0852] Panel 2D Summary: Ag2874 The CG59293-01 gene is expressed at low levels in the tissues used for panel 2D. The highest expression is seen in a breast cancer sample (CT=34.2). Significant expression is also seen in single samples of ovarian, bladder, prostate and colon cancers compared with the normal adjacent tissue. This indicates that the expression of this gene might be associated with these forms of cancer and therapeutic modulation of this gene might be of use in the treatment or diagnosis of these cancers.


[0853] Panel 3D Summary: Ag2874 Highest expression of the CG59293-01 gene is seen in a pancreatic cancer cell line (CT=31.6). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel. In addition, significant expression of this gene is associated with samples derived from lung cancer cell lines (CTs=32-34), an ovarian cancer, gastric cancer and squamous cell carcinoma of tongue. Therefore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of these cancers.


[0854] Panel 4D Summary: Ag3498 The highest expression of the CG59293-01 gene is found in the kidney and in the pulmonary muco-epidermoid cell line NCI-H292 (CTs=31). The expression of this gene, although constitutive in the H292 cell line, is up regulated upon treatment with IL-4, II-9 and IL-13, cytokines that have been linked to the pathogenesis of asthma and/or COPD.


[0855] This gene is also found in small airway epithelium and keratinocytes treated with the inflammatory cytokines TNF-a and IL-1b. Therefore, modulation of the expression or activity of the protein encoded by this transcript through the application or small molecule therapeutics may be useful in the treatment of asthma, COPD, emphysema, psoriasis and wound healing.


[0856] Panel 4D Summary: Ag2874/Ag3532 The expression of the CG59293-01 transcript detected by two sets of primers was observed mostly in NCI-H292 (CFs=32-33). Up-regulation of this transcript in H292 was found upon treatment with IL-4 (Ag 3532) or IL-9 (Ag 2874), both cytokines are involved in the pathogenesis of asthma and/or COPD. This transcript was also detected in small airway epithelium and keratinocytes. Therefore, modulation of the expression or activity of the protein encoded by this transcript by small molecules could be useful for the treatment of asthma, COPD and or emphysema and also for the treatment of skin inflammatory diseases such as psoriasis or wound healing.



N. NOV19a (CG59284-01: SOLUTE CARRIER FAMILY 22)

[0857] Expression of gene CG59284-01 was assessed using the primer-probe set Ag3528, described in Table NA.
332TABLE NAProbe Name Ag3528StartPrimersSequencesLengthPositionForward5′-gtgtggatggctggqtctat-3′(SEQ ID NO:263)20437ProbeTET-5′-cagcatcttcacctccacaatcgtg-3′-TAMRA(SEQ ID NO:264)25462Revers5′-ttcagagcatgagagtcacaca-3′(SEQ ID NO:265)22503


[0858] CNS_neurodegeneration_v1.0 Summary: Ag3528 Expression of the CG59284-01 gene is low/undetectable in all samples on this panel (CTs>35).


[0859] General_screen_panel_v1.4 Summary: Ag3528 Expression of the CG59284-01 gene is low/undetectable in all samples on this panel (CTs>35).


[0860] Panel 4.1D Summary: Ag3528 Expression of the CG59284-01 gene is low/undetectable in all samples on this panel (CTs>35).



O. NOV20a (CG59278-01: OLFACTORY RECEPTOR P2)

[0861] Expression of gene CG59278-01 was assessed using the primer-probe set Ag3526, described in Table OA. Results of the RTQ-PCR runs are shown in Table OB.
333TABLE OAProbe Name Ag3526StartPrimersSequencesLengthPositionForward5′-gtagtgccaaggccttctctac-3′(SEQ ID NO:266)22738ProbeTET-5′-ctcccacgtaactgtggtggcactat-3′-TAMRA(SEQ ID NO:267)26766Reverse5′-actgtgaaggcagaagcataga-3′(SEQ ID NO:268)22792


[0862]

334





TABLE OB










Panel 4.1D











Rel. Exp.(%)

Rel. Exp.(%)



Ag3526, Run

Ag3526, Run


Tissue Name
169840752
Tissue Name
169840752













Secondary Th1 act
0.0
HUVEC IL-1 beta
0.0


Secondary Th2 act
0.0
HUVEC IFN gamma
0.0


Secondary Tr1 act
0.5
HUVEC TNF alpha + IFN
0.0




gamma


Secondary Th1 rest
0.0
HUVEC TNF alpha + IL4
0.0


Secondary Th2 rest
0.0
HUVEC IL-11
0.0


Secondary Tr1 rest
0.0
Lung Microvascular EC
0.0




none


Primary Th1 act
0.0
Lung Microvascular EC
0.0




TNF alpha + IL-1 beta


Primary Th2 act
0.3
Microvascular Dermal EC
0.0




none


Primary Tr1 act
0.0
Microsvasular Dermal EC
0.0




TNF alpha + IL-1 beta


Primary Th1 rest
0.0
Bronchial epithelium
0.0




TNF alpha + IL1 beta


Primary Th2 rest
0.0
Small airway epithelium
0.0




none


Primary Tr1 rest
0.0
Small airway epithelium
0.0




TNF alpha + IL-1 beta


CD45RA CD4
0.0
Coronery artery SMC rest
0.0


lymphocyte act


CD45RO CD4
0.0
Coronery artery SMC
0.0


lymphocyte act

TNF alpha + IL-1 beta


CD8 lymphocyte act
0.0
Astrocytes rest
0.0


Secondary CD8
0.0
Astrocytes TNF alpha + IL-
0.0


lymphocyte rest

1 beta


Secondary CD8
0.0
KU-812 (Basophil) rest
0.0


lymphocyte act


CD4 lymphocyte none
0.0
KU-812 (Basophil)
0.0




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
0.0
CCD1106 (Keratinocytes)
0.0


CD95 CH11

none


LAK cells rest
0.0
CCD1106 (Keratinocytes)
0.0




TNF alpha + IL-1 beta


LAK cells IL-2
0.0
Liver cirrhosis
0.0


LAK cells IL-2 + IL-12
0.0
NCI-H292 none
0.0


LAK cells IL-2 + IFN
0.0
NCI-H292 IL-4
0.0


gamma


LAK cells IL-2 + IL-18
0.0
NCI-H292 IL-9
0.0


LAK cells
0.4
NCI-H292 IL-13
0.0


PMA/ionomycin


NK Cells IL-2 rest
0.0
NCI-H292 IFN gamma
0.0


Two Way MLR 3 day
0.0
HPAEC none
0.0


Two Way MLR 5 day
0.0
HPAEC TNF alpha + IL-1
0.0




beta


Two Way MLR 7 day
0.0
Lung fibroblast none
0.0


PBMC rest
0.0
Lung fibroblast TNF
0.0




alpha + IL-1 beta


PBMC PWM
0.0
Lung fibroblast IL-4
0.8


PBMC PHA-L
0.0
Lung fibroblast IL-9
0.0


Ramos (B cell) none
0.0
Lung fibroblast IL-13
0.4


Ramos (B cell)
0.0
Lung fibroblast IFN
0.0


ionomycin

gamma


B lymphocytes PWM
0.0
Dermal fibroblast
0.0




CCD1070 rest


B lymphocytes CD40L
0.0
Dermal fibroblast
0.0


and IL-4

CCD1070 TNF alpha


EOL-1 dbcAMP
0.0
Dermal fibroblast
0.0




CCD1070 IL-1 beta


EOL-1 dbcAMP
0.0
Dermal fibroblast IFN
0.0


PMA/ionomycin

gamma


Dendritic cells none
0.0
Dermal fibroblast IL-4
0.0


Dendritic cells LPS
0.6
Dermal Fibroblasts rest
0.0


Dendritic cells anti-
0.3
Neutrophils TNFa + LPS
0.4


CD40


Monocytes rest
7.0
Neutrophils rest
100.0


Monocytes LPS
5.6
Colon
0.0


Macrophages rest
0.7
Lung
0.4


Macrophages LPS
0.0
Thymus
0.7


HUVEC none
0.0
Kidney
0.0


HUVEC starved
0.0










[0863] CNS_neurodegeneration_v1.0 Summary: Ag3526 Expression of the CG59278-01 gene is low/undetectable in all samples on this panel (CTs>35).


[0864] General_screening_panel_v1.4 Summary: Ag3526 Expression of the CG59278-01 gene is low/undetectable in all samples on this panel (CTs>35). (Data not shown). This gene encodes a G protein-coupled receptor (GPCR), a type of cell surface receptor involved in signal transduction. This gene product is most similar to members of the odorant receptor subfamily of GPCRs. Based on analogy to other odorant receptor genes, we predict that expression of this gene may be highest in nasal epithelium, a sample not represented on this panel.


[0865] Panel 4.1 D Summary: Ag3526 Expression of the CG59278-01 gene is restricted to a sample derived from resting neutrophils (CT=28.2). Thus, expression of this gene could be used as a marker of these cells. This expression is markedly reduced (CT=36.3) in neutrophils activated by TNF-alpha+LPS. This expression profile suggest that the protein encoded by this gene is produced by resting neutrophils but not by activated neutrophils. Therefore, the gene product may reduce activation of these inflammatory cells and be useful as a protein therapeutic to reduce or eliminate the symptoms in patients with Crohn's disease, ulcerative colitis, multiple sclerosis, chronic obstructive pulmonary disease, asthma, emphysema, rheumatoid arthritis, lupus erythematosus, or psoriasis. In addition, small molecule or antibody antagonists of this gene product may be effective in increasing the immune response in patients with AIDS or other immunodeficiencies.



P. NOV21a and NOV21b (CG59274-01 and CG59274-02: LIPOMA HMGIC FUSION PARTNER)

[0866] Expression of gene CG59274-01 and CG59274-02 was assessed using the primer-probe set Ag3525, described in Table PA. Results of the RTQ-PCR runs are shown in Tables PB, PC and PD. Please note that CG59274-02 represents a full-length physical clone of the CG59274-01 gene, validating the prediction of the gene sequence.
335TABLE PAProbe Name Ag3525StartPrimerSequencesLengthPositionForward5′-gagagcatcatgaggaatacca-3′(SEQ ID NO:269)22664ProbeTET-5′-accattgcctcaaaccttgagctttg-3′-TAMRA(SEQ ID NO:270)26707Reverse5′-ccaccctctccaatcttcttt-3′(SEQ ID NO:271)21733


[0867]

336





TABLE PB










CNS_neurodegeneration_v1.0











Rel. Exp.(%) Ag3525,

Rel. Exp.(%) Ag3525,


Tissue Name
Run 210630172
Tissue Name
Run 210630172













AD 1 Hippo
8.7
Control (Path) 3
8.1




Temporal Ctx


AD 2 Hippo
50.0
Control (Path) 4
39.2




Temporal Ctx


AD 3 Hippo
4.2
AD 1 Occipital Ctx
7.6


AD 4 Hippo
10.4
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 hippo
36.3
AD 3 Occipital Ctx
1.1


AD 6 Hippo
100.0
AD 4 Occipital Ctx
15.4


Control 2 Hippo
28.5
AD 5 Occipital Ctx
7.9


Control 4 Hippo
31.9
AD 6 Occipital Ctx
18.0


Control (Path) 3
7.2
Control 1 Occipital
0.0


Hippo

Ctx


AD 1 Temporal Ctx
18.4
Control 2 Occipital
20.7




Ctx


AD 2 Temporal Ctx
39.0
Control 3 Occipital
6.0




Ctx


AD 3 Temporal Ctx
3.0
Control 4 Occipital
16.6




Ctx


AD 4 Temporal Ctx
26.6
Control (Path) 1
49.0




Occipital Ctx


AD 5 Inf Temporal
40.9
Control (Path) 2
6.4


Ctx

Occipital Ctx


AD 5 SupTemporal
60.7
Control (Path) 3
3.1


Ctx

Occipital Ctx


AD 6 Inf Temporal
50.3
Control (Path) 4
4.5


Ctx

Occipital Ctx


AD 6 Sup Temporal
49.0
Control 1 Parietal
0.6


Ctx

Ctx


Control 1 Temporal
0.6
Control 2 Parietal
30.6


Ctx

Ctx


Control 2 Temporal
22.1
Control 3 Parietal
5.3


Ctx

Ctx


Control 3 Temporal
12.2
Control (Path) 1
30.6


Ctx

Parietal Ctx


Control 4 Temporal
28.9
Control (Path) 2
23.8


Ctx

Parietal Ctx


Control (Path) 1
30.6
Control (Path) 3
2.6


Temporal Ctx

Parietal Ctx


Control (Path) 2
23.7
Control (Path) 4
19.8


Temporal Ctx

Parietal Ctx










[0868]

337





TABLE PC










General_screening_panel_v1.4











Rel. Exp.(%) Ag3525,

Rel. Exp.(%) Ag3525,


Tissue Name
Run 220356041
Tissue Name
Run 220356041













Adipose
1.9
Renal ca. TK-10
0.7


Melanoma*
0.0
Bladder
0.6


Hs688(A).T


Melanoma*
0.0
Gastric ca. (liver met.)
1.9


Hs688(B).T

NCI-N87


Melanoma* M14
0.7
Gastric ca. KATO III
0.0


Melanoma*
0.0
Colon ca. SW-948
0.0


LOXIMVI


Melanoma* SK-
0.0
Colon ca. SW480
0.6


MEL-5


Squamous cell
0.7
Colon ca.* (SW480
0.0


carcinoma SCC-4

met) SW620


Testis Pool
2.6
Colon ca. HT29
0.0


Prostate ca.* (bone
0.0
Colon ca. HCT-116
0.0


met) PC-3


Prostate Pool
5.3
Colon ca. CaCo-2
0.7


Placenta
1.2
Colon cancer tissue
0.0


Uterus Pool
0.9
Colon ca. SW1116
0.0


Ovarian ca. OVCAR-3
11.9
Colon ca.Colo-205
0.0


Ovarian ca. SK-OV-3
0.0
Colon ca. SW-48
0.0


Ovarian ca. OVCAR-4
0.0
Colon Pool
3.6


Ovarian ca. OVCAR-5
0.0
Small Intestine Pool
4.2


Ovarian ca. IGROV-1
1.4
Stomach Pool
0.4


Ovarian ca. OVCAR-8
2.0
Bone Marrow Pool
1.7


Ovary
8.5
Fetal Heart
4.2


Breast ca. MCF-7
1.8
Heart Pool
3.1


Breast ca. MDA-
0.0
Lymph Node Pool
2.7


MB-231


Breast ca. BT 549
1.9
Fetal Skeletal Muscle
0.5


Breast ca. T47D
1.1
Skeletal Muscle Pool
5.4


Breast ca. MDA-N
2.7
Spleen Pool
6.7


Breast Pool
0.7
Thymus Pool
9.9


Trachea
39.8
CNS cancer (glio/astro)
0.0




U87-MG


Lung
5.0
CNS cancer (glio/astro)
0.0




U-118-MG


Fetal Lung
13.7
CNS cancer (neuro; met)
0.6




SK-N-AS


Lung ca. NCI-N417
0.0
CNS cancer (astro) SF-
0.0




539


Lung ca. LX-1
0.0
CNS cancer (astro)
4.6




SNB-75


Lung ca. NCI-H146
4.8
CNS cancer (glio) SNB-19
0.7


Lung ca. SHP-77
0.0
CNS cancer (glio) SF-295
5.9


Lung ca. A549
0.0
Brain (Amygdala) Pool
46.3


Lung ca. NCI-H526
0.0
Brain (cerebellum)
4.6


Lung ca. NCI-H23
1.1
Brain (fetal)
6.4


Lung ca. NCI-H460
0.0
Brain (Hippocampus)
70.2




Pool


Lung ca.HOP-62
0.0
Cebrebral Cortex Pool
49.7


Lung ca. NCI-H522
0.0
Brain (Substantia nigra)
23.5




Pool


Liver
0.0
Brain (Thalamus) Pool
100.0


Fetal Liver
1.3
Brain (whole)
21.8


Liver ca. HepG2
0.0
Spinal Cord Pool
18.4


Kidney Pool
8.4
Adrenal Gland
3.1


Fetal Kidney
8.5
Pituitary gland Pool
50.3


Renal ca. 786-0
0.0
Salivary Gland
7.7


Renal ca. A498
0.0
Thyroid (female)
17.0


Renal ca. ACHN
0.0
Pancreatic ca. CAPAN2
0.0


Renal ca. UO-31
0.4
Pancreas Pool
0.0










[0869]

338





TABLE PD










Panel 4D











Rel. Exp.(%)

Rel. Exp.(%)



Ag3525, Run

Ag3525, Run


Tissue Name
166446262
Tissue Name
166446262













Secondary Th1 act
0.0
HUVEC IL-1 beta
0.0


Secondary Th2 act
6.6
HUVEC IFN gamma
0.0


Secondary Tr1 act
4.5
HUVEC TNF alpha + IFN
0.0




gamma


Secondary Th1 rest
0.0
HUVEC TNF alpha + IL4
0.0


Secondary Th2 rest
3.3
HUVEC IL-11
0.0


Secondary Tr1 rest
6.7
Lung Microvasular EC
8.5




none


Primary Th1 act
0.0
Lung Microvascular EC
20.4




TNF alpha + IL-1 beta


Primary Th2 act
6.3
Microvascular Dermal EC
0.0




none


Primary Tr1 act
6.7
Microsvascular Dermal EC
0.0




TNF alpha + IL-1 beta


Primary Th1 rest
33.4
Bronchial epithelium
0.0




TNF alpha + IL-1 beta


Primary Th2 rest
18.4
Small airway epithelium
0.0




none


Primary Tr1 rest
14.4
Small airway epithelium
3.0




TNF alpha + IL-1 beta


CD45RA CD4
6.0
Coronery artery SMC rest
9.7


lymphocyte act


CD45RO CD4
5.1
Coronery artery SMC
10.8


lymphocyte act

TNF alpha + IL-1 beta


CD8 lymphocyte act
21.6
Astrocytes rest
3.6


Secondary CD8
3.3
Astrocytes TNF alpha + IL-
30.4


lymphocyte rest

1 beta


Secondary CD8
5.1
KU-812 (Basophil) rest
0.0


lymphocyte act


CD4 lymphocyte none
2.7
KU-812 (Basophil)
0.0




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
13.2
CCD1106 (Keratinocytes)
0.0


CD95 CH11

none


LAK cells rest
3.6
CCD1106 (Keratinocytes)
3.3




TNF alpha + IL-1 beta


LAK cells IL-2
45.7
Liver cirrhosis
83.5


LAK cells IL-2 + IL-12
46.7
Lupus kidney
4.6


LAK cells IL-2 + IFN
40.1
NCI-H292 none
0.0


gamma


LAK cells IL-2 + IL-18
20.4
NCI-H292 IL-4
0.0


LAK cells
7.5
NCI-H292 IL-9
0.0


PMA/ionomycin


NK Cells IL-2 rest
8.0
NCI-H292 IL-13
0.0


Two Way MLR 3 day
100.0
NCI-H292 IFN gamma
3.8


Two Way MLR 5 day
13.7
HPAEC none
35.4


Two Way MLR 7 day
10.7
HPAEC TNF alpha + IL-1
3.0




beta


PBMC rest
6.6
Lung fibroblast none
3.4


PBMC PWM
9.4
Lung fibroblast TNF
0.0




alpha + IL-1 beta


PBMC PHA-L
0.0
Lung fibroblast IL-4
6.8


Ramos (B cell) none
0.0
Lung fibroblast IL-9
0.0


Ramos (B cell)
0.0
Lung fibroblast IL-13
3.3


ionomycin


B lymphocytes PWM
54.3
Lung fibroblast IFN
89.5




gamma


B lymphocytes CD40L
9.7
Dermal fibroblast
6.0


and IL-4

CCD1070 rest


EOL-1 dbcAMP
0.0
Dermal fibrobaslat
4.2




CCD1070 TNF alpha


EOL-1 dbcAMP
0.0
Dermal fibroblast
0.0


PMA/ionomycin

CCD1070 IL-1 beta


Dendritic cells none
3.3
Dermal fibroblast IFN
0.0




gamma


Dendritic cells LPS
0.0
Dermal fibroblast IL-4
0.0


Dendritic cells anti-
0.0
IBD Colitis 2
3.2


CD40


Monocytes rest
0.0
IBD Crohn's
18.6


Monocytes LPS
0.0
Colon
72.2


Macrophages rest
4.2
Lung
9.7


Macrophages LPS
0.0
Thymus
37.6


HUVEC none
0.0
Kidney
62.9


HUVEC starved
0.0










[0870] CNS_neurodegeneration_v1.0 Summary: Ag3525 This panel does not show differential expression of the CG59274-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.


[0871] General_screening_panel_v1.4 Summary: Ag3525 The CG59274-01 gene exhibits highly brain preferential expression, with moderate to low levels of expression seen in all regions of the brain examined in this panel. Thus, therapeutic modulation of the expression or function of this gene may be effective in the treatment of neurologic disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, stroke and schizophrenia.


[0872] Among metabolic tissues, expression of this gene is limited to the thyroid. Thus, this gene product may also be effective in treating thyroidopathies.


[0873] Panel 4D Summary: Ag3525 The CG59274-01 gene is expressed in normal kidney, thymus and colon as well as in activated LAK cells(CTs=-32-33). The gene is also expressed at lower but still significant levels in primary resting T cells, with highest expression seen in a sample derived from an MLR reaction (CT=32). Thus, the protein encoded by this transcript could be important in the function of LAK cells. LAK cells are important in immunosurveillance against bacterial and viral infected cells, as well as transformed cells. Therapeutics designed with this transcript or the protein encoded by it could be important in the treatment of viral and bacterial diseases and cancer.



Q. NOV23a and NOV23b (CG57734-01 and CG57734-02: LIPID ASSOCIATED PROTEIN)

[0874] Expression of gene CG57734-01 and CG57734-01 was assessed using the primer-probe set Ag572, described in Table QA. Please note that CG57734-02 represents a full-length physical clone of the CG57734-01 gene, validating the prediction of the gene sequence.
339TABLE QAProbe Name Ag572StartPrimersSequencesLengthPositionForward5′-ctgcgcttcgatgtgtacaac-3′(SEQ ID NO:272)21431ProbeTET-5′-actccaaaaccaacatctccaaaccgaag-3′-TAMRA(SEQ ID NO:273)29456Reverse5′-ggaacgcttgtcccaggaa-3′(SEQ ID NO:274)19488


[0875] Panel 1.1 Summary: Ag5734 Expression of the CG57734-01 gene is low/undetectable in all samples on this panel (CTs>35).



R. NOV25a (CG59885-01: HGFR)

[0876] Expression of gene CG59885-01 was assessed using the primer-probe set Ag1684, described in Table RA. Results of the RTQ-PCR runs are shown in Tables RB, RC, RD, RE, RF, and RG.
340TABLE RAProbe Name Ag1684StartPrimerSequencesLengthPositionForward5′-tgaagcaggaaggaactttaca-3′(SEQ ID NO:275)222582ProbeTET-5′-tggcatgtcaacatcgctctaattca-3′-TAMRA(SEQ ID NO:276)262605Reverse5′-gggaaggagtggtacaacaga-3′(SEQ ID NO:277)212638


[0877]

341





TABLE RB










CNS_neurodegeneration_v1.0











Rel. Exp.(%) Ag1684,

Rel. Exp.(%), Ag1684,


Tissue Name
Run 207624860
Tissue Name
Run 207624860













AD 1 Hippo
1.7
Control (Path) 3
2.3




Temporal Ctx


AD 2 Hippo
9.7
Control (Path) 4
8.2




Temporal Ctx


AD 3 Hippo
6.2
AD 1 Occipital Ctx
7.9


AD 4 Hippo
3.1
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 hippo
100.0
AD 3 Occipital Ctx
1.7


AD 6 Hippo
14.1
AD 4 Occipital Ctx
11.3


Control 2 Hippo
15.2
AD 5 Occipital Ctx
7.5


Control 4 Hippo
2.0
AD 6 Occipital Ctx
24.7


Control (Path) 3
3.3
Control 1 Occipital
2.0


Hippo

Ctx


AD 1 Temporal Ctx
1.1
Control 2 Occipital
76.3




Ctx


AD 2 Temporal Ctx
9.0
Control 3 Occipital
6.7




Ctx


AD 3 Temporal Ctx
1.8
Control 4 Occipital
2.8




Ctx


AD 4 Temporal Ctx
7.2
Control (Path) 1
60.7




Occipital Ctx


AD 5 Inf Temporal
53.6
Control (Path) 2
6.7


Ctx

Occipital Ctx


AD 5 SupTemporal
18.4
Control (Path) 3
1.7


Ctx

Occipital Ctx


AD 6 Inf Temporal
10.8
Control (Path) 4
6.8


Ctx

Occipital Ctx


AD 6 Sup Temporal
10.5
Control 1 Parietal
1.5


Ctx

Ctx


Control 1 Temporal
1.2
Control 2 Parietal
11.0


Ctx

Ctx


Control 2 Temporal
29.9
Control 3 Parietal
3.3


Ctx

Ctx


Control 3 Temporal
3.3
Control (Path) 1
37.9


Ctx

Parietal Ctx


Control 4 Temporal
2.0
Control (Path) 2
6.4


Ctx

Parietal Ctx


Control (Path) 1
28.1
Control (Path) 3
0.4


Temporal Ctx

Parietal Ctx


Control (Path) 2
12.2
Control (Path) 4
10.0


Temporal Ctx

Parietal Ctx










[0878]

342





TABLE RC










General_screening_panel_v1.4











Rel. Exp.(%) Ag1684,

Rel. Exp.(%) Ag1684,


Tissue Name
Run 208022075
Tissue Name
Run 208022075













Adipose
3.0
Renal ca. TK-10
23.2


Melanoma*
5.4
Bladder
3.9


Hs688(A).T


Melanoma*
5.8
Gastric ca. (liver met.)
27.9


Hs688(B).T

NCI-N87


Melanoma* M14
0.0
Gastric ca. KATO III
67.4


Melanoma*
10.2
Colon ca. SW-948
8.9


LOXIMVI


Melanoma* SK-
80.7
Colon ca. SW480
0.6


MEL-5


Squamous cell
15.2
Colon ca.* (SW480
9.6


carcinoma SCC-4

met) SW620


Testis Pool
0.2
Colon ca. HT29
14.7


Prostate ca.* (bone
37.6
Colon ca. HCT-116
36.6


met) PC-3


Prostate Pool
0.5
Colon ca. CaCo-2
23.5


Placenta
1.2
Colon cancer tissue
9.1


Uterus Pool
0.5
Colon ca. SW1116
1.7


Ovarian ca. OVCAR-3
5.1
Colon ca. Colo-205
2.0


Ovarian ca. SK-OV-3
14.8
Colon ca. SW-48
2.3


Ovarian ca. OVCAR-4
7.6
Colon Pool
0.9


Ovarian ca. OVCAR-5
29.9
Small Intestine Pool
0.5


Ovarian ca. IGROV-1
9.1
Stomach Pool
0.9


Ovarian ca. OVCAR-8
2.6
Bone Marrow Pool
0.4


Ovary
0.4
Fetal Heart
0.2


Breast ca. MCF-7
2.5
Heart Pool
0.5


Breast ca. MDA-
14.5
Lymph Node Pool
1.1


MB-231


Breast ca. BT 549
3.7
Fetal Skeletal Muscle
0.4


Breast ca. T47D
29.3
Skeletal Muscle Pool
1.9


Breast ca. MDA-N
15.4
Spleen Pool
1.7


Breast Pool
1.1
Thymus Pool
0.7


Trachea
1.7
CNS cancer (glio/astro)
25.7




U87-MG


Lung
0.2
CNS cancer (glio/astro)
38.2




U-118-MG


Fetal Lung
13.5
CNS cancer (neuro; met)
0.0




SK-N-AS


Lung ca. NCI-N417
1.1
CNS cancer (astro) SF-539
2.2


Lung ca. LX-1
16.6
CNS cancer (astro) SNB-75
12.6


Lung ca. NCI-H146
1.2
CNS cancer (glio) SNB-19
7.8


Lung ca. SHP-77
3.0
CNS cancer (glio) SF-295
19.1


Lung ca. A549
23.8
Brain (Amygdala) Pool
0.3


Lung ca. NCI-H526
2.8
Brain (cerebellum)
0.0


Lung ca. NCI-H23
7.7
Brain (fetal)
1.7


Lung ca. NCI-H460
4.8
Brain (Hippocampus) Pool
0.5


Lung ca. HOP-62
11.7
Cerebral Cortex Pool
1.0


Lung ca. NCI-H522
0.1
Brain (Substantia nigra)
0.2




Pool


Liver
1.5
Brain (Thalamus) Pool
1.6


Fetal Liver
8.8
Brain (whole)
2.1


Liver ca. HepG2
7.7
Spinal Cord Pool
0.2


Kidney Pool
1.2
Adrenal Gland
0.1


Fetal Kidney
2.6
Pituitary gland Pool
0.6


Renal ca. 786-0
26.1
Salivary Gland
0.3


Renal ca. A498
19.1
Thyroid (female)
3.3


Renal ca. ACHN
20.4
Pancreatic ca. CAPAN2
59.0


Renal ca. UO-31
100.0
Pancreas Pool
5.0










[0879]

343





TABLE RD










Panel 1.3D













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag1684, Run
Ag1684, Run

Ag1684, Run
Ag1684, Run


Tissue Name
158401632
165526993
Tissue Name
158401632
165526993















Liver
26.4
31.4
Kidney (fetal)
4.8
5.3


adenocarcinoma


Pancreas
0.4
0.9
Renal ca. 786-0
34.2
35.8


Pancreatic ca.
26.6
70.2
Renal ca. A498
95.3
73.7


CAPAN 2


Adrenal gland
0.3
0.3
Renal ca. RXF 393
13.3
55.9


Thyroid
3.7
2.7
Renal ca.
14.0
25.2





ACHN


Salivary gland
0.4
1.2
Renal ca. UO-31
28.9
35.4


Pituitary gland
1.3
1.3
Renal ca. TK-10
19.1
17.9


Brain (fetal)
1.5
2.5
Liver
1.1
1.1


Brain (whole)
2.6
0.0
Liver (fetal)
2.7
4.2


Brain (amygdala)
1.8
2.0
Liver ca.
9.5
7.1





(hepatoblast)





HepG2


Brain (cerebellum)
0.0
0.3
Lung
2.5
1.0


Brain
26.1
4.9
Lung (fetal)
3.0
1.5


(hippocampus)


Brain (substantia
0.1
0.2
Lung ca.
11.8
11.3


nigra)


(small cell)





LX-1


Brain (thalamus)
0.5
0.3
Lung ca.
13.6
3.4





(small cell)





NCI-H69


Cerebral Cortex
4.1
0.8
Lung ca. (s. cell
7.4
6.4





var.) SHP-77


Spinal cord
0.9
2.0
Lung ca. (large
2.9
15.9





cell) NCI-H460


glio/astro U87-MG
26.6
22.2
Lung ca. (non-
13.9
11.8





sm. cell) A549


glio/astro U-118-
100.0
100.0
Lung ca. (non-
7.5
6.7


MG


s. cell) NCI-H23


astrocytoma
53.2
62.4
Lung ca. (non-
11.3
17.0


SW1783


s. cell) HOP-62


neuro*; met SK-N-
0.2
0.1
Lung ca. (non-
0.2
0.1


AS


s. cl) NCI-H522


astrocytoma SF-
2.8
2.7
Lung ca.
45.4
92.0


539


(squam.) SW





900


astrocytoma SNB-
69.3
71.2
Lung ca.
1.6
5.3


75


(squam.) NCI-





H596


glioma SNB-19
7.5
12.2
Mammary
1.5
3.2





gland


glioma U251
3.6
18.2
Breast ca.*
3.9
4.2





(pl. ef) MCF-7


glioma SF-295
27.9
25.0
Breast ca.*
87.1
51.1





(pl. ef) MDA-





MB-231


Heart (fetal)
0.1
0.0
Breast ca.*
0.4
0.6





(pl. ef) T47D


Heart
0.4
1.9
Breast ca. BT-549
54.3
35.4


Skeletal muscle
4.6
0.5
Breast ca.
29.1
11.1


(fetal)


MDA-N


Skeletal muscle
2.0
8.9
Ovary
0.2
0.0


Bone marrow
0.1
0.0
Ovarian ca.
1.7
4.2





OVCAR-3


Thymus
0.1
0.2
Ovarian ca.
3.4
10.9





OVCAR-4


Spleen
1.3
1.0
Ovarian ca.
24.1
17.1





OVCAR-5


Lymph node
0.4
2.4
Ovarian ca.
6.8
3.2





OVCAR-8


Colorectal
1.6
0.9
Ovarian ca.
9.2
11.3





IGROV-1


Stomach
1.8
3.2
Ovarian ca.*
12.0
11.5





(ascites) SK-OV-3


Small intestine
1.3
1.8
Uterus
0.8
3.0


Colon ca. SW480
0.8
0.6
Placenta
6.8
5.8


Colon ca.*
15.2
12.9
Prostate
0.5
0.5


SW620(SW480


met)


Colon ca. HT29
18.9
10.1
Prostate ca.*
15.2
22.5





(bone met) PC-3


Colon ca. HCT-116
25.2
20.7
Testis
0.1
0.1


Colon ca. CaCo-2
15.0
11.3
Melanoma
3.6
3.7





Hs688(A).T


Colon ca.
22.4
11.0
Melanoma*
1.2
2.4


tissue(ODO3866)


(met)





Hs688(B).T


Colon ca. HCC-
44.4
14.4
Melanoma
0.3
2.5


2998


UACC-62


Gastric ca.* (liver
52.9
52.5
Melanoma
0.0
0.5


met) NCI-N87


M14


Bladder
2.9
3.1
Melanoma
5.6
2.9





LOX IMVI


Trachea
4.8
3.7
Melanoma*
55.1
44.1





(met) SK-MEL-5


Kidney
1.3
2.8
Adipose
4.1
1.9










[0880]

344





TABLE RE










Panel 2D













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag1684, Run
Ag1684, Run

Ag1684, Run
Ag1684, Run


Tissue Name
158403763
164981024
Tissue Name
158403763
164981024















Normal Colon
6.3
9.7
Kidney Margin
1.0
1.0





8120608


CC Well to Mod
8.8
12.6
Kidney Cancer
11.3
10.2


Diff (ODO3866)


8120613


CC Margin
1.5
1.9
Kidney Margin
2.7
1.7


(ODO3866)


8120614


CC Gr.2
0.7
0.8
Kidney Cancer
15.1
17.2


rectosigmoid


9010320


(ODO3868)


CC Margin
0.3
0.7
Kidney Margin
7.1
9.1


(ODO3868)


9010321


CC Mod Diff
4.3
6.1
Normal Uterus
0.6
0.9


(ODO3920)


CC Margin
1.1
1.0
Uterus Cancer
2.5
2.5


(ODO3920)


064011


CC Gr.2 ascend
21.8
17.3
Normal
3.6
2.9


colon


Thyroid


(ODO3921)


CC Margin
2.2
2.1
Thyroid
37.1
46.0


(ODO3921)


Cancer 064010


CC from Partial
32.3
22.5
Thyroid
31.6
26.6


Hepatectomy


Cancer


(ODO4309) Mets


A302152


Liver Margin
8.0
5.8
Thyroid
6.1
5.4


(ODO4309)


Margin





A302153


Colon mets to
5.4
2.9
Normal Breast
4.9
3.0


lung (OD04451-


01)


Lung Margin
2.7
3.5
Breast Cancer
0.3
0.2


(OD04451-02)


(OD04566)


Normal Prostate
0.5
3.0
Breast Cancer
1.4
1.3


6546-1


(OD04590-01)


Prostate Cancer
1.9
1.9
Breast Cancer
1.5
1.8


(OD04410)


Mets





(OD04590-03)


Prostate Margin
1.6
1.3
Breast Cancer
0.5
0.7


(OD04410)


Metastasis





(OD04655-05)


Prostate Cancer
3.7
2.7
Breast Cancer
1.0
1.1


(OD04720-01)


064006


Prostate Margin
6.7
5.7
Breast Cancer
3.3
3.0


(OD04720-02)


1024


Normal Lung
7.7
6.5
Breast Cancer
0.6
1.0


061010


9100266


Lung Met to
12.9
11.3
Breast Margin
0.7
0.8


Muscle


9100265


(ODO4286)


Muscle Margin
2.2
2.6
Breast Cancer
2.0
2.5


(ODO4286)


A209073


Lung Malignant
8.0
7.1
Breast Margin
1.8
1.6


Cancer


A209073


(OD03126)


Lung Margin
14.8
9.7
Normal Liver
4.3
5.1


(OD03126)


Lung Cancer
15.0
15.0
Liver Cancer
10.9
11.0


(OD04404)


064003


Lung Margin
7.8
14.7
Liver Cancer
3.2
2.4


(OD04404)


1025


Lung Cancer
7.6
10.7
Liver Cancer
2.1
2.3


(OD04565)


1026


Lung Margin
3.7
5.5
Liver Cancer
4.2
5.0


(OD04565)


6004-T


Lung Cancer
2.6
2.0
Liver Tissue
4.2
5.3


(OD04237-01)


6004-N


Lung Margin
4.6
4.7
Liver Cancer
2.2
2.6


(OD04237-02)


6005-T


Ocular Mel Met
24.3
21.0
Liver Tissue
1.1
1.2


to Liver


6005-N


(ODO4310)


Liver Margin
8.1
7.7
Normal
7.7
7.6


(ODO4310)


Bladder


Melanoma Mets
2.6
2.4
Bladder
0.7
0.9


to Lung


Cancer 1023


(OD04321)


Lung Margin
6.7
7.1
Bladder
4.0
4.1


(OD04321)


Cancer





A302173


Normal Kidney
15.5
15.2
Bladder
36.1
46.3





Cancer





(OD04718-01)


Kidney Ca,
100.0
100.0
Bladder
1.1
1.3


Nuclear grade 2


Normal


(OD04338)


Adjacent





(OD04718-03)


Kidney Margin
8.4
8.7
Normal Ovary
0.1
0.0


(OD04338)


Kidney Ca
11.6
10.4
Ovarian
29.3
29.3


Nuclear grade 1/2


Cancer 064008


(OD04339)


Kidney Margin
11.2
12.6
Ovarian
11.5
14.8


(OD04339)


Cancer





(OD04768-07)


Kidney Ca, Clear
50.3
43.8
Ovary Margin
0.9
1.2


cell type


(OD04768-08)


(OD04340)


Kidney Margin
8.5
8.9
Normal
3.2
3.9


(OD04340)


Stomach


Kidney Ca,
24.5
22.5
Gastric Cancer
0.5
1.1


Nuclear grade 3


9060358


(OD04348)


Kidney Margin
7.1
8.4
Stomach
2.2
3.3


(OD04348)


Margin





9060359


Kidney Cancer
9.5
12.0
Gastric Cancer
8.9
8.6


(OD04622-01)


9060395


Kidney Margin
1.0
1.6
Stomach
3.8
2.6


(OD04622-03)


Margin





9060394


Kidney Cancer
24.0
23.0
Gastric Cancer
17.0
33.7


(OD04450-01)


9060397


Kidney Margin
6.9
5.8
Stomach
1.2
1.4


(OD04450-03)


Margin





9060396


Kidney Cancer
6.0
6.5
Gastric Cancer
8.8
6.8


8120607


064005










[0881]

345





TABLE RF










Panel 4D











Rel. Exp.(%)

Rel. Exp.(%)



Ag1684, Run

Ag1684, Run


Tissue Name
158404018
Tissue Name
158404018













Secondary Th1 act
0.5
HUVEC IL-1 beta
9.3


Secondary Th2 act
0.1
HUVEC IFN gamma
22.5


Secondary Tr1 act
0.4
HUVEC TNF alpha + IFN
17.7




gamma


Secondary Th1 rest
0.0
HUVEC TNF alpha + IL4
9.7


Secondary Th2 rest
0.0
HUVEC IL-11
5.9


Secondary Tr1 rest
0.0
Lung Microvascular EC
7.2




none


Primary Th1 act
0.1
Lung Microvascular EC
5.2




TNF alpha + IL-1 beta


Primary Th2 act
0.5
Microvascular Dermal EC
20.2




none


Primary Tr1 act
0.2
Microsvasular Dermal EC
8.8




TNF alpha + IL-1 beta


Primary Th1 rest
0.0
Bronchial epithelium
11.8




TNF alpha + IL-1 beta


Primary Th2 rest
0.0
Small airway epithelium
10.6




none


Primary Tr1 rest
0.0
Small airway epithelium
97.3




TNF alpha + IL-1 beta


CD45RA CD4
7.7
Coronery artery SMC rest
4.2


lymphocyte act


CD45RO CD4
0.2
Coronery artery SMC
2.6


lymphocyte act

TNF alpha + IL-1 beta


CD8 lymphocyte act
0.0
Astrocytes rest
12.3


Secondary CD8
0.1
Astrocytes TNF alpha + IL-
11.2


lymphocyte rest

1 beta


Secondary CD8
0.3
KU-812 (Basophil) rest
0.1


lymphocyte act


CD4 lymphocyte none
0.0
KU-812 (Basophil)
0.8




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
0.0
CCD1106 (Keratinocytes)
17.3


CD95 CH11

none


LAK cells rest
0.1
CCD1106 (Keratinocytes)
7.5




TNF alpha + IL-1 beta


LAK cells IL-2
0.2
Liver cirrhosis
1.4


LAK cells IL-2 + IL-12
0.1
Lupus kidney
1.5


LAK cells IL-2 + IFN
0.4
NCI-H292 none
62.9


gamma


LAK cells IL-2 + IL-18
0.3
NCI-H292 IL-4
100.0


LAK cells
0.9
NCI-H292 IL-9
40.9


PMA/ionomycin


NK Cells IL-2 rest
0.0
NCI-H292 IL-13
46.0


Two Way MLR 3 day
0.1
NCI-H292 IFN gamma
49.3


Two Way MLR 5 day
0.1
HPAEC none
8.0


Two Way MLR 7 day
0.1
HPAEC TNF alpha + IL-1
11.8




beta


PBMC rest
0.0
Lung fibroblast none
4.5


PBMC PWM
0.7
Lung fibroblast TNF
1.7




alpha + IL-1 beta


PBMC PHA-L
0.5
Lung fibroblast IL-4
13.0


Ramos (B cell) none
0.0
Lung fibroblast IL-9
7.7


Ramos (B cell)
0.0
Lung fibroblast IL-13
5.7


ionomycin


B lymphocytes PWM
3.1
Lung fibroblast IFN
14.8




gamma


B lymphocytes CD40L
1.1
Dermal fibroblast
26.4


and IL-4

CCD1070 rest


EOL-1 dbcAMP
0.0
Dermal fibroblast
16.7




CCD1070 TNF alpha


EOL-1 dbcAMP
0.0
Dermal fibroblast
5.7


PMA/ionomycin

CCD1070 IL-1 beta


Dendritic cells none
0.1
Dermal fibroblast IFN
3.6




gamma


Dendritic cells LPS
0.2
Dermal fibroblast IL-4
1.9


Dendritic cells anti-
0.0
IBD Colitis 2
0.2


CD40


Monocytes rest
0.0
IBD Crohn's
0.0


Monocytes LPS
22.5
Colon
4.4


Macrophages rest
0.3
Lung
5.7


Macrophages LPS
1.2
Thymus
12.5


HUVEC none
11.7
Kidney
2.6


HUVEC starved
18.7










[0882]

346





TABLE RG










Panel 5 Islet











Rel. Exp.(%)

Rel. Exp.(%)



Ag1684, Run

Ag1684, Run


Tissue Name
224084580
Tissue Name
224084580













97457_Patient-
12.7
94709_Donor 2 AM - A_adipose
3.1


02go_adipose


97476_Patient-
2.8
94710_Donor 2 AM - B_adipose
15.4


07sk_skeletal muscle


97477_Patient-
1.2
94711_Donor 2 AM - C_adipose
9.0


07ut_uterus


97478_Patient-
15.4
94712_Donor 2 AD - A_adipose
14.7


07pl_placenta


99167_Bayer
30.6
94713_Donor 2 AD - B_adipose
9.5


Patient 1


97482_Patient-
2.1
94714_Donor 2 AD - C_adipose
17.0


08ut_uterus


97483_Patient-
13.5
94742_Donor 3 U -
1.5


08pl_placenta

A_Mesenchymal Stem Cells


97486_Patient-
1.6
94743_Donor 3 U -
38.4


09sk_skeletal muscle

B_Mesenchymal Stem Cells


97487_Patient-
2.8
94730_Donor 3 AM - A_adipose
37.6


09ut_uterus


97488_Patient-
7.3
94731_Donor 3 AM - B_adipose
9.9


09pl_placenta


97492_Patient-
9.2
94732_Donor 3 AM - C_adipose
4.0


10ut_uterus


97493_Patient-
22.5
94733_Donor 3 AD - A_adipose
17.9


10pl_placenta


97495_Patient-
15.5
94734_Donor 3 AD - B_adipose
4.7


11go_adipose


97496_Patient-
6.8
94735_Donor 3 AD - C_adipose
39.0


11sk_skeletal muscle


97497_Patient-
3.0
77138_Liver_HepG2untreated
27.4


11ut_uterus


97498_Patient-
13.2
73556_Heart_Cardiac stromal cells
2.5


11pl_placenta

(primary)


97500_Patient-
22.5
81735_Small Intestine
4.6


12go_adipose


97501_Patient-
12.2
72409_Kidney_Proximal
16.5


12sk_skeletal muscle

Convoluted Tubule


97502_Patient-
3.3
82685_Small intestine_Duodenum
3.5


12ut_uterus


97503_Patient-
16.0
90650_Adrenal_Adrenocortical
0.0


12pl_placenta

adenoma


94721_Donor 2 U -
11.1
72410_Kidney_HRCE
100.0


A_Mesenchymal


Stem Cells


94722_Donor 2 U -
6.9
72411_Kidney_HRE
50.7


B_Mesenchymal Stem


Cells


94723_Donor 2 U -
2.2
73139_Uterus_Uterine smooth
11.7


C_Mesenchymal Stem

muscle cells


Cells










[0883] CNS_neurodegeneration_v1.0 Summary: Ag1684 This panel does not show differential expression of the CG59885-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.


[0884] General_screening_panel_v1.4 Summary: Ag1684 Highest expression of the CG59885-01 gene is seen in a renal cancer cell line (CT=20). Overall, expression appears to be much higher in cancer cell lines than in samples from normal tissue. Significant levels of expression are also seen in cell lines derived from pancreatic, brain, colon, gastric, lung, breast, ovarian, and melanoma cancers. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of cancer. Furthermore, therapeutic modulation of the expression or function of this gene with a human monoclonal antibody is anticipated to limit or block the extent of metastasis and growth in most tumors.


[0885] Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.


[0886] In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system and may be a target of neurologic diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.


[0887] Panel 1.3D Summary: Ag1684 Expression of the CG59885-01 gene confirms the results of Panel 1.4. Please see Panel 1.4 for discussion of utility of this gene in cancer, metabolic disease and the central nervous system.


[0888] Panel 2D Summary: Ag1684 Two experiments with the same probe and primer produce results that are in excellent agreement, with highest expression of the CG59885-01 gene in kidney cancer (CTs=24-25). In addition, expression of this gene is higher in gastric, bladder, ovarian, thyroid, kidney and colon cancers when compared to expression in the corresponding normal adjacent tissue. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of cancer. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of these cancers.


[0889] Panel 3D Summary: Ag1684 Results from one experiment with the CG59885-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.


[0890] Panel 4D Summary: Ag1684 Highest expression of the CG59885-01 gene is seen in the NCI-H292 mucoepidermoid cell line treated with IL-4 (CT=25). Significant levels of expression are also seen in a cluster of treated and untreated NCI-H292 mucoepidermoid cells, IL-4, IL-9, IL-13 and IFN gamma activated lung fibroblasts, human pulmonary aortic endothelial cells (treated and untreated), small airway epithelium (treated and untreated), treated bronchial epithelium and lung microvascular endothelial cells (treated and untreated). The expression of this gene in cells derived from or within the lung suggests that this gene may be involved in normal conditions as well as pathological and inflammatory lung disorders that include chronic obstructive pulmonary disease, asthma, allergy and emphysema.


[0891] Moderate levels of expression are also detected in treated and untreated HUVECs (endothelial cells), coronary artery smooth muscle cells (treated and untreated), treated and untreated astrocytes, KU-812 basophils, keratinocytes, dermal fibroblasts, and normal tissues from lung, colon, thymus and kidney. Expression in these immune cell types and tissues suggests that therapeutic modulation of this gene product may ameliorate symptoms associated with infectious conditions as well as inflammatory and autoimmune disorders that include psoriasis, allergy, asthma, inflammatory bowel disease, rheumatoid arthritis and osteoarthritis.


[0892] Interestingly, expression of this gene is stimulated in TNFalpha+IL-1 beta treated small airway epithelium (CT=25) and LPS-treated monocytes (CT=27) as compared to their untreated counterparts (CTs=28-40). Thus, expression of this gene can be used to distinguish these treated cells from their untreated counterparts. This gene codes for a variant of hepatocyte growth factor receptor, HGFR-MET. HGFR-MET is a transmembrane tyrosine kinase proto-oncogene, required for the action of hepatocyte growth factor (HGF) (Ref. 1). Recently, it was shown that HGF modulates the function of monocytes in a paracrine/autocrine manner (Ref.2). The expression of the HGFR-MET gene in LPS-treated monocytes, suggests a role for this gene product in initiating inflammatory reactions. Therefore, modulation of the expression or activity of HGFR-MET through the application of monoclonal antibodies may reduce or prevent early stages of inflammation and reduce the severity of inflammatory diseases such as psoriasis, asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis and other lung inflammatory diseases.


[0893] References.


[0894] 1. Stella M C, Comoglio P M. (1999) HGF: a multifunctional growth factor controlling cell scattering. Int J Biochem Cell Biol December 1999;31(12):1357-62


[0895] 2. Galimi F, Cottone E, Vigna E, Arena N, Boccaccio C, Giordano S, Naldini L, Comoglio P M. (2001) Hepatocyte growth factor is a regulator of monocyte-macrophage function. J Immunol 166(2):1241-7.


[0896] Panel 5 Islet Summary: Ag1684 Highest expression of the CG59885-01 gene is seen in kidney-HRCE samples (CT=29.8). In addition, moderate to low expression is also detected in pancreatic islet cells (patient 1), adipose, mesenchymal stem cells, placenta, skeletal muscle from number of donor and patients. Please see panel 1.4 for the potential utility of this gene.



S. NOV26a (CG93443-01: Novel LIV-1 Like Gene)

[0897] Expression of gene CG93443-01 was assessed using the primer-probe sets Ag2552 and Ag3855, described in Tables SA and SB. Results of the RTQ-PCR runs are shown in Tables SC, SD, SE, SF, SG, and SH.
347TABLE SAProbe Name Ag2552StartPrimersSequencesLengthPositionForward5′-cttctgataccctgccctagtc-3′(SEQ ID NO:278)222167ProbeTET-5′-ccccacctttgacttaagatcccaca-3′-TAMRA(SEQ ID NO:282)262189Reverse5′-ctataggggcttctggtttctg-3′(SEQ ID NO:280)220


[0898]

348





TABLE SB










Probe Name Ag3855













Start


Primer
Sequences
Length
Position














Forward
5′-cagctgagtggagcctacac-3′
(SEQ ID NO:281)
20
1140





Probe
TET-5′-caggaccagctcagccagtcagag-3′-TAMRA
(SEQ ID NO:282)
24
1182





Reverse
5′-cagggagccgtacagatatct-3′
(SEQ ID NO:283)
21
1206










[0899]

349





TABLE SC










AI_comprehensive panel_v1.0











Rel. Exp.(%) Ag2552,

Rel. Exp.(%) Ag2552,


Tissue Name
Run 229393908
Tissue Name
Run 229393908













110967 COPD-F
8.3
112427 Match Control
19.6




Psoriasis-F


110980 COPD-F
5.6
112418 Psoriasis-M
14.8


110968 COPD-M
14.7
112723 Match Control
12.7




Psoriasis-M


110977 COPD-M
13.6
112419 Psoriasis-M
14.0


110989 Emphysema-F
23.3
112424 Match Control
12.1




Psoriasis-M


110992 Emphysema-F
23.5
112420 Psoriasis-M
29.1


110993 Emphysema-F
7.3
112425 Match Control
18.4




Psoriasis-M


110994 EmPhysema-F
2.5
104689 (MF) OA Bone-
10.2




Backus


110995 Emphysema-F
40.1
104690 (MF) Adj
4.8




“Normal” Bone-Backus


110996 Emphysema-F
20.6
104691 (MF) OA
4.5




Synovium-Backus


110997 Asthma-M
11.5
104692 (BA) OA
25.0




Cartilage-Backus


111001 Asthma-F
5.1
104694 (BA) OA Bone-
9.3




Backus


111002 Asthma-F
25.0
104695 (BA) Adj
4.8




“Normal” Bone-Backus


111003 Atopic
16.7
104696 (BA) OA
5.8


Asthma-F

Synovium-Backus


111004 Atopic
45.4
104700 (SS) OA Bone-
6.7


Asthma-F

Backus


111005 Atopic
22.5
104701 (SS) Adj
6.2


Asthma-F

“Normal” Bone-Backus


111006 Atopic
5.1
104702 (SS) OA
9.9


Asthma-F

Synovium-Backus


111417 Allergy-M
11.0
117093 OA Cartilage
8.4




Rep7


112347 Allergy-M
21.0
112672 OA Bone5
6.3


112349 Normal
12.5
112673 OA Synovium5
3.6


Lung-F


112357 Normal
31.2
112674 OA Synovial
3.0


Lung-F

Fluid cells5


112354 Normal
10.4
117100 OA Cartilage
9.9


Lung-M

Rep14


112374 Crohns-F
19.9
112756 OA Bone9
100.0


112389 Match Control
5.6
112757 OA Synovium9
3.0


Crohns-F


112375 Crohns-F
13.5
112758 OA Synovial
4.1




Fluid Cells9


112732 Match Control
10.4
117125 RA Cartilage
6.1


Crohns-F

Rep2


112725 Crohns-M
9.3
113492 Bone2 RA
6.8


112387 Match Control
6.6
113493 Synovium2 RA
4.0


Crohns-M


112378 Crohns-M
12.5
113494 Syn Fluid Cells
7.3




RA


112390 Match Control
13.4
113499 Cartilage4 RA
14.9


Crohns-M


112726 Crohns-M
15.6
113500 Bone4 RA
16.8


112731 Match Control
6.2
113501 Synovium4 RA
13.2


Crohns-M


112380 Ulcer Col-F
7.0
113502 Syn Fluid
12.2




Cells4 RA


112734 Match Control
23.5
113495 Cartilage3 RA
7.7


Ulcer Col-F


112384 Ulcer Col-F
22.7
113496 Bone3 RA
10.1


112737 Match Control
17.3
113497 Synovium3 RA
4.7


Ulcer Col-F


112386 Ulcer Col-F
0.5
113498 Syn Fluid
8.6




Cells3 RA


112738 Match Control
17.6
117106 Normal
5.7


Ulcer Col-F

Cartilage Rep20


112381 Ulcer Col-M
2.4
113663 Bone3 Normal
2.6


112735 Match Control
12.9
113664 Synovium3
4.3


Ulcer Col-M

Normal


112382 Ulcer Col-M
7.2
113665 Syn Fluid
4.0




Cells3 Normal


112394 Match Control
3.7
117107 Normal
1.1


Ulcer Col-M

Cartilage Rep22


112383 Ulcer Col-M
11.7
113667 Bone4 Normal
3.1


112736 Match Control
6.8
113668 Synovium4
7.2


Ulcer Col-M

Normal


112423 Psoriasis-F
8.1
113669 Syn Fluid
6.8




Cells4 Normal










[0900]

350





TABLE SD










Panel 1.3D













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag2552, Run
Ag2552, Run

Ag2552, Run
Ag2552, Run


Tissue Name
161905842
163728051
Tissue Name
161905842
163728051















Liver
0.8
0.7
Kidney (fetal)
16.3
17.0


adenocarcinoma


Pancreas
0.7
1.4
Renal ca. 786-0
6.9
4.7


Pancreatic ca.
26.4
18.6
Renal ca. A498
14.0
15.7


CAPAN 2


Adrenal gland
1.5
1.1
Renal ca. RXF
12.2
16.8





393


Thyroid
8.5
15.7
Renal ca.
5.0
4.0





ACHN


Salivary gland
1.7
0.8
Renal ca. UO-
10.6
5.1





31


Pituitary gland
0.8
0.2
Renal ca. TK-
16.4
10.4





10


Brain (fetal)
0.4
1.1
Liver
0.7
0.7


Brain (whole)
1.0
2.0
Liver (fetal)
3.2
3.4


Brain (amygdala)
3.1
2.5
Liver ca.
19.9
18.8





(hepatoblast)





HepG2


Brain (cerebellum)
0.6
0.5
Lung
3.8
4.6


Brain
5.4
3.2
Lung (fetal)
3.6
5.1


(hippocampus)


Brain (substantia
0.7
0.7
Lung ca.
9.8
8.2


nigra)


(small cell)





LX-1


Brain (thalamus)
0.4
0.1
Lung ca.
1.8
1.2





(small cell)





NCI-H69


Cerebral Cortex
10.6
12.1
Lung ca. (s.cell
13.7
16.3





var.) SHP-77


Spinal cord
2.1
3.3
Lung ca. (large
2.5
3.7





cell) NCI-H460


glio/astro U87-MG
14.8
18.0
Lung ca. (non-
6.0
7.3





sm. cell) A549


glio/astro U-118-
2.0
1.2
Lung ca. (non-
32.3
35.1


MG


s.cell) NCI-





H23


astrocytoma
9.5
10.2
Lung ca. (non-
8.8
10.0


SW1783


s.cell) HOP-62


neuro*; met SK-N-
11.9
11.4
Lung ca. (non-
7.5
6.5


AS


s.cl) NCI-H522


astrocytoma SF-
5.8
6.9
Lung ca.
5.3
8.4


539


(squam.) SW





900


astrocytoma SNB-
4.2
4.5
Lung ca.
6.1
4.4


75


(squam.) NCI-





H596


glioma SNB-19
0.2
0.1
Mammary
5.9
2.8





gland


glioma U251
0.5
1.2
Breast ca.*
23.8
29.7





(pl.ef) MCF-7


glioma SF-295
0.3
0.0
Breast ca.*
10.4
9.3





(pl.ef) MDA-





MB-231


Heart (fetal)
16.8
18.8
Breast ca.*
7.8
10.2





(pl.ef) T47D


Heart
1.6
1.9
Breast ca. BT-
5.3
6.6





549


Skeletal muscle
24.1
28.5
Breast ca.
7.7
10.0


(fetal)


MDA-N


Skeletal muscle
4.8
4.7
Ovary
15.4
15.9


Bone marrow
1.3
1.2
Ovarian ca.
10.1
7.6





OVCAR-3


Thymus
11.4
9.5
Ovarian ca.
11.0
14.6





OVCAR-4


Spleen
3.0
3.2
Ovarian ca.
4.7
2.7





OVCAR-5


Lymph node
0.8
0.7
Ovarian ca.
10.4
10.4





OVCAR-8


Colorectal
16.8
16.7
Ovarian ca.
35.8
31.4





IGROV-1


Stomach
2.7
2.6
Ovarian ca.*
17.4
18.7





(ascites) SK-





OV-3


Small intestine
20.3
15.8
Uterus
1.3
0.6


Colon ca. SW480
11.9
10.8
Placenta
1.8
2.2


Colon ca.*
8.8
6.9
Prostate
2.3
3.9


SW620(SW480


met)


Colon ca. HT29
7.5
6.7
Prostate ca.*





(bone met)PC-3
27.7
37.9


Colon ca. HCT-
16.6
17.3
Testis
6.5
5.2


116


Colon ca. CaCo-2
8.9
8.1
Melanoma
1.9
2.5





Hs688(A).T


Colon ca.
59.9
64.6
Melanoma*
1.5
2.5


tissue(ODO3866)


(met)





Hs688(B).T


Colon ca. HCC-
9.9
11.8
Melanoma
3.3
4.7


2998


UACC-62


Gastric ca.* (liver
100.0
100.0
Melanoma
3.1
3.3


met) NCI-N87


M14


Bladder
11.1
10.0
Melanoma
7.2
5.1





LOX IMVI


Trachea
6.5
5.7
Melanoma*
7.3
6.8





(met) SK-





MEL-5


Kidney
58.6
54.0
Adipose
4.0
1.5










[0901]

351





TABLE SE










Panel 2D













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag2552, Run
Ag2552, Run

Ag2552, Run
Ag2552, Run


Tissue Name
161905843
163578013
Tissue Name
161905843
163578013















Normal Colon
26.8
27.5
Kidney Margin
51.1
52.5





8120608


CC Well to Mod
25.9
36.6
Kidney Cancer
33.0
38.4


Diff(ODO3866)


8120613


CC Margin
10.3
13.6
Kidney Margin
81.8
65.1


(ODO3866)


8120614


CC Gr.2
20.9
27.9
Kidney Cancer
10.7
15.0


rectosigmoid


9010320


(ODO3868)


CC Margin
1.8
1.7
Kidney Margin
45.7
50.3


(ODO3868)


9010321


CC Mod Diff
42.6
52.5
Normal Uterus
1.6
2.2


(ODO3920)


CC Margin
7.5
9.0
Uterus Cancer
5.8
8.2


(ODO3920)


064011


CC Gr.2 ascend
100.0
94.6
Normal
2.8
7.5


colon


Thyroid


(ODO3921)


CC Margin
11.7
11.3
Thyroid
9.5
11.7


(ODO3921)


Cancer 064010


CC from Partial
81.8
95.9
Thyroid
3.9
6.3


Hepatectomy


Cancer


(ODO4309) Mets


A302152


Liver Margin
3.7
3.5
Thyroid
17.0
19.8


(ODO4309)


Margin





A302153


Colon mets to
19.1
14.7
Normal Breast
13.2
5.6


lung (OD04451-


01)


Lung Margin
5.0
5.9
Breast Cancer
11.7
12.9


(OD04451-02)


(OD04566)


Normal Prostate
2.0
20.2
Breast Cancer
11.8
13.5


6546-1


(OD04590-01)


Prostate Cancer
7.6
10.2
Breast Cancer
10.4
14.7


(OD04410)


Mets





(OD04590-03)


Prostate Margin
12.6
12.1
Breast Cancer
43.2
49.0


(OD04410)


Metastasis





(OD04655-05)


Prostate Cancer
6.1
6.2
Breast Cancer
12.6
15.8


(OD04720-01)


064006


Prostate Margin
8.4
10.3
Breast Cancer
17.0
17.0


(OD04720-02)


1024


Normal Lung
11.3
11.3
Breast Cancer
10.0
27.0


061010


9100265


Lung Met to
15.0
12.9
Breast Margin
7.4
11.2


Muscle


9100265


(ODO4286)


Muscle Margin
2.6
4.6
Breast Cancer
21.5
25.3


(ODO4286)


A209073


Lung Malignant
21.0
23.2
Breast Margin
8.2
8.8


Cancer


A209073


(OD03126)


Lung Margin
13.4
12.9
Normal Liver
1.5
3.0


(OD03126)


Lung Cancer
20.0
17.6
Liver Cancer
0.4
0.1


(OD04404)


064003


Lung Margin
2.6
4.5
Liver Cancer
1.4
1.6


(OD04404)


1025


Lung Cancer
9.5
13.1
Liver Cancer
10.7
15.2


(OD04565)


1026


Lung Margin
4.2
5.8
Liver Cancer
2.3
2.0


(OD04565)


6004-T


Lung Cancer
18.8
20.0
Liver Tissue
22.5
22.2


(OD04237-01)


6004-N


Lung Margin
6.3
6.7
Liver Cancer
11.0
10.6


(OD04237-02)


6005-T


Ocular Mel Met
20.2
28.1
Liver Tissue
1.4
1.9


to Liver


6005-N


(ODO4310)


Liver Margin
2.0
2.5
Normal
13.0
13.4


(ODO4310)


Bladder


Melanoma Mets
7.3
10.5
Bladder
8.1
6.3


to Lung


Cancer 1023


(OD04321)


Lung Margin
9.3
4.8
Bladder
4.8
5.6


(OD04321)


Cancer





A302173


Normal Kidney
26.6
19.9
Bladder
52.1
50.7





Cancer





(OD04718-01)


Kidney Ca,
2.1
2.4
Bladder
1.8
3.4


Nuclear grade 2


Normal


(OD04338)


Adjacent





(OD04718-03)


Kidney Margin
7.3
8.4
Normal Ovary
5.3
5.8


(OD04338)


Kidney Ca
12.2
11.3
Ovarian
76.8
83.5


Nuclear grade 1/2


Cancer 064008


(OD04339)


Kidney Margin
31.0
36.3
Ovarian
85.3
100.0


(OD04339)


Cancer





(OD04768-07)


Kidney Ca, Clear
6.0
7.9
Ovary Margin
2.3
1.2


cell type


(OD04768-08)


(OD04340)


Kidney Margin
24.5
22.1
Normal
4.3
2.9


(OD04340)


Stomach


Kidney Ca,
5.7
7.2
Gastric Cancer
3.6
5.5


Nuclear grade 3


9060358


(OD04348)


Kidney Margin
11.8
15.0
Stomach
9.0
8.3


(OD04348)


Margin





9060359


Kidney Cancer
6.7
8.4
Gastric Cancer
18.6
30.1


(OD04622-01)


9060395


Kidney Margin
5.0
4.8
Stomach
21.6
20.7


(OD04622-03)


Margin





9060394


Kidney Cancer
5.4
12.8
Gastric Cancer
84.7
81.8


(OD04450-01)


9060397


Kidney Margin
8.7
10.7
Stomach
9.2
10.1


(OD04450-03)


Margin





9060396


Kidney Cancer
4.8
6.0
Gastric Cancer
14.5
12.9


8120607


064005










[0902]

352





TABLE SF










Panel 3D











Rel. Exp.(%)

Rel. Exp.(%)



Ag2552, Run

Ag2552, Run


Tissue Name
163482707
Tissue Name
163482707













Daoy-Medulloblastoma
0.6
Ca Ski-Cervical epidermoid
47.3




carcinoma (metastasis)


TE671-Medulloblastoma
0.0
ES-2-Ovarian clear cell
10.2




carcinoma


D283 Med-
30.8
Ramos-Stimulated with
0.0


Medulloblastoma

PMA/ionomycin 6h


PFSK-1-Primitive
3.7
Ramos-Stimulated with
0.0


Neuroectodermal

PMA/ionomycin 14h


XF-498-CNS
1.8
MEG-01-Chronic




myelogenous leukemia
17.3




(megokaryoblast)


SNB-78-Glioma
0.4
Raji-Burkitt's lymphoma
9.3


SF-268-Glioblastoma
2.6
Daudi-Burkitt's lymphoma
0.0


T98G-Glioblastoma
0.2
U266-B-cell plasmacytoma
6.7


SK-N-SH-
7.6
CA46-Burkitt's lymphoma
12.2


Neuroblastoma


(metastasis)


SF-295-Glioblastoma
0.0
RL-non-Hodgkin's B-cell
6.6




lymphoma


Cerebellum
0.3
JM1-pre-B-cell lymphoma
9.9


Cerebellum
0.5
Jurkat-T cell leukemia
9.2


NCI-H292-
0.0
TF-1 -Erythroleukemia
74.7


Mucoepidermoid lung


carcinoma


DMS-114-Small cell
4.2
HUT 78-T-cell lymphoma
11.3


lung cancer


DMS-79-Small cell lung
54.0
U937-Histiocytic lymphoma
22.2


cancer


NCI-H146-Small cell
16.7
KU-812-Myelogenous
56.3


lung cancer

leukemia


NCI-H526-Small cell
31.0
769-P-Clear cell renal
16.2


lung cancer

carcinoma


NCI-N417-Small cell
7.9
Caki-2-Clear cell renal
23.2


lung cancer

carcinoma


NCI-H82-Small cell lung
10.5
SW 839-Clear cell renal
8.0


cancer

carcinoma


NCI-H157-Squamous
8.6
G401-Wilms'tumor
1.6


cell lung cancer


(metastasis)


NCI-H1155-Large cell
25.3
Hs766T-Pancreatic carcinoma
3.2


lung cancer

(LN metastasis)


NCI-H1299-Large cell
21.8
CAPAN-1-Pancreatic
19.1


lung cancer

adenocarcinoma (liver




metastasis)


NCI-H727-Lung
12.7
SU86.86-Pancreatic
11.3


carcinoid

carcinoma (liver metastasis)


NCI-UMC-11-Lung
19.2
BxPC-3-Pancreatic
18.7


carcinoid

adenocarcinoma


LX-1-Small cell lung
10.7
HPAC-Pancreatic
33.9


cancer

adenocarcinoma


Colo-205-Colon cancer
17.4
MIA PaCa-2-Pancreatic
2.0




carcinoma


KM12-Colon cancer
31.0
CFPAC-1-Pancreatic ductal
26.6




adenocarcinoma


KM20L2-Colon cancer
15.5
PANC-1-Pancreatic
12.9




epithelioid ductal carcinoma


NCI-H716-Colon cancer
17.9
T24-Bladder carcinma
7.7




(transitional cell)


SW-48-Colon
44.8
5637-Bladder carcinoma
15.0


adenocarcinoma


SW1116-Colon
4.7
HT-1197-Bladder carcinoma
13.2


adenocarcinoma


LS 174T-Colon
20.7
UM-UC-3-Bladder carcinma
0.8


adenocarcinoma

(transitional cell)


SW-948-Colon
4.1
A204-Rhabdomyosarcoma
1.6


adenocarcinoma


SW-480-Colon
16.8
HT-1080-Fibrosarcoma
3.4


adenocarcinoma


NCI-SNU-5-Gastric
13.8
MG-63-Osteosarcoma
3.9


carcinoma


KATO III-Gastric
100.0
SK-LMS-1-Leiomyosarcoma
3.9


carcinoma

(vulva)


NCI-SNU-16-Gastric
0.2
SJRH30-Rhabdomyosarcoma
0.1


carcinoma

(met to bone marrow)


NCI-SNU-1-Gastric
33.7
A431-Epidermoid carcinoma
6.9


carcinoma


RF-1-Gastric
0.0
WM266-4-Melanoma
5.0


adenocarcinoma


RF-48-Gastric
0.0
DU 145-Prostate carcinoma
0.1


adenocarcinoma

(brain metastasis)


MKN-45-Gastric
8.4
MDA-MB-468-Breast
4.7


carcinoma

adenocarcinoma


NCI-N87-Gastric
29.9
SCC-4-Squamous cell
0.3


carcinoma

carcinoma of tongue


OVCAR-5-Ovarian
3.7
SCC-9-Squamous cell
0.4


carcinoma

carcinoma of tongue


RL95-2-Uterine
13.6
SCC-15-Squamous cell
0.1


carcinoma

carcinoma of tongue


HelaS3-Cervical
2.7
CAL 27-Squamous cell
15.4


adenocarcinoma

carcinoma of tongue










[0903]

353





TABLE SG










Panel 4.1D











Rel. Exp.(%)

Rel. Exp.(%)



Ag3855, Run

Ag3855, Run


Tissue Name
170120695
Tissue Name
170120695













Secondary Th1 act
0.0
HUVEC IL-1 beta
0.0


Secondary Th2 act
0.0
HUVEC IFN gamma
0.0


Secondary Tr1 act
0.0
HUVEC TNF alpha + IFN
0.0




gamma


Secondary Th1 rest
0.0
HUVEC TNF alpha + IL4
0.0


Secondary Th2 rest
0.0
HUVEC IL-11
0.0


Secondary Tr1 rest
0.0
Lung Microvascular EC
0.0




none


Primary Th1 act
0.0
Lung Microvascular EC
0.0




TNF alpha + IL-1 beta


Primary Th2 act
0.0
Microvascular Dermal EC
0.0




none


Primary Tr1 act
0.0
Microvascular Dermal EC
0.0




TNF alpha + IL-1 beta


primary Th1 rest
0.0
Bronchial epithelium
0.0




TNF alpha + IL 1 beta


Primary Th2 rest
0.0
Small airway epithelium
0.0




none


Primary Tr1 rest
0.0
Small airway epithelium
0.0




TNF alpha + IL-1 beta


CD45RA CD4
0.0
Coronery artery SMC rest
0.0


lymphocyte act


CD45RO CD4
0.0
Coronery artery SMC
0.0


lymphocyte act

TNF alpha + IL-1 beta


CD8 lymphocyte act
0.0
Astrocytes rest
0.0


Secondary CD8
0.0
Astrocytes TNF alpha + IL-
0.0


lymphocyte rest

1 beta


Secondary CD8
0.0
KU-812 (Basophil) rest
0.1


lymphocyte act


CD4 lymphocyte none
0.0
KU-812 (Basophil)
0.0




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
0.0
CCD1106 (Keratinocytes)
0.0


CD95 CH11

none


LAK cells rest
0.0
CCD1106 (Keratinocytes)
0.0




TNF alpha + IL-1 beta


LAK cells IL-2
0.0
Liver cirrhosis
0.0


LAK cells IL-2 + IL-12
0.0
NCI-H292 none
0.0


LAK cells IL-2 + IFN
0.0
NCI-H292 IL-4
0.0


gamma


LAK cells IL-2 + IL-18
0.0
NCI-H292 IL-9
0.0


LAK cells
0.0
NCI-H292 IL-13
0.0


PMA/ionomycin


NK Cells IL-2 rest
0.0
NCI-H292 IFN gamrna
0.0


Two Way MLR 3 day
0.0
HPAEC none
0.0


Two Way MLR 5 day
0.0
HPAEC TNF alpha + IL-1
0.0




beta


Two Way MLR 7 day
0.0
Lung fibroblast none
0.0


PBMC rest
0.0
Lung fibroblast TNF
0.0




alpha + IL-1 beta


PBMC PWM
0.0
Lung fibroblast IL-4
0.0


PBMC PHA-L
0.0
Lung fibroblast IL-9
0.0


Ramos (B cell) none
0.0
Lung fibroblast IL-13
0.0


Ramos (B cell)
100.0
Lung fibroblast IFN
0.0


ionomycin

gamma


B lymphocytes PWM
0.0
Dermal fibroblast
0.0




CCD1070 rest


B lymphocytes CD40L
0.0
Dermal fibroblast
0.0


and IL-4

CCD1070 TNF alpha


EOL-1 dbcAMP
0.0
Dermal fibroblast
0.0




CCD1070 IL-1 beta


EOL-1 dbcAMP
0.0
Dermal fibroblast IFN
0.0


PMA/ionomycin

gamma


Dendritic cells none
0.0
Dermal fibroblast IL-4
0.0


Dendritic cells LPS
0.0
Dermal Fibroblasts rest
0.0


Dendritic cells anti-
0.0
Neutrophils TNFa + LPS
0.0


CD40


Monocytes rest
0.0
Neutrophils rest
0.0


Monocytes LPS
0.0
Colon
1.8


Macrophages rest
0.0
Lung
0.0


Macrophages LPS
0.0
Thymus
0.0


HUVEC none
0.0
Kidney
1.5


HUVEC starved
0.0










[0904]

354





TABLE SH










Panel 4D















Rel.
Rel.
Rel.

Rel.
Rel.
Rel.



Exp.(%)
Exp.(%)
Exp.(%)

Exp.(%)
Exp.(%)
Exp.(%)



Ag2552,
Ag2552,
Ag2552,

Ag2552,
Ag2552,
Ag2552,



Run
Run
Run

Run
Run
Run


Tissue Name
161905844
163724375
163727960
Tissue Name
161905844
163724375
163727960

















Secondary Th1 act
5.9
9.7
9.9
HUVEC IL-
1.0
1.2
0.8






1 beta


Secondary Th2 act
8.8
7.9
9.7
HUVEC IFN
5.6
2.9
3.1






gamma


Secondary Tr1 act
10.6
8.6
11.7
HUVEC TNF
2.9
3.5
4.0






alpha + IFN






gamma


Secondary Th1
1.1
0.5
1.7
HUVEC TNF
3.6
5.0
4.2


rest



alpha + IL4


Secondary Th2
2.1
1.5
1.7
HUVEC IL-11
2.3
3.4
3.0


rest


Secondary Tr1
1.0
1.3
1.5
Lung
4.3
6.7
6.6


rest



Microvascular






EC none


Primary Th1 act
7.0
5.7
5.7
Lung
2.2
4.9
5.8






Microvascular






EC TNF alpha +






IL-1 beta


Primary Th2 act
4.8
6.5
4.4
Microvascular
5.1
5.7
5.4






Dermal EC none


Primary Tr1 act
8.7
6.6
7.4
Microsvascular
3.4
3.0
2.7






Dermal EC






TNF alpha + IL-






1 beta


Primary Th1 rest
8.7
9.9
12.7
Bronchial
2.6
14.6
14.6






epithelium






TNF alpha +






IL1 beta


Primary Th2 rest
6.7
4.8
4.5
Small airway
7.1
6.9
7.3






epithelium none


Primary Tr1 rest
12.4
6.7
10.8
Small airway
26.8
23.3
27.9






epithelium






TNF alpha + IL-






1 beta


CD45RA CD4
4.3
5.7
6.6
Coronery artery
1.6
1.7
2.3


lymphocyte act



SMC rest


CD45RO CD4
8.1
8.5
9.9
Coronery artery
1.1
1.6
1.3


lymphocyte act



SMC TNF alpha +






IL-1 beta


CD8 lymphocyte
9.9
7.6
12.1
Astrocytes rest
6.1
5.6
5.8


act


Secondary CD8
15.9
11.7
14.9
Astrocytes
3.2
3.7
5.3


lymphocyte rest



TNF alpha + IL-






1 beta


Secondary CD8
2.6
4.1
3.5
KU-812
81.2
78.5
90.1


lymphocyte act



(Basophil) rest


CD4 lymphocyte
1.7
1.6
1.5
KU-812
100.0
100.0
100.0


none



(Basophil)






PMA/ionomycin


2ry
2.9
3.8
5.1
CCD1106
15.4
18.6
21.9


Th1/Th2/Tr1_anti-



(Keratinocytes)


CD95 CH11



none


LAK cells rest
4.1
3.5
4.0
CCD1106
2.6
10.6
15.1






(Keratinocytes)






TNF alpha + IL-






1 beta


LAK cells IL-2
6.8
6.0
8.5
Liver cirrhosis
1.2
1.2
1.6


LAK cells IL-
6.2
7.5
5.8
Lupus kidney
1.7
1.6
2.7


2 + IL-12


LAK cells IL-
10.2
6.6
7.5
NCI-H292 none
0.1
0.0
0.0


2 + IFN gamma


LAK cells IL-2 +
13.5
8.0
6.8
NCI-H292 IL-4
0.1
0.1
0.1


IL-18


LAK cells
2.5
2.8
3.1
NCI-H292 IL-9
0.0
0.1
0.2


PMA/ionomycin


NK Cells IL-2 rest
3.2
3.4
3.3
NCI-H292 IL-
0.1
0.2
0.0






13


Two Way MLR 3
5.2
4.9
6.1
NCI-H292 IFN
0.1
0.0
0.2


day



gamma


Two Way MLR 5
4.2
4.7
6.0
HPAEC none
3.1
4.8
6.1


day


Two Way MLR 7
4.3
5.6
5.6
HPAEC TNF
2.7
3.5
3.0


day



alpha + IL-1






beta


PBMC rest
2.3
2.4
2.5
Lung fibroblast
7.6
6.7
7.6






none


PBMC PWM
14.4
16.7
18.7
Lung fibroblast
4.1
3.8
4.2






TNF alpha + IL-






1 beta


PBMC PHA-L
10.2
10.5
12.3
Lung fibroblast
12.0
10.7
14.2






IL-4


Ramos (B cell)
0.0
0.0
0.0
Lung fibroblast
11.1
10.9
11.4


none



IL-9


Ramos (B cell)
0.0
0.0
0.0
Lung fibroblast
8.9
9.8
9.2


ionomycin



IL-13


B lymphocytes
73.2
42.0
48.6
Lung fibroblast
9.2
12.1
17.0


PWM



IFN gamma


B lymphocytes
31.9
13.4
15.5
Dermal
8.7
8.8
11.2


CD40L and IL-4



fibroblast






CCD1070 rest


EOL-1 dbcAMP
29.5
26.1
26.4
Dermal
15.4
11.0
13.6






fibroblast






CCD1070 TNF






alpha


EOL-1 dbcAMP
14.0
13.1
11.4
Dermal
6.0
5.9
4.4


PMA/ionomycin



fibroblast






CCD1070 IL-1






beta


Dendritic cells
5.1
4.2
3.9
Dermal
1.7
2.7
3.1


none



fibroblast IFN






gamma


Dendritic cells
3.5
1.9
3.3
Dermal
3.3
3.3
3.9


LPS



fibroblast IL-4


Dendritic cells
5.5
7.2
7.4
IBD Colitis 2
0.5
0.3
0.4


anti-CD40


Monocytes rest
5.7
5.3
6.8
IBD Crohn's
6.4
6.6
10.9


Monocytes LPS
1.0
0.9
1.6
Colon
68.8
67.4
68.8


Macrophages rest
10.9
8.7
9.9
Lung
8.8
8.1
7.6


Macrophages LPS
1.9
1.3
2.8
Thymus
53.6
51.4
59.9


HUVEC none
4.3
3.1
3.2
Kidney
7.9
8.2
7.8


HUVEC starved
20.3
4.4
3.8










[0905] AI_comprehensive panel_v1.0 Summary: Ag2552 Highest expression of the CG93443-01 gene is detected in 112756 osteoarthritis bone9 sample (CT=28). Moderate expression of this gene is seen most of the samples used in this panel. Please see panel 4D for the potential utility of this gene. Results from a second experiment with this gene suggests that expression of this gene is low/undetectable (CTs>35) across all of the samples on this panel.


[0906] CNS_neurodegeneration_v1.0 Summary: Ag3855 Expression of the CG93443-01 gene is low/undetectable (CTs>35) across all of the samples on this panel.


[0907] General_screening_panel_v1.4 Summary: Ag3855 Results from one experiment with the CG93443-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.


[0908] Panel 1.3D Summary: Ag2552 Two experiments with the same probe and primer produce results that are in excellent agreement, with highest expression of the CG93443-01 gene in gastric cancer NCI-N87 cell line (CTs=27-28). In addition, significant expression of this gene is seen in renal, ovarian, breast, lung, liver, pancreatic and colon cancer cell lines, as well as in melanomas. Thus, therapeutic modulation of the expression or function of this gene may be effective in the treatment of these cancers.


[0909] Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancrease, adipose, adrenal gland, thyroid, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.


[0910] Interestingly, this gene is expressed at much higher levels in fetal (CTs=30) when compared to adult heart (CTs=33.4-34). This observation suggests that expression of this gene can be used to distinguish fetal from adult heart.


[0911] In addition, this gene is expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.


[0912] Panel 2D Summary: Ag2552 Two experiments with the same probe and primer produce results that are in excellent agreement, with high expression of the CG93443-01 gene in colon cancer grade 2 ascend colon (ODO3921), colon cancer from Partial hepatectomy (ODO4309) metastasis, and ovarian cancer (CTs=27). In addition, expression of this gene is higher in gastric, bladder, ovarian, and colon cancers when compared to expression in the corresponding normal adjacent tissue. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of cancer. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of these cancers.


[0913] Panel 3D Summary: Ag2552 Highest expression of the CG93443-01 gene is detected in KATO III-gastric carcinoma (CT=25.5). In addition, expression of this gene is higher in medulloblastoma, small cell lung cancer, gastric, cervical epidermoid carcinoma, B and T cell leukemia and lymphomas, erythroleukemia, KU-812 myelogenous leukemia, pancreatic, bladder and colon cancers. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of cancer. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of these cancers.


[0914] Panel 4.1D Summary: Ag3855 Highest expression of the CG93443-01 gene is detected exclusively in ionomycin treated Ramos B cells (CT=26.8). Furthermore, expression of this gene is low/undetectable in resting Ramos B cells (CT=40). Thus, expression of this gene can be used to distinguish ionomycin treated Ramos cells from the untreated cells and also from other samples used in this panel. Also, expression of this gene in stimulated Ramos B cells suggests that this gene may be involved in rheumatic disease including rheumatoid arthritis, lupus, osteoarthritis, and hyperproliferative B cell disorders.


[0915] In addition, low but significant expression of this gene is also seen in colon and kidney (CTs=32). Furthermore, expression of this gene is decreased in colon samples from patients with IBD colitis and Crohn's disease relative to normal colon. Therefore, therapeutic modulation of the activity of this gene product may be useful in the treatment of inflammatory bowel disease and kidney related disease such as lupus and glomerulonephritis.


[0916] Panel 4D Summary: Ag2552 Three experiments with the same probe and primer produce results that are in excellent agreement, with highest expression of the CG93443-01 gene in KU-812 (Basophil) cells (CTs=26-27). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_v1.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.



T. NOV27a (CG50838-01: LEUCINE-RICH REPEAT TRANSMEMBRANE PROTEIN FLRT3)

[0917] Expression of gene CG50838-01 was assessed using the primer-probe sets Ag92, Ag2763 and Ag92b, described in Tables TA, TB and TC. Results of the RTQ-PCR runs are shown in Tables TD, TE, TF, TG, TH, TI and TJ.
355TABLE TAProbe Name Ag92StartPrimersSequencesLengthPositionForward5′-ggctaaatcctgtccatctgtgt-3′(SEQ ID NO:284)23538ProbeTET-5′-atgaaacccgcatcgcagcga-3′-TAMRA(SEQ ID NO:285)21562Reverse5′-aatggatgtcagaaagcgatca-3′(SEQ ID NO:286)22592


[0918]

356





TABLE TB










Probe Name Ag2763













Start


Primers
Sequences
Length
Position














Forward
5′-gcttggatgataatcgcatatc-3′
(SEQ ID NO:287)
22
999





Probe
TET-5′-ttcatcaccatctcttcaaggtcatca-3′-TAMRA
(SEQ ID NO:288)
26
1027





Reverse
5′-tgattgttcaacaggtttccat-3′
(SEQ ID NO:289)
22
1077










[0919]

357





TABLE TC










Probe Name Ag92b













Start


Primer
Sequences
Length
Position














Forward
5′-gcagttagcatagaagagggagca-3′
(SEQ ID NO:290)
24
881





Probe
TET-5′-tccgagacagcaactatctccgactgc-3′-TAMRA
(SEQ ID NO:291)
27
906





Reverse
5′-taagqtgattacgggacaggaaa-3′
(SEQ ID NO:292)
23
934










[0920]

358





TABLE TD










AI_comprehensive panel_v1.0











Rel. Exp.(%) Ag92,

Rel. Exp.(%) Ag92,


Tissue Name
Run 228157507
Tissue Name
Run 228157507













110967 COPD-F
6.3
112427 Match Control
31.0




Psoriasis-F


110980 COPD-F
1.6
112418 Psoriasis-M
4.5


110968 COPD-M
3.9
112723 Match Control
35.6




Psoriasis-M


110977 COPD-M
6.7
112419 Psoriasis-M
8.0


110989 Emphysema-F
10.1
112424 Match Control
6.4




Psoriasis-M


110992 Emphysema-F
4.1
112420 Psoriasis-M
14.6


110993 Emphysema-F
4.7
112425 Match Control
25.7




Psoriasis-M


110994 Ernphysema-F
2.2
104689 (MF) OA Bone-
9.8




Backus


110995 Emphysema-F
9.0
104690 (MF) Adj
2.8




“Normal” Bone-Backus


110996 Emphysema-F
2.5
104691 (MF) OA
0.6




Synovium-Backus


110997 Asthma-M
3.6
104692 (BA) OA
0.4




Cartilage-Backus


111001 Asthma-F
12.5
104694 (BA) OA Bone-
11.0




Backus


111002 Asthma-F
12.7
104695 (BA) Adj
2.7




“Normal” Bone-Backus


111003 Atopic
10.0
104696 (BA) OA
0.4


Asthma-F

Synovium-Backus


111004 Atopic
8.7
104700 (SS) OA Bone-
8.0


Asthma-F

Backus


111005 Atopic
8.1
104701 (SS) Adj
5.3


Asthma-F

“Normal” Bone-Backus


111006 Atopic
2.6
104702 (SS) OA
1.1


Asthma-F

Synovium-Backus


111417 Allergy-M
9.7
117093 OA Cartilage
7.7




Rep7


1112347 Allergy-M
5.2
112672 OA Bone5
7.2


112349 Normal Lung-F
6.0
112673 OA Synovium5
2.7


112357 Normal Lung-F
35.4
112674 OA Synovial
2.4




Fluid cells5


112354 Normal Lung-M
14.0
117100 OA Cartilage
1.5




Rep14


112374 Crohns-F
4.8
112756 OA Bone9
9.7


112389 Match Control
3.5
112757 OA Synovium9
1.4


Crohns-F


112375 Crohns-F
3.7
112758 OA Synovial
6.5




Fluid Cells9


112732 Match Control
0.1
117125 RA Cartilage
4.0


Crohns-F

Rep2


112725 Crohns-M
6.9
113492 Bone2 RA
87.1


112387 Match Control
2.0
113493 Synovium2 RA
38.4


Crohns-M


112378 Crohns-M
11.4
113494 Syn
64.6




Fluid Cells RA


112390 Match Control
16.7
113499 Cartilage4 RA
88.9


Crohns-M


112726 Crohns-M
5.8
113500 Bone4 RA
83.5


112731 Match Control
6.3
113501 Synovium4 RA
55.1


Crohns-M


112380 Ulcer Col-F
11.7
113502 Syn Fluid Cells4
51.4




RA


112734 Match Control
1.5
113495 Cartilage3 RA
79.6


Ulcer Col-F


112384 Ulcer Col-F
10.1
113496 Bone3 RA
94.6


112737 Match Control
2.7
113497 Synovium3 RA
47.0


Ulcer Col-F


112386 Ulcer Col-F
2.5
113498 Syn Fluid Cells3
100.0




RA


112738 Match Control
2.8
117106 Normal
1.1


Ulcer Col-F

Cartilage Rep20


112381 Ulcer Col-M
2.4
113663 Bone3 Normal
6.1


112735 Match Control
14.6
113664 Synovium3
2.9


Ulcer Col-M

Normal


112382 Ulcer Col-M
5.4
113665 Syn Fluid Cells3
4.5




Normal


112394 Match Control
1.6
117107 Normal
2.8


Ulcer Col-M

Cartilage Rep22


112383 Ulcer Col-M
6.4
113667 Bone4 Normal
2.9


112736 Match Control
1.9
113668 Synovium4
3.4


Ulcer Col-M

Normal


112423 Psoriasis-F
11.0
113669 Syn Fluid Cells4
2.9




Normal










[0921]

359





TABLE TE










CNS_neurodegeneration_v1.0















Rel.

Rel.

Rel.

Rel.



Exp.(%)
Rel.
Exp.(%)

Exp.(%)
Rel.
Exp.(%)



Ag2763,
Exp.(%)
Ag92b,

Ag2763,
Exp.(%)
Ag92b,


Tissue
Run
Ag92, Run
Run
Tissue
Run
Ag92, Run
Run


Name
206985755
206974451
225000617
Name
206985755
206974451
225000617

















AD 1
2.5
7.8
12.4
Control
0.5
2.4
1.4


Hippo



(Path) 3






Temporal






Ctx


AD 2
4.0
9.8
13.3
Control
8.4
26.2
26.8


Hippo



(Path) 4






Temporal






Ctx


AD 3
0.8
3.1
4.1
AD 1
4.8
18.4
16.2


Hippo



Occipital






Ctx


AD 4
0.5
3.1
2.8
AD 2
0.0
0.0
0.0


Hippo



Occipital






Ctx






(Missing)


AD 5
37.6
100.0
100.0
AD 3
0.7
2.4
3.0


Hippo



Occipital






Ctx


AD 6
15.2
33.9
28.1
AD 4
3.3
13.5
11.5


Hippo



Occipital






Ctx


Control 2
7.4
23.2
15.0
AD 5
18.6
46.0
12.9


Hippo



Occipital






Ctx


Control 4
0.9
2.1
4.5
AD 6
6.2
15.4
35.8


Hippo



Occipital






Ctx


Control
0.9
3.4
3.3
Control 1
0.1
0.9
1.5


(Path) 3



Occipital


Hippo



Ctx


AD 1
1.9
8.7
7.6
Control 2
40.1
68.3
65.1


Temporal



Occipital


Ctx



Ctx


AD 2
7.9
23.3
26.8
Control 3
5.4
13.4
21.9


Temporal



Occipital


Ctx



Ctx


AD 3
100.0
2.4
1.7
Control 4
0.7
2.1
1.2


Temporal



Occipital


Ctx



Ctx


AD 4
3.2
12.9
14.2
Control
28.5
69.3
58.6


Temporal



(Path) 1


Ctx



Occipital






Ctx


AD 5 Inf
28.5
75.3
14.3
Control
3.3
10.8
12.9


Temporal



(Path) 2


Ctx



Occipital






Ctx


AD 5 Sup
8.9
21.2
29.5
Control
0.1
1.5
0.9


Temporal



(Path) 3


Ctx



Occipital






Ctx


AD 6 Inf
9.2
27.9
27.7
Control
5.3
17.4
13.1


Temporal



(Path) 4


Ctx



Occipital






Ctx


AD 6 Sup
12.0
31.4
14.1
Control 1
0.5
1.6
1.6


Temporal



Parietal


Ctx



Ctx


Control 1
0.3
2.0
1.9
Control 2
9.9
23.3
27.5


Temporal



Parietal


Ctx



Ctx


Control 2
16.5
25.7
28.3
Control 3
3.8
11.9
14.0


Temporal



Parietal


Ctx



Ctx


Control 3
2.8
11.3
13.6
Control
26.1
50.0
45.7


Temporal



(Path) 1


Ctx



Parietal






Ctx


Control 3
1.0
4.3
3.8
Control
5.6
13.5
9.8


Temporal



(Path) 2


Ctx



Parietal






Ctx


Control
18.9
37.9
25.7
Control
0.2
1.7
1.5


(Path) 1



(Path) 3


Temporal



Parietal


Ctx



Ctx


Control
8.0
26.4
26.2
Control
13.2
39.5
14.5


(Path) 2



(Path) 4


Temporal



Parietal


Ctx



Ctx










[0922]

360





TABLE 1F










Panel I















Rel.

Rel.

Rel.

Rel.



Exp.(%)
Rel.
Exp.(%)

Exp.(%)
Rel.
Exp.(%)



Ag92,
Exp.(%)
Ag92b,

Ag92,
Exp.(%)
Ag92b,



Run
Ag92, Run
Run
Tissue
Run
Ag92, Run
Run


Tissue Name
87586687
124961889
87584661
Name
87586687
124961889
87584661

















Endothelial
0.0
0.0
0.1
Renal ca.
0.5
0.0
1.0


cells



786-0


Endothelial
0.1
0.0
0.2
Renal ca.
0.4
0.0
0.9


cells (treated)



A498


Pancreas
1.6
0.0
1.9
Renal ca.
0.4
0.0
0.9






RXF 393


Pancreatic ca.
3.3
0.0
4.2
Renal ca.
0.9
0.0
2.7


CAPAN 2



ACHN


Adrenal gland
0.9
0.0
1.1
Renal ca.
0.8
0.0
1.8






UO-31


Thyroid
4.1
0.0
4.6
Renal ca.
7.8
0.7
22.1






TK-10


Salivary gland
0.2
0.0
0.8
Liver
2.6
0.0
3.9


Pituitary gland
0.6
0.0
0.5
Liver (fetal)
2.9
0.0
6.7


Brain (fetal)
2.6
0.0
3.0
Liver ca.
0.0
0.0
0.0






(hepatoblast)






HepG2


Brain (whole)
16.3
27.7
21.5
Lung
3.1
19.9
5.5


Brain
0.4
0.0
4.6
Lung (fetal)
10.7
3.0
21.2


(amygdala)


Brain
100.0
100.0
100.0
Lung ca.
0.9
0.0
3.8


(cerebellum)



(small cell)






LX-1


Brain
12.2
0.0
10.1
Lung ca.
5.3
0.0
8.2


(hippocampus)



(small cell)






NCI-H69


Brain
0.2
0.0
2.5
Lung ca.
0.0
0.0
2.9


(substantia



(s.cell var.)


nigra)



SHP-77


Brain
2.9
0.0
6.2
Lung ca.
0.0
4.1
3.5


(thalamus)



(large






cell)NCI-






H460


Brain
1.5
0.0
2.6
Lung ca.
5.8
0.4
13.7


(hypothalamus)



(non-sm.






cell) A549


Spinal cord
1.1
0.0
4.5
Lung ca.
0.3
0.0
0.2






(non-s.cell)






NCI-H23


glio/astro U87-
0.1
0.0
0.1
Lung ca.
2.7
0.0
3.9


MG



(non-s.cell)






HOP-62


glio/astro U-
0.1
0.0
0.1
Lung ca.
1.6
0.0
4.2


118-MG



(non-s.cl)






NCI-H522


astrocytoma
0.2
0.0
0.5
Lung ca.
4.3
0.0
7.0


SW1783



(squam.) SW






900


neuro*; met
1.1
0.0
2.7
Lung ca.
6.0
0.0
5.5


SK-N-AS



(squam.)






NCI-H596


astrocytoma
0.0
0.0
0.0
Mammary
2.5
0.0
6.7


SF-539



gland


astrocytoma
9.5
5.0
23.2
Breast ca.*
4.5
0.0
3.7


SNB-75



(pl.ef)






MCF-7


glioma SNB-19
4.4
0.0
10.6
Breast ca.*
0.0
0.0
0.0






(pl.ef)






MDA-MB-






231


glioma U251
0.0
0.0
0.1
Breast ca.*
0.1
0.0
1.8






(pl. ef)






T47D


glioma SF-295
0.0
0.0
0.0
Breast ca.
0.0
0.0
2.0






BT-549


Heart
0.5
0.0
0.6
Breast ca.
1.5
0.0
2.1






MDA-N


Skeletal muscle
2.2
0.0
1.9
Ovary
0.9
0.0
3.0


Bone marrow
0.0
0.0
0.2
Ovarian ca.
0.8
0.0
0.9






OVCAR-3


Thymus
13.8
0.0
15.2
Ovarian ca.
0.6
0.0
0.7






OVCAR-4


Spleen
0.0
0.0
0.4
Ovarian ca.
16.3
9.6
28.3






OVCAR-5


Lymph node
0.2
0.0
0.6
Ovarian ca.
0.6
0.0
0.3






OVCAR-8


Colon
3.4
0.0
3.6
Ovarian ca.
6.9
0.1
15.2


(ascending)



IGROV-1


Stomach
13.1
0.1
14.9
Ovarian ca.
2.8
0.0
7.0






(ascites) SK-






OV-3


Small intestine
1.2
0.0
2.6
Uterus
10.2
18.8
19.5


Colon ca.
0.1
0.0
0.1
Placenta
1.6
0.0
2.5


SW480


Colon ca.*
0.0
0.0
0.1
Prostate
6.4
0.0
11.3


SW620


(SW480 met)


Colon ca.
1.0
0.0
1.4
Prostate ca.*
0.0
0.2
1.4


HT29



(bone met)






PC-3


Colon ca.
0.0
0.0
0.2
Testis
22.2
25.5
19.1


HCT-116


Colon ca.
20.9
25.0
45.7
Melanoma
0.2
0.0
0.3


CaCo-2



Hs688(A).T


Colon ca.
0.8
0.0
0.4
Melanoma*
0.1
0.0
0.4


HCT-15



(met)






Hs688(B).T


Colon ca.
0.4
0.0
1.6
Melanoma
1.3
0.0
0.9


HCC-2998



UACC-62


Gastric ca.*
19.9
36.3
46.7
Melanoma
1.3
0.0
0.7


(liver met)



M14


NCI-N87


Bladder
2.0
0.1
3.1
Melanoma
0.1
0.0
0.5






LOX IMVI


Trachea
4.5
0.0
7.6
Melanoma*
0.6
0.0
0.3






(met) SK-






MEL-5


Kidney
7.7
0.0
19.2
Melanoma
1.0
0.0
1.2






SK-MEL-28


Kidney (fetal)
20.7
3.9
31.2










[0923]

361





TABLE TG










Panel 1.3D













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag2763, Run
Ag92b, Run

Ag2763, Run
Ag92b, Run


Tissue Name
165527214
165974816
Tissue Name
165527214
165974816















Liver
4.1
3.8
Kidney (fetal)
35.1
51.8


adenocarcinoma


Pancreas
1.5
1.7
Renal ca. 786-0
2.0
2.6


Pancreatic ca.
14.0
25.9
Renal ca. A498
3.7
3.1


CAPAN 2


Adrenal gland
0.9
4.3
Renal ca. RXF
4.0
4.1





393


Thyroid
5.6
4.5
Renal ca.
3.2
9.3





ACHN


Salivary gland
1.5
1.1
Renal ca. UO-
10.5
18.4





31


Pituitary gland
4.3
6.3
Renal ca. TK-
22.1
33.9





10


Brain (fetal)
20.4
20.6
Liver
3.1
4.8


Brain (whole)
47.3
95.3
Liver (fetal)
18.7
20.7


Brain (amygdala)
24.0
38.2
Liver ca.
0.0
0.0





(hepatoblast)





HepG2


Brain (cerebellum)
49.0
64.6
Lung
23.7
44.1


Brain
28.3
36.1
Lung (fetal)
18.0
50.0


(hippocampus)


Brain (substantia
3.8
6.8
Lung ca.
7.1
15.4


nigra)


(small cell)





LX-1


Brain (thalamus)
32.1
45.1
Lung ca.
6.1
43.8





(small cell)





NCI-H69


Cerebral Cortex
15.7
26.2
Lung ca. (s.cell
4.7
3.7





var.) SHP-77


Spinal cord
6.2
22.4
Lung ca. (large
9.3
3.8





cell)NCI-H460


glio/astro U87-MG
0.6
0.0
Lung ca. (non-
14.1
19.8





sm. cell) A549


glio/astro U-118-
1.2
0.6
Lung ca. (non-
0.0
0.8


MG


s.cell) NCI-
0.0
0.8





H23


astrocytoma
0.9
4.7
Lung ca. (non-
10.5
16.2


SW1783


s.cell) HOP-62


neuro*; met SK-N-
6.6
5.6
Lung ca. (non-
2.0
2.9


AS


s.cl) NCI-H522


astrocytoma SF-
0.0
1.7
Lung ca.
3.5
12.4


539


(squam.) SW





900


astrocytoma SNB-
15.6
11.3
Lung ca.
9.0
15.9


75


(squam.) NCI-





H596


glioma SNB-19
12.7
39.0
Mammary
2.8
1.2





gland


glioma U251
0.3
0.0
Breast ca.*
3.1
3.5





(pl.ef) MCF-7


glioma SF-295
0.0
0.0
Breast ca.*
0.2
0.0





(pl.ef) MDA-





MB-231


Heart (fetal)
0.3
0.3
Breast ca.*
1.1
2.9





(pl.ef) T47D


Heart
1.6
0.6
Breast ca. BT-
6.7
2.9





549


Skeletal muscle
3.4
1.0
Breast ca.
0.8
2.8


(fetal)


MDA-N


Skeletal muscle
8.2
9.9
Ovary
0.4
1.2


Bone marrow
0.0
2.4
Ovarian ca.
3.2
3.2





OVCAR-3


Thymus
2.6
6.9
Ovarian ca.
1.8
7.7





OVCAR-4


Spleen
0.4
0.6
Ovarian ca.
48.6
100.0





OVCAR-5


Lymph node
0.3
4.0
Ovarian ca.
1.5
0.5





OVCAR-8


Colorectal
1.7
2.4
Ovarian ca.
22.4
88.3





IGROV-1


Stomach
11.6
11.9
Ovarian ca.*
6.8
34.2





(ascites) SK-





OV-3


Small intestine
9.6
2.5
Uterus
2.2
2.0


Colon ca. SW480
0.3
1.4
Placenta
1.1
8.5


Colon ca.*
0.8
4.1
Prostate
12.2
4.7


SW620(SW480


met)


Colon ca. HT29
1.6
1.9
Prostate ca.*
1.6
0.0





(bone met)PC-3


Colon ca. HCT-
0.4
0.5
Testis
2.6
2.5


116


Colon ca. CaCo-2
34.6
92.7
Melanoma
0.5
0.9





Hs688(A).T


Colon ca.
1.9
6.2
Melanoma*
0.3
0.7


tissue(ODO3866)


(met)





Hs688(B).T


Colon ca. HCC-
4.2
1.4
Melanoma
7.2
9.9


2998


UACC-62


Gastric ca.* (liver
100.0
79.0
Melanoma
2.6
1.7


met) NCI-N87


M14


Bladder
11.2
19.8
Melanoma
0.0
0.0





LOX IMVI


Trachea
3.8
5.9
Melanoma*
0.4
0.0





(met) SK-





MEL-5


Kidney
27.7
33.2
Adipose
9.0
19.6










[0924]

362





TABLE TH










Panel 2D















Rel.
Rel.
Rel.

Rel.
Rel.
Rel.



Exp. (%)
Exp. (%)
Exp. (%)

Exp. (%)
Exp. (%)
Exp. (%)



Ag2763,
Ag92,
Ag92b,

Ag2763,
Ag92,
Ag92b,


Tissue
Run
Run
Run
Tissue
Run
Run
Run


Name
162555842
149912056
151275585
Name
162555842
149912056
151275585

















Normal
9.7
7.0
7.5
Kidney
5.1
6.8
4.4


Colon



Margin






8120608


CC Well to
0.7
0.5
0.7
Kidney
0.2
0.2
0.1


Mod Diff



Cancer


(ODO3866)



8120613


CC Margin
1.2
1.3
0.7
Kidney
3.4
3.1
3.3


(ODO3866)



Margin






8120614


CC Gr.2
1.0
0.5
0.9
Kidney
2.6
4.2
2.5


rectosigmoid



Cancer


(ODO3868)



9010320


CC Margin
0.6
0.8
0.6
Kidney
11.0
13.7
15.3


(ODO3868)



Margin






9010321


CC Mod
1.0
0.5
1.0
Normal
2.2
1.2
0.9


Diff



Uterus


(ODO3920)


CC Margin
2.1
1.5
2.2
Uterus
4.5
3.5
3.8


(ODO3920)



Cancer






064011


CC Gr.2
4.5
2.0
2.5
Normal
3.2
2.7
2.3


ascend colon



Thyroid


(ODO3921)


CC Margin
2.2
1.6
1.3
Thyroid
7.9
21.9
16.5


(ODO3921)



Cancer






064010


CC from
4.4
4.1
3.1
Thyroid
10.4
12.7
10.6


Partial



Cancer


Hepatectomy



A302152


(ODO4309)


Mets


Liver Margin
4.9
3.0
4.1
Thyroid
8.5
6.0
4.8


(ODO4309)



Margin






A302153


Colon mets
3.1
2.2
3.1
Normal
5.2
4.1
3.2


to lung



Breast


(OD04451-


01)


Lung Margin
12.3
11.3
9.7
Breast
0.9
0.7
0.7


(OD04451-



Cancer


02)



(OD04566)


Normal
42.0
5.9
6.2
Breast
2.9
2.5
2.0


Prostate



Cancer


6546-1



(OD04590-






01)


Prostate
6.7
6.4
5.4
Breast
2.1
1.8
1.4


Cancer



Cancer


(OD04410)



Mets






(OD04590-






03)


Prostate
10.4
7.7
8.2
Breast
44.8
50.3
30.4


Margin



Cancer


(OD04410)



Metastasis






(OD04655-






05)


Prostate
15.9
13.3
12.6
Breast
1.5
1.2
1.2


Cancer



Cancer


(OD04720-



064006


01)


Prostate
35.8
27.7
30.6
Breast
2.0
2.1
1.8


Margin



Cancer


(OD04720-



1024


02)


Normal
30.6
21.5
19.9
Breast
3.9
2.1
2.1


Lung 061010



Cancer






9100266


Lung Met to
0.5
0.4
0.3
Breast
0.9
0.9
1.1


Muscle



Margin


(ODO4286)



9100265


Muscle
1.1
0.3
0.3
Breast
8.7
5.6
5.6


Margin



Cancer


(ODO4286)



A209073


Lung
14.7
10.4
9.3
Breast
2.6
3.4
2.6


Malignant



Margin


Cancer



A209073


(OD03126)


Lung Margin
80.1
56.6
53.6
Normal
1.7
1.2
1.3


(OD03126)


Lung Cancer
19.1
22.1
15.6
Liver
0.1
0.4
0.5


(OD04404)



Cancer






064003


Lung Margin
26.8
36.6
22.1
Liver
1.5
1.7
1.3


(OD04404)



Cancer






1025


Lung Cancer
6.1
4.9
5.0
Liver
0.9
0.5
0.6


(OD04565)



Cancer






1026


Lung Margin
14.7
19.2
15.5
Liver
1.5
2.4
1.6


(OD04565)



Cancer






6004-T


Lung Cancer
5.6
5.3
4.3
Liver
0.4
0.3
0.5


(OD04237-



Tissue


01)



6004-N


Lung Margin
28.7
32.5
28.7
Liver
0.6
0.9
0.7


(OD04237-



Cancer


02)



6005-T


Ocular Mel
0.4
0.1
0.1
Liver
0.2
0.2
0.3


Met to Liver



Tissue


(ODO4310)



6005-N


Liver Margin
5.8
3.5
3.6
Normal
9.7
11.0
10.4


(ODO4310)



Bladder


Melanoma
6.0
5.0
4.7
Bladder
0.2
0.2
0.5


Mets to



Cancer


Lung



1023


(OD04321)


Lung Margin
62.9
57.8
38.7
Bladder
2.0
1.8
1.4


(OD04321)



Cancer






A302173


Normal
45.4
55.9
25.3
Bladder
1.2
0.7
1.2


Kidney



Cancer






(OD04718-






01)


Kidney Ca,
69.7
55.1
49.3
Bladder
2.7
3.4
3.5


Nuclear



Normal


grade 2



Adjacent


(OD04338)



(OD04718-






03)


Kidney
21.3
24.7
19.2
Normal
1.2
0.9
0.9


Margin



Ovary


(OD04338)


Kidney Ca
16.2
19.9
27.9
Ovarian
3.3
3.7
2.5


Nuclear



Cancer


grade 1/2



064008


(OD04339)


Kidney
41.2
33.9
29.5
Ovarian
0.9
0.5
0.7


Margin



Cancer


(OD04339)



(OD04768-






07)


Kidney Ca,
29.3
34.9
25.0
Ovary
1.0
1.6
0.9


Clear cell



Margin


type



(OD04768-


(OD04340)



08)


Kidney
20.0
26.6
19.6
Normal
6.9
7.2
7.0


Margin



Stomach


(OD04340)


Kidney Ca,
0.6
0.3
0.4
Gastric
0.5
0.7
0.5


Nuclear



Cancer


grade 3



9060358


(OD04348)


Kidney
30.8
20.9
21.5
Stomach
3.7
2.8
2.5


Margin



Margin


(OD04348)



9060359


Kidney
0.7
0.3
0.6
Gastric
6.3
6.9
5.6


Cancer



Cancer


(OD04622-



9060395


01)


Kidney
2.9
2.9
4.5
Stomach
2.4
3.6
2.5


Margin



Margin


(OD04622-



9060394


03)


Kidney
100.0
100.0
100.0
Gastric
5.1
4.3
3.8


Cancer



Cancer


(OD04450-



9060397


01)


Kidney
36.1
29.3
24.1
Stomach
1.5
0.9
1.3


Margin



Margin


(OD04450-



9060396


03)


Kidney
1.8
1.5
1.3
Gastric
10.7
7.0
10.4


Cancer



Cancer


8120607



064005










[0925]

363





TABLE TI










Panel 3D











Rel. Exp.(%)

Rel. Exp.(%)



Ag92b, Run

Ag92b, Run


Tissue Name
165919165
Tissue Name
165919165













Daoy-Medulloblastoma
0.4
Ca Ski-Cervical epidermoid
0.1




carcinoma (metastasis)


TE671-Medulloblastoma
0.4
ES-2-Ovarian clear cell
0.2




carcinoma


D283 Med-
3.3
Ramos-Stimulated with
0.0


Medulloblastoma

PMA/ionomycin 6h


PFSK-1-Primitive
15.1
Ramos-Stimulated with
0.0


Neuroectodermal

PMA/ionomycin 14h


XF-498-CNS
100.0
MEG-01-Chronic
0.5




myelogenous leukemia




(megokaryoblast)


SNB-78-Glioma
0.1
Raji-Burkitt's lymphoma
0.0


SF-268-Glioblastoma
0.0
Daudi-Burkitt's lymphoma
0.1


T98G-Glioblastoma
1.0
U266-B-cell plasmacytoma
0.0


SK-N-SH-Neuroblastoma
6.3
CA46-Burkitt's lymphoma
0.0


(metastasis)


SF-295-Glioblastoma
0.0
RL-non-Hodgkin's B-cell
0.0




lymphoma


Cerebellum
41.2
JM1-pre-B-cell lymphoma
0.0


Cerebellum
1.8
Jurkat-T cell leukemia
0.0


NCI-H292-
0.7
TF-1-Erythroleukemia
0.1


Mucoepidermoid lung


carcinoma


DMS-114-Small cell
0.2
HUT 78-T-cell lymphoma
0.0


lung cancer


DMS-79-Small cell lung
0.9
U937-Histiocytic lymphoma
0.0


cancer


NCI-H146-Small cell
5.5
KU-812-Myelogenous
0.3


lung cancer

leukemia


NCI-H526-Small cell
0.8
769-P-Clear cell renal
0.8


lung cancer

carcinoma


NCI-N417-Small cell
1.7
Caki-2-Clear cell renal
18.8


lung cancer

carcinoma


NCI-H82-Small cell lung
3.8
SW 839-Clear cell renal
1.2


cancer

carcinoma


NCI-H157-Squamous
0.0
G401-Wilms'tumor
0.0


cell lung cancer


(metastasis)


NCI-H1155-Large cell
0.2
Hs766T-Pancreatic carcinoma
0.3


lung cancer

(LN metastasis)


NCI-H1299-Large cell
0.2
CAPAN-1-Pancreatic
2.0


lung cancer

adenocarcinoma (liver




metastasis)


NCI-H727-Lung
84.1
SU86.86-Pancreatic
1.8


carcinoid

carcinoma (liver metastasis)


NCI-UMC-11-Lung
24.3
BxPC-3-Pancreatic
6.9


carcinoid

adenocarcinoma


LX-1-Small cell lung
5.8
HPAC-Pancreatic
6.9


cancer

adenocarcinoma


Colo-205-Colon cancer
0.4
MIA PaCa-2-Pancreatic
0.1




carcinoma


KM12-Colon cancer
1.2
CFPAC-1-Pancreatic ductal
6.0




adenocarcinoma


KM20L2-Colon cancer
1.9
PANC-1-Pancreatic
0.4




epithelioid ductal carcinoma


NCI-H716-Colon cancer
40.9
T24-Bladder carcinma
4.6




(transitional cell)


SW-48-Colon
0.0
5637-Bladder carcinoma
2.6


adenocarcinoma


SW1116-Colon
1.4
HT-1197-Bladder carcinoma
0.0


adenocarcinoma


LS 174T-Colon
1.2
UM-UC-3-Bladder carcinma
0.0


adenocarcinoma

(transitional cell)


SW-948-Colon
0.2
A204-Rhabdomyosarcoma
0.0


adenocarcinoma


SW-480-Colon
0.1
HT-1080-Fibrosarcoma
1.2


adenocarcinoma


NCI-SNU-5-Gastric
0.1
MG-63-Osteosarcoma
1.4


carcinoma


KATO III-Gastric
17.3
SK-LMS-1-Leiomyosarcoma
0.8


carcinoma

(vulva)


NCI-SNU-16-Gastric
0.9
SJRH30-Rhabdomyosarcoma
1.6


carcinoma

(met to bone marrow)


NCI-SNU-1-Gastric
6.0
A431-Epidermoid carcinoma
0.0


carcinoma


RF-1-Gastric
0.1
WM266-4-Melanoma
7.0


adenocarcinoma


RF-48-Gastric
0.5
DU 145-Prostate carcinoma
0.0


adenocarcinoma

(brain metastasis)


MKN-45-Gastric
7.2
MDA-MB-468-Breast
0.3


carcinoma

adenocarcinoma


NCI-N87-Gastric
6.7
SCC-4-Squamous cell
0.0


carcinoma

carcinoma of tongue


OVCAR-5-Ovarian
1.1
SCC-9-Squamous cell
0.0


carcinoma

carcinoma of tongue


RL95-2-Uterine
0.6
SCC-15-Squamous cell
0.1


carcinoma

carcinoma of tongue


HelaS3-Cervical
0.3
CAL 27-Squamous cell
0.5


adenocarcinoma

carcinoma of tongue










[0926]

364





TABLE TJ










Panel 4D















Rel.
Rel.
Rel.

Rel.
Rel.
Rel.



Exp.(%)
Exp.(%)
Exp.(%)

Exp.(%)
Exp.(%)
Exp.(%)



Ag2763,
Ag92,
Ag92b,

Ag2763,
Ag92,
Ag92b,



Run
Run
Run

Run
Run
Run


Tissue Name
162015245
149912706
151965831
Tissue Name
162015245
149912706
151965831

















Secondary Th1 act
0.0
0.0
0.1
HUVEC IL-
0.1
0.2
0.6






1 beta


Secondary Th2 act
0.0
0.0
0.2
HUVEC IFN
0.1
0.3
0.2






gamma


Secondary Tr1 act
0.0
0.0
0.0
HUVEC TNF
0.1
0.1
0.1






alpha + IFN






gamma


Secondary Th1
0.0
0.0
0.0
HUVEC TNF
1.4
0.9
1.1


rest



alpha + IL4


Secondary Th2
0.0
0.0
0.0
HUVEC IL-11
0.1
0.1
0.2


rest


Secondary Tr1
0.0
0.0
0.0
Lung
0.0
0.0
0.2


rest



Microvascular






EC none


Primary Th1 act
0.0
0.0
0.0
Lung
0.0
0.0
0.1






Microvascular






EC TNF alpha +






IL-1 beta


Primary Th2 act
0.0
0.0
0.0
Microvascular
0.0
0.0
0.1






Dermal EC none


Primary Tr1 act
0.0
0.0
0.1
Microsvasular
0.0
0.0
0.0






Dermal EC






TNF alpha + IL-






1 beta


Primary Th1 rest
0.0
0.0
0.0
Bronchial
34.9
15.0
4.0






epithelium






TNF alpha +






IL1 beta


Primary Th2 rest
0.0
0.0
0.0
Small airway
11.5
11.2
10.1






epithelium none


Primary Tr1 rest
0.0
0.0
0.0
Small airway
77.9
81.2
87.1






epithelium






TNF alpha + IL-






1 beta


CD45RA CD4
0.6
1.4
1.3
Coronery artery
0.2
0.2
0.3


lymphocyte act



SMC rest


CD45RO CD4
0.0
0.0
0.0
Coronery artery
0.1
0.1
0.2


lymphocyte act



SMC TNF alpha +






IL-1 beta


CD8 lymphocyte
0.0
0.0
0.0
Astrocytes rest
2.6
3.1
2.8


act


Secondary CD8
0.0
0.0
0.0
Astrocytes
1.1
1.2
1.4


lymphocyte rest



TNF alpha + IL-






1 beta


Secondary CD8
0.0
0.0
0.0
KU-812
1.0
1.5
1.3


lymphocyte act



(Basophil) rest


CD4 lymphocyte
0.0
0.0
0.0
KU-812
2.1
1.4
1.1


none



(Basophil)






PMA/ionomycin


2ry
0.0
0.0
0.0
CCD1106
100.0
81.2
60.3


Th1/Th2/Tr1_anti-



(Keratinocytes)


CD95 CH11



none


LAK cells rest
0.0
0.0
0.0
CCD1106
14.7
5.1
2.9






(Keratinocytes)






TNF alpha + IL-






1 beta


LAK cells IL-2
0.0
0.0
0.0
Liver cirrhosis
4.6
5.1
4.9


LAK cells IL-
0.0
0.0
0.0
Lupus kidney
5.9
6.3
8.0


2 + IL-12


LAK cells IL-
0.0
0.0
0.0
NCI-H292 none
2.1
2.0
1.4


2 + IFN gamma


LAK cells IL-2 +
0.1
0.0
0.0
NCI-H292 IL-4
1.9
1.4
1.3


IL-18


LAK cells
0.0
0.0
0.0
NCI-H292 IL-9
1.7
3.4
1.5


PMA/ionomycin


NK Cells IL-2 rest
0.0
0.0
0.0
NCI-H292 IL-
0.9
1.8
0.8






13


Two Way MLR 3
0.0
0.0
0.0
NCI-H292 IFN
0.5
0.4
0.6


day



gamma


Two Way MLR 5
0.0
0.0
0.0
HPAEC none
0.4
0.4
1.1


day


Two Way MLR 7
0.0
0.0
0.0
HPAEC TNF
0.0
0.0
0.3


day



alpha + IL-1






beta


PBMC rest
0.0
0.0
0.0
Lung fibroblast
6.9
9.6
9.2






none


PBMC PWM
0.0
0.0
0.2
Lung fibroblast
11.8
4.6
15.5






TNF alpha + IL-






1 beta


PBMC PHA-L
0.1
0.0
0.0
Lung fibroblast
37.9
42.3
47.3






IL-4


Ramos (B cell)
0.0
0.0
0.2
Lung fibroblast
18.8
18.3
23.3


none



IL-9


Ramos (B cell)
0.0
0.0
0.0
Lung fibroblast
17.3
20.0
23.8


ionomycin



IL-13


B lymphocytes
0.0
0.0
0.2
Lung fibroblast
14.1
11.8
12.7


PWM



IFN gamma


B lymphocytes
0.1
0.1
0.1
Dermal
4.9
4.4
4.4


CD40L and IL-4



fibroblast






CCD1070 rest


EOL-1 dbcAMP
0.0
0.0
0.0
Dermal
1.3
1.9
2.9






fibroblast






CCD1070 TNF






alpha


EOL-1 dbcAMP
0.0
0.0
0.0
Dermal
0.7
1.5
1.6


PMA/ionomycin



fibroblast






CCD1070 IL-1






beta


Dendritic cells
0.0
0.0
0.0
Dermal
0.3
0.2
0.7


none



fibroblast IFN






gamma


Dendritic cells
0.0
0.1
0.1
Dermal
3.6
6.6
6.6


LPS



fibroblast IL-4


Dendritic cells
0.0
0.0
0.0
IBD Colitis 2
0.4
0.2
0.0


anti-CD40


Monocytes rest
0.0
0.0
0.0
IBD Crohn's
0.6
0.3
0.4


Monocytes LPS
0.0
0.0
0.0
Colon
5.5
6.5
4.1


Macrophages rest
0.0
0.0
0.1
Lung
58.6
57.0
69.3


Macrophages LPS
0.0
0.0
0.0
Thymus
84.7
100.0
100.0


HUVEC none
0.5
0.5
0.5
Kidney
13.5
15.1
25.0


HUVEC starved
1.0
0.4
0.5










[0927] AI_comprehensive panel_v1.0 Summary: Ag92 Highest expression of the CG50838-01 gene is found in in rheumatoid arthritis (RA) synovium fluid cells (CT=28). This gene shows higher expression in synovium, cartilage and bone samples from rheumatide arthritis patient (CTs=28-29) as compared to orthoarthritis patients (CTs=31-35). Therefore, therapeutic modulation of the activity of the GPCR encoded by this gene may be useful in the treatment of patients suffering from rheumatoid arthritis.


[0928] In addition, low expression of this gene is seen in almost all the samples derived from normal and diseased patients. Please see panel 4D for potential utility of this gene.


[0929] CNS_neurodegeneration_v1.0 Summary: Ag92b This panel does not show differential expression of the CG50838-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1 and 1.3D for discussion of utility of this gene in the central nervous system. Results from two additional experiments with the probe and primer sets Ag92 and Ag2763 are not included. The amp plot indicates that there were experimental difficulties with these runs.


[0930] Panel 1 Summary: Ag92/Ag92b Three experiments show highest expression of the CG50838-01 gene in the cerebellum (CTs=24-27). In addition, expression is seen in the hippocampus, thalamus and hypothalamus. This gene encodes a fibronectin leucine rich transmembrane protein 3 (FLRT3), a member of the leucine rich repeats (LRR) protein family. FLRT proteins may play a role in cell adhesion and/or receptor signaling (Ref. 1). Several of LRR proteins, such as connectin, slit, chaoptin, and Toll have pivotal roles in neuronal development in Drosophila and may play significant but distinct roles in neural development and in the adult nervous system of humans (Ref. 2). In Drosophilia, the LRR region of axon guidance proteins has been shown to be critical for their function (especially in axon repulsion). Since the leucine-rich-repeat protein encoded by this gene shows high expression in the cerebellum, it is an excellent candidate neuronal guidance protein for axons, dendrites and/or growth cones in general. Therefore, therapeutic modulation of the levels of this protein, or possible signaling via this protein, may be of utility in enhancing/directing compensatory synaptogenesis and fiber growth in the CNS in response to neuronal death (stroke, head trauma), axon lesion (spinal cord injury), or neurodegeneration (Alzheimer's, Parkinson's, Huntington's, vascular dementia or any neurodegenerative disease).


[0931] Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adrenal gland, pancreas, thyroid, skeletal muscle, heart, and adult and fetal liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.


[0932] In addition, there is expression in cell lines derived from pancreatic, gastric, colon, ovarian and lung cancer cell lines. Thus, based upon this pattern of gene expression, the therapeutic modulation of the activity of the this gene product might be of use in the treatment of these cancers.


[0933] Reference.


[0934] 1. Lacy S E, Bonnemann C G, Buzney E A, Kunkel L M. Identification of FLRT1, FLRT2, and FLRT3: a novel family of transmembrane leucine-rich repeat proteins. Genomics Dec. 15, 1999; 15;62(3):417-26


[0935] 2. Battye R., Stevens A., Perry R. L., Jacobs J. R. (2001) Repellent signaling by Slit requires the leucine-rich repeats. J. Neurosci. 21: 4290-4298.


[0936] Panel 1.3D Summary: Ag2763/Ag92b Two experiments with the different probe and primer sets produce results that are in excellent agreement, with high expression of the CG50838-01 gene in gastric cancer NCI-N87, colon cancer CoCa2, ovarian cancer OVCAR-5 (CTs=29-31). Thus, expression of this gene can be used as a marker for detection these cancers. In addition, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of these cancers.


[0937] Among tissues with metabolic or endocrine function, this gene is expressed at high to moderate levels in adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.


[0938] In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease epilepsy, multiple sclerosis, schizophrenia and depression.


[0939] Panel 2D Summary: Ag2763/Ag92/Ag92b Three experiments with the different probe and primer sets produce results that are in excellent agreement, with highest expression of the CG50838-01 gene in the kidney cancer (OD04450-01) sample (CTs=27). In addition, expression of this gene is much lower in the corresponding control margin sample (CT=29). Significant expression of this gene is also seen in nuclear grade 2 kidney cancer and breast cancers. Therefore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of kidney or breast cancer.


[0940] Panel 3D Summary: Ag92b Highest expression of the CG50838-01 gene is detected in a sample derived from a brain cancer cell line (XF-498) and NCI-H727-lung carcinoid (CTs=27). Therefore, expression of this gene can be used to distinguish these samples from other samples in this panel. In addition, substantial expression of this gene is also seen in primitive neuroectodermal, medulloblastoma, mucoepidermoid lung carcinoma, small cell lung cancer, gastric cancer, ovarian cancer, pancreatic cancer, osteosarcoma, fibrosarcoma and colon cancer cell lines. Therefore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of these cancers.


[0941] In addition this panel also confirms expression of this gene in CNS, especially cerebellum. See panel 1 for potential utility of this gene.


[0942] Panel 4D Summary: Ag2763, 92a, 92b Three experiments with the different probe and primer sets produce results that are in excellent agreement, with high expression of this gene in untreated CCD1106 (keratinocytes), thymus, TNFalpha+IL-1beta treated small airway epithelium, and lung (CTs=27-28). Therefore, expression of this gene can be used to distinguish this sample from other samples in the panel. Interestingly, expression of this gene considerably reduced in untreated small airway epithelium and TNFalpha+IL-1beta treated keratinocytes. Thus, expression of this gene can be used to distinguish between these treated versus untreated cells.


[0943] In addition, significant expression of this gene is also seen in activated CD45RA CD4 lymphocyte, TNFalpha+IL1beta treated bronchial epithelium, NCI-H292 cells, lung and dermal fibroblasts, liver cirrhosis, lupus kidney, lung and kidney. This gene codes for a fibronectin leucine rich transmembrane protein 3 (FLRT3) like molecule, a member of the fibronectin leucine rich transmembrane protein (FLRT) family. These proteins may play a role in cell adhesion and/or receptor signaling (See Ref. 1 in panel 1). This gene may play a role in maintaining normal integrity of lung, and kidney tissue. Therefore, therapeutic modulation of the activity of the FLRT3 encoded by this gene may be beneficial for the reduction or elimination of the symptoms caused by inflammation in lung epithelia in chronic obstructive pulmonary disease, and in asthma, allergy, emphysema, kidney related diseases such as lupus and glomerulonephritis and liver cirrhosis.



U. NOV28a (CG58567-01: PROTOCADHERIN)

[0944] Expression of gene CG58567-01 was assessed using the primer-probe set Ag2897, described in Table UA. Results of the RTQ-PCR runs are shown in Tables UB, UC, UD, UE, UF, UG and UH.
365TABLE UAProbe Name Ag2897StartPrimersSequencesLengthPositionForward5′-tgacaggggatattcatgctaa-3′(SEQ ID NO:293)221565ProbeTET-5′-tggcaataaatactgcctcacagtcca-3′-TAMRA(SEQ ID NO:294)271608Reverse5′-agttgcatcacctttgtctttg-3′(SEQ ID NO:295)221638


[0945]

366





TABLE UB










AI_comprehensive panel_v1.0











Rel. Exp.(%) Ag2897,

Rel. Exp.(%) Ag2897,


Tissue Name
Run 229662505
Tissue Name
Run 229662505













110967 COPD-F
4.7
112427 Match Control
100.0




Psoriasis-F


110980 COPD-F
22.5
112418 Psoriasis-M
2.8


110968 COPD-M
8.5
112723 Match Control
14.3




Psoriasis-M


110977 COPD-M
51.8
112419 Psoriasis-M
10.7


110989 Emphysema-F
51.8
112424 Match Control
8.7




Psoriasis-M


110992 Emphysema-F
5.0
112420 Psoriasis-M
40.1


110993 Emphysema-F
5.6
112425 Match Control
65.1




Psoriasis-M


110994 Emphysema-F
3.3
104689 (MF) OA Bone-
1.7




Backus


110995 Emphysema-F
13.2
104690 (MF) Adj
4.5




“Normal” Bone-Backus


110996 Emphysema-F
0.6
104691 (MF) OA
9.5




Synovium-Backus


110997 Asthma-M
1.4
104692 (BA) OA
3.1




Cartilage-Backus


111001 Asthma-F
8.1
104694 (BA) OA Bone-
1.3




Backus


111002 Asthma-F
12.5
104695 (BA) Adj
1.8




“Normal” Bone-Backus


111003 Atopic
12.8
104696 (BA) OA
5.0


Asthma-F

Synovium-Backus


111004 Atopic
12.3
104700 (SS) OA Bone-
5.2


Asthma-F

Backus


111005 Atopic
6.1
104701 (SS) Adj
7.0


Asthma-F

“Normal” Bone-Backus


111006 Atopic
3.7
104702 (SS) OA
12.7


Asthma-F

Synovium-Backus


111417 Allergy-M
7.7
117093 OA Cartilage
15.1




Rep7


112347 Allergy-M
0.8
112672 OA Bone5
15.9


112349 Normal
0.8
112673 OA Synovium5
8.2


Lung-F


112357 Normal
20.2
112674 OA Synovial
7.9


Lung-F

Fluid cells5


112354 Normal
2.1
117100 OA Cartilage
1.3


Lung-M

Rep14


112374 Crohns-F
4.7
112756 OA Bone9
0.8


112389 Match Control
2.1
112757 OA Synovium9
0.4


Crohns-F


112375 Crohns-F
6.7
112758 OA Synovial
10.2




Fluid Cells9


112732 Match Control
2.2
117125 RA Cartilage
6.5


Crohns-F

Rep2


112725 Crohns-M
18.9
113492 Bone2 RA
2.2


112387 Match Control
11.2
113493 Synovium2 RA
0.2


Crohns-M


112378 Crohns-M
1.3
113494 Syn Fluid Cells
2.0




RA


112390 Match Control
62.4
113499 Cartilage4 RA
1.6


Crohns-M


112726 Crohns-M
9.6
113500 Bone4 RA
1.3


112731 Match Control
16.0
113501 Synovium4 RA
1.9


Crohns-M


112380 Ulcer Col-F
21.2
113502 Syn Fluid
1.0




Cells4 RA


112734 Match Control
4.5
113495 Cartilage3 RA
1.1


Ulcer Col-F


112384 Ulcer Col-F
17.3
113496 Bone3 RA
1.4


112737 Match Control
5.2
113497 Synovium3 RA
0.2


Ulcer Col-F


112386 Ulcer Col-F
5.3
113498 Syn Fluid
1.2




Cells3 RA


112738 Match Control
2.7
117106 Normal
0.3


Ulcer Col-F

Cartilage Rep20


112381 Ulcer Col-M
0.3
113663 Bone3 Normal
2.8


112735 Match Control
23.7
113664 Synovium3
0.2


Ulcer Col-M

Normal


112382 Ulcer Col-M
5.8
113665 Syn Fluid
1.3




Cells3 Normal


112394 Match Control
6.5
117107 Normal
9.2


Ulcer Col-M

Cartilage Rep22


112383 Ulcer Col-M
1.6
113667 Bone4 Normal
9.5


112736 Match Control
1.3
113668 Synovium4
6.1


Ulcer Col-M

Normal


112423 Psoriasis-F
7.9
113669 Syn Fluid
10.2




Cells4 Normal










[0946]

367





TABLE UC










CNS_neurodegeneration_v1.0











Rel. Exp.(%) Ag2897,

Rel. Exp.(%) Ag2897,


Tissue Name
Run 209734745
Tissue Name
Run 209734745













AD 1 Hippo
6.5
Control (Path) 3
8.9




Temporal Ctx


AD 2 Hippo
31.9
Control (Path) 4
46.7




Temporal Ctx


AD 3 Hippo
1.6
AD 1 Occipital Ctx
5.6


AD 4 Hippo
7.3
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 hippo
46.3
AD 3 Occipital Ctx
6.1


AD 6 Hippo
44.4
AD 4 Occipital Ctx
23.0


Control 2 Hippo
24.0
AD 5 Occipital Ctx
11.3


Control 4 Hippo
15.7
AD 6 Occipital Ctx
22.5


Control (Path) 3
0.0
Control 1 Occipital
1.6


Hippo

Ctx


AD 1 Temporal Ctx
3.0
Control 2 Occipital
17.7




Ctx


AD 2 Temporal Ctx
38.7
Control 3 Occipital
9.1




Ctx


AD 3 Temporal Ctx
3.5
Control 4 Occipital
8.7




Ctx


AD 4 Temporal Ctx
23.0
Control (Path) 1
92.0




Occipital Ctx


AD 5 Inf Temporal
79.0
Control (Path) 2
0.8


Ctx

Occipital Ctx


AD 5 Sup Temporal
43.5
Control (Path) 3
1.6


Ctx

Occipital Ctx


AD 6 Inf Temporal
41.8
Control (Path) 4
7.6


Ctx

Occipital Ctx


AD 6 Sup Temporal
41.2
Control 1 Parietal
4.2


Ctx

Ctx


Control 1 Temporal
12.3
Control 2 Parietal
47.3


Ctx

Ctx


Control 2 Temporal
50.3
Control 3 Parietal
10.1


Ctx

Ctx


Control 3 Temporal
17.8
Control (Path) 1
100.0


Ctx

Parietal Ctx


Control 4 Temporal
9.3
Control (Path) 2
13.4


Ctx

Parietal Ctx


Control (Path) 1
70.2
Control (Path) 3
4.2


Temporal Ctx

Parietal Ctx


Control (Path) 2
29.3
Control (Path) 4
33.2


Temporal Ctx

Parietal Ctx










[0947]

368





TABLE UD










Panel 1.3D













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag2897, Run
Ag2897, Run

Ag2897, Run
Ag2897, Run


Tissue Name
161905860
165518166
Tissue Name
161905860
165518166















Liver
0.0
0.0
Kidney (fetal)
2.8
2.4


adenocarcinoma


Pancreas
1.4
2.4
Renal ca. 786-0
0.9
3.3


Pancreatic ca.
0.0
0.0
Renal ca. A498
13.9
23.7


CAPAN 2


Adrenal gland
1.4
0.0
Renal ca. RXF
0.0
0.0





393


Thyroid
0.0
0.0
Renal ca.
0.0
0.0





ACHN



Salivary gland
0.0
0.0
Renal ca. UO-
0.0
0.0





31


Pituitary gland
4.1
9.0
Renal ca. TK-
0.0
0.0





10


Brain (fetal)
7.1
17.8
Liver
0.0
2.9


Brain (whole)
21.0
59.0
Liver (fetal)
0.4
0.0


Brain (amygdala)
24.7
37.9
Liver ca.
0.0
0.0





(hepatoblast)





HepG2


Brain (cerebellum)
5.6
28.5
Lung
1.4
0.0


Brain
25.2
25.3
Lung (fetal)
6.8
11.0


(hippocampus)


Brain (substantia
0.9
17.1
Lung ca.
0.0
0.0


nigra)


(small cell)





LX-1


Brain (thalamus)
4.1
23.0
Lung ca.
0.0
4.1





(small cell)





NCI-H69


Cerebral Cortex
100.0
22.2
Lung ca. (s.cell
1.0
0.0





var.) SHP-77


Spinal cord
68.8
100.0
Lung ca. (large
0.0
0.0





cell) NCI-H460


glio/astro U87-MG
54.3
10.4
Lung ca. (non-
0.0
0.0





sm. cell) A549


glio/astro U-118-
1.5
20.4
Lung ca. (non-
0.0
3.0


MG


s.cell) NCI-





H23


astrocytoma
16.3
0.0
Lung ca. (non-
0.6
7.5


SW1783


s.cell) HOP-62


neuro*; met SK-N-
0.0
0.0
Lung ca. (non-
0.0
0.0


AS


s.cl) NCI-H522


astrocytoma SF-
0.0
4.3
Lung ca.
4.6
8.6


539


(squam.) SW





900


astrocytoma SNB-
18.4
28.7
Lung ca.
0.0
0.0


75


(squam.) NCI-





H596


glioma SNB-19
0.0
2.6
Mammary
7.9
17.1





gland


glioma U251
3.1
27.0
Breast ca.*
0.0
0.0





(pl.ef) MCF-7


glioma SF-295
4.8
2.2
Breast ca.*
0.0
14.5





(pl.ef) MDA-





MB-231


Heart (fetal)
0.0
0.0
Breast ca.*
0.0
0.0





(pl.ef) T47D


Heart
1.4
0.0
Breast ca. BT-
0.0
12.2





549


Skeletal muscle
77.4
0.0
Breast ca.
0.0
0.0


(fetal)


MDA-N


Skeletal muscle
1.1
14.1
Ovary
12.1
6.1


Bone marrow
0.0
2.5
Ovarian ca.
3.8
12.1





OVCAR-3


Thymus
2.1
2.4
Ovarian ca.
0.0
0.0





OVCAR-4


Spleen
0.0
4.4
Ovarian ca.
32.5
25.5





OVCAR-5


Lymph node
0.0
4.8
Ovarian ca.
1.9
0.0





OVCAR-8


Colorectal
10.7
0.0
Ovarian ca.
0.0
0.0





IGROV-1


Stomach
8.7
64.6
Ovarian ca.*
0.0
0.0





(ascites) SK-





OV-3


Small intestine
7.2
18.9
Uterus
12.4
66.4


Colon ca. SW480
0.0
0.0
Placenta
0.0
2.3


Colon ca.*
0.0
0.0
Prostate
0.0
0.0


SW620(SW480


met)


Colon ca. HT29
0.0
0.0
Prostate ca.*
0.0
0.0





(bone met)PC-3


Colon ca. HCT-
0.0
0.0
Testis
56.3
68.8


116


Colon ca. CaCo-2
0.0
0.0
Melanoma
1.3
8.2





Hs688(A).T


Colon ca.
1.7
8.1
Melanoma*
2.5
4.8


tissue(ODO3866)


(met)





Hs688(B).T


Colon ca. HCC-
0.0
0.0
Melanoma
1.5
2.8


2998


UACC-62


Gastric ca.* (liver
10.3
7.7
Melanoma
0.0
0.0


met) NCI-N87


M14


Bladder
14.2
29.3
Melanoma
0.0
0.0





LOX IMVI


Trachea
4.1
0.0
Melanoma*
0.0
0.0





(met) SK-





MEL-5


Kidney
0.0
0.0
Adipose
7.2
0.0










[0948]

369





TABLE UE










Panel 2D













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag2897, Run
Ag2897, Run

Ag2897, Run
Ag2897, Run


Tissue Name
161905861
164997312
Tissue Name
161905861
164997312















Normal Colon
83.5
90.1
Kidney Margin
1.3
0.9





8120608


CC Well to Mod
0.0
7.2
Kidney Cancer
1.4
1.6


Diff (ODO3866)


8120613


CC Margin
16.0
16.6
Kidney Margin
0.9
1.5


(ODO3866)


8120614


CC Gr.2
0.0
0.0
Kidney Cancer
21.6
16.0


rectosigmoid


9010320


(ODO3868)


CC Margin
6.3
3.6
Kidney Margin
1.9
0.5


(ODO3868)


9010321


CC Mod Diff
0.9
2.1
Normal Uterus
9.5
10.9


(ODO3920)


CC Margin
19.1
11.7
Uterus Cancer
68.3
71.2


(ODO3920)


064011


CC Gr.2 ascend
8.8
9.2
Normal
3.3
0.8


colon


Thyroid


(ODO3921)


CC Margin
6.9
7.5
Thyroid
2.0
6.9


(ODO3921)


Cancer 064010


CC from Partial
0.9
3.3
Thyroid
8.9
12.2


Hepatectomy


Cancer


(ODO4309) Mets


A302152


Liver Margin
0.7
2.0
Thyroid
1.0
0.7


(ODO4309)


Margin





A302153


Colon mets to
0.0
0.0
Normal Breast
15.9
15.3


lung (OD04451-


01)


Lung Margin
1.9
1.0
Breast Cancer
4.3
6.3


(OD04451-02)


(OD04566)


Normal Prostate
3.9
10.7
Breast Cancer
7.3
2.8


6546-1


(OD04590-01)


Prostate Cancer
17.3
11.6
Breast Cancer
9.4
4.8


(OD04410)


Mets





(OD04590-03)


Prostate Margin
25.0
15.5
Breast Cancer
3.6
0.9


(OD04410)


Metastasis





(OD04655-05)


Prostate Cancer
28.3
11.7
Breast Cancer
8.4
11.6


(OD04720-01)


064006


Prostate Margin
29.9
20.4
Breast Cancer
2.6
4.3


(OD04720-02)


1024


Normal Lung
16.2
15.1
Breast Cancer
1.9
2.0


061010


9100266



Lung Met to
1.2
0.0
Breast Margin
7.4
5.4


Muscle


9100265


(ODO4286)


Muscle Margin
8.2
1.6
Breast Cancer
20.0
13.6


(ODO4286)


A209073


Lung Malignant
7.0
2.2
Breast Margin
5.0
12.0


Cancer


A209073


(OD03126)


Lung Margin
2.3
3.0
Normal Liver
0.9
1.0


(OD03126)


Lung Cancer
8.2
3.1
Liver Cancer
0.0
0.0


(OD04404)


064003


Lung Margin
11.1
10.2
Liver Cancer
2.4
0.0


(OD04404)


1025


Lung Cancer
0.0
0.9
Liver Cancer
0.0
0.0


(OD04565)


1026


Lung Margin
1.9
5.0
Liver Cancer
0.0
1.0


(OD04565)


6004-T


Lung Cancer
95.3
55.9
Liver Tissue
0.0
0.0


(OD04237-01)


6004-N


Lung Margin
4.0
2.3
Liver Cancer
0.0
0.0


(OD04237-02)


6005-T


Ocular Mel Met
0.0
0.0
Liver Tissue
0.0
0.0


to Liver


6005-N


(ODO4310)


Liver Margin
2.7
0.8
Normal
18.0
13.8


(ODO4310)


Bladder


Melanoma Mets
0.0
1.7
Bladder
1.0
0.7


to Lung


Cancer 1023


(OD04321)


Lung Margin
10.1
6.6
Bladder
10.9
2.6


(OD04321)


Cancer





A302173


Normal Kidney
14.8
16.4
Bladder
0.0
1.9





Cancer





(OD04718-01)


Kidney Ca,
93.3
100.0
Bladder
33.2
31.0


Nuclear grade 2


Normal


(OD04338)


Adjacent





(OD04718-03)


Kidney Margin
14.3
2.0
Normal Ovary
0.0
4.8


(OD04338)


Kidney Ca
5.0
2.0
Ovarian
100.0
62.0


Nuclear grade 1/2


Cancer 064008


(OD04339)


Kidney Margin
4.1
3.0
Ovarian
49.7
38.7


(OD04339)


Cancer





(OD04768-07)


Kidney Ca, Clear
27.0
17.4
Ovary Margin
6.3
2.5


cell type


(OD04768-08)


(OD04340)


Kidney Margin
6.4
12.7
Normal
28.1
18.7


(OD04340)


Stomach


Kidney Ca,
1.9
2.1
Gastric Cancer
11.0
14.1


Nuclear grade 3


9060358


(OD04348)


Kidney Margin
4.7
6.2
Stomach
15.9
29.7


(OD04348)


Margin





9060359


Kidney Cancer
50.0
38.4
Gastric Cancer
15.0
6.8


(OD04622-01)


9060395


Kidney Margin
4.2
0.0
Stomach
26.6
26.4


(OD04622-03)


Margin





9060394


Kidney Cancer
2.6
3.6
Gastric Cancer
2.7
1.7


(OD04450-01)


9060397


Kidney Margin
14.2
10.5
Stomach
28.1
33.0


(OD04450-03)


Margin





9060396


Kidney Cancer
1.9
0.0
Gastric Cancer
27.7
33.4


8120607


064005










[0949]

370





TABLE UF










Panel 3D











Rel. Exp.(%)

Rel. Exp.(%)



Ag2897, Run

Ag2897, Run


Tissue Name
164629841
Tissue Name
164629841













Daoy-Medulloblastoma
0.0
Ca Ski-Cervical epidermoid
0.0




carcinoma (metastasis)


TE671-Medulloblastoma
0.0
ES-2-Ovarian clear cell
0.8




carcinoma


D283 Med-
0.0
Ramos-Stimulated with
0.0


Medulloblastoma

PMA/ionomycin 6h


PFSK-1-Primitive
0.0
Ramos-Stimulated with
0.0


Neuroectodermal

PMA/ionomycin 14h


XF-498-CNS
0.6
MEG-01-Chronic
0.0




myelogenous leukemia




(megokaryoblast)


SNB-78-Glioma
6.0
Raji-Burkitt's lymphoma
0.0


SF-268-Glioblastoma
0.0
Daudi-Burkitt's lymphoma
0.0


T98G-Glioblastoma
0.0
U266-B-cell plasmacytoma
0.0


SK-N-SH-
0.0
CA46-Burkitt's lymphoma
0.0


Neuroblastoma


(metastasis)


SF-295-Glioblastoma
0.0
RL-non-Hodgkin's B-cell
0.0




lymphoma


Cerebellum
7.1
JM1-pre-B-cell lymphoma
0.0


Cerebellum
0.0
Jurkat-T cell leukemia
0.0


NCI-H292-
0.0
TF-1-Erythroleukemia
0.0


Mucoepidermoid lung


carcinoma


DMS-114-Small cell
0.0
HUT 78-T-cell lymphoma
0.0


lung cancer


DMS-79-Small cell lung
0.8
U937-Histiocytic lymphoma
0.0


cancer


NCI-H146-Small cell
1.3
KU-812-Myelogenous
0.0


lung cancer

leukemia


NCI-H526-Small cell
100.0
769-P-Clear cell renal
0.0


lung cancer

carcinoma


NCI-N417-Small cell
0.0
Caki-2-Clear cell renal
0.9


lung cancer

carcinoma


NCI-H82-Small cell lung
0.0
SW 839-Clear cell renal
0.0


cancer

carcinoma


NCI-H157-Squamous
0.0
G401-Wilms'tumor
0.0


cell lung cancer


(metastasis)


NCI-H1155-Large cell
3.2
Hs766T-Pancreatic carcinoma
0.0


lung cancer

(LN metastasis)


NCI-H1299-Large cell
1.9
CAPAN-1-Pancreatic
0.0


lung cancer

adenocarcinoma (liver




metastasis)


NCI-H727-Lung
0.0
SU86.86-Pancreatic
0.6


carcinoid

carcinoma (liver metastasis)


NCI-UMC-11-Lung
2.1
BxPC-3-Pancreatic
0.0


carcinoid

adenocarcinoma


LX-1-Small cell lung
0.0
HPAC-Pancreatic
0.0


cancer

adenocarcinoma


Colo-205-Colon cancer
0.0
MIA PaCa-2-Pancreatic
0.0




carcinoma


KM12-Colon cancer
2.6
CFPAC-1-Pancreatic ductal
0.4




adenocarcinoma


KM20L2-Colon cancer
0.0
PANC-1-Pancreatic
0.0




epithelioid ductal carcinoma


NCI-H716-Colon cancer
31.0
T24-Bladder carcinma
0.0




(transitional cell)


SW-48-Colon
0.0
5637-Bladder carcinoma
0.0


adenocarcinoma


SW1116-Colon
0.0
HT-1197-Bladder carcinoma
0.0


adenocarcinoma


LS 174T-Colon
0.0
UM-UC-3-Bladder carcinma
0.0


adenocarcinoma

(transitional cell)


SW-948-Colon
0.0
A204-Rhabdomyosarcoma
0.0


adenocarcinoma


SW-480-Colon
1.5
HT-1080-Fibrosarcoma
0.8


adenocarcinoma


NCI-SNU-5-Gastric
0.0
MG-63-Osteosarcoma
0.0


carcinoma


KATO III-Gastric
0.0
SK-LMS-1-Leiomyosarcoma
0.0


carcinoma

(vulva)


NCI-SNU-16-Gastric
0.8
SJRH30-Rhabdomyosarcoma
0.0


carcinoma

(met to bone marrow)


NCI-SNU-1-Gastric
0.0
A431-Epidermoid carcinoma
0.0


carcinoma


RF-1-Gastric
0.0
WM266-4-Melanoma
1.2


adenocarcinoma


RF-48-Gastric
0.8
DU 145-Prostate carcinoma
0.0


adenocarcinoma

(brain metastasis)


MKN-45-Gastric
0.0
MDA-MB-468-Breast
0.8


carcinoma

adenocarcinoma


NCI-N87-Gastric
0.3
SCC-4-Squamous cell
0.0


carcinoma

carcinoma of tongue


OVCAR-5-Ovarian
0.0
SCC-9-Squamous cell
0.0


carcinoma

carcinoma of tongue


RL95-2-Uterine
0.0
SCC-15-Squamous cell
0.0


carcinoma

carcinoma of tongue


HelaS3-Cervical
0.0
CAL 27-Squamous cell
0.0


adenocarcinoma

carcinoma of tongue










[0950]

371





TABLE UG










Panel 4D













Rel.
Rel.

Rel.
Rel.



Exp.(%)
Exp.(%)

Exp.(%)
Exp.(%)



Ag2897,
Ag2897,

Ag2897,
Ag2897,



Run
Run

Run
Run


Tissue Name
161905862
163586314
Tissue Name
161905862
163586314















Secondary Th1 act
0.0
0.0
HUVEC IL-1 beta
0.0
0.0


Secondary Th2 act
0.0
0.0
HUVEC IFN
0.0
0.0





gamma


Secondary Tr1 act
0.0
0.0
HUVEC TNF
0.0
0.0





alpha + IFN





gamma


Secondary Th1 rest
0.0
0.0
HUVEC TNF
0.0
0.0





alpha + IL4


Secondary Th2 rest
0.0
0.0
HUVEC IL-11
0.0
0.0


Secondary Tr1 rest
0.0
0.0
Lung
0.0
0.0





Microvascular EC





none


Primary Th1 act
0.0
0.0
Lung
7.9
22.8





Microvascular EC





TNF alpha + IL-





1 beta


Primary Th2 act
0.0
0.0
Microvascular
0.0
0.0





Dermal EC none


Primary Tr1 act
0.0
0.0
Microsvasular
16.2
0.0





Dermal EC





TNF alpha + IL-





1 beta


Primary Th1 rest
9.3
20.7
Bronchial
4.4
0.0





epithelium





TNF alpha +





IL1 beta


Primary Th2 rest
0.0
9.0
Small airway
10.4
9.7





epithelium none


Primary Tr1 rest
9.8
0.0
Small airway
100.0
75.8





epithelium





TNF alpha + IL-





1 beta


CD45RA CD4
0.0
0.0
Coronery artery
0.0
9.9


lymphocyte act


SMC rest


CD45RO CD4
0.0
0.0
Coronery artery
16.8
9.0


lymphocyte act


SMC TNF alpha +





IL-1 beta


CD8 lymphocyte
0.0
0.0
Astrocytes rest
40.6
0.0


act


Secondary CD8
0.0
0.0
Astrocytes
56.6
100.0


lymphocyte rest


TNF alpha + IL-





1 beta


Secondary CD8
0.0
0.0
KU-812 (Basophil)
0.0
0.0


lymphocyte act


rest


CD4 lymphocyte
0.0
0.0
KU-812 (Basophil)
0.0
0.0


none


PMA/ionomycin


2ry
0.0
0.0
CCD1106
0.0
0.0


Th1/Th2/Tr1_anti-


(Keratinocytes)


CD95 CH11


none


LAK cells rest
10.9
0.0
CCD1106
0.0
0.0





(Keratinocytes)





TNF alpha + IL-





1 beta


LAK cells IL-2
0.0
0.0
Liver cirrhosis
17.2
8.2


LAK cells IL-2 +
0.0
0.0
Lupus kidney
8.4
9.6


IL-12


LAK cells IL-
0.0
0.0
NCI-H292 none
0.0
0.0


2 + IFN gamma


LAK cells IL-2 +
0.0
0.0
NCI-H292 IL-4
0.0
0.0


IL-18


LAK cells
0.0
0.0
NCI-H292 IL-9
0.0
0.0


PMA/ionomycin


NK Cells IL-2 rest
0.0
0.0
NCI-H292 IL-13
0.0
0.0


Two Way MLR 3
0.0
9.3
NCI-H292 IFN
0.0
0.0


day


gamma


Two Way MLR 5
0.0
0.0
HPAEC none
0.0
0.0


day


Two Way MLR 7
0.0
0.0
HPAEC TNF
0.0
0.0


day


alpha + IL-1 beta


PBMC rest
0.0
0.0
Lung fibroblast
0.0
0.0





none


PBMC PWM
0.0
0.0
Lung fibroblast
0.0
18.8





TNF alpha + IL-1





beta


PBMC PHA-L
8.9
0.0
Lung fibroblast IL-4
0.0
17.7


Ramos (B cell)
0.0
0.0
Lung fibroblast IL-9
0.0
0.0


none


Ramos (B cell)
0.0
0.0
Lung fibroblast IL-
0.0
0.0


ionomycin


13


B lymphocytes
0.0
0.0
Lung fibroblast
0.0
0.0


PWM


IFN gamma


B lymphocytes
0.0
0.0
Dermal fibroblast
18.7
5.1


CD40L and IL-4


CCD1070 rest


EOL-1 dbcAMP
0.0
0.0
Dermal fibroblast
45.4
29.5





CCD1070 TNF





alpha


EOL-1 dbcAMP
0.0
0.0
Dermal fibroblast
33.7
85.9


PMA/ionomycin


CCD1070 IL-1





beta


Dendritic cells none
0.0
0.0
Dermal fibroblast
0.0
0.0





IFN gamma


Dendritic cells LPS
0.0
0.0
Dermal fibroblast
0.0
8.4





IL-4


Dendritic cells anti-
0.0
0.0
IBD Colitis 2
0.0
9.9


CD40


Monocytes rest
0.0
0.0
IBD Crohn's
7.7
0.0


Monocytes LPS
0.0
0.0
Colon
62.4
39.2


Macrophages rest
0.0
0.0
Lung
9.9
22.1


Macrophages LPS
0.0
0.0
Thymus
27.7
35.8


HUVEC none
0.0
0.0
Kidney
18.9
20.6


HUVEC starved
0.0
0.0










[0951]

372





TABLE UH










Panel CNS_1











Rel. Exp.(%)

Rel. Exp.(%)



Ag2897, Run

Ag2897, Run


Tissue Name
171688457
Tissue Name
171688457













BA4 Control
29.7
BA17 PSP
24.3


BA4 Control2
37.6
BA17 PSP2
0.0


BA4
0.0
Sub Nigra Control
25.9


Alzheimer's2


BA4 Parkinson's
23.8
Sub Nigra Control2
33.4


BA4
38.7
Sub Nigra
0.0


Parkinson's2

Alzheimer's2


BA4
18.4
Sub Nigra
26.6


Huntington's

Parkinson's2


BA4
0.0
Sub Nigra
13.9


Huntington's2

Huntington's


BA4 PSP
8.0
Sub Nigra
8.7




Huntington's2


BA4 PSP2
37.6
Sub Nigra PSP2
0.0


BA4 Depression
15.6
Sub Nigra
0.0




Depression


BA4
4.6
Sub Nigra
2.8


Depression2

Depression2


BA7 Control
56.6
Glob Palladus
4.1




Control


BA7 Control2
6.0
Glob Palladus
23.7




Control2


BA7
7.3
Glob Palladus
3.8


Alzheimer's2

Alzheimer's


BA7 Parkinson's
10.8
Glob Palladus
0.0




Alzheimer's2


BA7
27.2
Glob Palladus
51.1


Parkinson's2

Parkinson's


BA7
56.3
Glob Palladus
3.5


Huntington's

Parkinson's2


BA7
10.8
Glob Palladus PSP
0.0


Huntington's2


BA7 PSP
21.5
Glob Palladus PSP2
0.0


BA7 PSP2
21.3
Glob Palladus
0.0




Depression


BA7 Depression
5.4
Temp Pole Control
15.9


BA9 Control
31.6
Temp Pole Control2
37.9


BA9 Control2
100.0
Temp Pole
0.0




Alzheimer's


BA9 Alzheimer's
3.8
Temp Pole
0.0




Alzheimer's2


BA9
3.7
Temp Pole
34.2


Alzheimer's2

Parkinson's


BA9 Parkinson's
19.2
Temp Pole
10.8




Parkinson's2


BA9
30.6
Temp Pole
17.7


Parkinson's2

Huntington's


BA9
27.2
Temp Pole PSP
5.8


Huntington's


BA9
9.0
Temp Pole PSP2
0.0


Huntington's2


BA9 PSP
0.0
Temp Pole
15.3




Depression2


BA9 PSP2
16.5
Cing Gyr Control
76.3


BA9 Depression
2.7
Cing Gyr Control2
54.0


BA9
6.7
Cing Gyr
12.1


Depression2

Alzheimer's


BA17 Control
25.9
Cing Gyr
2.9




Alzheimer's2


BA17 Control2
14.8
Cing Gyr
26.6




Parkinson's


BA17
7.9
Cing Gyr
38.2


Alzheimer's2

Parkinson's2


BA17
9.5
Cing Gyr
36.1


Parkinson's

Huntington's


BA17
8.8
Cing Gyr
8.1


Parkinson's2

Huntington's2


BA17
18.3
Cing Gyr PSP
8.3


Huntington's


BA17
0.0
Cing Gry PSP2
4.0


Huntington's2


BA17
7.6
Cing Gyr
0.0


Depression

Depression


BA17
3.7
Cing Gyr
2.9


Depression2

Depression2










[0952] AI_comprehensive panel_v1.0 Summary: Ag2897 Highest expression of the CG58567-01 gene is detected in match control psoriasis sample (CT=30). Furthermore, this expression is down-regulated in the corresponding psoriasis sample (CT=33). Therefore expression of this gene can be used to distinguish between these samples. In addition, the expression of this gene is up-regulated in lung from emphysema and COPD patients, which is consistent with its expression in “stressed” small airway epithelium, lung fibroblasts and lung endothelium (treated with TNF-a and IL-1). Therapeutic modulation of the expression of this putative protein and/or signaling via this protein by antibodies, small molecules or protein therapeutics may inhibit inflammation in lung tissue clue to asthma, emphysema and other COPD type diseases


[0953] CNS_neurodegeneration_v1.0 Summary: Ag2897 This panel does not show differential expression of the CG58567-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.3D for discussion of utility of this gene in the central nervous system.


[0954] Panel 1.3D Summary: Ag2897 Two experiments with the same probe and primer show highest expression of this gene, a protocadherin homolog, in the spinal cord and the cerebral cortex (CTs=31.5). Low levels of expression are also seen in other regions of the brain including the amygdala and the hippocampus. The cadherins have been shown to be critical for CNS development, specifically for the guidance of axons, dendrites and/or growth cones in general. Therapeutic modulation of the levels of this protein, or possible signaling via this protein may be of utility in enhancing/directing compensatory synaptogenesis and fiber growth in the CNS in response to neuronal death (stroke, head trauma), axon lesion (spinal cord injury), or neurodegeneration (Alzheimer's, Parkinson's, Huntington's, vascular dementia or any neurodegenerative disease). Since protocadherins play an important role in synaptogenesis this gene product may also be involved in depression, schizophrenia, which also involve synaptogeneisis. Because this cadherin shows highest expression in the cerebellum, this is also an excellent candidate for the spinocerebellar ataxias as well.


[0955] Significant levels of expression are also seen in cell lines derived from ovarian, renal and brain cancers. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of ovarian, renal and brain cancers.


[0956] References:


[0957] Hilschmann N, Barnikol H U, Barnikol-Watanabe S, Gotz H, Kratzin H, Thinnes F P. The immunoglobulin-like genetic predetermination of the brain: the protocadherins, blueprint of the neuronal network. Naturwissenschaften January 2001;88(1):2-12


[0958] Panel 2D Summary: Ag2897 Two experiments with the same probe and primer produce results that are in reasonable agreement, with highest expression of the CG58567-01 gene in ovarian and kidney cancers (CTs=30.5). Significant levels of expression are also seen in lung and uterine cancers. In addition, higher levels of expression arc seen in these cancers than in the corresponding normal adjacent tissues. Thus, therapeutic targeting of this gene product with a human monoclonal antibody is anticipated to limit or block the extent of tumor cell migration and invasion, preferably in kidney, lung, uterine and ovarian tumor tumors.


[0959] Panel 3D Summary: Ag2897 Highest expression of the CG58567-01 gene is seen in a lung cancer cell line (CT=30.1). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel. Please see panel 2D for the utility of this gene.


[0960] Panel 4D Summary: Ag2897 Two experiments with the same probe and primer produce results that are in reasonable agreement, with the CG58567-01 gene highly up-regulated in small airway epithelium and astrocytes stimulated with TNF-alpha and IL-1 beta (CTs=33-34). Other tissues in the lung also up regulate the expression of this gene including lung microvascular endothelium and lung fibroblasts in response to TNF alpha or the Th2 elaborated cytokine IL-4. This suggests that this molecule could be expressed as a result of inflammation particularly during asthma since TNFalpha and IL-4 may play important roles in the pathology of this disease. Based on the expression profile of this transcript and the types of cytokines which induce it, antibodies to CG58567-01 may inhibit inflammation in lung tissue due to asthma, emphysema and other COPD type diseases.


[0961] Panel CNS1 Summary: Ag2897 The results of this panel confirm expression of the CG58567-01 gene in the brain. Please see Panel 1.3D for discussion of utility of this gene in the central nervous system.



V. NOV28b and NOV28c (CG58567-05, CG58567-06: PROTOCADHERIN LIKE)

[0962] Expression of gene CG58567-05 and CG58567-06 was assessed using the primer-probe sets Ag2897 and Ag705, described in Tables VA and VB. Results of the RTQ-PCR runs are shown in Tables VC, VD, VE, VF, VG, VH, VI and VJ.
373TABLE VAProbe Name Ag2897StartPrimersSequencesLengthPositionForward5′-tgacaggggatattcatgctaa-3′(SEQ ID NO:293)227385ProbeTET-5′-tggcaataaatactgcctcacagtcca-3′-TAMRA(SEQ ID NO:297)277428Reverse5′-agttgcatcacctttgtctttg-3′(SEQ ID NO:298)227458


[0963]

374





TABLE VB










Probe Name Ag705













Start


Primers
Sequences
Length
Position














Forward
5′-gcattcaccattgatcctatgt-3′
(SEQ ID NO:299)
22
2980





Probe
TET-5′-acattgaaaaccagcaacaccctcg-3′-TAMRA
(SEQ ID NO:300)
25
3007





Reverse
5′-gtatgctgagatctggcttcac-3′
(SEQ ID NO:301)
22
3035










[0964]

375





TABLE VC










AI_comprehensive panel_v1.0











Rel. Exp.(%) Ag2897,

Rel. Exp.(%) Ag2897,


Tissue Name
Run 229662505
Tissue Name
Run 229662505













110967 COPD-F
4.7
112427 Match Control
100.0




Psoriasis-F


110980 COPD-F
22.5
112418 Psoriasis-M
2.8


110968 COPD-M
8.5
112723 Match Control
14.3




Psoriasis-M


110977 COPD-M
51.8
112419 Psoriasis-M
10.7


110989 Emphysema-F
51.8
112424 Match Control
8.7




Psoriasis-M


110992 Emphysema-F
5.0
112420 Psoriasis-M
40.1


110993 Emphysema-F
5.6
112425 Match Control
65.1




Psoriasis-M


110994 Emphysema-F
3.3
104689 (MF) OA Bone-
1.7




Backus


110995 Emphysema-F
13.2
104690 (MF) Adj
4.5




“Normal” Bone-Backus


110996 Emphysema-F
0.6
104691 (MF) OA
9.5




Synovium-Backus


110997 Asthma-M
1.4
104692 (BA) OA
3.1




Cartilage-Backus


111001 Asthma-F
8.1
104694 (BA) OA Bone-
1.3




Backus


111002 Asthma-F
12.5
104695 (BA) Adj
1.8




“Normal” Bone-Backus


111003 Atopic
12.8
104696 (BA) OA
5.0


Asthma-F

Synovium-Backus


111004 Atopic
12.3
104700 (SS) OA Bone-
5.2


Asthma-F

Backus


111005 Atopic
6.1
104701 (SS) Adj
7.0


Asthma-F

“Normal” Bone-Backus


111006 Atopic
3.7
104702 (SS) OA
12.7


Asthma-F

Synovium-Backus


111417 Allergy-M
7.7
117093 OA Cartilage
15.1




Rep7


112347 Allergy-M
0.8
112672 OA Bone5
15.9


112349 Normal
0.8
112673 OA Synovium5
8.2


Lung-F


112357 Normal
20.2
112674 OA Synovial
7.9


Lung-F

Fluid cells5


112354 Normal
2.1
117100 OA Cartilage
1.3


Lung-M

Rep14


112374 Crohns-F
4.7
112756 OA Bone9
0.8


112389 Match Control
2.1
112757 OA Synovium9
0.4


Crohns-F


112375 Crohns-F
6.7
112758 OA Synovial
10.2




Fluid Cells9


112732 Match Control
2.2
117125 RA Cartilage
6.5


Crohns-F

Rep2


112725 Crohns-M
18.9
113492 Bone2 RA
2.2


112387 Match Control
11.2
113493 Synovium2 RA
0.2


Crohns-M


112378 Crohns-M
1.3
113494 Syn Fluid Cells
2.0




RA


112390 Match Control
62.4
113499 Cartilage4 RA
1.6


Crohns-M


112726 Crohns-M
9.6
113500 Bone4 RA
1.3


112731 Match Control
16.0
113501 Synovium4 RA
1.9


Crohns-M


112380 Ulcer Col-F
21.2
113502 Syn Fluid
1.0




Cells4 RA


112734 Match Control
4.5
113495 Cartilage3 RA
1.1


Ulcer Col-F


112384 Ulcer Col-F
17.3
113496 Bone3 RA
1.4


112737 Match Control
5.2
113497 Synovium3 RA
0.2


Ulcer Col-F


112386 Ulcer Col-F
5.3
113498 Syn Fluid
1.2




Cells3 RA


112738 Match Control
2.7
117106 Normal
0.3


Ulcer Col-F

Cartilage Rep20


112381 Ulcer Col-M
0.3
113663 Bone3 Normal
2.8


112735 Match Control
23.7
113664 Synovium3
0.2


Ulcer Col-M

Normal


112382 Ulcer Col-M
5.8
113665 Syn Fluid
1.3




Cells3 Normal


112394 Match Control
6.5
117107 Normal
9.2


Ulcer Col-M

Cartilage Rep22


112383 Ulcer Col-M
1.6
113667 Bone4 Normal
9.5


112736 Match Control
1.3
113668 Synovium4
6.1


Ulcer Col-M

Normal


112423 Psoriasis-F
7.9
113669 Syn Fluid
10.2




Cells4 Normal










[0965]

376





TABLE VD










CNS_neurodegeneration_v1.0











Rel. Exp.(%) Ag2897,

Rel. Exp.(%) Ag2897,


Tissue Name
Run 209734745
Tissue Name
Run 209734745













AD 1 Hippo
6.5
Control (Path) 3
8.9




Temporal Ctx


AD 2 Hippo
31.9
Control (Path) 4
46.7




Temporal Ctx


AD 3 Hippo
1.6
AD 1 Occipital Ctx
5.6


AD 4 Hippo
7.3
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 Hippo
46.3
AD 4 Occipital Ctx
6.1


AD 6 Hippo
44.4
AD 5 Occipital Ctx
23.0


Control 2 Hippo
24.0
AD 5 Occipital Ctx
11.3


Control 4 Hippo
15.7
AD 6 Occipital Ctx
22.5


Control (Path) 3
0.0
Control 1 Occipital
1.6


Hippo

Ctx


AD 1 Temporal Ctx
3.0
Control 2 Occipital
17.7




Ctx


AD 2 Temporal Ctx
38.7
Control 3 Occipital
9.1




Ctx


AD 3 Temporal Ctx
3.5
Control 4 Occipital
8.7




Ctx


AD 4 Temporal Ctx
23.0
Control (Path) 1
92.0




Occipital Ctx


AD 5 Inf Temporal
79.0
Control (Path) 2
0.8


Ctx

Occipital Ctx


AD 5 Sup Temporal
43.5
Control (Path) 3
1.6


Ctx

Occipital Ctx


AD 6 Inf Temporal
41.8
Control (Path) 4
7.6


Ctx

Occipital Ctx


AD 6 Sup Temporal
41.2
Control 1 Parietal
4.2


Ctx

Ctx


Control 1 Temporal
12.3
Control 2 Parietal
47.3


Ctx

Ctx


Control 2 Temporal
50.3
Control 3 Parietal
10.1


Ctx

Ctx


Control 3 Temporal
17.8
Control (Path) 1
100.0


Ctx

Parietal Ctx


Control 4 Temporal
9.3
Control (Path) 2
13.4


Ctx

Parietal Ctx


Control (Path) 1
70.2
Control (Path) 3
4.2


Temporal Ctx

Parietal Ctx


Control (Path) 2
29.3
Control (Path) 4
33.2


Temporal Ctx

Parietal Ctx










[0966]

377





TABLE VE










Panel 1.2













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag705, Run
Ag705, Run

Ag705, Run
Ag705, Run


Tissue Name
118753904
132960873
Tissue Name
118753904
132960873















Endothelial cells
0.0
0.0
Renal ca. 786-0
0.1
0.0


Heart (Fetal)
0.2
0.0
Renal ca. A498
2.7
0.0


Pancreas
5.0
0.0
Renal ca. RXF
0.0
0.0





393


Pancreatic ca.
0.0
0.0
Renal ca.
0.0
0.0


CAPAN 2


ACHN


Adrenal Gland
3.0
0.0
Renal ca. UO-
0.0
0.0





31


Thyroid
1.2
0.0
Renal ca. TK-
0.0
0.0





10


Salivary gland
0.8
0.0
Liver
0.4
0.0


Pituitary gland
19.8
0.3
Liver(fetal)
0.0
0.0


Brain (fetal)
4.9
0.0
Liver ca.
0.1
0.0





(hepatoblast)





HepG2


Brain (whole)
27.2
18.4
Lung
0.5
0.0


Brain (amygdala)
5.8
0.8
Lung (fetal)
2.3
0.0


Brain
0.5
0.0
Lung ca. (small
0.0
0.0


(cerebellum)


cell) LX-1


Brain
21.9
7.9
Lung ca. (small
0.0
0.0


(hippocampus)


cell) NCI-H69


Brain (thalamus)
2.8
0.0
Lung ca. (s.cell
0.0
0.0





var.) SHP-77


Cerebral Cortex
56.6
100.0
Lung ca. (large
0.0
0.0





cell) NCI-H460


Spinal cord
32.8
11.4
Lung ca. (non-
0.0
0.0





sm. cell) A549


glio/astro U87
62.4
19.1
Lung ca. (non-
0.2
0.0


MG


s.cell) NCI-





H23


glio/astro U-118-
0.2
0.0
Lung ca. (non-
1.6
0.0


MG


s.cell) HOP-62


astrocytoma
0.1
0.0
Lung ca. (non-
0.0
0.0


SW1783


s.cl) NCI-H522


neuro*; met SK-
0.0
0.0
Lung ca.
0.5
0.0


N-AS


(squam.) SW





900


astrocytoma SF-
0.1
0.0
Lung ca.
0.0
0.0


539


(squam.) NCI-





H596


astrocytoma
34.9
7.6
Mammary
14.2
5.4


SNB-75


gland


glioma SNB-19
0.4
0.0
Breast ca.*
0.0
0.0





(pl.ef) MCF-7


glioma U251
0.1
0.0
Breast ca.*
0.0
0.0





(pl.ef) MDA-





MB-231


glioma SF-295
0.4
0.0
Breast ca.* (pl.
0.7
0.0





ef) T47D


Heart
0.1
0.0
Breast ca. BT-
0.4
0.0





549


Skeletal Muscle
1.0
0.0
Breast ca.
0.0
0.0





MDA-N


Bone marrow
0.0
0.0
Ovary
2.0
0.1


Thymus
0.0
0.0
Ovarian ca.
14.5
0.9





OVCAR-3


Spleen
0.0
0.0
Ovarian ca.
0.0
0.0





OVCAR-4


Lymph node
0.6
0.0
Ovarian ca.
100.0
9.3





OVCAR-5


Colorectal Tissue
1.2
0.1
Ovarian ca.
0.4
0.0





OVCAR-8


Stomach
35.4
15.9
Ovarian ca.
0.0
0.0





IGROV-1


Small intestine
5.7
0.0
Ovarian ca.
0.0
0.0





(ascites) SK-





OV-3


Colon ca.
0.0
0.0
Uterus
5.0
2.0


SW480


Colon ca.*
0.0
0.0
Placenta
0.2
0.0


SW620 (SW480


met)


Colon ca. HT29
0.0
0.0
Prostate
2.6
0.5


Colon ca. HCT-
0.0
0.0
Prostate ca.*
0.0
0.0


116


(bone met)





PC-3


Colon ca. CaCo-2
0.1
0.0
Testis
96.6
9.5


Colon ca. Tissue
0.0
0.0
Melanoma
0.1
0.0


(ODO3866)


Hs688(A).T


Colon ca. HCC-
0.1
0.0
Melanoma*
4.2
0.0


2998


(met)





Hs688(B).T


Gastric ca.*
7.2
0.0
Melanoma
0.1
0.0


(liver met) NCI-


UACC-62


N87


Bladder
5.2
0.1
Melanoma
0.0
0.0





M14


Trachea
1.0
0.5
Melanoma
0.0
0.0





LOX IMVI


Kidney
1.5
0.0
Melanoma*
0.0
0.0





(met) SK-





MEL-5


Kidney (fetal)
6.4
0.2










[0967]

378





TABLE VF










Panel 1.3D













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag2897, Run
Ag2897, Run

Ag2897, Run
Ag2897, Run


Tissue Name
161905860
165518166
Tissue Name
161905860
165518166















Liver
0.0
0.0
Kidney (fetal)
2.8
2.4


adenocarcinoma


Pancreas
1.4
2.4
Renal ca. 786-0
0.9
3.3


Pancreatic ca.
0.0
0.0
Renal ca. A498
13.9
23.7


CAPAN 2


Adrenal gland
1.4
0.0
Renal ca. RXF
0.0
0.0





393


Thyroid
0.0
0.0
Renal ca.
0.0
0.0





ACHN


Salivary gland
0.0
0.0
Renal ca. UO-
0.0
0.0





31


Pituitary gland
4.1
9.0
Renal ca. TK-
0.0
0.0





10


Brain (fetal)
7.1
17.8
Liver
0.0
2.9


Brain (whole)
21.0
59.0
Liver (fetal)
0.4
0.0


Brain (amygdala)
24.7
37.9
Liver ca.
0.0
0.0





(hepatoblast)





HepG2


Brain (cerebellum)
5.6
28.5
Lung
1.4
0.0


Brain
25.2
25.3
Lung (fetal)
6.8
11.0


(hippocampus)


Brain (substantia
0.9
17.1
Lung ca.
0.0
0.0


nigra)


(small cell)





LX-1


Brain (thalamus)
4.1
23.0
Lung ca.
0.0
4.1





(small cell)





NCI-H69


Cerebral Cortex
100.0
22.2
Lung ca. (s.cell
1.0
0.0





var:) SHP-77


Spinal cord
68.8
100.0
Lung ca. (large
0.0
0.0





cell) NCI-H460


glio/astro U87-MG
54.3
10.4
Lung ca. (non-
0.0
0.0





sm. cell) A549


glio/astro U-118-
1.5
20.4
Lung ca. (non-
0.0
3.0


MG


s.cell) NCI-





H23


astrocytoma
16.3
0.0
Lung ca. (non-
0.6
7.5


SW1783


s.cell) HOP-62


neuro*; met SK-N-
0.0
0.0
Lung ca. (non-
0.0
0.0


AS


s.cl) NCI-H522


astrocytoma SF-
0.0
4.3
Lung ca.
4.6
8.6


539


(squam.) SW





900


astrocytoma SNB-
18.4
28.7
Lung ca.
0.0
0.0


75


(squam.) NCI-





H596


glioma SNB-19
0.0
2.6
Mammary
7.9
17.1





gland


glioma U251
3.1
27.0
Breast ca.*
0.0
0.0





(pl.ef) MCF-7


glioma SF-295
4.8
2.2
Breast ca.*
0.0
14.5





(pl.ef) MDA-





MB-231


Heart (fetal)
0.0
0.0
Breast ca.*
0.0
0.0





(pl.ef) T47D


Heart
1.4
0.0
Breast ca. BT-
0.0
12.2





549


Skeletal muscle
77.4
0.0
Breast ca.
0.0
0.0


(fetal)


MDA-N


Skeletal muscle
1.1
14.1
Ovary
12.1
6.1


Bone marrow
0.0
2.5
Ovarian ca.
3.8
12.1





OVCAR-3


Thymus
2.1
2.4
Ovarian ca.
0.0
0.0





OVCAR-4


Spleen
0.0
4.4
Ovarian ca.
32.5
25.5





OVCAR-5


Lymph node
0.0
4.8
Ovarian ca.
1.9
0.0





OVCAR-8


Colorectal
10.7
0.0
Ovarian ca.
0.0
0.0





IGROV-1


Stomach
8.7
64.6
Ovarian ca.*
0.0
0.0





(ascites) SK-





OV-3


Small intestine
7.2
18.9
Uterus
12.4
66.4


Colon ca. SW480
0.0
0.0
Placenta
0.0
2.3


Colon ca.*
0.0
0.0
Prostate
0.0
0.0


SW620(SW480


met)


Colon ca. HT29
0.0
0.0
Prostate ca.*
0.0
0.0





(bone met)PC-3


Colon ca. HCT-
0.0
0.0
Testis
56.3
68.8


116


Colon ca. CaCo-2
0.0
0.0
Melanoma
1.3
8.2





Hs688(A).T


Colon ca.
1.7
8.1
Melanoma*
2.5
4.8


tissue(ODO3866)


(met)





Hs688(B).T


Colon ca. HCC-
0.0
0.0
Melanoma
1.5
2.8


2998


UACC-62


Gastric ca.* (liver
10.3
7.7
Melanoma
0.0
0.0


met) NCI-N87


M14


Bladder
14.2
29.3
Melanoma
0.0
0.0





LOX IMVI


Trachea
4.1
0.0
Melanoma*
0.0
0.0





(met) SK-





MEL-5


Kidney
0.0
0.0
Adipose
7.2
0.0










[0968]

379





TABLE VG










Panel 2D













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag2897, Run
Ag2897, Run

Ag2897, Run
Ag2897, Run


Tissue Name
161905861
164997312
Tissue Name
161905861
164997312















Normal Colon
83.5
90.1
Kidney Margin
1.3
0.9





8120608


CC Well to Mod
0.0
7.2
Kidney Cancer
1.4
1.6


Diff (ODO3866)


8120613


CC Margin
16.0
16.6
Kidney Margin
0.9
1.5


(ODO3866)


8120614


CC Gr.2
0.0
0.0
Kidney Cancer
21.6
16.0


rectosigmoid


9010320


(ODO3868)



CC Margin
6.3
3.6
Kidney Margin
1.9
0.5


(ODO3868)


9010321


CC Mod Diff
0.9
2.1
Normal Uterus
9.5
10.9


(ODO3920)


CC Margin
19.1
11.7
Uterus Cancer
68.3
71.2


(ODO3920)


064011


CC Gr.2 ascend
8.8
9.2
Normal
3.3
0.8


colon


Thyroid


(ODO3921)


CC Margin
6.9
7.5
Thyroid
2.0
6.9


(ODO3921)


Cancer 064010


CC from Partial
0.9
3.3
Thyroid
8.9
12.2


Hepatectomy


Cancer


(ODO4309) Mets


A302152


Liver Margin
0.7
2.0
Thyroid
1.0
0.7


(ODO4309)


Margin





A302153


Colon mets to
0.0
0.0
Normal Breast
15.9
15.3


lung (OD04451-


01)


Lung Margin
1.9
1.0
Breast Cancer
4.3
6.3


(OD04451-02)


(OD04566)


Normal Prostate
3.9
10.7
Breast Cancer
7.3
2.8


6546-1


(OD04590-01)


Prostate Cancer
17.3
11.6
Breast Cancer
9.4
4.8


(OD04410)


Mets





(OD04590-03)


Prostate Margin
25.0
15.5
Breast Cancer
3.6
0.9


(OD04410)


Metastasis





(OD04655-05)


Prostate Cancer
28.3
11.7
Breast Cancer
8.4
11.6


(OD04720-01)


064006


Prostate Margin
29.9
20.4
Breast Cancer
2.6
4.3


(OD04720-02)


1024


Normal Lung
16.2
15.1
Breast Cancer
1.9
2.0


061010


9100266


Lung Met to
1.2
0.0
Breast Margin
7.4
5.4


Muscle


9100265


(ODO4286)


Muscle Margin
8.2
1.6
Breast Cancer
20.0
13.6


(ODO4286)


A209073


Lung Malignant
7.0
2.2
Breast Margin
5.0
12.0


Cancer


A209073


(OD03126)


Lung Margin
2.3
3.0
Normal Liver
0.9
1.0


(OD03126)


Lung Cancer
8.2
3.1
Liver Cancer
0.0
0.0


(OD04404)


064003


Lung Margin
11.1
10.2
Liver Cancer
2.4
0.0


(OD04404)


1025


Lung Cancer
0.0
0.9
Liver Cancer
0.0
0.0


(OD04565)


1026


Lung Margin
1.9
5.0
Liver Cancer
0.0
1.0


(OD04565)


6004-T


Lung Cancer
95.3
55.9
Liver Tissue
0.0
0.0


(OD04237-01)


6004-N


Lung Margin
4.0
2.3
Liver Cancer
0.0
0.0


(OD04237-02)


6005-T


Ocular Mel Met
0.0
0.0
Liver Tissue
0.0
0.0


to Liver


6005-N


(ODO4310)


Liver Margin
2.7
0.8
Normal
18.0
13.8


(ODO4310)


Bladder


Melanoma Mets
0.0
1.7
Bladder
1.0
0.7


to Lung


Cancer 1023


(OD04321)


Lung Margin
10.1
6.6
Bladder
10.9
2.6


(OD04321)


Cancer





A302173


Normal Kidney
14.8
16.4
Bladder
0.0
1.9





Cancer





(OD04718-01)


Kidney Ca,
93.3
100.0
Bladder
33.2
31.0


Nuclear grade 2


Normal


(OD04338)


Adjacent





(OD04718-03)


Kidney Margin
14.3
2.0
Normal Ovary
0.0
4.8


(OD04338)


Kidney Ca
5.0
2.0
Ovarian
100.0
62.0


Nuclear grade 1/2


Cancer 064008


(OD04339)


Kidney Margin
4.1
3.0
Ovarian
49.7
38.7


(OD04339)


Cancer





(OD04768-07)


Kidney Ca, Clear
27.0
17.4
Ovary Margin
6.3
2.5


cell type


(OD04768-08)


(OD04340)


Kidney Margin
6.4
12.7
Normal
28.1
18.7


(OD04340)


Stomach


Kidney Ca,
1.9
2.1
Gastric Cancer
11.0
14.1


Nuclear grade 3


9060358


(OD04348)


Kidney Margin
4.7
6.2
Stomach
15.9
29.7


(OD04348)


Margin





9060359


Kidney Cancer
50.0
38.4
Gastric Cancer
15.0
6.8


(OD04622-01)


9060395


Kidney Margin
4.2
0.0
Stomach
26.6
26.4


(OD04622-03)


Margin





9060394


Kidney Cancer
2.6
3.6
Gastric Cancer
2.7
1.7


(OD04450-01)


9060397


Kidney Margin
14.2
10.5
Stomach
28.1
33.0


(OD04450-03)


Margin





9060396


Kidney Cancer
1.9
0.0
Gastric Cancer
27.7
33.4


8120607


064005










[0969]

380





TABLE VH










Panel 3D











Rel. Exp.(%)

Rel. Exp.(%)



Ag2897, Run

Ag2897, Run


Tissue Name
164629841
Tissue Name
164629841













Daoy-Medulloblastoma
0.0
Ca Ski-Cervical epidermoid
0.0




carcinoma (metastasis)


TE671-Medulloblastoma
0.0
ES-2-Ovarian clear cell
0.8




carcinoma


D283 Med-
0.0
Ramos-Stimulated with
0.0


Medulloblastoma

PMA/ionomycin 6h


PFSK-1-Primitive
0.0
Ramos-Stimulated with
0.0


Neuroectodermal

PMA/ionomycin 14h


XF-498-CNS
0.6
MEG-01-Chronic
0.0




myelogenous leukemia




(megokaryoblast)


SNB-78-Glioma
6.0
Raji-Burkitt's lymphoma
0.0


SF-268-Glioblastoma
0.0
Daudi-Burkitt's lymphoma
0.0


T98G-Glioblastoma
0.0
U266-B-cell plasmacytoma
0.0


SK-N-SH-
0.0
CA46-Burkitt's lymphoma
0.0


Neuroblastoma


(metastasis)


SF-295-Glioblastoma
0.0
RL-non-Hodgkin's B-cell
0.0




lymphoma


Cerebellum
7.1
JM1-pre-B-cell lymphoma
0.0


Cerebellum
0.0
Jurkat-T cell leukemia
0.0


NCI-H292-
0.0
TF-1-Erythroleukemia
0.0


Mucoepidermoid lung


carcinoma


DMS-114-Small cell
0.0
HUT 78-T-cell lymphoma
0.0


lung cancer


DMS-79-Small cell lung
0.8
U937-Histiocytic lymphoma
0.0


cancer


NCI-H146-Small cell
1.3
KU-812-Myelogenous
0.0


lung cancer

leukemia


NCI-H526-Small cell
100.0
769-P-Clear cell renal
0.0


lung cancer

carcinoma


NCI-N417-Small cell
0.0
Caki-2-Clear cell renal
0.9


lung cancer

carcinoma


NCI-H82-Small cell lung
0.0
SW 839-Clear cell renal
0.0


cancer

carcinoma


NCI-H157-Squamous
0.0
G401-Wilms' tumor
0.0


cell lung cancer


(metastasis)


NCI-H1155-Large cell
3.2
Hs766T-Pancreatic carcinoma
0.0


lung cancer

(LN metastasis)


NCI-H1299-Large cell
1.9
CAPAN-1-Pancreatic
0.0


lung cancer

adenocarcinoma (liver




metastasis)


NCI-H727-Lung
0.0
SU86.86-Pancreatic
0.6


carcinoid

carcinoma (liver metastasis)


NCI-UMC-11-Lung
2.1
BxPC-3-Pancreatic
0.0


carcinoid

adenocarcinoma


LX-1-Small cell lung
0.0
HPAC-Pancreatic
0.0


cancer

adenocarcinoma


Colo-205-Colon cancer
0.0
MIA PaCa-2-Pancreatic
0.0




carcinoma


KM12-Colon cancer
2.6
CFPAC-1-Pancreatic ductal
0.4




adenocarcinoma


KM20L2-Colon cancer
0.0
PANC-1-Pancreatic
0.0




epithelioid ductal carcinoma


NCI-H716-Colon cancer
31.0
T24-Bladder carcinma
0.0




(transitional cell)


SW-48-Colon
0.0
5637-Bladder carcinoma
0.0


adenocarcinoma


SW1116-Colon
0.0
HT-1197-Bladder carcinoma
0.0


adenocarcinoma


LS 174T-Colon
0.0
UM-UC-3-Bladder carcinma
0.0


adenocarcinoma

(transitional cell)


SW-948-Colon
0.0
A204-Rhabdomyosarcoma
0.0


adenocarcinoma


SW-480-Colon
1.5
HT-1080-Fibrosarcoma
0.8


adenocarcinoma


NCI-SNU-5-Gastric
0.0
MG-63-Osteosarcoma
0.0


carcinoma


KATO III-Gastric
0.0
SK-LMS-1-Leiomyosarcoma
0.0


carcinoma

(vulva)


NCI-SNU-16-Gastric
0.8
SJRH30-Rhabdomyosarcoma
0.0


carcinoma

(met to bone marrow)


NCI-SNU-1-Gastric
0.0
A431-Epidermoid carcinoma
0.0


carcinoma


RF-1-Gastric
0.0
WM266-4-Melanoma
1.2


adenocarcinorna


RF-48-Gastric
0.8
DU 145-Prostate carcinoma
0.0


adenocarcinoma

(brain metastasis)


MKN-45-Gastric
0.0
MDA-MB-468-Breast
0.8


carcinoma

adenocarcinoma


NCI-N87-Gastric
0.3
SCC-4-Squamous cell
0.0


carcinoma

carcinoma of tongue


OVCAR-5-Ovarian
0.0
SCC-9-Squamous cell
0.0


carcinoma

carcinoma of tongue


RL95-2-Uterine
0.0
SCC-15-Squamous cell
0.0


carcinoma

carcinoma of tongue


HelaS3-Cervical
0.0
CAL 27-Squamous cell
0.0


adenocarcinoma

carcinoma of tongue










[0970]

381





TABLE VI










Panel 4D













Rel.
Rel.

Rel.
Rel.



Exp.(%)
Exp.(%)

Exp.(%)
Exp.(%)



Ag2897,
Ag2897,

Ag2897,
Ag2897,



Run
Run

Run
Run


Tissue Name
161905862
163586314
Tissue Name
161905862
163586314















Secondary Th1 act
0.0
0.0
HUVEC IL-1 beta
0.0
0.0


Secondary Th2 act
0.0
0.0
HUVEC IFN
0.0
0.0





gamma


Secondary Tr1 act
0.0
0.0
HUVEC TNF
0.0
0.0





alpha + IFN





gamma


Secondary Th1 rest
0.0
0.0
HUVEC TNF
0.0
0.0





alpha + IL4


Secondary Th2 rest
0.0
0.0
HUVEC IL-11
0.0
0.0


Secondary Tr1 rest
0.0
0.0
Lung
0.0
0.0





Microvascular EC





none


Primary Th1 act
0.0
0.0
Lung
7.9
22.8





Microvascular EC





TNF alpha + IL-





1 beta


Primary Th2 act
0.0
0.0
Microvascular
0.0
0.0





Dermal EC none


Primary Tr1 act
0.0
0.0
Microsvasular
16.2
0.0





Dermal EC





TNF alpha + IL-





1 beta


Primary Th1 rest
9.3
20.7
Bronchial
4.4
0.0





epithelium





TNF alpha +





IL1 beta


Primary Th2 rest
0.0
9.0
Small airway
10.4
9.7





epithelium none


Primary Tr1 rest
9.8
0.0
Small airway
100.0
75.8





epithelium





TNF alpha + IL-





1 beta


CD45RA CD4
0.0
0.0
Coronery artery
0.0
9.9


lymphocyte act


SMC rest


CD45RO CD4
0.0
0.0
Coronery artery
16.8
9.0


lymphocyte act


SMC TNF alpha +





IL-1 beta


CD8 lymphocyte
0.0
0.0
Astrocytes rest
40.6
0.0


act


Secondary CD8
0.0
0.0
Astrocytes
56.6
100.0


lymphocyte rest


TNF alpha + IL-





1 beta


Secondary CD8
0.0
0.0
KU-812 (Basophil)
0.0
0.0


lymphocyte act


rest


CD4 lymphocyte
0.0
0.0
KU-812 (Basophil)
0.0
0.0


none


PMA/ionomycin


2ry
0.0
0.0
CCD1106
0.0
0.0


Th1/Th2/Tr1_anti-


(Keratinocytes)


CD95 Ch11


none


LAK cells rest
10.9
0.0
CCD1106
0.0
0.0





(Keratinocytes)





TNF alpha + IL-





1 beta


LAK cells IL-2
0.0
0.0
Liver cirrhosis
17.2
8.2


LAK cells IL-2 +
0.0
0.0
Lupus kidney
8.4
9.6


IL-12


LAK cells IL-
0.0
0.0
NCI-H292 none
0.0
0.0


2 + IFN gamma


LAK cells IL-2 +
0.0
0.0
NCI-H292 IL-4
0.0
0.0


IL-18


LAK cells
0.0
0.0
NCI-H292 IL-9
0.0
0.0


PMA/ionomycin


NK Cells IL-2 rest
0.0
0.0
NCI-H292 IL-13
0.0
0.0


Two Way MLR 3
0.0
9.3
NCI-H292 IFN
0.0
0.0


day


gamma


Two Way MLR 5
0.0
0.0
HPAEC none
0.0
0.0


day


Two Way MLR 7
0.0
0.0
HPAEC TNF
0.0
0.0


day


alpha + IL-1 beta


PBMC rest
0.0
0.0
Lung fibroblast
0.0
0.0





none


PBMC PWM
0.0
0.0
Lung fibroblast
0.0
18.8





TNF alpha + IL-1





beta


PBMC PHA-L
8.9
0.0
Lung fibroblast IL-4
0.0
17.7


Ramos (B cell)
0.0
0.0
Lung fibroblast IL-9
0.0
0.0


none


Ramos (B cell)
0.0
0.0
Lung fibroblast IL-
0.0
0.0


ionomycin


13


B lymphocytes
0.0
0.0
Lung fibroblast
0.0
0.0


PWM


IFN gamma


B lymphocytes
0.0
0.0
Dermal fibroblast
18.7
5.1


CD40L and IL-4


CCD1070 rest


EOL-1 dbcAMP
0.0
0.0
Dermal fibroblast
45.4
29.5





CCD1070 TNF





alpha


EOL-1 dbcAMP
0.0
0.0
Dermal fibroblast
33.7
85.9


PMA/ionomycin


CCD1070 IL-1





beta


Dendritic cells none
0.0
0.0
Dermal fibroblast
0.0
0.0





IFN gamma


Dendritic cells LPS
0.0
0.0
Dermal fibroblast
0.0
8.4





IL-4


Dendritic cells anti-
0.0
0.0
IBD Colitis 2
0.0
9.9


CD40


Monocytes rest
0.0
0.0
IBD Crohn's
7.7
0.0


Monocytes LPS
0.0
0.0
Colon
62.4
39.2


Macrophages rest
0.0
0.0
Lung
9.9
22.1


Macrophages LPS
0.0
0.0
Thymus
27.7
35.8


HUVEC none
0.0
0.0
Kidney
18.9
20.6


HUVEC starved
0.0
0.0










[0971]

382





TABLE VJ










Panel CNS_1











Rel. Exp.(%)

Rel. Exp.(%)



Ag2897, Run

Ag2897, Run


Tissue Name
171688457
Tissue Name
171688457













BA4 Control
29.7
BA17 PSP
24.3


BA4 Control2
37.6
BA17 PSP2
0.0


BA4
0.0
Sub Nigra Control
25.9


Alzheimer's2


BA4 Parkinson's
23.8
Sub Nigra Control2
33.4


BA4
38.7
Sub Nigra
0.0


Parkinson's2

Alzheimer's2


BA4
18.4
Sub Nigra
26.6


Huntington's

Parkinson's2


BA4
0.0
Sub Nigra
13.9


Huntington's2

Huntington's


BA4 PSP
8.0
Sub Nigra
8.7




Huntington's2


BA4 PSP2
37.6
Sub Nigra PSP2
0.0


BA4 Depression
15.6
Sub Nigra
0.0




Depression


BA4
4.6
Sub Nigra
2.8


Depression2

Depression2


BA7 Control
56.6
Glob Palladus
4.1




Control


BA7 Control2
6.0
Glob Palladus
23.7




Control2


BA7
7.3
Glob Palladus
3.8


Alzheimer's2

Alzheimer's


BA7 Parkinson's
10.8
Glob Palladus
0.0




Alzheimer's2


BA7
27.2
Glob Palladus
51.1


Parkinson's2

Parkinson's


BA7
56.3
Glob Palladus
3.5


Huntington's

Parkinson's2


BA7
10.8
Glob Palladus PSP
0.0


Huntington's2


BA7 PSP
21.5
Glob Palladus PSP2
0.0


BA7 PSP2
21.3
Glob Palladus
0.0




Depression


BA7 Depression
5.4
Temp Pole Control
15.9


BA9 Control
31.6
Temp Pole Control2
37.9


BA9 Control2
100.0
Temp Pole
0.0




Alzheimer's


BA9 Alzheimer's
3.8
Temp Pole
0.0




Alzheimer's2


BA9
3.7
Temp Pole
34.2


Alzheimer's2

Parkinson's


BA9 Parkinson's
19.2
Temp Pole
10.8




Parkinson's2


BA9
30.6
Temp Pole
17.7


Parkinson's2

Huntington's


BA9
27.2
Temp Pole PSP
5.8


Huntington's


BA9
9.0
Temp Pole PSP2
0.0


Huntington's


BA9 PSP
0.0
Temp Pole
15.3




Depression2


BA9 PSP2
16.5
Cing Gyr Control
76.3


BA9 Depression
2.7
Cing Gyr Control2
54.0


BA9
6.7
Cing Gyr
12.1


Depression2

Alzheimer's


BA17 Control
25.9
Cing Gyr
2.9




Alzheimer's2


BA17 Control2
14.8
Cing Gyr
26.6




Parkinson's


BA17
7.9
Cing Gyr
38.2


Alzheimer's2

Parkinson's2


BA17
9.5
Cing Gyr
36.1


Parkinson's

Huntington's


BA17
8.8
Cing Gyr
8.1


Parkinson's2

Huntington's2


BA17
18.3
Cing Gyr PSP
8.3


Huntington's


BA17
0.0
Cing Gyr PSP2
4.0


Huntington's2


BA17
7.6
Cing Gyr
0.0


Depression

Depression


BA17
3.7
Cing Gyr
2.9


Depression2

Depression2










[0972] AI_comprehensive panel_v1.0 Summary: Ag2897 Highest expression of the CG58567-01 gene is detected in 112427 match control psoriasis sample-F (CT=30). Furthermore, this expression is down-regulated in the corresponding psoriasis sample (CT=33). Therefore expression of this gene can be used to distinguish between these samples. In addition, the expression of this gene is up-regulated in lung from emphysema and COPD patients, which is consistent with its expression in “stressed” small airway epithelium, lung fibroblasts and lung endothelium (treated with TNF-a and IL-1). Therapeutic modulation of the expression of this putative protein and/or signaling via this protein by antibodies, small moleculesvor protein therapeutics may inhibit inflammation in lung tissue due to asthma, emphysema and other COPD type diseases


[0973] CNS_neurodegeneration_v1.0 Summary: Ag2897 This panel does not show differential expression of the CG58567-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see panel 1.3D for discussion of utility of this gene in the central nervous system.


[0974] Panel 1.2 Summary: Ag705 Two experiments with the same probe and primer show highest expression of the CG58567-05 gene in an ovarian cancer cell line and the cerebral cortex (CTs=25-26). This gene is also expressed in other parts of the central nervous system, including the spinal cord, amygdala, and hippocampus. Please see Panel 1.3D for further discussion of utility of this gene in the central nervous system.


[0975] In addition to expression in the ovarian cancer cell line, this gene is also expressed in a cluster of cell lines derived from ovarian and brain cancers. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of ovarian and brain cancers.


[0976] Panel 1.3D Summary: Ag2897 Tow experiments with the same probe and primer show highest expression of this gene, a protocadherin homolog, in the spinal cord and the cerebral cortex (CTs=31.5). Low levels of expression are also seen in other regions of the brain including the amygdala and the hippocampus. The cadherins have been shown to be critical for CNS development, specifically for the guidance of axons, dendrites and/or growth cones in general. Therapeutic modulation of the levels of this protein, or possible signaling via this protein may be of utility in enhancing/directing compensatory synaptogenesis and fiber growth in the CNS in response to neuronal death (stroke, head trauma), axon lesion (spinal cord injury), or neurodegeneration (Alzheimer's, Parkinson's, Huntingdon's, vascular dementia or any neurodegenerative disease). Since protocadherins play an important role in synaptogenesis this gene product may also be involved in depression, schizophrenia, which also involve synaptogenesis. Because this cadherin shows highest expression in the cerebellum, this is also an excellent candidate for the spinocerebellar ataxias as well.


[0977] Significant levels of expression are also seen in cell lines derived from ovarian, renal and brain cancers. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of ovarian, renal and brain cancers.


[0978] References:


[0979] Hilschmann N, Barnikol H U, Barnikol-Watanabe S, Gotz H, Kratzin H, Thinnes F P. The immunoglobulin-like genetic predetermination of the brain; the protocadherins, blueprint of the neuronal network. Naturwissenschaften January 2001;88(1):2-12


[0980] Panel 2D Summary: Ag2897 Two experiments with the same probe and primer produce results that are in reasonable agreement, with highest expression of the CG58567-01 gene in ovarian and kidney cancers (CTs=30.5). Significant levels of expression are also seen in lung and uterine cancers. In addition, higher levels of expression are seen in these cancers than in the corresponding normal adjacent tissues. Thus, therapeutic targeting of this gene product with a human monoclonal antibody is anticipated to limit or block the extent of tumor cell migration and invasion, preferably in kidney, lung, uterine and ovarian tumor tumors.


[0981] Panel 3D Summary: Ag2897 Highest expression of the CG58567-01 gene is seen in a lung cancer cell line (CT=30.1). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel. Please see Panel 2D for further discussion of utility of this gene in cancer.


[0982] Panel 4D Summary: Ag2897 Two experiments with the same probe and primer produce results that are in reasonable agreement, with the CG58567-01 gene highly up-regulated in small airway epithelium and astrocytes stimulated with TNF-alpha and IL-1 beta (CTs=33-34). Other tissues in the lung also up regulate the expression of this gene including lung microvascular endothelium and lung fibroblasts in response to TNF alpha or the Th2 elaborated cytokine IL-4. This suggests that this molecule could be expressed as a result of inflammation particularly during asthma since TNFalpha and IL-4 may play important roles in the pathology of this disease. Based on the expression profile of this transcript and the types of cytokines which induce it, antibodies to CG58567-01 may inhibit inflammation in lung tissue due to asthma, emphysema and other COPD type diseases.


[0983] Panel CNS1 Summary: Ag2897 The results of this panel confirm expression of the CG58567-01 gene in the brain. Please see Panel 1.3D for discussion of utility of this gene in the central nervous system.



W. NOV29and NOV29c (CG59243-01 and CG59243-02; MITOCHONDRIAL CARRIER PROTEIN)

[0984] Expression of gene CG59243-01 and CG59243-02 was assessed using the primer-probe set Ag3415, described in Table WA. Results of the RTQ-PCR runs are shown in Tables WB, WC, WD, and WE. Please note that CG59243-02 represents a full-length physical clone of the CG59243-01 gene, validating the prediction of the gene sequence.
383TABLE WAProbe Name Ag3415StartPrimersSequencesLengthPositionForward5′-tataaggttgtgttccggca-3′(SEQ ID NO:302)20145ProbeTET-5′-gcagtgtcagaggctgtgagacagct-3′-TAMRA(SEQ ID NO:303)26181Reverse5′-tattgaggaccctcatgcca-3′(SEQ ID NO:304)20208


[0985]

384





TABLE WB










CNS_neurodegeneration_v1.0











Rel. Exp.(%) Ag3415,

Rel. Exp.(%) Ag3415,


Tissue Name
Run 206533692
Tissue Name
Run 206533692













AD 1 Hippo
40.6
Control (Path) 3
15.5




Temporal Ctx


AD 2 Hippo
43.2
Control (Path) 4
28.3




Temporal Ctx


AD 3 Hippo
13.2
AD 1 Occipital Ctx
17.2


AD 4 Hippo
13.9
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 hippo
79.0
AD 3 Occipital Ctx
7.2


AD 6 Hippo
40.6
AD 4 Occipital Ctx
21.9


Control 2 Hippo
18.0
AD 5 Occipital Ctx
4.7


Control 4 Hippo
36.6
AD 6 Occipital Ctx
25.3


Control (Path) 3
8.4
Control 1 Occipital
8.0


Hippo

Ctx


AD 1 Temporal Ctx
28.9
Control 2 Occipital
48.6




Ctx


AD 2 Temporal Ctx
42.0
Control 3 Occipital
11.0




Ctx


AD 3 Temporal Ctx
13.8
Control 4 Occipital
16.5




Ctx


AD 4 Temporal Ctx
22.5
Control (Path) 1
100.0




Occipital Ctx


AD 5 Inf Temporal
73.7
Control (Path) 2
14.0


Ctx

Occipital Ctx


AD 5 Sup Temporal
65.5
Control (Path) 3
5.8


Ctx

Occipital Ctx


AD 6 Inf Temporal
27.0
Control (Path) 4
24.3


Ctx

Occipital Ctx


AD 6 Sup Temporal
20.0
Control 1 Parietal
21.0


Ctx

Ctx


Control 1 Temporal
18.7
Control 2 Parietal
49.0


Ctx

Ctx


Control 2 Temporal
27.9
Control 3 Parietal
9.0


Ctx

Ctx


Control 3 Temporal
9.3
Control (Path) 1
55.9


Ctx

Parietal Ctx


Control 4 Temporal
17.4
Control (Path) 2
31.4


Ctx

Parietal Ctx


Control (Path) 1
34.9
Control (Path) 3
4.6


Temporal Ctx

Parietal Ctx


Control (Path) 2
33.2
Control (Path) 4
44.4


Temporal Ctx

Parietal Ctx










[0986]

385





TABLE WC










Panel 1.3D











Rel. Exp.(%) Ag3415,

Rel. Exp.(%) Ag3415,


Tissue Name
Run 167617385
Tissue Name
Run 167617385













Liver adenocarcinoma
0.0
Kidney (fetal)
19.8


Pancreas
1.1
Renal ca. 786-0
13.7


Pancreatic ca. CAPAN 2
0.0
Renal ca. A498
2.6


Adrenal gland
0.9
Renal ca. RXF 393
9.1


Thyroid
0.0
Renal ca. ACHN
13.5


Salivary gland
0.0
Renal ca. UO-31
20.6


Pituitary gland
5.6
Renal ca. TK-10
32.8


Brain (fetal)
55.1
Liver
4.5


Brain (whole)
20.0
Liver (fetal)
0.0


Brain (amygdala)
23.2
Liver ca.
2.3




(hepatoblast) HepG2


Brain (cerebellum)
17.3
Lung
5.9


Brain (hippocampus)
12.5
Lung (fetal)
4.8


Brain (substantia nigra)
26.2
Lung ca. (small cell)
2.8




LX-1


Brain (thalamus)
23.8
Lung ca. (small cell)
2.7




NCI-H69


Cerebral Cortex
32.5
Lung ca. (s.cell var.)
89.5




SHP-77


Spinal cord
20.2
Lung ca. (large
2.6




cell) NCI-H460


glio/astro U87-MG
0.0
Lung ca. (non-sm.
0.0




cell) A549


glio/astro U-118-MG
2.1
Lung ca. (non-s.cell)
3.7




NCI-H23


astrocytoma SW1783
15.9
Lung ca. (non-s.cell)
8.2




HOP-62


neuro*; met SK-N-AS
8.3
Lung ca. (non-s.cl)
17.3




NCI-H522


astrocytoma SF-539
2.3
Lung ca. (squam.)
6.4




SW 900


astrocytoma SNB-75
6.7
Lung ca. (squam.)
18.8




NCI-H596


glioma SNB-19
0.0
Mammary gland
1.1


glioma U251
23.5
Breast ca.* (pl.ef)
2.2




MCF-7


glioma SF-295
0.0
Breast ca.* (pl.ef)
2.6




MDA-MB-231


Heart (fetal)
10.0
Breast ca.* (pl.ef)
1.3




T47D


Heart
4.6
Breast ca. BT-549
7.7


Skeletal muscle (fetal)
2.0
Breast ca. MDA-N
12.2


Skeletal muscle
3.4
Ovary
4.2


Bone marrow
3.8
Ovarian ca. OVCAR-3
17.7


Thymus
5.4
Ovarian ca. OVCAR-4
0.0


Spleen
24.8
Ovarian ca. OVCAR-5
0.0


Lymph node
43.5
Ovarian ca. OVCAR-8
3.5


Colorectal
6.0
Ovarian ca. IGROV-1
2.4


Stomach
6.8
Ovarian ca.* (ascites)
3.5




SK-OV-3


Small intestine
9.3
Uterus
4.4


Colon ca. SW480
6.5
Placenta
1.9


Colon ca.*
100.0
Prostate
0.0


SW620 (SW480 met)


Colon ca. HT29
0.0
Prostate ca.* (bone
0.0




met) PC-3


Colon ca. HCT-116
0.0
Testis
14.4


Colon ca. CaCo-2
3.8
Melanoma
0.0




Hs688(A).T


Colon ca.
0.0
Melanoma* (met)
0.0


tissue(ODO3866)

Hs688(B).T


Colon ca. HCC-2998
0.0
Melanoma UACC-62
5.1


Gastric ca.* (liver met)
0.0
Melanoma M14
0.0


NCI-N87


Bladder
6.4
Melanoma LOX
0.0




IMVI


Trachea
0.0
Melanoma* (met)
2.1




SK-MEL-5


Kidney
0.0
Adipose
3.3










[0987]

386





TABLE WD










Panel 2D











Rel. Exp.(%)

Rel. Exp.(%)



Ag3415, Run

Ag3415, Run


Tissue Name
169596730
Tissue Name
169596730













Normal Colon
39.0
Kidney Margin
0.0




8120608


CC Well to Mod Diff
8.7
Kidney Cancer
7.7


(ODO3866)

8120613


CC Margin (ODO3866)
0.0
Kidney Margin
0.0




8120614


CC Gr.2 rectosigmoid
11.7
Kidney Cancer
7.7


(ODO3868)

9010320


CC Margin (ODO3868)
0.8
Kidney Margin
0.0




9010321


CC Mod Diff (ODO3920)
7.6
Normal Uterus
2.0


CC Margin (ODO3920)
3.6
Uterus Cancer 064011
23.3


CC Gr.2 ascend colon
19.9
Normal Thyroid
2.0


(ODO3921)


CC Margin (ODO3921)
10.2
Thyroid Cancer
4.4




064010


CC from Partial
1.9
Thyroid Cancer
2.3


Hepatectomy (ODO4309)

A302152


Mets


Liver Margin (ODO4309)
3.1
Thyroid Margin
5.9




A302153


Colon mets to lung
3.6
Normal Breast
19.6


(OD04451-01)


Lung Margin (OD04451-
2.5
Breast Cancer
5.3


02)

(OD04566)


Normal Prostate 6546-1
1.1
Breast Cancer
16.5




(OD04590-01)


Prostate Cancer
14.5
Breast Cancer Mets
29.5


(OD04410)

(OD04590-03)


Prostate Margin
17.0
Breast Cancer
12.9


(OD04610)

Metastasis (OD04655-05)


Prostate Cancer
10.6
Breast Cancer 064006
13.6


(OD04720-01)


Prostate Margin
16.3
Breast Cancer 1024
7.4


(OD04720-02)


Normal Lung 061010
60.3
Breast Cancer
10.1




9100266


Lung Met to Muscle
1.8
Breast Margin
5.0


(ODO4286)

9100265


Muscle Margin
2.0
Breast Cancer
31.9


(ODO4286)

A209073


Lung Malignant Cancer
7.7
Breast Margin
10.5


(OD03126)

A209073


Lung Margin (OD03126)
12.6
Normal Liver
4.3


Lung Cancer (OD04404)
15.5
Liver Cancer 064003
0.0


Lung Margin (OD04404)
7.6
Liver Cancer 1025
1.9


Lung Cancer (OD04565)
1.8
Liver Cancer 1026
1.9


Lung Margin (OD04565)
22.5
Liver Cancer 6004-T
4.9


Lung Cancer (OD04237-
100.0
Liver Tissue 6004-N
6.6


01)


Lung Margin (OD04237-
7.2
Liver Cancer 6005-T
14.7


02)


Ocular Mel Met to Liver
0.0
Liver Tissue 6005-N
5.3


(ODO4310)


Liver Margin (ODO4310)
3.6
Normal Bladder
34.2


Melanoma Mets to Lung
3.6
Bladder Cancer 1023
2.1


(OD04321)


Lung Margin (OD04321)
14.7
Bladder Cancer
23.5




A302173


Normal Kidney
4.7
Bladder Cancer
17.1




(OD04718-01)


Kidney Ca, Nuclear grade
19.9
Bladder Normal
4.1


2 (OD04338)

Adjacent (OD04718-




03)


Kidney Margin
3.2
Normal Ovary
3.4


(OD04338)


Kidney Ca Nuclear grade
25.2
Ovarian Cancer
14.2


1/2 (OD04339)

064008


Kidney Margin
2.2
Ovarian Cancer
4.1


(OD04339)

(OD04768-07)


Kidney Ca, Clear cell type
6.1
Ovary Margin
8.2


(OD04340)

(OD04768-08)


Kidney Margin
0.0
Normal Stomach
29.3


(OD04340)


Kidney Ca, Nuclear grade
0.0
Gastric Cancer
9.9


3 (OD04348)

9060358


Kidney Margin
11.4
Stomach Margin
10.7


(OD04348)

9060359


Kidney Cancer
23.8
Gastric Cancer
16.4


(OD04622-01)

9060395


Kidney Margin
7.0
Stomach Margin
17.0


(OD04622-03)

9060394


Kidney Cancer
15.9
Gastric Cancer
5.1


(OD04450-01)

9060397


Kidney Margin
1.7
Stomach Margin
7.7


(OD04450-03)

9060396


Kidney Cancer 8120607
4.4
Gastric Cancer 064005
34.6










[0988]

387





TABLE WE










Panel 4D











Rel. Exp.(%)

Rel. Exp.(%)



Ag3415, Run

Ag3415, Run


Tissue Name
166385451
Tissue Name
166385451













Secondary Th1 act
1.4
HUVEC IL-1 beta
1.5


Secondary Th2 act
0.4
HUVEC IFN gamma
1.7


Secondary Tr1 act
3.1
HUVEC TNF alpha + IFN
1.3




gamma


Secondary Th1 rest
1.6
HUVEC TNF alpha + IL4
4.2


Secondary Th2 rest
0.8
HUVEC IL-11
1.6


Secondary Tr1 rest
0.5
Lung Microvascular EC
3.3




none


Primary Th1 act
3.6
Lung Microvascular EC
4.7




TNF alpha + IL-1 beta


Primary Th2 act
2.0
Microvascular Dermal EC
1.3




none


Primary Tr1 act
0.9
Microvascular Dermal EC
1.1




TNF alpha + IL-1 beta


Primary Th1 rest
3.9
Bronchial epithelium
0.0




TNF alpha + IL-1 beta


Primary Th2 rest
1.5
Small airway epithelium
0.0




none


Primary Tr1 rest
0.9
Small airway epithelium
0.2




TNF alpha + IL-1 beta


CD45RA CD4
2.6
Coronery artery SMC rest
0.1


lymphocyte act


CD45RO CD4
8.5
Coronery artery SMC
0.0


lymphocyte act

TNF alpha + IL-1 beta


CD8 lymphocyte act
17.1
Astrocytes rest
3.1


Secondary CD8
4.9
Astrocytes TNF alpha + IL-
0.5


lymphocyte rest

1 beta


Secondary CD8
5.9
KU-812 (Basophil) rest
1.2


lymphocyte act


CD4 lymphocyte none
2.1
KU-812 (Basophil)
4.3




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
1.9
CCD1106 (Keratinocytes)
2.2


CD95 CH11

none


LAK cells rest
7.9
CCD1106 (Keratinocytes)
0.8




TNFa1pha + IL-1 beta


LAK cells IL-2
30.8
Liver cirrhosis
2.7


LAK cells IL-2 + IL-12
6.0
Lupus kidney
0.0


LAK cells IL-2 + IFN
7.4
NCI-H292 none
0.3


gamma


LAK cells IL-2 + IL-18
11.7
NCI-H292 IL-4
0.0


LAK cells
1.1
NCI-H292 IL-9
0.0


PMA/ionomycin


NK Cells IL-2 rest
19.8
NCI-H292 IL-13
0.0


Two Way MLR 3 day
9.5
NCI-H292 IFN gamma
0.7


Two Way MLR 5 day
4.1
HPAEC none
1.5


Two Way MLR 7 day
12.5
HPAEC TNF alpha + IL-1
0.5




beta


PBMC rest
4.1
Lung fibroblast none
0.0


PBMC PWM
28.3
Lung fibroblast TNF
0.2




alpha + IL-1 beta


PBMC PHA-L
10.8
Lung fibroblast IL-4
2.1


Ramos (B cell) none
34.6
Lung fibroblast IL-9
0.5


Ramos (B cell)
100.0
Lung fibroblast IL-13
0.8


ionomycin


B lymphocytes PWM
32.3
Lung fibroblast IFN
0.8




gamma


B lymphocytes CD40L
7.0
Dermal fibroblast
0.7


and IL-4

CCD1070 rest


EOL-1 dbcAMP
0.0
Dermal fibroblast
28.7




CCD1070 TNF alpha


EOL-1 dbcAMP
0.5
Dermal fibroblast
0.0


PMA/ionomycin

CCD1070 IL-1 beta


Dendritic cells none
0.4
Dermal fibroblast IFN
0.0




gamma


Dendritic cells LPS
0.2
Dermal fibroblast IL-4
0.3


Dendritic cells anti-
0.3
IBD Colitis 2
0.7


CD40


Monocytes rest
0.2
IBD Crohn's
0.0


Monocytes LPS
1.6
Colon
4.0


Macrophages rest
0.5
Lung
1.1


Macrophages LPS
0.2
Thymus
0.7


HUVEC none
2.1
Kidney
3.0


HUVEC starved
3.1










[0989] AI_comprehensive panel_v1.0 Summary: Ag3415 Results from one experiment with the CG59243-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.


[0990] CNS_neurodegeneration_v1.0 Summary: Ag3415 This panel confirms the expression of the CG59243-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's disease postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.3D for a discussion of the potential utility of this gene in treatment of central nervous system disorders.


[0991] Panel 1.3D Summary: Ag3415 Highest expression of the CG59243-01 gene is seen in a colon cancer cell line (CT=33.2), with significant expression also seen in a lung cancer cell line. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of colon or lung cancer. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of colon or lung cancer.


[0992] In addition, this gene is expressed at low levels in fetal brain and cerebral cortex. Therefore, this gene may play a role in central nervous system development and CNS disorders such as Alzheimer's disease, Parkinson's disease, seizures, epilepsy, multiple sclerosis, schizophrenia and depression.


[0993] Panel 2D Summary: Ag3415 Highest expression of the CG59243-01 gene is seen in a lung cancer (CT=32.5), consistent with expression in Panel 1.3D. Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel. Please see Panel 1.3D for a discussion of the potential utility of this gene in treatment of cancer.


[0994] Panel 4D Summary: Ag3415 Highest expression of the CG59243-01 gene is seen in the B cell line Ramos, treated with ionomycin (CT=29.5). Low, but significant levels of expression of this transcript are also seen in activated B cells (B cells treated with PWM or CD40L+IL4). This transcript is also expressed in PBMC treated with the B cell mitogen, PWM, confirming the importance of this gene's expression in activated B cells. B cells represent a principle component of immunity and contribute to the immune response in a number of important functional roles, including antibody production. For example, production of antibodies against self-antigens is a major component in an autoimmune disorders such a systemic lupus erythematosus. Since B cells play an important role in autoimmunity, inflammatory processes and inflammatory cascades, therapeutic modulation of this gene product may reduce or eliminate the symptoms or patients suffering from asthma, allergies, chronic obstructive pulmonary disease, emphysema, Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, osteoarthritis, and other autoimmune disorders including systemic lupus erythematosus.



X. NOV30a (CG59534-01: MEMBRANE GLYCOPROTEIN)

[0995] Expression of gene CG59534-01 was assessed using the primer-probe sets Ag5041 and Ag5043, described in Tables XA and XB. Results of the RTQ-PCR runs are shown in Tables XC and XD.
388TABLE XAProbe Name Ag5041StartPrimersSequencesLengthPositionForward5′-ggtgttggtacctgtggattt-3′(SEQ ID NO:305)214154ProbeTET-5′-tctatactgatgttttcgttttgccaa-3′-TAMRA(SEQ ID NO:306)274176Reverse5′-cccaaggccaatgtaatactc-3′(SEQ ID NO:307)214209


[0996]

389





TABLE XB










Probe Name Ag5043













Start


Primers
Sequences
Length
Position














Forward
5′-cacaagcaaaaggtcagaaca-3′
(SEQ ID NO:308)
21
4024





Probe
TET-5′-aaacactgcctttcctcctcctctta-3′-TAMRA
(SEQ ID NO:309)
26
4048





Reverse
5′-ggccacatttgcttttatcata-3′
(SEQ ID NO:310)
22
4077










[0997]

390





TABLE XC










General_screening_panel_v1.5













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag5041, Run
Ag5043, Run

Ag5041, Run
Ag5043, Run


Tissue Name
228967328
228969275
Tissue Name
228967328
228969275















Adipose
1.1
4.3
Renal ca. TK-10
2.4
10.3


Melanoma*
0.8
4.2
Bladder
3.7
15.2


Hs688(A).T


Melanoma*
1.1
2.7
Gastric ca. (liver
100.0
5.5


Hs688(B).T


met.) NCI-N87


Melanoma*
0.6
2.6
Gastric ca. KATO
13.8
77.9


M14


III


Melanoma*
2.4
7.7
Colon ca. SW-
1.4
4.0


LOXIMVI


948


Melanoma*
1.0
5.5
Colon ca. SW480
3.0
12.2


SK-MEL-5


Squamous cell
0.7
3.0
Colon ca.*
5.3
23.0


carcinoma


(SW480 met)


SCC-4


SW620


Testis Pool
2.1
5.9
Colon ca. HT29
1.3
5.5


Prostate ca.*
0.3
1.3
Colon ca. HCT-
0.9
4.0


(bone met)


116


PC-3


Prostate Pool
4.6
11.0
Colon ca. CaCo-2
5.4
25.7


Placenta
0.2
1.0
Colon cancer
2.2
9.3





tissue


Uterus Pool
2.7
3.5
Colon ca.
0.7
2.2





SW1116


Ovarian ca.
3.0
13.7
Colon ca. Colo-
1.3
3.6


OVCAR-3


205


Ovarian ca.
1.6
7.3
Colon ca. SW-48
1.3
3.5


SK-OV-3


Ovarian ca.
0.9
2.9
Colon Pool
3.4
0.6


OVCAR-4


Ovarian ca.
10.7
65.5
Small Intestine
3.4
15.6


OVCAR-5


Pool


Ovarian ca.
11.8
71.7
Stomach Pool
3.6
11.7


IGROV-1


Ovarian ca.
5.0
25.3
Bone Marrow
2.4
5.2


OVCAR-8


Pool


Ovary
1.1
6.2
Fetal Heart
2.6
4.4


Breast ca.
3.6
20.0
Heart Pool
1.7
3.0


MCF-7


Breast ca.
2.3
9.7
Lymph Node
6.9
24.1


MDA-MB-


Pool


231


Breast ca. BT
0.8
2.0
Fetal Skeletal
2.1
10.3


549


Muscle


Breast ca.
10.3
24.8
Skeletal Muscle
8.3
28.3


T47D


Pool


Breast ca.
1.6
6.0
Spleen Pool
0.8
2.1


MDA-N


Breast Pool
4.3
22.8
Thymus Pool
3.5
12.5


Trachea
2.5
11.3
CNS cancer
7.4
36.1





(glio/astro) U87-





MG


Lung
1.9
8.2
CNS cancer
17.0
100.0





(glio/astro) U-





118-MG


Fetal Lung
5.6
29.1
CNS cancer
1.2
5.1





(neuro;met) SK-





N-AS


Lung ca. NCI-
0.8
3.8
CNS cancer
3.3
13.5


N417


(astro) SF-539


Lung ca. LX-1
2.8
11.1
CNS cancer
7.1
34.4





(astro) SNB-75


Lung ca. NCI-
0.6
2.8
CNS cancer (glio)
14.0
80.1


H146


SNB-19


Lung ca. SHP-
3.6
20.9
CNS cancer (glio)
2.9
11.9


77


SF-295


Lung ca. A549
1.1
2.8
Brain (Amygdala)
2.7
10.6





Pool


Lung ca. NCI-
0.6
2.4
Brain
7.8
50.0


H526


(cerebellum)


Lung ca. NCI-
1.6
5.6
Brain (fetal)
2.8
16.8


H23


Lung ca. NCI-
1.2
2.8
Brain
4.9
20.2


H460


(Hippocampus)





Pool


Lung ca.
1.2
4.3
Cerebral Cortex
5.0
18.8


HOP-62


Pool


Lung ca. NCI-
0.4
1.3
Brain (Substantia
3.0
11.0


H522


nigra) Pool


Liver
0.1
0.4
Brain (Thalamus)
6.5
24.1





Pool


Fetal Liver
0.7
3.1
Brain (whole)
2.4
11.3


Liver ca.
2.8
12.1
Spinal Cord Pool
4.2
14.1


HepG2


Kidney Pool
5.0
21.6
Adrenal Gland
0.6
2.2


Fetal Kidney
1.5
4.8
Pituitary gland
1.5
5.1





Pool


Renal ca. 786-0
0.4
1.9
Salivary Gland
0.7
2.1


Renal ca.
0.3
0.8
Thyroid (female)
0.9
3.3


A498


Renal ca.
0.4
1.8
Pancreatic ca.
0.5
1.5


ACHN


CAPAN2


Renal ca. UO-
1.8
8.5
Pancreas Pool
5.8
28.9


31










[0998]

391





TABLE XD










Panel 4.1D













Rel.
Rel.

Rel.
Rel.



Exp.(%)
Exp.(%)

Exp.(%)
Exp.(%)



Ag5041,
Ag5043,

Ag5041,
Ag5043,



Run
Run

Run
Run


Tissue Name
223784808
223785123
Tissue Name
223784808
223785123















Secondary Th1 act
37.4
15.3
HUVEC IL-1 beta
37.6
28.5


Secondary Th2 act
25.3
9.6
HUVEC IFN
31.6
9.0





gamma


Secondary Tr1 act
33.0
14.1
HUVEC TNF
19.6
10.2





alpha + IFN





gamma


Secondary Th1 rest
14.7
8.2
HUVEC TNF
29.3
19.2





alpha + IL4


Secondary Th2 rest
13.5
10.5
HUVEC IL-11
13.5
7.5


Secondary Tr1 rest
10.8
8.1
Lung
28.5
11.7





Microvascular EC





none


Primary Th1 act
33.7
20.2
Lung
28.7
16.7





Microvascular EC





TNF alpha + IL-





1 beta


Primary Th2 act
47.6
19.3
Microvascular
9.6
6.2





Dermal EC none


Primary Tr1 act
32.5
19.2
Microsvasular
23.8
11.4





Dermal EC





TNF alpha + IL-





1 beta


Primary Th1 rest
15.9
5.2
Bronchial
11.4
5.6





epithelium





TNF alpha +





IL1 beta


Primary Th2 rest
13.0
6.6
Small airway
3.6
2.3





epithelium none


Primary Tr1 rest
17.7
11.0
Small airway
4.1
3.7





epithelium





TNF alpha + IL-





1 beta


CD45RA CD4
40.1
11.0
Coronery artery
12.8
6.0


lymphocyte act


SMC rest


CD45RO CD4
30.6
15.4
Coronery artery
22.4
11.0


lymphocyte act


SMC TNF alpha +





IL-1 beta


CD8 lymphocyte
28.9
16.3
Astrocytes rest
17.4
8.3


act


Secondary CD8
29.3
17.6
Astrocytes
37.1
38.7


lymphocyte rest


TNF alpha + IL-





1 beta


Secondary CD8
18.7
9.9
KU-812 (Basophil)
9.0
4.5


lymphocyte act


rest


CD4 lymphocyte
33.0
12.3
KU-812 (Basophil)
9.5
6.6


none


PMA/ionomycin


2ry
33.7
13.8
CCD1106
16.7
10.6


Th1/Th2/Tr1_anti-


(Keratinocytes)


CD95 CH11


none


LAK cells rest
24.7
10.1
CCD1106
7.4
4.0





(Keratinocytes)





TNF alpha + IL-





1 beta


LAK cells IL-2
26.1
8.4
Liver cirrhosis
10.4
3.9


LAK cells IL-2 +
28.1
11.3
NCI-H292 none
8.1
4.9


IL-12


LAK cells IL-
28.9
14.6
NCI-H292 IL-4
6.7
4.0


2 + IFN gamma


LAK cells IL-2 +
30.4
14.9
NCI-H292 IL-9
7.2
4.0


IL-18


LAK cells
36.6
21.9
NCI-H292 IL-13
10.6
4.7


PMA/ionomycin


NK Cells IL-2 rest
28.7
17.8
NCI-H292 IFN
7.1
2.1





gamma


Two Way MLR 3
26.4
10.5
HPAEC none
21.9
11.6


day


Two Way MLR 5
22.5
9.2
HPAEC TNF
81.2
37.1


day


alpha + IL-1 beta


Two Way MLR 7
16.0
15.8
Lung fibroblast
46.3
24.3


day


none


PBMC rest
11.2
5.6
Lung fibroblast
73.7
29.5





TNF alpha + IL-1





beta


PBMC PWM
31.6
14.0
Lung fibroblast IL-4
49.0
22.1


PBMC PHA-L
20.2
9.8
Lung fibroblast IL-9
39.5
100.0


Ramos (B cell)
78.5
49.7
Lung fibroblast IL-
54.7
28.1


none


13


Ramos (B cell)
100.0
53.6
Lung fibroblast
55.5
36.1


ionomycin


IFN gamma


B lymphocytes
20.6
6.8
Dermal fibroblast
15.3
8.6


PWM


CCD1070 rest


B lymphocytes
22.1
8.7
Dermal fibroblast
33.4
25.5


CD40L and IL-4


CCD1070 TNF





alpha


EOL-1 dbcAMP
3.8
1.3
Dermal fibroblast
57.4
27.4





CCD1070 IL-1





beta


EOL-1 dbcAMP
3.2
1.1
Dermal fibroblast
25.9
14.3


PMA/ionomycin


IFN gamma


Dendritic cells none
4.5
1.9
Dermal fibroblast
29.3
9.0





IL-4


Dendritic cells LPS
5.5
2.8
Dermal Fibroblasts
10.4
4.9





rest


Dendritic cells anti-
3.3
1.7
Neutrophils
3.5
1.2


CD40


TNFa + LPS


Monocytes rest
6.3
3.5
Neutrophils rest
3.8
2.2


Monocytes LPS
6.4
4.3
Colon
12.2
8.5


Macrophages rest
4.8
2.8
Lung
11.2
8.2


Macrophages LPS
1.1
0.9
Thymus
14.6
8.4


HUVEC none
15.9
9.2
Kidney
33.4
25.5


HUVEC starved
28.5
19.1










[0999] General_screening_panel_v1.5 Summary: Ag5041 l/Ag5043 Two experiments with two different probe and primer sets show highest expression of the CG59534-01 gene, a putative membrane glycoprotein, in cell lines derived from brain cancer and gastric cancer (CTs=24-29). Significant expression of this gene is also seen in cell lines derived from brain cancer, ovarian cancer, and gastric cancer. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of colon, ovarian, and brain cancers.


[1000] Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.


[1001] In addition, this molecule novel membrane glycoprotein is expressed at moderate to low levels in the CNS and may be a small molecule target for the treatment of neurologic diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.


[1002] Panel 4.1D Summary: Ag5041/Ag5043 Two experiments with two different probe and primer sets show highest expression of the CG59534-01 gene, a putative membrane glycoprotein, in IL-9 treated fibroblasts and the B cell line Ramos treated with ionomycin (CTs=29-30). This gene is also gene is expressed at moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_v1.5 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.



Y. NOV31a and NOV31b (CG59289-01 and CG59289-02: CRUMBS LIKE)

[1003] Expression of gene CG59289-01 and CG59289-02 was assessed using the primer-probe sets Ag3530 and Ag1932, described in Tables YA and YB. Results of the RTQ-PCR runs are shown in Tables YC, and YD.
392TABLE YAProbe Name Ag3530StartPrimersSequencesLengthPositionForward5′-gtgctgggatttcacagtacac-3′(SEQ ID NO:311)22123ProbeTET-5′-tgctacttgcctaggcaaagtcacgt-3′-TAMRA(SEQ ID NO:312)26147Reverse5′-ccagtctgtcctcgttttgtag-3′(SEQ ID NO: 313)22186


[1004]

393





TABLE YB










Probe Name Ag1932













Start


Primers
Sequences
Length
Position














Forward
5′-gagtctggggtccacagttac-3′
(SEQ ID NO:314)
21
1588





Probe
TET-5′-acctggtacccatggaccgttctgt-3′-TAMRA
(SEQ ID NO:315)
25
1623





Reverse
5′-ccatcacagagaaggtggtatt-3′
(SEQ ID NO:316)
22
1654










[1005]

394





TABLE YC










CNS_neurodegeneration_v1.0











Rel. Exp.(%) Ag3530,

Rel. Exp.(%) Ag3530,


Tissue Name
Run 210631247
Tissue Name
Run 210631247













AD 1 Hippo
23.7
Control (Path) 3
6.3




Temporal Ctx


AD 2 Hippo
52.1
Control (Path) 4
53.2




Temporal Ctx


AD 3 Hippo
10.2
AD 1 Occipital Ctx
25.3


AD 4 Hippo
24.7
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 hippo
46.0
AD 3 Occipital Ctx
10.2


AD 6 Hippo
51.8
AD 4 Occipital Ctx
12.4


Control 2 Hippo
23.2
AD 5 Occipital Ctx
2.4


Control 4 Hippo
25.9
AD 6 Occipital Ctx
18.3


Control (Path) 3
8.5
Control 1 Occipital
8.7


Hippo

Ctx


AD 1 Temporal Ctx
13.8
Control 2 Occipital
31.2




Ctx


AD 2 Temporal Ctx
20.7
Control 3 Occipital
14.5




Ctx


AD 3 Temporal Ctx
14.4
Control 4 Occipital
18.9




Ctx


AD 4 Temporal Ctx
37.6
Control (Path) 1
100.0




Occipital Ctx


AD 5 Inf Temporal
63.3
Control (Path) 2
24.7


Ctx

Occipital Ctx


AD 5 Sup Temporal
72.2
Control (Path) 3
7.2


Ctx

Occipital Ctx


AD 6 Inf Temporal
48.3
Control (Path) 4
20.3


Ctx

Occipital Ctx


AD 6 Sup Temporal
61.6
Control 1 Parietal
24.5


Ctx

Ctx


Control 1 Temporal
7.8
Control 2 Parietal
70.2


Ctx

Ctx


Control 2 Temporal
19.9
Control 3 Parietal
23.0


Ctx

Ctx


Control 3 Temporal
9.0
Control (Path) 1
79.6


Ctx

Parietal Ctx


Control 4 Temporal
6.4
Control (Path) 2
37.6


Ctx

Parietal Ctx


Control (Path) 1
39.8
Control (Path) 3
0.0


Temporal Ctx

Parietal Ctx


Control (Path) 2
35.1
Control (Path) 4
37.1


Temporal Ctx

Parietal Ctx










[1006]

395





TABLE YD










Panel 4D













Rel.
Rel.

Rel.
Rel.



Exp.(%)
Exp.(%)

Exp.(%)
Exp.(%)



Ag1932,
Ag3530,

Ag1932,
Ag3530,



Run
Run

Run
Run


Tissue Name
161561619
166446356
Tissue Name
161561619
166446356















Secondary Th1 act
0.0
0.0
HUVEC IL-1 beta
0.0
0.0


Secondary Th2 act
0.0
0.0
HUVEC IFN
0.0
0.0





gamma


Secondary Tr1 act
0.0
0.0
HUVEC TNF
0.0
0.0





alpha + IFN





gamma


Secondary Th1 rest
0.0
0.0
HUVEC TNF
0.0
0.0





alpha + IL4


Secondary Th2 rest
0.0
0.0
HUVEC IL-11
0.0
0.0


Secondary Tr1 rest
0.0
0.0
Lung
0.0
0.0





Microvascular EC





none


Primary Th1 act
1.7
0.0
Lung
0.0
0.0





Microvascular EC





TNF alpha + IL-





1 beta


Primary Th2 act
0.0
1.3
Microvascular
0.0
0.0





Dermal EC none


Primary Tr1 act
0.0
0.0
Microsvasular
0.0
0.0





Dermal EC





TNF alpha + IL-





1 beta


Primary Th1 rest
0.0
0.0
Bronchial
0.0
0.0





epithelium





TNF alpha +





IL1 beta


Primary Th2 rest
2.9
0.0
Small airway
2.3
0.0





epithelium none


Primary Tr1 rest
3.0
2.0
Small airway
0.0
0.0





epithelium





TNF alpha + IL-





1 beta


CD45RA CD4
1.5
3.5
Coronery artery
62.9
0.0


lymphocyte act


SMC rest


CD45RO CD4
0.0
0.0
Coronery artery
0.0
0.0


lymphocyte act


SMC TNF alpha +





IL-1 beta


CD8 lymphocyte
0.0
0.0
Astrocytes rest
12.9
1.2


act


Secondary CD8
0.0
0.0
Astrocytes
4.3
6.1


lymphocyte rest


TNF alpha + IL-
4.3
6.1





1 beta


Secondary CD8
1.7
0.0
KU-812 (Basophil)
36.9
7.2


lymphocyte act


rest


CD4 lymphocyte
8.9
2.4
KU-812 (Basophil)
23.0
14.2


none


PMA/ionomycin


2ry
0.0
1.0
CCD1106
0.0
0.0


Th1/Th2/Tr1_anti-


(Keratinocytes)


CD95 CH11


none


LAK cells rest
1.7
2.6
CCD1106
0.0
0.0





(Keratinocytes)





TNF alpha + IL-





1 beta


LAK cells IL-2
0.0
0.0
Liver cirrhosis
8.5
35.6


LAK cells IL-2 +
2.1
0.8
Lupus kidney
4.3
4.0


IL-12


LAK cells IL-
0.0
1.5
NCI-H292 none
0.0
0.0


2 + IFN gamma


LAK cells IL-2 +
0.7
5.7
NCI-H292 IL-4
6.4
0.0


IL-18


LAK cells
0.0
0.0
NCI-H292 IL-9
0.0
0.0


PMA/ionomycin


NK Cells IL-2 rest
0.0
0.0
NCI-H292 IL-13
0.0
0.0


Two Way MLR 3
5.8
8.0
NCI-H292 IFN
11.7
0.0


day


gamma


Two Way MLR 5
1.7
0.0
HPAEC none
0.0
0.0


day


Two Way MLR 7
0.0
0.0
HPAEC TNF
0.0
0.0


day


alpha + IL-1 beta


PBMC rest
19.5
4.5
Lung fibroblast
0.0
0.0





none


PBMC PWM
0.5
0.0
Lung fibroblast
0.0
0.0





TNF alpha + IL-1





beta


PBMC PHA-L
0.0
2.8
Lung fibroblast IL-4
0.0
0.0


Ramos (B cell)
4.0
50.3
Lung fibroblast IL-9
0.0
0.0


none


Ramos (B cell)
16.2
9.6
Lung fibroblast IL-
0.0
0.0


ionomycin


13


B lymphocytes
4.7
7.0
Lung fibroblast
0.0
1.2


PWM


IFN gamma


B lymphocytes
26.6
90.1
Dermal fibroblast
0.0
0.0


CD40L and IL-4


CCD1070 rest


EOL-1 dbcAMP
0.0
0.6
Dermal fibroblast
6.6
2.4





CCD1070 TNF





alpha


EOL-1 dbcAMP
3.2
0.0
Dermal fibroblast
0.0
0.0


PMA/ionomycin


CCD1070 IL-1





beta


Dendritic cells none
69.3
50.0
Dermal fibroblast
0.0
0.0





IFN gamma


Dendritic cells LPS
4.8
10.0
Dermal fibroblast
2.4
0.0





IL-4


Dendritic cells anti-
95.9
99.3
IBD Colitis 2
0.0
2.8


CD40


Monocytes rest
20.6
7.9
IBD Crohn's
0.0
0.0


Monocytes LPS
4.4
0.0
Colon
39.5
100.0


Macrophages rest
0.0
0.0
Lung
13.1
12.0


Macrophages LPS
0.0
0.0
Thymus
100.0
8.9


HUVEC none
0.0
0.0
Kidney
8.4
5.5


HUVEC starved
0.0
0.0










[1007] CNS_neurodegeneration_v1.0 Summary: Ag3530 This panel confirms the expression of CG59289-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment.


[1008] The CG59289-01 gene codes for Drosophila CRUMB1 (CRB1) homologue, a protein essential for establishing and maintaining epithelial polarity. In mouse, Crb1 was shown to be expressed exclusively in the eye, and the central nervous system (Ref. 1). Therefore, similar to the mouse orthologue, the CG59289-01 gene may be expressed in eye and central nervous system and may play a role in retinal and central nervous system disorders such as retinal dystrophies, Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.


[1009] Reference.


[1010] 1. den Hollander A I, Ghiani M, de Kok Y J, Wijnholds J, Ballabio A, Cremers F P, Broccoli V. (2002) Isolation of Crb1, a mouse homologue of Drosophila crumbs, and analysis of its expression pattern in eye and brain. Mech Dev 110(1-2):203-7


[1011] General_screening_panel_v1.4 Summary: Ag3530 Results from one experiment with the CG59289-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.


[1012] Panel 4D Summary: Ag3530 Highest expression of the CG59289-01 gene is seen in normal colon (CT=31). Therefore, expression of this gene may be used to distinguish colon from the other tissues on this panel. Furthermore, expression of this gene is decreased in colon samples from patients with IBD colitis and Crohn's disease relative to normal colon. Therefore, therapeutic modulation of the activity of the protein encoded by this gene may be useful in the treatment of inflammatory bowel disease.


[1013] Significant expression is also seen in dendritic cells (DC) and is upregulated in response to CD40. In addition, expression in colon may also result from dendritic cells present in these tissue. Therefore, therapeutic utilization of the protein encoded by this transcript may be important in the treatment of diseases where antigen presentation, a function of mature dendritic cells, plays an important role such as asthma, rheumatoid arthritis, IBD, and psoriasis.


[1014] Results from a second experiment with the probe primer set Ag1932 are not included. The amp plot indicates that there were experimental difficulties with this run.



Z. NOV32a (CG57111-01: PROTOCADHERIN)

[1015] Expression of gene CG57111-01 was assessed using the primer-probe sets Ag3242, Ag1012, Ag1096 and Ag704, described in Tables ZA, ZB, ZC and ZD. Results of the RTQ-PCR runs are shown in Tables ZE, ZF, ZG, ZH, ZI, ZJ, and ZK.
396TABLE ZAProbe Name Ag3242StartPrimersSequencesLengthPositionForward5′-gggaccaatgctcaaattactt-3′(SEQ ID NO:317)221038 ProbeTET-5′-tcagaaagttccacaagcatctaagga-3′-TAMRA(SEQ ID NO:318)271070Reverse5′-atgactccagtgttttcatcca-3′(SEQ ID NO:319)221108


[1016]

397





TABLE ZB










Probe Name Ag1012













Start


Primers
Sequences
Length
Position














Forward
5′-catcatcatagctgaggatggt-3′
(SEQ ID NO:320)
22
0





Probe
TET-5′-acttttgggcagtgcactctcaccat-3′-TAMRA
(SEQ ID NO:321)
26
0





Reverse
5′-agggcaattgtcattaatgtca-3′
(SEQ ID NO:322)
22
923










[1017]

398





TABLE ZC










Probe Name Ag1096













Start


Primers
Sequences
Length
Position














Forward
5′-actttggaagaggcattgct-3′
(SEQ ID NO:323)
20
2403





Probe
TET-5′-cagacagattatgggctccatcgctt3′-TAMRA
(SEQ ID NO:324)
26
2424





Reverse
5′-ctcgggataaccatgatcact-3′
(SEQ ID NO:325)
21
2463










[1018]

399





TABLE ZD










Probe Name Ag704













Start


Primers
Sequences
Length
Position














Forward
5′-agacttggggaccaatgct-3′
(SEQ ID NO:326)
19
1031





Probe
TET-5′-tcagaaagttccacaagcatctaagga-3′-TAMRA
(SEQ ID NO:327)
27
1070
271
1070





Reverse
5′-tgactccagtgtttcatcca-3′
(SEQ ID NO:328)
21
1108










[1019]

400





TABLE ZE










AI_comprehensive panel_v1.0











Rel. Exp.(%) Ag3242,

Rel. Exp.(%) Ag3242,


Tissue Name
Run 253058919
Tissue Name
Run 253058919













110967 COPD-F
28.9
112427 Match Control
55.9




Psoriasis-F


110980 COPD-F
6.7
112418 Psoriasis-M
25.7


110968 COPD-M
19.9
112723 Match Control
0.0




Psoriasis-M


110977 COPD-M
8.4
112419 Psoriasis-M
66.0


110989 Emphysema-F
49.3
112424 Match Control
42.0




Psoriasis-M


110992 Emphysema-F
22.8
112420 Psoriasis-M
44.4


110993 Emphysema-F
31.0
112425 Match Control
24.3




Psoriasis-M


110994 Emphysema-F
12.7
104689 (MF) OA Bone-
81.2




Backus


110995 Emphysema-F
25.5
104690 (MF) Adj
16.6




“Normal” Bone-Backus


110996 Emphysema-F
15.8
104691 (MF) OA
1.5




Synovium-Backus


110997 Asthma-M
7.5
104692 (BA) OA
7.4




Cartilage-Backus


111001 Asthma-F
30.4
104694 (BA) OA Bone-
56.3




Backus


111002 Asthma-F
45.4
104695 (BA) Adj
31.6




“Normal” Bone-Backus


111003 Atopic
45.1
104696 (BA) OA
0.0


Asthma-F

Synovium-Backus


111004 Atopic
22.4
104700 (SS) OA Bone-
63.7


Asthma-F

Backus


111005 Atopic
25.3
104701 (SS) Adj
63.3


Asthma-F

“Normal” Bone-Backus


111006 Atopic
13.9
104702 (SS) OA
6.1


Asthma-F

Synovium-Backus


111417 Allergy-M
15.1
117093 OA Cartilage
16.3




Rep7


112347 Allergy-M
5.0
112672 OA Bone5
13.2


112349 Normal
1.9
112673 OA Synovium5
5.4


Lung-F


112357 Normal
5.1
112674 OA Synovial
7.7


Lung-F

Fluid cells5


112354 Normal
11.6
117100 OA Cartilage
4.5


Lung-M

Rep14


112374 Crohns-F
32.5
112756 OA Bone9
17.1


112389 Match Control
14.4
112757 OA Synovium9
21.8


Crohns-F


112375 Crohns-F
36.1
112758 OA Synovial
13.3




Fluid Cells9


112732 Match Control
0.0
117125 RA Cartilage
28.1


Crohns-F

Rep2


112725 Crohns-M
45.4
113492 Bone2 RA
34.2


112387 Match Control
18.3
113493 Synovium2 RA
8.9


Crohns-M


112378 Crohns-M
3.8
113494 Syn Fluid Cells
25.7




RA


112390 Match Control
22.4
113499 Cartilage4 RA
45.1


Crohns-M


112726 Crohns-M
45.7
113500 Bone4 RA
47.3


112731 Match Control
12.6
113501 Synovium4 RA
42.6


Crohns-M


112380 Ulcer Col-F
28.3
113502 Syn Fluid
25.5




Cells4 RA


112734 Match Control
0.8
113495 Cartilage3 RA
33.7


Ulcer Col-F


112384 Ulcer Col-F
100.0
113496 Bone3 RA
38.7


112737 Match Control
28.1
113497 Synovium3 RA
18.2


Ulcer Col-F


112386 Ulcer Col-F
25.5
113498 Syn Fluid
30.8




Cells3 RA


112738 Match Control
2.1
117106 Normal
0.0


Ulcer Col-F

Cartilage Rep20


112381 Ulcer Col-M
2.3
113663 Bone3 Normal
2.8


112735 Match Control
53.6
113664 Synovium3
0.0


Ulcer Col-M

Normal


112382 Ulcer Col-M
15.3
113665 Syn Fluid
2.9




Cells3 Normal


112394 Match Control
10.2
117107 Normal
10.5


Ulcer Col-M

Cartilage Rep22


112383 Ulcer Col-M
45.4
113667 Bone4 Normal
17.2


112736 Match Control
4.0
113668 Synovium4
17.0


Ulcer Col-M

Normal


112423 Psoriasis-F
90.1
113669 Syn Fluid
36.3




Cells4 Normal










[1020]

401





TABLE ZF










CNS_neurodegeneration_v1.0















Rel.
Rel.
Rel.

Rel.
Rel.
Rel.



Exp.(%)
Exp.(%)
Exp.(%)

Exp.(%)
Exp.(%)
Exp.(%)



Ag1012,
Ag1096,
Ag3242,

Ag1012,
Ag1096,
Ag3242,



Run
Run
Run
Tissue
Run
Run
Run


Tissue Name
206989720
206231465
206533581
Name
206989720
206231465
206533581

















AD 1 Hippo
34.6
27.0
16.5
Control
1.0
0.9
1.4






(Path) 3






Temporal






Ctx


AD 2 Hippo
18.6
11.5
16.8
Control
11.2
11.8
4.9






(Path) 4






Temporal






Ctx


AD 3 Hippo
6.0
8.8
5.3
AD 1
5.0
6.2
2.9






Occipital






Ctx


AD 4 Hippo
2.6
2.0
1.9
AD 2
0.0
0.0
0.0






Occipital






Ctx






(Missing)


AD 5 hippo
44.8
46.7
36.6
AD 3
4.1
5.6
2.8






Occipital






Ctx


AD 6 Hippo
100.0
100.0
100.0
AD 4
3.8
6.3
4.1






Occipital






Ctx


Control 2
46.3
51.1
35.1
AD 5
5.7
25.0
16.8


Hippo



Occipital






Ctx


Control 4
5.6
5.3
4.0
AD 6
24.3
5.3
1.0


Hippo



Occipital






Ctx


Control
4.0
4.6
1.0
Control 1
0.2
0.8
0.3


(Path) 3



Occipital


Hippo



Ctx


AD 1
4.7
3.6
2.7
Control 2
22.1
17.1
19.5


Temporal



Occipital


Ctx



Ctx


AD 2
13.3
12.5
7.5
Control 3
3.9
3.1
3.5


Temporal



Occipital


Ctx



Ctx


AD 3
0.9
2.5
1.0
Control 4
1.0
1.4
0.8


Temporal



Occipital


Ctx



Ctx


AD 4
5.4
6.3
3.3
Control
36.9
34.6
30.1


Temporal



(Path) 1


Ctx



Occipital






Ctx


AD 5 Inf
80.7
74.7
59.5
Control
2.5
2.2
0.6


Temporal



(Path) 2


Ctx



Occipital






Ctx


AD 5
74.2
66.0
61.6
Control
1.0
0.7
0.4


SupTemporal



(Path) 3


Ctx



Occipital






Ctx


AD 6 Inf
12.1
12.2
12.2
Control
2.1
3.2
1.4


Temporal



(Path) 4


Ctx



Occipital






Ctx


AD 6 Sup
13.6
14.7
12.3
Control 1
1.3
1.3
1.4


Temporal



Parietal


Ctx



Ctx


Control 1
1.6
1.9
2.2
Control 2
20.3
21.8
19.6


Temporal



Parietal


Ctx



Ctx


Control 2
27.4
21.8
22.2
Control 3
5.9
5.9
5.7


Temporal



Parietal


Ctx



Ctx


Control 3
4.8
5.9
4.6
Control
40.3
38.7
38.7


Temporal



(Path) 1


Ctx



Parietal






Ctx


Control 4
1.3
1.7
0.9
Control
8.4
9.5
4.3


Temporal



(Path) 2


Ctx



Parietal






Ctx


Control
35.1
33.9
28.7
Control
1.4
1.4
0.5


(Path) 1



(Path) 3


Temporal



Parietal


Ctx



Ctx


Control
15.1
17.3
12.3
Control
15.0
16.8
15.5


(Path) 2



(Path) 4


Temporal



Parietal


Ctx



Ctx










[1021]

402





TABLE ZG










Panel 1.2













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag1096,
Ag1096,

Ag1096,
Ag1096,



Run
Run

Run
Run


Tissue Name
125094875
134204525
Tissue Name
125094875
134204525















Endothelial cells
0.0
0.0
Renal ca. 786-0
0.0
0.0


Heart (Fetal)
4.5
5.6
Renal ca. A498
0.0
0.0


Pancreas
0.2
0.3
Renal ca. RXF
0.1
0.1





393


Pancreatic ca.
0.0
0.0
Renal ca.
31.4
80.1


CAPAN 2


ACHN


Adrenal Gland
1.6
2.8
Renal ca. UO-
0.0
0.0





31


Thyroid
0.1
0.4
Renal ca. TK-
1.0
1.3





10


Salivary gland
3.0
4.8
Liver
1.9
5.3


Pituitary gland
2.7
6.7
Liver (fetal)
0.8
1.7


Brain (fetal)
2.1
7.9
Liver ca.
0.0
0.0





(hepatoblast)





HepG2


Brain (whole)
9.9
39.8
Lung
1.7
5.9


(amugdala)
15.0
34.2
Lung (fetal)
1.8
9.9


Brain
0.8
1.9
Lung ca. (small
0.4
1.2


(cerebellum)


cell) LX-1


Brain
39.0
73.2
Lung ca. (small
0.2
0.5


(hippocampus)


cell) NCI-H69


Brain (thalamus)
2.5
9.2
Lung ca. (s.cell
2.3
2.6





var.) SHP-77


Cerebral Cortex
27.0
56.3
Lung ca. (large
50.7
100.0





cell) NCI-H460


Spinal cord
2.2
4.8
Lung ca. (non-
0.1
0.0





sin. cell) A549


glio/astro U87-
0.1
0.2
Lung ca. (non-
5.4
4.0


MG


s.cell) NCI-





H23


glio/astro U-118-
0.1
0.2
Lung ca. (non-
15.3
33.2


MG


s.cell) HOP-62


astrocytoma
0.0
0.0
Lung ca. (non-
0.0
0.0


SW1783


s.cl) NCI-H522


neuro*; met SK-
6.9
7.3
Lung ca.
5.4
12.5


N-AS


(squam.) SW





900


astrocytoma SF-
0.0
0.0
Lung ca.
0.0
0.1


539


(squam.) NCI-





H596


astrocytoma
7.0
6.8
Mammary
0.6
2.7


SNB-75


gland


glioma SNB-19
2.4
2.2
Breast ca.*
0.0
0.0





(pl.ef) MCF-7


glioma U251
5.5
11.6
Breast ca.*
0.0
0.0





(pl.ef) MDA-





MB-231


glioma SF-295
0.0
0.0
Breast ca.* (pl.
0.9
1.1





ef) T47D


Heart
13.2
15.5
Breast ca. BT-
0.7
0.7





549


Skeletal Muscle
1.1
1.2
Breast ca.
0.0
0.0





MDA-N


Bone marrow
0.0
0.1
Ovary
0.6
0.4


Thymus
0.5
1.7
Ovarian ca.
0.5
0.3





OVCAR-3


Spleen
0.4
0.8
Ovarian ca.
0.5
0.3





OVCAR-4


Lymph node
0.2
0.2
Ovarian ca.
15.4
15.2





OVCAR-5


Colorectal
4.3
8.1
Ovarian ca.
0.4
1.2


Tissue


OVCAR-8


Stomach
3.9
8.8
Ovarian ca.
0.1
0.0





IGROV-1


Small intestine
1.9
3.7
Ovarian ca.
1.9
1.3





(ascites) SK-





OV-3


Colon ca.*
0.0
0.1
Uterus
2.2
10.6


SW480


Colon ca.*
0.1
0.2
Placenta
8.2
10.1


SW620 (SW480


met)


Colon ca. HT29
0.0
0.1
Prostate
3.4
3.5


Colon ca. HCT-
0.0
0.0
Prostate
2.6
3.5


116


(bone met)





PC-3


Colon ca. CaCo-2
0.0
0.0
Testis
1.3
2.1


Colon ca. Tissue
0.3
1.1
Melanoma
0.0
0.0


(ODO3866)


Hs688(A).T


Colon ca. HCC-
2.9
4.3
Melanoma*
0.0
0.1


2998


(met)





Hs688(B).T


Gastric ca.*
0.0
0.0
Melanoma
0.0
0.0


(liver met) NCI-


UACC-62


N87


Bladder
0.4
0.7
Melanoma
0.5
0.1





M14


Trachea
3.6
16.5
Melanoma
0.1
0.0





LOX IMVI


Kidney
13.2
2.7
Melanoma*
100.0
86.5





(met) SK-





MEL-5


Kidney (fetal)
7.2
10.3










[1022]

403





TABLE ZH










Panel 1.3D















Rel.
Rel.
Rel.

Rel.
Rel.
Rel.



Exp.(%)
Exp.(%)
Exp.(%)

Exp.(%)
Exp.(%)
Exp.(%)



Ag1012,
Ag1012,
Ag3242,

Ag1012,
Ag1012,
Ag3242,



Run
Run
Run
Tissue
Run
Run
Run


Tissue Name
157255773
165486783
165524415
Name
157255773
165486783
165524415

















Liver
0.0
0.0
0.0
Kidney
3.1
3.0
2.7


adenocarcinoma



(fetal)


Pancreas
0.1
0.7
1.0
Renal ca.
0.0
0.0
0.0






786-0


Pancreatic ca.
0.0
0.0
0.0
Renal ca.
0.5
1.3
0.0


CAPAN 2



A498


Adrenal gland
0.8
0.9
0.3
Renal ca.
0.3
1.2
0.4






RXF 393


Thyroid
0.2
0.0
0.0
Renal ca.
44.8
95.9
100.0






ACHN


Salivary gland
0.4
2.4
0.6
Renal ca.
0.0
2.5
0.0






UO-31


Pituitary gland
2.6
3.9
4.8
Renal ca.
1.1
2.4
1.1






TK-10


Brain (fetal)
6.3
11.7
11.8
Liver
0.2
1.6
1.0


Brain (whole)
11.4
37.9
40.6
Liver (fetal)
0.3
1.3
0.0


Brain (amygdala)
19.5
38.4
31.6
Liver ca.
0.0
0.0
0.0






(hepatoblast)






HepG2


Brain
0.3
3.1
3.0
Lung
4.2
3.9
4.8


(cerebellum)


Brain
100.0
78.5
76.3
Lung (fetal)
3.8
2.9
2.2


(hippocampus)


Brain (substantia
1.9
6.3
2.1
Lung ca.
0.9
0.7
3.7


nigra)



(small cell)






LX-1


Brain (thalamus)
4.7
17.0
6.3
Lung ca.
0.4
1.3
0.0






(small cell)






NCI-H69


Cerebral Cortex
34.4
40.6
27.7
Lung ca.
16.7
17.3
16.0






(s.cell var.)






SHP-77


Spinal cord
1.9
4.2
7.7
Lung ca.
8.2
51.1
46.0






(large






cell) NCI-






H460


glio/astro U87-
0.4
1.5
0.6
Lung ca.
0.0
0.0
0.0


MG



(non-sm.






cell) A549


gilo/astro U-118-
0.3
0.0
0.5
Lung ca.
3.8
6.3
8.0


MG



(non-s.cell)






NCI-H23


astrocytoma
0.0
0.0
0.0
Lung ca.
9.5
21.6
13.6


SW1783



(non-s.cell)






HOP-62


neuro*; met SK-
27.4
11.9
7.5
Lung ca.
0.0
0.0
0.0


N-AS



(non-s.cl)






NCI-H522


astrocytoma SF-
0.2
0.0
0.0
Lung ca.
8.0
19.8
18.8


539



(squam.)






SW 900


astrocytoma
12.6
15.0
8.4
Lung ca.
0.0
0.6
0.0


SNB-75



(squam.)






NCI-H596


glioma SNB-19
2.8
3.8
3.0
Mammary
0.9
0.8
1.4






gland


glioma U251
14.0
100.0
66.4
Breast ca.*
0.0
0.0
0.0






(pl.ef) MCF-7


glioma SF-295
0.0
0.0
0.6
Breast ca.*
0.0
0.0
0.0






(pl.ef)






MDA-MB-






231


Heart (fetal)
8.3
4.9
3.7
Breast ca.*
1.1
2.0
1.4






(pl.ef) T47D


Heart
1.3
2.8
1.7
Breast ca.
2.0
1.2
1.6






BT-549


Skeletal muscle
36.1
11.9
6.9
Breast ca.
0.0
0.0
0.0


(fetal)



MDA-N


Skeletal muscle
0.3
2.7
1.9
Ovary
1.1
0.0
1.5


Bone marrow
0.0
0.0
0.0
Ovarian ca.
0.4
2.1
1.4






OVCAR-3


Thymus
1.7
0.7
0.4
Ovarian ca.
0.0
0.0
0.0






OVCAR-4


Spleen
0.6
1.2
0.0
Ovarian ca.
17.7
20.9
24.8






OVCAR-5


Lymph node
0.2
0.0
0.0
Ovarian ca.
1.2
0.9
0.6






OVCAR-8


Colorectal
7.0
9.1
3.5
Ovarian ca.
0.0
0.0
0.0






IGROV-1


Stomach
1.4
5.6
2.5
Ovarian ca.*
2.0
2.2
5.4






(ascites) SK-






OV-3


Small intestine
1.0
9.4
7.2
Uterus
3.8
12.4
15.5


Colon ca. SW480
0.0
0.0
0.0
Placenta
3.5
4.6
1.1


Colon ca.*
0.5
0.0
0.0
Prostate
0.7
3.1
1.4


SW620(SW480


met)


Colon ca. HT29
0.0
0.0
0.0
Prostate ca.*
0.4
2.5
0.4






(bone






met)PC-3


Colon ca. HCT-
0.0
0.0
0.0
Testis
2.1
1.5
2.3


116


Colon ca. CaCo-2
0.4
0.0
0.0
Melanoma
0.0
0.0
0.0






Hs688(A).T


Colon ca.
0.3
0.7
0.0
Melanoma*
0.0
0.0
0.0


tissue(ODO3866)



(met)






Hs688(B).T


Colon ca. HCC-
12.4
5.1
2.1
Melanoma
0.2
0.0
0.0


2998



UACC-62


Gastric ca.*
0.0
0.0
0.0
Melanoma
0.0
1.5
1.6


(liver met) NCI-



M14


N87


Bladder
0.3
0.7
0.0
Melanoma
1.6
0.0
0.0






LOX IMVI


Trachea
9.2
7.5
9.0
Melanoma*
68.8
50.7
58.6






(met) SK-






MEL-5


Kidney
1.3
5.5
1.5
Adipose
1.1
1.2
1.5










[1023]

404





TABLE ZI










Panel 2.2











Rel. Exp.(%)

Rel. Exp.(%)



Ag3242, Run

Ag3242, Run


Tissue Name
174443348
Tissue Name
174443348













Normal Colon
4.4
Kidney Margin
1.0




(OD04348)


Colon cancer (OD06064)
1.8
Kidney malignant
0.4




cancer (OD06204B)


Colon Margin
8.9
Kidney normal adjacent
1.8


(OD06064)

tissue (OD06204E)


Colon cancer (OD06159)
2.0
Kidney Cancer
2.3




(OD04450-01)


Colon Margin
7.1
Kidney Margin
0.9


(OD06159)

(OD04450-03)


Colon cancer (OD06297-
2.4
Kidney Cancer 8120613
0.0


04)


Colon Margin
2.2
Kidney Margin 8120614
0.4


(OD06297-05)


CC Gr.2 ascend colon
0.9
Kidney Cancer 9010320
1.4


(ODO3921)


CC Margin (ODO3921)
3.8
Kidney Margin 9010321
1.3


Colon cancer metastasis
0.7
Kidney Cancer 8120607
0.8


(OD06104)


Lung Margin (OD06104)
0.0
Kidney Margin 8120608
0.2


Colon mets to lung
1.7
Normal Uterus
5.3


(OD04451-01)


Lung Margin (OD04451-
10.1
Uterine Cancer 064011
0.5


02)


Normal Prostate
0.4
Normal Thyroid
0.0


Prostate Cancer
0.3
Thyroid Cancer 064010
0.7


(OD04410)


Prostate Margin
0.0
Thyroid Cancer
0.9


(OD04410)

A302152


Normal Ovary
0.0
Thyroid Margin
0.0




A302153


Ovarian cancer
0.0
Normal Breast
0.6


(OD06283-03)


Ovarian Margin
0.0
Breast Cancer
0.0


(OD06283-07)

(OD04566)


Ovarian Cancer 064008
1.9
Breast Cancer 1024
2.1


Ovarian cancer
0.0
Breast Cancer
0.0


(OD06145)

(OD04590-01)


Ovarian Margin
0.0
Breast Cancer Mets
0.0


(OD06145)

(OD04590-03)


Ovarian cancer
0.0
Breast Cancer
0.4


(OD06455-03)

Metastasis (OD04655-




05)


Ovarian Margin
1.2
Breast Cancer 064006
0.7


(OD06455-07)


Normal Lung
2.3
Breast Cancer 9100266
0.7


Invasive poor diff. lung
1.1
Breast Margin 9100265
0.2


adeno (ODO4945-01


Lung Margin
1.6
Breast Cancer A209073
0.0


(ODO4945-03)


Lung Malignant Cancer
0.7
Breast Margin
0.0


(OD03126)

A2090734


Lung Margin (OD03126)
1.2
Breast cancer
0.4




(OD06083)


Lung Cancer
1.2
Breast cancer node
0.9


(OD05014A)

metastasis (OD06083)


Lung Margin
4.4
Normal Liver
1.3


(OD05014B)


Lung cancer (OD06081)
0.8
Liver Cancer 1026
0.3


Lung Margin (OD06081)
2.8
Liver Cancer 1025
0.0


Lung Cancer (OD04237-
0.0
Liver Cancer 6004-T
0.0


01)


Lung Margin (OD04237-
6.0
Liver Tissue 6004-N
0.0


02)


Ocular Melanoma
100.0
Liver Cancer 6005-T
2.7


Metastasis


Ocular Melanoma
0.7
Liver Tissue 6005-N
3.3


Margin (Liver)


Melanoma Metastasis
1.2
Liver Cancer 064003
7.1


Melanoma Margin
4.9
Normal Bladder
0.0


(Lung)


Normal Kidney
0.0
Bladder Cancer 1023
0.0


Kidney Ca, Nuclear
1.3
Bladder Cancer
0.3


grade 2 (OD04338)

A302173


Kidney Margin
0.4
Normal Stomach
5.8


(OD04338)


Kidney Ca Nuclear grade
0.6
Gastric Cancer 9060397
0.0


1/2 (OD04339)


Kidney Margin
1.6
Stomach Margin
2.6


(OD04339

9060396


Kidney Ca, Clear cell
0.0
Gastric Cancer 9060395
2.2


type (OD04340)


Kidney Margin
1.1
Stomach Margin
3.4


(OD04340)

9060394


Kidney Ca, Nuclear
0.0
Gastric Cancer 064005
0.3


grade 3 (OD04348)










[1024]

405





TABLE ZJ










Panel 4D












Rel. Exp.(%)
Rel. Exp.(%)
Rel. Exp.(%)
Rel. Exp.(%)



Ag1012, Run
Ag1012, Run
Ag1096, Run
Ag3242, Run


Tissue Name
157263859
164036950
160353275
164390548














Secondary Th1 act
0.0
0.0
0.0
0.0


Secondary Th2 act
0.0
0.0
0.0
0.0


Secondary Tr1 act
0.0
0.0
0.0
0.0


Secondary Th1 rest
0.0
0.0
0.0
0.0


Secondary Th2 rest
0.0
0.0
0.0
0.0


Secondary Tr1 rest
0.0
0.0
0.0
0.0


Primary Th1 act
0.0
0.0
0.0
0.0


Primary Th2 act
0.0
0.7
0.0
0.0


Primary Tr1 act
0.0
0.0
0.0
0.0


Primary Th1 rest
0.0
0.0
0.0
0.0


Primary Th2 rest
0.0
0.0
0.0
0.0


Primary Tr1 rest
0.7
0.0
0.0
0.0


CD45RA CD4
0.0
0.9
0.0
0.0


lymphocyte act


CD45RO CD4
0.0
0.0
0.0
0.0


lymphocyte act


CD8 lymphocyte act
100.0
0.0
1.3
0.0


Secondary CD8
0.0
0.0
0.7
0.0


lymphocyte rest


Secondary CD8
0.0
0.0
0.0
0.0


lymphocyte act


CD4 lymphocyte none
0.0
0.0
0.0
0.0


2ry Th1/Th2/Tr1_anti-
0.0
0.0
0.0
0.0


CD95 CH11


LAK cells rest
0.0
0.0
0.0
0.0


LAK cells IL-2
0.0
0.0
0.0
0.0


LAK cells IL-2 + IL-12
0.0
2.3
0.0
0.0


LAK cells IL-2 + IFN
0.0
0.0
0.8
0.0


gamma


LAK cells IL-2 + IL-18
0.3
0.0
0.0
0.0


LAK cells
0.0
0.0
0.0
0.0


PMA/ionomycin


NK Cells IL-2 rest
0.0
1.9
0.8
0.0


Two Way MLR 3 day
0.0
0.0
0.0
0.0


Two Way MLR 5 day
0.0
0.0
0.0
0.0


Two Way MLR 7 day
0.0
0.0
1.5
0.0


PBMC rest
0.0
0.0
0.0
0.0


PBMC PWM
0.0
0.0
0.0
0.0


PBMC PHA-L
0.0
0.0
0.0
0.0


Ramos (B cell) none
0.0
0.0
0.0
0.0


Ramos (B cell)
0.0
0.0
0.0
0.0


ionomycin


B lymphocytes PWM
0.0
0.0
0.0
0.0


B lymphocytes CD40L
0.0
0.4
0.0
0.0


and IL-4


EOL-1 dbcAMP
0.0
0.0
0.0
0.0


EOL-1 dbcAMP
0.0
0.0
0.0
0.0


PMA/ionomycin


Dendritic cells none
0.0
0.0
0.0
0.0


Dendritic cells LPS
0.0
0.0
0.0
0.0


Dendritic cells anti-
0.0
0.0
0.0
0.0


CD40


Monocytes rest
0.0
0.0
0.0
0.0


Monocytes LPS
0.0
0.0
1.7
0.0


Macrophages rest
0.0
0.0
0.0
0.0


Macrophages LPS
0.6
0.0
0.0
0.0


HUVEC none
0.7
0.0
0.0
0.0


HUVEC starved
0.0
0.0
0.0
0.0


HUVEC IL-1 beta
0.0
0.0
0.0
0.0


HUVEC IFN gamma
0.0
0.0
0.4
0.0


HUVEC TNF alpha +
0.0
0.0
0.0
0.0


IFN gamma


HUVEC TNF alpha +
0.0
0.0
2.0
0.0


IL4


HUVEC IL-11
0.0
0.0
0.0
0.0


Lung Microvascular EC
0.0
0.0
0.0
0.0


none


Lung Microvascular EC
0.0
0.0
0.0
0.0


TNF alpha + IL-1 beta


Microvascular Dermal
0.0
0.0
0.0
0.0


EC none


Microsvasular Dermal
0.0
0.0
0.0
0.0


EC TNF alpha + IL-


1 beta


Bronchial epithelium
0.0
1.1
0.0
0.0


TNF alpha + IL-1 beta


Small airway epithelium
0.9
1.2
0.0
0.0


none


Small airway epithelium
12.6
9.4
6.5
11.7


TNF alpha + IL-1 beta


Coronery artery SMC
0.0
0.0
0.7
0.0


rest


Coronery artery SMC
0.0
0.0
0.0
0.0


TNF alpha + IL-1 beta


Astrocytes rest
10.7
15.4
13.9
16.8


AstrocytesTNF alpha +
3.8
9.1
3.6
5.3


IL-1 beta


KU-812 (Basophil) rest
1.5
0.0
0.9
1.0


KU-812 (Basophil)
90.8
100.0
100.0
100.0


PMA/ionomycin


CCD1106
0.0
0.0
0.0
0.0


(Keratinocytes) none


CCD1106
0.7
0.0
0.0
0.0


(Keratinocytes)


TNF alpha + IL-1 beta


Liver cirrhosis
8.1
5.4
1.9
3.8


Lupus kidney
0.0
1.1
1.3
1.4


NCI-H292 none
44.1
58.2
42.9
48.0


NCI-H292 IL-4
21.8
19.3
14.7
14.8


NCI-H292 IL-9
40.9
60.3
40.6
36.6


NCI-H292 IL-13
5.9
7.4
12.2
7.4


NCI-H292 IFN gamma
11.3
11.8
16.8
10.9


HPAEC none
0.0
0.0
0.0
0.0


HPAEC TNF alpha +
0.0
0.0
0.0
0.0


IL-1 beta


Lung fibroblast none
0.0
0.0
0.0
1.7


Lung fibroblast TNF
0.0
0.0
0.0
0.0


alpha + IL-1 beta


Lung fibroblast IL-4
0.0
0.0
1.7
0.0


Lung fibroblast IL-9
0.0
0.0
0.0
0.0


Lung fibroblast IL-13
0.0
0.0
0.7
0.0


Lung fibroblast IFN
0.0
0.0
0.0
0.0


gamma


Dermal fibroblast
0.0
0.0
0.0
0.0


CCD1070 rest


Dermal fibroblast
0.0
0.0
0.0
0.0


CCD1070 TNF alpha


Dermal fibroblast
0.0
0.0
0.9
0.0


CCD1070 IL-1 beta


Dermal fibroblast IFN
0.0
2.1
0.0
0.0


gamma


Dermal fibroblast IL-4
0.0
0.0
0.0
0.0


IBD Colitis 2
0.0
0.5
0.8
2.6


IBD Crohn's
0.9
2.1
0.0
2.0


Colon
22.1
14.6
28.1
23.2


Lung
74.7
38.7
34.9
51.4


Thymus
23.2
27.4
35.1
28.3


Kidney
8.0
11.7
8.2
7.4










[1025]

406





TABLE ZK










Panel CNS_1











Rel. Exp.(%)

Rel. Exp.(%)



Ag1012, Run

Ag1012, Run


Tissue Name
171629312
Tissue Name
171629312













BA4 Control
29.1
BA17 PSP
1.9


BA4 Control2
52.1
BA17 PSP2
3.1


BA4
1.4
Sub Nigra Control
21.2


Alzheimer's2


BA4 Parkinson's
24.0
Sub Nigra Control2
5.3


BA4
49.7
Sub Nigra
18.9


Parkinson's2

Alzheimer's2


BA4
19.1
Sub Nigra
65.1


Huntington's

Parkinson's2


BA4
1.3
Sub Nigra
45.4


Huntington's2

Huntington's


BA4 PSP
6.2
Sub Nigra
100.0




Huntington's2


BA4 PSP2
9.7
Sub Nigra PSP2
4.7


BA4 Depression
13.0
Sub Nigra
2.9




Depression


BA4
2.4
Sub Nigra
25.2


Depression2

Depression2


BA7 Control
36.1
Glob Palladus
7.5




Control


BA7 Control2
22.8
Glob Palladus
14.2




Control2


BA7
2.4
Glob Palladus
7.1


Alzheimer's2

Alzheimer's


BA7 Parkinson's
6.9
Glob Palladus
4.7




Alzheimer's2


BA7
34.4
Glob Palladus
36.1


Parkinson's2

Parkinson's


BA7
36.6
Globa Palladus
10.5


Huntington's

Parkinson's2


BA7
32.5
Glob Palladus PSP
1.1


Huntington's2


BA7 PSP
26.4
Glob Palladus PSP2
5.4


BA7 PSP2
12.9
Glob Palladus
1.0




Depression


BA7 Depression
1.1
Temp Pole Control
16.5


BA9 Control
17.0
Temp Pole Control2
59.0


BA9 Control2
90.1
Temp Pole
1.2




Alzheimer's


BA9 Alzheimer's
0.0
Temp Pole
2.7




Alzheimer's2


BA9
2.8
Temp Pole
8.1


Alzheimer's2

Parkinson's


BA9 Parkinson's
11.8
Temp Pole
20.3




Parkinson's2


BA9
43.2
Temp Pole
30.6


Parkinson's2

Huntington's


BA9
25.5
Temp Pole PSP
1.1


Huntington's


BA9
3.7
Temp Pole PSP2
2.1


Huntington's 2


BA9 PSP
10.7
Temp Pole
1.6




Depression2


BA9 PSP2
0.0
Cing Gyr Control
64.6


BA9 Depression
3.8
Cing Gyr Control2
42.9


BA9
8.0
Cing Gyr
16.3


Depression2

Alzheimer's


BA17 Control
15.0
Cing Gyr
0.7




Alzheimer's2


BA17 Control2
24.5
Cing Gyr
17.8




Parkinson's


BA17
2.8
Cing Gyr
28.5


Alzheimer's2

Parkinson's2


BA17
13.2
Cing Gyr
68.8


Parkinson's

Huntington's


BA17
23.3
Cing Gyr
18.4


Parkinson's2

Huntington's2


BA17
15.3
Cing Gyr PSP
9.9


Huntington's


BA17
5.0
Cing Gyr PSP2
3.2


Huntington's2


BA17
1.7
Cing Gyr
3.5


Depression

Depression


BA17
19.9
Cing Gyr
10.5


Depression2

Depression2










[1026] AI_comprehensive panel_v1.0 Summary: Ag3242 Expression of the CG59985-01 gene is ubiquitous in this panel, with high expression in samples derived from patients suffering from ulcerative colitis, Crohn's disease and psoriasis (CTs=33). In addition, significant expression is also seen in samples derived from synovium, cartilage and bone of rheumatoid arthritis. Therefore, antibody or small molecule therapies designed with the protein encoded for by this gene may be useful in the treatment of inflammatory bowel diseases and rheumatoid arthritis.


[1027] CNS_neurodegeneration_v1.0 Summary: AG1012/Ag1096/Ag3242. Three experiments with three different probe and primer sets produce results that are in excellent agreement, with highest expression of the CG57448-01 gene in the hippocampus of a patient with Alzheimer's disease. No change is detected in the expression of this gene in the postmortem Alzheimer'diseased brain when compared to controls; however this panel confirms the expression of this gene in the CNS in an independent group of patients. See panel 1.2 for a discussion of utility. A third experiment with the probe and primer set Ag704 shows low/undetectable levels of expression (CTs>35). (Data not shown) The data suggest that there is a probability of a probe failure.


[1028] Panel 1.2 Summary: Ag1096/Ag3242 Two experiments with two different probe and primer sets produce results that are in excellent agreement, with highest expression of the CG57448-01 gene in cancer cell lines derived from lung cancer and melanoma (CTs=24-25). Significant levels of expression are also seen in a renal cancer cell line, ovarian cancer cell lines and brain cancer cell lines. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a diagnostic marker for the presence of these cancers. This gene encodes a protein that is homologous to cadherin, a cell-adhesion molecule. Therefore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of lung, renal and melanoma cancers.


[1029] Expression of the this gene is also high in many regions of the brain, including the amygdala, thalamus, cerebellum, and cerebral cortex, with highest expression in the hippocampus. Expression is also detected in the spinal cord. Cadherins can act as axon guidance and cell adhesion proteins, specifically during development and in the response to injury (ref 1). Therefore, manipulation of levels of this protein may be of use in inducing a compensatory synaptogenic response to neuronal death in Alzheimer's disease, Parkinson's disease, Huntingdon's disease, spinocerebellar ataxia, progressive supranuclear palsy, ALS, head trauma, stroke, or any other disease/condition associated with neuronal loss.


[1030] Among tissues with metabolic function, this gene is moderately expressed in pituitary gland, adrenal gland, thyroid, pancrease, skeletal muscle, and liver, reflecting the widespread role of cadherins in cell-cell adhesion. This expression suggests that this gene product may play a role in normal metabolic and neuroendocrine function and that dysregulated expression of this gene may contribute to metabolic diseases (such as obesity and diabetes) or neuroendocrine disorders.


[1031] References:


[1032] Ranscht B. (2000) Cadherins: molecular codes for axon guidance and synapse formation. Int. J. Dev. Neurosci. 18: 643-651.


[1033] Panel 1.3D Summary: Ag3242 Highest expression of the CG57448-01 gene is seen in a renal cancer cell line (CT=31.1). Significant expression is also seen in cell lines derived from ovarian cancer, lung cancer, brain cancer and melanoma. This is in concordance with the results in the previous panel. Please see Panel 1.2 for discussion of utility of this gene in the treatment of cancer.


[1034] As in the previous panel, this gene is also highly expressed in the central nervous system. Please see Panel 1.2 for a fuller discussion of utility of this gene in the central nervous system.


[1035] Results from a second experiment with the probe primer set Ag704 are not included. The amp plot indicates that there is high probability of a probe failure.


[1036] Panel 2.2 Summary: Ag3242 Highest expression of the CG57448-01 gene is seen in a sample derived from an ocular melanoma metastasis (CT=29). Thus, expression of this gene could be used to differentiate between this sample and other samples on this pane.


[1037] Panel 2D Summary: Ag704 Results from one experiment with the CG57448-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.


[1038] Panel 3D Summary: Ag1012 Results from one experiment with the CG57448-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.


[1039] Panel 4D Summary: Ag1096/Ag3242 Two experiments with two different probe and primer sets produce results that are in excellent agreement, with highest expression of the CG57448-01 gene in the basophil cell line (KU-812) treated with PMA/ionomycin (CTs=30-32). Significant expression is also seen in a cluster of treated and untreated samples derived from the muco-epidermoid cell line NCI-H292. Thus, this gene, which encodes a cadherin homolog, is expressed in both a cell line that is often used as a model of airway epithelium (NCI-H292) and a cell line that is a reasonable model for the inflammatory cells that contribute to various inflammatory lung diseases. This suggests that therapeutic modulation of this gene product may reduce or eliminate the symptoms of patients suffering from pathological and inflammatory lung disorders, including chronic obstructive pulmonary disease, asthma, allergy and emphysema.


[1040] Low but significant levels of expression are also seen in the samples derived from normal colon, kidney, lung and thymus. This suggests that this gene product may play a role in the homeostasis of these tissues. Therefore, therapeutic modulation of the expression or function of the gene product may be important for maintaining or restoring normal function to this organs during inflammation.


[1041] Results from a third experiment with the probe primer set Ag704 are not included. The amp plot indicates that there is a high probability of a probe failure.


[1042] Panel CNS1 Summary: Ag1012 This panel confirms the expression of the CG57448-01 gene at low levels in the brains of an independent group of individuals. Please see Panel 1.2 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.



AA. NOV33c (CG59363-03: BAB26184 LIKE)

[1043] Expression of gene CG59363-03 was assessed using the primer-probe set Ag5254, described in Table AAA.
407TABLE AAAProbe Name Ag5254StartPrimersSequencesLengthPositionForward5′-gtcggtgctgcgctt-3′(SEQ ID NO:329)15881ProbeTET-5′-cctagcctgtcagactgccttggtc-3′-TAMRA(SEQ ID NO:330)25908Reverse5′-agggccctggggaa-3′(SEQ ID NO:331)14933


[1044] CNS_neurodegeneration_v.1.0 Summary: Ag5254 Expression of the CG55966-03 gene is low/undetectable in all samples on this panel (CTs>35).


[1045] General_screening_panel_v1.5 Summary: Ag5254 Expression of the CG55966-03 gene is low/undetectable in all samples on this panel (CTs>35).


[1046] Panel 4.1D Summary: Ag5254 Expression of the CG55966-03 gene is low/undetectable in all samples on this panel (CTs>35).



AB. NOV34a 9CG59301-01: ANDROGEN RECEPTOR-LIKE)

[1047] Expression of gene CG59301-01 was assessed using the primer-probe set Ag3536, described in Table ABA. Results of the RTQ-PCR runs are shown in Tables ABB, ABC, ABD, and ABE.
408TABLE ABAProbe Name Ag3536StartPrimersSequencesLengthPositionForward5′-cagctctgcccatcttcat-3′(SEQ ID NO:332)19919ProbeTET-5′-ccagctctctggccagtgcctct-3′-TAMRA(SEQ ID NO:333)23957(SEQ ID231~"Reverse5′-gcaggtggtgacaccatcta-3′(SEQ ID NO:334)20980


[1048]

409





TABLE ABB










CNS_neurodegeneration_v1.0











Rel. Exp.(%) Ag3536,

Rel. Exp.(%) Ag3536,


Tissue Name
Run 210631621
Tissue Name
Run 210631621













AD 1 Hippo
51.1
Control (Path) 3
7.5




Temporal Ctx


AD 2 Hippo
48.3
Control (Path) 4
13.4




Temporal Ctx


AD 3 Hippo
37.4
AD 1 Occipital Ctx
4.0


AD 4 Hippo
11.5
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 hippo
44.1
AD 3 Occipital Ctx
44.4


AD 6 Hippo
15.3
AD 4 Occipital Ctx
26.1


Control 2 Hippo
54.7
AD 5 Occipital Ctx
15.2


Control 4 Hippo
21.0
AD 6 Occipital Ctx
19.6


Control (Path) 3
0.0
Control 1 Occipital
18.9


Hippo

Ctx


AD 1 Temporal Ctx
62.9
Control 2 Occipital
11.5




Ctx


AD 2 Temporal Ctx
20.4
Control 3 Occipital
70.2




Ctx


AD 3 Temporal Ctx
42.0
Control 4 Occipital
21.3




Ctx


AD 4 Temporal Ctx
38.4
Control (Path) 1
37.4




Occipital Ctx


AD 5 Inf Temporal
41.2
Control (Path) 2
25.9


Ctx

Occipital Ctx


AD 5 Sup Temporal
67.8
Control (Path) 3
10.1


Ctx

Occipital Ctx


AD 6 Inf Temporal
88.9
Control (Path) 4
0.0


Ctx

Occipital Ctx


AD 6 Sup Temporal
88.9
Control 1 Parietal
9.0


Ctx

Ctx


Control 1 Temporal
19.8
Control 2 Parietal
100.0


Ctx

Ctx


Control 2 Temporal
11.0
Control 3 Parietal
13.4


Ctx

Ctx


Control 3 Temporal
46.0
Control (Path) 1
46.0


Ctx

Parietal Ctx


Control 4 Temporal
23.7
Control (Path) 2
43.5


Ctx

Parietal Ctx


Control (Path) 1
73.7
Control (Path) 3
0.0


Temporal Ctx

Parietal Ctx


Control (Path) 2
27.2
Control (Path) 4
86.5


Temporal Ctx

Parietal Ctx










[1049]

410





TABLE ABC










General_screening_panel_v1.4











Rel. Exp.(%) Ag3536,

Rel. Exp.(%) Ag3536,


Tissue Name
Run 213391032
Tissue Name
Run 213391032













Adipose
0.0
Renal ca. TK-10
13.9


Melanoma*
1.6
Bladder
9.5


Hs688(A).T


Melanoma*
1.5
Gastric ca. (liver met.)
20.3


Hs688(B).T

NCI-N87


Melanoma* M14
0.0
Gastric ca. KATO III
3.6


Melanoma*
1.2
Colon ca. SW-948
0.9


LOXIMVI


Melanoma* SK-
5.5
Colon ca. SW480
33.9


MEL-5


Squamous cell
2.0
Colon ca.* (SW480
12.9


carcinoma SCC-4

met) SW620


Testis Pool
4.8
Colon ca. HT29
6.9


Prostate ca.* (bone
12.6
Colon ca. HCT-116
6.0


met) PC-3


Prostate Pool
15.9
Colon ca. CaCo-2
32.3


Placenta
0.0
Colon cancer tissue
1.7


Uterus Pool
1.1
Colon ca. SW1116
1.5


Ovarian ca. OVCAR-3
4.7
Colon ca. Colo-205
0.0


Ovarian ca. SK-OV-3
82.4
Colon ca. SW-48
1.3


Ovarian ca. OVCAR-4
2.5
Colon Pool
1.5


Ovarian ca. OVCAR-5
29.5
Small Intestine Pool
17.3


Ovarian ca. IGROV-1
15.5
Stomach Pool
2.9


Ovarian ca. OVCAR-8
4.9
Bone Marrow Pool
4.1


Ovary
0.0
Fetal Heart
4.1


Breast ca. MCF-7
35.8
Heart Pool
4.1


Breast ca. MDA-
4.5
Lymph Node Pool
9.8


MB-231


Breast ca. BT 549
12.1
Fetal Skeletal Muscle
3.0


Breast ca. T47D
87.1
Skeletal Muscle Pool
4.9


Breast ca. MDA-N
10.2
Spleen Pool
4.2


Breast Pool
2.9
Thymus Pool
4.3


Trachea
2.7
CNS cancer (glio/astro)
2.4




U87-MG


Lung
3.2
CNS cancer (glio/astro)
14.2




U-118-MG


Fetal Lung
1.4
CNS cancer (neuro; met)
0.0




SK-N-AS


Lung ca. NCI-N417
0.0
CNS cancer (astro) SF-
3.7




539


Lung ca. LX-1
28.3
CNS cancer (astro)
18.9




SNB-75


Lung ca. NCI-H146
3.6
CNS cancer (glio) SNB-
11.7




19


Lung ca. SHP-77
4.3
CNS cancer (glio) SF-
15.0




295


Lung ca. A549
2.5
Brain (Amygdala) Pool
3.5


Lung ca. NCI-H526
0.0
Brain (cerebellum)
33.7


Lung ca. NCI-H23
100.0
Brain (fetal)
8.9


Lung ca. NCI-H460
8.2
Brain (Hippocampus)
5.8




Pool


Lung ca. HOP-62
3.8
Cerebral Cortex Pool
4.1


Lung ca. NCI-H522
26.2
Brain (Substantia nigra)
4.5




Pool


Liver
0.0
Brain (Thalamus) Pool
5.0


Fetal Liver
3.4
Brain (whole)
4.8


Liver ca. HepG2
0.9
Spinal Cord Pool
0.0


Kidney Pool
7.3
Adrenal Gland
1.2


Fetal Kidney
6.7
Pituitary gland Pool
1.3


Renal ca. 786-0
9.6
Salivary Gland
0.9


Renal ca. A498
4.6
Thyroid (female)
1.1


Renal ca. ACHN
4.3
Pancreatic ca. CAPAN2
2.5


Renal ca. UO-31
11.2
Pancreas Pool
3.6










[1050]

411





TABLE ABD










Panel 2.2











Rel. Exp.(%)

Rel. Exp.(%)



Ag3536, Run

Ag3536, Run


Tissue Name
173761868
Tissue Name
173761868













Normal Colon
0.0
Kidney Margin
11.9




(OD04348)


Colon cancer (OD06064)
0.0
Kidney malignant
36.6




cancer (OD06204B)


Colon Margin
0.0
Kidney normal adjacent
0.0


(OD06064)

tissue (OD06204E)


Colon cancer (OD06159)
0.0
Kidney Cancer
10.5




(OD04450-01)


Colon Margin
0.0
Kidney Margin
10.7


(OD06159)

(OD04450-03)


Colon cancer (OD06297-
0.0
Kidney Cancer 8120613
10.7


04)


Colon Margin
0.0
Kidney Margin 8120614
0.0


(OD06297-05)


CC Gr.2 ascend colon
0.0
Kidney Cancer 9010320
0.0


(ODO3921)


CC Margin (ODO3921)
0.0
Kidney Margin 9010321
0.0


Colon cancer metastasis
0.0
Kidney Cancer 8120607
0.0


(OD06104)


Lung Margin (OD06104)
0.0
Kidney Margin 8120608
0.0


Colon mets to lung
0.0
Normal Uterus
0.0


(OD04451-01)


Lung Margin (OD04451-
4.5
Uterine Cancer 064011
9.7


02)


Normal Prostate
23.3
Normal Thyroid
0.0


Prostate Cancer
0.0
Thyroid Cancer 064010
0.0


(OD04410)


Prostate Margin
32.1
Thyroid Cancer
0.0


(OD04410)

A302152


Normal Ovary
11.7
Thyroid Margin
0.0




A302153


Ovarian cancer
9.3
Normal Breast
0.0


(OD06283-03)


Ovarian Margin
0.0
Breast Cancer
3.3


(OD06283-07)

(OD04566)


Ovarian Cancer 064008
6.4
Breast Cancer 1024
39.0


Ovarian cancer
0.0
Breast Cancer
50.3


(OD06145)

(OD04590-01)


Ovarian Margin
0.0
Breast Cancer Mets
42.9


(OD06145)

(OD04590-03)


Ovarian cancer
9.3
Breast Cancer
100.0


(OD06455-03)

Metastasis (OD04655-




05)


Ovarian Margin
5.8
Breast Cancer 064006
11.8


(OD06455-07)


Normal Lung
0.0
Breast Cancer 9100266
3.9


Invasive poor diff. lung
0.0
Breast Margin 9100265
0.0


adeno (ODO4945-01


Lung Margin
0.0
Breast Cancer A209073
0.0


(ODO4945-03)


Lung Malignant Cancer
0.0
Breast Margin
59.5


(OD03126)

A2090734


Lung Margin (OD03126)
11.4
Breast cancer
25.3




(OD06083)


Lung Cancer
8.4
Breast cancer node
76.8


(OD05014A)

metastasis (OD06083)


Lung Margin
0.0
Normal Liver
0.0


(OD05014B)


Lung cancer (OD06081)
0.0
Liver Cancer 1026
0.0


Lung Margin (OD06081)
0.0
Liver Cancer 1025
11.0


Lung Cancer (OD04237-
0.0
Liver Cancer 6004-T
18.8


01)


Lung Margin (OD04237-
0.0
Liver Tissue 6004-N
0.0


02)


Ocular Melanoma
7.3
Liver Cancer 6005-T
12.8


Metastasis


Ocular Melanoma
0.0
Liver Tissue 6005-N
0.0


Margin (Liver)


Melanoma Metastasis
0.0
Liver Cancer 064003
0.0


Melanoma Margin
0.0
Normal Bladder
0.0


(Lung)


Normal Kidney
0.0
Bladder Cancer 1023
0.0


Kidney Ca, Nuclear
0.0
Bladder Cancer
0.0


grade 2 (OD04338)

A302173


Kidney Margin
7.9
Normal Stomach
0.0


(OD04338)


Kidney Ca Nuclear grade
24.3
Gastric Cancer 9060397
0.0


1/2 (OD04339)


Kidney Margin
7.1
Stomach Margin
0.0


(OD04339)

9060396


Kidney Ca, Clear cell
0.0
Gastric Cancer 9060395
25.0


type (OD04340)


Kidney Margin
0.0
Stomach Margin
0.0


(OD04340)

9060394


Kidney Ca, Nuclear
0.0
Gastric Cancer 064005
11.5


grade 3 (OD04348)










[1051]

412





TABLE ABE










Panel 4D











Rel. Exp.(%)

Rel. Exp.(%)



Ag3536, Run

Ag3536, Run


Tissue Name
166444751
Tissue Name
166444751













Secondary Th1 act
2.2
HUVEC IL-1 beta
0.0


Secondary Th2 act
0.0
HUVEC IFN gamma
0.0


Secondary Tr1 act
0.0
HUVEC TNF alpha + IFN
2.3




gamma


Secondary Th1 rest
0.5
HUVEC TNF alpha + IL4
0.9


Secondary Th2 rest
0.0
HUVEC IL-11
2.8


Secondary Tr1 rest
3.7
Lung Microvascular EC
7.6




none


Primary Th1 act
0.0
Lung Microvascular EC
1.9




TNF alpha + IL-1 beta


Primary Th2 act
5.8
Microvascular Dermal EC
4.8




none


Primary Tr1 act
0.8
Microvascular Dermal EC
1.0




TNF alpha + IL-1 beta


Primary Th1 rest
5.1
Bronchial epithelium
9.7




TNF alpha + IL1 beta


Primary Th2 rest
6.3
Small airway epithelium
1.2




none


Primary Tr1 rest
4.8
Small airway epithelium
6.3




TNF alpha + IL-1 beta


CD45RA CD4
0.0
Coronery artery SMC rest
1.1


lymphocyte act


CD45RO CD4
2.5
Coronery artery SMC
1.0


lymphocyte act

TNF alpha + IL-1 beta


CD8 lymphocyte act
1.0
Astrocytes rest
5.1


Secondary CD8
0.0
Astrocytes TNF alpha + IL-
17.3


lymphocyte rest

1 beta


Secondary CD8
0.0
KU-812 (Basophil) rest
0.0


lymphocyte act


CD4 lymphocyte none
0.7
KU-812 (Basophil)
0.0




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
1.2
CCD1106 (Keratinocytes)
4.0


CD95 CH11

none


LAK cells rest
0.0
CCD1106 (Keratinocytes)
14.7




TNF alpha + IL-1 beta


LAK cells IL-2
5.0
Liver cirrhosis
33.0


LAK cells IL-2 + IL-12
4.1
Lupus kidney
10.0


LAK cells IL-2 + IFN
8.4
NCI-H292 none
2.0


gamma


LAK cells IL-2 + IL-18
4.5
NCI-H292 IL-4
3.8


LAK cells
1.3
NCI-H292 IL-9
8.1


PMA/ionomycin


NK Cells IL-2 rest
3.8
NCI-H292 IL-13
10.3


Two Way MLR 3 day
2.0
NCI-H292 IFN gamma
5.0


Two Way MLR 5 day
1.2
HPAEC none
5.2


Two Way MLR 7 day
1.2
HPAEC TNF alpha + IL-1
3.6




beta


PBMC rest
0.0
Lung fibroblast none
8.8


PBMC PWM
2.4
Lung fibroblast TNF
2.6




alpha + IL-1 beta


PBMC PHA-L
0.0
Lung fibroblast IL-4
3.3


Ramos (B cell) none
0.0
Lung fibroblast IL-9
1.1


Ramos (B cell)
0.0
Lung fibroblast IL-13
0.0


ionomycin


B lymphocytes PWM
1.1
Lung fibroblast IFN
0.0




gamma


B lymphocytes CD40L
2.7
Dermal fibroblast
3.4


and IL-4

CCD1070 rest


EOL-1 dbcAMP
0.0
Dermal fibroblast
9.7




CCD1070 TNF alpha


EOL-1 dbcAMP
1.9
Dermal fibroblast
2.6


PMA/ionomycin

CCD1070 IL-1 beta


Dendritic cells none
0.0
Dermal fibroblast IFN
3.1




gamma


Dendritic cells LPS
0.0
Dermal fibroblast IL-4
0.0


Dendritic cells anti-
0.8
IBD Colitis 2
1.0


CD40


Monocytes rest
0.0
IBD Crohn's
0.0


Monocytes LPS
1.8
Colon
100.0


Macrophages rest
1.9
Lung
23.8


Macrophages LPS
0.9
Thymus
4.6


HUVEC none
6.3
Kidney
12.7


HUVEC starved
4.5










[1052] CNS_neurodegeneration_v.1.0 Summary: Ag3536 This panel confirms the expression of the CG59301-01 gene at low levels in the brain in an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.


[1053] General_screening_panel_v.1.4 Summary: Ag3536 Highest expression of the CG59301-01 gene is detected in one of the lung cancer cell line NCI-H23 (CT=30.8). In addition, high expression of this gene is also detected in a breast cancer cell line T47D and ovarian cancer cell line SK-OV-3 (CTs=31). Therefore, expression of this gene can be use to distinguish these samples from other samples used in this panel and as marker in detection of these cancer. Also, significant expression of this gene is seen in CNS cancer, colon cancer, gastric cancer, lung cancer, breast cancer, renal cancer and prostate cancer cell lines. Therefore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of these cancer.


[1054] Low expression of this gene is also observed in samples derived from prostate, kidney and bladder. Therefore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of disease associated with these tissues.


[1055] This gene is expressed at low to moderate levels in cerebellum, hippocampus, and fetal brain (CTs=32-35). Therefore, this gene may play a role in central nervous system disorders such as, Parkinson's disease, epilepsy, seizure, ataxia, autism, schizophrenia and depression.


[1056] Panel 2.2 Summary: Ag3536 Significant expression of the CG59301-01 gene is seen in two of the breast cancer metastasis samples in this panel (CTs=34-34.5). Therefore, expression of this gene may be used to distinguish breast cancers from the other samples on this panel. Furthermore, therapeutic modulation of the activity of this gene product may be beneficial in the treatment of breast cancer.


[1057] Panel 4D Summary: Ag3536 Highest expression of CG59301-01 is detected in colon (CT=30.83). Therefore, expression of this gene may be used to distinguish colon from the other tissues on this panel. Furthermore, expression of this gene is decreased in colon samples from patients with IBD colitis and Crohn's disease (CT>35) relative to normal colon. Therefore, therapeutic modulation of the this gene product may be useful in the treatment of inflammatory bowel disease.


[1058] Low to moderate expression of this gene is also seen samples derived from lung, activated and resting primary Th2, IL-2+IFN gamma treated LAK cells, HUVEC, lung microvascular EC, TNFalpha+IL1beta treated bronchial epithelium, TNFalpha+IL1beta treated small airway epithelium, TNFalpha+IL-1beta treated astrocytes, TNFalpha+IL-1beta treated CCF1106 (keratinocytes), lung fibroblast, TNF alpha treated dermal fibroblast CCD1070 cells and in liver cirrhosis samples. Therefore, therapeutic modulation of this gene or its protein product may be beneficial in the treatment of general autoimmunity, allergies, asthma, psoriasis and emphysema.


[1059] Panel CNS1 Summary: Ag3536 Expression of this gene is low/undetectable (CTs>35) across all of the samples on this panel.



AC. NOV35a (CG59525-01: CARCINOEMBRYONIC ANTIGEN CGM1)

[1060] Expression of gene CG59525-01 was assessed using the primer-probe set Ag3457, described in Table ACA. Results of the RTQ-PCR runs are shown in Tables ACB, and ACC.
413TABLE ACAProbe Name Ag3457StartPrimersSequencesLengthPositionForward5′-tcccatctatgaggaattgcta-3′(SEQ ID NO:335)22703ProbeTET-5′-ccatgacacaaacatttactgctggg-3′-TAMRA(SEQ ID NO:336)26727Reverse5′-aagaaaccacatctgctttgtg-3′(SEQ ID NO:337)22758


[1061]

414





TABLE ACB










General_screening_panel_v1.4











Rel. Exp.(%) Ag3457,

Rel. Exp.(%) Ag3457,


Tissue Name
Run 217044328
Tissue Name
Run 217044328













Adipose
0.0
Renal ca. TK-10
0.0


Melanoma*
0.0
Bladder
0.0


Hs688(A).T


Melanoma*
0.0
Gastric ca. (liver met.)
0.0


Hs688(B).T

NCI-N87


Melanoma* M14
0.0
Gastric ca. KATO III
4.3


Melanoma*
0.0
Colon ca. SW-948
0.0


LOXIMVI


Melanoma* SK-
0.0
Colon ca. SW480
100.0


MEL-5


Squamous cell
0.0
Colon ca.* (SW480
11.7


carcinoma SCC-4

met) SW620


Testis Pool
5.6
Colon ca. HT29
0.0


Prostate ca.* (bone
0.0
Colon ca. HCT-116
0.0


met) PC-3


Prostate Pool
0.0
Colon ca. CaCo-2
0.0


Placenta
0.0
Colon cancer tissue
13.5


Uterus Pool
0.0
Colon ca. SW1116
0.0


Ovarian ca. OVCAR-3
0.0
Colon ca. Colo-205
0.0


Ovarian ca. SK-OV-3
0.0
Colon ca. SW-48
0.0


Ovarian ca. OVCAR-4
0.0
Colon Pool
10.2


Ovarian ca. OVCAR-5
0.0
Small Intestine Pool
0.0


Ovarian ca. IGROV-1
0.0
Stomach Pool
0.0


Ovarian ca. OVCAR-8
0.0
Bone Marrow Pool
4.8


Ovary
0.0
Fetal Heart
5.3


Breast ca. MCF-7
0.0
Heart Pool
0.0


Breast ca. MDA-
0.0
Lymph Node Pool
8.4


MB-231


Breast ca. BT 549
0.0
Fetal Skeletal Muscle
0.0


Breast ca. T47D
16.0
Skeletal Muscle Pool
0.0


Breast ca. MDA-N
5.3
Spleen Pool
20.7


Breast Pool
21.3
Thymus Pool
6.5


Trachea
0.0
CNS cancer (glio/astro)
0.0




U87-MG


Lung
6.1
CNS cancer (glio/astro)
4.8




U-118-MG


Fetal Lung
15.5
CNS cancer (neuro;met)
0.0




SK-N-AS


Lung ca. NCI-N417
0.0
CNS cancer (astro) SF-
0.0




539


Lung ca. LX-1
24.0
CNS cancer (astro)
0.0




SNB-75


Lung ca. NCI-H146
0.0
CNS cancer (glio) SNB-
0.0




19


Lung ca. SHP-77
5.1
CNS cancer (glio) SF-
0.0




295


Lung ca. A549
0.0
Brain (Amygdala) Pool
0.0


Lung ca. NCI-H526
0.0
Brain (cerebellum)
0.0


Lung ca. NCI-H23
0.0
Brain (fetal)
3.4


Lung ca. NCI-H460
0.0
Brain (Hippocampus)
4.0




Pool


Lung ca. HOP-62
0.0
Cerebral Cortex Pool
17.3


Lung ca. NCI-H522
0.0
Brain (Substantia nigra)
0.0




Pool


Liver
0.0
Brain (Thalamus) Pool
0.0


Fetal Liver
10.7
Brain (whole)
0.0


Liver ca. HepG2
0.0
Spinal Cord Pool
10.6


Kidney Pool
6.7
Adrenal Gland
0.0


Fetal Kidney
4.6
Pituitary gland Pool
0.0


Renal ca.786-0
0.0
Salivary Gland
0.0


Renal ca. A498
0.0
Thyroid (female)
0.0


Renal ca. ACHN
0.0
Pancreatic ca. CAPAN2
0.0


Renal ca. UO-31
0.0
Pancreas Pool
18.3










[1062]

415





TABLE ACC










Panel 4D











Rel. Exp.(%)

Rel. Exp.(%)



Ag3457, Run

Ag3457, Run


Tissue Name
166417095
Tissue Name
166417095













Secondary Th1 act
100.0
HUVEC IL-1 beta
0.0


Secondary Th2 act
24.0
HUVEC IFN gamma
0.0


Secondary Tr1 act
60.3
HUVEC TNF alpha + IFN
0.0




gamma


Secondary Th1 rest
76.8
HUVEC TNF alpha + IL4
0.0


Secondary Th2 rest
55.1
HUVEC IL-11
0.0


Secondary Tr1 rest
57.4
Lung Microvascular EC
8.7




none


Primary Th1 act
11.3
Lung Microvascular EC
1.2




TNF alpha + IL-1 beta


Primary Th2 act
28.1
Microvascular Dermal EC
6.0




none


Primary Tr1 act
44.4
Microsvasular Dermal EC
1.4




TNF alpha + IL-1 beta


Primary Th1 rest
96.6
Bronchial epithelium
0.0




TNF alpha + IL1 beta


Primary Th2 rest
52.9
Small airway epithelium
0.0




none


Primary Tr1 rest
26.6
Small airway epithelium
0.0




TNF alpha + IL-1 beta


CD45RA CD4
6.6
Coronery artery SMC rest
0.0


lymphocyte act


CD45RO CD4
36.6
Coronery artery SMC
0.0


lymphocyte act

TNF alpha + IL-1 beta


CD8 lymphocyte act
8.6
Astrocytes rest
0.0


Secondary CD8
10.7
Astrocytes TNF alpha + IL-
0.0


lymphocyte rest

1 beta


Secondary CD8
27.0
KU-812 (Basophil) rest
0.0


lymphocyte act


CD4 lymphocyte none
24.5
KU-812 (Basophil)
0.0




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
33.2
CCD1106 (Keratinocytes)
0.0


CD95 CH11

none


LAK cells rest
7.6
CCD1106 (Keratinocytes)
0.0




TNF alpha + IL-1 beta


LAK cells IL-2
24.0
Liver cirrhosis
4.4


LAK cells IL-2 + IL-12
18.6
Lupus kidney
0.0


LAK cells IL-2 + IFN
22.2
NCI-H292 none
0.0


gamma


LAK cells IL-2 + IL-18
12.3
NCI-H292 IL-4
0.0


LAK cells
8.7
NCI-H292 IL-9
0.0


PMA/ionomycin


NK Cells IL-2 rest
12.8
NCI-H292 IL-13
0.0


Two Way MLR 3 day
11.8
NCI-H292 IFN gamma
0.0


Two Way MLR 5 day
1.0
HPAEC none
0.0


Two Way MLR 7 day
10.7
HPAEC TNF alpha + IL-1
0.0




beta


PBMC rest
14.3
Lung fibroblast none
0.0


PBMC PWM
6.4
Lung fibroblast TNF
0.0




alpha + IL-1 beta


PBMC PHA-L
1.0
Lung fibroblast IL-4
0.0


Ramos (B cell) none
7.3
Lung fibroblast IL-9
0.0


Ramos (B cell)
6.4
Lung fibroblast IL-13
0.0


ionomycin


B lymphocytes PWM
43.5
Lung fibroblast IFN
0.0




gamma


B lymphocytes CD40L
52.9
Dermal fibroblast
0.0


and IL-4

CCD1070 rest


EOL-1 dbcAMP
28.9
Dermal fibroblast
54.3




CCD1070 TNF alpha


EOL-1 dbcAMP
21.5
Dermal fibroblast
0.0


PMA/ionomycin

CCD1070 IL-1 beta


Dendritic cells none
15.5
Dermal fibroblast IFN
0.0




gamma


Dendritic cells LPS
4.0
Dermal fibroblast IL-4
0.0


Dendritic cells anti-
31.2
IBD Colitis 2
2.9


CD40


Monocytes rest
16.0
IBD Crohn's
0.0


Monocytes LPS
0.8
Colon
11.3


Macrophages rest
17.7
Lung
11.1


Macrophages LPS
8.5
Thymus
0.8


HUVEC none
0.0
Kidney
15.4


HUVEC starved
0.0










[1063] CNS_neurodegeneration_v1.0 Summary: Ag3457 Expression of CG59525-01 gene is low/undetectable (CTs>34.5) across all of the samples on this panel.


[1064] General_screening_panel_v1.4 Summary: Ag3457 Significant expression of CG59525-01 gene is seen exclusively in a colon cancer cell line (CT=34.02). Therefore, expression of this gene may be used to distinguish colon cancers from the other samples on this panel. Furthermore, therapeutic modulation of the activity of the protein encoded by this gene may be beneficial in the treatment of colon cancer.


[1065] Panel 4D Summary: Ag3457 Low to moderate expression of CG59525-01 gene is detected in both resting and activated, primary and secondary Th1, Th2, Tr1 samples, activated secondary CD8 lymphocyte and 2ry Th1/Th2/Tr1_anti-CD95 CH11. In addition, this gene is down-regulated in activated primary Th1 cells (CT=35) as compared to resting primary Th1 cells (CT=32). Therefore, this gene may be important in regulation of T cell activation or participate in the function(s) of these T cells. Therapeutics designed with the protein encoded for by this transcript could be important in regulating T cell function and treating T cell mediated diseases such as asthma, arthritis, psoriasis, IBD, and systemic lupus erythematosus.


[1066] CG59525-01 gene codes for a carcinoembryonic antigen-related cell adhesion molecule (CEACAM). CEACAM1, a related protein, has been shown to regulate early maturation and activation of dentritic cells, thereby facilitating priming and polarization of T cell responses (Ref. 1). Low to moderate expression of this gene is also detected in untreated dendritic cells (CT=34) and anti-CD40 treated cells (CT=33). Thus, the protein encoded by this transcript may be important in dendritic cell differentiation and activation and also, in priming and polarization of T cell responses. Therefore, therapeutics designed with the protein encoded by this transcript could be important for the treatment of asthma, emphysema, inflammatory bowel disease, arthritis and psoriasis.


[1067] Expression of this gene is stimulated in IL-2, IL-2+IL12, IL-2+IFN gamma treated LAK cells, PWM/CD40L and IL-4 treated B lymphocytes, anti-CD40 treated dendritic cells, and CCD1070 TNF alpha treated dermal fibroblast. Therefore, therapeutic modulation of this gene or its protein product may be beneficial in the treatment of general autoimmunity, psoriasis and emphysema.


[1068] References.


[1069] 1. Kammerer R, Stober D, Singer B B, Obrink B, Reimann J. (2001) Carcinoembryonic antigen-related cell adhesion molecule 1 on murine dendritic cells is a potent regulator of T cell stimulation. J Immunol Jun. 1, 2001; 166(11 ):6537-44



AD. NOV36a (CG59484-01: TGF-BETA RESISTANCE-ASSOCIATED PROTEIN)

[1070] Expression of gene CG59484-01 was assessed using the primer-probe set Ag3448, described in Table ADA. Results of the RTQ-PCR runs are shown in Tables ADB, ADC and ADD.
416TABLE ADAProbe Name Ag3448StartPrimersSequencesLengthPositionForward5′-cagaacactccgtggtcatc-3′(SEQ ID NO:338)201390ProbeTET-5′-tcacatgtttgctatatcctcatcagg-3′-TAMRA(SEQ ID NO:339)211419Reverse5′-tttgatxataxxgagxtgaga-3′(SEQ ID NO:340)211446


[1071]

417





TABLE ADB










CNS_neurodegeneration_v1.0











Rel. Exp.(%) Ag3448,

Rel. Exp.(%) Ag3448,


Tissue Name
Run 210375137
Tissue Name
Run 210375137













AD 1 Hippo
8.1
Control (Path) 3
3.2




Temporal Ctx


AD 2 Hippo
23.7
Control (Path) 4
23.0




Temporal Ctx


AD 3 Hippo
4.4
AD 1 Occipital Ctx
9.2


AD 4 Hippo
3.8
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 Hippo
96.6
AD 3 Occipital Ctx
3.0


AD 6 Hippo
52.1
AD 4 Occipital Ctx
13.3


Control 2 Hippo
19.8
AD 5 Occipital Ctx
38.2


Control 4 Hippo
5.8
AD 6 Occipital Ctx
13.1


Control (Path) 3
4.3
Control 1 Occipital
1.5


Hippo

Ctx


AD 1 Temporal Ctx
9.9
Control 2 Occipital
66.0




Ctx


AD 2 Temporal Ctx
25.2
Control 3 Occipital
9.2




Ctx


AD 3 Temporal Ctx
3.8
Control 4 Occipital
4.6




Ctx


AD 4 Temporal Ctx
1.3
Control (Path) 1
79.6




Occipital Ctx


AD 5 Inf Temporal
100.0
Control (Path) 2
8.5


Ctx

Occipital Ctx


AD 5 Sup Temporal
41.8
Control (Path) 3
1.9


Ctx

Occipital Ctx


AD 6 Inf Temporal
54.3
Control (Path) 4
12.9


Ctx

Occipital Ctx


AD 6 Sup Temporal
50.0
Control 1 Parietal
3.6


Ctx

Ctx


Control 1 Temporal
3.3
Control 2 Parietal
36.3


Ctx

Ctx


Control 2 Temporal
45.1
Control 3 Parietal
14.9


Ctx

Ctx


Control 3 Temporal
7.6
Control (Path) 1
78.5


Ctx

Parietal Ctx


Control 3 Temporal
6.3
Control (Path) 2
18.3


Ctx

Parietal Ctx


Control (Path) 1
59.5
Control (Path) 3
2.1


Temporal Ctx

Parietal Ctx


Control (Path) 2
32.3
Control (Path) 4
35.1


Temporal Ctx

Parietal Ctx










[1072]

418





TABLE ADC










General_screening_panel_v1.4











Rel. Exp.(%) Ag3448,

Rel. Exp.(%) Ag3448,


Tissue Name
Run 217044206
Tissue Name
Run 217044206













Adipose
2.2
Renal ca.TK-10
3.1


Melanoma*
3.6
Bladder
5.2


Hs688(A).T


Melanoma*
4.6
Gastric ca. (liver met.)
3.5


Hs688(B).T

NCI-N87


Melanoma* M14
2.8
Gastric ca. KATO III
6.7


Melanoma*
2.7
Colon ca. SW-948
0.7


LOXIMVI


Melanoma* SK-
6.1
Colon ca. SW480
1.8


MEL-5


Squamous cell
1.3
Colon ca.* (SW480
2.1


carcinoma SCC-4

met) SW620


Testis Pool
2.6
Colon ca. HT29
1.4


Prostate ca.* (bone
9.0
Colon ca. HCT-116
5.5


met) PC-3


Prostate Pool
2.5
Colon ca. CaCo-2
2.0


Placenta
1.2
Colon cancer tissue
2.7


Uterus Pool
1.8
Colon ca. SW1116
0.7


Ovarian ca. OVCAR-3
4.9
Colon ca. Colo-205
0.5


Ovarian ca. SK-OV-3
5.8
Colon ca. SW-48
0.6


Ovarian ca. OVCAR-4
0.6
Colon Pool
100.0


Ovarian ca. OVCAR-5
2.6
Small Intestine Pool
5.1


Ovarian ca. IGROV-1
1.0
Stomach Pool
2.9


Ovarian ca. OVCAR-8
0.9
Bone Marrow Pool
2.7


Ovary
2.5
Fetal Heart
2.8


Breast ca. MCF-7
3.2
Heart Pool
2.3


Breast ca. MDA-
3.9
Lymph Node Pool
5.5


MB-231


Breast ca. BT 549
7.1
Fetal Skeletal Muscle
1.3


Breast ca. T47D
5.6
Skeletal Muscle Pool
3.0


Breast ca. MDA-N
1.4
Spleen Pool
5.8


Breast Pool
5.0
Thymus Pool
6.5


Trachea
3.8
CNS cancer (glio/astro)
3.0




U87-MG


Lung
1.0
CNS cancer (glio/astro)
17.7




U-118-MG


Fetal Lung
7.0
CNS cancer (neuro; met)
4.8




SK-N-AS


Lung ca. NCI-N417
1.0
CNS cancer (astro) SF-
2.3




539


Lung ca. LX-1
2.0
CNS cancer (astro)
9.2




SNB-75


Lung ca. NCI-H146
4.1
CNS cancer (glio) SNB-
1.1




19


Lung ca. SHP-77
7.8
CNS cancer (glio) SF-
10.4




295


Lung ca. A549
4.5
Brain (Amygdala) Pool
8.0


Lung ca. NCI-H526
1.7
Brain (cerebellum)
5.4


Lung ca. NCI-H23
5.6
Brain (fetal)
10.5


Lung ca. NCI-H460
2.6
Brain (Hippocampus)
9.0




Pool


Lung ca. HOP-62
1.5
Cerebral Cortex Pool
11.4


Lung ca. NCI-H522
4.7
Brain (Substantia nigra)
9.4




Pool


Liver
0.5
Brain (Thalamus) Pool
15.4


Fetal Liver
5.6
Brain (whole)
14.5


Liver ca. HepG2
0.9
Spinal Cord Pool
4.8


Kidney Pool
8.6
Adrenal Gland
4.7


Fetal Kidney
3.3
Pituitary gland Pool
2.4


Renal ca. 786-0
3.2
Salivary Gland
1.4


Renal ca. A498
0.7
Thyroid (female)
1.5


Renal ca. ACHN
1.8
Pancreatic ca. CAPAN2
2.5


Renal ca. UO-31
3.7
Pancreas Pool
5.1










[1073]

419





TABLE ADD










Panel 4D











Rel. Exp.(%)

Rel. Exp.(%)



Ag3448, Run

Ag3448, Run


Tissue Name
166397206
Tissue Name
166397206













Secondary Th1 act
29.9
HUVEC IL-1 beta
8.7


Secondary Th2 act
30.4
HUVEC IFN gamma
13.2


Secondary Tr1 act
48.6
HUVEC TNF alpha + IFN
7.1




gamma


Secondary Th1 rest
39.8
HUVEC TNF alpha + IL4
8.1


Secondary Th2 rest
20.7
HUVEC IL-11
5.3


Secondary Tr1 rest
31.0
Lung Microvascular EC
10.8




none


Primary Th1 act
15.0
Lung Microvascular EC
8.7




TNFalpha + IL-1 beta


Primary Th2 act
40.9
Microvascular Dermal EC
19.8




none


Primary Tr1 act
54.7
Microsvasular Dermal EC
7.6




TNFalpha + IL-1 beta


Primary Th1 rest
100.0
Bronchial epithelium
5.2




TNFalpha + IL1 beta


Primary Th2 rest
49.0
Small airway epithelium
3.6




none


Primary Tr1 rest
37.6
Small airway epithelium
20.7




TNFalpha + IL-1 beta


CD45RA CD4
15.3
Coronery artery SMC rest
6.8


lymphocyte act


CD45RO CD4
36.9
Coronery artery SMC
4.9


lymphocyte act

TNFalpha + IL-1 beta


CD8 lymphocyte act
21.3
Astrocytes rest
13.6


Secondary CD8
24.7
Astrocytes TNFalpha + IL-
15.2


lymphocyte rest

1 beta


Secondary CD8
25.3
KU-812 (Basophil) rest
6.1


lymphocyte act


CD4 lymphocyte none
18.8
KU-812 (Basophil)
23.2




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
48.6
CCD1106 (Keratinocytes)
4.8


CD95 CH11

none


LAK cells rest
21.3
CCD1106 (Keratinocytes)
21.6




TNFalpha + IL-1 beta


LAK cells IL-2
61.1
Liver cirrhosis
8.5


LAK cells IL-2 + IL-12
44.4
Lupus kidney
11.9


LAK cells IL-2 + IFN
48.0
NCI-H292 none
14.6


gamma


LAK cells IL-2 + IL-18
40.3
NCI-H292 IL-4
18.2


LAK cells
11.8
NCI-H292 IL-9
17.9


PMA/ionomycin


NK Cells IL-2 rest
28.3
NCI-H292 IL-13
10.1


Two Way MLR 3 day
28.1
NCI-H292 IFN gamma
13.3


Two Way MLR 5 day
22.7
HPAEC none
6.1


Two Way MLR 7 day
25.5
HPAEC TNF alpha + IL-1
8.5




beta


PBMC rest
12.5
Lung fibroblast none
13.1


PBMC PWM
28.7
Lung fibroblast TNF
14.9




alpha + IL-1 beta


PBMC PHA-L
9.5
Lung fibroblast IL-4
14.7


Ramos (B cell) none
24.7
Lung fibroblast IL-9
7.6


Ramos (B cell)
18.0
Lung fibroblast IL-13
9.8


ionomycin


B lymphocytes PWM
18.0
Lung fibroblast IFN
15.4




gamma


B lymphocytes CD40L
25.9
Dermal fibroblast
24.7


and IL-4

CCD1070 rest


EOL-1 dbcAMP
12.2
Dermal fibroblast
54.3




CCD1070 TNF alpha


EOL-1 dbcAMP
10.1
Dermal fibroblast
8.8


PMA/ionomycin

CCD1070 IL-1 beta


Dendritic cells none
40.1
Dermal fibroblast IFN
5.8




gamma


Dendritic cells LPS
24.3
Dermal fibroblast IL-4
13.6


Dendritic cells anti-
38.7
IBD Colitis 2
3.4


CD40


Monocytes rest
28.3
IBD Crohn's
4.0


Monocytes LPS
11.8
Colon
46.0


Macrophages rest
40.1
Lung
12.2


Macrophages LPS
14.8
Thymus
19.2


HUVEC none
12.2
Kidney
41.5


HUVEC starved
16.6










[1074] CNS_neurodegeneration_v1.0 Summary: Ag3448 This panel confirms the expression of CG59484-01 gene at low levels in the brain in an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.


[1075] General_screening_panel_v1.4 Summary: Ag3448 Highest expression of CG59484-01 gene is detected in colon (CT=24.9). Therefore, expression of this gene can used to distinguish this sample from other samples in the panel. Furthermore, expression of this gene is decreased in colon cancer tissue and the cell lines (Cts=30-32). Therefore, therapeutic modulation of the activity of the protein encoded by this gene may be useful in the treatment of colon related diseases such as colon cancers, Crohn's disease, and ulcerative colitis.


[1076] Among tissues with metabolic or endocrine function, this gene is expressed at moderate levels (CTs=29-30) in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.


[1077] This gene is expressed at significant (CTs=27-29) levels throughout the CNS, including in amygdala, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. However, moderate levels of expression of this gene are detected in areas outside of the central nervous system, suggesting the possibility of a wider role in intercellular signaling.


[1078] Panel 4D Summary: Ag3448 Highest expression of CG59484-01 gene is detected in resting primary Th1 cells. Thus expression of this gene can be used to distinguish this sample from other samples used in this panel. However, moderate levels of expression of this gene are detected in large number of samples used in this panel, suggesting the possibility of a wider role in intercellular signaling.


[1079] Interestingly, expression of this gene is decreased in colon samples from patients with IBD colitis (CT=31.22) and Crohn's disease (CT=30.99) relative to normal colon (CT=27.45). Therefore, therapeutic modulation of the activity of the protein encoded by this gene may be useful in the treatment of inflammatory bowel disease.



AE. NOV38a (CG59454-01: BUTYROPHILIN)

[1080] Expression of gene CG59454-01 was assessed using the primer-probe set Ag3444, described in Table AEA. Results of the RTQ-PCR runs are shown in Tables AEB, and AEC.
420TABLE ABAProbe Name Ag3444StartPrimersSequencesLengthPositionForward5′-gccttccttctgctcaacttt-3′(SEQ ID NO:341)2073ProbeTET-5′-cttcagctgctcatgcctcactcag-3′-TAMRA(SEQ ID NO:342)25112Reverse5′-agggtccaagcacagaaaac-3′(SEQ ID NO:343)20141


[1081]

421





TABLE AEB










CNS_neurodegeneration_v1.0











Rel. Exp.(%) Ag3444,

Rel. Exp.(%) Ag3444,


Tissue Name
Run 210374886
Tissue Name
Run 210374886













AD 1 Hippo
26.8
Control (Path) 3
17.3




Temporal Ctx


AD 2 Hippo
50.7
Control (Path) 4
25.3




Temporal Ctx


AD 3 Hippo
14.6
AD 1 Occipital Ctx
27.2


AD 4 Hippo
12.3
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 hippo
75.3
AD 3 Occipital Ctx
19.2


AD 6 Hippo
88.3
AD 4 Occipital Ctx
43.5


Control 2 Hippo
40.3
AD 5 Occipital Ctx
15.4


Control 4 Hippo
56.6
AD 6 Occipital Ctx
36.1


Control (Path) 3
10.4
Control 1 Occipital
14.9


Hippo

Ctx


AD 1 Temporal Ctx
39.2
Control 2 Occipital
74.7




Ctx


AD 2 Temporal Ctx
37.4
Control 3 Occipital
14.6




Ctx


AD 3 Temporal Ctx
11.0
Control 4 Occipital
27.7




Ctx


AD 4 Temporal Ctx
34.2
Control (Path) 1
100.0




Occipital Ctx


AD 5 Inf Temporal
72.2
Control (Path) 2
28.3


Ctx

Occipital Ctx


AD 5 Sup Temporal
69.3
Control (Path) 3
3.8


Ctx

Occipital Ctx


AD 6 Inf Temporal
33.2
Control (Path) 4
22.8


Ctx

Occipital Ctx


AD 6 Sup Temporal
50.7
Control 1 Parietal
27.7


Ctx

Ctx


Control 1 Temporal
24.7
Control 2 Parietal
27.5


Ctx

Ctx


Control 2 Temporal
45.1
Control 3 Parietal
21.6


Ctx

Ctx


Control 3 temporal
20.3
Control (Path) 1
66.0


Ctx

Parietal Ctx


Control 4 Temporal
12.2
Control (Path) 2
46.0


Ctx

Parietal Ctx


Control (Path) 1
60.3
Control (Path) 3
12.2


Temporal Ctx

Parietal Ctx


Control (Path) 2
58.6
Control (Path) 4
62.9


Temporal Ctx

Parietal Ctx










[1082]

422





TABLE AEC










Panel 4D











Rel. Exp.(%)

Rel. Exp.(%)



Ag3444, Run

Ag3444, Run


Tissue Name
166397205
Tissue Name
166397205













Secondary Th1 act
11.5
HUVEC IL-1 beta
4.1


Secondary Th2 act
26.4
HUVEC IFN gamma
13.0


Secondary Tr1 act
22.1
HUVEC TNF alpha + IFN
20.2




gamma


Secondary Th1 rest
43.8
HUVEC TNF alpha + IL4
9.4


Secondary Th2 rest
41.2
HUVEC IL-11
2.4


Secondary Tr1 rest
49.0
Lung Microvascular EC
3.8




none


Primary Th1 act
6.7
Lung Microvascular EC
20.2




TNFalpha + IL-1 beta


Primary Th2 act
17.6
Microvascular Dermal EC
5.8




none


Primary Tr1 act
18.3
Microsvasular Dermal EC
18.8




TNFalpha + IL-1 beta


Primary Th1 rest
98.6
Bronchial epithelium
4.4




TNFalpha + IL1 beta


Primary Th2 rest
53.2
Small airway epithelium
1.5




none


Primary Tr1 rest
29.1
Small airway epithelium
5.1




TNFalpha + IL-1 beta


CD45RA CD4
12.5
Coronery artery SMC rest
6.2


lymphocyte act


CD45RO CD4
22.4
Coronery artery SMC
5.5


lymphocyte act

TNFalpha + IL-1 beta


CD8 lymphocyte act
18.0
Astrocytes rest
3.1


Secondary CD8
20.0
Astrocytes TNFalpha + IL-
15.3


lymphocyte rest

1 beta


Secondary CD8
9.7
KU-812 (Basophil) rest
3.1


lymphocyte act


CD4 lymphocyte none
36.3
KU-812 (Basophil)
8.2




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
43.2
CCD1106 (Keratinocytes)
1.6


CD95 CH11

none


LAK cells rest
29.3
CCD1106 (Keratinocytes)
25.0




TNFalpha + IL-1 beta


LAK cells IL-2
76.8
Liver cirrhosis
10.2


LAK cells IL-2 + IL-12
59.5
Lupus kidney
6.0


LAK cells IL-2 + IFN
77.4
NCI-H292 none
10.5


gamma


LAK cells IL-2 + IL-18
61.1
NCI-H292 IL-4
13.3


LAK cells
8.0
NCI-H292 IL-9
11.0


PMA/ionomycin


NK Cells IL-2 rest
42.0
NCI-H292 IL-13
7.1


Two Way MLR 3 day
100.0
NCI-H292 IFN gamma
18.3


Two Way MLR 5 day
33.7
HPAEC none
3.1


Two Way MLR 7 day
13.7
HPAEC TNF alpha + IL-1
14.4




beta


PBMC rest
35.8
Lung fibroblast none
10.7


PBMC PWM
20.9
Lung fibroblast TNF
60.7




alpha + IL-1 beta


PBMC PHA-L
5.6
Lung fibroblast IL-1
5.7


Ramos (B cell) none
18.8
Lung fibroblast IL-9
4.3


Ramos (B cell)
10.4
Lung fibroblast IL-13
4.2


ionomycin


B lymphocytes PWM
16.7
Lung fibroblast IFN
18.2




gamma


B lymphocytes CD40L
26.4
Dermal fibroblast
7.9


and IL-4

CCD1070 rest


EOL-1 dbcAMP
2.0
Dermal fibroblast
36.6




CCD1070 TNF alpha


EOL-1 dbcAMP
0.6
Dermal fibroblast
10.2


PMA/ionomycin

CCD1070 IL-1 beta


Dendritic cells none
19.2
Dermal fibroblast IFN
24.1




gamma


Dendritic cells LPS
10.2
Dermal fibroblast IL-4
7.0


Dendritic cells anti-
8.1
IBD Colitis 2
3.9


CD40


Monocytes rest
30.8
IBD Crohn's
9.8


Monocytes LPS
16.7
Colon
92.7


Macrophages rest
22.7
Lung
16.5


Macrophages LPS
14.9
Thymus
8.9


HUVEC none
4.4
Kidney
30.1


HUVEC starved
8.5










[1083] CNS_neurodegeneration_v1.0 Summary: Ag3444 This panel confirms the expression of the CG59454-01 gene at low levels in the brain in an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment.


[1084] The CG59454-01 gene codes for butyrophilin protein (BTN), a milk protein. Recently it was demonstrated that active immunization of the dark Agouti rat with native BFN triggers an inflammatory response in the CNS characterized by the formation of scattered meningeal and perivascular infiltrates of T cells and microphages (see Ref. 1 in panel 4D).


[1085] General_screening_panel_v1.4 Summary: Ag3444 Results from one experiment with the CG59454-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.


[1086] Panel 4D Summary: Ag3444 Highest expression of CG59454-01 is detected in samples derived from two way MLR 3 day and resting primary Th1 cells (CTs=25). Thus, expression of this gene can be used to distinguish these two samples from other samples in the panel. In addition, expression of this gene is down-regulated in activated primary Th1 cells (CT=29) as compared to resting primary Th1 cells (CT-=25). Thus, therapeutics designed with the protein encoded for by this transcript could be important in treating T-cell mediated diseases such as asthma, emphysema, psoriasis, IBD, systemic lupus erythematosus, autoimmune encephalomyelitis, and parasitic disease.


[1087] CG59454-01 gene codes for butyrophilin protein, a milk protein. Recently, butyrophilin has been shown to modulates the encephalitogenic T cell response to myelin oligodendrocytc glycoprotein in experimental autoimmune encephalomyelitis (Ref. 1).


[1088] References.


[1089] 1. Stefferl A, Schubart A, Storch2 M, Amini A, Mather I, Lassmann H, Linington C. (2000) Butyrophilin, a milk protein, modulates the encephalitogenic T cell response to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis. J Immunol 165(5):2859-65



AF. NOV39a (CG59307-01: KIAA1769)

[1090] Expression of gene CG59307-01 was assessed using the primer-probc set Ag3539, described in Table AFA. Results of the RTQ-PCR runs are shown in Tables AFB, AFC and AFD.
423TABLE AFAProbe Name Ag3539StartPrimersSequencesLengthPositionForward5′-ctactcatctatggcccctttg-3′(SEQ ID NO:344)222617ProbeTET-5′-caagacctacacgctggccatgg-3′-TAMRA(SEQ ID NO:345)232646Reverse5′-agatgagcaccttggtttcag-3′(SEQ ID NO:345)212693


[1091]

424





TABLE AFB










CNS_neurodegeneration_v1.0











Rel. Exp.(%) Ag3539,

Rel. Exp.(%) Ag3539,


Tissue Name
Run 210638376
Tissue Name
Run 210638376













AD 1 Hippo
24.7
Control (Path) 3
55.5




Temporal Ctx


AD 2 Hippo
34.9
Control (Path) 4
34.6




Temporal Ctx


AD 3 Hippo
39.5
AD 1 Occipital Ctx
27.0


AD 4 Hippo
48.6
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 Hippo
56.3
AD 3 Occipital Ctx
39.5


AD 6 Hippo
85.3
AD 4 Occipital Ctx
49.0


Control 2 Hippo
43.8
AD 5 Occipital Ctx
57.4


Control 4 Hippo
62.9
AD 6 Occipital Ctx
70.2


Control (Path) 3
24.7
Control 1 Occipital
79.6


Hippo

Ctx


AD 1 Temporal Ctx
59.9
Control 2 Occipital
53.6




Ctx


AD 2 Temporal Ctx
29.1
Control 3 Occipital
25.3




Ctx


AD 3 Temporal Ctx
26.8
Control 4 Occipital
48.6




Ctx


AD 4 Temporal Ctx
50.3
Control (Path) 1
33.7




Occipital Ctx


AD 5 Inf Temporal
82.9
Control (Path) 2
17.1


Ctx

Occipital Ctx


AD 5 Sup Temporal
58.2
Control (Path) 3
26.4


Ctx

Occipital Ctx


AD 6 Inf Temporal
98.6
Control (Path) 4
36.9


Ctx

Occipital Ctx


AD 6 Sup Temporal
100.0
Control 1 Parietal
16.7


Ctx

Ctx


Control 1 Temporal
31.2
Control 2 Parietal
76.3


Ctx

Ctx


Control 2 Temporal
41.2
Control 3 Parietal
15.5


Ctx

Ctx


Control 3 Temporal
22.2
Control (Path) 1
28.7


Ctx

Parietal Ctx


Control 3 Temporal
49.3
Control (Path) 2
23.0


Ctx

Parietal Ctx


Control (Path) 1
53.6
Control (Path) 3
27.0


Temporal Ctx

Parietal Ctx


Control (Path) 2
41.8
Control (Path) 4
52.9


Temporal Ctx

Parietal Ctx










[1092]

425





TABLE AFC










General_screening_panel_v1.4











Rel. Exp.(%) Ag3539,

Rel. Exp.(%) Ag3539,


Tissue Name
Run 217049118
Tissue Name
Run 217049118













Adipose
2.4
Renal ca. TK-10
3.6


Melanoma*
1.2
Bladder
12.5


Hs688(A).T


Melanoma*
0.9
Gastric ca. (liver met.)
100.0


Hs688(B).T

NCI-N87


Melanoma* M14
2.7
Gastric ca: KATO III
5.4


Melanoma*
2.2
Colon ca. SW-948
1.1


LOXIMVI


Melanoma* SK-
2.9
Colon ca. SW480
8.3


MEL-5


Squamous cell
1.6
Colon ca.* (SW480
1.8


carcinoma SCC-4

met) SW620


Testis Pool
0.4
Colon ca. HT29
2.6


Prostate ca.* (bone
3.3
Colon ca. HCT-116
3.4


met) PC-3


Prostate Pool
1.2
Colon ca. CaCo-2
4.4


Placenta
0.7
Colon cancer tissue
5.5


Uterus Pool
0.2
Colon ca. SW1116
0.6


Ovarian ca. OVCAR-3
3.3
Colon ca. Colo-205
0.4


Ovarian ca. SK-OV-3
1.8
Colon ca. SW-48
1.0


Ovarian ca. OVCAR-4
1.5
Colon Pool
0.9


Ovarian ca. OVCAR-5
9.3
Small Intestine Pool
0.8


Ovarian ca. IGROV-1
6.3
Stomach Pool
0.8


Ovarian ca. OVCAR-8
5.8
Bone Marrow Pool
0.4


Ovary
1.7
Fetal Heart
0.4


Breast ca. MCF-7
7.0
Heart Pool
0.6


Breast ca. MDA-
5.4
Lymph Node Pool
0.8


MB-231


Breast ca. BT 549
40.9
Fetal Skeletal Muscle
0.5


Breast ca. T47D
21.5
Skeletal Muscle Pool
1.7


Breast ca. MDA-N
2.8
Spleen Pool
5.9


Breast Pool
0.8
Thymus Pool
1.7


Trachea
1.2
CNS cancer (glio/astro)
4.1




U87-MG


Lung
0.2
CNS cancer (glio/astro)
7.1




U-118-MG


Fetal Lung
3.3
CNS cancer (neuro;met)
3.0




SK-N-AS


Lung ca. NCI-N417
0.0
CNS cancer (astro) SF-
1.3




539


Lung ca. LX-1
3.0
CNS cancer (astro)
6.8




SNB-75


Lung ca. NCI-H146
0.2
CNS cancer (gilo) SNB-
5.7




19


Lung ca. SHP-77
1.9
CNS cancer (glio) SF-
11.3




295


Lung ca. A549
0.7
Brain (Amygdala) Pool
0.2


Lung ca. NCI-H526
0.2
Brain (cerebellum)
0.3


Lung ca. NCI-H23
6.7
Brain (fetal)
0.5


Lung ca. NCI-H460
0.6
Brain (Hippocampus)
0.2




Pool


Lung ca. HOP-62
2.8
Cerebral Cortex Pool
0.3


Lung ca. NCI-H522
23
Brain (Substantia nigra)
0.5




Pool


Liver
0.4
Brain (Thalamus) Pool
0.2


Fetal Liver
0.6
Brain (whole)
0.5


Liver ca. HepG2
0.7
Spinal Cord Pool
0.4


Kidney Pool
1.5
Adrenal Gland
1.4


Fetal Kidney
0.5
Pituitary gland Pool
0.3


Renal ca. 786-0
2.1
Salivary Gland
0.5


Renal ca. A498
1.4
Thyroid (female)
1.2


Renal ca. ACHN
2.4
Pancreatic ca. CAPAN2
4.0


Renal ca. UO-31
1.4
Pancreas Pool
1.3










[1093]

426





TABLE AFD










Panel 4D











Rel Exp.(%)

Rel. Exp.(%)



Ag3539, Run

Ag3539, Run


Tissue Name
166447031
Tissue Name
166447031













Secondary Th1 act
6.2
HUVEC IL-1 beta
3.4


Secondary Th2 act
57.0
HUVEC IFN gamma
18.6


Secondary Tr1 act
18.0
HUVEC TNF alpha + IFN
44.4




gamma


Secondary Th1 rest
23.0
HUVEC TNF alpha + IL4
14.6


Secondary Th2 rest
7.3
HUVEC IL-11
3.3


Secondary Tr1 rest
13.6
Lung Microvascular EC
6.8




none


Primary Th1 act
0.5
Lung Microvascular EC
14.8




TNFalpha + IL-1 beta


Primary Th2 act
2.4
Microvascular Dermal EC
5.9




none


Primary Tr1 act
2.1
Microsvasular Dermal EC
17.2




TNFalpha + IL-1 beta


Primary Th1 rest
16.2
Bronchial epithelium
7.0




TNFalpha + IL1 beta


Primary Th2 rest
3.6
Small airway epithelium
2.4




none


Primary Tr1 rest
2.5
Small airway epithelium
16.5




TNFalpha + IL-1 beta


CD45RA CD4
20.4
Coronery artery SMC rest
3.1


lymphocyte act


CD45RO CD4
12.2
Coronery artery SMC
3.3


lymphocyte act

TNFalpha + IL-1 beta


CD8 lymphocyte act
2.3
Astrocytes rest
3.5


Secondary CD8
17.8
Astrocytes TNFalpha + IL-
30.6


lymphocyte rest

1 beta


Secondary CD8
8.1
KU-812 (Basophil) rest
0.6


lymphocyte act


CD4 lymphocyte none
7.0
KU-812 (Basophil)
6.6




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
3.0
CCD1106 (Keratinocytes)
9.6


CD95 CH11

none


LAK cells rest
6.8
CCD1106 (Keratinocytes)
100.0




TNFalpha + IL-1 beta


LAK cells IL-2
23.7
Liver cirrhosis
5.2


LAK cells IL-2 + IL-12
33.4
Lupus kidney
4.0


LAK cells IL-2 + IFN
48.6
NCI-H292 none
8.2


gamma


LAK cells IL-2 + IL-18
35.8
NCI-H292 IL-4
13.0


LAK cells
19.2
NCI-H292 IL-9
9.4


PMA/ionomycin


NK Cells IL-2 rest
17.0
NCI-H292 IL-13
10.2


Two Way MLR 3 day
38.4
NCI-H292 IFN gamma
37.1


Two Way MLR 5 day
19.2
HPAEC none
2.6


Two Way MLR 7 day
6.1
HPAEC TNF alpha + IL-1
29.9




beta


PBMC rest
7.7
Lung fibroblast none
10.1


PBMC PWM
8.3
Lung fibroblast TNF
61.1




alpha + IL-1 beta


PBMC PHA-L
1.8
Lung fibroblast IL-4
10.3


Ramos (B cell) none
0.8
Lung fibroblast IL-9
4.8


Ramos (B cell)
0.3
Lung fibroblast IL-13
5.0


ionomycin


B lymphocytes PWM
4.0
Lung fibroblast IFN
41.8




gamma


B lymphocytes CD40L
7.8
Dermal fibroblast
4.2


and IL-4

CCD1070 rest


EOL-1 dbcAMP
5.4
Dermal fibroblast
10.9




CCD1070 TNF alpha


EOL-1 dbcAMP
10.4
Dermal fibroblast
8.4


PMA/ionomycin

CCD1070 IL-1 beta


Dendritic cells none
3.3
Dermal fibroblast IFN
23.7




gamma


Dendritic cells LPS
41.8
Dermal fibroblast IL-4
10.2


Dendritic cells anti-
1.9
IBD Colitis 2
2.2


CD40


Monocytes rest
13.3
IBD Crohn's
2.7


Monocytes LPS
57.0
Colon
26.8


Macrophages rest
3.3
Lung
7.3


Macrophages LPS
60.7
Thymus
2.8


HUVEC none
3.6
Kidney
9.2


HUVEC starved
7.1










[1094] CNS_neurodegeneration_v1.0 Summary: Ag3539 This panel confirms the expression of the CG59307-01 gene at low levels in the brain in an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.


[1095] General_screening_panel_v1.4 Summary: Ag3539 Highest expression of the CG59307-0l gene is detected in a sample derived from one of the gastric cancer cell line NCI-N87 (CT=23.9). Thus expression of this gene can be used to distinguish this sample from other samples in the panel. In addition low levels of expression of this gene is also associated with colon cancer, ovarian cancer, breast cancer, and CNS cancer cell lines. Therefore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of these cancers.


[1096] Among tissues with metabolic or endocrine function, this gene is expressed at moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract (CTs=27-31). Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.


[1097] In addition, this gene is expressed at low to moderate levels (CTs=31-33) in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.


[1098] Panel 4D Summary: Ag3539 Highest expression of the CG59307-01 gene is detected in a sample derived from TNFalpha+IL-1beta treated CCD1106 (Keratinocytes) (CT=26.45). Furthermore, expression of this gene is stimulated in activated secondary Th1 cells, LAK cells treated with IL-2/IL-2+IFN gamma/IL-2+IL-12/IL-2+IL-18, LPS treated dendritic cells, monocytes, and macrophages, TNF alpha+IFN gamma treated HUVEC, FNFalpha+IL-1beta treated astrocytes, CCD1106 (Keratinocytes), and lung fibroblasts. Therefore, therapeutics designed with the protein encoded for by this transcript could be important in regulating T cell function and treating T cell mediated diseases such as asthma, arthritis, psoriasis, IBD, cancer cell killing, improvement of host immunity to microbial and viral infections and systemic lupus erythematosus.



AG. NOV40a (CG59713-01: VAN GOGH)

[1099] Expression of gene CG59713-01 was assessed using the primer-probe set Ag3513, described in Table AGA. Results of the RTQ-PCR runs are shown in Tables AGB, AGC and AGD.
427TABLE AGAProbe Name Ag3513StartPrimersSequencesLengthPositionForward5′-gacttcagcctcgtagtcaatg-3′(SEQ ID NO:347)221474ProbeTET-5′-tgaagaaaattccattcattcatactcttctg-3′-TAMRA(SEQ ID NO:348)301496Reverse5′-tttgtgagatttggggtctatg-3′(SEQ ID NO:349)221533


[1100]

428





TABLE AGB










CNS_neurodegeneration_v1.0











Rel. Exp.(%) Ag3513,

Rel. Exp.(%) Ag3513,


Tissue Name
Run 210499622
Tissue Name
Run 210499622













AD 1 Hippo
32.3
Control (Path) 3
6.9




Temporal Ctx


AD 2 Hippo
46.0
Control (Path) 4
73.2




Temporal Ctx


AD 3 Hippo
12.3
AD 1 Occipital Ctx
12.1


AD 4 Hippo
12.1
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 hippo
82.4
AD 3 Occipital Ctx
19.6


AD 6 Hippo
92.7
AD 4 Occipital Ctx
22.1


Control 2 Hippo
20.6
AD 5 Occipital Ctx
10.0


Control 4 Hippo
28.1
AD 6 Occipital Ctx
25.5


Control (Path) 3
23.2
Control 1 Occipital
18.0


Hippo

Ctx


AD 1 Temporal Ctx
26.4
Control 2 Occipital
44.8




Ctx


AD 2 Temporal Ctx
25.9
Control 3 Occipital
21.0




Ctx


AD 3 Temporal Ctx
11.4
Control 4 Occipital
21.3




Ctx


AD 4 Temporal Ctx
33.7
Control (Path) 1
100.0




Occipital Ctx


AD 5 Inf Temporal
100.0
Control (Path) 2
16.6


Ctx

Occipital Ctx


AD 5 Sup Temporal
100.0
Control (Path) 3
5.9


Ctx

Occipital Ctx


AD 6 Inf Temporal
40.6
Control (Path) 4
21.0


Ctx

Occipital Ctx


AD 6 Sup Temporal
72.2
Control 1 Parietal
13.5


Ctx

Ctx


Control 1 Temporal
12.8
Control 2 Parietal
49.3


Ctx

Ctx


Control 2 Temporal
16.8
Control 3 Parietal
11.8


Ctx

Ctx


Control 3 Temporal
16.3
Control (Path) 1
50.0


Ctx

Parietal Ctx


Control 4 Temporal
10.6
Control (Path) 2
48.0


Ctx

Parietal Ctx


Control (Path) 1
78.5
Control (Path) 3
12.9


Temporal Ctx

Parietal Ctx


Control (Path) 2
22.2
Control (Path) 4
71.2


Temporal Ctx

Parietal Ctx










[1101]

429





TABLE AGC










General_screening_panel_v1.4











Rel. Exp.(%) Ag3513,

Rel. Exp.(%) Ag3513,


Tissue Name
Run 217240777
Tissue Name
Run 217240777













Adipose
5.6
Renal ca. TK-10
37.4


Melanoma*
25.7
Bladder
17.7


Hs688(A).T


Melanoma*
29.3
Gastric ca. (liver met.)
85.3


Hs688(B).T

NCI-N87


Melanoma* M14
68.8
Gastric ca. KATO III
78.5


Melanoma*
20.3
Colon ca. SW-948
19.3


LOXIMVI


Melanoma* SK-
31.0
Colon ca. SW480
84.1


MEL-5


Squamous cell
36.1
Colon ca.* (SW480
27.2


carcinoma SCC-4

met) SW620


Testis Pool
5.3
Colon ca. HT29
26.6


Prostate ca.* (bone
37.9
Colon ca. HCT-116
73.7


met) PC-3


Prostate Pool
8.4
Colon CaCo-2
18.4


Placenta
4.4
Colon cancer tissue
13.4


Uterus Pool
4.7
Colon ca. SW1116
7.9


Ovarian ca. OVCAR-3
48.0
Colon ca. Colo-205
17.0


Ovarian ca. SK-OV-3
100.0
Colon ca. SW-48
10.6


Ovarian ca. OVCAR-4
26.1
Colon Pool
18.2


Ovarian ca. OVCAR-5
37.1
Small Intestine Pool
8.8


Ovarian ca. IGROV-1
24.0
Stomach Pool
8.9


Ovarian ca. OVCAR-8
17.7
Bone Marrow Pool
9.2


Ovary
9.5
Fetal Heart
7.0


Breast ca. MCF-7
67.4
Heart Pool
8.5


Breast ca. MDA-
67.4
Lymph Node Pool
22.1


MB-231


Breast ca. BT 549
71.2
Fetal Skeletal Muscle
4.0


Breast ca. T47D
82.9
Skeletal Muscle Pool
2.7


Breast ca. MDA-N
29.7
Spleen Pool
5.2


Breast Pool
16.7
Thymus Pool
11.7


Trachea
14.1
CNS cancer (glio/astro)
49.3




U87-MG


Lung
2.4
CNS cancer (glio/astro)
34.4




U-118-MG


Fetal Lung
19.5
CNS cancer (neuro; met)
19.3




SK-N-AS


Lung ca. NCI-N417
3.2
CNS cancer (astro) SF-
54.7




539


Lung ca. LX-1
17.6
CNS cancer (astro)
62.9




SNB-75


Lung ca. NCI-H146
9.5
CNS cancer (glio) SNB-19
21.9




19


Lung ca. SHP-77
53.6
CNS cancer (glio) SF-
16.0




295


Lung ca. A549
35.6
Brain (Amygdala) Pool
1.2


Lung ca. NCI-H526
6.8
Brain (cerebellum)
1.6


Lung ca. NCI-H23
33.4
Brain (fetal)
7.2


Lung ca. NCI-H460
41.2
Brain (Hippocampus)
1.3




Pool


Lung ca. HOP-62
11.5
Cerebral Cortex Pool
1.4


Lung ca. NCI-H522
16.5
Brain (Substantia nigra)
1.4




Pool


Liver
1.3
Brain (Thalamus) Pool
2.2


Fetal Liver
28.3
Brain (whole)
3.8


Liver ca. HepG2
21.3
Spinal Cord Pool
1.8


Kidney Pool
24.1
Adrenal Gland
16.8


Fetal Kidney
8.7
Pituitary gland Pool
0.5


Renal ca. 786-0
55.9
Salivary Gland
8.8


Renal ca. A498
14.6
Thyroid (female)
11.2


Renal ca. ACHN
17.2
Pancreatic ca. CAPAN2
35.8


Renal ca. UO-31
24.0
Pancreas Pool
22.8










[1102]

430





TABLE AGD










Panel 4D











Rel. Exp.(%)

Rel. Exp.(%)



Ag3513, Run

Ag3513, Run


Tissue Name
166407114
Tissue Name
166407114













Secondary Th1 act
21.3
HUVEC IL-1 beta
17.9


Secondary Th2 act
26.4
HUVEC IFN gamma
18.8


Secondary Tr1 act
33.7
HUVEC TNF alpha + IFN
11.6




gamma


Secondary Th1 rest
11.6
HUVEC TNF alpha + IL4
15.8


Secondary Th2 rest
8.7
HUVEC IL-11
7.3


Secondary Tr1 rest
10.2
Lung Microvascular EC
18.7




none


Primary Th1 act
6.8
Lung Microvascular EC
14.4




TNFalpha + IL-1 beta


Primary Th2 act
20.2
Microvascular Dermal EC
26.6




none


Primary Tr1 act
23.2
Microsvasular Dermal EC
21.9




TNFalpha + IL-1 beta


Primary Th1 rest
47.0
Bronchial epithelium
21.2




TNFalpha + IL 1 beta


Primary Th2 rest
18.3
Small airway epithelium
13.8




none


Primary Tr1 rest
16.4
Small airway epithelium
89.5




TNFalpha + IL-1 beta


CD45RA CD4
10.2
Coronery artery SMC rest
10.5


lymphocyte act


CD45RO CD4
19.2
Coroncry artery SMC
8.4


lymphocyte act

TNFalpha + IL-1 beta


CD8 lymphocyte act
4.4
Astrocytes rest
15.3


Secondary CD8
6.9
Astrocytes TNFalpha + IL-
23.3


lympnocyte rest

1 beta


Secondary CD8
11.0
KU-812 (Basophil) rest
21.2


lymphocyte act


CD4 lymphocyte none
1.4
KU-812 (Basophil)
34.6




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
13.2
CCD1106 (Keratinocytes)
32.5


CD95 CH11

none


LAK cells rest
2.1
CCD1106 (Keratinocytes)
100.0




TNFalpha + IL-1 beta


LAK cells IL-2
37.4
Liver cirrhosis
2.9


LAK cells IL-2 + IL-12
12.4
Lupus kidney
5.6


LAK cells IL-2 + IFN
18.7
NCI-H292 none
36.6


gamma


LAK cells IL-2 + IL-18
17.7
NCI-H292 IL-4
69.3


LAK cells
0.6
NCI-H292 IL-9
56.6


PMA/ionomycin


NK Cells IL-2 rest
21.5
NCI-H292 IL-13
35.4


Two Way MLR 3 day
3.8
NCI-H292 IFN gamma
29.3


Two Way MLR 5 day
5.6
HPAEC none
12.0


Two Way MLR 7 day
5.1
HPAEC TNF alpha + IL-1
10.8




beta


PBMC rest
2.6
Lung fibroblast none
11.2


PBMC PWM
4.5
Lung fibroblast TNF
13.9




alpha + IL-1 beta


PBMC PHA-L
4.1
Lung fibroblast IL-4
16.5


Ramos (B cell) none
0.2
Lung fibroblast IL-9
11.4


Ramos (B cell)
0.0
Lung fibroblast IL-13
8.6


ionomycin


B lymphocytes PWM
11.3
Lung fibroblast IFN
19.8




gamma


B lymphocytes CD40L
4.9
Dermal fibroblast
44.8


and IL-4

CCD 1070 rest


EOL-1 dbcAMP
5.5
Dermal fibroblast
49.7




CCD1070 TNF alpha


EOL-1 dbcAMP
3.5
Dermal fibroblast
19.6


PMA/ionomyein

CCD1070 IL-1 beta


Dendritic cells none
2.9
Dermal fibroblast IFN
11.7




gamma


Dendritic cells LPS
1.7
Dermal fibroblast IL-4
21.5


Dendritic cell anti-
3.6
IBD Colitis 2
1.2


CD 40


Monocytes rest
1.1
IBD Crohn's
1.8


Monocytes LPS
0.4
Colon
23.0


Macrophages rest
5.6
Lung
9.4


Macrophages LPS
1.6
Thymus
16.2


HUVEC none
35.6
Kidney
16.2


HUVEC starved
40.3










[1103] CNS_neurodegeneration_v1.0 Summary: Ag3513 This panel confirms the expression of the CG59713-01 gene at low levels in the brain in an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.


[1104] General_screening_panel_v1.4 Summary: Ag3513 Highest expression of the CG59713-01 is detected in sample derived from one of the ovarian cancer SK-OV-3(CT=28). Furthermore, significant expression of this gene is associated with number of cancer samples (pancreatic cancer, CNS cancer, colon cancer, gastric cancer, renal cancer, lung cancer, breast cancer, prostate cancer, melanoma cell lines) used in this panel. Therefore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, or antibodies, might be beneficial in the treatment of all these cancers.


[1105] Interestingly, this gene is expressed at much higher levels in fetal (CT=30) when compared to adult liver (CT=34). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may be required for growth and development of the liver in fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of liver related diseases.


[1106] Among tissues with metabolic or endocrine function, this gene is expressed at high to moderate levels (CTs=30-32) in pancreas, adipose, adrenal gland, thyroid, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.


[1107] In addition, this gene is expressed at low levels (CTs=32-34) in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.


[1108] Panel 4D Summary: Ag3513 Highest expression of the CG59713-01 is detected in TNFalpha+IL-1beta treated keratinocytes (CT=27.9). Therefore, expression of this gene can be used to distinguish TNFalpha+IL-1beta treated keratinocytes from other samples used in this panel.


[1109] In addition, expression of this gene is stimulated in activated secondary Th1, Th2, and Tr1 cells, LAK cells treated with IL-2, TNFalpha+IL-1beta treated small airway epithelium and NCI-H292 treated with IL-4. Therefore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, or antibodies, might be beneficial in the treatment of psoriasis, asthma, emphysema, cancer, microbial and viral infections.



AH. NOV41a (CG59570-01: AQUAPORIN)

[1110] Expression of gene CG59570-01 was assessed using the primer-probe set Ag3475, described in Table AHA. Results of the RTQ-PCR runs are shown in Tables AHB, and AHC.
431TABLE AHAProbe Name Ag3475StartPrimersSequencesLengthPositonForward5′-acaaaacatggttcaagcatct-3′(SEQ ID NO:350)222ProbeTET-5′-ccaaaatggtctcctggtccgtgata-3′-TAMRA(SEQ ID NO: 351)2649Reverse5′-accatatttcctggatctttgc-3′(SEQ ID NO:352)2275


[1111]

432





TABLE AHB










General_screening_panel_v1.4











Rel. Exp.(%) Ag3475,

Rel. Exp.(%) Ag3475,


Tissue Name
Run 222691300
Tissue Name
Run 222691300













Adipose
100.0
Renal ca. TK-10
1.1


Melanoma*
0.0
Bladder
3.4


Hs688(A).T


Melanoma*
0.1
Gastric ca. (liver met.)
8.5


Hs688(B).T

NCI-N87


Melanoma* M14
0.2
Gastric ca. KATO III
0.2


Melanoma*
1.1
Colon ca. SW-948
1.2


LOXIMVI


Melanoma* SK-
0.0
Colon ca. SW480
0.0


MEL-5


Squamous cell
0.0
Colon ca.* (SW480
0.4


carcinoma SCC-4

met) SW620


Testis Pool
10.2
Colon ca. HT29
0.2


Prostate ca.* (bone
2.2
Colon HCT-116
0.6


met) PC-3


Prostate Pool
0.6
Colon ca. CaCo-2
0.0


Placenta
0.3
Colon cancer tissue
9.6


Uterus Pool
0.8
Colon ca. SW1116
0.0


Ovarian ca. OVCAR-3
0.5
Colon ca. Colo-205
0.0


Ovarian ca. SK-OV-3
0.1
Colon ca. SW-48
0.0


Ovarian ca. OVCAR-4
0.3
Colon Pool
1.5


Ovarian ca. OVCAR-5
0.3
Small Intestine Pool
0.6


Ovarian ca. IGROV-1
5.0
Stomach Pool
2.2


Ovarian ca. OVCAR-8
0.3
Bone Marrow Pool
0.8


Ovary
0.1
Fetal Heart
1.2


Breast ca. MCF-7
0.1
Heart Pool
20.6


Breast ca. MDA-
0.1
Lymph Node Pool
1.3


MB-231


Breast ca. BT 549
0.3
Fetal Skeletal Muscle
4.7


Breast ca. T47D
0.5
Skeletal Muscle Pool
14.3


Breast ca. MDA-N
0.5
Spleen Pool
1.9


Breast Pool
1.0
Thymus Pool
6.0


Trachea
4.0
CNS cancer (glio/astro)
0.7




U87-MG


Lung
0.2
CNS cancer (glio/astro)
4.7




U-118-MG


Fetal Lung
0.4
CNS cancer (neuro; met)
0.2




SK-N-AS


Lung ca. NCI-N417
0.0
CNS cancer (astro) SF-
0.0




539


Lung ca. LX-1
0.7
CNS cancer (astro)
2.8




SNB-75


Lung ca. NCI-H146
0.0
CNS cancer (glio) SNB-
3.8




19


Lung ca. SHP-77
0.0
CNS cancer (glio) SF-
0.2




295


Lung ca. A549
0.2
Brain (Amygdala) Pool
0.7


Lung ca. NCI-H526
0.0
Brain (cerebellum)
13.2


Lung ca. NCI-H23
0.1
Brain (fetal)
0.1


Lung ca. NCI-H460
0.3
Brain (Hippocampus)
1.3




Pool


Lung ca. HOP-62
0.3
Cerebral Cortex Pool
0.1


Lung ca. NCI-H522
1.7
Brain (Substantia nigra)
0.8




Pool


Liver
0.0
Brain (Thalamus) Pool
0.1


Fetal Liver
0.0
Brain (whole)
0.2


Liver ca. HepG2
2.0
Spinal Cord Pool
1.3


Kidney Pool
3.6
Adrenal Gland
10.2


Fetal Kidney
0.9
Pituitary gland Pool
0.0


Renal ca.786-0
1.3
Salivary Gland
2.5


Renal ca. A498
0.5
Thyroid (female)
0.7


Renal ca. ACHN
0.0
Pancreatic ca. CAPAN2
0.0


Renal ca. UO-31
0.1
Pancreas Pool
1.1










[1112]

433





TABLE AHC










Panel 4D











Rel. Exp. (%)

Rel. Exp. (%)



Ag3475, Run

Ag3475, Run


Tissue Name
166420470
Tissue Name
166420470













Secondary Th1 act
1.9
HUVEC IL-1 beta
1.6


Secondary Th2 act
0.7
HUVEC IFN gamma
3.5


Secondary Tr1 act
0.9
HUVEC TNF alpha + IFN
0.5




gamma


Secondary Th1 rest
1.5
HUVEC TNF alpha + IL4
2.0


Secondary Th2 rest
1.5
HUVEC IL-11
3.1


Secondary Tr1 rest
0.6
Lung Microvascular EC
50.3




none


Primary Th1 act
0.0
Lung Microvascular EC
22.1




TNFalpha + IL-1beta


Primary Th2 act
1.2
Microvascular Dermal EC
0.8




none


Primary Tr1 act
1.0
Microvascular Dermal EC
1.3




THFalpha + IL-1beta


Primary Th1 rest
3.3
Bronchial epithelium
0.6




TNFalpha + IL1beta


Primary Th2 rest
2.2
Small airway epithelium
2.7




none


Primary Tr1 rest
1.1
Small airway epithelium
17.8




TNFalpha + IL-1beta


CD45RA CD4
0.0
Coronery artery SMC rest
1.7


lymphocyte act


CD45RO CD4
0.0
Coronery artery SMC
0.0


lymphocyte act

TNFalpha + IL-1beta


CD8 lymphocyte act
0.0
Astrocytes rest
2.6


Secondary CD8
1.4
Astrocytes TNFalpha + IL-
6.6


lymphocyte rest

1 beta


Secondary CD8
0.0
KU-812 (Basophil) rest
0.0


lymphocyte act


CD4 lymphocyte none
0.0
KU-812 (Basophil)
1.0




PMA/ionomycin


2ry TH1/TH2/TR1_anti-
5.1
CCD1106 (Keratinocytes)
1.2


CD95 CH11

none


LAK cells rest
0.0
CCD1106 (Keratinocytes)
3.1




TNFalpha + IL-1beta


LAK cells IL-2
0.0
Liver cirrhosis
4.5


LAK cells IL-2 + IL-12
0.5
Lupus kidney
13.4


LAK cells IL-2 + IFN
0.0
NCI-H292 none
3.0


gamma


LAK cells IL-2 + IL-18
0.3
NCI-H292 IL-4
0.8


LAK cells
0.7
NCI-H292 IL-9
4.3


PMA/ionomycin


NK Cells IL-2 rest
1.0
NCI-H292 IL-13
3.3


Two Way MLR 3 day
0.0
NCI-H292 IFN gamma
1.7


Two Way MLR 5 day
0.0
HPAEC none
100.0


Two Way MLR 7 day
0.6
HPAEC TNF alpha + IL-1
78.5




beta


PBMC rest
0.6
Lung fibroblast none
5.8


PBMC PWM
0.0
Lung fibroblasts TNF
2.7




alpha + IL-1 beta


PBMC PHA-L
0.0
Lung fibroblast IL-4
3.8


Ramos (B cell) none
0.2
Lung fibroblast IL-9
1.3


Ramos (B cell)
0.0
Lung fibroblast IL-13
0.3


ionomycin


B lymphocytes PWM
0.0
Lung fibroblast IFN
3.5




gamma


B lymphocytes CD40L
0.0
Dermal fibroblast
3.1


and IL-4

CCD1070 rest


EOL-1 dbcAMP
0.0
Dermal fibroblast
2.0




CCD1070 TNF alpha


EOL-1 dbcAMP
0.4
Dermal fibroblast
0.0


PMA/ionomycin

CCD1070 IL-1 beta


Dendritic cells none
0.0
Dermal fibroblast IFN
0.0




gamma


Dendritic cells LPS
0.0
Dermal fibroblast IL-4
0.0


Dendritic cells anti-
1.8
IBD Colitis 2
2.5


CD40


Monocytes rest
0.0
IBD Crohn's
12.3


Monocytes LPS
0.0
Colon
25.7


Macrophages rest
0.0
Lung
1.3


Macrophages LPS
0.0
Thymus
38.4


HUVEC none
3.1
Kidney
20.9


HUVEC starved
4.5










[1113] CNS_neurodegeneration_v1.0 Summary: Ag3475 Expression of the CG59570-01 gene is low/undetectable (CTs>34.5) across all of the samples on this panel.


[1114] General_screening_panel_v1.4 Summary: Ag3475 High expression of the CG59570-01 gene is detected exclusively in adipose tissue sample (CT=27.73). Thus expression of this gene can be used to distinguish adipose sample from other samples in this panel. In addition to adipose tissue, low levels of expression of this gene is also seen in other tissues with metabolic or endocrine function such as pancreas, adrenal gland, thyroid, skeletal muscle, heart, and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.


[1115] CG59570-01 codes for protein similar to aquaporin 7. Aquaporins are water channels that are usually found in tissues where water movements are abundant and/or physiologically important. In a systematic analysis of genes expressed in human adipose tissue, Kuniyama et al. (Ref. 1) identified AQP7L, a predicted 342-amino acid protein. They showed that this aquaporin participates in glycerol transport in adipocytes. Thus, we predict that protein encoded by this transcript may also play a role in glycerol transport in adipocytes.


[1116] Interestingly, this gene is expressed at much higher levels in adult (CT=30) when compared to fetal heart (CT=34). This observation suggests that expression of this gene can be used to distinguish fetal from adult heart. Furthermore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of heart related diseases.


[1117] In addition, this gene is expressed at significant levels in some regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, and cerebellum (CTs=30-34). Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, seizure, ataxia, autism, schizophrenia and depression.


[1118] Reference.


[1119] 1. Kuriyama, H.; Kawamoto, S.; Ishida, N.; Ohno, I.; Mita, S.; Matsuzawa, Y.; Matsubara, K.; Okubo, K. (1997) Molecular cloning and expression of a novel human aquaporin from adipose tissue with glycerol permeability. Biochem. Biophys. Res. Commun. 241: 53-58.


[1120] Panel 4D Summary: Ag3475 High expression of the CG59570-01 is detected untreated and TNF alpha+IL-1beta treated (CTs=30) HPAEC cells. Thus expression of this gene can be used to distinguish these two samples from other samples in this panel. In addition, low levels of expression of this gene is also detected in lung fibroblast, IFN-gamma treated lung fibroblast, IL-9 treated NCI-H292 cells, starved and IFN-gama treated HUVEC cells, anti-CD95 CH11 treated secondary Th1/Th2/Tr1 cells, and TNFalpha+IL-1beta treated small airway epithelium. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of lung related diseases such as asthma, allergies, emphysema, COPD.


[1121] Interestingly, this gene is expressed at much higher levels in TNFalpha+IL-1beta treated (CT=32) as compared to untreated small airway epithelium (CT=35). Thus, expression of this gene can be used to distinguish TNFalpha+IL-1beta treated from the untreated small airway epithelium cells.


[1122] Expression of this gene is detected at low levels (CT=34.5) in liver cirrhosis, but not in normal liver (no expression in normal liver is detected on Panel 1.4). The protein encoded for by this gene could potentially allow cells within the liver to respond to specific microenvironmental signals. Therefore, therapies designed with the protein encoded for by this gene may potentially modulate liver function and play a role in the identification and treatment of inflammatory or autoimmune diseases which effect the liver including liver cirrhosis and fibrosis.


[1123] In addition, moderate expression of this gene is also observed in kidney, thymus and colon. Therefore, antibody or small molecule therapies designed with the protein encoded for by this gene may be important in the treatment of inflammatory or autoimmune diseases that affect these tissues.



AI. NOV42a (CG56162-02: LYSOPHOSPHOLIPASE-LIKE)

[1124] Expression of gene CG56162-02 was assessed using the primer-probe set Ag2042, described in Table AIA. Results of the RTQ-PCR runs are shown in Tables AIB and AIC. Please note that CG56162-02 represents a full-length physical clone.
434TABLE AIAProbe Name Ag2042StartPrimersSequencesLengthPositionForward5′-cataatggaaacaggacctgaa-3′(SEQ ID NO:353)2232ProbeTET-5′-ccttccagcatgccagaggaaagtt-3′-TAMRA(SEQ ID NO:354)2557Reverse5′-aggtcctggtagggaatgct-3′(SEQ ID NO:355)20102


[1125]

435





TABLE AIB










Panel 1.3D











Rel. Exp. (%) Ag 2042,

Rel. Exp. (%) Ag2042,


Tissue Name
Run 165627321
Tissue Name
Run 165627321













Liver adenocarcinoma
5.8
Kidney (fetal)
6.4


Pancreas
0.8
Renal ca. 786-0
25.7


Pancreatic ca. CAPAN
8.5
Renal ca. A498
27.0


2


Adrenal gland
1.6
Renal ca. RXF 393
46.0


Thyroid
1.4
Renal ca. ACHN
14.7


Salivary gland
6.2
Renal ca. UO-31
41.8


Pituitary gland
1.6
Renal ca. TK-10
8.5


Brain (fetal)
33.7
Liver
3.5


Brain (whole)
92.0
Liver (fetal)
0.9


Brain (amygdala)
37.9
Liver ca.
0.0




(hepatoblast) HepG2


Brain (cerebellum)
94.6
Lung
8.8


Brain (hippocampus)
50.7
Lung (fetal)
12.1


Brain (subtantia nigra)
11.6
Lung ca. (small cell)
2.1




LX-1


Brain (thalamus)
51.1
Lung ca. (small cell)
6.1




NCI-H69


Cerebral Cortex
76.3
Lung ca. (s.cell var.)
0.0




SHP-77


Spinal cord
12.0
Lung ca. (large
1.6




cell) NCI-H460


glio/astro U87-MG
28.3
Lung ca. (non-sm.
6.4




cell) A549


glio/astro U-118-MG
100.0
Lung ca. (non-s.cell)
0.4




NCI-H23


astrocytoma SW1783
3.2
Lung ca. (non-s.cell)
0.0




HOP-62


neuro*; met SK-N-AS
0.3
Lung ca. (non-s.cl)
0.0




NCI-H522


astrocytoma SF-539
40.9
Lung ca. (squam.)
12.6




SW 900


astrocytoma SNB-75
12.3
Lung ca. (squam.)
9.0




NCI-H596


glioma SNB-19
4.1
Mammary gland
9.5


glioma U251
1.5
Breast ca.* (pl.ef)
5.8




MCF-7


glioma SF-295
1.4
Breast ca.* (pl.ef)
21.9




MDA-MB-231


Heart (fetal)
6.0
Breast ca.* (pl.ef)
0.4




T47D


Heart
12.8
Breast ca. BT-549
0.3


Skeletal muscle (fetal)
8.5
Breast ca. MDA-N
1.3


Skeletal muscle
6.2
Ovary
2.1


Bone marrow
2.3
Overian ca. OVCAR-
0.0




3


Thymus
1.0
Ovarian ca. OVCAR-
7.6




4


Spleen
13.3
Ovarian ca. OVCAR-
10.2




5


Lymph node
5.7
Ovarian ca. OVCAR-
10.6




8


Colorectal
10.5
Ovarian ca. IGROV-1
3.2


Stomach
5.5
Ovarian ca.* (ascites)
45.7




SK-OV-3


Small intestine
10.2
Uterus
8.7


Colon ca. SW480
0.3
Placenta
4.3


Colon ca.*
0.0
Prostate
1.3


SW620 (SW480 met)


Colon ca. HT29
8.1
Prostate ca.* (bone
22.2




met) PC-3


Colon ca. HCT-116
2.4
Testis
0.8


Colon ca. CaCo-2
0.8
Melanoma
1.4




Hs688(A).T


Colon ca.
10.8
Melanoma* (met)
4.5


tissue (ODO3866)

Hs688(B).T


Colon ca. HCC-2998
2.2
Melanonma UACC-62
3.0


Gastric ca.* (liver met)
7.3
Melanoma M14
0.0


NCI-N87


Bladder
1.5
Melanoma LOX
1.4




IMVI


Trachea
11.6
Melanoma* (met)
0.1




SK-MEL-5


Kidney
5.1
Adipose
9.2










[1126]

436





TABLE AIC










Panel 4D











Rel. Exp. (%)

Rel. Exp. (%)



Ag2042, Run

Ag2042, Run


Tissue Name
161383006
Tissue Name
161383006













Secondary TH1 act
0.3
HUVEC IL-1beta
22.8


Secondary Th2 act
0.7
HUVEC IFN gamma
17.4


Secondary Tr1 act
1.0
HUVEC TNF alpha + IFN
59.0




gamma


Secondary Th1 rest
0.0
HUVEC TNF alpha + IL4
54.0


Secondary Th2 rest
1.5
HUVEC IL-11
14.1


Secondary Tr1 rest
0.9
Lung Microvascular EC
42.0




none


Primary Th1 act
0.9
Lung Microvascular EC
79.6




TNFalpha + IL-1beta


Primary Th2 act
1.9
Microvascular Dermal EC
54.3




none


Primary Tr1 act
0.4
Microvascular Dermal EC
54.3




TNFalpha + IL-1beta


Primary Th1 rest
1.2
Bronchial epithelium
7.8




TNFalpha + IL1beta


Primary Th2 rest
1.5
Small airway epithelium
12.8




none


Primary Tr1 rest
0.8
Small airway epithelium
41.5




TNFalpha + IL-1beta


CD45RA CD4
15.3
Coronery artery SMC rest
0.0


lymphocyte act


CD45RO CD4
0.4
Coronery artery SMC
7.3


lymphocyte act

TNFalpha + IL-1beta


CD8 lymphocyte act
1.2
Astrocytes rest
0.7


Secondary CD8
0.2
Astrocytes TNFalpha + IL-
3.6


lymphocyte rest

1beta


Secondary CD8
3.0
KU-812 (Basophil) rest
0.0


lymphocyte act


CD4 lymphocyte none
0.1
KU-812 (Basophil)
0.3




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
1.3
CCD1106 (Keratinocytes)
18.0


CD95 CH11

none


LAK cells rest
3.3
CCD1106 (Keratinocytes)
1.0




TNFalpha + IL-1beta


LAK cells IL-2
0.2
Liver cirrhosis
3.5


LAK cells IL-2 + IL-12
1.2
Lupus kidney
5.4


LAK cells IL-2 + IFN
3.2
NCI-H292 none
16.3


gamma


LAK cells IL-2 + IL-18
1.7
NCI-H292 IL-4
24.1


LAK cells
2.1
NCI-H292 IL-9
23.3


PMA/ionomycin


NK Cells IL-2 rest
0.0
NCI-H292 IL-13
11.9


Two Way MLR 3 day
7.3
NCI-H292 IFN gamma
21.9


Two Way MLR 5 day
2.5
HPAEC none
25.7


Two Way MLR 7 day
1.3
HPAEC TNF alpha + IL-1
64.6




beta


PBMC rest
0.4
Lung fibroblast none
18.8


PBMC PWM
9.2
Lung fibroblast TNF
33.7




alpha + IL-1 beta


PBMC PHA-L
2.4
Lung fibroblast IL-4
29.5


Ramos (B cell) none
0.0
Lung fibroblast IL-9
43.2


Ramos (B cell)
0.0
Lung fibroblast IL-13
18.7


ionomycin


B lymphocytes PWM
10.7
Lung fibroblast IFN
29.1




gamma


B lymphocytes CD40L
8.3
Dermal fibroblast
64.6


and IL-4

CCD1070 rest


EOL-1 dbcAMP
0.0
Dermal fibroblast
100.0




CCD1070 TNF alpha


EOL-1 dbcAMP
0.1
Dermal fibroblast
48.0


PMA/ionomycin

CCD1070 IL-1 beta


Dendritic cells none
7.3
Dermal fibroblast IFN
24.0




gamma


Dendritic cells LPS
28.1
Dermal fibroblast IL-4
41.5


Dendritic cells anti-
13.0
IBD Colitis 2
0.4


CD40


Monocytes rest
0.1
IBD Crohn's
1.0


Monocytes LPS
16.5
Colon
18.4


Macrophages rest
51.4
Lung
44.1


Macrophages LPS
18.0
Thymus
17.2


HUVEC none
45.1
Kidney
5.4


HUVEC starved
54.7










[1127] Panel 1.3D Summary: Ag1906/Ag2042 The expression of CG56162-02 gene was assessed in two independent runs using 2 different probe/primer pairs, with good concordance between the runs. Highest expression in this panel is seen in brain derived tissue, including the cerebral cortex and a brain cancer (CTs=25-27). Thus, the expression of this gene could be used to distinguish these samples from other samples in the panel.


[1128] This gene encodes a lysophosphase homolog that also has high levels of expression in many of the endocrine/metabolic tissues found on this panel, including adipose, liver, pancreas, pituitary, skeletal muscle and small intestine. Lysophospholipids are detergent-like intermediates in phospholipid metabolism. Lysophospholipases are important enzymes in the regulation of hormone biosynthesis and metabolism, and have been shown to be important in the regulation of insulin secretion (see reference below). Increased lysophospholipids levels have been detected in a variety of diseases including atherosclerosis and hyperlipidemia. In some cases, increased levels of lysophospholipids are hypothesized to result from a dysfunction of lysophospholipids-regulating enzymes including lysophospholipases, which act on biologic membranes to regulate the level of lysophospholipids by hydrolysis. Thus, this gene product may be useful in the treatment of diseases associated with increased lysophospholipids.


[1129] This gene also shows high expression in the brain. Lysophospholipases are critical enzymes that regulate brain membrane phospholipids. Alterations in their activity have been associated with a host of neurological disorders, including schizophrenia, Parkinson's disease, and Alzheimer's disease. Thus, therapeutic modulation of the expression or function of this gene or gene product may be useful in the treatment of these diseases. Please note that results from a third experiment with the probe/primer set Ag1952 are not included. The amp plot indicates that there were experimental difficulties with this run.


[1130] References:


[1131] 1. Capito K, Reinsmark R, Thams P. Mechanism of fat-induced attenuation of glucose-induced insulin secretion from mouse pancreatic islets. Acta Diabetol December 1999;36(3): 119-25


[1132] 2. Ross B M, Turenne S, Moszczynska A, Warsh J J, Kish S J. Differential alteration of phospholipase A2 activities in brain of patients with schizophrenia. Brain Res Mar. 13, 1999; 821 (2):407-13


[1133] 3. Ross B M, Moszczynska A, Erlich J, Kish S J. Low activity of key phospholipid catabolic and anabolic enzymes in human substantia nigra: possible implications for Parkinson's disease. Neuroscience April 1998;83(3):791-8


[1134] 4. Ross B M, Moszczynska A, Erlich J, Kish S J. Phospholipid-metabolizing enzymes in Alzheimer's disease: increased lysophospholipid acyltransferase activity and decreased phospholipase A2 activity. J Neurochem February 1998;70(2):786-93


[1135] Panel 4D Summary: Ag1906/Ag1952/Ag2042 The expression ofCG56162-02 gene was assessed in three independent runs using three different probe/primer pairs, with good concordance between the runs. This gene is expressed at moderate levels in a wide variety of cells including resting macrophages, TNF-alpha-activated dermal fibroblasts, LPS-stimulated dendritic cells, TN-alpha+IL-1-beta-activated pulmonary artery endothelial cells, TNF-alpha+IL-1-beta-activated lung microvascular cells, and TNF-alpha+IFN-gamma-activated umbilical vein endothelial cells (CTs=27-28). Thus, antibodies and small molecules that antagonize the function of the CG120803-01 geen product may be useful to reduce or eliminate the symptoms in patients with inflammatory and autoimmune diseases, such as lupus erythematosus, asthma, emphysema, Crohn's disease, ulcerative colitis, multiple sclerosis, rheumatoid arthritis, osteoarthritis, and psoriasis.



AJ. NOV45a and NOV45b (CG59859-01 and CG59859-02: TESTIS EXPRESSED PROTEIN 261 (TEG-261))

[1136] Expression of genes CG59859-01 and CG59859-02 was assessed using the primer-probe set Ag3623, described in Table AJA. Results of the RTQ-PCR runs arc shown in Tables AJB, AJC and AJD. Please note that CG59859-02 represents a full-length physical clone of the CG59859-01 gene, validating the prediction of the gene sequence.
437TABLE AJAProbe Name Ag3623StartPrimersSequencesLengthPositionForward5′-cgtctccaattatttcaccaaa-3′(SEQ ID NO:356)22534ProbeTET-5′-agggatccttggttgtcttctccttca-3′-TAMRA(SEQ ID NO:357)26576Reverse5′-cttctgacgactgggtagaatg-3′(SEQ ID NO:358)22612


[1137]

438





TABLE AJB










CNS_neurodegeneration_v1.0











Rel. Exp. (%) Ag3623,

Rel. Exp. (%) Ag2623,


Tissue Name
Run 211005294
Tissue Name
Run 211005294













AD 1 Hippo
22.4
Control (Path) 3
12.2




Temporal Ctx


AD 2 Hippo
42.9
Control (Path) 4
25.9




Temporal Ctx


AD 3 Hippo
16.6
AD 1 Occipital Ctx
21.6


AD 4 Hippo
9.5
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 hippo
76.3
AD 3 Occipital Ctx
21.2


AD 6 Hippo
50.7
AD 4 Occipital Ctx
22.7


Control 2 Hippo
32.8
AD 5 Occipital Ctx
5.8


Control 4 Hippo
28.5
AD 6 Occipital Ctx
39.0


Control (Path) 3
9.8
Control 1 Occipital
14.3


Hippo

Ctx


AD 1 Temporal Ctx
27.7
Control 2 Occipital
80.1




Ctx


AD 2 Temporal Ctx
48.0
Control 3 Occipital
18.8




Ctx


AD 3 Temporal Ctx
15.4
Control 4 Occipital
13.9




Ctx


AD 4 Temporal Ctx
13.9
Control (Path) 1
100.0




Occipital Ctx


AD 5 Inf Temporal
86.5
Control (Path) 2
15.3


Ctx

Occipital Ctx


AD 5 Sup Temporal
64.6
Control (Path) 3
9.4


Ctx

Occipital Ctx


AD 6 Inf Temporal
62.4
Control (Path) 4
18.9


Ctx

Occipital Ctx


AD 6 Sup Temporal
63.7
Control 1 Parietal
17.8


Ctx

Ctx


Control 1 Temporal
14.1
Control 2 Parietal
40.1


Ctx

Ctx


Control 2 Temporal
40.1
Control 3 Parietal
16.2


Ctx

Ctx


Control 3 Temporal
21.9
Control (Path) 1
94.0


Ctx

Parietal Ctx


Control 4 Temporal
13.9
Control (Path) 2
36.3


Ctx

Parietal Ctx


Control (Path) 1
67.8
Control (Path) 3
11.7


Temporal Ctx

Parietal Ctx


Control (Path) 2
37.4
Control (Path) 4
36.1


Temporal Ctx

Parietal Ctx










[1138]

439





TABLE AJC










General_screening_panel_v1.4











Rel. Exp. (%) Ag3623,

Rel. Exp. (%) Ag3623,


Tissue Name
Run 218211559
Tissue Name
Run 218211559













Adipose
3.9
Renal ca. TK-10
33.2


Melanoma*
22.8
Bladder
9.1


Hs688(A).T


Melanoma*
27.7
Gastric ca. (liver met.)
29.7


Hs688(B).T

NCI-N87


Melanoma* M14
29.1
Gastric ca. KATO III
100.0


Melanoma*
27.4
Colon ca. SW-948
15.0


LOXIMVI


Melanoma* SK-
14.8
Colon ca. SW480
45.4


MEL-5


Squamous cell
9.1
Colon ca.* (SW480
23.7


carcinoma SCC-4

met) SW620


Testis Pool
8.4
Colon ca. HT29
12.7


Prostate ca.* (bone
29.5
Colon ca. HCT-116
28.7


met) PC-3


Prostate Pool
3.2
Colon ca. CaCo-2
17.8


Placenta
16.0
Colon cancer tissue
13.8


Uterus Pool
1.8
Colon ca. SW1116
7.4


Ovarian ca. OVCAR-
13.1
Colon ca. Colo-205
11.5


3


Ovarian ca. SK-OV-
39.8
Colon ca. SW-48
13.5


3


Ovarian ca. OVCAR-
25.0
Colon Pool
8.0


4


Ovarian ca. OVCAR-
40.9
Small Intestine Pool
6.9


5


Ovarian ca. IGROV-
19.9
Stomach Pool
3.4


1


Ovarian ca. OVCAR-
14.5
Bone Marrow Pool
2.8


8


Ovary
6.7
Fetal Heart
9.2


Breast ca. MCF-7
23.3
Heart Pool
3.5


Breast ca. MDA-
40.3
Lymph Node Pool
8.7


MB-231


Breast ca. BT 549
11.8
Fetal Skeletal Muscle
3.7


Breast ca. T47D
69.7
Skeletal Muscle Pool
7.8


Breast ca. MDA-N
15.4
Spleen Pool
3.4


Breast Pool
7.3
Thymus Pool
6.8


Trachea
8.8
CNS cancer (glio/astro)
28.9




U87-MG


Lung
1.0
CNS cancer (glio/astro)
52.9




U-118-MG


Fetal Lung
6.7
CNS cancer (neuro; met)
20.2




SK-N-AS


Lung ca. NCI-N417
7.2
CNS cancer (astro) SF-
12.8




539


Lung ca. LX-1
19.2
CNS cancer (astro)
54.3




SNB-75


Lung ca. NCI-H146
12.1
CNS cancer (glio) SNB-
21.8




19


Lung ca. SHP-77
23.5
CNS cancer (glio) SF-
50.7




295


Lung ca. A549
28.7
Brain (Amygdala) Pool
3.7


Lung ca. NCI-H526
13.8
Brain (cerebellum)
9.2


Lung ca. NCI-H23
26.6
Brain (fetal)
11.3


Lung ca. NCI-H460
7.6
Brain (Hippocampus)
3.6




Pool


Lung ca. HOP-62
14.4
Cerebral Cortex Pool
4.0


Lung ca. MCI-H522
19.9
Brain (Substantia nigra)
5.6




Pool


Liver
2.9
Brain (Thalamus) Pool
5.6


Fetal Liver
13.6
Brain (whole)
6.3


Liver ca. HepG2
12.8
Spinal Cord Pool
5.2


Kidney Pool
18.4
Adrenal Gland
12.7


Fetal Kidney
5.2
Pituitary gland Pool
2.5


Renal ca. 786-0
14.7
Salivary Gland
11.5


Renal ca. A498
7.3
Thyroid (female)
13.0


Renal ca. ACHN
7.6
Pancreatic ca. CAPAN2
20.9


Renal ca. UO-31
15.9
Pancreas Pool
12.7










[1139]

440





TABLE AJD










Panel 4.1D











Rel. Exp. (%)

Rel. Exp. (%)



Ag3623, Run

Ag3623, Run


Tissue Name
169944863
Tissue Name
169944863













Secondary Th1 act
73.7
HUVEC IL-1 beta
68.8


Secondary Th2 act
100.0
HUVEC IFN gamma
51.8


Secondary Tr1 act
84.7
HUVEC TNF alpha + IFN
49.0




gamma


Secondary Th1 rest
16.4
HUVEC TNF alpha + IL4
53.6


Secondary Th2 rest
30.4
HUVEC IL-11
20.6


Secondary Tr1 rest
28.3
Lung Microvascular EC
79.0




none


Primary Th1 act
88.3
Lung Microvascular EC
71.7




TNFalpha + IL-1beta


Primary Th2 act
85.9
Microvascular Dermal EC
56.6




none


Primary Tr1 act
97.9
Microvascular Dermal EC
36.6




TNFalpha + IL-1beta


Primary Th1 rest
29.7
Bronchial epithelium
31.4




TNFalpha + IL1beta


Primary Th2 rest
34.2
Small airway epithelium
32.3




none


Primary Tr1 rest
39.5
Small airway epithelium
54.3




TNFalpha + IL-1beta


CD45RA CD4
76.3
Coronery artery SMC rest
43.2


lymphocyte act


CD45RO CD4
74.2
Coronery artery SMC
47.3


lymphocyte act

TNFalpha + IL-1beta


CD8 lymphocyte act
81.8
Astrocytes rest
37.1


Secondary CD8
75.3
Astrocytes TNFalpha + IL-
37.4


lymphocyte rest

1beta


Secondary CD8
48.0
KU-812 (Basophil) rest
18.0


lymphocyte act


CD4 lymphocyte none
13.0
KU-812 (Basophil)
47.6




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
36.1
CCD1106 (Keratinocytes)
59.9


CD95 CH11

none


LAK cells rest
36.3
CCD1106 (Keratinocytes)
36.1




TNFalpha + IL-1beta


LAK cells IL-2
51.4
Liver cirrhosis
6.1


LAK cells IL-2 + IL-12
62.4
NCI-H292 none
30.6


LAK cells IL-2 + IFN
67.8
NCI-H292 IL-4
54.7


gamma


LAK cells IL-2 + IL-18
62.4
NCI-H292 IL-9
74.7


LAK cells
31.6
NCI-H292 IL-13
61.1


PMA/ionomycin


NK Cells IL-2 rest
44.1
NCI-H292 IFN gamma
72.7


Two Way MLR 3 day
47.0
HPAEC none
42.3


Two Way MLR 5 day
49.3
HPAEC TNF alpha + IL-1
63.3




beta


Two Way MLR 7 day
33.4
Lung fibroblast none
40.6


PBMC rest
15.3
Lung fibroblast TNF
27.5




alpha + IL-1 beta


PBMC PWM
79.6
Lung fibroblast IL-4
67.4


PBMC PHA-L
62.4
Lung fibroblast IL-9
86.5


Ramos (B cell) none
97.9
Lung fibroblast IL-13
71.2


Ramos (B cell)
77.9
Lung fibroblast IFN
77.4


ionomycin

gamma


B lymphocytes PWM
67.8
Dermal fibroblast
77.9




CCD1070 rest


B lymphocytes CD40L
39.8
Dermal fibroblast
87.1


and IL-4

CCD1070 TNF alpha


EOL-1 dbcAMP
33.2
Dermal fibroblast
47.0




CCD1070 IL-1 beta


EOL-1 dbcAMP
38.7
Dermal fibroblast IFN
40.6


PMA/ionomycin

gamma


Dendritic cells none
48.3
Dermal fibroblast IL-4
75.3


Dendritic cells LPS
40.6
Dermal Fibroblasts rest
59.0


Dendritic cells anti-
59.5
Neutrophils TNFa + LPS
2.6


CD40


Monocytes rest
40.3
Neutrophils rest
9.1


Monocytes LPS
45.1
Colon
18.7


Macrophages rest
41.8
Lung
34.4


Macrophages LPS
24.3
Thymus
29.5


HUVEC none
41.2
Kidney
38.7


HUVEC starved
43.2










[1140] CNS_neurodegeneration_v1.0 Summary: Ag3623 This panel confirms the expression of the CG59859-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.


[1141] General_screening_panel_v1.4 Summary: Ag3623 Highest expression of the CG59859-01 gene is detected in samples derived from gastric cancer KATO III cell line (CT=25). Furthermore, high expression of this gene is seen in samples derived from CNS cancer, colon cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer and melanoma cells. Therefore, expression of this gene can be used to distinguish these samples from other samples in the panel and also as a marker in detection of these cancers. In addition, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of these cancers.


[1142] In addition, this gene is expressed at significant levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.


[1143] Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.


[1144] Panel 4.1D Summary: Ag3623 Highest expression of the CG59859-01 gene is detected in activated secondary Th2 cells (CT=28.8). In high expression of this gene is seen in activated primary and secondary—Th1, Th2 and Tr1 cells (CTs=29) as compared to corresponding resting cells (CTs=30-31). Therefore expression of this gene can be used to distinguish between these activated versus resting cells.


[1145] Also, this gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_v1.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.


[1146] Interestingly, expression of this gene is stimulated in PWM/PHA-L treated PBMC cells and PMA/ionomycin treated KU-812 cells (basophils) (CTs=29) as compared to the corresponding untreated/resting cells (CTs=31). Therefore, expression of this gene can be used to distinguish these treated versus untreated cells. In addition, antibody or small molecule therapies designed with the protein encoded for by this gene could block or inhibit inflammation or tissue damage due to basophil activation or PBMC activation in response to systemic lupus erythematosus, Crohn's disease, ulcerative colitis, multiple sclerosis, chronic obstructive pulmonary disease, asthma, emphysema, rheumatoid arthritis, allergies, hypersensitivity reactions, psoriasis, and viral infections.



AK. NOV46a (CG59913-01: ATP-BINDING CASSETTE TRANSPORTER)

[1147] Expression of gene CG59913-01 was assessed using the primer-probe set Ag363 1, described in Table AKA. Results of the RTQ-PCR runs are shown in Tables AKB, AKC and AKD.
441TABLE AKAProbe Name Ag3631StartPrimersSequencesLengthPositionForward5′-cagttccaacatcaggttcagt-3′(SEQ ID NO:359)221614ProbeTET-5′-aatcacacactttcaagaatggctga-3′-TAMRA(SEQ ID NO:360)261646Reverse5′-ttgtggacaaaatccagtgaa-3′(SEQ ID NO:361)211691


[1148]

442





TABLE AKB










CNS_neurodegeneration_v1.0











Rel. Exp. (%) Ag3631,

Rel. Exp. (%) Ag3631,


Tissue Name
Run 211020526
Tissue Name
Run 211020526













AD 1 Hippo
6.8
Control (Path) 3
3.3




Temporal Ctx


AD 2 Hippo
16.7
Control (Path) 4
37.6




Temporal Ctx


AD 3 Hippo
4.2
AD 1 Occipital Ctx
11.9


AD 4 Hippo
3.3
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 Hippo
100.0
AD 3 Occipital Ctx
5.7


AD 6 Hippo
24.7
AD 4 Occipital Ctx
14.9


Control 2 Hippo
4.8
AD 5 Occipital Ctx
22.4


Control 4 Hippo
8.0
AD 6 Occipital Ctx
17.4


Control (Path) 3
6.1
Control 1 Occipital
3.3


Hippo

Ctx


AD 1 Temporal Ctx
14.7
Control 2 Occipital
33.2




Ctx


AD 2 Temporal Ctx
16.0
Control 3 Occipital
9.9




Ctx


AD 3 Temporal Ctx
5.0
Control 4 Occipital
1.6




Ctx


AD 4 Temporal Ctx
13.2
Control (Path) 1
55.5




Occipital Ctx


AD 5 Inf Temporal
61.1
Control (Path) 2
10.2


Ctx

Occipital Ctx


AD 5 Sup Temporal
27.7
Control (Path) 3
4.2


Ctx

Occipital Ctx


AD 6 Inf Temporal
35.6
Control (Path) 4
28.9


Ctx

Occipital Ctx


AD 6 Sup Temporal
31.6
Control 1 Parietal
5.6


Ctx

Ctx


Control 1 Temporal
6.5
Control 2 Parietal
31.4


Ctx

Ctx


Control 2 Temporal
10.6
Control 3 Parietal
7.0


Ctx

Ctx


Control 3 Temporal
9.5
Control (Path) 1
42.6


Ctx

Parietal Ctx


Control 3 Temporal
3.5
Control (Path) 2
27.4


Ctx

Parietal Ctx


Control (Path) 1
44.4
Control (Path) 3
3.8


Temporal Ctx

Parietal Ctx


Control (Path) 2
26.6
Control (Path) 4
44.8


Temporal Ctx

Parietal Ctx










[1149]

443





TABLE AKC










General_screening_panel_v1.4











Rel. Exp. (%) Ag3631,

Rel. Exp. (%) Ag3631,


Tissue Name
Run 218233412
Tissue Name
Run 218233412













Adipose
36.1
Renal ca. TK-10
0.1


Melanoma*
3.0
Bladder
10.9


Hs688 (A).T


Melanoma*
2.0
Gastric ca. (liver met.)
0.0


Hs688 (B).T

NCI-N87


Melanoma* M14
0.4
Gastric ca. KATO III
0.0


Melanoma*
0.0
Colon ca. SW-948
0.1


LOXIMVI


Melanoma* SK-
0.5
Colon ca. SW480
0.0


MEL-5


Squamous cell
0.0
Colon ca.* (SW480
0.0


carcinoma SCC-4

met) SW620


Testis Pool
14.0
Colon ca. HT29
0.0


Prostate ca.* (bone
0.1
Colon ca. HCT-116
0.0


met) PC-3


Prostate Pool
2.9
Colon ca. CaCo-2
0.4


Placenta
0.2
Colon cancer tissue
2.1


Uterus Pool
20.4
Colon ca. SW1116
0.0


Ovarian ca. OVCAR-
0.1
Colon ca. Colo-205
0.0


3


Ovarian ca. SK-OV-
0.7
Colon ca. SW-48
0.0


3


Ovarian ca. OVCAR-
0.0
Colon Pool
36.9


4


Ovarian ca. OVCAR-
0.4
Small Intestine Pool
28.5


5


Ovarian ca. IGROV-
0.3
Stomach Pool
14.5


1


Ovarian ca. OVCAR-
0.0
Bone Marrow Pool
9.5


8


Ovary
21.5
Fetal Heart
23.7


Breast ca. MCF-7
0.2
Heart Pool
21.9


Breast ca. MDA-
0.0
Lymph Node Pool
27.7


MB-231


Breast ca. BT 549
0.3
Fetal Skeletal Muscle
15.2


Breast ca. T47D
0.1
Skeletal Muscle Pool
21.2


Breast ca. MDA-N
3.4
Spleen Pool
5.8


Breast Pool
25.3
Thymus Pool
12.3


Trachea
16.5
CNS cancer (glio/astro)
0.0




U87-MG


Lung
28.5
CNS cancer (glio/astro)
0.0




U-118-MG


Fetal Lung
20.9
CNS cancer (neuro; met)
0.6




SK-N-AS


Lung ca. NCI-N417
0.0
CNS cancer (astro) SF-
0.0




539


Lung ca. LX-1
0.4
CNS cancer (astro)
0.0




SNB-75


Lung ca. NCI-H146
0.2
CNS cancer (glio) SNB-
0.1




19


Lung ca. SHP-77
0.0
CNS cancer (glio) SF-
0.7




295


Lung ca. A549
0.0
Brain (Amygdala) Pool
4.4


Lung ca. NCI-H526
0.0
Brain (cerebellum)
1.5


Lung ca. NCI-H23
0.5
Brain (fetal)
3.3


Lung ca. NCI-H460
0.4
Brain (Hippocampus)
4.3




Pool


Lung ca. HOP-62
0.3
Cerebral Cortex Pool
5.6


Lung ca. NCI-H522
0.0
Brain (Substansia nigra)
4.4




Pool


Liver
0.9
Brain (Thalamus) Pool
7.3


Fetal Liver
11.4
Brain (whole)
4.3


Liver ca. HepG2
0.2
Spinal Cord Pool
6.7


Kidney Pool
100.0
Adrenal Gland
5.7


Fetal Kidney
3.6
Pituitary gland Pool
2.8


Renal ca. 786-0
0.0
Salivary Gland
1.8


Renal ca. A498
0.0
Thyroid (female)
4.2


Renal ca. ACHN
0.0
Pancreatic ca. CAPAN2
0.0


Renal ca. UO-31
1.4
Pancreas Pool
20.9










[1150]

444





TABLE AKD










Panel 4.1D











Rel. Exp. (%)

Rel. Exp. (%)



Ag3631, Run

Ag3631, Run


Tissue Name
169960855
Tissue Name
169960855













Secondary Th1 act
0.0
HUVEC IL-1 beta
7.1


Secondary Th2 act
0.0
HUVEC IFN gamma
32.1


Secondary Tr1 act
0.0
HUVEC TNF alpha + IFN
1.2




gamma


Secondary Th1 rest
0.8
HUVEC TNF alpha + IL4
3.8


Secondary Th2 rest
2.7
HUVEC IL-11
8.6


Secondary Tr1 rest
3.2
Lung Microvascular EC
14.8




none


Primary Th1 act
0.0
Lung Microvascular EC
8.2




TNFalpha + IL-1 beta


Primary Th2 act
0.5
Microvascular Dermal EC
14.7




none


Primary Tr1 act
0.0
Microvascular Dermal EC
9.3




TNFalpha + IL-1beta


Primary Th1 rest
0.9
Bronchial epithelium
9.6




TNFalpha + IL1beta


Primary Th2 rest
9.3
Small airway epithelium
2.3




none


Primary Tr1 rest
0.5
Small airway epithelium
3.0




TNFalpha + IL-1beta


CD45RA CD4
0.8
Coronery artery SMC rest
96.6


lymphocyte act


CD45RO CD4
1.4
Coronery artery SMC
81.2


lymphocyte act

TNFalpha + IL-1beta


CD8 lymphocyte act
0.0
Astrocytes rest
0.0


Secondary CD8
0.0
Astrocytes TNFalpha + IL-
0.6


lymphocyte rest

1beta


Secondary CD8
0.0
KU-812 (Basophil) rest
0.0


lymphocyte act


CD4 lymphocyte none
0.4
KU-812 (Basophil)
0.0




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
3.8
CCD1106 (Keratinocytes)
0.0


CD95 CH11

none


LAK cells rest
1.6
CCD1106 (Keratinocytes)
0.6




TNF-alpha + IL-1beta


LAK cells IL-2
0.0
Liver cirrhosis
33.0


LAK cells IL-2 + IL-12
1.3
NCI-H292 none
0.0


LAK cells IL-2 + IFN
1.0
NCI-H292 IL-4
0.0


gamma


LAK cells IL-2 + IL-18
0.3
NCI-H292 IL-9
0.0


LAK cells
1.4
NCI-H292 IL-13
0.0


PMA/ionomycin


NK Cells IL-2 rest
0.6
NCI-H292 IFN gamma
0.0


Two Way MLR 3 day
1.9
HPAEC none
94.0


Two Way MLR 5 day
1.6
HPAEC TNF alpha + IL-1
100.0




beta


Two Way MLR 7 day
0.0
Lung fibroblast none
1.0


PBMC rest
0.0
Lung fibroblast TNF
0.6




alpha + IL-1 beta


PBMC PWM
0.9
Lung fibroblast IL-4
0.5


PBMC PHA-L
0.0
Lung fibroblast IL-9
0.5


Ramos (B cell) none
0.0
Lung fibroblast IL-13
0.0


Ramos (B cell)
0.0
Lung fibroblast IFN
2.2


ionomycin

gamma


B lymphocytes PWM
0.0
Dermal fibroblast
0.5




CCD1070 rest


B lymphocytes CD40L
1.0
Dermal fibroblast
0.0


and IL-4

CCD1070 TNF alpha


EOL-1 dbcAMP
0.9
Dermal fibroblast
0.4




CCD1070 IL-1 beta


EOL-1 dbcAMP
0.5
Dermal fibroblast IFN
68.3


PMA/ionomycin

gamma


Dendritic cells none
0.9
Dermal fibroblast IL-4
24.1


Dendritic cells LPS
2.4
Dermal Fibroblasts rest
27.5


Dendritic cells anti-
1.9
Neutrophils TNFa + LPS
0.0


CD40


Monocytes rest
3.0
Neutrophils rest
0.0


Monocytes LPS
5.9
Colon
17.1


Macrophages rest
1.2
Lung
16.7


Macrophages LPS
0.7
Thymus
23.7


HUVEC none
4.7
Kidney
13.2


HUVEC starved
4.6










[1151] CNS_neurodegeneration_v1.0 Summary: Ag3631 This panel confirms the expression of the CG59913-01 gene at low levels in the brain in an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.


[1152] General_screening_panel_v1.4 Summary: Ag3631 The expression of the CG59913-01 is highest in sample derived from kidney (CT=28.23). Furhtermore, expression of this gene is very low in fetal kidney (CT=33). Thus, expression of this gene can be used in distinguishing the adult kidney from fetal kidney and also from other samples in this panel.


[1153] Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, fetal liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.


[1154] In addition, this gene is expressed at significant levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.


[1155] CG59913-01 gene codes for a variant of ATP-binding casette A9 protein, an ATP-binding cassette (ABC) transporter belonging to ABCA sub-family. The ABC superfamily comprises of myriad transmembrane proteins involved in the transport of vitamins, peptides, steroid hormones, ions, sugars, and amino acids (ref. 1). Known genetic diseases resulting from dysfunctional ABC transporters are cystic fibrosis, Zellweger syndrome, adrenoleukodystrophy, multidrug resistance, Stargardt macular dystrophy, Tangier disease (TD) and familial HDL deficiency (FHA) (ref. 2, 3). Recently, it has been shown that functional loss of ABCA1, a transporter belonging to ABCA subfamily, in mice causes severe placental malformation, aberrant lipid distribution, and kidney glomerulonephritis, as well as, high-density lipoprotein cholesterol deficiency (ref 3). CG59913-01 gene is expressed in large number of the normal tissue used in this panel. In analogy to ABCA1, this gene may also play a wider role in lipid metabolism, renal inflammation, and cardiovascular disease and CNS disorders.


[1156] References.


[1157] 1. Higgins C F. (1992) ABC transporters: from microorganisms to man. Annu Rev Cell Biol 8:67-113


[1158] PMID: 1282354


[1159] 2. Decottignies A, Goffeau A. (1997) Complete inventory of the yeast ABC proteins. Nat Genet 15(2):137-45.


[1160] The complete sequence of the yeast genome predicts the existence of 29 proteins belonging to the ubiquitous ATP-binding cassette (ABC) superfamily. Using binary comparison, phylogenetic classification and detection of conserved amino acid residues, the yeast ABC proteins have been classified in a total of six clusters, including ten subclusters of distinct predicted topology and presumed distinct function. Study of the yeast ABC proteins provides insight into the physiological function and biochemical mechanisms of their human homologues, such as those involved in cystic fibrosis, adrenoleukodystrophy, Zellweger syndrome, multidrug resistance and the antiviral activity of interferons.


[1161] PMID: 9020838


[1162] 3. Christiansen-Weber T A, Voland J R, Wu Y, Ngo K, Roland B L, Nguyen S, Peterson P A, Fung-Leung W P. (2000) Functional loss of ABCA1 in mice causes severe placental malformation, aberrant lipid distribution, and kidney glomerulonephritis as well as high-density lipoprotein cholesterol deficiency. Am J Pathol September 2000;157(3):1017-29


[1163] Tangier disease (TD) and familial HDL deficiency (FHA) have recently been linked to mutations in the human ATP-binding cassette transporter 1 (hABCA1), a member of the ABC superfamily. Both diseases are characterized by the lowering or lack of high-density lipoprotein cholesterol (HDL-C) and low serum cholesterol. The murine ABCA1−/− phenotype corroborates the human TD linkage to ABCA1. Similar to TD in humans, HDL-C is virtually absent in ABCA1−/− mice accompanied by a reduction in serum cholesterol and lipid deposition in various tissues. In addition, the placenta of ABCA1−/− mice is malformed, resulting in severe embryo growth retardation, fetal loss, and neonatal death. The basis for these defects appears to be altered steroidogenesis, a direct result of the lack of HDL-C. By 6 months of age, ABCA1−/− animals develop membranoproliferative glomerulonephritis due to deposition of immunocomplexes followed by cardiomegaly with ventricular dilation and hypertrophy, ultimately succumbing to congestive heart failure. This murine model of TD will be very useful in the study of lipid metabolism, renal inflammation, and cardiovascular disease and may reveal previously unsuspected relationships between them.


[1164] PMID: 10980140


[1165] Panel 4.1D Summary: Ag3631 The expression of the CG59913-01 gene is high in sample derived from HPAEC and coronary artery SMC cell lines(CTs=30). Thus, expression of this gene can be used to distinguish these samples from other samples in this panel.


[1166] Interestingly, expression of this gene is stimulated on treatment of dermal fibroblast and HUVEC cells with IFN gama (CTs=31-32). Therefore, therapeutics designed with the protein encoded for by this transcript could be important treating diseases such as asthma, arthritis, psoriasis, IBD, and systemic lupus erythematosus.


[1167] Significant expression of this gene is also detected in a liver cirrhosis sample (CT=32). Furthermore, expression of this gene is low/undetectable in normal liver (CT=35)in Panel 1.4, suggesting that its expression is unique to liver cirrhosis. Therefore, antibodies or small molecule therapeutics could reduce or inhibit fibrosis that occurs in liver cirrhosis.


[1168] This gene is expressed at moderate levels in the normal colon, lung, thymus and kidney tissues (CTs=32-33). This ubiquitous pattern of expression in normal tissues suggests that this gene product may be involved in homeostatic processes for these tissues. This pattern is in agreement with the expression profile in General_screening_panel_v1.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.



AL. NOV47a (CG59909-01: ATP-BINDING CASSETTE TRANSPORTER)

[1169] Expression of gene CG59909-01 was assessed using the primer-probe set Ag3630, described in Table ALA. Results of the RTQ-PCR runs are shown in Tables ALB, ALC and ALD.
445TABLE ALAProbe Name Ag3630StartPrimersSequencesLengthPositionForward5′-ttccaacaccaaaggactaatg-3′(SEQ ID NO:362)221339ProbeTET-5′-aaatcgatgctgagcatccctctgat-3′-TAMRA(SEQ ID NO:363)261379Reverse5′-ttcaggagctactggttcaaaa-3′(SEQ ID NO:364)221410


[1170]

446





TABLE ALB










CNS_neurodegeneration_v1.0













Rel. Exp.(%)
Rel. Exp.(%)

Rel. Exp.(%)
Rel. Exp.(%)



Ag3630, Run
Ag3630, Run
Tissue
Ag3630, Run
Ag3630, Run


Tissue Name
211020447
224079049
Name
211020447
224079049















AD 1 Hippo
10.7
10.7
Control
4.4
3.2





(Path) 3





Temporal





Ctx


AD 2 Hippo
26.1
25.5
Control
21.6
22.4





(Path) 4





Temporal





Ctx


AD 3 Hippo
6.5
8.4
AD 1
19.9
26.8





Occipital





Ctx


AD 4 Hippo
9.3
8.1
AD 2
0.0
0.0





Occipital





Ctx





(Missing)


AD 5 hippo
77.9
79.0
AD 3
8.8
12.6





Occipital





Ctx


AD 6 Hippo
64.2
51.4
AD 4
20.4
24.3





Occipital





Ctx


Control 2 Hippo
10.8
11.4
AD 5
29.7
35.1





Occipital





Ctx


Control 4 Hippo
6.8
5.5
AD 6
18.7
22.1





Occipital





Ctx


Control (Path) 3
9.1
9.9
Control 1
1.9
3.3


Hippo


Occipital





Ctx


AD 1 Temporal
26.1
29.7
Control 2
30.8
35.6


Ctx


Occipital





Ctx


AD 2 Temporal
21.0
31.2
Control 3
19.5
23.5


Ctx


Occipital





Ctx


AD 3 Temporal
8.0
8.7
Control 4
2.4
3.3


Ctx


Occipital





Ctx


AD 4 Temporal
20.6
25.5
Control
53.2
81.2


Ctx


(Path) 1





Occipital





Ctx


AD 5 Inf
100.0
100.0
Control
10.9
14.0


Temporal Ctx


(Path) 2





Occipital





Ctx


AD 5
32.5
50.7
Control
5.4
5.4


SupTemporal


(Path) 3


Ctx


Occipital





Ctx


AD 6 Inf
56.3
69.3
Control
17.0
23.7


Temporal Ctx


(Path) 4





Occipital





Ctx


AD 6 Sup
52.1
62.4
Control 1
4.4
4.9


Temporal Ctx


Parietal Ctx


Control 1
4.0
6.0
Control 2
57.4
54.3


Temporal Ctx


Parietal Ctx


Control 2
10.0
20.9
Control 3
18.4
20.9


Temporal Ctx


Parietal Ctx


Control 3
11.3
12.5
Control
29.3
48.0


Temporal Ctx


(Path) 1





Parietal Ctx


Control 4
7.1
7.2
Control
19.8
24.0


Temporal Ctx


(Path) 2





Parietal Ctx


Control (Path) 1
29.1
31.6
Control
4.8
5.5


Temporal Ctx


(Path) 3





Parietal Ctx


Control (Path) 2
20.9
25.5
Control
38.2
45.4


Temporal Ctx


(Path) 4





Parietal Ctx










[1171]

447





TABLE ALC










General_screening_panel_v1.4











Rel. Exp. (%) Ag3630,

Rel. Exp. (%) Ag3630,


Tissue Name
Run 218212091
Tissue Name
Run 218212091













Adipose
0.9
Renal ca. TK-10
0.0


Melanoma*
3.6
Bladder
52.9


Hs688 (A).T


Melanoma*
1.7
Gastric ca. (liver met.)
0.7


Hs688 (B).T

NCI-N87


Melanoma* M14
0.4
Gastric ca. KATO III
0.0


Melanoma*
0.1
Colon ca. SW-948
0.0


LOXIMVI


Melanoma* SK-
0.5
Colon ca. SW480
0.0


MEL-5


Squamous cell
0.0
Colon ca.* (SW480
0.1


carcinoma SCC-4

met) SW620


Testis Pool
11.8
Colon ca. HT29
0.0


Prostate ca.* (bone
0.2
Colon ca. HCT-116
0.2


met) PC-3


Prostate Pool
6.4
Colon ca. CaCo-2
0.4


Placenta
0.2
Colon cancer tissue
5.7


Uterus Pool
20.7
Colon ca. SW1116
0.0


Ovarian ca. OVCAR-
0.0
Colon ca. Colo-205
0.8


3


Ovarian ca. SK-OV-
0.9
Colon ca. SW-48
0.0


3


Ovarian ca. OVCAR-
0.0
Colon Pool
38.7


4


Ovarian ca. OVCAR-
0.8
Small Intestine Pool
41.8


5


Ovarian ca. IGROV-
0.2
Stomach Pool
31.4


1


Ovarian ca. OVCAR-
0.1
Bone Marrow Pool
13.0


8


Ovary
47.6
Fetal Heart
20.7


Breast ca. MCF-7
0.7
Heart Pool
18.4


Breast ca. MDA-
0.2
Lymph Node Pool
24.1


MB-231


Breast ca. BT 549
0.9
Fetal Skeletal Muscle
27.0


Breast ca. T47D
0.5
Skeletal Muscle Pool
29.5


Breast ca. MDA-N
0.0
Spleen Pool
21.5


Breast Pool
39.0
Thymus Pool
20.7


Trachea
24.1
CNS cancer (glio/astro)
0.1




U87-MG


Lung
29.9
CNS cancer (glio/astro)
0.0




U-118-MG


Fetal Lung
100.0
CNS cancer (neuro; met)
0.0




SK-N-AS


Lung ca. NCI-N417
0.0
CNS cancer (astro) SF-
0.1




539


Lung ca. LX-1
0.0
CNS cancer (astro)
0.1




SNB-75


Lung ca. NCI-H146
0.0
CNS cancer (glio) SNB-
0.2




19


Lung ca. SHP-77
0.0
CNS cancer (glio) SF-
5.3




295


Lung ca. A549
0.0
Brain (Amygdala) Pool
7.6


Lung ca. NCI-H526
0.0
Brain (cerebellum)
5.0


Lung ca. NCI-H23
3.7
Brain (fetal)
2.5


Lung ca. NCI-H460
3.0
Brain (Hippocampus)
7.8




Pool


Lung ca. HOP-62
2.5
Cerebral Cortex Pool
9.7


Lung ca. NCI-H522
0.0
Brain (Substantia nigra)
6.2




Pool


Liver
5.8
Brain (Thalamus) Pool
15.3


Fetal Liver
80.1
Brain (whole)
11.7


Liver ca. HepG2
0.0
Spinal Cord Pool
21.2


Kidney Pool
79.0
Adrenal Gland
16.3


Fetal Kidney
5.2
Pituitary gland Pool
3.7


Renal ca. 786-0
0.0
Salivary Gland
4.6


Renal ca. A498
0.1
Thyroid (female)
3.2


Renal ca. ACHN
0.0
Pancreatic ca. CAPAN2
0.0


Renal ca. UO-31
0.2
Pancreas Pool
25.5










[1172]

448





TABLE ALD










Panel 4.1D











Rel. Exp.(%)

Rel. Exp.(%)



Ag3630, Run

Ag3630, Run


Tissue Name
169960853
Tissue Name
169960853













Secondary Th1 act
0.4
HUVEC IL-1 beta
20.3


Secondary Th2 act
0.3
HUVEC IFN gamma
57.4


Secondary Tr1 act
0.0
HUVEC TNF alpha + IFN
8.5




gamma


Secondary Th1 rest
0.3
HUVEC TNF alpha + IL4
8.0


Secondary Th2 rest
0.7
HUVEC IL-11
28.5


Secondary Tr1 rest
0.2
Lung Microvascular EC
10.4




none


Primary Th1 act
0.2
Lung Microvascular EC
6.6




TNF alpha + IL-1 beta


Primary Th2 act
0.0
Microvascular Dermal EC
24.3




none


Primary Tr1 act
0.2
Microsvasular Dermal EC
16.7




TNF alpha + IL-1 beta


Primary Th1 rest
0.5
Bronchial epithelium
3.0




TNF alpha + IL1 beta


Primary Th2 rest
0.3
Small airway epithelium
3.5




none


Primary Tr1 rest
0.7
Small airway epithelium
2.2




TNF alpha + IL-1 beta


CD45RA CD4
1.0
Coronery artery SMC rest
68.3


lymphocyte act


CD45RO CD4
0.1
Coronery artery SMC
44.1


lymphocyte act

TNF alpha + IL-1 beta


CD8 lymphocyte act
0.0
Astrocytes rest
0.0


Secondary CD8
0.0
Astrocytes TNF alpha + IL-
0.1


lymphocyte rest

1 beta


Secondary CD8
0.0
KU-812 (Basophil) rest
0.0


lymphocyte act


CD4 lymphocyte none
1.7
KU-812 (Basophil)
0.0




PMA/ionomycin


2ry Th1/Th2/Tr1_anti-
0.8
CCD1106 (Keratinocytes)
0.5


CD95 CH11

none


LAK cells rest
1.9
CCD1106 (Keratinocytes)
0.6




TNF alpha + IL-1 beta


LAK cells IL-2
0.3
Liver cirrhosis
37.1


LAK cells IL-2 + IL-12
0.4
NCI-H292 none
0.2


LAK cells IL-2 + IFN
1.7
NCI-H292 IL-4
0.0


gamma


LAK cells IL-2 + IL-18
1.6
NCI-H292 IL-9
0.0


LAK cells
0.6
NCI-H292 IL-13
0.0


PMA/ionomycin


NK Cells IL-2 rest
0.4
NCI-H292 IFN gamma
0.0


Two Way MLR 3 day
1.1
HPAEC none
73.2


Two Way MLR 5 day
0.4
HPAEC TNF alpha + IL-1
100.0




beta


Two Way MLR 7 day
0.0
Lung fibroblast none
1.8


PBMC rest
0.1
Lung fibroblast TNF
6.0




alpha + IL-1 beta


PBMC PWM
0.2
Lung fibroblast IL-4
1.3


PBMC PHA-L
0.2
Lung fibroblast IL-9
1.6


Ramos (B cell) none
0.0
Lung fibroblast IL-13
1.3


Ramos (B cell)
0.0
Lung fibroblast IFN
2.0


ionomycin

gamma


B lymphocytes PWM
0.0
Dermal fibroblast
0.3




CCD1070 rest


B lymphocytes CD40L
0.9
Dermal fibroblast
0.3


and IL-4

CCD1070 TNF alpha


EOL-1 dbcAMP
0.0
Dermal fibroblast
0.5




CCD1070 IL-1 beta


EOL-1 dbcAMP
0.0
Dermal fibroblast IFN
53.6


PMA/ionomycin

gamma


Dendritic cells none
2.5
Dermal fibroblast IL-4
37.6


Dendritic cells LPS
2.8
Dermal Fibroblasts rest
25.2


Dendritic cells anti-
4.9
Neutrophils TNFa + LPS
0.0


CD40


Monocytes rest
0.4
Neutrophils rest
0.3


Monocytes LPS
5.9
Colon
11.3


Macrophages rest
0.9
Lung
27.4


Macrophages LPS
8.7
Thymus
24.7


HUVEC none
5.8
Kidney
19.8


HUVEC starved
9.8










[1173] CNS_neurodegeneration_v1.0 Summary: Ag3630,Two experiments with the same probe and primer set produce results that are in excellent agreement. This panel confirms the expression of this gene at low to moderate levels in the brains of an independent group of individuals. Expression of this gene is found to be up-regulated in the temporal cortex of Alzheimer's disease patients. Therefore, blockade of this protein product may be of use in reversing the dementia/memory loss associated with Alzheimer's disease and neuronal death.


[1174] General_screening_panel_v1.4 Summary: Ag3630 The CG59909-01 gene is expressed primarily in normal tissue samples, with highest expression in the fetal lung (CT=26.3).


[1175] This gene has low-to-moderate expression in adipose, liver, heart, skeletal muscle, adrenal, pituitary and pancreas. By homology, this gene product is a lipid or cholesterol transporter and can be expected to play a critical role in metabolic processes. Therapeutic modulation of ag3630 may be a treatment for endocrine or metabolic disease, including Types 1 and 2 diabetes and obesity.


[1176] Interestingly, this gene is expressed at much higher levels in fetal (CT=26.3) when compared to adult liver (CT=30.5). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver.


[1177] In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.


[1178] Panel 4.1D Summary: Ag3630 Highest expression of the CG59909-01 gene is detected in TNF alpha+IL-1beta treated HPAEC (CT=28.5). In addition, this gene is expressed in endothelium, smooth muscle cells and fibroblasts. It is also expressed in normal kidney, lung, colon, and thymus. The transcript was particularly induced by gamma interferon in HUVEC cells. HUVEC cells have been used in many in vitro models to examine leukocyte extravsation. Gamma interferon treatment induces the expression many proteins in HUVEC cells that induce leukocyte rolling and binding, necessary steps in the movement of leukocytes from the blood into the periphery. The putative transporter encoded for by this transcript could be important in endothelium mediated leukocyte recruitment and thus be an important target for the treatment of inflammation associated with asthma, emphysema, psoriasis, and arthritis.


[1179] Reference.


[1180] 1. Lidington E A, Moyes D L, McCormack A M, Rose M L. (1999) A comparison of primary endothelial cells and endothelial cell lines for studies of immune interactions. Transpl Immunol December 1999;7(4):239-46



AM. NOV48a (CG59945-01: STEROID HORMONE RECEPTOR)

[1181] Expression of gene CG59945-01 was assessed using the primer-probe sets Ag3632 and ag3666, described in Tables AMA and AMB. Results of the RTQ-PCR runs are shown in Tables AMC, and AMD.
449TABLE AMAProbe Name Ag3632StartPrimersSequencesLengthPositionForward5′-atggtggttgagcctgaga-3′(SEQ ID NO:365)19904ProbeTET-5′-agctctatgccttgcccgaccct-3′-TAMRA(SEQ ID NO:366)23923Reverse5′-tcggtcaaagaggtcacaga-3′(SEQ ID NO:367)20983


[1182]

450





TABLE AMB










Probe Name ag3666













Start


Primers
Sequences
Length
Position














Forward
5′-gttcccttgatggaaaatgaag-3′
(SEQ ID NO:368)
21
14





Probe
TET-5′-cctcatctactgactctcccatccaa-3′-TAMRA
(SEQ ID NO:369)
26
35





Reverse
5′-gtgggaacttttgtcctcctt-3′
(SEQ ID NO:370)
21
76










[1183]

451





TABLE AMC










CNS_neurodegeneration_v1.0











Rel. Exp.(%) Ag3632,

Rel. Exp.(%) Ag3632,


Tissue Name
Run 211020527
Tissue Name
Run 211020527













AD 1 Hippo
26.8
Control (Path) 3
0.0




Temporal Ctx


AD 2 Hippo
40.9
Control (Path) 4
4.8




Temporal Ctx


AD 3 Hippo
28.1
AD 1 Occipital Ctx
1.7


AD 4 Hippo
0.0
AD 2 Occipital Ctx
0.0




(Missing)


AD 5 hippo
36.3
AD 3 Occipital Ctx
0.0


AD 6 Hippo
100.0
AD 4 Occipital Ctx
1.7


Control 2 Hippo
44.8
AD 5 Occipital Ctx
1.1


Control 4 Hippo
22.7
AD 6 Occipital Ctx
21.5


Control (Path) 3
50.3
Control 1 Occipital
0.0


Hippo

Ctx


AD 1 Temporal Ctx
0.0
Control 2 Occipital
7.4




Ctx


AD 2 Temporal Ctx
1.1
Control 3 Occipital
1.4




Ctx


AD 3 Temporal Ctx
0.0
Control 4 Occipital
1.5




Ctx


AD 4 Temporal Ctx
36.3
Control (Path) 1
49.0




Occipital Ctx


AD 5 Inf Temporal
13.2
Control (Path) 2
0.0


Ctx

Occipital Ctx


AD 5 SupTemporal
41.8
Control (Path) 3
1.2


Ctx

Occipital Ctx


AD 6 Inf Temporal
42.6
Control (Path) 4
17.8


Ctx

Occipital Ctx


AD 6 Sup Temporal
77.4
Control 1 Parietal
0.0


Ctx

Ctx


Control 1 Temporal
0.0
Control 2 Parietal
16.4


Ctx

Ctx


Control 2 Temporal
7.5
Control 3 Parietal
0.0


Ctx

Ctx


Control 3 Temporal
1.1
Control (Path) 1
14.6


Ctx

Parietal Ctx


Control 4 Temporal
1.9
Control (Path) 2
7.9


Ctx

Parietal Ctx


Control (Path) 1
6.3
Control (Path) 3
0.0


Temporal Ctx

Parietal Ctx


Control (Path) 2
7.6
Control (Path) 4
6.7


Temporal Ctx

Parietal Ctx










[1184]

452





TABLE AMD










General_screening_panel_v1.4











Rel. Exp.(%) Ag3632,

Rel. Exp.(%) Ag3632,


Tissue Name
Run 218233723
Tissue Name
Run 218233723













Adipose
0.0
Renal ca. TK-10
0.0


Melanoma*
0.0
Bladder
0.0


Hs688(A).T


Melanoma*
0.0
Gastric ca. (liver met.)
0.0


Hs688(B).T

NCI-N87


Melanoma* M14
0.0
Gastric ca. KATO III
0.0


Melanoma*
0.0
Colon ca. SW-948
0.0


LOXIMVI


Melanoma*
0.0
Colon ca. SW480
0.0


SK-MEL-5


Squamous cell
0.0
Colon ca.* (SW480
0.0


carcinoma SCC-4

met) SW620


Testis Pool
100.0
Colon ca. HT29
3.3


Prostate ca.* (bone
0.0
Colon ca. HCT-116
0.0


met) PC-3


Prostate Pool
0.0
Colon ca. CaCo-2
0.0


Placenta
1.5
Colon cancer tissue
0.0


Uterus Pool
4.6
Colon ca. SW1116
0.0


Ovarian ca. OVCAR-3
0.0
Colon ca. Colo-205
0.0


Ovarian ca. SK-OV-3
2.4
Colon ca. SW-48
0.0


Ovarian ca. OVCAR-4
0.0
Colon Pool
0.0


Ovarian ca. OVCAR-5
0.0
Small Intestine Pool
0.0


Ovarian ca. IGROV-1
0.0
Stomach Pool
0.0


Ovarian ca. OVCAR-8
0.0
Bone Marrow Pool
0.0


Ovary
0.0
Fetal Heart
0.0


Breast ca. MCF-7
0.0
Heart Pool
0.0


Breast ca. MDA-
0.0
Lymph Node Pool
0.0


MB-231


Breast ca. BT 549
0.0
Fetal Skeletal Muscle
0.0


Breast ca. T47D
0.0
Skeletal Muscle Pool
0.0


Breast ca. MDA-N
0.0
Spleen Pool
0.0


Breast Pool
0.0
Thymus Pool
0.0


Trachea
0.0
CNS cancer (glio/astro)
0.0




U87-MG


Lung
0.0
CNS cancer (glio/astro)
0.0




U-118-MG


Fetal Lung
0.0
CNS cancer (neuro; met)
0.0




SK-N-AS


Lung ca. NCI-N417
0.0
CNS cancer (astro) SF-
0.0




539


Lung ca. LX-1
0.0
CNS cancer (astro)
0.0




SNB-75


Lung ca. NCI-H146
0.0
CNS cancer (glio) SNB-
0.0




19


Lung ca. SHP-77
0.0
CNS cancer (glio) SF-
0.0




295


Lung ca. A549
0.0
Brain (Amygdala) Pool
0.0


Lung ca. NCI-H526
0.0
Brain (cerebellum)
0.0


Lung ca. NCI-H23
0.0
Brain (fetal)
0.0


Lung ca. NCI-H460
0.0
Brain (Hippocampus)
11.9




Pool


Lung ca. HOP-62
0.0
Cerebral Cortex Pool
0.0


Lung ca. NCI-H522
0.0
Brain (Substantia nigra)
0.0




Pool


Liver
0.0
Brain (Thalamus) Pool
2.9


Fetal Liver
0.0
Brain (whole)
0.0


Liver ca. HepG2
0.0
Spinal Cord Pool
0.0


Kidney Pool
1.6
Adrenal Gland
0.0


Fetal Kidney
1.9
Pituitary gland Pool
0.0


Renal ca. 786-0
0.0
Salivary Gland
0.0


Renal ca. A498
0.0
Thyroid (female)
0.0


Renal ca. ACHN
0.0
Pancreatic ca. CAPAN2
3.3


Renal ca. UO-31
0.0
Pancreas Pool
0.0










[1185] CNS_neurodegeneration_v1.0 Summary: Ag3632 This panel confirms the expression of The CG59945-01 gene at significant levels in the brain in an independent group of individuals. This gene is found to be upregulated in the temporal cortex of Alzheimer's disease patients. Blockade of this receptor may be of use in the treatment of this disease and decrease neuronal death.


[1186] The CG59945-01 gene, a steroid hormone receptor homolog. Steroid hormones play a role in brain development and modulating emotion, among other functions. Based on the expression of this gene in the brain and its homology to a steroid hormone receptor, this gene product may play a role in normal neurologic development and function.


[1187] Ag3666 Results from one experiment with this gene are not included. The amp plot indicates that there were experimental difficulties with this run.


[1188] References:


[1189] 1. Kawata M, Matsuda K, Nishi M, Ogawa H, Ochiai I. Intracellular dynamics of steroid hormone receptor. Neurosci Res July 2001;40(3):197-203


[1190] General_screening_panel_v1.4 Summary: Ag3632 Expression of the CG59945-01 gene is restricted to the testis (CT=33.9). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel and as a marker of testicular tissue. Furthermore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of male infertility or hypogonadism.


[1191] General_screening_panel_v1.5 Summary: Ag3666 Expression of the CG59945-01 gene is low/undetectable in all samples on this panel (CTs>35).


[1192] Panel 4.1D Summary: Ag3632/Ag3666 Expression of the CG59945-01 gene is low/undetectable in all samples on this panel (CTs>35).


[1193] Panel CNS1 Summary: Ag3666 Expression of the CG59945-01 gene is low/undetectable in all samples on this panel (CTs>35).



Example D

[1194] Identification of Single Nucleotide Polymorphisms in NOVX Nucleic Acid Sequences


[1195] Variant sequences are also included in this application. A variant sequence can include a single nucleotide polymorphism (SNP). A SNP can, in some instances, be referred to as a “cSNP” to denote that the nucleotide sequence containing the SNP originates as a cDNA. A SNP can arise in several ways. For example, a SNP may be due to a substitution of one nucleotide for another at the polymorphic site. Such a substitution can be either a transition or a transversion. A SNP can also arise from a deletion of a nucleotide or an insertion of a nucleotide, relative to a reference allele. In this case, the polymorphic site is a site at which one allele bears a gap with respect to a particular nucleotide in another allele. SNPs occurring within genes may result in an alteration of the amino acid encoded by the gene at the position of the SNP. Intragenic SNPs may also be silent, when a codon including a SNP encodes the same amino acid as a result of the redundancy of the genetic code. SNPs occurring outside the region of a gene, or in an intron within a gene, do not result in changes in any amino acid sequence of a protein but may result in altered regulation of the expression pattern. Examples include alteration in temporal expression, physiological response regulation, cell type expression regulation, intensity of expression, and stability of transcribed message.


[1196] SeqCalling assemblies produced by the exon linking process were selected and extended using the following criteria. Genomic clones having regions with 98% identity to all or part of the initial or extended sequence were identified by BLASTN searches using the relevant sequence to query human genomic databases. The genomic clones that resulted were selected for further analysis because this identity indicates that these clones contain the genomic locus for these SeqCalling assemblies. These sequences were analyzed for putative coding regions as well as for similarity to the known DNA and protein sequences. Programs used for these analyses include Grail, Genscan, BLAST, HMMER, FASTA, Hybrid and other relevant programs.


[1197] Some additional genomic regions may have also been identified because selected SeqCalling assemblies map to those regions. Such SeqCalling sequences may have overlapped with regions defined by homology or exon prediction. They may also be included because the location of the fragment was in the vicinity of genomic regions identified by similarity or exon prediction that had been included in the original predicted sequence. The sequence so identified was manually assembled and then may have been extended using one or more additional sequences taken from CuraGen Corporation's human SeqCalling database. SeqCalling fragments suitable for inclusion were identified by the CuraTools™ program SeqExtend or by identifying SeqCalling fragments mapping to the appropriate regions of the genomic clones analyzed.


[1198] The regions defined by the procedures described above were then manually integrated and corrected for apparent inconsistencies that may have arisen, for example, from miscalled bases in the original fragments or from discrepancies between predicted exon junctions, EST locations and regions of sequence similarity, to derive the final sequence disclosed herein. When necessary, the process to identify and analyze SeqCalling assemblies and genomic clones was reiterated to derive the full length sequence (Alderborn et al., Determination of Single Nucleotide Polymorphisms by Real-time Pyrophosphate DNA Sequencing. Genome Research. 10 (8) 1249-1265, 2000).


[1199] Variants are reported individually but any combination of all or a select subset of variants are also included as contemplated NOVX embodiments of the invention.



RESULTS


NOV2a SNP Data

[1200] One polymorphic variant of NOV2a has been identified and is shown in Table 3A.
453TABLE 3ANucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant1337721369TC15ThrThr



NOV4a SNP Data

[1201] Four polymorphic variants of NOV5a have been identified and are shown in Table 3B.
454TABLE 3BNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant13377217137AT40GlnHis13377216231AC72IleLeu13377215401GA128ValVal13377214417CT134GlnEnd



NOV5a SNP Data

[1202] Four polymorphic variants of NOV5a have been identified and are shown in Table 3C.
455TABLE 3CNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant133756501871AG616LysArg133756491895AG624AsnSer133756481900AG626ThrAla133756471931TC636ValAla



NOV7a SNP Data

[1203] Two polymorphic variants of NOV7a have been identified and arc shown in Table 3D.
456TABLE 3DNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant1337721890CT013377219185TC29LeuPro



NOV10s SNP Data

[1204] Two polymorphic variants of NOV10a have been identified and are shown in Table 3E.
457TABLE 3ENucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant13377221668TC6LeuLeu13377220803AT51LeuLeu



NOV11a SNP Data

[1205] Seven polymorphic variants of NOV11a have been identified and are shown in Table 3F.
458TABLE 3FNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant13374741856AG271ProPro13377222994CT317CysCys133772231234AG397ProPro133772241417CT458CysCys133747551736GA565GlySer133772262012GT657GluEnd133772272073TC677LeuPro



NOV15a SNP Data

[1206] One polymorphic variant of NOV15a has been identified and is shown in Table 3G.
459TABLE 3GNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant13377231202CT54AspAsp



NOV19a SNP Data

[1207] Two polymorphic variants of NOV19a has been identified and are shown in Table 3H.
460TABLE 3HNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant13377233348CT86HisHis13377232516TC142HisHis



NOV21a SNP Data

[1208] One polymorphic variant of NOV21 a has been identified and is shown in Table 3I.
461TABLE 3INucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant13377234438TC125PhePhe



NOV23a SNP Data

[1209] Eight polymorphic variants of NOV23a have been identified and are shown in Table 3J.
462TABLE 3JNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant13374631498AG142GlnArg13374630643GT190GlnHis13374633672AG200AspGly13377237715CT214SerSer13377238903CT277ThrIle13374632983AG304LysGlu133772401419TC449ValAla133746291547TC492SerPro



NOV24a SNP Data

[1210] Six polymorphic variants of NOV24a have been identified and are shown in Table 3K.
463TABLE 3KNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant13377245596CT013377246779AC42SerArg133772441327GA224ProPro133772431586GA311AlaThr133772421764CT0133772411825AG0



NOV25a SNP Data

[1211] Eight polymorphic variants of NOV25a have been identified and are shown in Table 3L.
464TABLE 3LNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant133752672963AG925LeuLeu133752663213CT1009ProSer133752653313TC1042ValAla133752643981GA1265ValMet133752634023AG1279ThrAla133752624051GT1288GlyVal133752614105AG1306AsnSer133752604117TC1310IleThr



NOV27a SNP Data

[1212] Three polymorphic variants of NOV27a have been identified and are shown in Table 3M.
465TABLE 3MNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant13377249233TC0133772481714CT419ThrThr133772472008AG517GlnGln



NOV29a SNP Data

[1213] Three polymorphic variants of NOV29a have been identified and are shown in Table 3N.
466TABLE 3NNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant13375558132GA44LeuLeu13375557149AC50LysThr13375556187TC63SerPro



NOV30a SNP Data

[1214] Six polymorphic variants of NOV30a have been identified and are shown in Table 3O.
467TABLE XXNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant133747521871AG599MetVal133747531970AG632MetVal133747542001TC642PheSer133772542249CT725LeuLeu133772533186AC1037GlnPro133772523318CT0



NOV31 a SNP Data

[1215] Fifteen polymorphic variants of NOV31a have been identified and are shown in Table 3P.
468TABLE 3PNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant133772561335CT434AsnAsn133772571415AG461AspGly133772581476AG481AlaAla133772591526TC498ValAla133772601613GA527CysTyr133772611630AG533ThrAla133772621812AT593AlaAla133772631929GA632AlaAla133772641942CT637ArgTrp133772652343TC770GlyGly133747452418CT795SerSer133747442535CT834LeuLeu133747432549AG839AspGly133772662642TC870LeuPro133772672649CT872AspAsp



NOV33a SNP Data

[1216] Two polymorphic variants of NOV33a have been identified and are shown in Table 3Q.
469TABLE 3QNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant1337727079TC17LeuPro13377269400TC124ValAla



NOV36a SNP Data

[1217] Three polymorphic variants of NOV36a have been identified and are reported in Table 3R.
470TABLE 3RNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant1337727391CG24AlaAla13377272230TC71SerPro133772714250AG1411ThrAla



NOV37a SNP Data

[1218] Two polymorphic variants of NOV37a have been identified and are reported in Table 3S.
471TABLE 3SNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant13377274266AG73ArgArg13377276702AG219IleVal



NOV39a SNP Data

[1219] Two polymorphic variants of NOV39a have been identified and are shown in Table 3T.
472TABLE 3TNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant133772776369TC2123SerSer133772788094GA2698ProPro



NOV40a SNP Data

[1220] One polymorphic variant of NOV40a has been identified and is shown in Table 3U.
473TABLE 3UNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant13377279355GA115AlaThr



NOV42a SNP Data

[1221] One polymorphic variant of NOV42a has been identified and is shown in Table 3V.
474TABLE 3VNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant13377280698AG221LeuLeu



NOV43a SNP Data

[1222] One polymorphic variant of NOV43a has been identified and is shown in Table 3W.
475TABLE 3WNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant133772811371TC433HisHis



NOV44a SNP Data

[1223] Four polymorphic variants of NOV44a have been identified and are shown in Table 3X.
476TABLE 3XNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant13377282604AG45AsnSer13377283684AG72ThrAla133772841123GA218ArgHis133772851489TC340ValAla



NOV45a SNP Data

[1224] One polymorphic variant of NOV45a has been identified and is shown in Table 3Y.
477TABLE 3YNucleotidesAmino AcidsBaseBaseVariantPosition ofWild-Position ofWild-No.SNPtypeVariantSNPtypeVariant13377286624TC191SerSer



OTHER EMBODIMENTS

[1225] Although particular embodiments have been disclosed herein in detail, this has been done by way of example for purposes of illustration only, and is not intended to be limiting with respect to the scope of the appended claims, which follow. In particular, it is contemplated by the inventors that various substitutions, alterations, and modifications may be made to the invention without departing from the spirit and scope of the invention as defined by the claims. The choice of nucleic acid starting material, clone of interest, or library type is believed to be a matter of routine for a person of ordinary skill in the art with knowledge of the embodiments described herein. The claims presented are representative of the inventions disclosed herein. Other, unclaimed inventions are also contemplated. Applicants reserve the right to pursue such inventions in later claims.


Claims
  • 1. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of: a) a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1-101; b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1-101, wherein any amino acid in the mature form is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; c) the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1-101; d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1-101, wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; and e) a fragment of any of a) through d).
  • 2. The polypeptide of claim 1 that is a naturally occurring allelic variant of the sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1-101.
  • 3. The polypeptide of claim 2, wherein said allelic variant comprises an amino acid sequence that is the translation of a nucleic acid sequence differing by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID NO:2n−1, wherein n is an integer between 1-101.
  • 4. The polypeptide of claim 1 that is a variant polypeptide described therein, wherein any amino acid specified in the chosen sequence is changed to provide a conservative substitution.
  • 5. A pharmaceutical composition comprising the polypeptide of claim 1 and a pharmaceutically acceptable carrier.
  • 6. A kit comprising in one or more containers, the pharmaceutical composition of claim 5.
  • 7. The use of a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease, the disease selected from a pathology associated with the polypeptide of claim 1, wherein said therapeutic is the polypeptide of claim 1.
  • 8. A method for determining the presence or amount of the polypeptide of claim 1 in a sample, the method comprising: (a) providing said sample; (b) introducing said sample to an antibody that binds immunospecifically to the polypeptide; and (c) determining the presence or amount of antibody bound to said polypeptide, thereby determining the presence or amount of polypeptide in said sample.
  • 9. A method for determining the presence of or predisposition to a disease associated with altered levels of the polypeptide of claim 1 in a first mammalian subject, the method comprising: a) measuring the level of expression of the polypeptide in a sample from the first mammalian subject; and b) comparing the amount of said polypeptide in the sample of step (a) to the amount of the polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, said disease, wherein an alteration in the expression level of the polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to said disease.
  • 10. A method for modulating the activity of the polypeptide of claim 1, the method comprising introducing a cell sample expressing the polypeptide of said claim with an antibody that binds to said polypeptide in an amount sufficient to modulate the activity of the polypeptide.
  • 11. The method of claim 10, wherein said subject is a human.
  • 12. An isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: a) a mature form of the amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1-101; b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1-101, wherein any amino acid in the mature form of the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; c) the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1-101; d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1-101, in which any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; e) a nucleic acid fragment encoding at least a portion of a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1-101, or any variant of said polypeptide wherein any amino acid of the chosen sequence is changed to a different amino acid, provided that no more than 10% of the amino acid residues in the sequence are so changed; and f) the complement of any of said nucleic acid molecules.
  • 13. The nucleic acid molecule of claim 12, wherein the nucleic acid molecule comprises the nucleotide sequence of a naturally occurring allelic nucleic acid variant.
  • 14. The nucleic acid molecule of claim 12 that encodes a variant polypeptide, wherein the variant polypeptide has the polypeptide sequence of a naturally occurring polypeptide variant.
  • 15. The nucleic acid molecule of claim 12, wherein the nucleic acid molecule differs by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID NO:2n−1, wherein n is an integer between 1-101.
  • 16. The nucleic acid molecule of claim 12, wherein said nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of a) the nucleotide sequence selected from the group consisting of SEQ ID NO:2n−1, wherein n is an integer between 1-101; b) a nucleotide sequence wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO:2n−1, wherein n is an integer between 1-101, is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed; c) a nucleic acid fragment of the sequence selected from the group consisting of SEQ ID NO:2n−1, wherein n is an integer between 1-101; and d) a nucleic acid fragment wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO:2n−1, wherein n is an integer between 1-101, is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed.
  • 17. The nucleic acid molecule of claim 12, wherein said nucleic acid molecule hybridizes under stringent conditions to the nucleotide sequence selected from the group consisting of SEQ ID NO:2n−1, wherein n is an integer between 1-101, or a complement of said nucleotide sequence.
  • 18. The nucleic acid molecule of claim 12, wherein the nucleic acid molecule comprises a nucleotide sequence in which any nucleotide specified in the coding sequence of the chosen nucleotide sequence is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides in the chosen coding sequence are so changed, an isolated second polynucleotide that is a complement of the first polynucleotide, or a fragment of any of them.
  • 19. A vector comprising the nucleic acid molecule of claim 12.
  • 20. The vector of claim 19, further comprising a promoter operably linked to said nucleic acid molecule.
  • 21. A cell comprising the vector of claim 20.
  • 22. A method for determining the presence or amount of the nucleic acid molecule of claim 12 in a sample, the method comprising: (a) providing said sample; (b) introducing said sample to a probe that binds to said nucleic acid molecule; and (c) determining the presence or amount of said probe bound to said nucleic acid molecule, thereby determining the presence or amount of the nucleic acid molecule in said sample.
  • 23. The method of claim 22 wherein presence or amount of the nucleic acid molecule is used as a marker for cell or tissue type.
  • 24. The method of claim 23 wherein the cell or tissue type is cancerous.
  • 25. A method for determining the presence of or predisposition to a disease associated with altered levels of the nucleic acid molecule of claim 12 in a first mammalian subject, the method comprising: a) measuring the amount of the nucleic acid in a sample from the first mammalian subject; and b) comparing the amount of said nucleic acid in the sample of step (a) to the amount of the nucleic acid present in a control sample from a second mammalian subject known not to have or not be predisposed to, the disease; wherein an alteration in the level of the nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.
  • 26. An antibody that binds immunospecifically to the polypeptide of claim 1.
  • 27. The antibody of claim 26, wherein said antibody is a monoclonal antibody.
  • 28. The antibody of claim 26, wherein the antibody is a humanized antibody.
  • 29. The antibody of claim 26, wherein the antibody is a fully human antibody
  • 30. The antibody of claim 26, wherein the dissociation constant for the binding of the polypeptide to the antibody is less than 1×10−9 M.
  • 31. The antibody of claim 26, wherein the antibody neutralizes an activity of the polypeptide.
  • 32. A pharmaceutical composition comprising the antibody of claim 26 and a pharmaceutically acceptable carrier.
  • 33. A kit comprising in one or more containers, the pharmaceutical composition of claim 29.
  • 34. The use of a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease, the disease selected from a pathology associated with the polypeptide of claim 1, wherein said therapeutic is a NOVX antibody.
  • 35. A method of treating or preventing a NOVX-associated disorder, said method comprising administering to a subject in which such treatment or prevention is desired the antibody of claim 26 in an amount sufficient to treat or prevent said NOVx-associated disorder in said subject.
  • 36. A method of treating a pathological state in a mammal, the method comprising administering to the mammal the antibody of claim 26 in an amount sufficient to alleviate the pathological state.
  • 37. A method of treating or preventing a pathology associated within the polypeptide of claim 1, said method comprising administering to a subject in which such treatment or prevention is desired a NOVX antibody in an amount sufficient to treat or prevent said pathology in said subject.
  • 38. The method of claim 37, wherein the subject is a human.
RELATED APPLICATIONS

[0001] This application claims priority to U.S. Ser. No. 60/274,322 filed on Mar. 8, 2001 (Cura 590); U.S. Ser. No. 60/283,675 filed on Apr. 13, 2001 (Cura 590D1); U.S. Ser. No. 60/338,092 filed on Dec. 3, 2001 (Cura 590D2); U.S. Ser. No. 60/274,281 filed on Mar. 8, 2001 (Cura 591); U.S. Ser. No. 60/274,101 filed on Mar. 8, 2001 (Cura 592); U.S. Ser. No. 60/325,681 filed on Sep. 27, 2001 (Cura 592J1); U.S. Ser. No. 60/304,354 filed on Jul. 10, 2001 (Cura 592I1); U.S. Ser. No. 60/279,995 filed on Mar. 30, 2001 (Cura 592H1); U.S. Ser. No. 60/294,899 filed on May 31, 2001 (Cura 592E1); U.S. Ser. No. 60/287,424 filed on Apr. 30,2001 (Cura 592D1); U.S. Ser. No. 60/299,027 filed on Jun. 18, 2001 (Cura 592D2); U.S. Ser. No. 60/309,198 filed on Jul. 31, 2001 (Cura 592C1); U.S. Ser. No. 60/281,194 filed on Apr. 4, 2001 (Cura 592A1); U.S. Ser. No. 60/274,194 filed on Mar. 8, 2001 (Cura 593); U.S. Ser. No. 60/274,849 filed on Mar. 9, 2001 (Cura 594); U.S. Ser. No. 60/330,380 filed on Oct. 18, 2001 (Cura 594C1); U.S. Ser. No. 60/275,235 filed on Mar. 12, 2001 (Cura 595); U.S. Ser. No. 60/288,342 filed on May 3, 2001 (Cura 595J1); U.S. Ser. No. 60/275,578 filed on Mar. 13, 2001 (Cura 596); U.S. Ser. No. 60/291,240 filed on May 16, 2001 (Cura 596I1); U.S. Ser. No. 60/294,485 filed on May 30,2001 (Cura 596B1); U.S. Ser. No. 60/299,310 filed on Jun. 19, 2001 (Cura 596A1); U.S. Ser. No. 60/275,579 filed on Mar. 13, 2001 (Cura 597); U.S. Ser. No. 60/275,601 filed on Mar. 13, 2001 (Cura 598); U.S. Ser. No. 60/276,000 filed on Mar. 14, 2001 (Cura 599); U.S. Ser. No. 60/280,900 filed on Apr. 2, 2001 (Cura 599E1); U.S. Ser. No. 60/276,776 filed on Mar. 16, 2001 (Cura 600); U.S. Ser. No. 60/294,889 filed on May 31, 2001 (Cura 600G1); U.S. Ser. No. 60/318,770 filed on Sep. 12, 2001 (Cura 600E1); U.S. Ser. No. 60/276,994 filed on Mar. 19, 2001 (Cura 604); U.S. Ser. No. 60/277,338 filed on Mar. 20, 2001 (Cura 607); U.S. Ser. No. 60/325,430 filed on Sep. 27, 2001 (Cura 607J1); U.S. Ser. No. 60/332,094 filed on Nov. 21, 2001 (Cura 607C1); U.S. Ser. No. 60/299,303 filed on Jun. 19, 2001 (Cura 607B1); U.S. Ser. No. 60/288,066 filed on May 2, 2001 (Cura 607A1); U.S. Ser. No. 60/277,321 filed on Mar. 20, 2001 (Cura 608); U.S. Ser. No. 60/280,822 filed on Apr. 2, 2001 (Cura 608A); U.S. Ser. No. 60/277,239 filed on Mar. 20, 2001 (Cura 609); U.S. Ser. No. 60/277,327 filed on Mar. 20, 2001 (Cura 610); U.S. Ser. No. 60/277,791 filed on Mar. 21, 2001 (Cura 611); U.S. Ser. No. 60/333,184 filed on Nov. 14, 2001 (Cura 611H1); U.S. Ser. No. 60/277,833 filed on Mar. 22, 2001 (Cura 612); U.S. Ser. No. 60/318,462 filed on Sep. 10, 2001 (Cura 612J1); U.S. Ser. No. 60/288,528 filed on May 3, 2001 (Cura 612A1); U.S. Ser. No. 60/278,152 filed on Mar. 23, 2001 (Cura 613); U.S. Ser. No. 60/332,272 filed on Nov. 14, 2001 (Cura 613D1); U.S. Ser. No. 60/278,894 filed on Mar. 26, 2001 (Cura 614); U.S. Ser. No. 60/312,903 filed on Aug. 16, 2001 (Cura 614C1); U.S. Ser. No. 60/333,272 filed on Nov. 14, 2001 (Cura 614C2); U.S. Ser. No. 60/279,036 filed on Mar. 27, 2001 (Cura 615); U.S. Ser. No. 60/332,172 filed on Nov. 14, 2001 (Cura 615I1); U.S. Ser. No. 60/337,426 filed on Dec. 3, 2001 (Cura 615I2); U.S. Ser. No. 60/278,999 filed on Mar. 27, 2001 (Cura 616); U.S. Ser. No. 60/279,344 filed on Mar. 28, 2001 (Cura 617); U.S. Ser. No. 60/332,271 filed on Nov. 14, 2001 (Cura 617J1); U.S. Ser. No. 60/291,099 filed on May 16, 2001 (Cura 617H1); U.S. Ser. No. 60/291,190 filed on May 15, 2001 (Cura 617E1); U.S. Ser. No. 60/280,233 filed on Mar. 30, 2001 (Cura 618); U.S. Ser. No. 60/280,802 filed on Apr. 2, 2001 (Cura 621); U.S. Ser. No. 60/335,301 filed on Oct. 31, 2001 (Cura 621F1); U.S. Ser. No. 60/337,185 filed on Dec. 4, 2001 (Cura 621D1); and U.S. Ser. No. 60/345,705 filed on Jan. 3, 2002 (Cura 621B1), each of which is incorporated by reference in its entirety.

Provisional Applications (62)
Number Date Country
60274322 Mar 2001 US
60283675 Apr 2001 US
60338092 Dec 2001 US
60274281 Mar 2001 US
60274101 Mar 2001 US
60325681 Sep 2001 US
60304354 Jul 2001 US
60279995 Mar 2001 US
60294899 May 2001 US
60287424 Apr 2001 US
60299027 Jun 2001 US
60309198 Jul 2001 US
60281194 Apr 2001 US
60274194 Mar 2001 US
60274849 Mar 2001 US
60330380 Oct 2001 US
60275235 Mar 2001 US
60288342 May 2001 US
60275578 Mar 2001 US
60291240 May 2001 US
60294485 May 2001 US
60299310 Jun 2001 US
60275579 Mar 2001 US
60275601 Mar 2001 US
60276000 Mar 2001 US
60280900 Apr 2001 US
60276776 Mar 2001 US
60294889 May 2001 US
60318770 Sep 2001 US
60276994 Mar 2001 US
60277338 Mar 2001 US
60325430 Sep 2001 US
60332094 Nov 2001 US
60299303 Jun 2001 US
60288066 May 2001 US
60277321 Mar 2001 US
60280822 Apr 2001 US
60277239 Mar 2001 US
60277327 Mar 2001 US
60277791 Mar 2001 US
60333184 Nov 2001 US
60277833 Mar 2001 US
60318462 Sep 2001 US
60288528 May 2001 US
60278152 Mar 2001 US
60332272 Nov 2001 US
60278894 Mar 2001 US
60312903 Aug 2001 US
60333272 Nov 2001 US
60279036 Mar 2001 US
60332172 Nov 2001 US
60337426 Dec 2001 US
60278999 Mar 2001 US
60279344 Mar 2001 US
60332271 Nov 2001 US
60291099 May 2001 US
60291190 May 2001 US
60280233 Mar 2001 US
60280802 Apr 2001 US
60335301 Oct 2001 US
60337185 Dec 2001 US
60345705 Jan 2002 US