Nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of prostate cancer

Information

  • Patent Grant
  • 7368548
  • Patent Number
    7,368,548
  • Date Filed
    Thursday, January 27, 2005
    19 years ago
  • Date Issued
    Tuesday, May 6, 2008
    16 years ago
Abstract
Novel markers for prostate cancer that are both sensitive and accurate. Furthermore, these markers are able to distinguish between prostate cancer and benign prostate hyperplasia (“BPH”). These markers are overexpressed in prostate cancer specifically, as opposed to normal prostate tissue and/or BPH. The measurement of these markers, alone or in combination, in patient samples provides information that the diagnostician can correlate with a probable diagnosis of prostate cancer. The markers of the present invention, alone or in combination, show a high degree of differential detection between prostate cancer and non-cancerous states.
Description
FIELD OF THE INVENTION

The present invention is related to novel nucleotide and protein sequences that are diagnostic markers for prostate cancer, and assays and methods of use thereof.


BACKGROUND OF THE INVENTION

Prostate cancer is the most commonly diagnosed malignancy and the second most frequent cause of cancer-related deaths in the western male population. Prostate cancer therapies are most effective in the earlier stages of the disease, before metastasis has occurred. Treatment is expected to be even more effective before significant local growth of the cancerous tissue has taken place. Therefore, efforts to control the disease (i.e., to decrease prostate cancer mortality) have focused on increasing detection of the cancer while it is still locally confined and potentially curable, through diagnostic assays that are suitable for early detection of prostate cancer. Unfortunately, such detection also has significant drawbacks, because diagnostic assays that use currently available prostate cancer markers lead to high numbers of false positive diagnoses, and/or are not sufficiently sensitive (potentially leading to high numbers of false negative diagnoses).


Measurements of serum concentrations of prostatic marker enzymes have recognized value in the clinical detection, diagnosis and management of prostate cancer. The two most widely used prostatic marker enzymes are prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA). Normally, both enzymes are secreted from the prostatic epithelial cells into the seminal fluid, but in patients with prostatic disease they leak into the circulation, where they can be detected by means of immunological assays (Armbruster, Clin. Che. 39:181-95 (1993)).


Prostatic acid phosphatase, one of the earliest serum markers for prostate, has an as yet undetermined function and is one of the most predominant protein components in human prostatic secretions. The use of PAP as a marker for prostatic tumors is complicated by the reported structural similarities between the prostate-specific acid phosphatase and the lysosomal acid phosphatase occurring in all tissues. Furthermore, there is a tendency towards lower PAP mRNA and protein levels in prostate cancer in comparison with benign prostatic hyperplasia (BPH). In recent years, PAP measurements were superseded by serum PSA measurements in the clinical management of prostate cancer.


Prostate-specific antigen (PSA) was identified by several groups as a prostate-specific protein from the seminal fluid, and was subsequently determined to be an antigen from prostate cancer tissue. PSA is produced exclusively by the columnar epithelial cells of the prostate and periuretural glands. Normal prostate epithelium and benign hyperplastic tissue actually produce more PSA mRNA and protein than does prostate cancer tissue. Furthermore, it was shown that loss of differentiation of prostatic carcinomas is associated with a decrease in the level of intraprostatic PSA.


Prostate-specific membrane antigen (PSM) was originally identified using an antibody developed by immunizing mice with the membrane fraction of LNCaP human prostatic adenocarcinoma cells. Like PAP and PSA, PSM can be detected in normal prostate, BPH and prostate cancer and is absent from most other tissues. However, the usefulness of PSM as marker for prostatic cancer has not been fully established.


Other markers have recently been considered. For example, PCA3 DD3 is a new marker from DiagnoCure, which has been described as being useful in a urine-based test (PCA3 itself is described in PCT Application Nos. WO 98/45420 and WO 2000/123550). This marker is apparently only expressed in prostate cancer, and therefore may be used to distinguish between BPH and prostate cancer. However, as described in greater detail below, the sensitivity and accuracy of this marker may be improved when used in combination with one or more additional markers.


Therefore, PSA is recognized as the best available marker for prostate cancer, being useful for screening selected populations of patients with symptoms indicative of prostate cancer and for monitoring patients after therapy, especially after surgical prostatectomy. However, PSA has significant drawbacks in terms of false positive measurements, since it cannot distinguish prostate cancer from BPH. It may also lead to false negative measurements, since de-differentiation of prostate cancerous tissue (which may occur with some types of prostate cancers) also leads to decreased expression of this marker. New markers are currently being developed to overcome this problem, but these markers have their own drawbacks. Clearly, new markers are required.


SUMMARY OF THE INVENTION

The background art does not teach or suggest markers for prostate cancer that are sufficiently sensitive and/or accurate, alone or in combination.


The present invention overcomes these deficiencies of the background art by providing novel markers for prostate cancer that are both sensitive and accurate. Furthermore, at least some of these markers are able to distinguish between prostate cancer and benign prostate hyperplasia (“BPH”). These markers are differentially expressed, and preferably overexpressed in prostate cancer specifically, as opposed to normal prostate tissue and/or BPH. The measurement of these markers, alone or in combination, in patient samples (biological samples) provides information that the diagnostician can correlate with a probable diagnosis of prostate cancer. The markers of the present invention, alone or in combination, show a high degree of differential detection between prostate cancer and non-cancerous states.


According to preferred embodiments of the present invention, examples of suitable biological samples include but are not limited to blood, serum, plasma, blood cells, urine, sputum, saliva, stool, spinal fluid or CSF, lymph fluid, the external secretions of the skin, respiratory, intestinal, and genitourinary tracts, tears, milk, neuronal tissue, prostate tissue or mucous and any human organ or tissue, or any sample obtained by lavage (for example of the bronchial system), and also samples of in vivo cell culture constituents. In a preferred embodiment, the biological sample comprises prostate tissue and/or other tissues of the male genitalia, or reproductive or urinary tracts, and/or a serum (and/or any blood) sample and/or a urine sample and/or a semen sample and/or any other tissue or liquid sample. The sample can optionally be diluted with a suitable eluant before contacting the sample to an antibody and/or performing any other diagnostic assay.


Information given in the text with regard to cellular localization was determined according to four different software programs: (i) tmhmm (from Center for Biological Sequence Analysis, Technical University of Denmark DTU, cbsdot dtudot dk/services/TMHMM/TMHMM2dot 0bdot guidedot php) or (ii) tmpred (from EMBnet, maintained by the ISREC Bionformatics group and the LICR Information Technology Office, Ludwig Institute for Cancer Research, Swiss Institute of Bioinformatics, chdot embnetdot org/software/TMPRED_formdot html) for transmembrane region prediction; (iii) signalp_hmm or (iv) signalp_nn (both from Center for Biological Sequence Analysis, Technical University of Denmark DTU, cbsdot dtudot dk/services/SignalP/background/predictiondot php) for signal peptide prediction. The terms “signalp_hmm” and “signalp_nn” refer to two modes of operation for the program SignalP: hmm refers to Hidden Markov Model, while nn refers to neural networks. Localization was also determined through manual inspection of known protein localization and/or gene structure, and the use of heuristics by the individual inventor. In some cases for the manual inspection of cellular localization prediction inventors used the ProLoc computational platform [Einat Hazkani-Covo, Erez Levanon, Galit Rotman, Dan Graur and Amit Novik; (2004) “Evolution of multicellularity in metazoa: comparative analysis of the subcellular localization of proteins in Saccharomyces, Drosophila and Caenorhabditis.” Cell Biology International 2004;28(3):171-8.], which predicts protein localization based on various parameters including, protein domains (e.g., prediction of trans-membranous regions and localization thereof within the protein), pl, protein length, amino acid composition, homology to pre-annotated proteins, recognition of sequence patterns which direct the protein to a certain organelle (such as, nuclear localization signal, NLS, mitochondria localization signal), signal peptide and anchor modeling and using unique domains from Pfam that are specific to a single compartment.


Information is given in the text with regard to SNPs (single nucleotide polymorphisms). A description of the abbreviations is as follows. “T->C”, for example, means that the SNP results in a change at the position given in the table from T to C. Similarly, “M->Q”, for example, means that the SNP has caused a change in the corresponding amino acid sequence, from methionine (M) to glutamine (Q). If, in place of a letter at the right hand side for the nucleotide sequence SNP, there is a space, it indicates that a frameshift has occurred. A frameshift may also be indicated with a hyphen (-). A stop codon is indicated with an asterisk at the right hand side (*). As part of the description of an SNP, a comment may be found in parentheses after the above description of the SNP itself. This comment may include an FTId, which is an identifier to a SwissProt entry that was created with the indicated SNP. An FTId is a unique and stable feature identifier, which allows construction of links directly from position-specific annotation in the feature table to specialized protein-related databases. The FTId is always the last component of a feature in the description field, as follows: FTId=XXX_number, in which XXX is the 3-letter code for the specific feature key, separated by an underscore from a 6-digit number. In the table of the amino acid mutations of the wild type proteins of the selected splice variants of the invention, the header of the first column is “SNP position(s) on amino acid sequence”, representing a position of a known mutation on amino acid sequence.


SNPs may optionally be used as diagnostic markers according to the present invention, alone or in combination with one or more other SNPs and/or any other diagnostic marker. Preferred embodiments of the present invention comprise such SNPs, including but not limited to novel SNPs on the known (WT or wild type) protein sequences given below, as well as novel nucleic acid and/or amino acid sequences formed through such SNPs, and/or any SNP on a variant amino acid and/or nucleic acid sequence described herein.


Information given in the text with regard to the Homology to the known proteins was determined by Smith-Waterman version 5.1.2 using special (non default) parameters as follows:

    • model=sw.model
    • GAPEXT=0
    • GAPOP=100.0
      • MATRIX=blosum 100


Information is given with regard to overexpression of a cluster in cancer based on ESTs. A key to the p values with regard to the analysis of such overexpression is as follows:

    • library-based statistics: P-value without including the level of expression in cell-lines (P1)
    • library based statistics: P-value including the level of expression in cell-lines (P2)
    • EST clone statistics: P-value without including the level of expression in cell-lines (SP1)
    • EST clone statistics: predicted overexpression ratio without including the level of expression in cell-lines (R3)
    • EST clone statistics: P-value including the level of expression in cell-lines (SP2)
    • EST clone statistics: predicted overexpression ratio including the level of expression in cell-lines (R4)


Library-based statistics refer to statistics over an entire library, while EST clone statistics refer to expression only for ESTs from a particular tissue or cancer.


Information is given with regard to overexpression of a cluster in cancer based on microarrays. As a microarray reference, in the specific segment paragraphs, the unabbreviated tissue name was used as the reference to the type of chip for which expression was measured. There are two types of microarray results: those from microarrays prepared according to a design by the present inventors, for which the microarray fabrication procedure is described in detail in Materials and Experimental Procedures section herein; and those results from microarrays using Affymetrix technology. As a microarray reference, in the specific segment paragraphs, the unabbreviated tissue name was used as the reference to the type of chip for which expression was measured. For microarrays prepared according to a design by the present inventors, the probe name begins with the name of the cluster (gene), followed by an identifying number. Oligonucleotide microarray results taken from Affymetrix data were from chips available from Affymetrix lnc, Santa Clara, Calif., USA (see for example data regarding the Human Genome U133 (HG-U133) Set at affymetrixdot com/products/arrays/specific/hgu 133dot affx; GeneChip Human Genome U133A 2.0 Array at affymetrixdot com/products/arrays/specific/hgu133av2dot affx; and Human Genome U133 Plus 2.0 Array ataffymetrixdot com/products/arrays/specific/hgu133plusdot affx). The probe names follow the Affymetrix naming convention. The data is available from NCBI Gene Expression Omnibus (see ncbidot nlmdot nihdot gov/projects/geo/ and Edgar et al, Nucleic Acids Research, 2002, Vol. 30, No. 1 207-210). The dataset (including results) is available from ncbidot nlmdot nihdot gov/geo/query/accdot cgi?acc=GSE1133 for the Series GSE1133 database (published on March 2004); a reference to these results is as follows: Su et al (Proc Natl Acad Sci U S A. 2004 Apr. 20;101(16):6062-7. Epub 2004 Apr. 09). A list of probes designed according to the present inventors is given below.










>H53626_0_16_0











(SEQ ID NO:520)1









ATGCGGGCATGTACATCTGCCTTGGCGCCAACACCATGGGCTACAGCTTC











>H53626_0_0_8391










(SEQ ID NO:521)









GGGTCTGGGGTGCTCTCCTGGTCTTTGTGTCGGCGTTCCCCTCCCTACCT











>HSMUC1A_0_37_0










(SEQ ID NO:522)









AAAAGGAGACTTCGGCTACCCAGAGAAGTTCAGTGCCCAGCTCTACTGAG











>HSMUC1A_0_0_11364










(SEQ ID NO:523)









AAAGGCTGGCATAGGGGGAGGTTTCCCAGGTAGAAGAAGAAGTGTCAGCA











>HSMUC1A_0_0_11365










(SEQ ID NO:524)









AATTAACCCTTTGAGAGCTGGCCAGGACTCTGGACTGATTACCCCAGCCT











>HSSTROL3_0_0_12518










(SEQ ID NO:525)









ATGAGAGTAACCTCACCCGTGCACTAGTTTACAGAGCATTCACTGCCCCA











>HSSTROL3_0_0_12517










(SEQ ID NO:526)









CAGAGATGAGAGCCTGGAGCATTGCAGATGCCAGGGACTTCACAAATGAA











>HSCOC4_0_0_9892










(SEQ ID NO:527)









AAGGACCAGAGTCCATGCCAAGACCACCCTTCAGCTTCCAAGGCCCTCCA











>HSCOC4_0_39_0










(SEQ ID NO:528)









ATCCTCCAGCCATGAGGCTGCTCTGGGGGCTGATCTGGGCATCCAGCTTC











>HSCOC4_0_0_9883










(SEQ ID NO:539)









CCTGTTTGCTCTGACACCAACTTCCTACCCTCTCAGCCTCAAAGTAACTC











>HSCOC4_0_0_9885










(SEQ ID NO:530)









GCTGAGGTGTGGCCGAGGACCTGACCATCTGGAAGTGTGAAAATCCCCTT







The following list of abbreviations for tissues was used in the TAA histograms. The term “TAA” stands for “Tumor Associated Antigen”, and the TAA histograms, given in the text, represent the cancerous tissue expression pattern as predicted by the biomarkers selection engine, as described in detail in examples 1-5 below:

    • “BONE” for “bone”;
      • “COL” for “colon”;
      • “EPI” for “epithelial”;
      • “GEN” for “general”;
      • “LIVER” for “liver”;
      • “LUN” for “lung”;
      • “LYMPH” for “lymph nodes”;
      • “MARROW” for “bone marrow”;
      • “OVA” for “ovary”;
      • “PANCREAS” for “pancreas”;
      • “PRO” for “prostate”;
      • “STOMACH” for “stomach”;
      • “TCELL” for “T cells”;
      • “THYROID” for “Thyroid”;
      • “MAM” for “breast”;
      • “BRAIN” for “brain”;
      • “UTERUS” for “uterus”;
      • “SKIN” for “skin”;
      • “KIDNEY” for “kidney”;
      • “MUSCLE” for “muscle”;
      • “ADREN” for “adrenal”;
      • “HEAD” for “head and neck”;
      • “BLADDER” for “bladder”;


It should be noted that the terms “segment”, “seg” and “node” are used interchangeably in reference to nucleic acid sequences of the present invention; they refer to portions of nucleic acid sequences that were shown to have one or more properties as described below. They are also the building blocks that were used to construct complete nucleic acid sequences as described in greater detail below. Optionally and preferably, they are examples of oligonucleotides which are embodiments of the present invention, for example as amplicons, hybridization units and/or from which primers and/or complementary oligonucleotides may optionally be derived, and/or for any other use.


As used herein the phrase “prostate cancer” refers to cancers of the prostate tissue and/or other tissues of the male genitalia, or reproductive or urinary tracts.


The term “marker” in the context of the present invention refers to a nucleic acid fragment, a peptide, or a polypeptide, which is differentially present in a sample taken from subjects (patients) having prostate cancer as compared to a comparable sample taken from subjects who do not have prostate cancer.


The phrase “differentially present” refers to differences in the quantity of a marker present in a sample taken from patients having prostate cancer as compared to a comparable sample taken from patients who do not have prostate cancer. For example, a nucleic acid fragment may optionally be differentially present between the two samples if the amount of the nucleic acid fragment in one sample is significantly different from the amount of the nucleic acid fragment in the other sample, for example as measured by hybridization and/or NAT-based assays. A polypeptide is differentially present between the two samples if the amount of the polypeptide in one sample is significantly different from the amount of the polypeptide in the other sample. It should be noted that if the marker is detectable in one sample and not detectable in the other, then such a marker can be considered to be differentially present.


As used herein the phrase “diagnostic” means identifying the presence or nature of a pathologic condition. Diagnostic methods differ in their sensitivity and specificity. The “sensitivity” of a diagnostic assay is the percentage of diseased individuals who test positive (percent of “true positives”). Diseased individuals not detected by the assay are “false negatives.” Subjects who are not diseased and who test negative in the assay are termed “true negatives.” The “specificity” of a diagnostic assay is 1 minus the false positive rate, where the “false positive” rate is defined as the proportion of those without the disease who test positive. While a particular diagnostic method may not provide a definitive diagnosis of a condition, it suffices if the method provides a positive indication that aids in diagnosis.


As used herein the phrase “diagnosing” refers to classifying a disease or a symptom, determining a severity of the disease, monitoring disease progression, forecasting an outcome of a disease and/or prospects of recovery. The term “detecting” may also optionally encompass any of the above.


Diagnosis of a disease according to the present invention can be affected by determining a level of a polynucleotide or a polypeptide of the present invention in a biological sample obtained from the subject, wherein the level determined can be correlated with predisposition to, or presence or absence of the disease. It should be noted that a “biological sample obtained from the subject” may also optionally comprise a sample that has not been physically removed from the subject, as described in greater detail below.


As used herein, the term “level” refers to expression levels of RNA and/or protein or to DNA copy number of a marker of the present invention.


Typically the level of the marker in a biological sample obtained from the subject is different (i.e., increased or decreased) from the level of the same variant in a similar sample obtained from a healthy individual (examples of biological samples are described herein).


Numerous well known tissue or fluid collection methods can be utilized to collect the biological sample from the subject in order to determine the level of DNA, RNA and/or polypeptide of the variant of interest in the subject.


Examples include, but are not limited to, fine needle biopsy, needle biopsy, core needle biopsy and surgical biopsy (e.g., brain biopsy), and lavage. Regardless of the procedure employed, once a biopsy/sample is obtained the level of the variant can be determined and a diagnosis can thus be made.


Determining the level of the same variant in normal tissues of the same origin is preferably effected along-side to detect an elevated expression and/or amplification and/or a decreased expression, of the variant as opposed to the normal tissues.


A “test amount” of a marker refers to an amount of a marker in a subject's sample that is consistent with a diagnosis of prostate cancer. A test amount can be either in absolute amount (e.g., microgram/ml) or a relative amount (e.g., relative intensity of signals).


A “control amount” of a marker can be any amount or a range of amounts to be compared against a test amount of a marker. For example, a control amount of a marker can be the amount of a marker in a patient with prostate cancer or a person without prostate cancer. A control amount can be either in absolute amount (e.g., microgram/ml) or a relative amount (e.g., relative intensity of signals).


“Detect” refers to identifying the presence, absence or amount of the object to be detected.


A “label” includes any moiety or item detectable by spectroscopic, photo chemical, biochemical, immunochemical, or chemical means. For example, useful labels include 32P, 35S, fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin-streptavadin, dioxigenin, haptens and proteins for which antisera or monoclonal antibodies are available, or nucleic acid molecules with a sequence complementary to a target. The label often generates a measurable signal, such as a radioactive, chromogenic, or fluorescent signal, that can be used to quantify the amount of bound label in a sample. The label can be incorporated in or attached to a primer or probe either covalently, or through ionic, van der Waals or hydrogen bonds, e.g., incorporation of radioactive nucleotides, or biotinylated nucleotides that are recognized by streptavadin. The label may be directly or indirectly detectable. Indirect detection can involve the binding of a second label to the first label, directly or indirectly. For example, the label can be the ligand of a binding partner, such as biotin, which is a binding partner for streptavadin, or a nucleotide sequence, which is the binding partner for a complementary sequence, to which it can specifically hybridize. The binding partner may itself be directly detectable, for example, an antibody may be itself labeled with a fluorescent molecule. The binding partner also may be indirectly detectable, for example, a nucleic acid having a complementary nucleotide sequence can be a part of a branched DNA molecule that is in turn detectable through hybridization with other labeled nucleic acid molecules (see, e.g., P. D. Fahrlander and A. Klausner, Bio/Technology 6:1165 (1988)). Quantitation of the signal is achieved by, e.g., scintillation counting, densitometry, or flow cytometry.


Exemplary detectable labels, optionally and preferably for use with immunoassays, include but are not limited to magnetic beads, fluorescent dyes, radiolabels, enzymes (e.g., horse radish peroxide, alkaline phosphatase and others commonly used in an ELISA), and calorimetric labels such as colloidal gold or colored glass or plastic beads. Alternatively, the marker in the sample can be detected using an indirect assay, wherein, for example, a second, labeled antibody is used to detect bound marker-specific antibody, and/or in a competition or inhibition assay wherein, for example, a monoclonal antibody which binds to a distinct epitope of the marker are incubated simultaneously with the mixture.


“Immunoassay” is an assay that uses an antibody to specifically bind an antigen. The immunoassay is characterized by the use of specific binding properties of a particular antibody to isolate, target, and/or quantify the antigen.


The phrase “specifically (or selectively) binds” to an antibody or “specifically (or selectively) immunoreactive with,” when referring to a protein or peptide (or other epitope), refers to a binding reaction that is determinative of the presence of the protein in a heterogeneous population of proteins and other biologics. Thus, under designated immunoassay conditions, the specified antibodies bind to a particular protein at least two times greater than the background (non-specific signal) and do not substantially bind in a significant amount to other proteins present in the sample. Specific binding to an antibody under such conditions may require an antibody that is selected for its specificity for a particular protein. For example, polyclonal antibodies raised to seminal basic protein from specific species such as rat, mouse, or human can be selected to obtain only those polyclonal antibodies that are specifically immunoreactive with seminal basic protein and not with other proteins, except for polymorphic variants and alleles of seminal basic protein. This selection may be achieved by subtracting out antibodies that cross-react with seminal basic protein molecules from other species. A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein (see, e.g., Harlow & Lane, Antibodies, A Laboratory Manual (1988), for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity). Typically a specific or selective reaction will be at least twice background signal or noise and more typically more than 10 to 100 times background.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 1,2, 3 and 4.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88 and 89.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 327, 328, 329, 330.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: SEQ ID NOs. 5, 6, 7, 8, 9 and 10.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114 and 115.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 331, 332, 333, 334 and 335.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 11.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128 and 129.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 336.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 12.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 130, 131, 132, 133, 134 and 135.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 337.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 34, 35, 36, 37, 38 and 39.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236 and 237.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 359, 360, 361, 362 and 363.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 and 33.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220 and 221.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357 and 358.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 13 and 14.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 136, 137, 138, 139, 140, 141 and 142.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 338 and 339.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 40, 41 and 42.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269 and 270.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 364, 365 and 366.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 43.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283 and 284.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 367.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 44 and 45.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303 and 304.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 368 and 369.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58 and 59.


According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325 and 326.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382 and 383.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 383, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-45 of SEQ ID NO. 398, which also corresponds to amino acids 1-45 of SEQ ID NO. 383, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 46-85 of SEQ ID NO. 383, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 383, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 46-85 in SEQ ID NO. 383.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NOs. 359, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-163 of SEQ ID NOs. 391, which also corresponds to amino acids 1-163 of SEQ ID NOs. 359, a bridging amino acid H corresponding to amino acid 164 of SEQ ID NOs. 359, a second amino acid sequence being at least 90% homologous to corresponding to amino acids 165-445 of SEQ ID NOs. 391, which also corresponds to amino acids 165-445 of SEQ ID NO. 359, and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 446-496 of SEQ ID NO. 359, wherein said first amino acid sequence, bridging amino acid, second amino acid sequence and third amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 359, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 446-496 in SEQ ID NO. 359.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NOs. 360, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-163 of SEQ ID NOs. 391, which also corresponds to amino acids 1-163 of SEQ ID NO. 360, a bridging amino acid H corresponding to amino acid 164 of SEQ ID NO. 360, a second amino acid sequence being at least 90% homologous to corresponding to amino acids 165-358 of SEQ ID NOs. 391, which also corresponds to amino acids 165-358 of SEQ ID NO. 360, and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 359-382 of SEQ ID NO. 360, wherein said first amino acid sequence, bridging amino acid, second amino acid sequence and third amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 360, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 359-382 in SEQ ID NO. 360.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 361, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-163 of SEQ ID NOs. 391, which also corresponds to amino acids 1-163 of SEQ ID NO. 361, a bridging amino acid H corresponding to amino acid 164 of SEQ ID NO. 361, a second amino acid sequence being at least 90% homologous to corresponding to amino acids 165-359 of SEQ ID NOs. 391, which also corresponds to amino acids 165-359 of SEQ ID NO. 361, and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 360-370 of SEQ ID NO. 361, wherein said first amino acid sequence, bridging amino acid, second amino acid sequence and third amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 361, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 360-370 in SEQ ID NO. 361.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 362, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-163 of SEQ ID NOs. SEQ ID NOs. 391, which also corresponds to amino acids 1-163 of SEQ ID NO. 362, a bridging amino acid H corresponding to amino acid 164 of SEQ ID NO. 362, a second amino acid sequence being at least 90% homologous to corresponding to amino acids 165-286 of SEQ ID NOs. 391, which also corresponds to amino acids 165-286 of SEQ ID NO. 362, and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 287-301 of SEQ ID NO. 362, wherein said first amino acid sequence, bridging amino acid, second amino acid sequence and third amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 362, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 287-301 in SEQ ID NO. 362.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 363, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-96 of SEQ ID NOs. 391, which also corresponds to amino acids 1-96 of SEQ ID NO. 363, a second amino acid sequence being at least 90% homologous to corresponding to amino acids 113-163 of SEQ ID NOs. 391, which also corresponds to amino acids 97-147 of SEQ ID NO. 363, a bridging amino acid H corresponding to amino acid 148 of SEQ ID NO. 363, a third amino acid sequence being at least 90% homologous to corresponding to amino acids 165-359 of SEQ ID NOs. 391, which also corresponds to amino acids 149-343 of SEQ ID NO. 363, and a fourth amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 344-354 of SEQ ID NO. 363, wherein said first amino acid sequence, second amino acid sequence, bridging amino acid, third amino acid sequence and fourth amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for an edge portion of SEQ ID NO. 363, comprising a polypeptide having a length “n”, wherein n is at least about 10 amino acids in length, optionally at least about 20 amino acids in length, preferably at least about 30 amino acids in length, more preferably at least about 40 amino acids in length and most preferably at least about 50 amino acids in length, wherein at least two amino acids comprise KR, having a structure as follows: a sequence starting from any of amino acid numbers 96-x to 96; and ending at any of amino acid numbers 97+((n−2)−x), in which x varies from 0 to n−2.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 363, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence in SEQ ID NO. 363.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 340, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-865 of CO4_HUMAN, which also corresponds to amino acids 1-865 of SEQ ID NO. 340, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 866-887 of SEQ ID NO. 340, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 340, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 866-887 in SEQ ID NO. 340.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 341, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-818 of CO4_HUMAN, which also corresponds to amino acids 1-818 of SEQ ID NO. 341, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 819-843 of SEQ ID NO. 341, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 341, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 819-843 in SEQ ID NO. 341.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ SEQ ID NO. 342, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-1052 of CO4_HUMAN, which also corresponds to amino acids 1-1052 of SEQ ID NO. 342, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1053-1084 of SEQ ID NO. 342, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 342, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence in SEQ ID NO. 342.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 343, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-1380 of SEQ ID NO. 389, which also corresponds to amino acids 1-1380 of SEQ ID NO. 343, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1381-1397 of SEQ ID NO. 343, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ SEQ ID NO. 343, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence in SEQ ID NO. 343.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 344, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-1359 of SEQ ID NO. 389, which also corresponds to amino acids 1-1359 of SEQ ID NO. 344, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1360-1415 of SEQ ID NO. 344, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 344, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1360-1415 in SEQ ID NO. 344.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 345, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-1457 of SEQ ID NO. 389, which also corresponds to amino acids 1-1457 of SEQ ID NO. 345, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 1458-1483 of SEQ ID NO. 345, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 345, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1458-1483 in SEQ ID NO. 345.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 346, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-1303 of SEQ ID NO. 389, which also corresponds to amino acids 1-1303 of SEQ ID NO. 346, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1304-1349 of SEQ ID NO. 346, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 346, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence in SEQ ID NO. 346.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 347, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-1529 of SEQ ID NO. 389, which also corresponds to amino acids 1-1529 of SEQ ID NO. 347, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1530-1533 of SEQ ID NO. 347, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 347, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1530-1533 in SEQ ID NO. 347.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 348, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-1653 of SEQ ID NO. 389, which also corresponds to amino acids 1-1653 of SEQ ID NO. 348, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1654-1670 of SEQ ID NO. 348, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 348, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1654-1670 in SEQ ID NO. 348.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 349, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-1626 of SEQ ID NO. 389, which also corresponds to amino acids 1-1626 of SEQ ID NO. 349, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1627-1685 of SEQ ID NO. 349, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 349, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1627-1685 in SEQ ID NO. 349.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 350, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-1528 of SEQ ID NO. 389, which also corresponds to amino acids 1-1528 of SEQ ID NO. 350, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1529-1579 of SEQ ID NO. 350, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 350, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1529-1579 in SEQ ID NO. 350.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 351, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-1593 of SEQ ID NO. 389, which also corresponds to amino acids 1-1593 of SEQ ID NO. 351, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1594-1657 of SEQ ID NO. 351, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 351, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1594-1657 in SEQ ID NO. 351.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 352, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-1593 of SEQ ID NO. 389, which also corresponds to amino acids 1-1593 of SEQ ID NO. 352, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1594-1691 of SEQ ID NO. 352, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 352, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1594-1691 in SEQ ID NO. 352.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 353, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-1232 of SEQ ID NO. 390, which also corresponds to amino acids 1-1232 of SEQ ID NO. 353, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1233-1253 of SEQ ID NO. 353, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 353, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1233-1253 in SEQ ID NO. 353.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 354, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-818 of CO4_HUMAN, which also corresponds to amino acids 1-818 of SEQ ID NO. 354, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 819-843 of SEQ ID NO. 354, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 354, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to to amino acids 819-843 in SEQ ID NO. 354.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 355, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-387 of CO4_HUMAN, which also corresponds to amino acids 1-387 of SEQ ID NO. 355, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 388-394 of SEQ SEQ ID NO. 355, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 355, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 388-394 in SEQ ID NO. 355.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 356, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-236 of CO4_HUMAN, which also corresponds to amino acids 1-236 of SEQ ID NO. 356, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 237-263 of SEQ ID NO. 356, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 356, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 237-263 in SEQ ID NO. 356.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 357, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-1529 of SEQ ID NO. 389, which also corresponds to amino acids 1-1529 of SEQ ID NO. 357, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1530-1533 of SEQ ID NO. 357, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 357, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SGER (SEQ ID NO: 551) in SEQ ID NO. 357.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 358, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-1473 of SEQ ID NO. 389, which also corresponds to amino acids 1-1473 of SEQ ID NO. 358, a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1474-1511 of SEQ ID NO. 358, a third amino acid sequence being at least 90% homologous to corresponding to amino acids 1474-1503 of SEQ ID NO. 389, which also corresponds to amino acids 1512-1541 of SEQ ID NO. 358, and a fourth amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 1542-1555 of SEQ ID NO. 358, wherein said first amino acid sequence, second amino acid sequence, third amino acid sequence and fourth amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for an edge portion of SEQ ID NO. 358, comprising an amino acid sequence being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1474-1511, corresponding to SEQ ID NO. 358.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 358, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1542-1555 in SEQ ID NO. 358.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 339, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-27 of SEQ ID NO. 387, which also corresponds to amino acids 1-27 of SEQ ID NO. 339, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 28-41 of SEQ ID NO. 339, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 339, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 28-41 in SEQ ID NO. 339.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 364, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-1617 of SEQ ID NO. 393, which also corresponds to amino acids 1-1617 of SEQ ID NO. 364, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 1618-1645 of SEQ ID NO. 364, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 364, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1618-1645 in SEQ ID NO. 364.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 365, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-2062 of SEQ ID NO. 393, which also corresponds to amino acids 1-2062 of SEQ ID NO. 365, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 2063-2074 of SEQ ID NO. 365, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 365, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 2063-2074 in SEQ ID NO. 365.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 366, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-587 of SEQ ID NO. 393, which also corresponds to amino acids 1-587 of SEQ ID NO. 366, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 588-603 of SEQ ID NO. 366, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 366, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 588-603 in SEQ ID NO. 366.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 367, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-238 of SEQ ID NOs. 396, which also corresponds to amino acids 1-238 of SEQ ID NO. 367, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 239-310 of SEQ ID NO. 367, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 367, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 239-310 in SEQ ID NO. 367.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 367, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-257 of SEQ ID NO. 395, which also corresponds to amino acids 1-257 of SEQ ID NO. 367, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 258-310 of SEQ ID NO. 367, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 367, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 258-310 in SEQ ID NO. 367.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 367, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-257 of SEQ ID NO. 397, which also corresponds to amino acids 1-257 of SEQ ID NO. 367, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 258-310 of SEQ ID NO. 367, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 367, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 258-310 in SEQ ID NO. 367.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 368, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-357 of Q8N441, which also corresponds to amino acids 1-357 of SEQ ID NO. 368, second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 358-437 of SEQ ID NO. 368, and a third amino acid sequence being at least 90% homologous to corresponding to amino acids 358-504 of Q8N441, which also corresponds to amino acids 438-584 of SEQ ID NO. 368, wherein said first, second and third amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for an edge portion of SEQ ID NO. 368, comprising an amino acid sequence being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 358-437, corresponding to SEQ ID NO. 368.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 369, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-269 of Q9H4D7, which also corresponds to amino acids 1-269 of SEQ ID NO. 369, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 270-490 of SEQ ID NO. 369, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 369, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 270-490 in SEQ ID NO. 369.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 369, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-269 of Q8N441, which also corresponds to amino acids 1-269 of SEQ ID NO. 369, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 270-490 of SEQ ID NO. 369, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 369, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 270-490 in SEQ ID NO. 369.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 327, comprising a first amino acid sequence being at least 90% homologous to to amino acids 1-274 of SEQ ID NO. 384, which also corresponds to amino acids 1-274 of SEQ ID NO. 327, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 275-322 of SEQ ID NO. 327, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 327, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 275-322 in SEQ ID NO. 327.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 327, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-274 of Q9UII8, which also corresponds to amino acids 1-274 of SEQ ID NO. 327, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 275-322 of SEQ ID NO. 327, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ SEQ ID NO. 327, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 275-322 in SEQ ID NO. 327.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 327, comprising a first amino acid sequence being at least 90% homologous to amino acids 1-274 of CAD1_HUMAN, which also corresponds to amino acids 1-274 of SEQ ID NO. 327, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 275-322 of SEQ ID NO. 327, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 327, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 275-322 in SEQ ID NO. 327.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 328, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-379 of SEQ ID NO. 384, which also corresponds to amino acids 1-379 of SEQ ID NO. 328, and a second amino acid sequence VIL corresponding to amino acids 380-382 of SEQ ID NO. 328, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 328, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-379 of SEQ ID NO. 384, which also corresponds to amino acids 1-379 of SEQ ID NO. 328, and a second amino acid sequence VIL corresponding to amino acids 380-382 of SEQ ID NO. 328, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 328, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-379 of SEQ ID NO. 384, which also corresponds to amino acids 1-379 of SEQ ID NO. 328, and a second amino acid sequence corresponding to 380-382 of SEQ ID NO. 328, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 329, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-336 of SEQ ID NO. 384, which also corresponds to amino acids 1-336 of SEQ ID NO. 329, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 337-373 of SEQ ID NO. 329, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 329, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 337-373 in SEQ ID NO. 329.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 329, comprising a first amino acid sequence being at least 90% homologous to amino acids 1-336 of SEQ ID NO. 384, which also corresponds to amino acids 1-336 of SEQ ID NO. 329, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 337-373 of SEQ ID NO. 329, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 329, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 337-373 in SEQ ID NO. 329.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 329, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-336 of SEQ ID NO. 384, which also corresponds to amino acids 1-336 of SEQ ID NO. 329, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 337-373 of SEQ ID NO. 329, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 329, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 337-373 in SEQ ID NO. 329.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 330, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-229 of SEQ ID NO. 384, which also corresponds to amino acids 1-229 of SEQ ID NO. 330, and a second amino acid sequence VSIS corresponding to amino acids 230-233 of SEQ ID NO. 330 wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 330, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-229 of SEQ ID NO. 384, which also corresponds to amino acids 1-229 of SEQ ID NO. 330, and a second amino acid sequence VSIS corresponding to amino acids 230-233 of SEQ ID NO. 330 wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 330, comprising a first amino acid sequence being at least 90% homologous to corresponding to amino acids 1-229 of SEQ ID NO. 384, which also corresponds to amino acids 1-229 of SEQ ID NO. 330, and a second amino acid sequence VSIS corresponding to amino acids 230-233 of SEQ ID NO. 330 wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 332, comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1-110 of SEQ ID NO. 332, and a second amino acid sequence being at least 90% homologous to TQ corresponding to amino acids 1-112 of Q8IXM0, which also corresponds to amino acids 111-222 of SEQ ID NO. 332, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a head of SEQ ID NO. 332, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1-110 of SEQ ID NO. 332.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 332, comprising a first amino acid sequence being at least 90% homologous to amino acids 1-83 of Q96AC2, which also corresponds to amino acids 1-83 of SEQ ID NO. 332, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 84-222 of SEQ ID NO. 332, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 332, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 84-222 in SEQ ID NO. 332.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 332, comprising a first amino acid sequence being at least 90% homologous to amino acids 1-83 of Q8N2G4, which also corresponds to amino acids 1-83 of SEQ ID NO. 332, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 84-222 of SEQ ID NO. 332, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 332, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 84-222 in SEQ ID NO. 332.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 332, comprising a first amino acid sequence being at least 90% homologous to amino acids 24-106 of BAC85518, which also corresponds to amino acids 1-83 of SEQ ID NO. 332, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 84-222 of SEQ ID NO. 332, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 332, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 84-222 in SEQ ID NO. 332.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 333, comprising a first amino acid sequence being at least 90% homologous to amino acids 1-64 of Q96AC2, which also corresponds to amino acids 1-64 of SEQ ID NO. 333, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 65-93 of SEQ ID NO. 333, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 333, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 65-93 in SEQ ID NO. 333.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 333, comprising a first amino acid sequence being at least 90% homologous to amino acids 1-64 of Q8N2G4, which also corresponds to amino acids 1-64 of SEQ ID NO. 333, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 65-93 of SEQ ID NO. 333, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 333, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 65-93 in SEQ ID NO. 333.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 333, comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1-5 of SEQ ID NO. 333, second amino acid sequence being at least 90% homologous to amino acids 22-80 of BAC85273, which also corresponds to amino acids 6-64 of SEQ ID NO. 333, and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 65-93 of SEQ ID NO. 333, wherein said first, second and third amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a head of SEQ ID NO. 333, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1-5 of SEQ ID NO. 333.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 333, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 65-93 in SEQ ID NO. 333.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 333, comprising a first amino acid sequence being at least 90% homologous to amino acids 24-87 of BAC85518, which also corresponds to amino acids 1-64 of SEQ ID NO. 333, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 65-93 of SEQ ID NO. 333, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 333, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 65-93 in SEQ ID NO. 333.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 334, comprising a first amino acid sequence being at least 90% homologous to amino acids 1-63 of Q96AC2, which also corresponds to amino acids 1-63 of SEQ ID NO. 334, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 64-84 of SEQ ID NO. 334, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 334, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 64-84 in SEQ ID NO. 334.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 335, comprising a first amino acid sequence being at least 90% homologous to amino acids 1-63 of SEQ ID NOs. Q96AC2, which also corresponds to amino acids 1-63 of SEQ ID NO. 335, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 64-90 of SEQ ID NO. 335, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 335, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 64-90 in SEQ ID NO. 335.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 335, comprising a first amino acid sequence being at least 90% homologous to amino acids 1-63 of Q8N2G4, which also corresponds to amino acids 1-63 of SEQ ID NO. 335, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 64-90 of SEQ ID NO. 335, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 335, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 64-90 in SEQ ID NO. 335.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 335, comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1-5 of SEQ ID NO. 335, second amino acid sequence being at least 90% homologous to amino acids 22-79 of BAC85273, which also corresponds to amino acids 6-63 of SEQ ID NO. 335, and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 64-90 of SEQ ID NO. 335, wherein said first, second and third amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a head of SEQ ID NO. 335, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1-5 of SEQ ID NO. 335.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 335, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the amino acids 64-90 in SEQ ID NO. 335.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 335, comprising a first amino acid sequence being at least 90% homologous to amino acids 24-86 of BAC85518, which also corresponds to amino acids 1-63 of SEQ ID NO. 335, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 64-90 of SEQ ID NO. 335, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 335, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 64-90 in SEQ ID NO. 335.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 336, comprising a first amino acid sequence being at least 90% homologous to amino acids 1-247 of SEQ ID NO. 385, which also corresponds to amino acids 1-247 of SEQ ID NO. 336, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 248-255 of SEQ ID NO. 336, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 336, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 248-255 in SEQ ID NO. 336.


According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 337, comprising a first amino acid sequence being at least 90% homologous to amino acids 1-66 of SEQ ID NO. 386, which also corresponds to amino acids 1-66 of SEQ ID NO. 337, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 67-80 of SEQ ID NO. 337, wherein said first and second amino acid sequences are contiguous and in a sequential order.


According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 337, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 67-80 in SEQ ID NO. 337.


According to preferred embodiments of the present invention, there is provided an antibody from cluster HSECADH, R11723, S78694, HUMTREFAC, HSCOC4, HSSTROL3, HUMF5A, Z40511, H53626 and HSMUC1A, capable of specifically binding to an epitope of an amino acid sequence.


Optionally the amino acid sequence corresponds to a bridge, edge portion, tail, head or insertion.


Optionally the antibody is capable of differentiating between a splice variant having said epitope and a corresponding known protein.


According to preferred embodiments of the present invention, there is provided a kit for detecting prostate cancer, comprising a kit from cluster HSECADH, R11723, S78694, HUMTREFAC, HSCOC4, HSSTROL3, HUMF5A, Z40511, H53626 and HSMUC1A for detecting overexpression of a splice variant.


Optionally the kit comprises a NAT-based technology.


Optionally the kit further comprises at least one primer pair capable of selectively hybridizing to a nucleic acid sequence.


Optionally the kit further comprises at least one oligonucleotide capable of selectively hybridizing to a nucleic acid sequence.


Optionally the kit comprises an antibody.


Optionally the kit further comprises at least one reagent for performing an ELISA or a Western blot.


According to preferred embodiments of the present invention, there is provided a method for detecting prostate cancer, comprising detecting overexpression of a splice variant from cluster HSECADH, R11723, S78694, HUMTREFAC, HSCOC4, HSSTROL3, HUMF5A, Z40511, H53626 and HSMUC1A.


Optionally detecting overexpression is performed with a NAT-based technology.


Optionally detecting overexpression is performed with an immunoassay.


Optionally the immunoassay comprises an antibody.


According to preferred embodiments of the present invention, there is provided a biomarker capable of detecting prostate cancer, comprising nucleic acid sequences or a fragment thereof, or amino acid sequences or a fragment thereof from cluster HSECADH, R11723, S78694, HUMTREFAC, HSCOC4, HSSTROL3, HUMF5A, Z40511, H53626 and HSMUC1A.


According to preferred embodiments of the present invention, there is provided a method for screening for prostate cancer, comprising detecting prostate cancer cells with a biomarker or an antibody or a method or assay from cluster HSECADH, R11723, S78694, HUMTREFAC, HSCOC4, HSSTROL3, HUMF5A, Z40511, H53626 and HSMUC1A.


According to preferred embodiments of the present invention, there is provided a method for diagnosing prostate cancer, comprising detecting prostate cancer cells with a biomarker or an antibody or a method or assay from cluster HSECADH, R11723, S78694, HUMTREFAC, HSCOC4, HSSTROL3, HUMF5A, Z40511, H53626 and HSMUC1A.


According to preferred embodiments of the present invention, there is provided a method for monitoring disease progression, treatment efficacy, relapse of prostate cancer, comprising detecting prostate cancer cells with a biomarker or an antibody or a method or assay from cluster HSECADH, R11723, S78694, HUMTREFAC, HSCOC4, HSSTROL3, HUMF5A, Z40511, H53626 and HSMUC1A.


According to preferred embodiments of the present invention, there is provided a method of selecting a therapy for prostate cancer, comprising detecting prostate cancer cells with a biomarker or an antibody or a method or assay from cluster HSECADH, R11723, S78694, HUMTREFAC, HSCOC4, HSSTROL3, HUMF5A, Z40511, H53626 and HSMUC1A.


According to preferred embodiments of the present invention, preferably any of the above nucleic acid and/or amino acid sequences further comprises any sequence having at least about 70%, preferably at least about 80%, more preferably at least about 90%, most preferably at least about 95% homology thereto.


All nucleic acid sequences and/or amino acid sequences shown herein as embodiments of the present invention relate to their isolated form, as isolated polynucleotides (including for all transcripts), oligonucleotides (including for all segments, amplicons and primers), peptides (including for all tails, bridges, insertions or heads, optionally including other antibody epitopes as described herein) and/or polypeptides (including for all proteins). It should be noted that oligonucleotide and polynucleotide, or peptide and polypeptide, may optionally be used interchangeably.


Unless otherwise noted, all experimental data relates to variants of the present invention, named according to the segment being tested (as expression was tested through RT-PCR as described).


Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. The following references provide one of skill with a general definition of many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). All of these are hereby incorporated by reference as if fully set forth herein. As used herein, the following terms have the meanings ascribed to them unless specified otherwise.





BRIEF DESCRIPTION OF DRAWINGS

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FIG. 1 is a schematic description of the cancer biomarker selection engine.



FIG. 2 is a schematic illustration, depicting grouping of transcripts of a given cluster based on presence or absence of unique sequence regions.



FIG. 3 is a schematic summary of quantitative real-time PCR analysis.



FIG. 4 is a schematic presentation of the oligonucleotide based microarray fabrication.



FIG. 5 is a schematic summary of the oligonucleotide based microarray experimental flow.



FIG. 6 is a histogram is a histogram showing Cancer and cell-line vs. normal tissue expression for Cluster HSECADH, demonstrating overexpression in a mixture of malignant tumors from different tissues and ovarian carcinoma.



FIG. 7 is a histogram showing Cancer and cell-line vs. normal tissue expression for Cluster R11723, demonstrating overexpression in epithelial malignant tumors, a mixture of malignant tumors from different tissues and kidney malignant tumors.



FIG. 8 is a histogram showing over expression of the R11723 transcripts which are detectable by amplicon as depicted in sequence name R11723 seg13 (SEQ ID NO:492) in cancerous prostate samples relative to the normal samples.



FIG. 9 is a histogram showing expression of R11723 transcripts, which are detectable by amplicon as depicted in sequence name R11723seg13 (SEQ ID NO:492), in different normal tissues.



FIG. 10A are histograms showing over expression of the R11723 transcripts, which are detectable by amplicon as depicted in sequence name R11723 junc11-18 (SEQ ID NO:495) in cancerous prostate samples relative to the normal samples (FIG. 10A) or expression in normal tissues (FIG. 10B).



FIG. 11 is a histogram showing Cancer and cell-line vs. normal tissue expression for Cluster HUMTREFAC, demonstrating overexpression in a mixture of malignant tumors from different tissues, breast malignant tumors, pancreas carcinoma and prostate cancer.



FIG. 12 is a histogram showing Cancer and cell-line vs. normal tissue expression for Cluster HSCOC4, demonstrating overexpression in brain malignant tumors, a mixture of malignant tumors from different tissues, breast malignant tumors, pancreas carcinoma and prostate cancer.



FIG. 13 is a histogram showing Cancer and cell-line vs. normal tissue expression for Cluster HSSTROL3, demonstrating overexpression in transitional cell carcinoma, epithelial malignant tumors, a mixture of malignant tumors from different tissues and pancreas carcinoma.



FIG. 14 is a histogram showing the over expression of the Stromelysin-3 precursor (SEQ ID NO:391) transcripts, which are detectable by amplicon as depicted in sequence name HSSTROL3 seg24 (SEQ ID NO:499), in cancerous Prostate samples relative to the normal samples.



FIG. 15 is a histogram demonstrating the expression of Stromelysin-3 transcripts which are detectable by amplicon_as depicted in sequence name HSSTROL3 seg24 (SEQ ID NO:499) in different normal tissues.



FIG. 16 is a histogram showing Cancer and cell-line vs. normal tissue expression for Cluster H53626, demonstrating overexpression in epithelial malignant tumors, a mixture of malignant tumors from different tissues and myosarcoma.



FIG. 17 is a histogram showing Cancer and cell-line vs. normal tissue expression for Cluster HSMUC1A, demonstrating overexpression in a mixture of malignant tumors from different tissues, breast malignant tumors, pancreas carcinoma and prostate cancer.



FIG. 18A-B is a histogram showing the relative expression of AA315457 variants in normal, benign and tumor derived prostate samples as determined by real time PCR using primers for SEQ ID NO: 413. FIG. 18B is a duplicate experiment.



FIG. 19 is a histogram showing the relative expression of Thrombospondin 1 (THBS1) variants in normal, benign and tumor derived prostate samples as determined by real time PCR using primers for SEQ ID NO: 421.



FIG. 20 is a histogram showing the relative expression of Thrombospondin 1 (THBS1) variants in normal, benign and tumor derived prostate samples as determined by real time PCR using primers for SEQ ID NO: 418.



FIG. 21 is a histogram showing the relative expression of transcripts detectable by SEQ ID NOs: 413, 418 and 421 in normal, benign and tumor derived prostate samples as determined by real time PCR.



FIG. 22 is a histogram showing the relative expression of DD3/PCA3 variants in normal, benign and tumor derived prostate samples as determined by real time PCR using primers for SEQ ID NO:475.



FIG. 23 is a histogram showing the relative expression of Thrombospondin 1 (THBS1) variants (e.g., variants no. 4, 6, 8, 11, 14, 15, 26, 27, 28, 30) in normal, benign and tumor derived prostate samples as determined by oligonucleotide-based micro-array experiments with SEQ ID NOs: 477, 478, 479, 480, 481, 482. For every oligonucleotide (SEQ ID NOs: 477, 478, 479, 480, 481, 482) the averaged intensity determined for every sample was divided by the averaged intensity of all the normal samples.





DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention is of novel markers for prostate cancer that are both sensitive and accurate. Biomolecular sequences (amino acid and/or nucleic acid sequences) uncovered using the methodology of the present invention and described herein can be efficiently utilized as tissue or pathological markers and/or as drugs or drug targets for treating or preventing a disease.


These markers are specifically released to the bloodstream under conditions of prostate cancer and/or other prostate pathology, and/or are otherwise expressed at a much higher level and/or specifically expressed in prostate cancer tissue or cells. The measurement of these markers, alone or in combination, in patient samples provides information that the diagnostician can correlate with a probable diagnosis of prostate cancer and/or pathology.


The present invention therefore also relates to diagnostic assays for prostate cancer and/or prostate pathology, and methods of use of such markers for detection of prostate cancer and/or prostate pathology, optionally and preferably in a sample taken from a subject (patient), which is more preferably some type of blood sample.


The markers of the present invention, alone or in combination, can be used for prognosis, prediction, screening, early diagnosis, staging, therapy selection and treatment monitoring of prostate cancer. For example, optionally and preferably, these markers may be used for staging prostate cancer and/or monitoring the progression of the disease. Furthermore, the markers of the present invention, alone or in combination, can be used for detection of the source of metastasis found in anatomical places other then prostate. Also, one or more of the markers may optionally be used in combination with one or more other prostate cancer markers (other than those described herein).


Biomolecular sequences (amino acid and/or nucleic acid sequences) uncovered using the methodology of the present invention and described herein can be efficiently utilized as tissue or pathological markers and/or as drugs or drug targets for treating or preventing a disease.


These markers are specifically released to the bloodstream under conditions of prostate cancer (or one of the above indicative conditions), and/or are otherwise expressed at a much higher level and/or specifically expressed in prostate cancer tissue or cells, and/or tissue or cells under one of the above indicative conditions. The measurement of these markers, alone or in combination, in patient samples provides information that the diagnostician can correlate with a probable diagnosis of prostate cancer and/or a condition that it is indicative of a higher risk for prostate cancer.


The present invention therefore also relates to diagnostic assays for prostate cancer and/or an indicative condition, and methods of use of such markers for detection of prostate cancer and/or an indicative condition, optionally and preferably in a sample taken from a subject (patient), which is more preferably some type of blood sample.


According to a preferred embodiment of the present invention, use of the marker optionally and preferably permits a non-cancerous prostate disease state to be distinguished from prostate cancer and/or an indicative condition. A non limiting example of a non-cancerous prostate disease state includes BPH. According to another preferred embodiment of the present invention, use of the marker optionally and preferably permits an indicative condition to be distinguished from prostate cancer.


In another embodiment, the present invention relates to bridges, tails, heads and/or insertions, and/or analogs, homologs and derivatives of such peptides. Such bridges, tails, heads and/or insertions are described in greater detail below with regard to the Examples.


As used herein a “tail” refers to a peptide sequence at the end of an amino acid sequence that is unique to a splice variant according to the present invention. Therefore, a splice variant having such a tail may optionally be considered as a chimera, in that at least a first portion of the splice variant is typically highly homologous (often 100% identical) to a portion of the corresponding known protein, while at least a second portion of the variant comprises the tail.


As used herein a “head” refers to a peptide sequence at the beginning of an amino acid sequence that is unique to a splice variant according to the present invention. Therefore, a splice variant having such a head may optionally be considered as a chimera, in that at least a first portion of the splice variant comprises the head, while at least a second portion is typically highly homologous (often 100% identical) to a portion of the corresponding known protein.


As used herein “an edge portion” refers to a connection between two portions of a splice variant according to the present invention that were not joined in the wild type or known protein. An edge may optionally arise due to a join between the above “known protein” portion of a variant and the tail, for example, and/or may occur if an internal portion of the wild type sequence is no longer present, such that two portions of the sequence are now contiguous in the splice variant that were not contiguous in the known protein. A “bridge” may optionally be an edge portion as described above, but may also include a join between a head and a “known protein” portion of a variant, or a join between a tail and a “known protein” portion of a variant, or a join between an insertion and a “known protein” portion of a variant.


Optionally and preferably, a bridge between a tail or a head or a unique insertion, and a “known protein” portion of a variant, comprises at least about 10 amino acids, more preferably at least about 20 amino acids, most preferably at least about 30 amino acids, and even more preferably at least about 40 amino acids, in which at least one amino acid is from the tail/head/insertion and at least one amino acid is from the “known protein” portion of a variant. Also optionally, the bridge may comprise any number of amino acids from about 10 to about 40 amino acids (for example, 10, 11, 12, 13 . . . 37, 38, 39, 40 amino acids in length, or any number in between).


It should be noted that a bridge cannot be extended beyond the length of the sequence in either direction, and it should be assumed that every bridge description is to be read in such manner that the bridge length does not extend beyond the sequence itself.


Furthermore, bridges are described with regard to a sliding window in certain contexts below. For example, certain descriptions of the bridges feature the following format: a bridge between two edges (in which a portion of the known protein is not present in the variant) may optionally be described as follows: a bridge portion of CONTIG-NAME_P1 (representing the name of the protein), comprising a polypeptide having a length “n”, wherein n is at least about 10 amino acids in length, optionally at least about 20 amino acids in length, preferably at least about 30 amino acids in length, more preferably at least about 40 amino acids in length and most preferably at least about 50 amino acids in length, wherein at least two amino acids comprise XX (2 amino acids in the center of the bridge, one from each end of the edge), having a structure as follows (numbering according to the sequence of CONTIG-NAME_P1): a sequence starting from any of amino acid numbers 49−x to 49 (for example); and ending at any of amino acid numbers 50+((n−2)−x) (for example), in which x varies from 0 to n−2. In this example, it should also be read as including bridges in which n is any number of amino acids between 10-50 amino acids in length. Furthermore, the bridge polypeptide cannot extend beyond the sequence, so it should be read such that 49−x (for example) is not less than 1, nor 50+((n−2)−x) (for example) greater than the total sequence length.


In another embodiment, this invention provides antibodies specifically recognizing the splice variants and polypeptide fragments thereof of this invention. Preferably such antibodies differentially recognize splice variants of the present invention but do not recognize a corresponding known protein (such known proteins are discussed with regard to their splice variants in the Examples below).


In another embodiment, this invention provides an isolated nucleic acid molecule encoding for a splice variant according to the present invention, having a nucleotide sequence as set forth in any one of the sequences listed herein, or a sequence complementary thereto. In another embodiment, this invention provides an isolated nucleic acid molecule, having a nucleotide sequence as set forth in any one of the sequences listed herein, or a sequence complementary thereto. In another embodiment, this invention provides an oligonucleotide of at least about 12 nucleotides, specifically hybridizable with the nucleic acid molecules of this invention. In another embodiment, this invention provides vectors, cells, liposomes and compositions comprising the isolated nucleic acids of this invention.


In another embodiment, this invention provides a method for detecting a splice variant according to the present invention in a biological sample, comprising: contacting a biological sample with an antibody specifically recognizing a splice variant according to the present invention under conditions whereby the antibody specifically interacts with the splice variant in the biological sample but do not recognize known corresponding proteins (wherein the known protein is discussed with regard to its splice variant(s) in the Examples below), and detecting said interaction; wherein the presence of an interaction correlates with the presence of a splice variant in the biological sample.


In another embodiment, this invention provides a method for detecting a splice variant nucleic acid sequences in a biological sample, comprising: hybridizing the isolated nucleic acid molecules or oligonucleotide fragments of at least about a minimum length to a nucleic acid material of a biological sample and detecting a hybridization complex; wherein the presence of a hybridization complex correlates with the presence of a splice variant nucleic acid sequence in the biological sample.


According to the present invention, the splice variants described herein are non-limiting examples of markers for diagnosing prostate cancer and/or prostate pathology. Each splice variant marker of the present invention can be used alone or in combination, for various uses, including but not limited to, prognosis, prediction, screening, early diagnosis, determination of progression, therapy selection and treatment monitoring of prostate cancer and/or prostate pathology.


According to optional but preferred embodiments of the present invention, any marker according to the present invention may optionally be used alone or combination. Such a combination may optionally comprise a plurality of markers described herein, optionally including any subcombination of markers, and/or a combination featuring at least one other marker, for example a known marker. Furthermore, such a combination may optionally and preferably be used as described above with regard to determining a ratio between a quantitative or semi-quantitative measurement of any marker described herein to any other marker described herein, and/or any other known marker, and/or any other marker. With regard to such a ratio between any marker described herein (or a combination thereof) and a known marker, more preferably the known marker comprises the “known protein” as described in greater detail below with regard to each cluster or gene.


According to other preferred embodiments of the present invention, a splice variant protein or a fragment thereof, or a splice variant nucleic acid sequence or a fragment thereof, may be featured as a biomarker for detecting prostate cancer and/or prostate pathology, such that a biomarker may optionally comprise any of the above.


According to still other preferred embodiments, the present invention optionally and preferably encompasses any amino acid sequence or fragment thereof encoded by a nucleic acid sequence corresponding to a splice variant protein as described herein. Any oligopeptide or peptide relating to such an amino acid sequence or fragment thereof may optionally also (additionally or alternatively) be used as a biomarker, including but not limited to the unique amino acid sequences of these proteins that are depicted as tails, heads, insertions, edges or bridges. The present invention also optionally encompasses antibodies capable of recognizing, and/or being elicited by, such oligopeptides or peptides.


The present invention also optionally and preferably encompasses any nucleic acid sequence or fragment thereof, or amino acid sequence or fragment thereof, corresponding to a splice variant of the present invention as described above, optionally for any application.


Non-limiting examples of methods or assays are described below.


The present invention also relates to kits based upon such diagnostic methods or assays.


Nucleic Acid Sequences and Oligonucleotides


Various embodiments of the present invention encompass nucleic acid sequences described hereinabove; fragments thereof, sequences hybridizable therewith, sequences homologous thereto, sequences encoding similar polypeptides with different codon usage, altered sequences characterized by mutations, such as deletion, insertion or substitution of one or more nucleotides, either naturally occurring or artificially induced, either randomly or in a targeted fashion.


The present invention encompasses nucleic acid sequences described herein; fragments thereof, sequences hybridizable therewith, sequences homologous thereto [e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 95% or more say 100% identical to the nucleic acid sequences set forth below], sequences encoding similar polypeptides with different codon usage, altered sequences characterized by mutations, such as deletion, insertion or substitution of one or more nucleotides, either naturally occurring or man induced, either randomly or in a targeted fashion. The present invention also encompasses homologous nucleic acid sequences (i.e., which form a part of a polynucleotide sequence of the present invention) which include sequence regions unique to the polynucleotides of the present invention.


In cases where the polynucleotide sequences of the present invention encode previously unidentified polypeptides, the present invention also encompasses novel polypeptides or portions thereof, which are encoded by the isolated polynucleotide and respective nucleic acid fragments thereof described hereinabove.


A “nucleic acid fragment” or an “oligonucleotide” or a “polynucleotide” are used herein interchangeably to refer to a polymer of nucleic acids. A polynucleotide sequence of the present invention refers to a single or double stranded nucleic acid sequences which is isolated and provided in the form of an RNA sequence, a complementary polynucleotide sequence (cDNA), a genomic polynucleotide sequence and/or a composite polynucleotide sequences (e.g., a combination of the above).


As used herein the phrase “complementary polynucleotide sequence” refers to a sequence, which results from reverse transcription of messenger RNA using a reverse transcriptase or any other RNA dependent DNA polymerase. Such a sequence can be subsequently amplified in vivo or in vitro using a DNA dependent DNA polymerase.


As used herein the phrase “genomic polynucleotide sequence” refers to a sequence derived (isolated) from a chromosome and thus it represents a contiguous portion of a chromosome.


As used herein the phrase “composite polynucleotide sequence” refers to a sequence, which is composed of genomic and cDNA sequences. A composite sequence can include some exonal sequences required to encode the polypeptide of the present invention, as well as some intronic sequences interposing therebetween. The intronic sequences can be of any source, including of other genes, and typically will include conserved splicing signal sequences. Such intronic sequences may further include cis acting expression regulatory elements.


Preferred embodiments of the present invention encompass oligonucleotide probes.


An example of an oligonucleotide probe which can be utilized by the present invention is a single stranded polynucleotide which includes a sequence complementary to the unique sequence region of any variant according to the present invention, including but not limited to a nucleotide sequence coding for an amino sequence of a bridge, tail, head and/or insertion according to the present invention, and/or the equivalent portions of any nucleotide sequence given herein (including but not limited to a nucleotide sequence of a node, segment or amplicon described herein).


Alternatively, an oligonucleotide probe of the present invention can be designed to hybridize with a nucleic acid sequence encompassed by any of the above nucleic acid sequences, particularly the portions specified above, including but not limited to a nucleotide sequence coding for an amino sequence of a bridge, tail, head and/or insertion according to the present invention, and/or the equivalent portions of any nucleotide sequence given herein (including but not limited to a nucleotide sequence of a node, segment or amplicon described herein).


Oligonucleotides designed according to the teachings of the present invention can be generated according to any oligonucleotide synthesis method known in the art such as enzymatic synthesis or solid phase synthesis. Equipment and reagents for executing solid-phase synthesis are commercially available from, for example, Applied Biosystems. Any other means for such synthesis may also be employed; the actual synthesis of the oligonucleotides is well within the capabilities of one skilled in the art and can be accomplished via established methodologies as detailed in, for example, “Molecular Cloning: A laboratory Manual” Sambrook et al., (1989); “Current Protocols in Molecular Biology” Volumes I-III Ausubel, R. M., ed. (1994); Ausubel et al., “Current Protocols in Molecular Biology”, John Wiley and Sons, Baltimore, Md. (1989); Perbal, “A Practical Guide to Molecular Cloning”, John Wiley & Sons, New York (1988) and “Oligonucleotide Synthesis” Gait, M. J., ed. (1984) utilizing solid phase chemistry, e.g. cyanoethyl phosphoramidite followed by deprotection, desalting and purification by for example, an automated trityl-on method or HPLC.


Oligonucleotides used according to this aspect of the present invention are those having a length selected from a range of about 10 to about 200 bases preferably about 15 to about 150 bases, more preferably about 20 to about 100 bases, most preferably about 20 to about 50 bases. Preferably, the oligonucleotide of the present invention features at least 17, at least 18, at least 19, at least 20, at least 22, at least 25, at least 30 or at least 40, bases specifically hybridizable with the biomarkers of the present invention.


The oligonucleotides of the present invention may comprise heterocylic nucleosides consisting of purines and the pyrimidines bases, bonded in a 3′ to 5′ phosphodiester linkage.


Preferably used oligonucleotides are those modified at one or more of the backbone, internucleoside linkages or bases, as is broadly described hereinunder.


Specific examples of preferred oligonucleotides useful according to this aspect of the present invention include oligonucleotides containing modified backbones or non-natural internucleoside linkages. Oligonucleotides having modified backbones include those that retain a phosphorus atom in the backbone, as disclosed in U.S. Pat. Nos. 4,469,863; 4,476,301; 5,023,243; 5,177,196; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466, 677; 5,476,925; 5,519,126; 5,536,821; 5,541,306; 5,550,111; 5,563,253; 5,571,799; 5,587,361; and 5,625,050.


Preferred modified oligonucleotide backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkyl phosphotriesters, methyl and other alkyl phosphonates including 3′-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3′-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3′-5′ linkages, 2′-5′ linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3′-5′ to 5′-3′ or 2′-5′ to 5′-2′. Various salts, mixed salts and free acid forms can also be used.


Alternatively, modified oligonucleotide backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH2 component parts, as disclosed in U.S. Pat. Nos. 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,264,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,610,289; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437; and 5,677,439.


Other oligonucleotides which can be used according to the present invention, are those modified in both sugar and the internucleoside linkage, i.e., the backbone, of the nucleotide units are replaced with novel groups. The base units are maintained for complementation with the appropriate polynucleotide target. An example for such an oligonucleotide mimetic, includes peptide nucleic acid (PNA). United States patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos. 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Other backbone modifications, which can be used in the present invention are disclosed in U.S. Pat. No. 6,303,374.


Oligonucleotides of the present invention may also include base modifications or substitutions. As used herein, “unmodified” or “natural” bases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). Modified bases include but are not limited to other synthetic and natural bases such as 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine. Further bases particularly useful for increasing the binding affinity of the oligomeric compounds of the invention include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2° C. and are presently preferred base substitutions, even more particularly when combined with 2′-O-methoxyethyl sugar modifications.


Another modification of the oligonucleotides of the invention involves chemically linking to the oligonucleotide one or more moieties or conjugates, which enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. Such moieties include but are not limited to lipid moieties such as a cholesterol moiety, cholic acid, a thioether, e.g., hexyl-S-tritylthiol, a thiocholesterol, an aliphatic chain, e.g., dodecandiol or undecyl residues, a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethylammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate, a polyamine or a polyethylene glycol chain, or adamantane acetic acid, a palmityl moiety, or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety, as disclosed in U.S. Pat. No. 6,303,374.


It is not necessary for all positions in a given oligonucleotide molecule to be uniformly modified, and in fact more than one of the aforementioned modifications may be incorporated in a single compound or even at a single nucleoside within an oligonucleotide.


It will be appreciated that oligonucleotides of the present invention may include further modifications for more efficient use as diagnostic agents and/or to increase bioavailability, therapeutic efficacy and reduce cytotoxicity.


To enable cellular expression of the polynucleotides of the present invention, a nucleic acid construct according to the present invention may be used, which includes at least a coding region of one of the above nucleic acid sequences, and further includes at least one cis acting regulatory element. As used herein, the phrase “cis acting regulatory element” refers to a polynucleotide sequence, preferably a promoter, which binds a trans acting regulator and regulates the transcription of a coding sequence located downstream thereto.


Any suitable promoter sequence can be used by the nucleic acid construct of the present invention.


Preferably, the promoter utilized by the nucleic acid construct of the present invention is active in the specific cell population transformed. Examples of cell type-specific and/or tissue-specific promoters include promoters such as albumin that is liver specific, lymphoid specific promoters [Calame et al., (1988) Adv. Immunol. 43:235-275]; in particular promoters of T-cell receptors [Winoto et al., (1989) EMBO J. 8:729-733] and immunoglobulins; [Banerji et al. (1983) Cell 33729-740], neuron-specific promoters such as the neurofilament promoter [Byrne et al. (1989) Proc. Natl. Acad. Sci. USA 86:5473-5477], pancreas-specific promoters [Edlunch et al. (1985) Science 230:912-916] or mammary gland-specific promoters such as the milk whey promoter (U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). The nucleic acid construct of the present invention can further include an enhancer, which can be adjacent or distant to the promoter sequence and can function in up regulating the transcription therefrom.


The nucleic acid construct of the present invention preferably further includes an appropriate selectable marker and/or an origin of replication. Preferably, the nucleic acid construct utilized is a shuttle vector, which can propagate both in E. coli (wherein the construct comprises an appropriate selectable marker and origin of replication) and be compatible for propagation in cells, or integration in a gene and a tissue of choice. The construct according to the present invention can be, for example, a plasmid, a bacmid, a phagemid, a cosmid, a phage, a virus or an artificial chromosome.


Examples of suitable constructs include, but are not limited to, pcDNA3, pcDNA3.1 (+/−), pGL3, PzeoSV2 (+/−), pDisplay, pEF/myc/cyto, pCMV/myc/cyto each of which is commercially available from Invitrogen Co. (invitrogen dot com). Examples of retroviral vector and packaging systems are those sold by Clontech, San Diego, Calif., including Retro-X vectors pLNCX and pLXSN, which permit cloning into multiple cloning sites and the transgene is transcribed from CMV promoter. Vectors derived from Mo-MuLV are also included such as pBabe, where the transgene will be transcribed from the 5′LTR promoter.


Currently preferred in vivo nucleic acid transfer techniques include transfection with viral or non-viral constructs, such as adenovirus, lentivirus, Herpes simplex I virus, or adeno-associated virus (AAV) and lipid-based systems. Useful lipids for lipid-mediated transfer of the gene are, for example, DOTMA, DOPE, and DC-Chol [Tonkinson et al., Cancer Investigation, 14(1): 54-65 (1996)]. The most preferred constructs for use in gene therapy are viruses, most preferably adenoviruses, AAV, lentiviruses, or retroviruses. A viral construct such as a retroviral construct includes at least one transcriptional promoter/enhancer or locus-defining element(s), or other elements that control gene expression by other means such as alternate splicing, nuclear RNA export, or post-translational modification of messenger. Such vector constructs also include a packaging signal, long terminal repeats (LTRs) or portions thereof, and positive and negative strand primer binding sites appropriate to the virus used, unless it is already present in the viral construct. In addition, such a construct typically includes a signal sequence for secretion of the peptide from a host cell in which it is placed. Preferably the signal sequence for this purpose is a mammalian signal sequence or the signal sequence of the polypeptide variants of the present invention. Optionally, the construct may also include a signal that directs polyadenylation, as well as one or more restriction sites and a translation termination sequence. By way of example, such constructs will typically include a 5′ LTR, a tRNA binding site, a packaging signal, an origin of second-strand DNA synthesis, and a 3′ LTR or a portion thereof. Other vectors can be used that are non-viral, such as cationic lipids, polylysine, and dendrimers.


Hybridization Assays


Detection of a nucleic acid of interest in a biological sample may optionally be effected by hybridization-based assays using an oligonucleotide probe (non-limiting examples of probes according to the present invention were previously described).


Traditional hybridization assays include PCR, RT-PCR, Real-time PCR, RNase protection, in-situ hybridization, primer extension, Southern blots (DNA detection), dot or slot blots (DNA, RNA), and Northern blots (RNA detection) (NAT type assays are described in greater detail below). More recently, PNAs have been described (Nielsen et al. 1999, Current Opin. Biotechnol. 10:71-75). Other detection methods include kits containing probes on a dipstick setup and the like.


Hybridization based assays which allow the detection of a variant of interest (i.e., DNA or RNA) in a biological sample rely on the use of oligonucleotides which can be 10, 15, 20, or 30 to 100 nucleotides long preferably from 10 to 50, more preferably from 40 to 50 nucleotides long.


Thus, the isolated polynucleotides (oligonucleotides) of the present invention are preferably hybridizable with any of the herein described nucleic acid sequences under moderate to stringent hybridization conditions.


Moderate to stringent hybridization conditions are characterized by a hybridization solution such as containing 10% dextrane sulfate, 1. M NaCl, 1% SDS and 5×106 cpm 32P labeled probe, at 65° C., with a final wash solution of 0.2×SSC and 0.1% SDS and final wash at 65° C. and whereas moderate hybridization is effected using a hybridization solution containing 10% dextrane sulfate, 1 M NaCl, 1% SDS and 5×106 cpm 32P labeled probe, at 65° C., with a final wash solution of 1×SSC and 0.1% SDS and final wash at 50° C.


More generally, hybridization of short nucleic acids (below 200 bp in length, e.g. 17-40 bp in length) can be effected using the following exemplary hybridization protocols which can be modified according to the desired stringency; (i) hybridization solution of 6×SSC and 1% SDS or 3 M TMACI, 0.01 M sodium phosphate (pH 6.8), 1 mM EDTA (pH 7.6), 0.5% SDS, 100 μg/ml denatured salmon sperm DNA and 0.1% nonfat dried milk, hybridization temperature of 1-1.5° C. below the Tm, final wash solution of 3 M TMACI, 0.01 M sodium phosphate (pH 6.8), 1 mM EDTA (pH 7.6), 0.5% SDS at 1-1.5° C. below the Tm; (ii) hybridization solution of 6×SSC and 0.1% SDS or 3 M TMACI, 0.01 M sodium phosphate (pH 6.8), 1 mM EDTA (pH 7.6), 0.5% SDS, 100 μg/ml denatured salmon sperm DNA and 0.1% nonfat dried milk, hybridization temperature of 2-2.5° C. below the Tm, final wash solution of 3 M TMACI, 0.01 M sodium phosphate (pH 6.8), 1 mM EDTA (pH 7.6), 0.5% SDS at 1-1.5° C. below the Tm, final wash solution of 6×SSC, and final wash at 22° C.; (iii) hybridization solution of 6×SSC and 1% SDS or 3 M TMACI, 0.01 M sodium phosphate (pH 6.8), 1 mM EDTA (pH 7.6), 0.5% SDS, 100 μg/ml denatured salmon sperm DNA and 0.1% nonfat dried milk, hybridization temperature.


The detection of hybrid duplexes can be carried out by a number of methods. Typically, hybridization duplexes are separated from unhybridized nucleic acids and the labels bound to the duplexes are then detected. Such labels refer to radioactive, fluorescent, biological or enzymatic tags or labels of standard use in the art. A label can be conjugated to either the oligonucleotide probes or the nucleic acids derived from the biological sample.


Probes can be labeled according to numerous well known methods. Non-limiting examples of radioactive labels include 3H, 14C, 32P, and 35S. Non-limiting examples of detectable markers include ligands, fluorophores, chemiluminescent agents, enzymes, and antibodies. Other detectable markers for use with probes, which can enable an increase in sensitivity of the method of the invention, include biotin and radio-nucleotides. It will become evident to the person of ordinary skill that the choice of a particular label dictates the manner in which it is bound to the probe.


For example, oligonucleotides of the present invention can be labeled subsequent to synthesis, by incorporating biotinylated dNTPs or rNTP, or some similar means (e.g., photo-cross-linking a psoralen derivative of biotin to RNAs), followed by addition of labeled streptavidin (e.g., phycoerythrin-conjugated streptavidin) or the equivalent. Alternatively, when fluorescently-labeled oligonucleotide probes are used, fluorescein, lissamine, phycoerythrin, rhodamine (Perkin Elmer Cetus), Cy2, Cy3, Cy3.5, Cy5, Cy5.5, Cy7, Fluor X (Amersham) and others [e.g., Kricka et al. (1992), Academic Press San Diego, Calif.] can be attached to the oligonucleotides.


Those skilled in the art will appreciate that wash steps may be employed to wash away excess target DNA or probe as well as unbound conjugate. Further, standard heterogeneous assay formats are suitable for detecting the hybrids using the labels present on the oligonucleotide primers and probes.


It will be appreciated that a variety of controls may be usefully employed to improve accuracy of hybridization assays. For instance, samples may be hybridized to an irrelevant probe and treated with RNAse A prior to hybridization, to assess false hybridization.


Although the present invention is not specifically dependent on the use of a label for the detection of a particular nucleic acid sequence, such a label might be beneficial, by increasing the sensitivity of the detection. Furthermore, it enables automation. Probes can be labeled according to numerous well known methods.


As commonly known, radioactive nucleotides can be incorporated into probes of the invention by several methods. Non-limiting examples of radioactive labels include 3H, 14C, 32P, and 35S.


Those skilled in the art will appreciate that wash steps may be employed to wash away excess target DNA or probe as well as unbound conjugate. Further, standard heterogeneous assay formats are suitable for detecting the hybrids using the labels present on the oligonucleotide primers and probes.


It will be appreciated that a variety of controls may be usefully employed to improve accuracy of hybridization assays.


Probes of the invention can be utilized with naturally occurring sugar-phosphate backbones as well as modified backbones including phosphorothioates, dithionates, alkyl phosphonates and a-nucleotides and the like. Probes of the invention can be constructed of either ribonucleic acid (RNA) or deoxyribonucleic acid (DNA), and preferably of DNA.


NAT Assays


Detection of a nucleic acid of interest in a biological sample may also optionally be effected by NAT-based assays, which involve nucleic acid amplification technology, such as PCR for example (or variations thereof such as real-time PCR for example).


As used herein, a “primer” defines an oligonucleotide which is capable of annealing to (hybridizing with) a target sequence, thereby creating a double stranded region which can serve as an initiation point for DNA synthesis under suitable conditions.


Amplification of a selected, or target, nucleic acid sequence may be carried out by a number of suitable methods. See generally Kwoh et al., 1990, Am. Biotechnol. Lab. 8:14 Numerous amplification techniques have been described and can be readily adapted to suit particular needs of a person of ordinary skill. Non-limiting examples of amplification techniques include polymerase chain reaction (PCR), ligase chain reaction (LCR), strand displacement amplification (SDA), transcription-based amplification, the q3 replicase system and NASBA (Kwoh et al., 1989, Proc. Natl. Acad. Sci. USA 86, 1173-1177; Lizardi et al., 1988, BioTechnology 6:1197-1202; Malek et al., 1994, Methods Mol. Biol., 28:253-260; and Sambrook et al., 1989, supra).


The terminology “amplification pair” (or “primer pair”) refers herein to a pair of oligonucleotides (oligos) of the present invention, which are selected to be used together in amplifying a selected nucleic acid sequence by one of a number of types of amplification processes, preferably a polymerase chain reaction. Other types of amplification processes include ligase chain reaction, strand displacement amplification, or nucleic acid sequence-based amplification, as explained in greater detail below. As commonly known in the art, the oligos are designed to bind to a complementary sequence under selected conditions.


In one particular embodiment, amplification of a nucleic acid sample from a patient is amplified under conditions which favor the amplification of the most abundant differentially expressed nucleic acid. In one preferred embodiment, RT-PCR is carried out on an mRNA sample from a patient under conditions which favor the amplification of the most abundant mRNA. In another preferred embodiment, the amplification of the differentially expressed nucleic acids is carried out simultaneously. It will be realized by a person skilled in the art that such methods could be adapted for the detection of differentially expressed proteins instead of differentially expressed nucleic acid sequences.


The nucleic acid (i.e. DNA or RNA) for practicing the present invention may be obtained according to well known methods.


Oligonucleotide primers of the present invention may be of any suitable length, depending on the particular assay format and the particular needs and targeted genomes employed. Optionally, the oligonucleotide primers are at least 12 nucleotides in length, preferably between 15 and 24 molecules, and they may be adapted to be especially suited to a chosen nucleic acid amplification system. As commonly known in the art, the oligonucleotide primers can be designed by taking into consideration the melting point of hybridization thereof with its targeted sequence (Sambrook et al., 1989, Molecular Cloning—A Laboratory Manual, 2nd Edition, CSH Laboratories; Ausubel et al., 1989, in Current Protocols in Molecular Biology, John Wiley & Sons Inc., N.Y.).


It will be appreciated that antisense oligonucleotides may be employed to quantify expression of a splice isoform of interest. Such detection is effected at the pre-mRNA level. Essentially the ability to quantitate transcription from a splice site of interest can be effected based on splice site accessibility. Oligonucleotides may compete with splicing factors for the splice site sequences. Thus, low activity of the antisense oligonucleotide is indicative of splicing activity.


The polymerase chain reaction and other nucleic acid amplification reactions are well known in the art (various non-limiting examples of these reactions are described in greater detail below). The pair of oligonucleotides according to this aspect of the present invention are preferably selected to have compatible melting temperatures (Tm), e.g., melting temperatures which differ by less than that 7° C., preferably less than 5° C., more preferably less than 4° C., most preferably less than 3° C., ideally between 3° C. and 0° C.


Polymerase Chain Reaction (PCR): The polymerase chain reaction (PCR), as described in U.S. Pat. Nos. 4,683,195 and 4,683,202 to Mullis and Mullis et al., is a method of increasing the concentration of a segment of target sequence in a mixture of genomic DNA without cloning or purification. This technology provides one approach to the problems of low target sequence concentration. PCR can be used to directly increase the concentration of the target to an easily detectable level. This process for amplifying the target sequence involves the introduction of a molar excess of two oligonucleotide primers which are complementary to their respective strands of the double-stranded target sequence to the DNA mixture containing the desired target sequence. The mixture is denatured and then allowed to hybridize. Following hybridization, the primers are extended with polymerase so as to form complementary strands. The steps of denaturation, hybridization (annealing), and polymerase extension (elongation) can be repeated as often as needed, in order to obtain relatively high concentrations of a segment of the desired target sequence.


The length of the segment of the desired target sequence is determined by the relative positions of the primers with respect to each other, and, therefore, this length is a controllable parameter. Because the desired segments of the target sequence become the dominant sequences (in terms of concentration) in the mixture, they are said to be “PCR-amplified.”


Ligase Chain Reaction (LCR or LAR): The ligase chain reaction [LCR; sometimes referred to as “Ligase Amplification Reaction” (LAR)] has developed into a well-recognized alternative method of amplifying nucleic acids. In LCR, four oligonucleotides, two adjacent oligonucleotides which uniquely hybridize to one strand of target DNA, and a complementary set of adjacent oligonucleotides, which hybridize to the opposite strand are mixed and DNA ligase is added to the mixture. Provided that there is complete complementarity at the junction, ligase will covalently link each set of hybridized molecules. Importantly, in LCR, two probes are ligated together only when they base-pair with sequences in the target sample, without gaps or mismatches. Repeated cycles of denaturation, and ligation amplify a short segment of DNA. LCR has also been used in combination with PCR to achieve enhanced detection of single-base changes: see for example Segev, PCT Publication No. W09001069 A1 (1990). However, because the four oligonucleotides used in this assay can pair to form two short ligatable fragments, there is the potential for the generation of target-independent background signal. The use of LCR for mutant screening is limited to the examination of specific nucleic acid positions.


Self-Sustained Synthetic Reaction (3SR/NASBA): The self-sustained sequence replication reaction (3SR) is a transcription-based in vitro amplification system that can exponentially amplify RNA sequences at a uniform temperature. The amplified RNA can then be utilized for mutation detection. In this method, an oligonucleotide primer is used to add a phage RNA polymerase promoter to the 5′ end of the sequence of interest. In a cocktail of enzymes and substrates that includes a second primer, reverse transcriptase, RNase H, RNA polymerase and ribo-and deoxyribonucleoside triphosphates, the target sequence undergoes repeated rounds of transcription, cDNA synthesis and second-strand synthesis to amplify the area of interest. The use of 3SR to detect mutations is kinetically limited to screening small segments of DNA (e.g., 200-300 base pairs).


Q-Beta (Qβ) Replicase: In this method, a probe which recognizes the sequence of interest is attached to the replicatable RNA template for Qβ replicase. A previously identified major problem with false positives resulting from the replication of unhybridized probes has been addressed through use of a sequence-specific ligation step. However, available thermostable DNA ligases are not effective on this RNA substrate, so the ligation must be performed by T4 DNA ligase at low temperatures (37 degrees C.). This prevents the use of high temperature as a means of achieving specificity as in the LCR, the ligation event can be used to detect a mutation at the junction site, but not elsewhere.


A successful diagnostic method must be very specific. A straight-forward method of controlling the specificity of nucleic acid hybridization is by controlling the temperature of the reaction. While the 3SR/NASBA, and Qβ systems are all able to generate a large quantity of signal, one or more of the enzymes involved in each cannot be used at high temperature (i.e., >55 degrees C.). Therefore the reaction temperatures cannot be raised to prevent non-specific hybridization of the probes. If probes are shortened in order to make them melt more easily at low temperatures, the likelihood of having more than one perfect match in a complex genome increases. For these reasons, PCR and LCR currently dominate the research field in detection technologies.


The basis of the amplification procedure in the PCR and LCR is the fact that the products of one cycle become usable templates in all subsequent cycles, consequently doubling the population with each cycle. The final yield of any such doubling system can be expressed as: (1+X)n=y, where “X” is the mean efficiency (percent copied in each cycle), “n” is the number of cycles, and “y” is the overall efficiency, or yield of the reaction. If every copy of a target DNA is utilized as a template in every cycle of a polymerase chain reaction, then the mean efficiency is 100%. If 20 cycles of PCR are performed, then the yield will be 220, or 1,048,576 copies of the starting material. If the reaction conditions reduce the mean efficiency to 85%, then the yield in those 20 cycles will be only 1.8520, or 220,513 copies of the starting material. In other words, a PCR running at 85% efficiency will yield only 21% as much final product, compared to a reaction running at 100% efficiency. A reaction that is reduced to 50% mean efficiency will yield less than 1% of the possible product.


In practice, routine polymerase chain reactions rarely achieve the theoretical maximum yield, and PCRs are usually run for more than 20 cycles to compensate for the lower yield. At 50% mean efficiency, it would take 34 cycles to achieve the million-fold amplification theoretically possible in 20, and at lower efficiencies, the number of cycles required becomes prohibitive. In addition, any background products that amplify with a better mean efficiency than the intended target will become the dominant products.


Also, many variables can influence the mean efficiency of PCR, including target DNA length and secondary structure, primer length and design, primer and dNTP concentrations, and buffer composition, to name but a few. Contamination of the reaction with exogenous DNA (e.g., DNA spilled onto lab surfaces) or cross-contamination is also a major consideration. Reaction conditions must be carefully optimized for each different primer pair and target sequence, and the process can take days, even for an experienced investigator. The laboriousness of this process, including numerous technical considerations and other factors, presents a significant drawback to using PCR in the clinical setting. Indeed, PCR has yet to penetrate the clinical market in a significant way. The same concerns arise with LCR, as LCR must also be optimized to use different oligonucleotide sequences for each target sequence. In addition, both methods require expensive equipment, capable of precise temperature cycling.


Many applications of nucleic acid detection technologies, such as in studies of allelic variation, involve not only detection of a specific sequence in a complex background, but also the discrimination between sequences with few, or single, nucleotide differences. One method of the detection of allele-specific variants by PCR is based upon the fact that it is difficult for Taq polymerase to synthesize a DNA strand when there is a mismatch between the template strand and the 3′ end of the primer. An allele-specific variant may be detected by the use of a primer that is perfectly matched with only one of the possible alleles; the mismatch to the other allele acts to prevent the extension of the primer, thereby preventing the amplification of that sequence. This method has a substantial limitation in that the base composition of the mismatch influences the ability to prevent extension across the mismatch, and certain mismatches do not prevent extension or have only a minimal effect.


A similar 3′-mismatch strategy is used with greater effect to prevent ligation in the LCR. Any mismatch effectively blocks the action of the thermostable ligase, but LCR still has the drawback of target-independent background ligation products initiating the amplification. Moreover, the combination of PCR with subsequent LCR to identify the nucleotides at individual positions is also a clearly cumbersome proposition for the clinical laboratory.


The direct detection method according to various preferred embodiments of the present invention may be, for example a cycling probe reaction (CPR) or a branched DNA analysis.


When a sufficient amount of a nucleic acid to be detected is available, there are advantages to detecting that sequence directly, instead of making more copies of that target, (e.g., as in PCR and LCR). Most notably, a method that does not amplify the signal exponentially is more amenable to quantitative analysis. Even if the signal is enhanced by attaching multiple dyes to a single oligonucleotide, the correlation between the final signal intensity and amount of target is direct. Such a system has an additional advantage that the products of the reaction will not themselves promote further reaction, so contamination of lab surfaces by the products is not as much of a concern. Recently devised techniques have sought to eliminate the use of radioactivity and/or improve the sensitivity in automatable formats. Two examples are the “Cycling Probe Reaction” (CPR), and “Branched DNA” (bDNA).


Cycling probe reaction (CPR): The cycling probe reaction (CPR), uses a long chimeric oligonucleotide in which a central portion is made of RNA while the two termini are made of DNA. Hybridization of the probe to a target DNA and exposure to a thermostable RNase H causes the RNA portion to be digested. This destabilizes the remaining DNA portions of the duplex, releasing the remainder of the probe from the target DNA and allowing another probe molecule to repeat the process. The signal, in the form of cleaved probe molecules, accumulates at a linear rate. While the repeating process increases the signal, the RNA portion of the oligonucleotide is vulnerable to RNases that may carried through sample preparation.


Branched DNA: Branched DNA (bDNA), involves oligonucleotides with branched structures that allow each individual oligonucleotide to carry 35 to 40 labels (e.g., alkaline phosphatase enzymes). While this enhances the signal from a hybridization event, signal from non-specific binding is similarly increased.


The detection of at least one sequence change according to various preferred embodiments of the present invention may be accomplished by, for example restriction fragment length polymorphism (RFLP analysis), allele specific oligonucleotide (ASO) analysis, Denaturing/Temperature Gradient Gel Electrophoresis (DGGE/TGGE), Single-Strand Conformation Polymorphism (SSCP) analysis or Dideoxy fingerprinting (ddF).


The demand for tests which allow the detection of specific nucleic acid sequences and sequence changes is growing rapidly in clinical diagnostics. As nucleic acid sequence data for genes from humans and pathogenic organisms accumulates, the demand for fast, cost-effective, and easy-to-use tests for as yet mutations within specific sequences is rapidly increasing.


A handful of methods have been devised to scan nucleic acid segments for mutations. One option is to determine the entire gene sequence of each test sample (e.g., a bacterial isolate). For sequences under approximately 600 nucleotides, this may be accomplished using amplified material (e.g., PCR reaction products). This avoids the time and expense associated with cloning the segment of interest. However, specialized equipment and highly trained personnel are required, and the method is too labor-intense and expensive to be practical and effective in the clinical setting.


In view of the difficulties associated with sequencing, a given segment of nucleic acid may be characterized on several other levels. At the lowest resolution, the size of the molecule can be determined by electrophoresis by comparison to a known standard run on the same gel. A more detailed picture of the molecule may be achieved by cleavage with combinations of restriction enzymes prior to electrophoresis, to allow construction of an ordered map. The presence of specific sequences within the fragment can be detected by hybridization of a labeled probe, or the precise nucleotide sequence can be determined by partial chemical degradation or by primer extension in the presence of chain-terminating nucleotide analogs.


Restriction fragment length polymorphism (RFLP): For detection of single-base differences between like sequences, the requirements of the analysis are often at the highest level of resolution. For cases in which the position of the nucleotide in question is known in advance, several methods have been developed for examining single base changes without direct sequencing. For example, if a mutation of interest happens to fall within a restriction recognition sequence, a change in the pattern of digestion can be used as a diagnostic tool (e.g., restriction fragment length polymorphism [RFLP] analysis).


Single point mutations have been also detected by the creation or destruction of RFLPs. Mutations are detected and localized by the presence and size of the RNA fragments generated by cleavage at the mismatches. Single nucleotide mismatches in DNA heteroduplexes are also recognized and cleaved by some chemicals, providing an alternative strategy to detect single base substitutions, generically named the “Mismatch Chemical Cleavage” (MCC). However, this method requires the use of osmium tetroxide and piperidine, two highly noxious chemicals which are not suited for use in a clinical laboratory.


RFLP analysis suffers from low sensitivity and requires a large amount of sample. When RFLP analysis is used for the detection of point mutations, it is, by its nature, limited to the detection of only those single base changes which fall within a restriction sequence of a known restriction endonuclease. Moreover, the majority of the available enzymes have 4 to 6 base-pair recognition sequences, and cleave too frequently for many large-scale DNA manipulations. Thus, it is applicable only in a small fraction of cases, as most mutations do not fall within such sites.


A handful of rare-cutting restriction enzymes with 8 base-pair specificities have been isolated and these are widely used in genetic mapping, but these enzymes are few in number, are limited to the recognition of G+C-rich sequences, and cleave at sites that tend to be highly clustered. Recently, endonucleases encoded by group I introns have been discovered that might have greater than 12 base-pair specificity, but again, these are few in number.


Allele specific oligonucleotide (ASO): If the change is not in a recognition sequence, then allele-specific oligonucleotides (ASOs), can be designed to hybridize in proximity to the mutated nucleotide, such that a primer extension or ligation event can bused as the indicator of a match or a mis-match. Hybridization with radioactively labeled allelic specific oligonucleotides (ASO) also has been applied to the detection of specific point mutations. The method is based on the differences in the melting temperature of short DNA fragments differing by a single nucleotide. Stringent hybridization and washing conditions can differentiate between mutant and wild-type alleles. The ASO approach applied to PCR products also has been extensively utilized by various researchers to detect and characterize point mutations in ras genes and gsp/gip oncogenes. Because of the presence of various nucleotide changes in multiple positions, the ASO method requires the use of many oligonucleotides to cover all possible oncogenic mutations.


With either of the techniques described above (i.e., RFLP and ASO), the precise location of the suspected mutation must be known in advance of the test. That is to say, they are inapplicable when one needs to detect the presence of a mutation within a gene or sequence of interest.


Denaturing/Temperature Gradient Gel Electrophoresis (DGGE/TGGE): Two other methods rely on detecting changes in electrophoretic mobility in response to minor sequence changes. One of these methods, termed “Denaturing Gradient Gel Electrophoresis” (DGGE) is based on the observation that slightly different sequences will display different patterns of local melting when electrophoretically resolved on a gradient gel. In this manner, variants can be distinguished, as differences in melting properties of homoduplexes versus heteroduplexes differing in a single nucleotide can detect the presence of mutations in the target sequences because of the corresponding changes in their electrophoretic mobilities. The fragments to be analyzed, usually PCR products, are “clamped” at one end by a long stretch of G-C base pairs (30-80) to allow complete denaturation of the sequence of interest without complete dissociation of the strands. The attachment of a GC “clamp” to the DNA fragments increases the fraction of mutations that can be recognized by DGGE. Attaching a GC clamp to one primer is critical to ensure that the amplified sequence has a low dissociation temperature. Modifications of the technique have been developed, using temperature gradients, and the method can be also applied to RNA:RNA duplexes.


Limitations on the utility of DGGE include the requirement that the denaturing conditions must be optimized for each type of DNA to be tested. Furthermore, the method requires specialized equipment to prepare the gels and maintain the needed high temperatures during electrophoresis. The expense associated with the synthesis of the clamping tail on one oligonucleotide for each sequence to be tested is also a major consideration. In addition, long running times are required for DGGE. The long running time of DGGE was shortened in a modification of DGGE called constant denaturant gel electrophoresis (CDGE). CDGE requires that gels be performed under different denaturant conditions in order to reach high efficiency for the detection of mutations.


A technique analogous to DGGE, termed temperature gradient gel electrophoresis (TGGE), uses a thermal gradient rather than a chemical denaturant gradient. TGGE requires the use of specialized equipment which can generate a temperature gradient perpendicularly oriented relative to the electrical field. TGGE can detect mutations in relatively small fragments of DNA therefore scanning of large gene segments requires the use of multiple PCR products prior to running the gel.


Single-Strand Conformation Polymorphism (SSCP): Another common method, called “Single-Strand Conformation Polymorphism” (SSCP) was developed by Hayashi, Sekya and colleagues and is based on the observation that single strands of nucleic acid can take on characteristic conformations in non-denaturing conditions, and these conformations influence electrophoretic mobility. The complementary strands assume sufficiently different structures that one strand may be resolved from the other. Changes in sequences within the fragment will also change the conformation, consequently altering the mobility and allowing this to be used as an assay for sequence variations.


The SSCP process involves denaturing a DNA segment (e.g., a PCR product) that is labeled on both strands, followed by slow electrophoretic separation on a non-denaturing polyacrylamide gel, so that intra-molecular interactions can form and not be disturbed during the run. This technique is extremely sensitive to variations in gel composition and temperature. A serious limitation of this method is the relative difficulty encountered in comparing data generated in different laboratories, under apparently similar conditions.


Dideoxy fingerprinting (ddF): The dideoxy fingerprinting (ddF) is another technique developed to scan genes for the presence of mutations. The ddF technique combines components of Sanger dideoxy sequencing with SSCP. A dideoxy sequencing reaction is performed using one dideoxy terminator and then the reaction products are electrophoresed on nondenaturing polyacrylamide gels to detect alterations in mobility of the termination segments as in SSCP analysis. While ddF is an improvement over SSCP in terms of increased sensitivity, ddF requires the use of expensive dideoxynucleotides and this technique is still limited to the analysis of fragments of the size suitable for SSCP (i.e., fragments of 200-300 bases for optimal detection of mutations).


In addition to the above limitations, all of these methods are limited as to the size of the nucleic acid fragment that can be analyzed. For the direct sequencing approach, sequences of greater than 600 base pairs require cloning, with the consequent delays and expense of either deletion sub-cloning or primer walking, in order to cover the entire fragment. SSCP and DGGE have even more severe size limitations. Because of reduced sensitivity to sequence changes, these methods are not considered suitable for larger fragments. Although SSCP is reportedly able to detect 90% of single-base substitutions within a 200 base-pair fragment, the detection drops to less than 50% for 400 base pair fragments. Similarly, the sensitivity of DGGE decreases as the length of the fragment reaches 500 base-pairs. The ddF technique, as a combination of direct sequencing and SSCP, is also limited by the relatively small size of the DNA that can be screened.


According to a presently preferred embodiment of the present invention the step of searching for any of the nucleic acid sequences described here, in tumor cells or in cells derived from a cancer patient is effected by any suitable technique, including, but not limited to, nucleic acid sequencing, polymerase chain reaction, ligase chain reaction, self-sustained synthetic reaction, Qβ-Replicase, cycling probe reaction, branched DNA, restriction fragment length polymorphism analysis, mismatch chemical cleavage, heteroduplex analysis, allele-specific oligonucleotides, denaturing gradient gel electrophoresis, constant denaturant gel electrophoresis, temperature gradient gel electrophoresis and dideoxy fingerprinting.


Detection may also optionally be performed with a chip or other such device. The nucleic acid sample which includes the candidate region to be analyzed is preferably isolated, amplified and labeled with a reporter group. This reporter group can be a fluorescent group such as phycoerythrin. The labeled nucleic acid is then incubated with the probes immobilized on the chip using a fluidics station, describe the fabrication of fluidics devices and particularly microcapillary devices, in silicon and glass substrates.


Once the reaction is completed, the chip is inserted into a scanner and patterns of hybridization are detected. The hybridization data is collected, as a signal emitted from the reporter groups already incorporated into the nucleic acid, which is now bound to the probes attached to the chip. Since the sequence and position of each probe immobilized on the chip is known, the identity of the nucleic acid hybridized to a given probe can be determined.


It will be appreciated that when utilized along with automated equipment, the above described detection methods can be used to screen multiple samples for a disease and/or pathological condition both rapidly and easily.


Amino Acid Sequences and Peptides


The terms “polypeptide,” “peptide” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residue is an analog or mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers. Polypeptides can be modified, e.g., by the addition of carbohydrate residues to form glycoproteins. The terms “polypeptide,” “peptide” and “protein” include glycoproteins, as well as non-glycoproteins.


Polypeptide products can be biochemically synthesized such as by employing standard solid phase techniques. Such methods include but are not limited to exclusive solid phase synthesis, partial solid phase synthesis methods, fragment condensation, classical solution synthesis. These methods are preferably used when the peptide is relatively short (i.e., 10 kDa) and/or when it cannot be produced by recombinant techniques (i.e., not encoded by a nucleic acid sequence) and therefore involves different chemistry.


Solid phase polypeptide synthesis procedures are well known in the art and further described by John Morrow Stewart and Janis Dillaha Young, Solid Phase Peptide Syntheses (2nd Ed., Pierce Chemical Company, 1984).


Synthetic polypeptides can optionally be purified by preparative high performance liquid chromatography [Creighton T. (1983) Proteins, structures and molecular principles. WH Freeman and Co. N.Y.], after which their composition can be confirmed via amino acid sequencing.


In cases where large amounts of a polypeptide are desired, it can be generated using recombinant techniques such as described by Bitter et al., (1987) Methods in Enzymol. 153:516-544, Studier et al. (1990) Methods in Enzymol. 185:60-89, Brisson et al. (1984) Nature 310:511-514, Takamatsu et al. (1987) EMBO J. 6:307-311, Coruzzi et al. (1984) EMBO J. 3:1671-1680 and Brogli et al., (1984) Science 224:838-843, Gurley et al. (1986) Mol. Cell. Biol. 6:559-565 and Weissbach & Weissbach, 1988, Methods for Plant Molecular Biology, Academic Press, NY, Section VIII, pp 421-463.


The present invention also encompasses polypeptides encoded by the polynucleotide sequences of the present invention, as well as polypeptides according to the amino acid sequences described herein. The present invention also encompasses homologues of these polypeptides, such homologues can be at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 95% or more say 100% homologous to the amino acid sequences set forth below, as can be determined using BlastP software of the National Center of Biotechnology Information (NCBI) using default parameters, optionally and preferably including the following: filtering on (this option filters repetitive or low-complexity sequences from the query using the Seg (protein) program), scoring matrix is BLOSUM62 for proteins, word size is 3, E value is 10, gap costs are 11, 1 (initialization and extension), and number of alignments shown is 50. Optionally and preferably, nucleic acid sequence identity/homology is determined with BlastN software of the National Center of Biotechnology Information (NCBI) using default parameters, which preferably include using the DUST filter program, and also preferably include having an E value of 10, filtering low complexity sequences and a word size of 11. Finally, the present invention also encompasses fragments of the above described polypeptides and polypeptides having mutations, such as deletions, insertions or substitutions of one or more amino acids, either naturally occurring or artificially induced, either randomly or in a targeted fashion.


It will be appreciated that peptides identified according the present invention may be degradation products, synthetic peptides or recombinant peptides as well as peptidomimetics, typically, synthetic peptides and peptoids and semipeptoids which are peptide analogs, which may have, for example, modifications rendering the peptides more stable while in a body or more capable of penetrating into cells. Such modifications include, but are not limited to N terminus modification, C terminus modification, peptide bond modification, including, but not limited to, CH2-NH, CH2-S, CH2-S═O, O═C—NH, CH2-O, CH2-CH2, S═C—NH, CH═CH or CF═CH, backbone modifications, and residue modification. Methods for preparing peptidomimetic compounds are well known in the art and are specified. Further details in this respect are provided hereinunder.


Peptide bonds (—CO—NH—) within the peptide may be substituted, for example, by N-methylated bonds (—N(CH3)-CO—), ester bonds (—C(R)H—C—O—O—C(R)—N—), ketomethylen bonds (—CO—CH2-), α-aza bonds (—NH—N(R)—CO—), wherein R is any alkyl, e.g., methyl, carba bonds (—CH2-NH—), hydroxyethylene bonds (—CH(OH)—CH2-), thioamide bonds (—CS—NH—), olefinic double bonds (—CH═CH—), retro amide bonds (—NH—CO—), peptide derivatives (—N(R)—CH2-CO—), wherein R is the “normal” side chain, naturally presented on the carbon atom.


These modifications can occur at any of the bonds along the peptide chain and even at several (2-3) at the same time.


Natural aromatic amino acids, Trp, Tyr and Phe, may be substituted for synthetic non-natural acid such as Phenylglycine, TIC, naphthylelanine (Nol), ring-methylated derivatives of Phe, halogenated derivatives of Phe or o-methyl-Tyr.


In addition to the above, the peptides of the present invention may also include one or more modified amino acids or one or more non-amino acid monomers (e.g. fatty acids, complex carbohydrates etc).


As used herein in the specification and in the claims section below the term “amino acid” or “amino acids” is understood to include the 20 naturally occurring amino acids; those amino acids often modified post-translationally in vivo, including, for example, hydroxyproline, phosphoserine and phosphothreonine; and other unusual amino acids including, but not limited to, 2-aminoadipic acid, hydroxylysine, isodesmosine, nor-valine, nor-leucine and ornithine. Furthermore, the term “amino acid” includes both D- and L-amino acids.


Table I non-conventional or modified amino acids which can be used with the present invention.












TABLE 1







Non-conventional amino acid
Code









α-aminobutyric acid
Abu



α-amino-α-methylbutyrate
Mgabu



aminocyclopropane-
Cpro



Carboxylate




aminoisobutyric acid
Aib



aminonorbornyl-
Norb



Carboxylate




Cyclohexylalanine
Chexa



Cyclopentylalanine
Cpen



D-alanine
Dal



D-arginine
Darg



D-aspartic acid
Dasp



D-cysteine
Dcys



D-glutamine
Dgln



D-glutamic acid
Dglu



D-histidine
Dhis



D-isoleucine
Dile



D-leucine
Dleu



D-lysine
Dlys



D-methionine
Dmet



D-ornithine
Dorn



D-phenylalanine
Dphe



D-proline
Dpro



D-serine
Dser



D-threonine
Dthr



D-tryptophan
Dtrp



D-tyrosine
Dtyr



D-valine
Dval



D-α-methylalanine
Dmala



D-α-methylarginine
Dmarg



D-α-methylasparagine
Dmasn



D-α-methylaspartate
Dmasp



D-α-methylcysteine
Dmcys



D-α-methylglutamine
Dmgln



D-α-methylhistidine
Dmhis



D-α-methylisoleucine
Dmile



D-α-methylleucine
Dmleu



D-α-methyllysine
Dmlys



D-α-methylmethionine
Dmmet



D-α-methylornithine
Dmorn



D-α-methylphenylalanine
Dmphe



D-α-methylproline
Dmpro



D-α-methylserine
Dmser



D-α-methylthreonine
Dmthr



D-α-methyltryptophan
Dmtrp



D-α-methyltyrosine
Dmty



D-α-methylvaline
Dmval



D-α-methylalnine
Dnmala



D-α-methylarginine
Dnmarg



D-α-methylasparagine
Dnmasn



D-α-methylasparatate
Dnmasp



D-α-methylcysteine
Dnmcys



D-N-methylleucine
Dnmleu



D-N-methyllysine
Dnmlys



N-methylcyclohexylalanine
Nmchexa



D-N-methylornithine
Dnmorn



N-methylglycine
Nala



N-methylaminoisobutyrate
Nmaib



N-(1-methylpropyl)glycine
Nile



N-(2-methylpropyl)glycine
Nile



N-(2-methylpropyl)glycine
Nleu



D-N-methyltryptophan
Dnmtrp



D-N-methyltyrosine
Dnmtyr



D-N-methylvaline
Dnmval



γ-aminobutyric acid
Gabu



L-t-butylglycine
Tbug



L-ethylglycine
Etg



L-homophenylalanine
Hphe



L-α-methylarginine
Marg



L-α-methylaspartate
Masp



L-α-methylcysteine
Mcys



L-α-methylglutamine
Mgln



L-α-methylhistidine
Mhis



L-α-methylisoleucine
Mile



D-N-methylglutamine
Dnmgln



D-N-methylglutamate
Dnmglu



D-N-methylhistidine
Dnmhis



D-N-methylisoleucine
Dnmile



D-N-methylleucine
Dnmleu



D-N-methyllysine
Dnmlys



N-methylcyclohexylalanine
Nmchexa



D-N-methylornithine
Dnmorn



N-methylglycine
Nala



N-methylaminoisobutyrate
Nmaib



N-(1-methylpropyl)glycine
Nile



N-(2-methylpropyl)glycine
Nleu



D-N-methyltryptophan
Dnmtrp



D-N-methyltyrosine
Dnmtyr



D-N-methylvaline
Dnmval



γ-aminobutyric acid
Gabu



L-t-butylglycine
Tbug



L-ethylglycine
Etg



L-homophenylalanine
Hphe



L-α-methylarginine
Marg



L-α-methylaspartate
Masp



L-α-methylcysteine
Mcys



L-α-methylglutamine
Mgln



L-α-methylhistidine
Mhis



L-α-methylisoleucine
Mile



L-α-methylleucine
Mleu



L-α-methylmethionine
Mmet



L-α-methylnorvaline
Mnva



L-α-methylphenylalanine
Mphe



L-α-methylserine
Mser



L-α-methylvaline
Mtrp



L-α-methylleucine
Mval




Nnbhm



N-(N-(2,2-diphenylethyl)
Nnbhm



carbamylmethyl-glycine



1-carboxy-1-(2,2-diphenyl
Nmbc



ethylamino)cyclopropane



L-N-methylalanine
Nmala



L-N-methylarginine
Nmarg



L-N-methylasparagine
Nmasn



L-N-methylaspartic acid
Nmasp



L-N-methylcysteine
Nmcys



L-N-methylglutamine
Nmgin



L-N-methylglutamic acid
Nmglu



L-N-methylhistidine
Nmhis



L-N-methylisolleucine
Nmile



L-N-methylleucine
Nmleu



L-N-methyllysine
Nmlys



L-N-methylmethionine
Nmmet



L-N-methylnorleucine
Nmnle



L-N-methylnorvaline
Nmnva



L-N-methylornithine
Nmorn



L-N-methylphenylalanine
Nmphe



L-N-methylproline
Nmpro



L-N-methylserine
Nmser



L-N-methylthreonine
Nmthr



L-N-methyltryptophan
Nmtrp



L-N-methyltyrosine
Nmtyr



L-N-methylvaline
Nmval



L-N-methylethylglycine
Nmetg



L-N-methyl-t-butylglycine
Nmtbug



L-norleucine
Nle



L-norvaline
Nva



α-methyl-aminoisobutyrate
Maib



α-methyl-γ-aminobutyrate
Mgabu



α-methylcyclohexylalanine
Mchexa



α-methylcyclopentylalanine
Mcpen



α-methyl-α-napthylalanine
Manap



α-methylpenicillamine
Mpen



N-(4-aminobutyl)glycine
Nglu



N-(2-aminoethyl)glycine
Naeg



N-(3-aminopropyl)glycine
Norn



N-amino-α-methylbutyrate
Nmaabu



α-napthylalanine
Anap



N-benzylglycine
Nphe



N-(2-carbamylethyl)glycine
Ngln



N-(carbamylmethyl)glycine
Nasn



N-(2-carboxyethyl)glycine
Nglu



N-(carboxymethyl)glycine
Nasp



N-cyclobutylglycine
Ncbut



N-cycloheptylglycine
Nchep



N-cyclohexylglycine
Nchex



N-cyclodecylglycine
Ncdec



N-cyclododeclglycine
Ncdod



N-cyclooctylglycine
Ncoct



N-cyclopropylglycine
Ncpro



N-cycloundecylglycine
Ncund



N-(2,2-diphenylethyl)glycine
Nbhm



N-(3,3-diphenylpropyl)glycine
Nbhe



N-(3-indolylyethyl) glycine
Nhtrp



N-methyl-γ-aminobutyrate
Nmgabu



D-N-methylmethionine
Dnmmet



N-methylcyclopentylalanine
Nmcpen



D-N-methylphenylalanine
Dnmphe



D-N-methylproline
Dnmpro



D-N-methylserine
Dnmser



D-N-methylserine
Dnmser



D-N-methylthreonine
Dnmthr



N-(1-methylethyl)glycine
Nva



N-methyla-napthylalanine
Nmanap



N-methylpenicillamine
Nmpen



N-(p-hydroxyphenyl)glycine
Nhtyr



N-(thiomethyl)glycine
Ncys



Penicillamine
Pen



L-α-methylalanine
Mala



L-α-methylasparagine
Masn



L-α-methyl-t-butylglycine
Mtbug



L-methylethylglycine
Metg



L-α-methylglutamate
Mglu



L-α-methylhomo
Mhphe



phenylalanine



N-(2-methylthioethyl)glycine
Nmet



N-(3-guanidinopropyl)glycine
Narg



N-(1-hydroxyethyl)glycine
Nthr



N-(hydroxyethyl)glycine
Nser



N-(imidazolylethyl)glycine
Nhis



N-(3-indolylyethyl)glycine
Nhtrp



N-methyl-γ-aminobutyrate
Nmgabu



D-N-methylmethionine
Dnmmet



N-methylcyclopentylalanine
Nmcpen



D-N-methylphenylalanine
Dnmphe



D-N-methylproline
Dnmpro



D-N-methylserine
Dnmser



D-N-methylthreonine
Dnmthr



N-(1-methylethyl)glycine
Nval



N-methyla-napthylalanine
Nmanap



N-methylpenicillamine
Nmpen



N-(p-hydroxyphenyl)glycine
Nhtyr



N-(thiomethyl)glycine
Ncys



Penicillamine
Pen



L-α-methylalanine
Mala



L-α-methylasparagine
Masn



L-α-methyl-t-butylglycine
Mtbug



L-methylethylglycine
Metg



L-α-methylglutamate
Mglu



L-α-methylhomophenylalanine
Mhphe



N-(2-methylthioethyl)glycine
Nmet



L-α-methyllysine
Mlys



L-α-methylnorleucine
Mnle



L-α-methylornithine
Morn



L-α-methylproline
Mpro



L-α-methylthreonine
Mthr



L-α-methyltyrosine
Mtyr



L-N-methylhomophenylalanine
Nmhphe



N-(N-(3,3-diphenylpropyl)
Nnbhe



Carbamylmethyl(1)glycine










Since the peptides of the present invention are preferably utilized in diagnostics which require the peptides to be in soluble form, the peptides of the present invention preferably include one or more non-natural or natural polar amino acids, including but not limited to serine and threonine which are capable of increasing peptide solubility due to their hydroxyl-containing side chain.


The peptides of the present invention are preferably utilized in a linear form, although it will be appreciated that in cases where cyclicization does not severely interfere with peptide characteristics, cyclic forms of the peptide can also be utilized.


The peptides of present invention can be biochemically synthesized such as by using standard solid phase techniques. These methods include exclusive solid phase synthesis well known in the art, partial solid phase synthesis methods, fragment condensation, classical solution synthesis. These methods are preferably used when the peptide is relatively short (i.e., 10 kDa) and/or when it cannot be produced by recombinant techniques (i.e., not encoded by a nucleic acid sequence) and therefore involves different chemistry.


Synthetic peptides can be purified by preparative high performance liquid chromatography and the composition of which can be confirmed via amino acid sequencing.


In cases where large amounts of the peptides of the present invention are desired, the peptides of the present invention can be generated using recombinant techniques such as described by Bitter et al., (1987) Methods in Enzymol. 153:516-544, Studier et al. (1990) Methods in Enzymol. 185:60-89, Brisson et al. (1984) Nature 310:511-514, Takamatsu et al. (1987) EMBO J. 6:307-311, Coruzzi et al. (1984) EMBO J. 3:1671-1680 and Brogli et al., (1984) Science 224:838-843, Gurley et al. (1986) Mol. Cell. Biol. 6:559-565 and Weissbach & Weissbach, 1988, Methods for Plant Molecular Biology, Academic Press, NY, Section VIII, pp 421-463 and also as described above.


Antibodies


“Antibody” refers to a polypeptide ligand that is preferably substantially encoded by an immunoglobulin gene or immunoglobulin genes, or fragments thereof, which specifically binds and recognizes an epitope (e.g., an antigen). The recognized immunoglobulin genes include the kappa and lambda light chain constant region genes, the alpha, gamma, delta, epsilon and mu heavy chain constant region genes, and the myriad-immunoglobulin variable region genes. Antibodies exist, e.g., as intact immunoglobulins or as a number of well characterized fragments produced by digestion with various peptidases. This includes, e.g., Fab′ and F(ab)′2 fragments. The term “antibody,” as used herein, also includes antibody fragments either produced by the modification of whole antibodies or those synthesized de novo using recombinant DNA methodologies. It also includes polyclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized antibodies, or single chain antibodies. “Fc” portion of an antibody refers to that portion of an immunoglobulin heavy chain that comprises one or more heavy chain constant region domains, CH1, CH2 and CH3, but does not include the heavy chain variable region.


The functional fragments of antibodies, such as Fab, F(ab′)2, and Fv that are capable of binding to macrophages, are described as follows: (1) Fab, the fragment which contains a monovalent antigen-binding fragment of an antibody molecule, can be produced by digestion of whole antibody with the enzyme papain to yield an intact light chain and a portion of one heavy chain; (2) Fab′, the fragment of an antibody molecule that can be obtained by treating whole antibody with pepsin, followed by reduction, to yield an intact light chain and a portion of the heavy chain; two Fab′ fragments are obtained per antibody molecule; (3) (Fab′)2, the fragment of the antibody that can be obtained by treating whole antibody with the enzyme pepsin without subsequent reduction; F(ab′)2 is a dimer of two Fab′ fragments held together by two disulfide bonds; (4) Fv, defined as a genetically engineered fragment containing the variable region of the light chain and the variable region of the heavy chain expressed as two chains; and (5) Single chain antibody (“SCA”), a genetically engineered molecule containing the variable region of the light chain and the variable region of the heavy chain, linked by a suitable polypeptide linker as a genetically fused single chain molecule.


Methods of producing polyclonal and monoclonal antibodies as well as fragments thereof are well known in the art (See for example, Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York, 1988, incorporated herein by reference).


Antibody fragments according to the present invention can be prepared by proteolytic hydrolysis of the antibody or by expression in E. coli or mammalian cells (e.g. Chinese hamster ovary cell culture or other protein expression systems) of DNA encoding the fragment. Antibody fragments can be obtained by pepsin or papain digestion of whole antibodies by conventional methods. For example, antibody fragments can be produced by enzymatic cleavage of antibodies with pepsin to provide a 5S fragment denoted F(ab′)2. This fragment can be further cleaved using a thiol reducing agent, and optionally a blocking group for the sulfhydryl groups resulting from cleavage of disulfide linkages, to produce 3.5S Fab′ monovalent fragments. Alternatively, an enzymatic cleavage using pepsin produces two monovalent Fab′ fragments and an Fc fragment directly. These methods are described, for example, by Goldenberg, U.S. Pat. Nos. 4,036,945 and 4,331,647, and references contained therein, which patents are hereby incorporated by reference in their entirety. See also Porter, R. R. [Biochem. J. 73: 119-126 (1959)]. Other methods of cleaving antibodies, such as separation of heavy chains to form monovalent light-heavy chain fragments, further cleavage of fragments, or other enzymatic, chemical, or genetic techniques may also be used, so long as the fragments bind to the antigen that is recognized by the intact antibody.


Fv fragments comprise an association of VH and VL chains. This association may be noncovalent, as described in Inbar et al. [Proc. Nat'l Acad. Sci. USA 69:2659-62 (19720]. Alternatively, the variable chains can be linked by an intermolecular disulfide bond or cross-linked by chemicals such as glutaraldehyde. Preferably, the Fv fragments comprise VH and VL chains connected by a peptide linker. These single-chain antigen binding proteins (sFv) are prepared by constructing a structural gene comprising DNA sequences encoding the VH and VL domains connected by an oligonucleotide. The structural gene is inserted into an expression vector, which is subsequently introduced into a host cell such as E. coli. The recombinant host cells synthesize a single polypeptide chain with a linker peptide bridging the two V domains. Methods for producing sFvs are described, for example, by [Whitlow and Filpula, Methods 2: 97-105 (1991); Bird et al., Science 242:423-426 (1988); Pack et al., Bio/Technology 11:1271-77 (1993); and U.S. Pat. No. 4,946,778, which is hereby incorporated by reference in its entirety.


Another form of an antibody fragment is a peptide coding for a single complementarity-determining region (CDR). CDR peptides (“minimal recognition units”) can be obtained by constructing genes encoding the CDR of an antibody of interest. Such genes are prepared, for example, by using the polymerase chain reaction to synthesize the variable region from RNA of antibody-producing cells. See, for example, Larrick and Fry [Methods, 2: 106-10 (1991)].


Humanized forms of non-human (e.g., murine) antibodies are chimeric molecules of immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab′, F(ab′) or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may 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 FR 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., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992)].


Methods for humanizing non-human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as import residues, which are typically taken from an import variable domain. Humanization can be essentially 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. Accordingly, such humanized antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.


Human antibodies can also be produced using various techniques known in the art, including phage display libraries [Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)]. The techniques of Cole et al. and Boemer et al. are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boemer et al., J. Immunol., 147(1):86-95 (1991)]. Similarly, human antibodies can be made by introduction of 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 the following scientific publications: Marks et al., Bio/Technology 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).


Preferably, the antibody of this aspect of the present invention specifically binds at least one epitope of the polypeptide variants of the present invention. As used herein, the term “epitope” refers to any antigenic determinant on an antigen to which the paratope of an antibody binds.


Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or carbohydrate side chains and usually have specific three dimensional structural characteristics, as well as specific charge characteristics.


Optionally, a unique epitope may be created in a variant due to a change in one or more post-translational modifications, including but not limited to glycosylation and/or phosphorylation, as described below. Such a change may also cause a new epitope to be created, for example through removal of glycosylation at a particular site.


An epitope according to the present invention may also optionally comprise part or all of a unique sequence portion of a variant according to the present invention in combination with at least one other portion of the variant which is not contiguous to the unique sequence portion in the linear polypeptide itself, yet which are able to form an epitope in combination. One or more unique sequence portions may optionally combine with one or more other non-contiguous portions of the variant (including a portion which may have high homology to a portion of the known protein) to form an epitope.


Immunoassays


In another embodiment of the present invention, an immunoassay can be used to qualitatively or quantitatively detect and analyze markers in a sample. This method comprises: providing an antibody that specifically binds to a marker; contacting a sample with the antibody; and detecting the presence of a complex of the antibody bound to the marker in the sample.


To prepare an antibody that specifically binds to a marker, purified protein markers can be used. Antibodies that specifically bind to a protein marker can be prepared using any suitable methods known in the art.


After the antibody is provided, a marker can be detected and/or quantified using any of a number of well recognized immunological binding assays. Useful assays include, for example, an enzyme immune assay (EIA) such as enzyme-linked immunosorbent assay (ELISA), a radioimmune assay (RIA), a Western blot assay, or a slot blot assay see, e.g., U.S. Pat. Nos. 4,366,241; 4,376,110; 4,517,288; and 4,837,168). Generally, a sample obtained from a subject can be contacted with the antibody that specifically binds the marker.


Optionally, the antibody can be fixed to a solid support to facilitate washing and subsequent isolation of the complex, prior to contacting the antibody with a sample. Examples of solid supports include but are not limited to glass or plastic in the form of, e.g., a microtiter plate, a stick, a bead, or a microbead. Antibodies can also be attached to a solid support.


After incubating the sample with antibodies, the mixture is washed and the antibody-marker complex formed can be detected. This can be accomplished by incubating the washed mixture with a detection reagent. Alternatively, the marker in the sample can be detected using an indirect assay, wherein, for example, a second, labeled antibody is used to detect bound marker-specific antibody, and/or in a competition or inhibition assay wherein, for example, a monoclonal antibody which binds to a distinct epitope of the marker are incubated simultaneously with the mixture.


Throughout the assays, incubation and/or washing steps may be required after each combination of reagents. Incubation steps can vary from about 5 seconds to several hours, preferably from about 5 minutes to about 24 hours. However, the incubation time will depend upon the assay format, marker, volume of solution, concentrations and the like. Usually the assays will be carried out at ambient temperature, although they can be conducted over a range of temperatures, such as 10° C. to 40° C.


The immunoassay can be used to determine a test amount of a marker in a sample from a subject. First, a test amount of a marker in a sample can be detected using the immunoassay methods described above. If a marker is present in the sample, it will form an antibody-marker complex with an antibody that specifically binds the marker under suitable incubation conditions described above. The amount of an antibody-marker complex can optionally be determined by comparing to a standard. As noted above, the test amount of marker need not be measured in absolute units, as long as the unit of measurement can be compared to a control amount and/or signal.


Preferably used are antibodies which specifically interact with the polypeptides of the present invention and not with wild type proteins or other isoforms thereof, for example. Such antibodies are directed, for example, to the unique sequence portions of the polypeptide variants of the present invention, including but not limited to bridges, heads, tails and insertions described in greater detail below. Preferred embodiments of antibodies according to the present invention are described in greater detail with regard to the section entitled “Antibodies”.


Radio-immunoassay (RIA): In one version, this method involves precipitation of the desired substrate and in the methods detailed hereinbelow, with a specific antibody and radiolabelled antibody binding protein (e.g., protein A labeled with I125) immobilized on a precipitable carrier such as agarose beads. The number of counts in the precipitated pellet is proportional to the amount of substrate.


In an alternate version of the RIA, a labeled substrate and an unlabelled antibody binding protein are employed. A sample containing an unknown amount of substrate is added in varying amounts. The decrease in precipitated counts from the labeled substrate is proportional to the amount of substrate in the added sample.


Enzyme linked immunosorbent assay (ELISA): This method involves fixation of a sample (e.g., fixed cells or a proteinaceous solution) containing a protein substrate to a surface such as a well of a microtiter plate. A substrate specific antibody coupled to an enzyme is applied and allowed to bind to the substrate. Presence of the antibody is then detected and quantitated by a colorimetric reaction employing the enzyme coupled to the antibody. Enzymes commonly employed in this method include horseradish peroxidase and alkaline phosphatase. If well calibrated and within the linear range of response, the amount of substrate present in the sample is proportional to the amount of color produced. A substrate standard is generally employed to improve quantitative accuracy.


Western blot: This method involves separation of a substrate from other protein by means of an acrylamide gel followed by transfer of the substrate to a membrane (e.g., nylon or PVDF). Presence of the substrate is then detected by antibodies specific to the substrate, which are in turn detected by antibody binding reagents. Antibody binding reagents may be, for example, protein A, or other antibodies. Antibody binding reagents may be radiolabelled or enzyme linked as described hereinabove. Detection may be by autoradiography, colorimetric reaction or chemiluminescence. This method allows both quantitation of an amount of substrate and determination of its identity by a relative position on the membrane which is indicative of a migration distance in the acrylamide gel during electrophoresis.


Immunohistochemical analysis: This method involves detection of a substrate in situ in fixed cells by substrate specific antibodies. The substrate specific antibodies may be enzyme linked or linked to fluorophores. Detection is by microscopy and subjective evaluation. If enzyme linked antibodies are employed, a colorimetric reaction may be required.


Fluorescence activated cell sorting (FACS): This method involves detection of a substrate in situ in cells by substrate specific antibodies. The substrate specific antibodies are linked to fluorophores. Detection is by means of a cell sorting machine which reads the wavelength of light emitted from each cell as it passes through a light beam. This method may employ two or more antibodies simultaneously.


Radio-Imaging Methods


These methods include but are not limited to, positron emission tomography (PET) single photon emission computed tomography (SPECT). Both of these techniques are non-invasive, and can be used to detect and/or measure a wide variety of tissue events and/or functions, such as detecting cancerous cells for example. Unlike PET, SPECT can optionally be used with two labels simultaneously. SPECT has some other advantages as well, for example with regard to cost and the types of labels that can be used. For example, U.S. Pat. No. 6,696,686 describes the use of SPECT for detection of breast cancer, and is hereby incorporated by reference as if fully set forth herein.


Display Libraries


According to still another aspect of the present invention there is provided a display library comprising a plurality of display vehicles (such as phages, viruses or bacteria) each displaying at least 6, at least 7, at least 8, at least 9, at least 10, 10-15, 12-17, 15-20, 15-30 or 20-50 consecutive amino acids derived from the polypeptide sequences of the present invention.


Methods of constructing such display libraries are well known in the art. Such methods are described in, for example, Young A C, et al., “The three-dimensional structures of a polysaccharide binding antibody to Cryptococcus neoformans and its complex with a peptide from a phage display library: implications for the identification of peptide mimotopes” J Mol Biol 1997 Dec. 12;274(4):622-34; Giebel LB et al. “Screening of cyclic peptide phage libraries identifies ligands that bind streptavidin with high affinities” Biochemistry 1995 Nov. 28;34(47):15430-5; Davies E L et al., “Selection of specific phage-display antibodies using libraries derived from chicken immunoglobulin genes” J Immunol Methods 1995 Oct. 12;186(1):125-35; Jones C RT al. “Current trends in molecular recognition and bioseparation” J Chromatogr A 1995 Jul. 14;707(1):3-22; Deng S J et al. “Basis for selection of improved carbohydrate-binding single-chain antibodies from synthetic gene libraries” Proc Natl Acad Sci USA 1995 May 23;92(11):4992-6; and Deng S J et al. “Selection of antibody single-chain variable fragments with improved carbohydrate binding by phage display” J Biol Chem 1994 Apr. 1;269(13):9533-8, which are incorporated herein by reference.


The following sections relate to Candidate Marker Examples.


CANDIDATE MARKER EXAMPLES SECTION

This Section relates to Examples of sequences according to the present invention, including illustrative methods of selection thereof.


Description of the Methodology Undertaken to Uncover the Biomolecular Sequences of the Present Invention


Human ESTs and cDNAs were obtained from GenBank versions 136 (Jun. 15, 2003 ftp.ncbi.nih.gov/genbank/release.notes/gb136.release.notes); NCBI genome assembly of April 2003; RefSeq sequences from June 2003; Genbank version 139 (December 2003); Human Genome from NCBI (Build 34) (from October 2003); and RefSeq sequences from December 2003; and the LifeSeq library from Incyte Corporation (Wilmington, Del., USA; ESTs only). With regard to GenBank sequences, the human EST sequences from the EST (GBEST) section and the human mRNA sequences from the primate (GBPRI) section were used; also the human nucleotide RefSeq mRNA sequences were used (see for example www.ncbi.nlm.nih.gov/Genbank/GenbankOverview.html and for a reference to the EST section, see www.ncbi.nlm.nih.gov/dbEST/; a general reference to dbEST, the EST database in GenBank, may be found in Boguski et al, Nat Genet. 1993 August; 4(4):332-3; all of which are hereby incorporated by reference as if fully set forth herein).


Novel splice variants were predicted using the LEADS clustering and assembly system as described in Sorek, R., Ast, G. & Graur, D. Alu-containing exons are alternatively spliced. Genome Res 12, 1060-7 (2002); U.S. Pat. No. 6,625,545; and U.S. patent application Ser. No. 10/426,002, published as U.S. 20040101876 on May 27, 2004; all of which are hereby incorporated by reference as if fully set forth herein. Briefly, the software cleans the expressed sequences from repeats, vectors and immunoglobulins. It then aligns the expressed sequences to the genome taking alternatively splicing into account and clusters overlapping expressed sequences into “clusters” that represent genes or partial genes.


These were annotated using the GeneCarta (Compugen, Tel-Aviv, Israel) platform. The GeneCarta platform includes a rich pool of annotations, sequence information (particularly of spliced sequences), chromosomal information, alignments, and additional information such as SNPs, gene ontology terms, expression profiles, functional analyses, detailed domain structures, known and predicted proteins and detailed homology reports.


A brief explanation is provided with regard to the method of selecting the candidates. However, it should noted that this explanation is provided for descriptive purposes only, and is not intended to be limiting in any way. The potential markers were identified by a computational process that was designed to find genes and/or their splice variants that are over-expressed in tumor tissues, by using databases of expressed sequences. Various parameters related to the information in the EST libraries, determined according to a manual classification process, were used to assist in locating genes and/or splice variants thereof that are over-expressed in cancerous tissues. The detailed description of the selection method is presented in Example 1 below. The cancer biomarkers selection engine and the following wet validation stages are schematically summarized in FIG. 1.


Example 1

Identification of Differentially Expressed Gene Products—Algorithm


In order to distinguish between differentially expressed gene products and constitutively expressed genes (i.e., house keeping genes) an algorithm based on an analysis of frequencies was configured. A specific algorithm for identification of transcripts over expressed in cancer is described hereinbelow.


Dry Analysis


Library annotation—EST libraries are manually classified according to:


(i) Tissue Origin

  • (ii) Biological source—Examples of frequently used biological sources for construction of EST libraries include cancer cell-lines; normal tissues; cancer tissues; fetal tissues; and others such as normal cell lines and pools of normal cell-lines, cancer cell-lines and combinations thereof. A specific description of abbreviations used below with regard to these tissues/cell lines etc is given above.
  • (iii) Protocol of library construction—various methods are known in the art for library construction including normalized library construction; non-normalized library construction; subtracted libraries; ORESTES and others. It will be appreciated that at times the protocol of library construction is not indicated in GenBank and/or other library annotaion.


The following rules are followed:


EST libraries originating from identical biological samples are considered as a single library.


EST libraries which included above-average levels of contamination, such as DNA contamination for example, were eliminated. The presence of such contamination was determined as follows. For each library, the number of unspliced ESTs that are not fully contained within other spliced sequences was counted. If the percentage of such sequences (as compared to all other sequences) was at least 4 standard deviations above the average for all libraries being analyzed, this library was tagged as being contaminated and was eliminated from further consideration in the below analysis (see also Sorek, R. & Safer, H. M. A novel algorithm for computational identification of contaminated EST libraries. Nucleic Acids Res 31, 1067-74 (2003) for further details).


Clusters (genes) having at least five sequences including at least two sequences from the tissue of interest were analyzed. Splice variants were identified by using the LEADS software package as described above.


Example 2

Identification of Genes Over Expressed in Cancer.


Two different scoring algorithms were developed.


Libraries score—candidate sequences which are supported by a number of cancer libraries, are more likely to serve as specific and effective diagnostic markers.


The basic algorithm—for each cluster the number of cancer and normal libraries contributing sequences to the cluster was counted. Fisher exact test was used to check if cancer libraries are significantly over-represented in the cluster as compared to the total number of cancer and normal libraries.


Library counting: Small libraries (e.g., less than 1000 sequences) were excluded from consideration unless they participate in the cluster. For this reason, the total number of libraries is actually adjusted for each cluster.


Clones no. score—Generally, when the number of ESTs is much higher in the cancer libraries relative to the normal libraries it might indicate actual over-expression.


The Algorithm—


Clone counting: For counting EST clones each library protocol class was given a weight based on our belief of how much the protocol reflects actual expression levels:


(i) non-normalized: 1


(ii) normalized: 0.2


(iii) all other classes: 0.1


Clones number score—The total weighted number of EST clones from cancer libraries was compared to the EST clones from normal libraries. To avoid cases where one library contributes to the majority of the score, the contribution of the library that gives most clones for a given cluster was limited to 2 clones.


The score was computed as








c
+
1

C



n
+
1

N





where:


c—weighted number of “cancer” clones in the cluster.


C—weighted number of clones in all “cancer” libraries.


n—weighted number of “normal” clones in the cluster.


N—weighted number of clones in all “normal” libraries.


Clones number score significance—Fisher exact test was used to check if EST clones from cancer libraries are significantly over-represented in the cluster as compared to the total number of EST clones from cancer and normal libraries.


Two search approaches were used to find either general cancer-specific candidates or tumor specific candidates.

    • Libraries/sequences originating from tumor tissues are counted as well as libraries originating from cancer cell-lines (“normal” cell-lines were ignored).
    • Only libraries/sequences originating from tumor tissues are counted


Example 3

Identification of Tissue Specific Genes


For detection of tissue specific clusters, tissue libraries/sequences were compared to the total number of libraries/sequences in cluster. Similar statistical tools to those described in above were employed to identify tissue specific genes. Tissue abbreviations are the same as for cancerous tissues, but are indicated with the header “normal tissue”.


The algorithm—for each tested tissue T and for each tested cluster the following were examined:


1. Each cluster includes at least 2 libraries from the tissue T. At least 3 clones (weighed—as described above) from tissue T in the cluster; and


2. Clones from the tissue T are at least 40% from all the clones participating in the tested cluster


Fisher exact test P-values were computed both for library and weighted clone counts to check that the counts are statistically significant.


Example 4

Identification of Splice Variants Over Expressed in Cancer of Clusters Which are Not Over Expressed in Cancer


Cancer-specific splice variants containing a unique region were identified.


Identification of Unique Sequence Regions in Splice Variants


A Region is defined as a group of adjacent exons that always appear or do not appear together in each splice variant.


A “segment” (sometimes referred also as “seg” or “node”) is defined as the shortest contiguous transcribed region without known splicing inside.


Only reliable ESTs were considered for region and segment analysis. An EST was defined as unreliable if:


(i) Unspliced;


(ii) Not covered by RNA;


(iii) Not covered by spliced ESTs; and


(iv) Alignment to the genome ends in proximity of long poly-A stretch or starts in proximity of long poly-T stretch.


Only reliable regions were selected for further scoring. Unique sequence regions were considered reliable if:


(i) Aligned to the genome; and


(ii) Regions supported by more than 2 ESTs.


The Algorithm


Each unique sequence region divides the set of transcripts into 2 groups:


(i) Transcripts containing this region (group TA).


(ii) Transcripts not containing this region (group TB).


The set of EST clones of every cluster is divided into 3 groups:


(i) Supporting (originating from) transcripts of group TA (S1).


(ii) Supporting transcripts of group TB (S2).


(iii) Supporting transcripts from both groups (S3).


Library and clones number scores described above were given to S1 group.


Fisher Exact Test P-values were used to check if:


S1 is significantly enriched by cancer EST clones compared to S2; and


S1 is significantly enriched by cancer EST clones compared to cluster background (S1+S2+S3).


Identification of unique sequence regions and division of the group of transcripts accordingly is illustrated in FIG. 2. Each of these unique sequence regions corresponds to a segment, also termed herein a “node”.

  • Region 1: common to all transcripts, thus it is not considered; Region 2: specific to Transcript 1: T1 unique regions (2+6) against T2+3 unique regions (3+4); Region 3: specific to Transcripts 2+3: T2+3 unique regions (3+4) against T1 unique regions (2+6); Region 4: specific to Transcript 3: T3 unique regions (4) against T1+2 unique regions (2+5+6); Region 5: specific to Transcript 1+2: T1+2 unique regions (2+5+6) against T3 unique regions (4); Region 6: specific to Transcript 1: same as region 2.


Example 5

Identification of Cancer Specific Splice Variants of Genes Over Expressed in Cancer


A search for EST supported (no mRNA) regions for genes of:


(i) known cancer markers


(ii) Genes shown to be over-expressed in cancer in published micro-array experiments.


Reliable EST supported-regions were defined as supported by minimum of one of the following:


(i) 3 spliced ESTs; or


(ii) 2 spliced ESTs from 2 libraries;


(iii) 10 unspliced ESTs from 2 libraries, or


(iv) 3 libraries.


Actual Marker Examples


The following examples relate to specific actual marker examples.


EXPERIMENTAL EXAMPLES SECTION

This Section relates to Examples describing experiments involving these sequences, and illustrative, non-limiting examples of methods, assays and uses thereof. The materials and experimental procedures are explained first, as all experiments used them as a basis for the work that was performed.


The markers of the present invention were tested with regard to their expression in various cancerous and non-cancerous tissue samples. A description of the samples used in the panel is provided in Table 2 below. A description of the samples used in the normal tissue panel is provided in Table 3 below. Tests were then performed as described in the “Materials and Experimental Procedures” section below.









TABLE 2







Tissue samples in testing panel












Lot No.
Pathology
Sex/Age
Source















66-A-Adeno G1 GS-4
160202
Adenocarcinoma Gleason score 4
M/64
ABS


73-A-Adeno G1 GS-4
16026T2
Acinar Adenocarcinoma Gleason score 4(2 + 2)
M/77
ABS


68-A-Adeno G1 GS-5
160172
Adenocarcinoma Gleason score 5
M/66
ABS


56-Am-Adeno G1 GS-5
36467
Adenocarcinoma, Gleason score 5(3 + 2); stage 2
M/72
Ambion


58-Am-Adeno G1 GS-5
37192
Adenocarcinoma, Gleason score 5; stage 2
M/52
Ambion


65-A-Adeno G2 GS-5
160022
Adenocarcinoma Gleason score 5;
M/66
ABS


69-A-Adeno GS-5
160182
Acinar Adenocarcinoma Gleason score 5
M/58
ABS


55-Am-Adeno GS-5
36464
Adenocarcinoma, Gleason score 5; stage 1
M/53
Ambion


64-A-Adeno G2 GS-6
160092
Acinar Adenocarcinoma Gleason score 6
M/71
ABS


70-A-Adeno G2 GS-6
160192
Adenocarcinoma Gleason score 6
M/53
ABS


18-A-Adeno GS-6
5610020069T
Adenocarcinoma, Gleason score 6 (3 + 3)
M
ABS


67-A-Adeno GS-6
160142
Acinar Adenocarcinoma Gleason score 6
M/62
ABS


25-A-Adeno GS-7
5605020052T
Adenocarcinoma, Gleason score 7 (4 + 3)
M
ABS


26-A-Adeno GS-7
5609020067T
Adenocarcinoma, Gleason score 7 (4 + 3)
M
ABS


72-A-Adeno GS-7
160122
Acinar Adenocarcinoma Gleason score 7
M/66
ABS


71-A-Adeno GS-7
160242
Acinar Adenocarcinoma Gleason score 7
M/70
ABS


57-Am-Adeno GS-7
26442
Adenocarcinoma, Gleason score 7
M/62
Ambion


32-A-Adeno GS-9
5604020042T
Adenocarcinoma, Gleason score 9 (5 + 4)
M
ABS


54-B-Adeno G3
A610031
Adenocarcinoma

Biochain


33-A-BPH
5607020058
BPH
M
ABS


34-A-BPH
5607020059
BPH
M
ABS


35-A-BPH
5607020060
BPH
M
ABS


43-B-PBH
A609267
BPH
M/66
Biochain


44-B-PBH
A609268
BPH
M/72
Biochain


45-B-PBH
A609269
BPH
M/69
Biochain


46-B-PBH
A609270
BPH
M/65
Biochain


47-B-PBH
A609271
BPH
M/71
Biochain


40-A-N M26
5609020067N
Normal Matched
M
ABS


41-A-N M32
5604020042N
Normal Matched
M
ABS


48-B-N
A609257
Normal PM
M/24
Biochain


49-B-N
A609256
Normal PM
M/36
Biochain


50-B-N
A609255
Normal PM
M/26
Biochain


51-B-N
A609258
Normal PM
M/27
Biochain


52-B-N
A609254
Normal PM
M/29
Biochain


53-Cl-N
1070317
Normal - Pool of 47
M&F
Clontech


42-Am-N
061P04A
Normal (IC BLEED)
M/47
ambion


59-Am-N
25955
Normal PM (Head trauma)
M/62
Ambion


60-Am-N
33605
Normal PM (Myocardial infraction)
M/69
Ambion


61-Am-N
34077
Normal PM (Alzheimer's)
M/71
Ambion


62-Am-N
31316
Normal (Renal failure)
M/79
Ambion


63-Am-N
30991
Normal (Gall Bladder cancer)
M/78
Ambion
















TABLE 3







Tissue samples in normal panel:













Lot no.
Source
Tissue
Pathology
Sex/Age
















1-Am-Colon (C71)
071P10B
Ambion
Colon
PM
F/43


2-B-Colon (C69)
A411078
Biochain
Colon
PM-Pool of 10
M & F


3-Cl-Colon (C70)
1110101
Clontech
Colon
PM-Pool of 3
M & F


4-Am-Small Intestine
091P0201A
Ambion
Small Intestine
PM
M/75


5-B-Small Intestine
A501158
Biochain
Small Intestine
PM
M/63


6-B-Rectum
A605138
Biochain
Rectum
PM
M/25


7-B-Rectum
A610297
Biochain
Rectum
PM
M/24


8-B-Rectum
A610298
Biochain
Rectum
PM
M/27


9-Am-Stomach
110P04A
Ambion
Stomach
PM
M/16


10-B-Stomach
A501159
Biochain
Stomach
PM
M/24


11-B-Esophagus
A603814
Biochain
Esophagus
PM
M/26


12-B-Esophagus
A603813
Biochain
Esophagus
PM
M/41


13-Am-Pancreas
071P25C
Ambion
Pancreas
PM
M/25


14-CG-Pancreas
CG-255-2
Ichilov
Pancreas
PM
M/75


15-B-Lung
A409363
Biochain
Lung
PM
F/26


16-Am-Lung (L93)
111P0103A
Ambion
Lung
PM
F/61


17-B-Lung (L92)
A503204
Biochain
Lung
PM
M/28


18-Am-Ovary (O47)
061P43A
Ambion
Ovary
PM
F/16


19-B-Ovary (O48)
A504087
Biochain
Ovary
PM
F/51


20-B-Ovary (O46)
A504086
Biochain
Ovary
PM
F/41


21-Am-Cervix
101P0101A
Ambion
Cervix
PM
F/40


22-B-Cervix
A408211
Biochain
Cervix
PM
F/36


23-B-Cervix
A504089
Biochain
Cervix
PM-Pool of 5
M & F


24-B-Uterus
A411074
Biochain
Uterus
PM-Pool of 10
M & F


25-B-Uterus
A409248
Biochain
Uterus
PM
F/43


26-B-Uterus
A504090
Biochain
Uterus
PM-Pool of 5
M & F


27-B-Bladder
A501157
Biochain
Bladder
PM
M/29


28-Am-Bladder
071P02C
Ambion
Bladder
PM
M/20


29-B-Bladder
A504088
Biochain
Bladder
PM-Pool of 5
M & F


30-Am-Placenta
021P33A
Ambion
Placenta
PB
F/33


31-B-Placenta
A410165
Biochain
Placenta
PB
F/26


32-B-Placenta
A411073
Biochain
Placenta
PB-Pool of 5
M & F


33-B-Breast (B59)
A607155
Biochain
Breast
PM
F/36


34-Am-Breast (B63)
26486
Ambion
Breast
PM
F/43


35-Am-Breast (B64)
23036
Ambion
Breast
PM
F/57


36-Cl-Prostate (P53)
1070317
Clontech
Prostate
PB-Pool of 47
M & F


37-Am-Prostate (P42)
061P04A
Ambion
Prostate
PM
M/47


38-Am-Prostate (P59)
25955
Ambion
Prostate
PM
M/62


39-Am-Testis
111P0104A
Ambion
Testis
PM
M/25


40-B-Testis
A411147
Biochain
Testis
PM
M/74


41-Cl-Testis
1110320
Clontech
Testis
PB-Pool of 45
M & F


42-CG-Adrenal
CG-184-10
Ichilov
Adrenal
PM
F/81


43-B-Adrenal
A610374
Biochain
Adrenal
PM
F/83


44-B-Heart
A411077
Biochain
Heart
PB-Pool of 5
M & F


45-CG-Heart
CG-255-9
Ichilov
Heart
PM
M/75


46-CG-Heart
CG-227-1
Ichilov
Heart
PM
F/36


47-Am-Liver
081P0101A
Ambion
Liver
PM
M/64


48-CG-Liver
CG-93-3
Ichilov
Liver
PM
F/19


49-CG-Liver
CG-124-4
Ichilov
Liver
PM
F/34


50-Cl-BM
1110932
Clontech
Bone Marrow
PM-Pool of 8
M & F


51-CGEN-Blood
WBC#5
CGEN
Blood

M


52-CGEN-Blood
WBC#4
CGEN
Blood

M


53-CGEN-Blood
WBC#3
CGEN
Blood

M


54-CG-Spleen
CG-267
Ichilov
Spleen
PM
F/25


55-CG-Spleen
111P0106B
Ambion
Spleen
PM
M/25


56-CG-Spleen
A409246
Biochain
Spleen
PM
F/12


56-CG-Thymus
CG-98-7
Ichilov
Thymus
PM
F/28


58-Am-Thymus
101P0101A
Ambion
Thymus
PM
M/14


59-B-Thymus
A409278
Biochain
Thymus
PM
M/28


60-B-Thyroid
A610287
Biochain
Thyroid
PM
M/27


61-B-Thyroid
A610286
Biochain
Thyroid
PM
M/24


62-CG-Thyroid
CG-119-2
Ichilov
Thyroid
PM
F/66


63-Cl-Salivary Gland
1070319
Clontech
Salivary Gland
PM-Pool of 24
M & F


64-Am-Kidney
111P0101B
Ambion
Kidney
PM-Pool of 14
M & F


65-Cl-Kidney
1110970
Clontech
Kidney
PM-Pool of 14
M & F


66-B-Kidney
A411080
Biochain
Kidney
PM-Pool of 5
M & F


67-CG-Cerebellum
CG-183-5
Ichilov
Cerebellum
PM
M/74


68-CG-Cerebellum
CG-212-5
Ichilov
Cerebellum
PM
M/54


69-B-Brain
A411322
Biochain
Brain
PM
M/28


70-Cl-Brain
1120022
Clontech
Brain
PM-Pool of 2
M & F


71-B-Brain
A411079
Biochain
Brain
PM-Pool of 2
M & F


72-CG-Brain
CG-151-1
Ichilov
Brain
PM
F/86


73-Am-Skeletal Muscle
101P013A
Ambion
Skeletal Muscle
PM
F/28


74-Cl-Skeletal Muscle
1061038
Clontech
Skeletal Muscle
PM-Pool of 2
M & F










Materials and Experimental Procedures


RNA preparation—RNA was obtained from Clontech (Franklin Lakes, N.J. USA 07417, clontech dot com), BioChain Inst. Inc. (Hayward, Calif. 94545 USA biochain dot com), ABS (Wilmington, Del. 19801, USA, absbioreagents dot com) or Ambion (Austin, Tex. 78744 USA, ambion dot com). Alternatively, RNA was generated from tissue samples using TRi-Reagent (Molecular Research Center), according to Manufacturer's instructions. Tissue and RNA samples were obtained from patients or from postmortem. Total RNA samples were treated with DNasel (Ambion) and purified using RNeasy columns (Qiagen).


RT PCR—Purified RNA (1 μg) was mixed with 150 ng Random Hexamer primers (Invitrogen) and 500 μM dNTP in a total volume of 15.6 μl. The mixture was incubated for 5 min at 65° C. and then quickly chilled on ice. Thereafter, 5 μl of 5×Superscriptll first strand buffer (Invitrogen), 2.4 μl 0.1M DTT and 40 units RNasin (Promega) were added, and the mixture was incubated for 10 min at 25° C., followed by further incubation at 42° C. for 2 min. Then, 1 μl (200units) of SuperscriptII (Invitrogen) was added and the reaction (final volume of 25 μl) was incubated for 50 min at 42° C. and then inactivated at 70° C. for 15 min. The resulting cDNA was diluted 1:20 in TE buffer (10 mM Tris pH=8, 1 mM EDTA pH=8).


Real-Time RT-PCR analysis—cDNA (5μl), prepared as described above, was used as a template in Real-Time PCR reactions using the SYBR Green I assay (PE Applied Biosystem) with specific primers and UNG Enzyme (Eurogentech or ABI or Roche). The amplification was effected as follows: 50° C. for 2 min, 95° C. for 10 min, and then 40 cycles of 95° C. for 15 sec, followed by 60° C. for 1 min. Detection was performed by using the PE Applied Biosystem SDS 7000. The cycle in which the reactions achieved a threshold level (Ct) of fluorescence was registered and was used to calculate the relative transcript quantity in the RT reactions. The relative quantity was calculated using the equation Q=efficiency^−Ct. The efficiency of the PCR reaction was calculated from a standard curve, created by using serial dilutions of several reverse transcription (RT) reactions. To minimize inherent differences in the RT reaction, the resulting relative quantities were normalized to the geometric mean of the relative quantities of several housekeeping (HSKP) genes. Schematic summary of quantitative real-time PCR analysis is presented in FIG. 3. As shown, the x-axis shows the cycle number. The CT=Threshold Cycle point, which is the cycle that the amplification curve crosses the fluorescence threshold that was set in the experiment. This point is a calculated cycle number in which PCR product signal is above the background level (passive dye ROX) and still in the Geometric/Exponential phase (as shown, once the level of fluorescence crosses the measurement threshold, it has a geometrically increasing phase, during which measurements are most accurate, followed by a linear phase and a plateau phase; for quantitative measurements, the latter two phases do not provide accurate measurements). The y-axis shows the normalized reporter fluorescence. It should be noted that this type of analysis provides relative quantification.


The sequences of the housekeeping genes measured in all the examples below on prostate panel were as follows:










SDHA (GenBank Accession No. NM_004168 (SEQ ID NO:508))






SDHA Forward primer (SEQ ID NO:405): TGGGAACAAGAGGGCATCTG





SDHA Reverse primer (SEQ ID NO:406): CCACCACTGCATCAAATTCATG





SDHA-amplicon (SEQ ID NO:407):


TGGGAACAAGAGGGCATCTGCTAAAGTTTCAGATTCCATTTCTGCTCAGTATCCAGTAGTGGATC





ATGAATTTGATGCAGTGGTGG





PBGD (GenBank Accession No. BC019323 (SEQ ID NO:509)),





PBGD Forward primer (SEQ ID NO:402): TGAGAGTGATTCGCGTGGG





PBGD Reverse primer (SEQ ID NO:403): CCAGGGTACGAGGCTTTCAAT





PBGD-amplicon (SEQ ID NO:404):


TGAGAGTGATTCGCGTGGGTACCCGCAAGAGCCAGCTTGCTCGCATACAGACGGACAGTGTGGTG





GCAACATTGAAAGCCTCGTACCCTGG





HPRT1 (GenBank Accession No. NM_000194 (SEQ ID NO:510)),





HPRT1 Forward primer (SEQ ID NO:399): TGACACTGGCAAAACAATGCA





HPRT1 Reverse primer (SEQ ID NO:400): GGTCCTTTTCACCAGCAAGCT





HPRT1-amplicon (SEQ ID NO:401):


TGACACTGGCAAAACAATGCAGACTTTGCTTTCCTTGGTCAGGCAGTATAATCCAAAGATGGTCA





AGGTCGCAAGCTTGCTGGTGAAAAGGACC





RPL19 (GenBank Accession No. NM_000981 (SEQ ID NO:511)





RPL19 Forward primer (SEQ ID NO:408): TGGCAAGAAGAAGGTCTGGTTAG





RPL19 Reverse primer (SEQ ID NO:409): TGATCAGCCCATCTTTGATGAG





RPL19-amplicon (SEQ ID NO:410):


TGGCAAGAAGAAGGTCTGGTTAGACCCCAATGAGACCAATGAAATCGCCAATGCCAACTCCCGTC





AGCAGATCCGGAAGCTCATCAAAGATGGGCTGATCA






The sequences of the housekeeping genes measured in all the examples on normal tissue samples panel were as follows:










RPL19 (GenBank Accession No. NM_000981 (SEQ ID NO:511)),






RPL19 Forward primer (SEQ ID NO:408): TGGCAAGAAGAAGGTCTGGTTAG





RPL19 Reverse primer (SEQ ID NO:409): TGATCAGCCCATCTTTGATGAG





RPL19-amplicon (SEQ ID NO:410):


TGGCAAGAAGAAGGTCTGGTTAGACCCCAATGAGACCAATGAAATCGCCAATGCCAACTCCCGTC





AGCAGATCCGGAAGCTCATCAAAGATGGGCTGATCA





TATA box (GenBank Accession No. NM_003194 (SEQ ID NO:512)),





TATA box Forward primer (SEQ ID NO:513): CGGTTTGCTGCGGTAATCAT





TATA box Reverse primer (SEQ ID NO:514): TTTCTTGCTGCCAGTCTGGAC





TATA box-amplicon (SEQ ID NO:515):


CGGTTTGCTGCGGTAATCATGAGGATAAGAGAGCCACGAACCACGGCACTGATTTTCAGTTCTGGGAAAAT





GGTGTGCACAGGAGCCAAGAGTGAAGAACAGTCCAGACTGGCAGCAAGAAA





UBC (GenBank Accession No. BC000449 (SEQ ID NO:516))





UBC Forward primer (SEQ ID NO:517): ATTTGGGTCGCGGTTCTTG





UBC Reverse primer (SEQ ID NO:518): TGCCTTGACATTCTCGATGGT





UBC-amplicon (SEQ ID NO:519):


ATTTGGGTCGCGGTTCTTGTTTGTGGATCGCTGTGATCGTCACTTGACAATGCAGATCTTCGTGAAGACTC





TGACTGGTAAGACCATCACCCTCGAGGTTGAGCCCAGTGACACCATCGAGAATGTCAAGGCA





SDHA (GenBank Accession No. NM_004168 (SEQ ID NO:508))





SDHA Forward primer (SEQ ID NO:405): TGGGAACAAGAGGGCATCTG





SDHA Reverse primer (SEQ ID NO:406): CCACCACTGCATCAAATTCATG





SDHA-amplicon (SEQ ID NO:407):


TGGGAACAAGAGGGCATCTGCTAAAGTTTCAGATTCCATTTCTGCTCAGTATCCAGTAGTGGATCATGAAT





TTGATGCAGTGGTGG






Oligonucleotide-Based Micro-Array Experiment Protocol—


Microarray Fabrication


Microarrays (chips) were printed by pin deposition using the MicroGrid II MGII 600 robot from BioRobtics Limited (Cambridge, UK). 50-mer oligonucleotides target sequences were designed by Compugen Ltd (Tel-Aviv, IL) as described by A. Shoshan et al, “Optical technologies and informatics”, Proceedings of SPIE. Vol 4266, pp. 86-95 (2001). The designed oligonucleotides were synthesized and purified by desalting with the Sigma-Genosys system (The Woodlands, Tex., US) and all of the oligonucleotides were joined to a C6 amino-modified linker at the 5′ end, or being attached directly to CodeLink slides (Cat #25-6700-01. Amersham Bioscience, Piscataway, N.J., US). The 50-mer oligonucleotides, forming the target sequences, were first suspended in Ultra-pure DDW (Cat # 01-866-1A Kibbutz Beit-Haemek, Israel) to a concentration of 50 μM. Before printing the slides, the oligonucleotides were resuspended in 300 mM sodium phosphate (pH 8.5) to final concentration of 150 mM and printed at 35-40% relative humidity at 21° C.


Each slide contained a total of 9792 features in 32 subarrays. Of these features, 4224 features were sequences of interest according to the present invention and negative controls that were printed in duplicate. An additional 288 features (96 target sequences printed in triplicate) contained housekeeping genes from Human Evaluation Library2, Compugen Ltd, Israel. Another 384 features are E. coli spikes 1-6, which are oligos to E-Coli genes which are commercially available in the Array Control product (Array control—sense oligo spots, Ambion Inc. Austin, Tex. Cat # 1781, Lot #112K06).


Post-Coupling Processing of Printed Slides


After the spotting of the oligonucleotides to the glass (CodeLink) slides, the slides were incubated for 24 hours in a sealed saturated NaCl humidification chamber (relative humidity 70-75%).


Slides were treated for blocking of the residual reactive groups by incubating them in blocking solution at 50° C. for 15 minutes (10 ml/slide of buffer containing 0.1M Tris, 50 mM ethanolamine, 0.1% SDS). The slides were then rinsed twice with Ultra-pure DDW (double distilled water). The slides were then washed with wash solution (10 ml/slide. 4×SSC, 0.1% SDS)) at 50° C. for 30 minutes on the shaker. The slides were then rinsed twice with Ultra-pure DDW, followed by drying by centrifugation for 3 minutes at 800 rpm.


Next, in order to assist in automatic operation of the hybridization protocol, the slides were treated with Ventana Discovery hybridization station barcode adhesives. The printed slides were loaded on a Bio-Optica (Milan, Italy) hematology staining device and were incubated for 10 minutes in 50 ml of 3-Aminopropyl Triethoxysilane (Sigma A3648 lot #122K589). Excess fluid was dried and slides were then incubated for three hours in 20 mm/Hg in a dark vacuum desiccator (Pelco 2251, Ted Pella, Inc. Redding Calif.).


The following protocol was then followed with the Genisphere 900-RP (random primer), with mini elute columns on the Ventana Discovery HybStation™, to perform the microarray experiments. Briefly, the protocol was performed as described with regard to the instructions and information provided with the device itself. The protocol included cDNA synthesis and labeling. cDNA concentration was measured with the TBS-380 (Turner Biosystems. Sunnyvale, Calif.) PicoFlour, which is used with the OliGreen ssDNA Quantitation reagent and kit.


Hybridization was performed with the Ventana Hybridization device, according to the provided protocols (Discovery Hybridization Station Tuscon Ariz.).


The slides were then scanned with GenePix 4000B dual laser scanner from Axon Instruments Inc, and analyzed by GenePix Pro 5.0 software.


Schematic summary of the oligonucleotide based microarray fabrication and the experimental flow is presented in FIGS. 4 and 5.


Briefly, as shown in FIG. 4, DNA oligonucleotides at 25 uM were deposited (printed) onto Amersham ‘CodeLink’ glass slides generating a well defined ‘spot’. These slides are covered with a long-chain, hydrophilic polymer chemistry that creates an active 3-D surface that covalently binds the DNA oligonucleotides 5′-end via the C6-amine modification. This binding ensures that the full length of the DNA oligonucleotides is available for hybridization to the cDNA and also allows lower background, high sensitivity and reproducibility.



FIG. 5 shows a schematic method for performing the microarray experiments. It should be noted that stages on the left-hand or right-hand side may optionally be performed in any order, including in parallel, until stage 4 (hybridization). Briefly, on the left-hand side, the target oligonucleotides are being spotted on a glass microscope slide (although optionally other materials could be used) to form a spotted slide (stage 1). On the right hand side, control sample RNA and cancer sample RNA are Cy3 and Cy5 labeled, respectively (stage 2), to form labeled probes. It should be noted that the control and cancer samples come from corresponding tissues (for example, normal prostate tissue and cancerous prostate tissue). Furthermore, the tissue from which the RNA was taken is indicated below in the specific examples of data for particular clusters, with regard to overexpression of an oligonucleotide from a “chip” (microarray), as for example “prostate” for chips in which prostate cancerous tissue and normal tissue were tested as described above. In stage 3, the probes are mixed. In stage 4, hybridization is performed to form a processed slide. In stage 5, the slide is washed and scanned to form an image file, followed by data analysis in stage 6.


Description for Cluster HSECADH


Cluster HSECADH features 4 transcript(s) and 30 segment(s) of interest, the names for which are given in Tables 4 and 5, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 6.









TABLE 4







Transcripts of interest










Transcript Name
Sequence ID No.







HSECADH_T11
1



HSECADH_T18
2



HSECADH_T19
3



HSECADH_T20
4

















TABLE 5







Segments of interest










Segment Name
Sequence ID No.







HSECADH_node_0
60



HSECADH_node_14
61



HSECADH_node_15
62



HSECADH_node_21
63



HSECADH_node_22
64



HSECADH_node_25
65



HSECADH_node_26
66



HSECADH_node_48
67



HSECADH_node_52
68



HSECADH_node_53
69



HSECADH_node_54
70



HSECADH_node_57
71



HSECADH_node_60
72



HSECADH_node_62
73



HSECADH_node_63
74



HSECADH_node_7
75



HSECADH_node_1
76



HSECADH_node_11
77



HSECADH_node_12
78



HSECADH_node_17
79



HSECADH_node_18
80



HSECADH_node_19
81



HSECADH_node_3
82



HSECADH_node_42
83



HSECADH_node_45
84



HSECADH_node_46
85



HSECADH_node_55
86



HSECADH_node_56
87



HSECADH_node_58
88



HSECADH_node_59
89

















TABLE 6







Proteins of interest










Protein Name
Sequence ID No.







HSECADH_P9
327



HSECADH_P13
328



HSECADH_P14
329



HSECADH_P15
330










These sequences are variants of the known protein Epithelial-cadherin precursor (SEQ ID NO:384) (SwissProt accession identifier CAD1_HUMAN (SEQ ID NO: 384); known also according to the synonyms E-cadherin; Uvomorulin; Cadherin-1; CAM 120/80), SEQ ID NO: 384, referred to herein as the previously known protein.


The variant proteins according to the present invention are variants of a known diagnostic marker, called E-Cadherin.


Protein Epithelial-cadherin is known or believed to have the following function(s): Cadherins are calcium dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. E-cadherin has a potent invasive suppressor role. It is also a ligand for integrin alpha-E/beta-7. The sequence for protein Epithelial-cadherin precursor (SEQ ID NO:384) is given at the end of the application, as “Epithelial-cadherin precursor (SEQ ID NO:384) amino acid sequence”. Known polymorphisms for this sequence are as shown in Table 7.









TABLE 7







Amino acid mutations for Known Protein








SNP position(s) on



amino acid sequence
Comment





123
H -> Y (in diffuse gastric cancer). /FTId = VAR_001306.


193
T -> P (in diffuse gastric cancer). /FTId = VAR_001307.


418-423
Missing (in gastric carcinoma). /FTId = VAR_001313.


463
E -> Q (in diffuse gastric cancer). /FTId = VAR_001314.


470
T -> I. /FTId = VAR_001315.


473
V -> D (in diffuse gastric cancer). /FTId = VAR_001317.


487
V -> A (in HDGC). /FTId = VAR_008713.


592
A -> T (in thyroid cancer; may play a role in colorectal



carcinogenesis). /FTId = VAR_001318.


598
R -> Q (in diffuse gastric cancer). /FTId = VAR_001319.


617
A -> T (in endometrial cancer; loss of heterozygosity).



/FTId = VAR_001320.


711
L -> V (in endometrial cancer). /FTId = VAR_001321.


838
S -> G (in ovarian cancer; loss of heterozygosity).



/FTId = VAR_001322.


244
D -> G (in HDGC). /FTId = VAR_008712.


 10
A -> G


16-51
QVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRV ->



RSPLGSQERSPPPCLTRELHVHGAPAPPEKRPR


68-75
YFSLDTRF -> IFLTPIP


 95-102
QIHFLVYA -> TDPFLGLR


483
A -> G


530
A -> R


543
S -> F


615
I -> H


634-636
ASA -> RVP


868
R -> P


270
S -> A (may contribute to prostate cancer). /FTId = VAR_013970.


882
D -> H


274-277
Missing (in gastric adenocarcinoma). /FTId = VAR_001308.


315
N -> S (in lobular breast carcinoma). /FTId = VAR_001309.


336
E -> D. /FTId = VAR_001310.


340
T -> A (in HDGC and colorectal cancer).



/FTId = VAR_013971.


370
D -> A (in diffuse gastric cancer). /FTId = VAR_001311.


400
Missing (in gastric carcinoma; loss of heterozygosity).



/FTId = VAR_001312.









Protein Epithelial-cadherin localization is believed to be Type I membrane protein.


The following GO Annotation(s) apply to the previously known protein. The following annotation(s) were found: cell adhesion; homophilic cell adhesion, which are annotation(s) related to Biological Process; calcium binding; protein binding, which are annotation(s) related to Molecular Function; and membrane; integral membrane protein, which are annotation(s) related to Cellular Component.


The GO assignment relies on information from one or more of the SwissProt/TremB1 Protein knowledgebase, available from expasydot ch/sprot/; or Locuslink, available from ncbidot nlmdot nihdot gov/projects/LocusLink/.


Cluster HSECADH can be used as a diagnostic marker according to overexpression of transcripts of this cluster in cancer. Expression of such transcripts in normal tissues is also given according to the previously described methods. The term “number” in the right hand column of the table and the numbers on the y-axis of FIG. 6 refer to weighted expression of ESTs in each category, as “parts per million” (ratio of the expression of ESTs for a particular cluster to the expression of all ESTs in that category, according to parts per million).


Overall, the following results were obtained as shown with regard to the histograms in FIG. 6 and Table 8. This cluster is overexpressed (at least at a minimum level) in the following pathological conditions: a mixture of malignant tumors from different tissues and ovarian carcinoma.









TABLE 8







Normal tissue distribution










Name of Tissue
Number














Bladder
41



Brain
3



Colon
299



Epithelial
190



General
67



head and neck
10



Kidney
103



Liver
9



Lung
93



Breast
52



Ovary
0



Pancreas
105



Prostate
279



Skin
457



Stomach
659



Thyroid
64



Uterus
118

















TABLE 9







P values and ratios for expression in cancerous tissue













Name of Tissue
P1
P2
SP1
R3
SP2
R4





Bladder
3.9e−01
3.4e−01
4.1e−01
1.7
3.8e−01
1.7


Brain
3.7e−01
4.9e−01
1
1.4
1
1.0


Colon
6.6e−01
7.4e−01
9.5e−01
0.6
9.3e−01
0.5


Epithelial
1.3e−01
6.8e−01
9.5e−01
0.8
1
0.5


General
1.6e−06
1.5e−03
6.3e−05
1.5
5.6e−01
0.9


head and neck
1.5e−01
2.7e−01
4.6e−01
2.1
7.5e−01
1.2


Kidney
8.3e−01
8.7e−01
9.9e−01
0.4
1
0.3


Liver
4.4e−01
6.9e−01
1
1.7
6.9e−01
1.5


Lung
7.2e−01
8.8e−01
7.5e−01
0.9
9.9e−01
0.4


Breast
7.5e−02
1.1e−01
3.1e−01
1.7
5.1e−01
1.2


Ovary
4.5e−02
3.6e−02
4.7e−03
3.8
1.4e−02
3.5


Pancreas
5.5e−01
6.5e−01
2.4e−01
0.9
5.2e−01
0.7


Prostate
8.1e−01
8.5e−01
6.4e−01
0.8
9.0e−01
0.6


Skin
5.7e−01
7.4e−01
1
0.0
1
0.1


Stomach
2.2e−01
5.2e−01
1
0.2
1
0.1


Thyroid
5.5e−01
5.5e−01
4.4e−01
1.6
4.4e−01
1.6


Uterus
5.0e−02
2.4e−01
1.0e−01
1.3
5.8e−01
0.8









As noted above, cluster HSECADH features 4 transcript(s), which were listed in Table 4 above. These transcript(s) encode for protein(s) which are variant(s) of protein Epithelial-cadherin precursor (SEQ ID NO:384). A description of each variant protein according to the present invention is now provided.


Variant protein HSECADH_P9 (SEQ ID NO:327) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSECADH_T11 (SEQ ID NO:1). An alignment is given to the known protein (Epithelial-cadherin precursor (SEQ ID NO:384)) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSECADH_P9 (SEQ ID NO:327) and Q9UII7 (SEQ ID NO:483):


1. An isolated chimeric polypeptide encoding for HSECADH_P9 (SEQ ID NO:327), comprising a first amino acid sequence being at least 90% homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEG corresponding to amino acids 1-274 of Q9UII7, which also corresponds to amino acids 1-274 of HSECADH_P9 (SEQ ID NO:327), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence TACRSRIANSCHSGDSWRNSCFANSDSAALAVSSEESGGQRALTAPRG (SEQ ID NO: 532) corresponding to amino acids 275-322 of HSECADH_P9 (SEQ ID NO:327), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSECADH_P9 (SEQ ID NO:327), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TACRSRIANSCHSGDSWRNSCFANSDSAALAVSSEESGGQRALTAPRG (SEQ ID NO: 532) in HSECADH_P9 (SEQ ID NO:327).


Comparison report between HSECADH_P9 (SEQ ID NO:327) and Q9UII8 (SEQ ID NO:484):


1. An isolated chimeric polypeptide encoding for HSECADH_P9 (SEQ ID NO:327) comprising a first amino acid sequence being at least 90% homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEG corresponding to amino acids 1-274 of Q9UII8, which also corresponds to amino acids 1-274 of HSECADH_P9 (SEQ ID NO:327), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence TACRSRIANSCHSGDSWRNSCFANSDSAALAVSSEESGGQRALTAPRG (SEQ ID NO: 532) corresponding to amino acids 275-322 of HSECADH_P9 (SEQ ID NO:327), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSECADH_P9 (SEQ ID NO:327) comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TACRSRIANSCHSGDSWRNSCFANSDSAALAVSSEESGGQRALTAPRG (SEQ ID NO: 532) in HSECADH_P9 (SEQ ID NO:327).


Comparison report between HSECADH_P9 (SEQ ID NO:327) and CAD1_HUMAN:


1. An isolated chimeric polypeptide encoding for HSECADH_P9 (SEQ ID NO:327) comprising a first amino acid sequence being at least 90% homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEG corresponding to amino acids 1-274 of CAD1_HUMAN, which also corresponds to amino acids 1-274 of HSECADH_P9 (SEQ ID NO:327), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence TACRSRIANSCHSGDSWRNSCFANSDSAALAVSSEESGGQRALTAPRG (SEQ ID NO: 532) corresponding to amino acids 275-322 of HSECADH_P9 (SEQ ID NO:327), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSECADH_P9 (SEQ ID NO:327) comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TACRSRIANSCHSGDSWRNSCFANSDSAALAVSSEESGGQRALTAPRG (SEQ ID NO: 532) in HSECADH_P9 (SEQ ID NO:327).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSECADH_P9 (SEQ ID NO:327) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 10, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSECADH_P9 (SEQ ID NO:327) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 10







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?





127
P -> T
No


141
T -> A
No


276
A -> V
No









Variant protein HSECADH_P9 (SEQ ID NO:327) is encoded by the following transcript(s): HSECADH_T11 (SEQ ID NO:1), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSECADH_T11 (SEQ ID NO:1) is shown in bold; this coding portion starts at position 125 and ends at position 1090. The transcript also has the following SNPs as listed in Table 11 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSECADH_P9 (SEQ ID NO:327) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 11







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












71
G -> C
Yes


469
G -> A
Yes


1487
C -> T
Yes


1556
C -> A
Yes


1556
C -> G
Yes


1556
C -> T
Yes


1603
G -> A
Yes


1604
G -> A
Yes


1688
A -> G
Yes


1712
T -> 
No


1890
T -> G
No


1895
T -> G
No


503
C -> A
No


2090
C -> T
Yes


2621
T -> A
Yes


2621
T -> C
Yes


2621
T -> G
Yes


2797
-> G 
No


2849
G -> A
No


2992
A -> C
No


3027
C -> G
No


3029
C -> A
No


3134
T -> 
No


545
A -> G
No


3211
T -> 
No


3258
A -> G
No


3336
T -> C
Yes


847
A -> G
No


951
C -> T
No


1331
T -> C
No


1377
G -> A
No


1487
C -> A
Yes


1487
C -> G
Yes









Variant protein HSECADH_P13 (SEQ ID NO:328) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSECADH_T18 (SEQ ID NO:2). An alignment is given to the known protein (Epithelial-cadherin precursor (SEQ ID NO:384) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSECADH_P13 (SEQ ID NO:328) and Q9UII7:


1. An isolated chimeric polypeptide encoding for HSECADH_P13 (SEQ ID NO:328), comprising a first amino acid sequence being at least 90% homologous to MPGWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNT YNAAIAYTILSQDPELPDKNMFTINRNTGVISVVTTGLDRESFPTYTLVVQAADLQGEGL STTATAVITVTDTNDNPPIFNPTT corresponding to amino acids 1-379 of Q9UII7, which also corresponds to amino acids 1-379 of HSECADH_P13 (SEQ ID NO:328), and a second amino acid sequence VIL corresponding to amino acids 380-382 of HSECADH_P13 (SEQ ID NO:328), wherein said first and second amino acid sequences are contiguous and in a sequential order.


Comparison report between HSECADH_P13 (SEQ ID NO:328) and Q9UII8:


1. An isolated chimeric polypeptide encoding for HSECADH_P13 (SEQ ID NO:328) comprising a first amino acid sequence being at least 90% homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNT YNAAIAYTILSQDPELPDKNMFTINRNTGVISVVTTGLDRESFPTYTLVVQAADLQGEGL STTATAVITVTDTNDNPPIFNPTT corresponding to amino acids 1-379 of Q9UII8, which also corresponds to amino acids 1-379 of HSECADH_P13 (SEQ ID NO:328), and a second amino acid sequence VIL corresponding to amino acids 380-382 of HSECADH_P13 (SEQ ID NO:328), wherein said first and second amino acid sequences are contiguous and in a sequential order.


Comparison report between HSECADH_P13 (SEQ ID NO:328) and CAD1_HUMAN:


1. An isolated chimeric polypeptide encoding for HSECADH_P13 (SEQ ID NO:328) comprising a first amino acid sequence being at least 90% homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNT YNAAIAYTILSQDPELPDKNMFTINRNTGVISVVTTGLDRSFPTYTLVVQAADLQGEGL STTATAVITVTDTNDNPPIFNPTT corresponding to amino acids 1-379 of CAD1_HUMAN, which also corresponds to amino acids 1-379 of HSECADH_P13 (SEQ ID NO:328), and a second amino acid sequence VIL corresponding to amino acids 380-382 of HSECADH_P13 (SEQ ID NO:328), wherein said first and second amino acid sequences are contiguous and in a sequential order.


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSECADH_P13 (SEQ ID NO:328) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 12, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSECADH_P13 (SEQ ID NO:328) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 12







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?





127
P -> T
No


141
T -> A
No









Variant protein HSECADH_P13 (SEQ ID NO:328) is encoded by the following transcript(s): HSECADH_T18 (SEQ ID NO:2), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSECADH_T18 (SEQ ID NO:2) is shown in bold; this coding portion starts at position 125 and ends at position 1270. The transcript also has the following SNPs as listed in Table 13 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSECADH_P13 (SEQ ID NO:328) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 13







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












71
G -> C
Yes


469
G -> A
Yes


503
C -> A
No


545
A -> G
No


847
A -> G
No


1545
A -> G
Yes









Variant protein HSECADH_P14 (SEQ ID NO:329) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSECADH_T19 (SEQ ID NO:3). An alignment is given to the known protein (Epithelial-cadherin precursor (SEQ ID NO:384)) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSECADH_P14 (SEQ ID NO:329) and Q9UII7:


1. An isolated chimeric polypeptide encoding for HSECADH_P14 (SEQ ID NO:329) comprising a first amino acid sequence being at least 90% homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNT YNAAIAYTILSQDPELPDKNMFTINRNTGVISVVTTGLDRE corresponding to amino acids 1-336 of Q9UII7, which also corresponds to amino acids 1-336 of HSECADH_P14 (SEQ ID NO:329), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence VRGQEDPEGVEDKCVLAQSRGQSKILLGQLSVNTVMV (SEQ ID NO: 533) corresponding to amino acids 337-373 of HSECADH_P14 (SEQ ID NO:329), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSECADH_P14 (SEQ ID NO:329) comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VRGQEDPEGVEDKCVLAQSRGQSKILLGQLSVNTVMV (SEQ ID NO: 533) in HSECADH_P14 (SEQ ID NO:329).


Comparison report between HSECADH_P14 (SEQ ID NO:329) and Q9UII8:


1. An isolated chimeric polypeptide encoding for HSECADH_P14 (SEQ ID NO:329), comprising a first amino acid sequence being at least 90% homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVS SN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNT YNAAIAYTILSQDPELPDKNMFTINRNTGVISVVTTGLDRE corresponding to amino acids 1-336 of Q9UII8, which also corresponds to amino acids 1-336 of HSECADH_P14 (SEQ ID NO:329), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence VRGQEDPEGVEDKCVLAQSRGQSKILLGQLSVNTVMV (SEQ ID NO: 533) corresponding to amino acids 337-373 of HSECADH_P14 (SEQ ID NO:329), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSECADH_P14 (SEQ ID NO:329) comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VRGQEDPEGVEDKCVLAQSRGQSKILLGQLSVNTVMV (SEQ ID NO: 533) in HSECADH_P14 (SEQ ID NO:329).


Comparison report between HSECADH_P14 (SEQ ID NO:329) and CAD1_HUMAN:


1. An isolated chimeric polypeptide encoding for HSECADH_P14 (SEQ ID NO:329), comprising a first amino acid sequence being at least 90% homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNT YNAAIAYTILSQDPELPDKNMFTINRNTGVISVVTTGLDRE corresponding to amino acids 1-336 of CAD1_HUMAN, which also corresponds to amino acids 1-336 of HSECADH_P14 (SEQ ID NO:329), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence VRGQEDPEGVEDKCVLAQSRGQSKILLGQLSVNTVMV (SEQ ID NO: 533) corresponding to amino acids 337-373 of HSECADH_P14 (SEQ ID NO:329), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSECADH_P14 (SEQ ID NO:329), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VRGQEDPEGVEDKCVLAQSRGQSKILLGQLSVNTVMV (SEQ ID NO: 533) in HSECADH_P14 (SEQ ID NO:329).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSECADH_P14 (SEQ ID NO:329) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 14, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSECADH_P14 (SEQ ID NO:329) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 14







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












127
P -> T
No


141
T -> A
No









Variant protein HSECADH_P14 (SEQ ID NO:329) is encoded by the following transcript(s): HSECADH_T19 (SEQ ID NO:3), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSECADH_T19 (SEQ ID NO:3) is shown in bold; this coding portion starts at position 125 and ends at position 1243. The transcript also has the following SNPs as listed in Table 15 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSECADH_P14 (SEQ ID NO:329) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 15







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












71
G -> C
Yes


469
G -> A
Yes


503
C -> A
No


545
A -> G
No


847
A -> G
No









Variant protein HSECADH_P15 (SEQ ID NO:330) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSECADH_T20 (SEQ ID NO:4). An alignment is given to the known protein (Epithelial-cadherin precursor (SEQ ID NO:384)) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSECADH_P15 (SEQ ID NO:330) and Q9UII7:


1. An isolated chimeric polypeptide encoding for HSECADH_P15 (SEQ ID NO:330), comprising a first amino acid sequence being at least 90% homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYT corresponding to amino acids 1-229 of Q9UII7, which also corresponds to amino acids 1-229 of HSECADH_P15 (SEQ ID NO:330), and a second amino acid sequence VSIS corresponding to amino acids 230-233 of HSECADH_P15 (SEQ ID NO:330), wherein said first and second amino acid sequences are contiguous and in a sequential order.


Comparison report between HSECADH_P15 (SEQ ID NO:330) and Q9UII8:


1. An isolated chimeric polypeptide encoding for HSECADH_P15 (SEQ ID NO:330), comprising a first amino acid sequence being at least 90% homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYT corresponding to amino acids 1-229 of Q9UII8, which also corresponds to amino acids 1-229 of HSECADH_P15 (SEQ ID NO:330), and a second amino acid sequence VSIS corresponding to amino acids 230-233 of HSECADH_P15 (SEQ ID NO:330), wherein said first and second amino acid sequences are contiguous and in a sequential order.


Comparison report between HSECADH_P15 (SEQ ID NO:330) and CAD1_HUMAN:


1. An isolated chimeric polypeptide encoding for HSECADH_P15 (SEQ ID NO:330), comprising a first amino acid sequence being at least 90% homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYT corresponding to amino acids 1-229 of CAD1_HUMAN, which also corresponds to amino acids 1-229 of HSECADH_P15 (SEQ ID NO:330), and a second amino acid sequence VSIS corresponding to amino acids 230-233 of HSECADH_P15 (SEQ ID NO:330), wherein said first and second amino acid sequences are contiguous and in a sequential order.


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSECADH_P15 (SEQ ID NO:330) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 16, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSECADH_P15 (SEQ ID NO:330) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 16







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?





127
P -> T
No


141
T -> A
No









Variant protein HSECADH_P15 (SEQ ID NO:330) is encoded by the following transcript(s): HSECADH_T20 (SEQ ID NO:4), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSECADH_T20 (SEQ ID NO:4) is shown in bold; this coding portion starts at position 125 and ends at position 823. The transcript also has the following SNPs as listed in Table 17 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSECADH_P 15 (SEQ ID NO:330) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 17







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












71
G -> C
Yes


469
G -> A
Yes


503
C -> A
No


545
A -> G
No


955
G -> A
Yes









As noted above, cluster HSECADH features 30 segment(s), which were listed in Table 2 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.


Segment cluster HSECADH_node0 (SEQ ID NO:60) according to the present invention is supported by 17 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1) HSECADH_T18 (SEQ ID NO:2), HSECADH_T19 (SEQ ID NO:3) and HSECADH_T20 (SEQ ID NO:4). Table 18 below describes the starting and ending position of this segment on each transcript.









TABLE 18







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
1
166


HSECADH_T18 (SEQ ID NO:2)
1
166


HSECADH_T19 (SEQ ID NO:3)
1
166


HSECADH_T20 (SEQ ID NO:4)
1
166









Segment cluster HSECADH_node14 (SEQ ID NO:61) according to the present invention is supported by 40 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1), HSECADH_T18 (SEQ ID NO:2), HSECADH_T19 (SEQ ID NO:3) and HSECADH_T20 (SEQ ID NO:4). Table 19 below describes the starting and ending position of this segment on each transcript.









TABLE 19







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
656
811


HSECADH_T18 (SEQ ID NO:2)
656
811


HSECADH_T19 (SEQ ID NO:3)
656
811


HSECADH_T20 (SEQ ID NO:4)
656
811









Segment cluster HSECADH_node15 (SEQ ID NO:62) according to the present invention is supported by 1 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T20 (SEQ ID NO:4). Table 20 below describes the starting and ending position of this segment on each transcript.









TABLE 20







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T20 (SEQ ID NO:4)
812
970









Segment cluster HSECADH_node21 (SEQ ID NO:63) according to the present invention is supported by 40 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T18 (SEQ ID NO:2) and HSECADH_T19 (SEQ ID NO:3). Table 21 below describes the starting and ending position of this segment on each transcript.









TABLE 21







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T18 (SEQ ID NO:2)
957
1132


HSECADH_T19 (SEQ ID NO:3)
957
1132









Segment cluster HSECADH_node22 (SEQ ID NO:64) according to the present invention is supported by 1 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T19 (SEQ ID NO:3). Table 22 below describes the starting and ending position of this segment on each transcript.









TABLE 22







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T19 (SEQ ID NO:3)
1133
1269









Segment cluster HSECADH_node25 (SEQ ID NO:65) according to the present invention is supported by 34 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T18 (SEQ ID NO:2). Table 23 below describes the starting and ending position of this segment on each transcript.









TABLE 23







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T18 (SEQ ID NO:2)
1133
1261









Segment cluster HSECADH_node26 (SEQ ID NO:66) according to the present invention is supported by 1 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T18 (SEQ ID NO:2). Table 24 below describes the starting and ending position of this segment on each transcript.









TABLE 24







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T18 (SEQ ID NO:2)
1262
1584









Segment cluster HSECADH_node48 (SEQ ID NO:67) according to the present invention is supported by 44 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1). Table 25 below describes the starting and ending position of this segment on each transcript.









TABLE 25







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
1149
1292









Segment cluster HSECADH_node52 (SEQ ID NO:68) according to the present invention is supported by 39 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1). Table 26 below describes the starting and ending position of this segment on each transcript.









TABLE 26







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
1293
1449









Segment cluster HSECADH_node53 (SEQ ID NO:69) according to the present invention is supported by 59 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1). Table 27 below describes the starting and ending position of this segment on each transcript.









TABLE 27







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
1450
1933









Segment cluster HSECADH_node54 (SEQ ID NO:70) according to the present invention is supported by 44 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1). Table 28 below describes the starting and ending position of this segment on each transcript.









TABLE 28







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
1934
2053









Segment cluster HSECADH_node57 (SEQ ID NO:71) according to the present invention is supported by 67 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1). Table 29 below describes the starting and ending position of this segment on each transcript.









TABLE 29







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
2241
2430









Segment cluster HSECADH_node60 (SEQ ID NO:72) according to the present invention is supported by 260 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1). Table 30 below describes the starting and ending position of this segment on each transcript.









TABLE 30







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
2504
3096









Segment cluster HSECADH_node62 (SEQ ID NO:73) according to the present invention is supported by 173 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1). Table 31 below describes the starting and ending position of this segment on each transcript.









TABLE 31







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
3097
3245









Segment cluster HSECADH_node63 (SEQ ID NO:74) according to the present invention is supported by 162 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH T11 (SEQ ID NO:1). Table 32 below describes the starting and ending position of this segment on each transcript.









TABLE 32







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
3246
3544









Segment cluster HSECADH_node7 (SEQ ID NO:75) according to the present invention is supported by 21 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1), HSECADH_T18 (SEQ ID NO:2), HSECADH_T19 (SEQ ID NO:3) and HSECADH_T20 (SEQ ID NO:4). Table 33 below describes the starting and ending position of this segment on each transcript.









TABLE 33







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
288
511


HSECADH_T18 (SEQ ID NO:2)
288
511


HSECADH_T19 (SEQ ID NO:3)
288
511


HSECADH_T20 (SEQ ID NO:4)
288
511









According to an optional embodiment of the present invention, short segments related to the above cluster are also provided. These segments are up to about 120 bp in length, and so are included in a separate description.


Segment cluster HSECADH_node1 (SEQ ID NO:76) according to the present invention can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1), HSECADH_T18 (SEQ ID NO:2), HSECADH_T19 (SEQ ID NO:3) and HSECADH_T20 (SEQ ID NO:4). Table 34 below describes the starting and ending position of this segment on each transcript.









TABLE 34







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
167
172


HSECADH_T18 (SEQ ID NO:2)
167
172


HSECADH_T19 (SEQ ID NO:3)
167
172


HSECADH_T20 (SEQ ID NO:4)
167
172









Segment cluster HSECADH_node11 (SEQ ID NO:77) according to the present invention is supported by 23 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1), HSECADH_T18 (SEQ ID NO:2), HSECADH_T19 (SEQ ID NO:3) and HSECADH_T20 (SEQ ID NO:4). Table 35 below describes the starting and ending position of this segment on each transcript.









TABLE 35







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
512
592


HSECADH_T18 (SEQ ID NO:2)
512
592


HSECADH_T19 (SEQ ID NO:3)
512
592


HSECADH_T20 (SEQ ID NO:4)
512
592









Segment cluster HSECADH_node12 (SEQ ID NO:78) according to the present invention is supported by 26 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1), HSECADH_T18 (SEQ ID NO:2), HSECADH_T19 (SEQ ID NO:3) and HSECADH_T20 (SEQ ID NO:4). Table 36 below describes the starting and ending position of this segment on each transcript.









TABLE 36







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
593
655


HSECADH_T18 (SEQ ID NO:2)
593
655


HSECADH_T19 (SEQ ID NO:3)
593
655


HSECADH_T20 (SEQ ID NO:4)
593
655









Segment cluster HSECADH_node17 (SEQ ID NO:79) according to the present invention can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1), HSECADH_T18 (SEQ ID NO:2) and HSECADH_T19 (SEQ ID NO:3). Table 37 below describes the starting and ending position of this segment on each transcript.









TABLE 37







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
812
827


HSECADH_T18 (SEQ ID NO:2)
812
827


HSECADH_T19 (SEQ ID NO:3)
812
827









Segment cluster HSECADH_node18 (SEQ ID NO:80) according to the present invention is supported by 41 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1), HSECADH_T18 (SEQ ID NO:2) and HSECADH_T19 (SEQ ID NO:3). Table 38 below describes the starting and ending position of this segment on each transcript.









TABLE 38







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
828
944


HSECADH_T18 (SEQ ID NO:2)
828
944


HSECADH_T19 (SEQ ID NO:3)
828
944









Segment cluster HSECADH_node19 (SEQ ID NO:81) according to the present invention can be found in the following transcript(s): HSECADH_T18 (SEQ ID NO:2) and HSECADH_T19 (SEQ ID NO:3). Table 39 below describes the starting and ending position of this segment on each transcript.









TABLE 39







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T18 (SEQ ID NO:2)
945
956


HSECADH_T19 (SEQ ID NO:3)
945
956









Segment cluster HSECADH_node3 (SEQ ID NO:82) according to the present invention is supported by 18 libraries. The number of libraries was determined as previously described.


This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1), HSECADH_T18 (SEQ ID NO:2), HSECADH_T19 (SEQ ID NO:3) and HSECADH_T20 (SEQ ID NO:4). Table 40 below describes the starting and ending position of this segment on each transcript.









TABLE 40







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
173
287


HSECADH_T18 (SEQ ID NO:2)
173
287


HSECADH_T19 (SEQ ID NO:3)
173
287


HSECADH_T20 (SEQ ID NO:4)
173
287









Segment cluster HSECADH_node42 (SEQ ID NO:83) according to the present invention is supported by 43 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1). Table 41 below describes the starting and ending position of this segment on each transcript.









TABLE 41







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
945
1017









Segment cluster HSECADH_node45 (SEQ ID NO:84) according to the present invention is supported by 39 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1). Table 42 below describes the starting and ending position of this segment on each transcript.









TABLE 42







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
1018
1051









Segment cluster HSECADH_node46 (SEQ ID NO:85) according to the present invention is supported by 40 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1). Table 43 below describes the starting and ending position of this segment on each transcript.









TABLE 43







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
1052
1148









Segment cluster HSECADH_node55 (SEQ ID NO:86) according to the present invention is supported by 36 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1). Table 44 below describes the starting and ending position of this segment on each transcript.









TABLE 44







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
2054
2166









Segment cluster HSECADH_node56 (SEQ ID NO:87) according to the present invention is supported by 42 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1). Table 45 below describes the starting and ending position of this segment on each transcript.









TABLE 45







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
2167
2240









Segment cluster HSECADH_node58 (SEQ ID NO:88) according to the present invention is supported by 61 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1). Table 46 below describes the starting and ending position of this segment on each transcript.









TABLE 46







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
2431
2481









Segment cluster HSECADH_node59 (SEQ ID NO:89) according to the present invention can be found in the following transcript(s): HSECADH_T11 (SEQ ID NO:1). Table 47 below describes the starting and ending position of this segment on each transcript.









TABLE 47







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSECADH_T11 (SEQ ID NO:1)
2482
2503










Variant Protein Alignment to the Previously Known Protein:














Sequence name: /tmp/2x0I2XZlA3/JXvUszCm3O:Q9UII7


Sequence documentation:


Alignment of: HSECADH_P9 (SEQ ID NO:327) x Q9UII7 . . .


Alignment segment 1/1:








Quality:
2727.00


Escore:
0


Matching length:
274


Total length:
274


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0







Alignment:







embedded image









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Sequence name: /tmp/2x0I2XZlA3/JXvUszCm3O:Q9UII8


Sequence documentation:


Alignment of: HSECADH_P9 (SEQ ID NO:327) x Q9UII8 . . .


Alignment segment 1/1:








Quality:
2727.00


Escore:
0


Matching length:
274


Total length:
274


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0







Alignment:







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Sequence name: /tmp/2x0I2XZlA3/JXvUszCm3O:CAD1_HUMAN


Sequence documentation:


Alignment of: HSECADH_P9 (SEQ ID NO:327) x CAD1_HUMAN . . .


Alignment segment 1/1:








Quality:
2727.00


Escore:
0


Matching length:
274


Total length:
274


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0







Alignment:







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Sequence name: /tmp/e5Y8HiBmjB/iwyb1d8ikl:Q9UII7


Sequence documentation:


Alignment of: HSECADH_P13 (SEQ ID NO:328) x Q9UII7 . . .


Alignment segment 1/1:








Quality:
3720.00


Escore:
0


Matching length:
379


Total length:
379


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0







Alignment:







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Sequence name: /tmp/e5Y8HiBmjB/iwyb1d8ikl:Q9UII8


Sequence documentation:


Alignment of: HSECADH_P13 (SEQ ID NO:328) x Q9UII8 . . .


Alignment segment 1/1:








Quality:
3720.00


Escore:
0


Matching length:
379


Total length:
379


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0







Alignment:







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Sequence name: /tmp/e5Y8HiBmjB/iwyb1d8ikl:CAD1_HUMAN


Sequence documentation:


Alignment of: HSECADH_P13 (SEQ ID NO:328) x CAD1_HUMAN . . .


Alignment segment 1/1:








Quality:
3720.00


Escore:
0


Matching length:
379


Total length:
379


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0







Alignment:







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Sequence name: /tmp/RtiX8vFyZe/iovNeRHKWU:Q9UII7


Sequence documentation:


Alignment of: HSECADH_P14 (SEQ ID NO:329) x Q9UII7 . . .


Alignment segment 1/1:








Quality:
3313.00


Escore:
0


Matching length:
336


Total length:
336


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0







Alignment:







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Sequence name: /tmp/RtiX8vFyZe/iovNeRHKWU:Q9UII8


Sequence documentation:


Alignment of: HSECADH_P14 (SEQ ID NO:329) x Q9UII8 . . .


Alignment segment 1/1:








Quality:
3313.00


Escore:
0


Matching length:
336


Total length:
336


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0







Alignment:







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Sequence name: /tmp/RtiX8vFyZe/iovNeRHKWU:CAD1_HUMAN


Sequence documentation:


Alignment of: HSECADH_P14 (SEQ ID NO:329) x CAD1_HUMAN . . .


Alignment segment 1/1:








Quality:
3313.00


Escore:
0


Matching length:
336


Total length:
336


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0







Alignment:







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Sequence name: /tmp/rMRrwmuokD/1rmk2jOfgw:Q9UII7


Sequence documentation:


Alignment of: HSECADH_P15 (SEQ ID NO:330) x Q9UII7 . . .


Alignment segment 1/1:








Quality:
2289.00


Escore:
0


Matching length:
229


Total length:
229


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0







Alignment:







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Sequence name: /tmp/rMRrwmuokD/1rmk2jOfgw:Q9UII8


Sequence documentation:


Alignment of: HSECADH_P15 (SEQ ID NO:330) x Q9UII8 . . .


Alignment segment 1/1:








Quality:
2289.00


Escore:
0


Matching length:
229


Total length:
229


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0







Alignment:







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Sequence name: /tmp/rMRrwmuokD/1rmk2jOfgw:CAD1_HUMAN


Sequence documentation:


Alignment of: HSECADH_P15 (SEQ ID NO:330) x CAD1_HUMAN . . .


Alignment segment 1/1:








Quality:
2289.00


Escore:
0


Matching length:
229


Total length:
229


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0







Alignment:







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Description for Cluster R11723


Cluster R11723 features 6 transcript(s) and 26 segment(s) of interest, the names for which are given in Tables 48 and 49, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 50.









TABLE 48







Transcripts of interest










Transcript Name
Sequence ID No.














R11723_PEA_1_T15
5



R11723_PEA_1_T17
6



R11723_PEA_1_T19
7



R11723_PEA_1_T20
8



R11723_PEA_1_T5
9



R11723_PEA_1_T6
10

















TABLE 49







Segments of interest










Segment Name
Sequence ID No.














R11723_PEA_1_node_13
90



R11723_PEA_1_node_16
91



R11723_PEA_1_node_19
92



R11723_PEA_1_node_2
93



R11723_PEA_1_node_22
94



R11723_PEA_1_node_31
95



R11723_PEA_1_node_10
96



R11723_PEA_1_node_11
97



R11723_PEA_1_node_15
98



R11723_PEA_1_node_18
99



R11723_PEA_1_node_20
100



R11723_PEA_1_node_21
101



R11723_PEA_1_node_23
102



R11723_PEA_1_node_24
103



R11723_PEA_1_node_25
104



R11723_PEA_1_node_26
105



R11723_PEA_1_node_27
106



R11723_PEA_1_node_28
107



R11723_PEA_1_node_29
108



R11723_PEA_1_node_3
109



R11723_PEA_1_node_30
110



R11723_PEA_1_node_4
111



R11723_PEA_1_node_5
112



R11723_PEA_1_node_6
113



R11723_PEA_1_node_7
114



R11723_PEA_1_node_8
115

















TABLE 50







Proteins of interest










Protein Name
Sequence ID No.







R11723_PEA_1_P2
331



R11723_PEA_1_P6
332



R11723_PEA_1_P7
333



R11723_PEA_1_P13
334



R11723_PEA_1_P10
335










Cluster R11723 can be used as a diagnostic marker according to overexpression of transcripts of this cluster in cancer. Expression of such transcripts in normal tissues is also given according to the previously described methods. The term “number” in the right hand column of the table and the numbers on the y-axis of FIG. 7 refer to weighted expression of ESTs in each category, as “parts per million” (ratio of the expression of ESTs for a particular cluster to the expression of all ESTs in that category, according to parts per million).


Overall, the following results were obtained as shown with regard to the histograms in FIG. 7 and Table 51. This cluster is overexpressed (at least at a minimum level) in the following pathological conditions: epithelial malignant tumors, a mixture of malignant tumors from different tissues and kidney malignant tumors.









TABLE 51







Normal tissue distribution










Name of Tissue
Number














Adrenal
0



Brain
30



Epithelial
3



General
17



head and neck
0



Kidney
0



Lung
0



Breast
0



Ovary
0



Pancreas
10



Skin
0



Uterus
0

















TABLE 52







P values and ratios for expression in cancerous tissue













Name of Tissue
P1
P2
SP1
R3
SP2
R4





Adrenal
4.2e−01
4.6e−01
4.6e−01
2.2
5.3e−01
1.9


Brain
2.2e−01
2.0e−01
1.2e−02
2.8
5.0e−02
2.0


Epithelial
3.0e−05
6.3e−05
1.8e−05
6.3
3.4e−06
6.4


General
7.2e−03
4.0e−02
1.3e−04
2.1
1.1e−03
1.7


head and neck
1
5.0e−01
1
1.0
7.5e−01
1.3


Kidney
1.5e−01
2.4e−01
4.4e−03
5.4
2.8e−02
3.6


Lung
1.2e−01
1.6e−01
1
1.6
1
1.3


Breast
5.9e−01
4.4e−01
1
1.1
6.8e−01
1.5


Ovary
1.6e−02
1.3e−02
1.0e−01
3.8
7.0e−02
3.5


Pancreas
5.5e−01
2.0e−01
3.9e−01
1.9
1.4e−01
2.7


Skin
1
4.4e−01
1
1.0
1.9e−02
2.1


Uterus
1.5e−02
5.4e−02
1.9e−01
3.1
1.4e−01
2.5









As noted above, cluster R11723 features 6 transcript(s), which were listed in Table 48 above. A description of each variant protein according to the present invention is now provided.


Variant protein R11723_PEA1_P2 (SEQ ID NO:331) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) R11723_PEA1_T6 (SEQ ID NO:10). The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein R11723_PEA1_P2 (SEQ ID NO:331) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 53, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein R11723_PEA1_P2 (SEQ ID NO:331) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 53







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












107
H -> P
Yes


70
G -> 
No


70
G -> C
No









Variant protein R11723_PEA1_P2 (SEQ ID NO:331) is encoded by the following transcript(s): R11723_PEA1_T6 (SEQ ID NO:10), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript R11723_PEA1_T6 (SEQ ID NO:10) is shown in bold; this coding portion starts at position 1716 and ends at position 2051. The transcript also has the following SNPs as listed in Table 54 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein R11723_PEA1_P2 (SEQ ID NO:331) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 54







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?





1231
C -> T
Yes


1278
G -> C
Yes


1923
G -> 
No


1923
G -> T
No


2035
A -> C
Yes


2048
A -> C
No


2057
A -> G
Yes









Variant protein R11723_PEA1_P6 (SEQ ID NO:332) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) R11723_PEA1_T15 (SEQ ID NO:5). One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between R11723_PEA1_P6 (SEQ ID NO:332) and Q8IXM0 (SEQ ID NO:485):


1. An isolated chimeric polypeptide encoding for R11723_PEA1_P6 (SEQ ID NO:332), comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAGIMYRKSCASSAACLIASAGSPCRGLAPGREEQRALHKAGAVGGGVR (SEQ ID NO: 534) corresponding to amino acids 1-110 of R11723_PEA1_P6 (SEQ ID NO:332), and MYAQALLVVGVLQRQAAAQHLHEHPPKLLRGHRVQERVDDRAEVEKRLREGEEDHV RPEVGPRPVVLGFGRSHDPPNLVGHPAYGQCHNNQPWADTSRRERQRKEKHSMRTQ corresponding to amino acids 1-112 of Q8IXM0, which also corresponds to amino acids 111-222 of R11723_PEA1_P6 (SEQ ID NO:332), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a head of R11723_PEA1_P6 (SEQ ID NO:332), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAGIMYRKSCASSAACLIASAGSPCRGLAPGREEQRALHKAGAVGGGVR of (SEQ ID NO: 534) R11723_PEA1_P6 (SEQ ID NO:332).


Comparison report between R11723_PEA1_P6 (SEQ ID NO:332) and Q96AC2 (SEQ ID NO:486):


1. An isolated chimeric polypeptide encoding for R11723_PEA1_P6 (SEQ ID NO:332), comprising a first amino acid sequence being at least 90% homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAGIMYRKSCASSAACLIASAG corresponding to amino acids 1-83 of Q96AC2, which also corresponds to amino acids 1-83 of R11723_PEA1_P6 (SEQ ID NO:332), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLVVGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPVVLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ (SEQ ID NO: 535) corresponding to amino acids 84-222 of R11723_PEA1_P6 (SEQ ID NO:332), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of R11723_PEA1_P6 (SEQ ID NO:332), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLVVGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPVVLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ (SEQ ID NO: 535) in R11723_PEA1_P6 (SEQ ID NO:332).


Comparison report between R11723_PEA1_P6 (SEQ ID NO:332) and Q8N2G4 (SEQ ID NO:487):


1. An isolated chimeric polypeptide encoding for R11723_PEA1_P6 (SEQ ID NO:332), comprising a first amino acid sequence being at least 90% homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAGIMYRKSCASSAACLIASAG corresponding to amino acids 1-83 of Q8N2G4, which also corresponds to amino acids 1-83 of R11723_PEA1_P6 (SEQ ID NO:332), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLVVGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPVVLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ (SEQ ID NO: 535) corresponding to amino acids 84-222 of R11723_PEA1_P6 (SEQ ID NO:332), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of R11723_PEA1_P6 (SEQ ID NO:332), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLVVGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPVVLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ (SEQ ID NO: 535) in R11723_PEA1_P6 (SEQ ID NO:332).


Comparison report between R11723_PEA1_P6 (SEQ ID NO:332) and BAC85518 (SEQ ID NO:488):


1. An isolated chimeric polypeptide encoding for R11723_PEA1_P6 (SEQ ID NO:332), comprising a first amino acid sequence being at least 90% homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAGIMYRKSCASSAACLIASAG corresponding to amino acids 24-106 of BAC85518, which also corresponds to amino acids 1-83 of R11723_PEA1_P6 (SEQ ID NO:332), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLVVGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPVVLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ (SEQ ID NO: 535) corresponding to amino acids 84-222 of R11723_PEA1_P6 (SEQ ID NO:332), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of R11723_PEA1_P6 (SEQ ID NO:332), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLVVGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPVVLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ (SEQ ID NO: 535) in R11723_PEA1_P6 (SEQ ID NO:332).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein R11723_PEA1_P6 (SEQ ID NO:332) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 55, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein R11723_PEA1_P6 (SEQ ID NO:332) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 55







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?





180
G -> 
No


180
G -> C
No


217
H -> P
Yes









Variant protein R11723_PEA1_P6 (SEQ ID NO:332) is encoded by the following transcript(s): R11723_PEA1_T15 (SEQ ID NO:5), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript R11723_PEA1_T15 (SEQ ID NO:5) is shown in bold; this coding portion starts at position 434 and ends at position 1099. The transcript also has the following SNPs as listed in Table 56 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein R11723_PEA1_P6 (SEQ ID NO:332) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 56







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












971
G -> 
No


971
G -> T
No


1083
A -> C
Yes


1096
A -> C
No


1105
A -> G
Yes









Variant protein R11723_PEA1_P7 (SEQ ID NO:333) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) R11723_PEA1_T17 (SEQ ID NO:6). One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between R11723_PEA1_P7 (SEQ ID NO:333) and Q96AC2:


1. An isolated chimeric polypeptide encoding for R11723_PEA1_P7 (SEQ ID NO:333), comprising a first amino acid sequence being at least 90% homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAG corresponding to amino acids 1-64 of Q96AC2, which also corresponds to amino acids 1-64 of R11723_PEA1_P7 (SEQ ID NO:333), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT (SEQ ID NO: 536) corresponding to amino acids 65-93 of R11723_PEA1_P7 (SEQ ID NO:333), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of R11723_PEA1_P7 (SEQ ID NO:333), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT (SEQ ID NO: 536) in R11723_PEA1_P7 (SEQ ID NO:333).


Comparison report between R11723_PEA1_P7 (SEQ ID NO:333) and Q8N2G4:


1. An isolated chimeric polypeptide encoding for R11723_PEA1_P7 (SEQ ID NO:333), comprising a first amino acid sequence being at least 90% homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAG corresponding to amino acids 1-64 of Q8N2G4, which also corresponds to amino acids 1-64 of R11723_PEA1_P7 (SEQ ID NO:333), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT (SEQ ID NO: 536) corresponding to amino acids 65-93 of R11723_PEA1_P7 (SEQ ID NO:333), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of R11723_PEA1_P7 (SEQ ID NO:333), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT (SEQ ID NO: 536) in R11723_PEA1_P7 (SEQ ID NO:333).


Comparison report between R11723_PEA1_P7 (SEQ ID NO:333) and BAC85273 (SEQ ID NO:489):


1. An isolated chimeric polypeptide encoding for R11723_PEA1_P7 (SEQ ID NO:333), comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MWVLG (SEQ ID NO: 537) corresponding to amino acids 1-5 of R11723_PEA1_P7 (SEQ ID NO:333), second amino acid sequence being at least 90% homologous to IAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEVMEQSAG corresponding to amino acids 22-80 of BAC85273, which also corresponds to amino acids 6-64 of R11723_PEA1_P7 (SEQ ID NO:333), and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT (SEQ ID NO: 536) corresponding to amino acids 65-93 of R11723_PEA1_P7 (SEQ ID NO:333), wherein said first, second and third amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a head of R11723_PEA1_P7 (SEQ ID NO:333), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence MWVLG (SEQ ID NO: 537) of R11723_PEA1_P7 (SEQ ID NO:333).


3. An isolated polypeptide encoding for a tail of R11723_PEA1_P7 (SEQ ID NO:333), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT (SEQ ID NO: 536) in R11723_PEA1_P7 (SEQ ID NO:333).


Comparison report between R11723_PEA1_P7 (SEQ ID NO:333) and BAC85518:


1. An isolated chimeric polypeptide encoding for R11723_PEA1_P7 (SEQ ID NO:333), comprising a first amino acid sequence being at least 90% homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAG corresponding to amino acids 24-87 of BAC85518, which also corresponds to amino acids 1-64 of R11723_PEA1_P7 (SEQ ID NO:333), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT (SEQ ID NO: 536) corresponding to amino acids 65-93 of R11723_PEA1_P7 (SEQ ID NO:333), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of R11723_PEA1_P7 (SEQ ID NO:333), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT (SEQ ID NO: 536) in R11723_PEA1_P7 (SEQ ID NO:333).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein R11723_PEA1_P7 (SEQ ID NO:333) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 57, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein R11723_PEA1_P7 (SEQ ID NO:333) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 57







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?





67
C -> S
Yes









Variant protein R11723_PEA1_P7 (SEQ ID NO:333) is encoded by the following transcript(s): R11723_PEA1_T17 (SEQ ID NO:6), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript R11723_PEA1_T17 (SEQ ID NO:6) is shown in bold; this coding portion starts at position 434 and ends at position 712. The transcript also has the following SNPs as listed in Table 58 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein R11723_PEA1_P7 (SEQ ID NO:333) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 58







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












625
G -> T
Yes


633
G -> C
Yes


1303
C -> T
Yes









Variant protein R11723_PEA1_P13 (SEQ ID NO:334) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) R11723_PEA1_T19 (SEQ ID NO:7) and R11723_PEA1_T5 (SEQ ID NO:9). One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between R11723_PEA1_P13 (SEQ ID NO:334) and Q96AC2:


1. An isolated chimeric polypeptide encoding for R11723_PEA1_P13 (SEQ ID NO:334), comprising a first amino acid sequence being at least 90% homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSA corresponding to amino acids 1-63 of Q96AC2, which also corresponds to amino acids 1-63 of R11723_PEA1_P13 (SEQ ID NO:334), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence DTKRTNTLLFEMRHFAKQLTT (SEQ ID NO: 538) corresponding to amino acids 64-84 of R11723_PEA1_P13 (SEQ ID NO:334), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of R11723_PEA1_P13 (SEQ ID NO:334), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DTKRTNTLLFEMRHFAKQLTT (SEQ ID NO: 538) in R11723_PEA1_P13 (SEQ ID NO:334).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein R11723_PEA1_P13 (SEQ ID NO:334) is encoded by the following transcript(s): R11723_PEA1_T19 (SEQ ID NO:7), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript R11723_PEA1_T19 (SEQ ID NO:7) is shown in bold; this coding portion starts at position 434 and ends at position 685. The transcript also has the following SNPs as listed in Table 59 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein R11723_PEA1_P13 (SEQ ID NO:334) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 59







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












778
G -> T
Yes


786
G -> C
Yes


1456
C -> T
Yes









Variant protein R11723_PEA1_P10 (SEQ ID NO:335) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) R11723_PEA1_T20 (SEQ ID NO:8). One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between R11723_PEA—1_P10 (SEQ ID NO:335) and Q96AC2:


1. An isolated chimeric polypeptide encoding for R 11723_PEA1_P10 (SEQ ID NO:335), comprising a first amino acid sequence being at least 90% homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSA corresponding to amino acids 1-63 of Q96AC2, which also corresponds to amino acids 1-63 of R11723_PEA1_P10 (SEQ ID NO:335), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK (SEQ ID NO: 539) corresponding to amino acids 64-90 of R11723_PEA1_P10 (SEQ ID NO:335), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of R11723_PEA1_P10 (SEQ ID NO:335), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK (SEQ ID NO: 539) in R11723_PEA1_P10 (SEQ ID NO:335).


Comparison report between R11723_PEA1_P10 (SEQ ID NO:335) and Q8N2G4:


1. An isolated chimeric polypeptide encoding for R11723_PEA1_P10 (SEQ ID NO:335), comprising a first amino acid sequence being at least 90% homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSA corresponding to amino acids 1-63 of Q8N2G4, which also corresponds to amino acids 1-63 of R11723_PEA1_P10 (SEQ ID NO:335), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK (SEQ ID NO: 539) corresponding to amino acids 64-90 of R11723_PEA1_P10 (SEQ ID NO:335), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of R11723_PEA1_P10 (SEQ ID NO:335), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK (SEQ ID NO: 539) in R11723_PEA1_P10(SEQ ID NO:335).


Comparison report between R11723_PEA1_P10 (SEQ ID NO:335) and BAC85273:


1. An isolated chimeric polypeptide encoding for R11723_PEA1_P10 (SEQ ID NO:335), comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MWVLG (SEQ ID NO: 537) corresponding to amino acids 1-5 of R11723_PEA1_P10 (SEQ ID NO:335), second amino acid sequence being at least 90% homologous to IAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEVMEQSA corresponding to amino acids 22-79 of BAC85273, which also corresponds to amino acids 6-63 of R11723_PEA1_P10 (SEQ ID NO:335), and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK (SEQ ID NO: 539) corresponding to amino acids 64-90 of R11723_PEA1_P10 (SEQ ID NO:335), wherein said first, second and third amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a head of R11723_PEA1_P10 (SEQ ID NO:335), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence MWVLG (SEQ ID NO: 537) of R11723_PEA1_P10 (SEQ ID NO:335).


3. An isolated polypeptide encoding for a tail of R11723_PEA1_P10 (SEQ ID NO:335), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK (SEQ ID NO: 539) in R11723_PEA_1_P10 (SEQ ID NO:335).


Comparison report between R11723_PEA1_P10 (SEQ ID NO:335) and BAC85518:


1. An isolated chimeric polypeptide encoding for R11723_PEA1_P10 (SEQ ID NO:335) comprising a first amino acid sequence being at least 90% homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSA corresponding to amino acids 24-86 of BAC85518, which also corresponds to amino acids 1-63 of R11723_PEA1_P10 (SEQ ID NO:335), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK (SEQ ID NO: 539) corresponding to amino acids 64-90 of R11723_PEA1_P10 (SEQ ID NO:335), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of R11723_PEA1_P10 (SEQ ID NO:335), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK (SEQ ID NO: 539) in R11723_PEA1_P10 (SEQ ID NO:335).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein R11723_PEA_L_P10 (SEQ ID NO:335) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 60, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein R11723_PEA1_P10 (SEQ ID NO:335) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 60







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?





66
V -> F
Yes









Variant protein R11723_PEA1_P10 (SEQ ID NO:335) is encoded by the following transcript(s): R11723_PEA1_T20 (SEQ ID NO:8), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript R11723_PEA1_T20 (SEQ ID NO:8) is shown in bold; this coding portion starts at position 434 and ends at position 703. The transcript also has the following SNPs as listed in Table 61 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein R11723_PEA1_P10 (SEQ ID NO:335) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 61







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












629
G -> T
Yes


637
G -> C
Yes


1307
C -> T
Yes









As noted above, cluster R11723 features 26 segment(s), which were listed in Table 49 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.


Segment cluster R11723_PEA1_node13 (SEQ ID NO:90) according to the present invention is supported by 5 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T19 (SEQ ID NO:7), R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 62 below describes the starting and ending position of this segment on each transcript.









TABLE 62







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T19 (SEQ
624
776


ID NO:7)


R11723_PEA_1_T5 (SEQ ID
624
776


NO:9)


R11723_PEA_1_T6 (SEQ ID
658
810


NO:10)









Segment cluster R11723_PEA1_node16 (SEQ ID NO:91) according to the present invention is supported by 3 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T17 (SEQ ID NO:6), R11723_PEA1_T19 (SEQ ID NO:7) and R11723_PEA1_T20 (SEQ ID NO:8). Table 63 below describes the starting and ending position of this segment on each transcript.









TABLE 63







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T17 (SEQ
624
1367


ID NO:6)


R11723_PEA_1_T19 (SEQ
777
1520


ID NO:7)


R11723_PEA_1_T20 (SEQ
628
1371


ID NO:8)









Segment cluster R11723_PEA1_node19 (SEQ ID NO:92) according to the present invention is supported by 45 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 64 below describes the starting and ending position of this segment on each transcript.









TABLE 64







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T5 (SEQ ID
835
1008


NO:9)


R11723_PEA_1_T6 (SEQ ID
869
1042


NO:10)









Segment cluster R11723_PEA1_node2 (SEQ ID NO:93) according to the present invention is supported by 29 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T15 (SEQ ID NO:5), R11723_PEA1_T17 (SEQ ID NO:6), R11723_PEA1_T19 (SEQ ID NO:7), R11723_PEA1_T20 (SEQ ID NO:8), R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 65 below describes the starting and ending position of this segment on each transcript.









TABLE 65







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T15 (SEQ
1
309


ID NO:5)


R11723_PEA_1_T17 (SEQ
1
309


ID NO:6)


R11723_PEA_1_T19 (SEQ
1
309


ID NO:7)


R11723_PEA_1_T20 (SEQ
1
309


ID NO:8)


R11723_PEA_1_T5 (SEQ ID
1
309


NO:9)


R11723_PEA_1_T6 (SEQ ID
1
309


NO:10)









Segment cluster R11723_PEA1_node22 (SEQ ID NO:94) according to the present invention is supported by 65 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 66 below describes the starting and ending position of this segment on each transcript.









TABLE 66







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T5 (SEQ ID
1083
1569


NO:9)


R11723_PEA_1_T6 (SEQ ID
1117
1603


NO:10)









Segment cluster R11723_PEA1_node31 (SEQ ID NO:95) according to the present invention is supported by 70 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_T15 (SEQ ID NO:5), R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 67 below describes the starting and ending position of this segment on each transcript (it should be noted that these transcripts show alternative polyadenylation).









TABLE 67







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T15 (SEQ
1060
1295


ID NO:5)


R11723_PEA_1_T5 (SEQ ID
1978
2213


NO:9)


R11723_PEA_1_T6 (SEQ ID
2012
2247


NO:10)









According to an optional embodiment of the present invention, short segments related to the above cluster are also provided. These segments are up to about 120 bp in length, and so are included in a separate description.


Segment cluster R11723_PEA1_node10 (SEQ ID NO:96) according to the present invention is supported by 38 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T15 (SEQ ID NO:5), R11723_PEA1_T17 (SEQ ID NO:6), R11723_PEA1_T19 (SEQ ID NO:7), R11723_PEA1_T20 (SEQ ID NO:8), R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 68 below describes the starting and ending position of this segment on each transcript.









TABLE 68







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T15 (SEQ
486
529


ID NO:5)


R11723_PEA_1_T17 (SEQ
486
529


ID NO:6)


R11723_PEA_1_T19 (SEQ
486
529


ID NO:7)


R11723_PEA_1_T20 (SEQ
486
529


ID NO:8)


R11723_PEA_1_T5 (SEQ ID
486
529


NO:9)


R11723_PEA_1_T6 (SEQ ID
520
563


NO:10)









Segment cluster R11723_PEA1_node11 (SEQ ID NO:97) according to the present invention is supported by 42 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T15 (SEQ ID NO:5), R11723_PEA1_T17 (SEQ ID NO:6), R11723_PEA1_T19 (SEQ ID NO:7), R11723_PEA1_T20 (SEQ ID NO:8), R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 69 below describes the starting and ending position of this segment on each transcript.









TABLE 69







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T15 (SEQ
530
623


ID NO:5)


R11723_PEA_1_T17 (SEQ
530
623


ID NO:6)


R11723_PEA_1_T19 (SEQ
530
623


ID NO:7)


R11723_PEA_1_T20 (SEQ
530
623


ID NO:8)


R11723_PEA_1_T5 (SEQ ID
530
623


NO:9)


R11723_PEA_1_T6 (SEQ ID
564
657


NO:10)









Segment cluster R11723_PEA1_node15 (SEQ ID NO:98) according to the present invention can be found in the following transcript(s): R11723_PEA1_T20 (SEQ ID NO:8) Table 70 below describes the starting and ending position of this segment on each transcript.









TABLE 70







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T20 (SEQ
624
627


ID NO:8)









Segment cluster R11723_PEA1_node18 (SEQ ID NO:99) according to the present invention is supported by 40 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T15 (SEQ ID NO:5), R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 71 below describes the starting and ending position of this segment on each transcript.









TABLE 72







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T15 (SEQ
624
681


ID NO:5)


R11723_PEA_1_T5 (SEQ ID
777
834


NO:9)


R11723_PEA_1_T6 (SEQ ID
811
868


NO:10)









Segment cluster R11723_PEA1_node20 (SEQ ID NO:100) according to the present invention can be found in the following transcript(s): R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 73 below describes the starting and ending position of this segment on each transcript.









TABLE 73







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T5 (SEQ ID
1009
1019


NO:9)


R11723_PEA_1_T6 (SEQ ID
1043
1053


NO:10)









Segment cluster R11723_PEA1_node21 (SEQ ID NO:101) according to the present invention is supported by 36 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 74 below describes the starting and ending position of this segment on each transcript.









TABLE 74







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T5 (SEQ ID
1020
1082


NO:9)


R11723_PEA_1_T6 (SEQ ID
1054
1116


NO:10)









Segment cluster R11723_PEA1_node23 (SEQ ID NO:102) according to the present invention is supported by 39 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 75 below describes the starting and ending position of this segment on each transcript.









TABLE 75







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T5 (SEQ ID
1570
1599


NO:9)


R11723_PEA_1_T6 (SEQ ID
1604
1633


NO:10)









Segment cluster R11723_PEA1_node24 (SEQ ID NO:103) according to the present invention is supported by 51 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T15 (SEQ ID NO:51, R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1T6 (SEQ ID NO:10). Table 76 below describes the starting and ending position of this segment on each transcript.









TABLE 76







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












R11723_PEA_1_T15 (SEQ
682
765


ID NO:5)


R11723_PEA_1_T5 (SEQ ID
1600
1683


NO:9)


R11723_PEA_1_T6 (SEQ ID
1634
1717


NO:10)









Segment cluster R11723_PEA1_node25 (SEQ ID NO:104) according to the present invention is supported by 54 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T15 (SEQ ID NO:5), R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 77 below describes the starting and ending position of this segment on each transcript.









TABLE 77







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












R11723_PEA_1_T15 (SEQ
766
791


ID NO:5)


R11723_PEA_1_T5 (SEQ ID
1684
1709


NO:9)


R11723_PEA_1_T6 (SEQ ID
1718
1743


NO:10)









Segment cluster R11723_PEA1_node26 (SEQ ID NO:105) according to the present invention is supported by 62 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T15 (SEQ ID NO:5), R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 78 below describes the starting and ending position of this segment on each transcript.









TABLE 78







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












R11723_PEA_1_T15 (SEQ
792
904


ID NO:5)


R11723_PEA_1_T5 (SEQ ID
1710
1822


NO:9)


R11723_PEA_1_T6 (SEQ ID
1744
1856


NO:10)









Segment cluster R11723_PEA1_node27 (SEQ ID NO:106) according to the present invention is supported by 67 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T15 (SEQ ID NO:5), R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 79 below describes the starting and ending position of this segment on each transcript.









TABLE 79







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












R11723_PEA_1_T15 (SEQ
905
986


ID NO:5)


R11723_PEA_1_T5 (SEQ ID
1823
1904


NO:9)


R11723_PEA_1_T6 (SEQ ID
1857
1938


NO:10)









Segment cluster R11723_PEA1_node28 (SEQ ID NO:107) according to the present invention can be found in the following transcript(s): R11723_PEA1_T15 (SEQ ID NO:5), R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 80 below describes the starting and ending position of this segment on each transcript.









TABLE 80







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












R11723_PEA_1_T15 (SEQ
987
1010


ID NO:5)


R11723_PEA_1_T5 (SEQ ID
1905
1928


NO:9)


R11723_PEA_1_T6 (SEQ ID
1939
1962


NO:10)









Segment cluster R11723_PEA1_node29 (SEQ ID NO:108) according to the present invention is supported by 69 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T15 (SEQ ID NO:5), R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 81 below describes the starting and ending position of this segment on each transcript.









TABLE 81







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T15 (SEQ
1011
1038


ID NO:5)


R11723_PEA_1_T5 (SEQ ID
1929
1956


NO:9)


R11723_PEA_1_T6 (SEQ ID
1963
1990


NO:10)









Segment cluster R11723_PEA1_node3 (SEQ ID NO:109) according to the present invention can be found in the following transcript(s): R11723_PEA1_T15 (SEQ ID NO:5), R11723_PEA1_T17 (SEQ ID NO:6), R11723_PEA1_T19 (SEQ ID NO:7), R11723_PEA1_T20 (SEQ ID NO:8), R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 82 below describes the starting and ending position of this segment on each transcript.









TABLE 82







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T15 (SEQ
310
319


ID NO:5)


R11723_PEA_1_T17 (SEQ
310
319


ID NO:6)


R11723_PEA_1_T19 (SEQ
310
319


ID NO:7)


R11723_PEA_1_T20 (SEQ
310
319


ID NO:8)


R11723_PEA_1_T5 (SEQ ID
310
319


NO:9)


R11723_PEA_1_T6 (SEQ ID
310
319


NO:10)









Segment cluster R11723_PEA1_node30 (SEQ ID NO:110) according to the present invention can be found in the following transcript(s): R11723_PEA1_T15 (SEQ ID NO:5), R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 83 below describes the starting and ending position of this segment on each transcript.









TABLE 83







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T15 (SEQ
1039
1059


ID NO:5)


R11723_PEA_1_T5 (SEQ ID
1957
1977


NO:9)


R11723_PEA_1_T6 (SEQ ID
1991
2011


NO:10)









Segment cluster R11723_PEA1_node4 (SEQ ID NO:111) according to the present invention is supported by 25 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T15 (SEQ ID NO:5), R11723_PEA1_T17 (SEQ ID NO:6), R11723_PEA1_T19 (SEQ ID NO:7), R11723_PEA1_T20 (SEQ ID NO:8), R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 84 below describes the starting and ending position of this segment on each transcript.









TABLE 84







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T15 (SEQ
320
371


ID NO:5)


R11723_PEA_1_T17 (SEQ
320
371


ID NO:6)


R11723_PEA_1_T19 (SEQ
320
371


ID NO:7)


R11723_PEA_1_T20 (SEQ
320
371


ID NO:8)


R11723_PEA_1_T5 (SEQ ID
320
371


NO:9)


R11723_PEA_1_T6 (SEQ ID
320
371


NO:10)









Segment cluster R11723_PEA1_node5 (SEQ ID NO:112) according to the present invention is supported by 26 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T15 (SEQ ID NO:5), R11723_PEA1_T17 (SEQ ID NO:6), R11723_PEA1_T19 (SEQ ID NO:7), R11723_PEA1_T20 (SEQ ID NO:8), R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 84 below describes the starting and ending position of this segment on each transcript.









TABLE 85







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T15 (SEQ
372
414


ID NO:5)


R11723_PEA_1_T17 (SEQ
372
414


ID NO:6)


R11723_PEA_1_T19 (SEQ
372
414


ID NO:7)


R11723_PEA_1_T20 (SEQ
372
414


ID NO:8)


R11723_PEA_1_T5 (SEQ ID
372
414


NO:9)


R11723_PEA_1_T6 (SEQ ID
372
414


NO:10)









Segment cluster R11723_PEA1_node6 (SEQ ID NO:113) according to the present invention is supported by 27 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T15 (SEQ ID NO:5), R11723_PEA1_T17 (SEQ ID NO:6), R11723_PEA1_T19 (SEQ ID NO:7), R11723_PEA1_T20 (SEQ ID NO:8), R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 86 below describes the starting and ending position of this segment on each transcript.









TABLE 86







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T15 (SEQ
415
446


ID NO:5)


R11723_PEA_1_T17 (SEQ
415
446


ID NO:6)


R11723_PEA_1_T19 (SEQ
415
446


ID NO:7)


R11723_PEA_1_T20 (SEQ
415
446


ID NO:8)


R11723_PEA_1_T5 (SEQ ID
415
446


NO:9)


R11723_PEA_1_T6 (SEQ ID
415
446


NO:10)









Segment cluster R11723_PEA1_node7 (SEQ ID NO:114) according to the present invention is supported by 29 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T15 (SEQ ID NO:5), R11723_PEA1_T17 (SEQ ID NO:6), R11723_PEA1_T19 (SEQ ID NO:7), R11723_PEA1_T20 (SEQ ID NO:8), R11723_PEA1_T5 (SEQ ID NO:9) and R11723_PEA1_T6 (SEQ ID NO:10). Table 87 below describes the starting and ending position of this segment on each transcript.









TABLE 87







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T15 (SEQ
447
485


ID NO:5)


R11723_PEA_1_T17 (SEQ
447
485


ID NO:6)


R11723_PEA_1_T19 (SEQ
447
485


ID NO:7)


R11723_PEA_1_T20 (SEQ
447
485


ID NO:8)


R11723_PEA_1_T5 (SEQ ID
447
485


NO:9)


R11723_PEA_1_T6 (SEQ ID
447
485


NO:10)









Segment cluster R11723_PEA1_node8 (SEQ ID NO:115) according to the present invention is supported by 2 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA1_T6 (SEQ ID NO:10). Table 88 below describes the starting and ending position of this segment on each transcript.









TABLE 88







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





R11723_PEA_1_T6 (SEQ ID
486
519


NO:10)









It should be noted that the variants of this cluster are variants of the hypothetical protein PSEC0181 (referred to herein as “PSEC”). Furthermore, use of the known protein (WT protein) for detection of ovarian cancer, alone or in combination with one or more variants of this cluster and/or of any other cluster and/or of any known marker, also comprises an embodiment of the present invention. It should be noted that the nucleotide transcript sequence of known protein (PSEC, also referred to herein as the “wild type” or WT protein) features at least one SNP that appears to affect the coding region, in addition to certain silent SNPs. This SNP does not have an effect on the R11723_PEA1_T5 (SEQ ID NO:9) splice variant sequence): “G->” resulting in a missing nucleotide (affects amino acids from position 91 onwards). The missing nucleotide creates a frame shift, resulting in a new protein. This SNP was not previously identified and is supported by 5 ESTs out of ˜70 ESTs in this exon.


Variant Protein Alignment to the Previously Known Protein:














Sequence name: /tmp/gp6eQTLWqk/mFtjUpUzhb:Q8IXM0


Sequence documentation:


Alignment of: R11723_PEA_1_P6 (SEQ ID NO:332) x Q8IXM0 . . .


Alignment segment 1/1:








Quality:
1128.00


Escore:
0


Matching length:
112


Total length:
112


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0










Alignment:




embedded image









embedded image









embedded image







Sequence name: /tmp/gp6eQTLWqk/mFtjUpUzhb:Q96AC2


Sequence documentation:


Alignment of: R11723_PEA_1_P6 (SEQ ID NO:332) x Q96AC2 . . .


Alignment segment 1/1:








Quality:
835.00


Escore:
0


Matching length:
83


Total length:
83


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0










Alignment:




embedded image









embedded image







Sequence name: /tmp/gp6eQTLWqk/mFtjUpUzhb:Q8N2G4


Sequence documentation:


Alignment of: R11723_PEA_1_P6 (SEQ ID NO:332) x Q8N2G4 . . .


Alignment segment 1/1:








Quality:
835.00


Escore:
0


Matching length:
83


Total length:
83


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0










Alignment:




embedded image









embedded image







Sequence name: /tmp/gp6eQTLWqk/mFtjUpUzhb:BAC85518


Sequence documentation:


Alignment of: R11723_PEA_1_P6 (SEQ ID NO:332) x BAC85518 . . .


Alignment segment 1/1:








Quality:
835.00


Escore:
0


Matching length:
83


Total length:
83


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0










Alignment:




embedded image









embedded image







Sequence name: /tmp/VXjdFlzdBX/bexTxTh0Th:Q96AC2


Sequence documentation:


Alignment of: R11723_PEA_1_P7 (SEQ ID NO:333) x Q96AC2 . . .


Alignment segment 1/1:








Quality:
654.00


Escore:
0


Matching length:
64


Total length:
64


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0










Alignment:




embedded image









embedded image







Sequence name: /tmp/VXjdFlzdBX/bexTxTh0Th:Q8N2G4


Sequence documentation:


Alignment of: R11723_PEA_1_P7 (SEQ ID NO:333) x Q8N2G4 . . .


Alignment segment 1/1:








Quality:
654.00


Escore:
0


Matching length:
64


Total length:
64


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0










Alignment:




embedded image









embedded image







Sequence name: /tmp/VXjdFlzdBX/bexTxTh0Th:BAC85273


Sequence documentation:


Alignment of: R11723_PEA_1_P7 (SEQ ID NO:333) x BAC85273 . . .


Alignment segment 1/1:








Quality:
600.00


Escore:
0


Matching length:
59


Total length:
59


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0










Alignment:




embedded image









embedded image







Sequence name: /tmp/VXjdFlzdBX/bexTxTh0Th:BAC85518


Sequence documentation:


Alignment of: R11723_PEA_1_P7 (SEQ ID NO:333) x BAC85518 . . .


Alignment segment 1/1:








Quality:
654.00


Escore:
0


Matching length:
64


Total length:
64


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0










Alignment:




embedded image









embedded image







Sequence name: /tmp/OLMSexEmIh/pc7Z7Xm1YR:Q96AC2


Sequence documentation:


Alignment of: R11723_PEA_1_P10 (SEQ ID NO:335) x Q96AC2 . . .


Alignment segment 1/1:








Quality:
645.00


Escore:
0


Matching length:
63


Total length:
63


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0










Alignment:




embedded image









embedded image







Sequence name: /tmp/OLMSexEmIh/pc7Z7Xm1YR:Q8N2G4


Sequence documentation:


Alignment of: R11723_PEA_1_P10 (SEQ ID NO:335) x Q8N2G4 . . .


Alignment segment 1/1:








Quality:
645.00


Escore:
0


Matching length:
63


Total length:
63


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0










Alignment:




embedded image









embedded image







Sequence name: /tmp/OLMSexEmIh/pc7Z7Xm1YR:BAC85273


Sequence documentation:


Alignment of: R11723_PEA_1_P10 (SEQ ID NO:335) x BAC85273 . . .


Alignment segment 1/1:








Quality:
591.00


Escore:
0


Matching length:
58


Total length:
58


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0










Alignment:




embedded image









embedded image







Sequence name: /tmp/OLMSexEmIh/pc7Z7Xm1YR:BAC85518


Sequence documentation:


Alignment of: R11723_PEA_1_P10 (SEQ ID NO:335) x BAC85518 . . .


Alignment segment 1/1:








Quality:
645.00


Escore:
0


Matching length:
63


Total length:
63


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0










Alignment:




embedded image









embedded image







Alignment of: R11723_PEA_1_P13 (SEQ ID NO:334) x Q96AC2 . . .


Alignment segment 1/1:








Quality:
645.00


Escore:
0


Matching length:
63


Total length:
63


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0










Alignment:




embedded image









embedded image












Expression of R11723 Transcripts Which are Detectable by Amplicon as Depicted in Sequence Name R11723 seg13 in Normal and Cancerous Prostate Tissues


Expression of transcripts detectable by or according to seg13, R11732seg13 (SEQ ID NO:492) amplicon_(s) and R11732seg13F (SEQ ID NO:490) and R11732seg13R (SEQ ID NO:491) primers was measured by real time PCR. In parallel the expression of four housekeeping genes—PBGD (GenBank Accession No. BC019323 (SEQ ID NO:509); amplicon—PBGD-amplicon, HPRT1 (GenBank Accession No. NM000194 (SEQ ID NO:510); amplicon—HPRT1-amplicon (SEQ ID NO:401), SDHA (GenBank Accession No. NM004168 (SEQ ID NO:508); amplicon—SDHA-, RPL19 (GenBank Accession No. NM000981 (SEQ ID NO:511); RPL19 amplicon (SEQ ID NO:410) was measured similarly. For each RT sample, the expression of the above amplicon was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal post-mortem (PM) samples (Sample Nos. 42,48-53,59-63, Table 1 above, “Tissue samples in testing panel”), to obtain a value of fold up-regulation for each sample relative to median of the normal PM samples.



FIG. 8 is a histogram showing over expression of the above-indicated transcripts in cancerous prostate samples relative to the normal samples. Values represent the average of duplicate experiments. Error bars indicate the minimal and maximal values obtained).


As is evident from FIG. 8, the expression of transcripts detectable by the above amplicon in cancer samples was higher than in the non-cancerous samples (Sample Nos. 42,48-53,59-63, Table 1 above, “Tissue samples in testing panel”). Notably an over-expression of at least 5 fold was found in 4 out of 19 adenocarcinoma samples


Statistical analysis was applied to verify the significance of these results, as described below.


The P value for the difference in the expression levels of transcripts detectable by the above amplicon_(s) in prostate cancer samples versus the normal tissue samples was determined by T test as 7.57E-02.


The above values demonstrate statistical significance of the results. Primer pairs are also optionally and preferably encompassed within the present invention; for example, for the above experiment, the following primer pair was used as a non-limiting illustrative example only of a suitable primer pair: R11732seg13F forward primer (SEQ ID NO:490); and R 11732seg13R reverse primer (SEQ ID NO:491).


The present invention also preferably encompasses any amplicon obtained through the use of any suitable primer pair; for example, for the above experiment, the following amplicon was obtained as a non-limiting illustrative example only of a suitable amplicon_: R11732seg13 (SEQ ID NO:492)










R11732seg13F (SEQ ID NO: 490)-



ACACTAAAAGAACAAACACCTTGCTC





R11732seg13R (SEQ ID NO: 491)-


TCCTCAGAAGGCACATGAAAGA





R11732seg13 (SEQ ID NO: 492) (SEQ ID NO: 492)-


ACACTAAAAGAACAAACACCTTGCTCTTCGAGATGAGACATTTTGCCAAG





CAGTTGACCACTTAGTTCTCAAGAAGCAACTATCTCTTTCATGTGCCTTC





TGAGGA






Expression of R11723 Transcripts Which are Detectable by Amplicon_as Depicted in Sequence Name R11723seg13 (SEQ ID NO:492) in Different Normal Tissues


Expression of R11723 transcripts detectable by or according to R 11723seg13 (SEQ ID NO:492) amplicon and R11723seg13F (SEQ ID NO:490), R11723seg13R (SEQ ID NO:491) was measured by real time PCR. In parallel the expression of four housekeeping genes: RPL19 (GenBank Accession No. NM000981 (SEQ ID NO:511); RPL19 amplicon (SEQ ID NO:410), TATA box (GenBank Accession No. NM003194 (SEQ ID NO:512); TATA amplicon (SEQ ID NO:515), Ubiquitin (GenBank Accession No. BC000449 (SEQ ID NO:516); amplicon_-Ubiquitin-amplicon (SEQ ID NO:519)) and SDHA (GenBank Accession No. NM004168 (SEQ ID NO:508); amplicon—SDHA-amplicon was measured similarly. For each RT sample, the expression of the above amplicon_was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the ovary samples (Sample Nos. 18-20 Table 2 “Tissue samples in normal panel”, above), to obtain a value of relative expression of each sample relative to median of the ovary samples. Primers and amplicon are as above.


The results are presented in FIG. 9, demonstrating the expression of R11723 transcripts which are detectable by amplicon as depicted in sequence name R11723seg13 (SEQ ID NO:492) in different normal tissues.


Expression of R11723 Transcripts, Which are Detectable by Amplicon as Depicted in Sequence Name R11723junc11-18 (SEQ ID NO:495) in Normal and Cancerous Prostate Tissues.


Expression of transcripts detectable by or according to junc11-18 R11732junc11-18 amplicon (SEQ ID NO:495) and R11732junc11-18F (SEQ ID NO:493) and R11732junc11-18R (SEQ ID NO:494) primers was measured by real time PCR (this junction is found in the known protein sequence or “wild type” (WT) sequence, also termed herein the PSEC sequence). In parallel the expression of four housekeeping genes—PBGD (GenBank Accession No. BC019323 (SEQ ID NO:509); amplicon=—PBGD-amplicon (SEQ ID NO:404)), HPRT1 (GenBank Accession No. NM000194 (SEQ ID NO:510); amplicon_—HPRT1-amplicon (SEQ ID NO:401)), SDHA (GenBank Accession No. NM004168 (SEQ ID NO:508); amplicon—SDHA-amplicon, and RPL19 (GenBank Accession No. NM000981 (SEQ ID NO:511); RPL19 amplicon (SEQ ID NO:410) was measured similarly. For each RT sample, the expression of the above amplicon was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal post-mortem (PM) samples (Sample Nos. 42,48-53,59-63 Table 1, above “Tissue samples in prostate cancer testing panel”), to obtain a value of fold up-regulation for each sample relative to median of the normal PM samples.



FIG. 10A is a histogram showing over expression of the above-indicated transcripts in cancerous prostate samples relative to the normal samples.


As is evident from FIG. 10A, the expression of transcripts detectable by the above amplicon in a few cancer samples was higher than in the non-cancerous samples (Sample Nos. 42, 48-53, 59-63, Table 1, above: “Tissue samples in prostate cancer testing panel”). Notably an over-expression of at least 5 fold was found in 2 out of 19 adenocarcinoma samples


Primer pairs are also optionally and preferably encompassed within the present invention; for example, for the above experiment, the following primer pair was used as a non-limiting illustrative example only of a suitable primer pair: R11732junc11-18F forward primer (SEQ ID NO:493); and R11732 junc11-18R reverse primer (SEQ ID NO:494).


The present invention also preferably encompasses any amplicon obtained through the use of any suitable primer pair; for example, for the above experiment, the following amplicon was obtained as a non-limiting illustrative example only of a suitable amplicon: R11732 junc11-18 (SEQ ID NO:495)










R11723junc11-18F (SEQ ID NO: 493) -



AGTGATGGAGCAAAGTGCCG





R11723junc11-18R (SEQ ID NO: 494)-


CAGCAGCTGATGCAAACTGAG





R11723junc11-18 (SEQ ID NO: 495)-


AGTGATGGAGCAAAGTGCCGGGATCATGTACCGCAAGTCCTGTGCATCAT





CAGCGGCCTGTCTCATCGCCTCTGCCGGGTACCAGTCCTTCTGCTCCCCA





GGGAAACTGAACTCAGTTTGCATCAGCTGCTG






Expression of R11723 Transcripts, Which Were Detected by Amplicon_As Depicted in the Sequence Name R11723 junc11-18 (SEQ ID NO:495) in Different Normal Tissues.


Expression of R11723 transcripts detectable by or according to R11723seg13 amplicon (SEQ ID NO:495) and R11723junc11-18F (SEQ ID NO:493), R11723junc11-18R (SEQ ID NO:494) was measured by real time PCR. In parallel the expression of four housekeeping genes RPL19 (GenBank Accession No. NM000981 (SEQ ID NO:511); RPL19 amplicon (SEQ ID NO:410), TATA box (GenBank Accession No. NM003194 (SEQ ID NO:512); TATA amplicon (SEQ ID NO:515), UBC (GenBank Accession No. BC000449 (SEQ ID NO:516); amplicon—Ubiquitin-amplicon (SEQ ID NO:519) and SDHA (GenBank Accession No. NM004168 (SEQ ID NO:508); amplicon_—SDHA-amplicon (SEQ ID NO:407) was measured similarly. For each RT sample, the expression of the above amplicon_was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the ovary samples (Sample Nos. 18-20, Table 2, “Tissue samples in normal panel”, above), to obtain a value of relative expression of each sample relative to median of the ovary samples. Results are shown in FIG. 10B; primers and amplicon are as above.


The expression of variant transcripts relating to the R11723 cluster (also known as PSEC) was found to be similar to that of the WT (known or wild type) protein; however in some cancers, expression of one or more variant transcripts was found to be higher (R11723_T5 for example in certain tissues).


Description for Cluster S78694


Cluster S78694 features 1 transcript(s) and 14 segment(s) of interest, the names for which are given in Tables 89 and 90, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 91.









TABLE 89







Transcripts of interest










Transcript Name
Sequence ID No.







S78694_T7
11

















TABLE 90







Segments of interest










Segment Name
Sequence ID No.







S78694_node_0
116



S78694_node_10
117



S78694_node_12
118



S78694_node_19
119



S78694_node_21
120



S78694_node_4
121



S78694_node_1
122



S78694_node_14
123



S78694_node_16
124



S78694_node_17
125



S78694_node_2
126



S78694_node_20
127



S78694_node_3
128



S78694_node_7
129

















TABLE 91







Proteins of interest










Protein Name
Sequence ID No.







S78694_P3
336










These sequences are variants of the known protein Protein-lysine 6-oxidase precursor (SEQ ID NO:385) (SwissProt accession identifier LYOX_HUMAN (SEQ ID NO 385):; known also according to the synonyms EC 1.4.3.13; Lysyl oxidase), SEQ ID NO: 385, referred to herein as the previously known protein.


Protein Protein-lysine 6-oxidase precursor (SEQ ID NO:385) is known or believed to have the following function(s): Responsible for the posttranslational oxidative deamination of peptidyl lysine residues in precursors to fibrous collagen and elastin. In addition to cross-linking of extracellular matrix proteins, may have a direct role in tumor suppression. The sequence for protein Protein-lysine 6-oxidase precursor (SEQ ID NO:385) is given at the end of the application, as “Protein-lysine 6-oxidase precursor (SEQ ID NO:385) amino acid sequence”. Known polymorphisms for this sequence are as shown in Table 92.









TABLE 92







Amino acid mutations for Known Protein










SNP position(s) on




amino acid sequence
Comment












158
R -> Q (in dbSNP: 1800449).



/FTId = VAR_004282.


102
A -> G


137
A -> R


139
A -> P


304-305
YD -> LY


315
V -> W









Protein Protein-lysine 6-oxidase precursor (SEQ ID NO:385) localization is believed to be Extracellular.


The following GO Annotation(s) apply to the previously known protein. The following annotation(s) were found: protein modification, which are annotation(s) related to Biological Process; protein-lysine 6-oxidase; copper binding; oxidoreductase, which are annotation(s) related to Molecular Function; and extracellular matrix, which are annotation(s) related to Cellular Component.


The GO assignment relies on information from one or more of the SwissProt/TremB1 Protein knowledgebase, available from expasydot ch/sprot/; or Locuslink, available from ncbidot nlmdot nihdot gov/projects/LocusLink/.


As noted above, cluster S78694 features 1 transcript(s), which were listed in Table 89 above. These transcript(s) encode for protein(s) which are variant(s) of protein Protein-lysine 6-oxidase precursor (SEQ ID NO:385). A description of each variant protein according to the present invention is now provided.


Variant protein S78694_P3 (SEQ ID NO:336) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) S78694_T7 (SEQ ID NO:11). An alignment is given to the known protein (Protein-lysine 6-oxidase precursor (SEQ ID NO:385) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between S78694_P3 (SEQ ID NO:336) and LYOX_HUMAN:


1. An isolated chimeric polypeptide encoding for S78694_P3 (SEQ ID NO:336) comprising a first amino acid sequence being at least 90% homologous to MRFAWTVLLLGPLQLCALVHCAPPAAGQQQPPREPPAAPGAWRQQIQWENNGQVFSL LSLGSQYQPQRRRDPGAAVPGAANASAQQPRTPILLIRDNRTAAARTRTAGSSGVTAGR PRPTARHWFQAGYSTSRAREAGASRAENQTAPGEVPALSNLRPPSRVDGMVGDDPYNP YKYSDDNPYYNYYDTYERPRPGGRYRPGYGTGYFQYGLPDLVADPYYIQASTYVQKM SMYNLRCAAEENCLAS corresponding to amino acids 1-247 of LYOX_HUMAN, which also corresponds to amino acids 1-247 of S78694_P3 (SEQ ID NO:336), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence IQGRCQRL (SEQ ID NO: 541) corresponding to amino acids 248-255 of S78694_P3 (SEQ ID NO:336), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of S78694_P3 (SEQ ID NO:336) comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence IQGRCQRL (SEQ ID NO: 541) in S78694_P3 (SEQ ID NO:336).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein S78694_P3 (SEQ ID NO:336) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 93, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein S78694_P3 (SEQ ID NO:336) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 93







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












137
A -> P
Yes


145
Q -> R
No


158
R -> Q
Yes


7
V -> A
No









Variant protein S78694_P3 (SEQ ID NO:336) is encoded by the following transcript(s): S78694_T7 (SEQ ID NO:11), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript S78694_T7 (SEQ ID NO:11) is shown in bold; this coding portion starts at position 381 and ends at position 1145. The transcript also has the following SNPs as listed in Table 94 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein S78694_P3 (SEQ ID NO:336) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 94







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












83
A -> 
No


138
C -> G
Yes


3221
T -> A
Yes


3222
T -> G
Yes


3401
C -> G
Yes


3406
T -> C
Yes


191
C -> 
No


400
T -> C
No


605
C -> G
Yes


789
G -> C
Yes


814
A -> G
No


853
G -> A
Yes


1193
G -> A
Yes


1194
G -> A
Yes









As noted above, cluster S78694 features 14 segment(s), which were listed in Table 90 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.


Segment cluster S78694_node0 (SEQ ID NO:116) according to the present invention is supported by 49 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7 (SEQ ID NO:11). Table 94 below describes the starting and ending position of this segment on each transcript.









TABLE 94







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





S78694_T7 (SEQ ID NO:11)
1
609









Segment cluster S78694_node10 (SEQ ID NO:117) according to the present invention is supported by 54 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7 (SEQ ID NO:11). Table 95 below describes the starting and ending position of this segment on each transcript.









TABLE 95







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





S78694_T7 (SEQ ID NO:11)
1121
1253









Segment cluster S78694_node12 (SEQ ID NO:118) according to the present invention is supported by 57 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7 (SEQ ID NO:11). Table 96 below describes the starting and ending position of this segment on each transcript.









TABLE 96







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





S78694_T7 (SEQ ID NO:11)
1254
1410









Segment cluster S78694_node19 (SEQ ID NO:119) according to the present invention is supported by 151 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7 (SEQ ID NO:11). Table 97 below describes the starting and ending position of this segment on each transcript.









TABLE 97







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





S78694_T7 (SEQ ID NO:11)
1623
3620









Segment cluster S78694_node21 (SEQ ID NO:120) according to the present invention is supported by 89 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7 (SEQ ID NO:11). Table 98 below describes the starting and ending position of this segment on each transcript.









TABLE 98







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





S78694_T7 (SEQ ID NO:11)
3629
3866









Segment cluster S78694_node4 (SEQ ID NO:121) according to the present invention is supported by 48 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7 (SEQ ID NO:11). Table 99 below describes the starting and ending position of this segment on each transcript.









TABLE 99







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





S78694_T7 (SEQ ID NO:11)
740
1011









According to an optional embodiment of the present invention, short segments related to the above cluster are also provided. These segments are up to about 120 bp in length, and so are included in a separate description.


Segment cluster S78694_node1 (SEQ ID NO:122) according to the present invention is supported by 39 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7 (SEQ ID NO:11). Table 100 below describes the starting and ending position of this segment on each transcript.









TABLE 100







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





S78694_T7 (SEQ ID NO:11)
610
668









Segment cluster S78694_node14 (SEQ ID NO:123) according to the present invention is supported by 51 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7 (SEQ ID NO:11). Table 101 below describes the starting and ending position of this segment on each transcript.









TABLE 101







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





S78694_T7 (SEQ ID NO:11)
1411
1506









Segment cluster S78694_node16 (SEQ ID NO:124) according to the present invention can be found in the following transcript(s): S78694_T7 (SEQ ID NO:11). Table 102 below describes the starting and ending position of this segment on each transcript.









TABLE 102







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





S78694_T7 (SEQ ID NO:11)
1507
1530









Segment cluster S78694_node17 (SEQ ID NO:125) according to the present invention is supported by 45 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7 (SEQ ID NO:11). Table 103 below describes the starting and ending position of this segment on each transcript.









TABLE 103







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












S78694_T7 (SEQ ID NO:11)
1531
1622









Segment cluster S78694_node2 (SEQ ID NO:126) according to the present invention can be found in the following transcript(s): S78694_T7 (SEQ ID NO:11). Table 104 below describes the starting and ending position of this segment on each transcript.









TABLE 104







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





S78694_T7 (SEQ ID NO:11)
669
676









Segment cluster S78694_node20 (SEQ ID NO:127) according to the present invention can be found in the following transcript(s): S78694_T7 (SEQ ID NO:1). Table 105 below describes the starting and ending position of this segment on each transcript.









TABLE 105







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





S78694_T7 (SEQ ID NO:11)
3621
3628









Segment cluster S78694_node3 (SEQ ID NO:128) according to the present invention is supported by 38 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7 (SEQ ID NO:11). Table 106 below describes the starting and ending position of this segment on each transcript.









TABLE 106







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





S78694_T7 (SEQ ID NO:11)
677
739









Segment cluster S78694_node7 (SEQ ID NO:129) according to the present invention is supported by 37 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7 (SEQ ID NO:11). Table 107 below describes the starting and ending position of this segment on each transcript.









TABLE 107







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





S78694_T7 (SEQ ID NO:11)
1012
1120










Variant Protein Alignment to the Previously Known Protein:














Sequence name: /tmp/Z5Xt1z65PJ/KPuD7VdmQ2:LYOX_HUMAN


Sequence documentation:


Alignment of: S78694_P3 (SEQ ID NO:336) x LYOX_HUMAN . . .


Alignment segment 1/1:








Quality:
2477.00


Escore:
0


Matching length:
247


Total length:
247


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0










Alignment:




embedded image









embedded image









embedded image









embedded image









embedded image












Description for Cluster W60282


Cluster W60282 features 1 transcript(s) and 6 segment(s) of interest, the names for which are given in Tables 108 and 109, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 110.









TABLE 108







Transcripts of interest










Transcript Name
Sequence ID No.







W60282_PEA_1_T11
12

















TABLE 109







Segments of interest










Segment Name
Sequence ID No.







W60282_PEA_1_node_10
130



W60282_PEA_1_node_18
131



W60282_PEA_1_node_22
132



W60282_PEA_1_node_5
133



W60282_PEA_1_node_21
134



W60282_PEA_1_node_8
135

















TABLE 110







Proteins of interest










Protein Name
Sequence ID No.







W60282_PEA_1_P14
337










These sequences are variants of the known protein Kallikrein 11 precursor (SEQ ID NO:386) (SwissProt accession identifier KLKB_HUMAN (SEQ ID NO: 386); known also according to the synonyms EC 3.4.21.-; Hippostasin; Trypsin-like protease), SEQ ID NO: 386, referred to herein as the previously known protein.


Protein Kallikrein 11 precursor (SEQ ID NO:386) is known or believed to have the following function(s): Possible multifunctional protease. Efficiently cleaves bz-Phe-Arg-4-methylcoumaryl-7-amide, a kallikrein substrate, and weakly cleaves other substrates for kallikrein and trypsin. The sequence for protein Kallikrein 11 precursor (SEQ ID NO:386) is given at the end of the application, as “Kallikrein 11 precursor (SEQ ID NO:386) amino acid sequence”. Protein Kallikrein 11 precursor (SEQ ID NO:386) localization is believed to be Secreted.


The following GO Annotation(s) apply to the previously known protein. The following annotation(s) were found: proteolysis and peptidolysis, which are annotation(s) related to Biological Process; and chymotrypsin; trypsin; serine-type peptidase; hydrolase, which are annotation(s) related to Molecular Function.


The GO assignment relies on information from one or more of the SwissProt/TremB1 Protein knowledgebase, available from expasydot ch/sprot/; or Locuslink, available from ncbidot nlmdot nihdot gov/projects/LocusLink/.


As noted above, cluster W60282 features 1 transcript(s), which were listed in Table 108 above. These transcript(s) encode for protein(s) which are variant(s) of protein Kallikrein 11 precursor (SEQ ID NO:386). A description of each variant protein according to the present invention is now provided.


Variant protein W60282_PEA1_P14 (SEQ ID NO:337) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) W60282_PEA1_T 11 (SEQ ID NO:12). An alignment is given to the known protein (Kallikrein 11 precursor (SEQ ID NO:386) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between W60282_PEA1_P14 (SEQ ID NO:337) and Q8IXD7 (SEQ ID NO:496):


1. An isolated chimeric polypeptide encoding for W60282_PEA1_P14 (SEQ ID NO:337), comprising a first amino acid sequence being at least 90% homologous to MRILQLILLALATGLVGGETRIIKGFECKPHSQPWQAALFEKTRLLCGATLIAPRWLLTA AHCLKP corresponding to amino acids 1-66 of Q81XD7, which also corresponds to amino acids 1-66 of W60282_PEA1_P14 (SEQ ID NO:337), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence TPASHLAMRQHHHH (SEQ ID NO: 542) corresponding to amino acids 67-80 of W60282_PEA1_P14 (SEQ ID NO:337), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of W60282_PEA1_P14 (SEQ ID NO:337), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TPASHLAMRQHHHH (SEQ ID NO: 542) in W60282_PEA1_P14 (SEQ ID NO:337).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein W60282_PEA1_P14 (SEQ ID NO:337) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 111, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein W60282_PEA1_P14 (SEQ ID NO:337) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 111







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?





17
G -> E
Yes


41
E -> K
No









Variant protein W60282_PEA1_P14 (SEQ ID NO:337) is encoded by the following transcript(s): W60282_PEA1_T 11 (SEQ ID NO:12), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript W60282_PEA1_T 11 (SEQ ID NO:12) is shown in bold; this coding portion starts at position 705 and ends at position 944. The transcript also has the following SNPs as listed in Table 112 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein W60282_PEA1_P14 (SEQ ID NO:337) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 112







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












219
A -> G
Yes


702
G -> A
Yes


754
G -> A
Yes


825
G -> A
No


1289
A -> G
Yes









As noted above, cluster W60282 features 6 segment(s), which were listed in Table 109 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.


Segment cluster W60282_PEA1_node10 (SEQ ID NO:130) according to the present invention is supported by 45 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): W60282_PEA1_T11 (SEQ ID NO:12). Table 113 below describes the starting and ending position of this segment on each transcript.









TABLE 113







Segment location on transcripts










Segment
Segment




ending


Transcript name
starting position
ending position





W60282_PEA_1_T11 (SEQ
745
901


ID NO:12)









Segment cluster W60282_PEA1_node18 (SEQ ID NO:131) according to the present invention is supported by 49 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): W60282_PEA1_T 11 (SEQ ID NO:12). Table 114 below describes the starting and ending position of this segment on each transcript.









TABLE 114







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





W60282_PEA_1_T11 (SEQ
902
1038


ID NO:12)









Segment cluster W60282_PEA1_node22 (SEQ ID NO:132) according to the present invention is supported by 67 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): W60282_PEA1_T 1 (SEQ ID NO:12). Table 115 below describes the starting and ending position of this segment on each transcript.









TABLE 115







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





W60282_PEA_1_T11 (SEQ
1072
1507


ID NO:12)









Segment cluster W60282_PEA1_node5 (SEQ ID NO:133) according to the present invention is supported by 20 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): W60282_PEA1_T 1 (SEQ ID NO:12). Table 116 below describes the starting and ending position of this segment on each transcript.









TABLE 116







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





W60282_PEA_1_T11 (SEQ
1
669


ID NO:12)









According to an optional embodiment of the present invention, short segments related to the above cluster are also provided. These segments are up to about 120 bp in length, and so are included in a separate description.


Segment cluster W60282_PEA1_node21 (SEQ ID NO:134) according to the present invention is supported by 48 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): W60282_PEA1_T 1 (SEQ ID NO:12). Table 117 below describes the starting and ending position of this segment on each transcript.









TABLE 117







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





W60282_PEA_1_T11 (SEQ
1039
1071


ID NO:12)









Segment cluster W60282_PEA1_node8 (SEQ ID NO:135) according to the present invention is supported by 39 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): W60282_PEA1_T 11 (SEQ ID NO:12). Table 118 below describes the starting and ending position of this segment on each transcript.









TABLE 118







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





W60282_PEA_1_T11 (SEQ
670
744


ID NO:12)










Variant Protein Alignment to the Previously Known Protein:














Sequence name: /tmp/rL7Wdc5hYg/eLOAfKIgqD:KLKB_HUMAN


Sequence documentation:


Alignment of: W60282_PEA_1_P14 (SEQ ID NO:337) x KLKB_HUMAN . . .


Alignment segment 1/1:








Quality:
645.00


Escore:
0


Matching length:
72


Total length:
72


Matching Percent Similarity:
94.44


Matching Percent Identity:
94.44


Total Percent Similarity:
94.44


Total Percent Identity:
94.44


Gaps:
0










Alignment:




embedded image









embedded image







Sequence name: /tmp/rL7Wdc5hYg/eLOAfKIgqD:Q8IXD7


Sequence documentation:


Alignment of: W60282_PEA_1_P14 (SEQ ID NO:337) x Q8IXD7 . . .


Alignment segment 1/1:








Quality:
642.00


Escore:
0


Matching length:
66


Total length:
66


Matching Percent Similarity:
100.00


Matching Percent Identity:
100.00


Total Percent Similarity:
100.00


Total Percent Identity:
100.00


Gaps:
0










Alignment:




embedded image









embedded image












Description for Cluster HUMTREFAC


Cluster HUMTREFAC features 2 transcript(s) and 7 segment(s) of interest, the names for which are given in Tables 119 and 120, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 121.









TABLE 119







Transcripts of interest










Transcript Name
Sequence ID No.







HUMTREFAC_PEA_2_T4
13



HUMTREFAC_PEA_2_T5
14

















TABLE 120







Segments of interest










Segment Name
Sequence ID No.







HUMTREFAC_PEA_2_node_0
136



HUMTREFAC_PEA_2_node_9
137



HUMTREFAC_PEA_2_node_2
138



HUMTREFAC_PEA_2_node_3
139



HUMTREFAC_PEA_2_node_4
140



HUMTREFAC_PEA_2_node_5
141



HUMTREFAC_PEA_2_node_8
142

















TABLE 121







Proteins of interest










Sequence



Protein Name
ID No.
Corresponding Transcript(s)





HUMTREFAC_PEA_2_P7
338
HUMTREFAC_PEA_2_T5




(SEQ ID NO:14)


HUMTREFAC_PEA_2_P8
339
HUMTREFAC_PEA_2_T4




(SEQ ID NO:13)









These sequences are variants of the known protein Trefoil factor 3 precursor (SEQ ID NO:387) (SwissProt accession identifier TFF3_HUMAN (SEQ ID NO 387); known also according to the synonyms Intestinal trefoil factor; hP1.B), SEQ ID NO: 387, referred to herein as the previously known protein.


Protein Trefoil factor 3 precursor (SEQ ID NO:387) is known or believed to have the following function(s): May have a role in promoting cell migration (motogen). The sequence for protein Trefoil factor 3 precursor (SEQ ID NO:387) is given at the end of the application, as “Trefoil factor 3 precursor (SEQ ID NO:387) amino acid sequence”. Known polymorphisms for this sequence are as shown in Table 122.









TABLE 122







Amino acid mutations for Known Protein








SNP position(s) on



amino acid sequence
Comment





74–76
QEA -> TRKT









Protein Trefoil factor 3 precursor (SEQ ID NO:387) localization is believed to be Secreted.


The following GO Annotation(s) apply to the previously known protein. The following annotation(s) were found: defense response; digestion, which are annotation(s) related to Biological Process; and extracellular, which are annotation(s) related to Cellular Component.


The GO assignment relies on information from one or more of the SwissProt/TremB1 Protein knowledgebase, available from expasydot ch/sprot/; or Locuslink, available from ncbidot nlmdot nihdot gov/projects/LocusLink/.


Cluster HUMTREFAC can be used as a diagnostic marker according to overexpression of transcripts of this cluster in cancer. Expression of such transcripts in normal tissues is also given according to the previously described methods. The term “number” in the left hand column of the table and the numbers on the y-axis of FIG. 11 refer to weighted expression of ESTs in each category, as “parts per million” (ratio of the expression of ESTs for a particular cluster to the expression of all ESTs in that category, according to parts per million).


Overall, the following results were obtained as shown with regard to the histograms in FIG. 11 and Table 123. This cluster is overexpressed (at least at a minimum level) in the following pathological conditions: a mixture of malignant tumors from different tissues, breast malignant tumors, pancreas carcinoma and prostate cancer.









TABLE 123







Normal tissue distribution










Name of Tissue
Number














Adrenal
40



Colon
797



Epithelial
95



General
39



Liver
0



Lung
57



Lymph nodes
3



Breast
0



Muscle
3



Pancreas
2



Prostate
16



Stomach
0



Thyroid
257



Uterus
54

















TABLE 124







P values and ratios for expression in cancerous tissue













Name of Tissue
P1
P2
SP1
R3
SP2
R4
















Adrenal
6.4e−01
6.9e−01
7.1e−01
1.1
7.8e−01
0.9


Colon
4.6e−01
5.7e−01
9.7e−01
0.5
1
0.4


Epithelial
2.4e−02
3.4e−01
9.5e−10
2.0
5.3e−02
1.1


General
2.5e−04
3.9e−02
1.4e−28
3.6
1.9e−10
1.9


Liver
1
6.8e−01
1
1.0
6.9e−01
1.4


Lung
4.8e−01
7.6e−01
2.2e−03
1.0
1.6e−01
0.5


Lymph nodes
5.1e−01
8.0e−01
2.3e−02
5.0
1.9e−01
2.1


Breast
7.6e−02
1.2e−01
3.1e−06
12.0
1.1e−03
6.5


Muscle
9.2e−01
4.8e−01
1
0.8
3.9e−01
2.1


Pancreas
1.2e−01
2.4e−01
5.7e−03
6.5
2.1e−02
4.6


Prostate
1.5e−01
2.7e−01
9.9e−10
8.1
3.1e−07
5.7


Stomach
3.0e−01
1.3e−01
5.0e−01
2.0
6.7e−02
2.8


Thyroid
6.4e−01
6.4e−01
9.6e−01
0.5
9.6e−01
0.5


Uterus
4.1e−01
7.3e−01
7.5e−02
1.3
4.0e−01
0.8









As noted above, cluster HUMTREFAC features 2 transcript(s), which were listed in Table 119 above. These transcript(s) encode for protein(s) which are variant(s) of protein Trefoil factor 3 precursor (SEQ ID NO:387). A description of each variant protein according to the present invention is now provided.


Variant protein HUMTREFAC_PEA2_P7 (SEQ ID NO:338) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HUMTREFAC_PEA2_T5 (SEQ ID NO:14). The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HUMTREFAC_PEA2_P7 (SEQ ID NO:338) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 125, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMTREFAC_PEA2_P7 (SEQ ID NO:338) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 125







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












5
A -> S
No


5
A -> T
No


14
A -> V
Yes


43
L -> M
No


60
P -> S
Yes


123
S -> *
Yes









Variant protein HUMTREFAC_PEA2_P7 (SEQ ID NO:338) is encoded by the following transcript(s): HUMTREFAC_PEA2_T5 (SEQ ID NO:14), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HUMTREFAC_PEA2_T5 (SEQ ID NO:14) is shown in bold; this coding portion starts at position 278 and ends at position 688. The transcript also has the following SNPs as listed in Table 126 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMTREFAC_PEA2_P7 (SEQ ID NO:338) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 126







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?





233
A -> G
Yes


290
G -> A
No


290
G -> T
No


318
C -> T
Yes


404
C -> A
No


404
C -> T
No


455
C -> T
Yes


645
C -> A
Yes


685
C -> T
No









Variant protein HUMTREFAC_PEA2_P8 (SEQ ID NO:339) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HUMTREFAC_PEA2_T4 (SEQ ID NO:13). An alignment is given to the known protein (Trefoil factor 3 precursor (SEQ ID NO:387)) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HUMTREFAC_PEA2_P8 (SEQ ID NO:339) and TFF3_HUMAN:


1. An isolated chimeric polypeptide encoding for HUMTREFAC_PEA2_P8 (SEQ ID NO:339), comprising a first amino acid sequence being at least 90% homologous to MAARALCMLGLVLALLSSSSAEEYVGL corresponding to amino acids 1-27 of TFF3_HUMAN, which also corresponds to amino acids 1-27 of HUMTREFAC_PEA2_P8 (SEQ ID NO:339), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence WKVHLPKGEGFSSG (SEQ ID NO: 543) corresponding to amino acids 28-41 of HUMTREFAC_PEA2_P8 (SEQ ID NO:339), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HUMTREFAC_PEA2_P8 (SEQ ID NO:339), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence WKVHLPKGEGFSSG (SEQ ID NO: 543) in HUMTREFAC_PEA2_P8 (SEQ ID NO:339).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HUMTREFAC_PEA2_P8 (SEQ ID NO:339) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 127, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMTREFAC_PEA2_P8 (SEQ ID NO:339) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 127







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












5
A -> S
No


5
A -> T
No


14
A -> V
Yes









Variant protein HUMTREFAC_PEA2_P8 (SEQ ID NO:339) is encoded by the following transcript(s): HUMTREFAC_PEA2_T4 (SEQ ID NO:13), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HUMTREFAC_PEA2_T4 (SEQ ID NO:13) is shown in bold; this coding portion starts at position 278 and ends at position 400. The transcript also has the following SNPs as listed in Table 128 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMTREFAC_PEA2_P8 (SEQ ID NO:339) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 128







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












233
A -> G
Yes


290
G -> A
No


290
G -> T
No


318
C -> T
Yes


515
C -> A
No


515
C -> T
No


566
C -> T
Yes


756
C -> A
Yes


796
C -> T
No


1265
A -> C
No


1266
A -> T
No









As noted above, cluster HUMTREFAC features 7 segment(s), which were listed in Table 2 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.


Segment cluster HUMTREFAC_PEA2_node0 (SEQ ID NO:136) according to the present invention is supported by 188 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMTREFAC_PEA2_T4 (SEQ ID NO:13) and HUMTREFAC_PEA2_T5 (SEQ ID NO:14) Table 129 below describes the starting and ending position of this segment on each transcript.









TABLE 129







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMTREFAC_PEA_2_T4
1
359


(SEQ ID NO:13)


HUMTREFAC_PEA_2_T5
1
359


(SEQ ID NO:14)









Segment cluster HUMTREFAC_PEA2_node9 (SEQ ID NO:137) according to the present invention is supported by 150 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMTREFAC_PEA2_T4 (SEQ ID NO:13) and HUMTREFAC_PEA2_T5 (SEQ ID NO:14) Table 130 below describes the starting and ending position of this segment on each transcript.









TABLE 130







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMTREFAC_PEA_2_T4
681
1266


(SEQ ID NO:13)


HUMTREFAC_PEA_2_T5
570
747


(SEQ ID NO:14)









According to an optional embodiment of the present invention, short segments related to the above cluster are also provided. These segments are up to about 120 bp in length, and so are included in a separate description.


Segment cluster HUMTREFAC_PEA2_node2 (SEQ ID NO:138) according to the present invention is supported by 4 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMTREFAC_PEA2_T4 (SEQ ID NO:13). Table 131 below describes the starting and ending position of this segment on each transcript.









TABLE 131







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMTREFAC_PEA_2_T4
360
470


(SEQ ID NO:13)









Segment cluster HUMTREFAC_PEA2_node3 (SEQ ID NO:139) according to the present invention is supported by 10 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMTREFAC_PEA2_T4 (SEQ ID NO:13) and HUMTREFAC_PEA2_T5 (SEQ ID NO:14) Table 132 below describes the starting and ending position of this segment on each transcript.









TABLE 132







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMTREFAC_PEA_2_T4
471
514


(SEQ ID NO:13)


HUMTREFAC_PEA_2_T5
360
403


(SEQ ID NO:14)









Segment cluster HUMTREFAC_PEA2_node4 (SEQ ID NO:140) according to the present invention is supported by 197 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMTREFAC_PEA2_T4 (SEQ ID NO:13) and HUMTREFAC_PEA2_T5 (SEQ ID NO:14) Table 133 below describes the starting and ending position of this segment on each transcript.









TABLE 133







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMTREFAC_PEA_2_T4
515
611


(SEQ ID NO:13)


HUMTREFAC_PEA_2_T5
404
500


(SEQ ID NO:14)









Segment cluster HUMTREFAC_PEA2_node5 (SEQ ID NO:141) according to the present invention is supported by 187 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMTREFAC_PEA2_T4 (SEQ ID NO:13) and HUMTREFAC_PEA2_T5 (SEQ ID NO:14) Table 134 below describes the starting and ending position of this segment on each transcript.









TABLE 134







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMTREFAC_PEA_2_T4
612
661


(SEQ ID NO:13)


HUMTREFAC_PEA_2_T5
501
550


(SEQ ID NO:14)









Segment cluster HUMTREFAC_PEA2_node8 (SEQ ID NO:142) according to the present invention can be found in the following transcript(s): HUMTREFAC_PEA2_T4 (SEQ ID NO:13) and HUMTREFAC_PEA2_T5 (SEQ ID NO:14). Table 135 below describes the starting and ending position of this segment on each transcript.









TABLE 135







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HUMTREFAC_PEA_2_T4 (SEQ
662
680


ID NO:13)


HUMTREFAC_PEA_2_T5 (SEQ
551
569


ID NO:14)










Variant Protein Alignment to the Previously Known Protein:

















Sequence name: TFF3_HUMAN



Sequence documentation:



Alignment of: HUMTREFAC_PEA_2_P8



(SEQ ID NO:339) x TFF3_HUMAN . . .



Alignment segment 1/1:










Quality:
246.00



Escore:
0



Matching length:
27



Total length:
27



Matching Percent Similarity:
100.00



Matching Percent Identity:
100.00



Total Percent Similarity:
100.00



Total Percent Identity:
100.00



Gaps:
0













Alignment:





embedded image













Description for Cluster HSCOC4


Cluster HSCOC4 features 19 transcript(s) and 79 segment(s) of interest, the names for which are given in Tables 136 and 137, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 138.









TABLE 136







Transcripts of interest










Transcript Name
Sequence ID No.














HSCOC4_PEA_1_T1
15



HSCOC4_PEA_1_T2
16



HSCOC4_PEA_1_T3
17



HSCOC4_PEA_1_T4
18



HSCOC4_PEA_1_T5
19



HSCOC4_PEA_1_T7
20



HSCOC4_PEA_1_T8
21



HSCOC4_PEA_1_T11
22



HSCOC4_PEA_1_T12
23



HSCOC4_PEA_1_T14
24



HSCOC4_PEA_1_T15
25



HSCOC4_PEA_1_T20
26



HSCOC4_PEA_1_T21_(
27



HSCOC4_PEA_1_T25
28



HSCOC4_PEA_1_T28
29



HSCOC4_PEA_1_T30
30



HSCOC4_PEA_1_T31
31



HSCOC4_PEA_1_T32
32



HSCOC4_PEA_1_T40
33

















TABLE 137







Segments of interest










Segment Name
Sequence ID No.







HSCOC4_PEA_1_node_1
143



HSCOC4_PEA_1_node_5
144



HSCOC4_PEA_1_node_7
145



HSCOC4_PEA_1_node_30
146



HSCOC4_PEA_1_node_33
147



HSCOC4_PEA_1_node_35
148



HSCOC4_PEA_1_node_37
149



HSCOC4_PEA_1_node_39
150



HSCOC4_PEA_1_node_43
151



HSCOC4_PEA_1_node_48
152



HSCOC4_PEA_1_node_49
153



HSCOC4_PEA_1_node_51
154



HSCOC4_PEA_1_node_58
155



HSCOC4_PEA_1_node_59
156



HSCOC4_PEA_1_node_62
157



HSCOC4_PEA_1_node_66
158



HSCOC4_PEA_1_node_72
159



HSCOC4_PEA_1_node_77
160



HSCOC4_PEA_1_node_79
161



HSCOC4_PEA_1_node_93
162



HSCOC4_PEA_1_node_100
163



HSCOC4_PEA_1_node_105
164



HSCOC4_PEA_1_node_107
165



HSCOC4_PEA_1_node_108
166



HSCOC4_PEA_1_node_109
167



HSCOC4_PEA_1_node_110
168



HSCOC4_PEA_1_node_112
169



HSCOC4_PEA_1_node_113
170



HSCOC4_PEA_1_node_2
171



HSCOC4_PEA_1_node_8
172



HSCOC4_PEA_1_node_10
173



HSCOC4_PEA_1_node_12
174



HSCOC4_PEA_1_node_14
175



HSCOC4_PEA_1_node_17
176



HSCOC4_PEA_1_node_19
177



HSCOC4_PEA_1_node_21
178



HSCOC4_PEA_1_node_22
179



HSCOC4_PEA_1_node_28
180



HSCOC4_PEA_1_node_29
181



HSCOC4_PEA_1_node_41
182



HSCOC4_PEA_1_node_45
183



HSCOC4_PEA_1_node_47
184



HSCOC4_PEA_1_node_50
185



HSCOC4_PEA_1_node_53
186



HSCOC4_PEA_1_node_55
187



HSCOC4_PEA_1_node_57
188



HSCOC4_PEA_1_node_60
189



HSCOC4_PEA_1_node_64
190



HSCOC4_PEA_1_node_69
191



HSCOC4_PEA_1_node_70
192



HSCOC4_PEA_1_node_71
193



HSCOC4_PEA_1_node_73
194



HSCOC4_PEA_1_node_74
195



HSCOC4_PEA_1_node_75
196



HSCOC4_PEA_1_node_76
197



HSCOC4_PEA_1_node_78
198



HSCOC4_PEA_1_node_80
199



HSCOC4_PEA_1_node_82
200



HSCOC4_PEA_1_node_83
201



HSCOC4_PEA_1_node_84
202



HSCOC4_PEA_1_node_85
203



HSCOC4_PEA_1_node_86
204



HSCOC4_PEA_1_node_87
205



HSCOC4_PEA_1_node_88
206



HSCOC4_PEA_1_node_89
207



HSCOC4_PEA_1_node_90
208



HSCOC4_PEA_1_node_91
209



HSCOC4_PEA_1_node_92
210



HSCOC4_PEA_1_node_94
211



HSCOC4_PEA_1_node_96
212



HSCOC4_PEA_1_node_97
213



HSCOC4_PEA_1_node_98
214



HSCOC4_PEA_1_node_99
215



HSCOC4_PEA_1_node_101
216



HSCOC4_PEA_1_node_102
217



HSCOC4_PEA_1_node_103
218



HSCOC4_PEA_1_node_104
219



HSCOC4_PEA_1_node_106
220



HSCOC4_PEA_1_node_111
221

















TABLE 138







Proteins of interest










Sequence



Protein Name
ID No.
Corresponding Transcript(s)












HSCOC4_PEA_1_P3
340
HSCOC4_PEA_1_T1 (SEQ




ID NO:15)


HSCOC4_PEA_1_P5
341
HSCOC4_PEA_1_T3 (SEQ




ID NO:17)


HSCOC4_PEA_1_P6
342
HSCOC4_PEA_1_T4 (SEQ




ID NO:18)


HSCOC4_PEA_1_P12
343
HSCOC4_PEA_1_T11 (SEQ




ID NO:22)


HSCOC4_PEA_1_P15
344
HSCOC4_PEA_1_T14 (SEQ




ID NO:24)


HSCOC4_PEA_1_P16
345
HSCOC4_PEA_1_T15 (SEQ




ID NO:25)


HSCOC4_PEA_1_P20
346
HSCOC4_PEA_1_T20 (SEQ




ID NO:26)


HSCOC4_PEA_1_P9
347
HSCOC4_PEA_1_T21 (SEQ




ID NO:27)


HSCOC4_PEA_1_P22
348
HSCOC4_PEA_1_T25 (SEQ




ID NO:28)


HSCOC4_PEA_1_P23
349
HSCOC4_PEA_1_T28 (SEQ




ID NO:29)


HSCOC4_PEA_1_P24
350
HSCOC4_PEA_1_T30 (SEQ




ID NO:30)


HSCOC4_PEA_1_P25
351
HSCOC4_PEA_1_T31 (SEQ




ID NO:31)


HSCOC4_PEA_1_P26
352
HSCOC4_PEA_1_T32 (SEQ




ID NO:32)


HSCOC4_PEA_1_P30
353
HSCOC4_PEA_1_T40 (SEQ




ID NO:33)


HSCOC4_PEA_1_P38
354
HSCOC4_PEA_1_T2 (SEQ




ID NO:16)


HSCOC4_PEA_1_P39
355
HSCOC4_PEA_1_T5 (SEQ




ID NO:19)


HSCOC4_PEA_1_P40
356
HSCOC4_PEA_1_T7 (SEQ




ID NO:20)


HSCOC4_PEA_1_P41
357
HSCOC4_PEA_1_T8 (SEQ




ID NO:21)


HSCOC4_PEA_1_P42
358
HSCOC4_PEA_1_T12 (SEQ




ID NO:23)









These sequences are variants of the known protein Complement C4 precursor [Contains: C4a anaphylatoxin] (SEQ ID NO:388) (SwissProt accession identifier CO4_HUMAN (SEQ ID NO: 388)), SEQ ID NO: 388, referred to herein as the previously known protein.


Protein Complement C4 precursor [Contains: C4a anaphylatoxin] (SEQ ID NO:388) is known or believed to have the following function(s): C4 plays a central role in the activation of the classical pathway of the complement system. It is processed by activated C1 which remove from the alpha chain the C4a anaphylatoxin; Derived from proteolytic degradation of complement C4, C4a anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes. The sequence for protein Complement C4 precursor [Contains: C4a anaphylatoxin] (SEQ ID NO:388) is given at the end of the application, as “Complement C4 precursor [Contains: C4a anaphylatoxin] (SEQ ID NO:388) amino acid sequence”. Known polymorphisms for this sequence are as shown in Table 139.









TABLE 139







Amino acid mutations for Known Protein








SNP position(s)



on amino


acid sequence
Comment





 477
R -> W (in allotype C4A6). /FTId = VAR_001987.


 726
P -> L (in allotype C4A3). /FTId = VAR_001988.


1073
D -> G (in allotype C4A1, allotype C4B1 and allotype



C4B3). /FTId = VAR_001989.


1120-1125
PCPVLD -> LSPVIH (in allotype C4B).



/FTId = VAR_001990.


1176
N -> S (in allotype C4A1, allotype C4B1, allotype C4B3



and allotype C4B5). /FTId = VAR_001991.


1201
S -> T (in allotype C4A6, allotype C4A3, allotype C4A1



and allotype C4B). /FTId = VAR_001992.


1207
V -> A (in allotype C4A1, allotype C4B1, allotype C4B2



and allotype C4B3). /FTId = VAR_001993.


1210
L -> R (in allotype C4A1, allotype C4B1, allotype C4B2



and allotype C4B3). /FTId = VAR_001994.


1286
S -> A (in allotype C4A6, allotype C4A1, allotype



C4A3A and allotype C4B). /FTId = VAR_001995.


 1-12
MRLLWGLIWASS -> PREVRSVCLSAT


 347
S -> Y


 418
V -> A


 727
D -> N


 907
A -> T


980-981
VT -> LQ


1013
Q -> E


1317
I -> F


1418-1420
Missing


1654
T -> RA


1698
H -> Q









The following GO Annotation(s) apply to the previously known protein. The following annotation(s) were found: muscle contraction regulation; inflammatory response; complement activation; complement activation, classical pathway, which are annotation(s) related to Biological Process; complement component; proteinase inhibitor, which are annotation(s) related to Molecular Function; and extracellular; extracellular space, which are annotation(s) related to Cellular Component.


The GO assignment relies on information from one or more of the SwissProt/TremB1 Protein knowledgebase, available from expasydot ch/sprot/; or Locuslink, available from ncbidot nlmdot nihdot gov/projects/LocusLink/.


Cluster HSCOC4 can be used as a diagnostic marker according to overexpression of transcripts of this cluster in cancer. Expression of such transcripts in normal tissues is also given according to the previously described methods. The term “number” in the left hand column of the table and the numbers on the y-axis of FIG. 12 refer to weighted expression of ESTs in each category, as “parts per million” (ratio of the expression of ESTs for a particular cluster to the expression of all ESTs in that category, according to parts per million).


Overall, the following results were obtained as shown with regard to the histograms in FIG. 12 and Table 140. This cluster is overexpressed (at least at a minimum level) in the following pathological conditions: brain malignant tumors, a mixture of malignant tumors from different tissues, breast malignant tumors, pancreas carcinoma and prostate cancer.









TABLE 140







Normal tissue distribution










Name of Tissue
Number














Adrenal
853



Bladder
328



Bone
6



Brain
111



Colon
245



Epithelial
264



General
163



head and neck
0



Kidney
141



Liver
4109



Lung
64



Lymph nodes
120



Breast
96



bone marrow
0



Ovary
116



Pancreas
20



Prostate
4



Stomach
36



T cells
0



Thyroid
12



Uterus
127

















TABLE 141







P values and ratios for expression in cancerous tissue













Name of Tissue
P1
P2
SP1
R3
SP2
R4





Adrenal
5.6e−01
5.9e−01
2.5e−06
0.3
4.3e−04
0.3


Bladder
5.0e−01
6.6e−01
6.3e−01
0.9
9.1e−01
0.6


Bone
5.5e−01
5.8e−01
1
1.1
7.0e−01
1.3


Brain
4.6e−03
6.2e−02
7.7e−11
3.0
3.2e−05
1.7


Colon
8.0e−01
8.3e−01
9.8e−01
0.4
9.9e−01
0.4


Epithelial
1.7e−01
9.2e−01
9.3e−07
1.3
9.7e−01
0.7


General
3.2e−04
6.1e−01
1.5e−31
2.1
1.9e−03
1.1


head and neck
1.2e−01
2.1e−01
1
1.2
1
1.1


Kidney
6.9e−01
8.1e−01
1.2e−04
2.4
1.5e−02
1.5


Liver
7.1e−01
7.2e−01
5.0e−04
0.2
1
0.1


Lung
2.9e−01
7.1e−01
4.2e−02
1.7
5.1e−01
0.8


Lymph nodes
6.3e−01
8.2e−01
9.0e−01
0.5
1
0.3


Breast
4.0e−02
1.8e−01
2.1e−06
6.0
3.9e−03
3.0


bone marrow
1
6.7e−01
1
1.0
2.8e−01
2.8


Ovary
6.6e−01
7.3e−01
1.3e−01
1.5
3.6e−01
1.1


Pancreas
1.7e−02
9.9e−02
4.8e−10
7.6
2.9e−07
5.1


Prostate
5.8e−01
6.3e−01
4.1e−02
3.9
1.8e−03
3.8


Stomach
2.7e−01
7.5e−01
1.1e−01
1.5
6.5e−01
0.8


T cells
1
6.7e−01
1
1.0
7.2e−01
1.4


Thyroid
3.4e−01
3.4e−01
3.0e−01
2.2
3.0e−01
2.2


Uterus
1.2e−01
5.3e−01
6.6e−02
1.4
5.4e−01
0.8









As noted above, cluster HSCOC4 features 19 transcript(s), which were listed in Table 136 above. These transcript(s) encode for protein(s) which are variant(s) of protein Complement C4 precursor [Contains: C4a anaphylatoxin]. A description of each variant protein according to the present invention is now provided.


Variant protein HSCOC4_PEA1_P3 (SEQ ID NO:340) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T1 (SEQ ID NO:15). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P3 (SEQ ID NO:340) and CO4_HUMAN:


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P3 (SEQ ID NO:340) comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTV corresponding to amino acids 1-865 of CO4_HUMAN, which also corresponds to amino acids 1-865 of HSCOC4_PEA1_P3 (SEQ ID NO:340), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence RPHRSLSIQELGEPGPSEGWGG (SEQ ID NO:544) corresponding to amino acids 866-887 of HSCOC4_PEA1_P3 (SEQ ID NO:340) wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P3 (SEQ ID NO:340), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence RPHRSLSIQELGEPGPSEGWGG (SEQ ID NO: 544) in HSCOC4_PEA1_P3 (SEQ ID NO:340).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSCOC4_PEA1_P3 (SEQ ID NO:340) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 142, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P3 (SEQ ID NO:340) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 142







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












128
Q ->
No


141
L -> V
Yes


183
G -> 
No


211
G -> 
No


322
A -> 
No


322
A -> V
No


347
S -> Y
Yes


423
Q -> 
No


478
P -> L
Yes


549
H -> P
Yes


608
L -> V
Yes


617
K -> E
Yes


726
P -> L
Yes


869
R -> G
Yes









The glycosylation sites of variant protein HSCOC4_PEA1_P3 (SEQ ID NO:340), as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 143 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the glycosylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).









TABLE 143







Glycosylation site(s)









Position(s) on known
Present in
Position in


amino acid sequence
variant protein?
variant protein?












1391
No



862
Yes
862


226
Yes
226


1328
No









The phosphorylation sites of variant protein HSCOC4_PEA1_P3 (SEQ ID NO:340), as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 144 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the phosphorylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).









TABLE 144







Phosphorylation site(s)









Position(s) on known
Present in
Position in


amino acid sequence
variant protein?
variant protein?





1420
No



1422
No


1417
No









Variant protein HSCOC4_PEA1_P3 (SEQ ID NO:340) is encoded by the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T1 (SEQ ID NO:15) is shown in bold; this coding portion starts at position 501 and ends at position 3161. The transcript also has the following SNPs as listed in Table 145 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P3 (SEQ ID NO:340) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 145







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1465
C -> 
No


1465
C -> T
No


1517
C -> T
Yes


1540
C -> A
Yes


1768
A -> 
No


1778
C -> T
Yes


1933
C -> T
Yes


1985
C -> T
Yes


2146
A -> C
Yes


2162
G -> A
Yes


2322
C -> G
Yes


2349
A -> G
Yes


2435
G -> A
Yes


2540
C -> T
No


2677
C -> T
Yes


2975
C -> T
Yes


3105
A -> G
Yes


3167
G -> A
Yes


3228
T -> C
Yes


3259
G -> T
Yes


3332
G -> A
Yes


3490
A -> C
Yes


3569
T -> C
Yes


3724
G -> T
Yes


3831
A -> G
Yes


3898
C -> A
Yes


3972
C -> T
Yes


3975
G -> C
Yes


3983
T -> A
Yes


3986
G -> C
Yes


3988
C -> T
Yes


4140
G -> A
Yes


4147
T -> C
Yes


4228
C -> G
Yes


4233
C -> T
Yes


4242
G -> T
Yes


4243
G -> C
Yes


4339
G -> A
Yes


4345
C -> G
Yes


4348
G -> A
Yes


4469
G -> T
Yes


4562
A -> T
Yes


4781
A -> G
No


4873
T -> C
Yes


5007
G -> 
No


5423
C -> G
Yes


5634
G -> C
No


5677
G -> A
Yes


5687
A -> C
Yes


5862
A -> C
Yes


5868
G -> A
Yes


5933
A -> C
Yes









Variant protein HSCOC4_PEA1_P5 (SEQ ID NO:341) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T3 (SEQ ID NO:17). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P5 (SEQ ID NO:341) and CO4_HUMAN:


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P5 (SEQ ID NO:341) comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKG corresponding to amino acids 1-818 of CO4_HUMAN, which also corresponds to amino acids 1-818 of HSCOC4_PEA1_P5 (SEQ ID NO:341), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence DVTLSGPQVTLLPFPCTPAPCSLCS (SEQ ID NO: 545) corresponding to amino acids 819-843 of HSCOC4_PEA1_P5 (SEQ ID NO:341), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P5 (SEQ ID NO:341), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DVTLSGPQVTLLPFPCTPAPCSLCS (SEQ ID NO: 545) in HSCOC4_PEA1_P5 (SEQ ID NO:341).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSCOC4_PEA1_P5 (SEQ ID NO:341) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 146, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P5 (SEQ ID NO:341) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 146







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












128
Q -> 
No


141
L -> V
Yes


183
G -> 
No


211
G -> 
No


322
A -> 
No


322
A -> V
No


347
S -> Y
Yes


423
Q -> 
No


478
P -> L
Yes


549
H -> P
Yes


608
L -> V
Yes


617
K -> E
Yes


726
P -> L
Yes


829
L -> P
Yes


830
L -> I 
Yes


840
S -> P
Yes









The glycosylation sites of variant protein HSCOC4_PEA1_P5 (SEQ ID NO:341), as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 147 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the glycosylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).









TABLE 147







Glycosylation site(s)









Position(s) on known
Present in
Position in


amino acid sequence
variant protein?
variant protein?












1391
No



862
No


226
Yes
226


1328
No









The phosphorylation sites of variant protein HSCOC4_PEA1_P5 (SEQ ID NO:341), as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 148 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the phosphorylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).









TABLE 148







Phosphorylation site(s)









Position(s) on known
Present in
Position in


amino acid sequence
variant protein?
variant protein?





1420
No



1422
No


1417
No









Variant protein HSCOC4_PEA1_P5 (SEQ ID NO:341) is encoded by the following transcript(s): HSCOC4_PEA1_T3 (SEQ ID NO:17), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T3 (SEQ ID NO:17) is shown in bold; this coding portion starts at position 501 and ends at position 3029. The transcript also has the following SNPs as listed in Table 149 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P5 (SEQ ID NO:341) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 149







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1465
C -> 
No


1465
C -> T
No


1517
C -> T
Yes


1540
C -> A
Yes


1768
A -> 
No


1778
C -> T
Yes


1933
C -> T
Yes


1985
C -> T
Yes


2146
A -> C
Yes


2162
G -> A
Yes


2322
C -> G
Yes


2349
A -> G
Yes


2435
G -> A
Yes


2540
C -> T
No


2677
C -> T
Yes


2986
T -> C
Yes


2988
C -> A
Yes


3018
T -> C
Yes


3070
C -> T
Yes


3081
C -> A
Yes


3093
A -> G
Yes


3101
G -> A
Yes


3106
G -> A
Yes


3174
G -> A
Yes


3193
A -> G
Yes


3201
T -> C
Yes


3233
C -> T
Yes


3363
A -> G
Yes


3425
G -> A
Yes


3486
T -> C
Yes


3517
G -> T
Yes


3590
G -> A
Yes


3748
A -> C
Yes


3827
T -> C
Yes


3982
G -> T
Yes


4089
A -> G
Yes


4156
C -> A
Yes


4230
C -> T
Yes


4233
G -> C
Yes


4241
T -> A
Yes


4244
G -> C
Yes


4246
C -> T
Yes


4398
G -> A
Yes


4405
T -> C
Yes


4486
C -> G
Yes


4491
C -> T
Yes


4500
G -> T
Yes


4501
G -> C
Yes


4597
G -> A
Yes


4603
C -> G
Yes


4606
G -> A
Yes


4727
G -> T
Yes


4820
A -> T
Yes


5039
A -> G
No


5131
T -> C
Yes


5265
G -> 
No


5681
C -> G
Yes


5892
G -> C
No


5935
G -> A
Yes


5945
A -> C
Yes


6120
A -> C
Yes


6126
G -> A
Yes


6191
A -> C
Yes









Variant protein HSCOC4_PEA1_P6 (SEQ ID NO:342) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T4 (SEQ ID NO:18). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P6 (SEQ ID NO:342) and CO4_HUMAN:


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P6 (SEQ ID NO:342) comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSVVPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKG corresponding to amino acids 1-1052 of CO4_HUMAN, which also corresponds to amino acids 1-1052 of HSCOC4_PEA1_P6 (SEQ ID NO:342), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SGCKGKQEGGQERTVTGRWTAQEATEGKKGGP (SEQ ID NO: 546) corresponding to amino acids 1053-1084 of HSCOC4_PEA1_P6 (SEQ ID NO:342), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P6 (SEQ ID NO:342), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SGCKGKQEGGQERTVTGRWTAQEATEGKKGGP (SEQ ID NO: 546) in HSCOC4_PEA1_P6 (SEQ ID NO:342).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSCOC4_PEA1_P6 (SEQ ID NO:342) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 150, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P6 (SEQ ID NO:342) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 150







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












128
Q ->
No


141
L -> V
Yes


183
G -> 
No


211
G -> 
No


322
A -> 
No


322
A -> V
No


347
S -> Y
Yes


423
Q -> 
No


478
P -> L
Yes


549
H -> P
Yes


608
L -> V
Yes


617
K -> E
Yes


726
P -> L
Yes


872
V -> A
Yes


907
A -> T
Yes


959
E -> D
Yes


1062
G -> V
Yes


1068
T -> 
Yes









The glycosylation sites of variant protein HSCOC4_PEA1_P6 (SEQ ID NO:342), as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 151 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the glycosylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).









TABLE 151







Glycosylation site(s)









Position(s) on known
Present in
Position in


amino acid sequence
variant protein?
variant protein?












1391
No



862
Yes
862


226
Yes
226


1328
No









The phosphorylation sites of variant protein HSCOC4_PEA1_P6 (SEQ ID NO:342), as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 152 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the phosphorylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).









TABLE 152







Phosphorylation site(s)









Position(s) on known
Present in
Position in


amino acid sequence
variant protein?
variant protein?





1420
No



1422
No


1417
No









Variant protein HSCOC4_PEA1_P6 (SEQ ID NO:342) is encoded by the following transcript(s): HSCOC4_PEA1_T4 (SEQ ID NO:18), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T4 (SEQ ID NO:18) is shown in bold; this coding portion starts at position 501 and ends at position 3752. The transcript also has the following SNPs as listed in Table 153 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P6 (SEQ ID NO:342) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 153







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1465
C -> 
No


1465
C -> T
No


1517
C -> T
Yes


1540
C -> A
Yes


1768
A -> 
No


1778
C -> T
Yes


1933
C -> T
Yes


1985
C -> T
Yes


2146
A -> C
Yes


2162
G -> A
Yes


2322
C -> G
Yes


2349
A -> G
Yes


2435
G -> A
Yes


2540
C -> T
No


2677
C -> T
Yes


2975
C -> T
Yes


3115
T -> C
Yes


3146
G -> T
Yes


3219
G -> A
Yes


3377
A -> C
Yes


3456
T -> C
Yes


3611
G -> T
Yes


3685
G -> T
Yes


3702
A -> 
Yes


3897
A -> G
Yes


3964
C -> A
Yes


4038
C -> T
Yes


4041
G -> C
Yes


4049
T -> A
Yes


4052
G -> C
Yes


4054
C -> T
Yes


4206
G -> A
Yes


4213
T -> C
Yes


4294
C -> G
Yes


4299
C -> T
Yes


4308
G -> T
Yes


4309
G -> C
Yes


4405
G -> A
Yes


4411
C -> G
Yes


4414
G -> A
Yes


4535
G -> T
Yes


4628
A -> T
Yes


4847
A -> G
No


4939
T -> C
Yes


5073
G -> 
No


5489
C -> G
Yes


5700
G -> C
No


5743
G -> A
Yes


5753
A -> C
Yes


5928
A -> C
Yes


5934
G -> A
Yes


5999
A -> C
Yes









Variant protein HSCOC4_PEA1_P12 (SEQ ID NO:343) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T11 (SEQ ID NO:22). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P12 (SEQ ID NO:343) and CO4_HUMAN_V1 (SEQ ID NO:389):


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P12 (SEQ ID NO:343), comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSVVPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKV corresponding to amino acids 1-1380 of CO4_HUMAN_V1 (SEQ ID NO:389), which also corresponds to amino acids 1-1380 of HSCOC4_PEA1_P12 (SEQ ID NO:343), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence RAREGVGPGTGGGEGVE (SEQ ID NO: 547) corresponding to amino acids 1381-1397 of HSCOC4_PEA1_P12 (SEQ ID NO:343), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P12 (SEQ ID NO:343), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence RAREGVGPGTGGGEGVE (SEQ ID NO: 547) in HSCOC4_PEA1_P12 (SEQ ID NO:343).


It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1 (SEQ ID NO:389). These changes were previously known to occur and are listed in the table below.









TABLE 154







Changes to CO4_HUMAN_V1 (SEQ ID NO:389)










SNP position(s) on




amino acid sequence
Type of change







1177
Variant



1202
Variant



1208
Variant



1211
Variant



1287
Variant










The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSCOC4_PEA1_P12 (SEQ ID NO:343) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 155, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P12 (SEQ ID NO:343) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 155







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












128
Q -> 
No


141
L -> V
Yes


183
G ->
No


211
G -> 
No


322
A -> 
No


322
A -> V
No


347
S -> Y
Yes


423
Q -> 
No


478
P -> L
Yes


549
H -> P
Yes


608
L -> V
Yes


617
K -> E
Yes


726
P -> L
Yes


872
V -> A
Yes


907
A -> T
Yes


959
E -> D
Yes


1073
D -> G
Yes


1120
P -> L
Yes


1121
C -> S
Yes


1124
L -> I 
Yes


1125
D -> H
Yes


1176
S -> N
Yes


1207
A -> V
Yes


1210
R -> L
Yes


1286
A -> S
Yes


1317
 I -> F
Yes









Variant protein HSCOC4_PEA1_P12 (SEQ ID NO:343) is encoded by the following transcript(s): HSCOC4_PEA1_T11 (SEQ ID NO:22), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T11 (SEQ ID NO:22) is shown in bold; this coding portion starts at position 501 and ends at position 4691. The transcript also has the following SNPs as listed in Table 156 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P12 (SEQ ID NO:343) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 156







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1465
C -> 
No


1465
C -> T
No


1517
C -> T
Yes


1540
C -> A
Yes


1768
A -> 
No


1778
C -> T
Yes


1933
C -> T
Yes


1985
C -> T
Yes


2146
A -> C
Yes


2162
G -> A
Yes


2322
C -> G
Yes


2349
A -> G
Yes


2435
G -> A
Yes


2540
C -> T
No


2677
C -> T
Yes


2975
C -> T
Yes


3115
T -> C
Yes


3146
G -> T
Yes


3219
G -> A
Yes


3377
A -> C
Yes


3456
T -> C
Yes


3611
G -> T
Yes


3718
A -> G
Yes


3785
C -> A
Yes


3859
C -> T
Yes


3862
G -> C
Yes


3870
T -> A
Yes


3873
G -> C
Yes


3875
C -> T
Yes


4027
G -> A
Yes


4034
T -> C
Yes


4115
C -> G
Yes


4120
C -> T
Yes


4129
G -> T
Yes


4130
G -> C
Yes


4226
G -> A
Yes


4232
C -> G
Yes


4235
G -> A
Yes


4356
G -> T
Yes


4449
A -> T
Yes


4859
C -> T
Yes


4876
C -> A
Yes


4882
C -> G
Yes


4924
G -> A
Yes


5205
C -> G
Yes


5596
C -> T
Yes


5717
A -> G
No


5809
T -> C
Yes


5943
G -> 
No


6359
C -> G
Yes


6570
G -> C
No


6613
G -> A
Yes


6623
A -> C
Yes


6798
A -> C
Yes


6804
G -> A
Yes


6869
A -> C
Yes









Variant protein HSCOC4_PEA1_P15 (SEQ ID NO:344) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T14 (SEQ ID NO:24). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P15 (SEQ ID NO:344) and CO4_HUMAN_V1 (SEQ ID NO:389):


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P15 (SEQ ID NO:344), comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSVVPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQ corresponding to amino acids 1-1359 of CO4_HUMAN_V1 (SEQ ID NO:389), which also corresponds to amino acids 1-1359 of HSCOC4_PEA1_P15 (SEQ ID NO:344), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence VNHSLVNHSLAWVARTPGPRGQARSRPQPPTRGIPAALLPGVFGGRLTSWLRDLEL (SEQ ID NO: 548) corresponding to amino acids 1360-1415 of HSCOC4_PEA1_P15 (SEQ ID NO:344), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P15 (SEQ ID NO:344) comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VNHSLVNHSLAWVARTPGPRGQARSRPQPPTRGIPAALLPGVFGGRLTSWLRDLEL in (SEQ ID NO: 548) HSCOC4_PEA1_P15 (SEQ ID NO:344).


It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1 (SEQ ID NO:389). These changes were previously known to occur and are listed in the table below.









TABLE 157







Changes to CO4_HUMAN_V1 (SEQ ID NO: 389)










SNP position(s) on




amino acid sequence
Type of change







1177
Variant



1202
Variant



1208
Variant



1211
Variant



1287
Variant










The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSCOC4_PEA1_P15 (SEQ ID NO:344) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 158, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P15 (SEQ ID NO:344) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 158







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












128
Q -> 
No


141
L -> V
Yes


183
G -> 
No


211
G -> 
No


322
A -> V
No


322
A -> 
No


347
S -> Y
Yes


423
Q -> 
No


478
P -> L
Yes


549
H -> P
Yes


608
L -> V
Yes


617
K -> E
Yes


726
P -> L
Yes


872
V -> A
Yes


907
A -> T
Yes


959
E -> D
Yes


1073
D -> G
Yes


1120
P -> L
Yes


1121
C -> S
Yes


1124
L -> I 
Yes


1125
D -> H
Yes


1176
S -> N
Yes


1207
A -> V
Yes


1210
R -> L
Yes


1286
A -> S
Yes


1317
 I -> F
Yes


1387
Q -> H
Yes


1411
R -> C
Yes









Variant protein HSCOC4_PEA1_P15 (SEQ ID NO:344) is encoded by the following transcript(s): HSCOC4_PEA1_T14 (SEQ ID NO:24), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T14 (SEQ ID NO:24) is shown in bold; this coding portion starts at position 501 and ends at position 4745. The transcript also has the following SNPs as listed in Table 159 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P15 (SEQ ID NO:344) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 159







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1465
C -> 
No


1465
C -> T
No


1517
C -> T
Yes


1540
C -> A
Yes


1768
A -> 
No


1778
C -> T
Yes


1933
C -> T
Yes


1985
C -> T
Yes


2146
A -> C
Yes


2162
G -> A
Yes


2322
C -> G
Yes


2349
A -> G
Yes


2435
G -> A
Yes


2540
C -> T
No


2677
C -> T
Yes


2975
C -> T
Yes


3115
T -> C
Yes


3146
G -> T
Yes


3219
G -> A
Yes


3377
A -> C
Yes


3456
T -> C
Yes


3611
G -> T
Yes


3718
A -> G
Yes


3785
C -> A
Yes


3859
C -> T
Yes


3862
G -> C
Yes


3870
T -> A
Yes


3873
G -> C
Yes


3875
C -> T
Yes


4027
G -> A
Yes


4034
T -> C
Yes


4115
C -> G
Yes


4120
C -> T
Yes


4129
G -> T
Yes


4130
G -> C
Yes


4226
G -> A
Yes


4232
C -> G
Yes


4235
G -> A
Yes


4356
G -> T
Yes


4449
A -> T
Yes


4661
A -> C
Yes


4731
C -> T
Yes


4872
A -> G
Yes


4905
C -> T
Yes


5061
A -> G
No


5153
T -> C
Yes


5287
G -> 
No


5703
C -> G
Yes


5914
G -> C
No


5957
G -> A
Yes


5967
A -> C
Yes


6142
A -> C
Yes


6148
G -> A
Yes


6213
A -> C
Yes









Variant protein HSCOC4_PEA1_P16 (SEQ ID NO:345) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T15 (SEQ ID NO:25). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P16 (SEQ ID NO:345) and CO4_HUMAN_V1 (SEQ ID NO:389):


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P116 (SEQ ID NO:345), comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSVVPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIEVTVKGHVE YTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNRRRREAPK corresponding to amino acids 1-1457 of CO4_HUMAN_V1 (SEQ ID NO:389), which also corresponds to amino acids 1-1457 of HSCOC4_PEA1_P16 (SEQ ID NO:345), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence AERQGGAVWHGHRGRHPPEWIPRPAC (SEQ ID NO: 549) corresponding to amino acids 1458-1483 of HSCOC4_PEA1_P16 (SEQ ID NO:345), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P16 (SEQ ID NO:345), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence AERQGGAVWHGHRGRHPPEWIPRPAC (SEQ ID NO: 549) in HSCOC4_PEA1_P16 (SEQ ID NO:345).


It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1 (SEQ ID NO:389). These changes were previously known to occur and are listed in the table below.









TABLE 160







Changes to CO4_HUMAN_V1 (SEQ ID NO: 389)










SNP position(s) on




amino acid sequence
Type of change







1177
Variant



1202
Variant



1208
Variant



1211
Variant



1287
Variant










The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because of manual inspection of known protein localization and/or gene structure.


Variant protein HSCOC4 PEA1_P16 (SEQ ID NO:345) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 161, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P16 (SEQ ID NO:345) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 161







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












128
Q -> 
No


141
L -> V
Yes


183
G -> 
No


211
G -> 
No


322
A -> 
No


322
A -> V
No


347
S -> Y
Yes


423
Q -> 
No


478
P -> L
Yes


549
H -> P
Yes


608
L -> V
Yes


617
K -> E
Yes


726
P -> L
Yes


872
V -> A
Yes


907
A -> T
Yes


959
E -> D
Yes


1073
D -> G
Yes


1120
P -> L
Yes


1121
C -> S
Yes


1124
L -> I 
Yes


1125
D -> H
Yes


1176
S -> N
Yes


1207
A -> V
Yes


1210
R -> L
Yes


1286
A -> S
Yes


1317
 I -> F
Yes


1390
K -> E
No









Variant protein HSCOC4_PEA1_P16 (SEQ ID NO:345) is encoded by the following transcript(s): HSCOC4_PEA1_T15 (SEQ ID NO:25), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T15 (SEQ ID NO:25) is shown in bold; this coding portion starts at position 501 and ends at position 4949. The transcript also has the following SNPs as listed in Table 162 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P16 (SEQ ID NO:345) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 162







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1465
C -> 
No


1465
C -> T
No


1517
C -> T
Yes


1540
C -> A
Yes


1768
A -> 
No


1778
C -> T
Yes


1933
C -> T
Yes


1985
C -> T
Yes


2146
A -> C
Yes


2162
G -> A
Yes


2322
C -> G
Yes


2349
A -> G
Yes


2435
G -> A
Yes


2540
C -> T
No


2677
C -> T
Yes


2975
C -> T
Yes


3115
T -> C
Yes


3146
G -> T
Yes


3219
G -> A
Yes


3377
A -> C
Yes


3456
T -> C
Yes


3611
G -> T
Yes


3718
A -> G
Yes


3785
C -> A
Yes


3859
C -> T
Yes


3862
G -> C
Yes


3870
T -> A
Yes


3873
G -> C
Yes


3875
C -> T
Yes


4027
G -> A
Yes


4034
T -> C
Yes


4115
C -> G
Yes


4120
C -> T
Yes


4129
G -> T
Yes


4130
G -> C
Yes


4226
G -> A
Yes


4232
C -> G
Yes


4235
G -> A
Yes


4356
G -> T
Yes


4449
A -> T
Yes


4668
A -> G
No


4760
T -> C
Yes


5263
C -> G
Yes


5474
G -> C
No


5517
G -> A
Yes


5527
A -> C
Yes


5702
A -> C
Yes


5708
G -> A
Yes


5773
A -> C
Yes









Variant protein HSCOC4_PEA1_P20 (SEQ ID NO:346) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T20 (SEQ ID NO:26). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P20 (SEQ ID NO:346) and CO4_HUMAN_V1(SEQ ID NO:389):


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P20 (SEQ ID NO:346), comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFS SRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSVVPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQ corresponding to amino acids 1-1303 of CO4_HUMAN_V1 (SEQ ID NO:389), which also corresponds to amino acids 1-1303 of HSCOC4_PEA1_P20 (SEQ ID NO:346), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence VGAVPGLWRGWVVLRPRACLSPGSTSLGHGDCPGCPVCLLDCLPHH (SEQ ID NO: 550) corresponding to amino acids 1304-1349 of HSCOC4_PEA1_P20 (SEQ ID NO:346), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P20 (SEQ ID NO:346), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VGAVPGLWRGWVVLRPRACLSPGSTSLGHGDCPGCPVCLLDCLPHH (SEQ ID NO: 550) in HSCOC4_PEA1_P20 (SEQ ID NO:346).


It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1 (SEQ ID NO:389). These changes were previously known to occur and are listed in the table below.









TABLE 163







Changes to CO4_HUMAN_V1 (SEQ ID NO: 389)










SNP position(s) on




amino acid sequence
Type of change







1177
Variant



1202
Variant



1208
Variant



1211
Variant



1287
Variant










The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSCOC4_PEA1_P20 (SEQ ID NO:346) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 164 (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P20 (SEQ ID NO:346) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 164







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












128
Q -> 
No


141
L -> V
Yes


183
G -> 
No


211
G -> 
No


322
A -> 
No


322
A -> V
No


347
S -> Y
Yes


423
Q -> 
No


478
P -> L
Yes


549
H -> P
Yes


608
L -> V
Yes


617
K -> E
Yes


726
P -> L
Yes


872
V -> A
Yes


907
A -> T
Yes


959
E -> D
Yes


1073
D -> G
Yes


1120
P -> L
Yes


1121
C -> S
Yes


1124
L -> I 
Yes


1125
D -> H
Yes


1176
S -> N
Yes


1207
A -> V
Yes


1210
R -> L
Yes


1286
A -> S
Yes


1312
R -> G
Yes


1344
D -> V
Yes









Variant protein HSCOC4_PEA1_P20 (SEQ ID NO:346) is encoded by the following transcript(s): HSCOC4_PEA1_T20 (SEQ ID NO:26), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T20 (SEQ ID NO:26) is shown in bold; this coding portion starts at position 501 and ends at position 4547. The transcript also has the following SNPs as listed in Table 165 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P20 (SEQ ID NO:346) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 165







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1465
C -> 
No


1465
C -> T
No


1517
C -> T
Yes


1540
C -> A
Yes


1768
A -> 
No


1778
C -> T
Yes


1933
C -> T
Yes


1985
C -> T
Yes


2146
A -> C
Yes


2162
G -> A
Yes


2322
C -> G
Yes


2349
A -> G
Yes


2435
G -> A
Yes


2540
C -> T
No


2677
C -> T
Yes


2975
C -> T
Yes


3115
T -> C
Yes


3146
G -> T
Yes


3219
G -> A
Yes


3377
A -> C
Yes


3456
T -> C
Yes


3611
G -> T
Yes


3718
A -> G
Yes


3785
C -> A
Yes


3859
C -> T
Yes


3862
G -> C
Yes


3870
T -> A
Yes


3873
G -> C
Yes


3875
C -> T
Yes


4027
G -> A
Yes


4034
T -> C
Yes


4115
C -> G
Yes


4120
C -> T
Yes


4129
G -> T
Yes


4130
G -> C
Yes


4226
G -> A
Yes


4232
C -> G
Yes


4235
G -> A
Yes


4356
G -> T
Yes


4434
C -> G
Yes


4531
A -> T
Yes


4743
A -> C
Yes


4813
C -> T
Yes


4954
A -> G
Yes


4987
C -> T
Yes


5143
A -> G
No


5235
T -> C
Yes


5369
G -> 
No


5785
C -> G
Yes


5996
G -> C
No


6039
G -> A
Yes


6049
A -> C
Yes


6224
A -> C
Yes


6230
G -> A
Yes


6295
A -> C
Yes









Variant protein HSCOC4_PEA1_P9 (SEQ ID NO:347) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T21 (SEQ ID NO:27). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P9 (SEQ ID NO:347) and CO4_HUMAN_V1 (SEQ ID NO:389):


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P9 (SEQ ID NO:347), comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSVVPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIEVTVKGHVE YTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNRRRREAPKVVEEQESRV HYTVCIWRNGKVGLSGMAIADVTLLSGFHALRADLEKLTSLSDRYVSHFETEGPHVLL YFDSV corresponding to amino acids 1-1529 of CO4_HUMAN_V1 (SEQ ID NO:389), which also corresponds to amino acids 1-1529 of HSCOC4_PEA1_P9 (SEQ ID NO:347) and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SGER (SEQ ID NO: 551) corresponding to amino acids 1530-1533 of HSCOC4_PEA1_P9 (SEQ ID NO:347), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P9 (SEQ ID NO:347), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SGER (SEQ ID NO: 551) in HSCOC4_PEA1_P9 (SEQ ID NO:347).


It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1 (SEQ ID NO:389). These changes were previously known to occur and are listed in the table below.









TABLE 166







Changes to CO4_HUMAN_V1 (SEQ ID NO:389)










SNP position(s) on




amino acid sequence
Type of change







1177
Variant



1202
Variant



1208
Variant



1211
Variant



1287
Variant










The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSCOC4_PEA1_P9 (SEQ ID NO:347) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 167, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P9 (SEQ ID NO:347) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 167







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












128
Q -> 
No


141
L -> V
Yes


183
G -> 
No


211
G -> 
No


322
A -> V
No


322
A -> 
No


347
S -> Y
Yes


423
Q -> 
No


478
P -> L
Yes


549
H -> P
Yes


608
L -> V
Yes


617
K -> E
Yes


726
P -> L
Yes


872
V -> A
Yes


907
A -> T
Yes


959
E -> D
Yes


1073
D -> G
Yes


1120
P -> L
Yes


1121
C -> S
Yes


1124
L -> I 
Yes


1125
D -> H
Yes


1176
S -> N
Yes


1207
A -> V
Yes


1210
R -> L
Yes


1286
A -> S
Yes


1317
 I -> F
Yes


1390
K -> E
No


1465
R -> 
No









Variant protein HSCOC4_PEA1_P9 (SEQ ID NO:347) is encoded by the following transcript(s): HSCOC4_PEA1_T21 (SEQ ID NO:27), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T21 (SEQ ID NO:27) is shown in bold; this coding portion starts at position 501 and ends at position 5099. The transcript also has the following SNPs as listed in Table 168 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P9 (SEQ ID NO:347) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 168







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1465
C -> 
No


1465
C -> T
No


1517
C -> T
Yes


1540
C -> A
Yes


1768
A -> 
No


1778
C -> T
Yes


1933
C -> T
Yes


1985
C -> T
Yes


2146
A -> C
Yes


2162
G -> A
Yes


2322
C -> G
Yes


2349
A -> G
Yes


2435
G -> A
Yes


2540
C -> T
No


2677
C -> T
Yes


2975
C -> T
Yes


3115
T -> C
Yes


3146
G -> T
Yes


3219
G -> A
Yes


3377
A -> C
Yes


3456
T -> C
Yes


3611
G -> T
Yes


3718
A -> G
Yes


3785
C -> A
Yes


3859
C -> T
Yes


3862
G -> C
Yes


3870
T -> A
Yes


3873
G -> C
Yes


3875
C -> T
Yes


4027
G -> A
Yes


4034
T -> C
Yes


4115
C -> G
Yes


4120
C -> T
Yes


4129
G -> T
Yes


4130
G -> C
Yes


4226
G -> A
Yes


4232
C -> G
Yes


4235
G -> A
Yes


4356
G -> T
Yes


4449
A -> T
Yes


4668
A -> G
No


4760
T -> C
Yes


4894
G -> 
No


5561
G -> A
Yes


6026
T -> G
Yes


6348
G -> C
Yes


6966
C -> G
Yes


7177
G -> C
No


7220
G -> A
Yes


7230
A -> C
Yes


7405
A -> C
Yes


7411
G -> A
Yes


7476
A -> C
Yes









Variant protein HSCOC4_PEA1_P22 (SEQ ID NO:348) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T25 (SEQ ID NO:28). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P22 (SEQ ID NO:348) and CO4_HUMAN_V1 (SEQ ID NO:389):


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P22 (SEQ ID NO:348), comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSVVPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIEVTVKGHVE YTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNRRRREAPKVVEEQESRV HYTVCIWRNGKVGLSGMAIADVTLLSGFHALRADLEKLTSLSDRYVSHFETEGPHVLL YFDSVPTSRECVGFEAVQEVPVGLVQPASATLYDYYNPERRCSVFYGAPSKSRLLATLC SAEVCQCAEGKCPRQRRALERGLQDEDGYRMKFACYYPRVEYGFQVKVLREDSRAAF RLFETKITQVLHF corresponding to amino acids 1-1653 of CO4_HUMAN_V1 (SEQ ID NO:389), which also corresponds to amino acids 1-1653 of HSCOC4_PEA1_P22 (SEQ ID NO:348), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SMKQTGEAGRAGGRQGG (SEQ ID NO: 552) corresponding to amino acids 1654-1670 of HSCOC4_PEA1_P22 (SEQ ID NO:348), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P22 (SEQ ID NO:348), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SMKQTGEAGRAGGRQGG (SEQ ID NO: 552) in HSCOC4_PEA1_P22 (SEQ ID NO:348).


It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1 (SEQ ID NO:389). These changes were previously known to occur and are listed in the table below.









TABLE 169







Changes to CO4_HUMAN_V1 (SEQ ID NO:389)










SNP position(s) on




amino acid sequence
Type of change







1177
Variant



1202
Variant



1208
Variant



1211
Variant



1287
Variant










The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSCOC4_PEA1_P22 (SEQ ID NO:348) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 170 (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P22 (SEQ ID NO:348) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 170







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












128
Q -> 
No


141
L -> V
Yes


183
G -> 
No


211
G -> 
No


322
A -> 
No


322
A -> V
No


347
S -> Y
Yes


423
Q -> 
No


478
P -> L
Yes


549
H -> P
Yes


608
L -> V
Yes


617
K -> E
Yes


726
P -> L
Yes


872
V -> A
Yes


907
A -> T
Yes


959
E -> D
Yes


1073
D -> G
Yes


1120
P -> L
Yes


1121
C -> S
Yes


1124
L -> I 
Yes


1125
D -> H
Yes


1176
S -> N
Yes


1207
A -> V
Yes


1210
R -> L
Yes


1286
A -> S
Yes


1317
 I -> F
Yes


1390
K -> E
No


1465
R -> 
No


1604
R -> G
Yes









Variant protein HSCOC4_PEA1_P22 (SEQ ID NO:348) is encoded by the following transcript(s): HSCOC4_PEA1_T25 (SEQ ID NO:28), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T25 (SEQ ID NO:28) is shown in bold; this coding portion starts at position 501 and ends at position 5510. The transcript also has the following SNPs as listed in Table 171 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P22 (SEQ ID NO:348) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 171







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1465
C -> 
No


1465
C -> T
No


1517
C -> T
Yes


1540
C -> A
Yes


1768
A -> 
No


1778
C -> T
Yes


1933
C -> T
Yes


1985
C -> T
Yes


2146
A -> C
Yes


2162
G -> A
Yes


2322
C -> G
Yes


2349
A -> G
Yes


2435
G -> A
Yes


2540
C -> T
No


2677
C -> T
Yes


2975
C -> T
Yes


3115
T -> C
Yes


3146
G -> T
Yes


3219
G -> A
Yes


3377
A -> C
Yes


3456
T -> C
Yes


3611
G -> T
Yes


3718
A -> G
Yes


3785
C -> A
Yes


3859
C -> T
Yes


3862
G -> C
Yes


3870
T -> A
Yes


3873
G -> C
Yes


3875
C -> T
Yes


4027
G -> A
Yes


4034
T -> C
Yes


4115
C -> G
Yes


4120
C -> T
Yes


4129
G -> T
Yes


4130
G -> C
Yes


4226
G -> A
Yes


4232
C -> G
Yes


4235
G -> A
Yes


4356
G -> T
Yes


4449
A -> T
Yes


4668
A -> G
No


4760
T -> C
Yes


4894
G -> 
No


5310
C -> G
Yes


5783
G -> C
No


5826
G -> A
Yes


5836
A -> C
Yes


5974
C -> T
Yes


5981
C -> T
Yes


6154
A -> C
Yes


6160
G -> A
Yes


6225
A -> C
Yes


6283
C -> T
Yes


6548
C -> T
Yes


6567
C -> T
Yes


7300
C -> A
Yes


7520
C -> T
Yes


7685
A -> C
Yes









Variant protein HSCOC4_PEA1_P23 (SEQ ID NO:349) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T28 (SEQ ID NO:29). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P23 (SEQ ID NO:349) and CO4_HUMAN_V1 (SEQ ID NO:389):


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P23 (SEQ ID NO:349), comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSVVPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIEVTVKGHVE YTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNRRRREAPKVVEEQESRV HYTVCIWRNGKVGLSGMAIADVTLLSGFHALRADLEKLTSLSDRYVSHFETEGPHVLL YFDSVPTSRECVGFEAVQEVPVGLVQPASATLYDYYNPERRCSVFYGAPSKSRLLATLC SAEVCQCAEGKCPRQRRALERGLQDEDGYRMKFACYYPRVEYG corresponding to amino acids 1-1626 of CO4_HUMAN_V1 (SEQ ID NO:389), which also corresponds to amino acids 1-1626 of HSCOC4_PEA1_P23 (SEQ ID NO:349), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence QSSHRGPGLTLPRGPAVLVSLGVACSSYRSCTQPVCSDTNFLPSQPQSNSPFPLLLTPS (SEQ ID NO: 553) corresponding to amino acids 1627-1685 of HSCOC4_PEA1_P23 (SEQ ID NO:349), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P23 (SEQ ID NO:349), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence QSSHRGPGLTLPRGPAVLVSLGVACSSYRSCTQPVCSDTNFLPSQPQSNSPFPLLLTPS in (SEQ ID NO: 553) HSCOC4_PEA1_P23 (SEQ ID NO:349).


It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1 (SEQ ID NO:389). These changes were previously known to occur and are listed in the table below.









TABLE 172







Changes to CO4_HUMAN_V1 (SEQ ID NO:389)










SNP position(s) on




amino acid sequence
Type of change







1177
Variant



1202
Variant



1208
Variant



1211
Variant



1287
Variant










The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because of manual inspection of known protein localization and/or gene structure.


Variant protein HSCOC4_PEA1_P23 (SEQ ID NO:349) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 173, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P23 (SEQ ID NO:349) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 173







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












128
Q -> 
No


141
L -> V
Yes


183
G -> 
No


211
G -> 
No


322
A -> V
No


322
A -> 
No


347
S -> Y
Yes


423
Q -> 
No


478
P -> L
Yes


549
H -> P
Yes


608
L -> V
Yes


617
K -> E
Yes


726
P -> L
Yes


872
V -> A
Yes


907
A -> T
Yes


959
E -> D
Yes


1073
D -> G
Yes


1120
P -> L
Yes


1121
C -> S
Yes


1124
L -> I 
Yes


1125
D -> H
Yes


1176
S -> N
Yes


1207
A -> V
Yes


1210
R -> L
Yes


1286
A -> S
Yes


1317
 I -> F
Yes


1390
K -> E
No


1465
R -> 
No


1604
R -> G
Yes


1634
G -> 
Yes









Variant protein HSCOC4_PEA1_P23 (SEQ ID NO:349) is encoded by the following transcript(s): HSCOC4_PEA1_T28 (SEQ ID NO:29), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T28 (SEQ ID NO:29) is shown in bold; this coding portion starts at position 501 and ends at position 5555. The transcript also has the following SNPs as listed in Table 174 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P23 (SEQ ID NO:349) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 174







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1465
C -> 
No


1465
C -> T
No


1517
C -> T
Yes


1540
C -> A
Yes


1768
A -> 
No


1778
C -> T
Yes


1933
C -> T
Yes


1985
C -> T
Yes


2146
A -> C
Yes


2162
G -> A
Yes


2322
C -> G
Yes


2349
A -> G
Yes


2435
G -> A
Yes


2540
C -> T
No


2677
C -> T
Yes


2975
C -> T
Yes


3115
T -> C
Yes


3146
G -> T
Yes


3219
G -> A
Yes


3377
A -> C
Yes


3456
T -> C
Yes


3611
G -> T
Yes


3718
A -> G
Yes


3785
C -> A
Yes


3859
C -> T
Yes


3862
G -> C
Yes


3870
T -> A
Yes


3873
G -> C
Yes


3875
C -> T
Yes


4027
G -> A
Yes


4034
T -> C
Yes


4115
C -> G
Yes


4120
C -> T
Yes


4129
G -> T
Yes


4130
G -> C
Yes


4226
G -> A
Yes


4232
C -> G
Yes


4235
G -> A
Yes


4356
G -> T
Yes


4449
A -> T
Yes


4668
A -> G
No


4760
T -> C
Yes


4894
G -> 
No


5310
C -> G
Yes


5402
C -> 
Yes


5426
T -> C
Yes


5965
G -> C
No


6008
G -> A
Yes


6018
A -> C
Yes


6156
C -> T
Yes


6163
C -> T
Yes


6336
A -> C
Yes


6342
G -> A
Yes


6407
A -> C
Yes


6465
C -> T
Yes


6730
C -> T
Yes


6749
C -> T
Yes


7482
C -> A
Yes


7702
C -> T
Yes


7867
A -> C
Yes









Variant protein HSCOC4_PEA1_P24 (SEQ ID NO:350) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T30 (SEQ ID NO:30). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P24 (SEQ ID NO:350) and CO4_HUMAN_V1 (SEQ ID NO:389):


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P24 (SEQ ID NO:350), comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSVVPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIEVTVKGHVE YTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNRRRREAPKVVEEQESRV HYTVCIWRNGKVGLSGMAIADVTLLSGFHALRADLEKLTSLSDRYVSHFETEGPHVLL YFDS corresponding to amino acids 1-1528 of CO4_HUMAN_VI (SEQ ID NO:389), which also corresponds to amino acids 1-1528 of HSCOC4_PEA1_P24 (SEQ ID NO:350), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SADVLCFTGHQVRADSWPPCVLLKSASVLRGSALASVAPWSGVCRTRMATG (SEQ ID NO: 554) corresponding to amino acids 1529-1579 of HSCOC4_PEA1_P24 (SEQ ID NO:350), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P24 (SEQ ID NO:350), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SADVLCFTGHQVRADSWPPCVLLKSASVLRGSALASVAPWSGVCRTRMATG (SEQ ID NO: 554) in HSCOC4_PEA1_P24 (SEQ ID NO:350).


It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1 (SEQ ID NO:389). These changes were previously known to occur and are listed in the table below.









TABLE 175







Changes to CO4_HUMAN_V1 (SEQ ID NO:389)










SNP position(s) on




amino acid sequence
Type of change







1177
Variant



1202
Variant



1208
Variant



1211
Variant



1287
Variant










The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSCOC4_PEA1_P24 (SEQ ID NO:350) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 176, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P24 (SEQ ID NO:350) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 176







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












128
Q -> 
No


141
L -> V
Yes


183
G -> 
No


211
G -> 
No


322
A -> 
No


322
A -> V
No


347
S -> Y
Yes


423
Q -> 
No


478
P -> L
Yes


549
H -> P
Yes


608
L -> V
Yes


617
K -> E
Yes


726
P -> L
Yes


872
V -> A
Yes


907
A -> T
Yes


959
E -> D
Yes


1073
D -> G
Yes


1120
P -> L
Yes


1121
C -> S
Yes


1124
L -> I 
Yes


1125
D -> H
Yes


1176
S -> N
Yes


1207
A -> V
Yes


1210
R -> L
Yes


1286
A -> S
Yes


1317
 I -> F
Yes


1390
K -> E
No


1465
R -> 
No


1569
S -> R
Yes









Variant protein HSCOC4_PEA1_P24 (SEQ ID NO:350) is encoded by the following transcript(s): HSCOC4_PEA1_T30 (SEQ ID NO:30), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T30 (SEQ ID NO:30) is shown in bold; this coding portion starts at position 501 and ends at position 5237. The transcript also has the following SNPs as listed in Table 177 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P24 (SEQ ID NO:350) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 177







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1465
C -> 
No


1465
C -> T
No


1517
C -> T
Yes


1540
C -> A
Yes


1768
A -> 
No


1778
C -> T
Yes


1933
C -> T
Yes


1985
C -> T
Yes


2146
A -> C
Yes


2162
G -> A
Yes


2322
C -> G
Yes


2349
A -> G
Yes


2435
G -> A
Yes


2540
C -> T
No


2677
C -> T
Yes


2975
C -> T
Yes


3115
T -> C
Yes


3146
G -> T
Yes


3219
G -> A
Yes


3377
A -> C
Yes


3456
T -> C
Yes


3611
G -> T
Yes


3718
A -> G
Yes


3785
C -> A
Yes


3859
C -> T
Yes


3862
G -> C
Yes


3870
T -> A
Yes


3873
G -> C
Yes


3875
C -> T
Yes


4027
G -> A
Yes


4034
T -> C
Yes


4115
C -> G
Yes


4120
C -> T
Yes


4129
G -> T
Yes


4130
G -> C
Yes


4226
G -> A
Yes


4232
C -> G
Yes


4235
G -> A
Yes


4356
G -> T
Yes


4449
A -> T
Yes


4668
A -> G
No


4760
T -> C
Yes


4894
G -> 
No


5207
C -> G
Yes


5418
G -> C
No


5461
G -> A
Yes


5471
A -> C
Yes


5646
A -> C
Yes


5652
G -> A
Yes


5717
A -> C
Yes









Variant protein HSCOC4_PEA1_P25 (SEQ ID NO:351) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T31 (SEQ ID NO:31). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P25 (SEQ ID NO:351) and CO4_HUMAN_V1 (SEQ ID NO:389):


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P25 (SEQ ID NO:351), comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSVVPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIEVTVKGHVE YTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNRRRREAPKVVEEQESRV HYTVCIWRNGKVGLSGMAIADVTLLSGFHALRADLEKLTSLSDRYVSHFETEGPHVLL YFDSVPTSRECVGFEAVQEVPVGLVQPASATLYDYYNPERRCSVFYGAPSKSRLLATLC SAEVCQCAEG corresponding to amino acids 1-1593 of CO4_HUMAN_V1 (SEQ ID NO:389), which also corresponds to amino acids 1-1593 of HSCOC4_PEA1_P25 (SEQ ID NO:351), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence ETEGLGRGSGGGMAGAPPTLSDGFPNFREVPSPASRPGAGSAGRGWLQDEVCLLLPPC GVRLPG (SEQ ID NO: 555) corresponding to amino acids 1594-1657 of HSCOC4_PEA1_P25 (SEQ ID NO:351), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P25 (SEQ ID NO:351), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence ETEGLGRGSGGGMAGAPPTLSDGFPNFREVPSPASRPGAGSAGRGWLQDEVCLLLPPC GVRLPG (SEQ ID NO: 555) in HSCOC4_PEA1_P25 (SEQ ID NO:351).


It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1 (SEQ ID NO:389). These changes were previously known to occur and are listed in the table below.









TABLE 178







Changes to CO4_HUMAN_V1 (SEQ ID NO:389)










SNP position(s) on




amino acid sequence
Type of change







1177
Variant



1202
Variant



1208
Variant



1211
Variant



1287
Variant










The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSCOC4_PEA1_P25 (SEQ ID NO:351) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 179, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P25 (SEQ ID NO:351) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 179







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












128
Q -> 
No


141
L -> V
Yes


183
G -> 
No


211
G -> 
No


322
A -> 
No


322
A -> V
No


347
S -> Y
Yes


423
Q -> 
No


478
P -> L
Yes


549
H -> P
Yes


608
L -> V
Yes


617
K -> E
Yes


726
P -> L
Yes


872
V -> A
Yes


907
A -> T
Yes


959
E -> D
Yes


1073
D -> G
Yes


1120
P -> L
Yes


1121
C -> S
Yes


1124
L -> I 
Yes


1125
D -> H
Yes


1176
S -> N
Yes


1207
A -> V
Yes


1210
R -> L
Yes


1286
A -> S
Yes


1317
 I -> F
Yes


1390
K -> E
No


1465
R -> 
No


1632
A -> G
Yes









Variant protein HSCOC4_PEA1_P25 (SEQ ID NO:351) is encoded by the following transcript(s): HSCOC4_PEA1_T31 (SEQ ID NO:31), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T31 (SEQ ID NO:31) is shown in bold; this coding portion starts at position 501 and ends at position 5471. The transcript also has the following SNPs as listed in Table 180 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P25 (SEQ ID NO:351) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 180







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1465
C -> 
No


1465
C -> T
No


1517
C -> T
Yes


1540
C -> A
Yes


1768
A -> 
No


1778
C -> T
Yes


1933
C -> T
Yes


1985
C -> T
Yes


2146
A -> C
Yes


2162
G -> A
Yes


2322
C -> G
Yes


2349
A -> G
Yes


2435
G -> A
Yes


2540
C -> T
No


2677
C -> T
Yes


2975
C -> T
Yes


3115
T -> C
Yes


3146
G -> T
Yes


3219
G -> A
Yes


3377
A -> C
Yes


3456
T -> C
Yes


3611
G -> T
Yes


3718
A -> G
Yes


3785
C -> A
Yes


3859
C -> T
Yes


3862
G -> C
Yes


3870
T -> A
Yes


3873
G -> C
Yes


3875
C -> T
Yes


4027
G -> A
Yes


4034
T -> C
Yes


4115
C -> G
Yes


4120
C -> T
Yes


4129
G -> T
Yes


4130
G -> C
Yes


4226
G -> A
Yes


4232
C -> G
Yes


4235
G -> A
Yes


4356
G -> T
Yes


4449
A -> T
Yes


4668
A -> G
No


4760
T -> C
Yes


4894
G -> 
No


5395
C -> G
Yes


5606
G -> C
No


5649
G -> A
Yes


5659
A -> C
Yes


5834
A -> C
Yes


5840
G -> A
Yes


5905
A -> C
Yes









Variant protein HSCOC4_PEA1_P26 (SEQ ID NO:352) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T32 (SEQ ID NO:32). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P26 (SEQ ID NO:352) and CO4_HUMAN_V1 (SEQ ID NO:389):


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P26 (SEQ ID NO:352), comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSVVPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIEVTVKGHVE YTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNRRRREAPKVVEEQESRV HYTVCIWRNGKVGLSGMAIADVTLLSGFHALRADLEKLTSLSDRYVSHFETEGPHVLL YFDSVPTSRECVGFEAVQEVPVGLVQPASATLYDYYNPERRCSVFYGAPSKSRLLATLC SAEVCQCAEG corresponding to amino acids 1-1593 of CO4_HUMAN_V1 (SEQ ID NO:389), which also corresponds to amino acids 1-1593 of HSCOC4_PEA1_P26 (SEQ ID NO:352), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence ETEGLGRGSGGGMAGAPPTLSDGFPNFREVPSPASRPGAGSAGRGWLQDEVCLLLPPC GVRSVFPPRPWPDPPSGTGCFGLSGCSLLLLQVMHAACLL (SEQ ID NO: 556) corresponding to amino acids 1594-1691 of HSCOC4_PEA1_P26 (SEQ ID NO:352) wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P26 (SEQ ID NO:352), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence ETEGLGRGSGGGMAGAPPTLSDGFPNFREVPSPASRPGAGSAGRGWLQDEVCLLLPPC GVRSVFPPRPWPDPPSGTGCFGLSGCSLLLLQVMHAACLL (SEQ ID NO: 556) in HSCOC4_PEA1_P26 (SEQ ID NO:352).


It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1 (SEQ ID NO:389). These changes were previously known to occur and are listed in the table below.









TABLE 181







Changes to CO4_HUMAN_V1 (SEQ ID NO:389)










SNP position(s) on




amino acid sequence
Type of change







1177
Variant



1202
Variant



1208
Variant



1211
Variant



1287
Variant










The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSCOC4_PEA1_P26 (SEQ ID NO:352) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 182, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P26 (SEQ ID NO:352) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 182







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












128
Q -> 
No


141
L -> V
Yes


183
G -> 
No


211
G -> 
No


322
A -> 
No


322
A -> V
No


347
S -> Y
Yes


423
Q -> 
No


478
P -> L
Yes


549
H -> P
Yes


608
L -> V
Yes


617
K -> E
Yes


726
P -> L
Yes


872
V -> A
Yes


907
A -> T
Yes


959
E -> D
Yes


1073
D -> G
Yes


1120
P -> L
Yes


1121
C -> S
Yes


1124
L -> I 
Yes


1125
D -> H
Yes


1176
S -> N
Yes


1207
A -> V
Yes


1210
R -> L
Yes


1286
A -> S
Yes


1317
 I -> F
Yes


1390
K -> E
No


1465
R -> 
No


1632
A -> G
Yes


1663
P -> 
Yes


1671
C -> R
Yes









Variant protein HSCOC4_PEA1_P26 (SEQ ID NO:352) is encoded by the following transcript(s): HSCOC4_PEA1_T32 (SEQ ID NO:32), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T32 (SEQ ID NO:32) is shown in bold; this coding portion starts at position 501 and ends at position 5573. The transcript also has the following SNPs as listed in Table 183 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P26 (SEQ ID NO:352) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 183







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1465
C -> 
No


1465
C -> T
No


1517
C -> T
Yes


1540
C -> A
Yes


1768
A -> 
No


1778
C -> T
Yes


1933
C -> T
Yes


1985
C -> T
Yes


2146
A -> C
Yes


2162
G -> A
Yes


2322
C -> G
Yes


2349
A -> G
Yes


2435
G -> A
Yes


2540
C -> T
No


2677
C -> T
Yes


2975
C -> T
Yes


3115
T -> C
Yes


3146
G -> T
Yes


3219
G -> A
Yes


3377
A -> C
Yes


3456
T -> C
Yes


3611
G -> T
Yes


3718
A -> G
Yes


3785
C -> A
Yes


3859
C -> T
Yes


3862
G -> C
Yes


3870
T -> A
Yes


3873
G -> C
Yes


3875
C -> T
Yes


4027
G -> A
Yes


4034
T -> C
Yes


4115
C -> G
Yes


4120
C -> T
Yes


4129
G -> T
Yes


4130
G -> C
Yes


4226
G -> A
Yes


4232
C -> G
Yes


4235
G -> A
Yes


4356
G -> T
Yes


4449
A -> T
Yes


4668
A -> G
No


4760
T -> C
Yes


4894
G -> 
No


5395
C -> G
Yes


5487
C -> 
Yes


5511
T -> C
Yes


6050
G -> C
No


6093
G -> A
Yes


6103
A -> C
Yes


6278
A -> C
Yes


6284
G -> A
Yes


6349
A -> C
Yes


6407
C -> T
Yes


6672
C -> T
Yes


6691
C -> T
Yes


7424
C -> A
Yes


7644
C -> T
Yes


7809
A -> C
Yes









Variant protein HSCOC4_PEA1_P30 (SEQ ID NO:353) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T40 (SEQ ID NO:33). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P30 (SEQ ID NO:353) and CO4_HUMAN_V3 (SEQ ID NO:390):


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P30 (SEQ ID NO:353), comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSVVPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGS corresponding to amino acids 1-1232 of CO4_HUMAN_V3 (SEQ ID NO:390), which also corresponds to amino acids 1-1232 of HSCOC4_PEA1_P30 (SEQ ID NO:353), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence RNPVRLLQPRAQMFCVLRGTK (SEQ ID NO: 557) corresponding to amino acids 1233-1253 of HSCOC4_PEA1_P30 (SEQ ID NO:353), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P30 (SEQ ID NO:353), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence RNPVRLLQPRAQMFCVLRGTK (SEQ ID NO: 557) in HSCOC4_PEA1_P30 (SEQ ID NO:353).


It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V3 (SEQ ID NO:390). These changes were previously known to occur and are listed in the table below.









TABLE 184







Changes to CO4_HUMAN_V3 (SEQ ID NO:390)










SNP position(s) on




amino acid sequence
Type of change







1177
Variant



1202
Variant



1208
Variant



1211
Variant










The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSCOC4_PEA1_P30 (SEQ ID NO:353) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 185, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P30 (SEQ ID NO:353) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 185







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












128
Q -> 
No


141
L -> V
Yes


183
G -> 
No


211
G -> 
No


322
A -> 
No


322
A -> V
No


347
S -> Y
Yes


423
Q -> 
No


478
P -> L
Yes


549
H -> P
Yes


608
L -> V
Yes


617
K -> E
Yes


726
P -> L
Yes


872
V -> A
Yes


907
A -> T
Yes


959
E -> D
Yes


1073
D -> G
Yes


1120
P -> L
Yes


1121
C -> S
Yes


1124
L -> I 
Yes


1125
D -> H
Yes


1176
S -> N
Yes


1207
A -> V
Yes


1210
R -> L
Yes









Variant protein HSCOC4_PEA1_P30 (SEQ ID NO:353) is encoded by the following transcript(s): HSCOC4_PEA1_T40 (SEQ ID NO:33), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T40 (SEQ ID NO:33) is shown in bold; this coding portion starts at position 501 and ends at position 4259. The transcript also has the following SNPs as listed in Table 186 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P30 (SEQ ID NO:353) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 186







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1465
C -> 
No


1465
C -> T
No


1517
C -> T
Yes


1540
C -> A
Yes


1768
A -> 
No


1778
C -> T
Yes


1933
C -> T
Yes


1985
C -> T
Yes


2146
A -> C
Yes


2162
G -> A
Yes


2322
C -> G
Yes


2349
A -> G
Yes


2435
G -> A
Yes


2540
C -> T
No


2677
C -> T
Yes


2975
C -> T
Yes


3115
T -> C
Yes


3146
G -> T
Yes


3219
G -> A
Yes


3377
A -> C
Yes


3456
T -> C
Yes


3611
G -> T
Yes


3718
A -> G
Yes


3785
C -> A
Yes


3859
C -> T
Yes


3862
G -> C
Yes


3870
T -> A
Yes


3873
G -> C
Yes


3875
C -> T
Yes


4027
G -> A
Yes


4034
T -> C
Yes


4115
C -> G
Yes


4120
C -> T
Yes


4129
G -> T
Yes


4130
G -> C
Yes


4348
C -> G
Yes


4559
G -> C
No


4602
G -> A
Yes


4612
A -> C
Yes


4787
A -> C
Yes


4793
G -> A
Yes


4858
A -> C
Yes









Variant protein HSCOC4_PEA1_P38 (SEQ ID NO:354) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T2 (SEQ ID NO:16). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P38 (SEQ ID NO:354) and CO4_HUMAN:


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P38 (SEQ ID NO:354), comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKG corresponding to amino acids 1-818 of CO4_HUMAN, which also corresponds to amino acids 1-818 of HSCOC4_PEA1_P38 (SEQ ID NO:354), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence DVTLSGPQVTLLPFPCTPAPCSLCS (SEQ ID NO: 545) corresponding to amino acids 819-843 of HSCOC4_PEA1_P38 (SEQ ID NO:354), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P38 (SEQ ID NO:354), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DVTLSGPQVTLLPFPCTPAPCSLCS (SEQ ID NO: 545) in HSCOC4_PEA1_P38 (SEQ ID NO:354).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSCOC4_PEA1_P38 (SEQ ID NO:354) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 187, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P38 (SEQ ID NO:354) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 187







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?





128
Q -> 
No


141
L -> V
Yes


183
G -> 
No


211
G -> 
No


322
A -> 
No


322
A -> V
No


347
S -> Y
Yes


423
Q -> 
No


478
P -> L
Yes


549
H -> P
Yes


608
L -> V
Yes


617
K -> E
Yes


726
P -> L
Yes


829
L -> P
Yes


830
L -> I 
Yes


840
S -> P
Yes









The glycosylation sites of variant protein HSCOC4_PEA1_P38 (SEQ ID NO:354), as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 188 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the glycosylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).









TABLE 188







Glycosylation site(s)









Position(s) on known
Present in
Position in


amino acid sequence
variant protein?
variant protein?












1391
No



862
No


226
Yes
226


1328
No









The phosphorylation sites of variant protein HSCOC4_PEA1_P38 (SEQ ID NO:354), as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 189 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the phosphorylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).









TABLE 189







Phosphorylation site(s)









Position(s) on known
Present in
Position in


amino acid sequence
variant protein?
variant protein?





1420
No



1422
No


1417
No









Variant protein HSCOC4_PEA1_P38 (SEQ ID NO:354) is encoded by the following transcript(s): HSCOC4_PEA1_T2 (SEQ ID NO:16), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T2 (SEQ ID NO:16) is shown in bold; this coding portion starts at position 501 and ends at position 3029. The transcript also has the following SNPs as listed in Table 190 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P38 (SEQ ID NO:354) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 190







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1465
C -> 
No


1465
C -> T
No


1517
C -> T
Yes


1540
C -> A
Yes


1768
A -> 
No


1778
C -> T
Yes


1933
C -> T
Yes


1985
C -> T
Yes


2146
A -> C
Yes


2162
G -> A
Yes


2322
C -> G
Yes


2349
A -> G
Yes


2435
G -> A
Yes


2540
C -> T
No


2677
C -> T
Yes


2986
T -> C
Yes


2988
C -> A
Yes


3018
T -> C
Yes


3070
C -> T
Yes


3081
C -> A
Yes


3093
A -> G
Yes


3101
G -> A
Yes


3106
G -> A
Yes


3174
G -> A
Yes


3193
A -> G
Yes


3201
T -> C
Yes


3233
C -> T
Yes


3373
T -> C
Yes


3404
G -> T
Yes


3477
G -> A
Yes


3635
A -> C
Yes


3714
T -> C
Yes


3869
G -> T
Yes


3976
A -> G
Yes


4043
C -> A
Yes


4117
C -> T
Yes


4120
G -> C
Yes


4128
T -> A
Yes


4131
G -> C
Yes


4133
C -> T
Yes


4285
G -> A
Yes


4292
T -> C
Yes


4373
C -> G
Yes


4378
C -> T
Yes


4387
G -> T
Yes


4388
G -> C
Yes


4484
G -> A
Yes


4490
C -> G
Yes


4493
G -> A
Yes


4614
G -> T
Yes


4707
A -> T
Yes


4926
A -> G
No


5018
T -> C
Yes


5152
G -> 
No


5568
C -> G
Yes


5779
G -> C
No


5822
G -> A
Yes


5832
A -> C
Yes


6007
A -> C
Yes


6013
G -> A
Yes


6078
A -> C
Yes









Variant protein HSCOC4_PEA1_P39 (SEQ ID NO:355) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T5 (SEQ ID NO:19). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P39 (SEQ ID NO:355) and CO4_HUMAN:


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P39 (SEQ ID NO:355), comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQ corresponding to amino acids 1-387 of CO4_HUMAN, which also corresponds to amino acids 1-387 of HSCOC4_PEA1_P39 (SEQ ID NO:355), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence VSSRGEG (SEQ ID NO: 559) corresponding to amino acids 388-394 of HSCOC4_PEA1_P39 (SEQ ID NO:355), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P39 (SEQ ID NO:355), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VSSRGEG (SEQ ID NO: 559) in HSCOC4_PEA1_P39 (SEQ ID NO:355).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSCOC4_PEA1_P39 (SEQ ID NO:355) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 191, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P39 (SEQ ID NO:355) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 191







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?





128
Q -> 
No


141
L -> V
Yes


183
G -> 
No


211
G -> 
No


322
A -> 
No


322
A -> V
No


347
S -> Y
Yes









The glycosylation sites of variant protein HSCOC4_PEA1_P39 (SEQ ID NO:355), as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 192 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the glycosylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).









TABLE 192







Glycosylation site(s)









Position(s) on known
Present in
Position in


amino acid sequence
variant protein?
variant protein?












1391
No



862
No


226
Yes
226


1328
No









The phosphorylation sites of variant protein HSCOC4_PEA1_P39 (SEQ ID NO:355), as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 193 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the phosphorylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).









TABLE 193







Phosphorylation site(s)










Position(s) on known
Present in



amino acid sequence
variant protein?







1420
No



1422
No



1417
No










Variant protein HSCOC4_PEA1_P39 (SEQ ID NO:355) is encoded by the following transcript(s): HSCOC4_PEA1_T5 (SEQ ID NO:19), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T5 (SEQ ID NO:19) is shown in bold; this coding portion starts at position 501 and ends at position 1682. The transcript also has the following SNPs as listed in Table 194 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC_C4_PEA1_P39 (SEQ ID NO:355) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 194







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1465
C -> 
No


1465
C -> T
No


1517
C -> T
Yes


1540
C -> A
Yes


1742
C -> A
Yes


1756
C -> A
Yes


1867
A -> 
No


1877
C -> T
Yes


2032
C -> T
Yes


2084
C -> T
Yes


2245
A -> C
Yes


2261
G -> A
Yes


2421
C -> G
Yes


2448
A -> G
Yes


2534
G -> A
Yes


2639
C -> T
No


2776
C -> T
Yes


3074
C -> T
Yes


3214
T -> C
Yes


3245
G -> T
Yes


3318
G -> A
Yes


3476
A -> C
Yes


3555
T -> C
Yes


3710
G -> T
Yes


3817
A -> G
Yes


3884
C -> A
Yes


3958
C -> T
Yes


3961
G -> C
Yes


3969
T -> A
Yes


3972
G -> C
Yes


3974
C -> T
Yes


4126
G -> A
Yes


4133
T -> C
Yes


4214
C -> G
Yes


4219
C -> T
Yes


4228
G -> T
Yes


4229
G -> C
Yes


4325
G -> A
Yes


4331
C -> G
Yes


4334
G -> A
Yes


4455
G -> T
Yes


4548
A -> T
Yes


4767
A -> G
No


4859
T -> C
Yes


4993
G -> 
No


5409
C -> G
Yes


5620
G -> C
No


5663
G -> A
Yes


5673
A -> C
Yes


5848
A -> C
Yes


5854
G -> A
Yes


5919
A -> C
Yes









Variant protein HSCOC4_PEA1_P40 (SEQ ID NO:356) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T7 (SEQ ID NO:20). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P40 (SEQ ID NO:356) and CO4_HUMAN:


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P40 (SEQ ID NO:356), comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKY corresponding to amino acids 1-236 of CO4_HUMAN, which also corresponds to amino acids 1-236 of HSCOC4_PEA1_P40 (SEQ ID NO:356), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence AGEWTEPHFPLKGRVPGRPGEAEYGHY (SEQ ID NO: 560) corresponding to amino acids 237-263 of HSCOC4_PEA1_P40 (SEQ ID NO:356), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P40 (SEQ ID NO:356), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence AGEWTEPHFPLKGRVPGRPGEAEYGHY (SEQ ID NO: 560) in HSCOC4_PEA1_P40 (SEQ ID NO:356).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSCOC4_PEA1_P40 (SEQ ID NO:356) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 195, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P40 (SEQ ID NO:356) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 195







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?





128
Q -> 
No


141
L -> V
Yes


183
G -> 
No


211
G -> 
No


254
R -> 
No









The glycosylation sites of variant protein HSCOC4_PEA1_P40 (SEQ ID NO:356), as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 196 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the glycosylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).









TABLE 196







Glycosylation site(s)









Position(s) on known
Present in
Position in


amino acid sequence
variant protein?
variant protein?












1391
No



862
No


226
Yes
226


1328
No









The phosphorylation sites of variant protein HSCOC4_PEA1_P40 (SEQ ID NO:356), as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 197 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the phosphorylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).









TABLE 197







Phosphorylation site(s)










Position(s) on known
Present in



amino acid sequence
variant protein?







1420
No



1422
No



1417
No










Variant protein HSCOC4_PEA1_P40 (SEQ ID NO:356) is encoded by the following transcript(s): HSCOC4_PEA1_T7 (SEQ ID NO:20), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T7 (SEQ ID NO:20) is shown in bold; this coding portion starts at position 501 and ends at position 1289. The transcript also has the following SNPs as listed in Table 198 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P40 (SEQ ID NO:356) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 198







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1262
C -> 
No


1262
C -> T
No


1314
C -> T
Yes


1337
C -> A
Yes


1565
A -> 
No


1575
C -> T
Yes


1730
C -> T
Yes


1782
C -> T
Yes


1943
A -> C
Yes


1959
G -> A
Yes


2119
C -> G
Yes


2146
A -> G
Yes


2232
G -> A
Yes


2337
C -> T
No


2474
C -> T
Yes


2772
C -> T
Yes


2912
T -> C
Yes


2943
G -> T
Yes


3016
G -> A
Yes


3174
A -> C
Yes


3253
T -> C
Yes


3408
G -> T
Yes


3515
A -> G
Yes


3582
C -> A
Yes


3656
C -> T
Yes


3659
G -> C
Yes


3667
T -> A
Yes


3670
G -> C
Yes


3672
C -> T
Yes


3824
G -> A
Yes


3831
T -> C
Yes


3912
C -> G
Yes


3917
C -> T
Yes


3926
G -> T
Yes


3927
G -> C
Yes


4023
G -> A
Yes


4029
C -> G
Yes


4032
G -> A
Yes


4153
G -> T
Yes


4246
A -> T
Yes


4465
A -> G
No


4557
T -> C
Yes


4691
G -> 
No


5107
C -> G
Yes


5318
G -> C
No


5361
G -> A
Yes


5371
A -> C
Yes


5546
A -> C
Yes


5552
G -> A
Yes


5617
A -> C
Yes









Variant protein HSCOC4_PEA1_P41 (SEQ ID NO:357) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T8 (SEQ ID NO:21). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P41 (SEQ ID NO:357) and CO4_HUMAN_V1 (SEQ ID NO:389):


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P41 (SEQ ID NO:357), comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSVVPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIEVTVKGHVE YTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNRRRREAPKVVEEQESRV HYTVCIWRNGKVGLSGMAIADVTLLSGFHALRADLEKLTSLSDRYVSHFETEGPHVLL YFDSV corresponding to amino acids 1-1529 of CO4_HUMAN_VI (SEQ ID NO:389), which also corresponds to amino acids 1-1529 of HSCOC4_PEA1_P41 (SEQ ID NO:357), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SGER (SEQ ID NO: 551) corresponding to amino acids 1530-1533 of HSCOC4_PEA1_P41 (SEQ ID NO:357), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P41 (SEQ ID NO:357), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SGER (SEQ ID NO: 551) in HSCOC4_PEA1_P41 (SEQ ID NO:357).


It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1 (SEQ ID NO:389). These changes were previously known to occur and are listed in the table below.









TABLE 199







Changes to CO4_HUMAN_V1 (SEQ ID NO:389)










SNP position(s) on




amino acid sequence
Type of change







1177
Variant



1202
Variant



1208
Variant



1211
Variant



1287
Variant










The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because of manual inspection of known protein localization and/or gene structure.


Variant protein HSCOC4_PEA1_P41 (SEQ ID NO:357) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 200, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P41 (SEQ ID NO:357) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 200







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












128
Q -> 
No


141
L -> V
Yes


183
G -> 
No


211
G -> 
No


322
A -> V
No


322
A -> 
No


347
S -> Y
Yes


423
Q -> 
No


478
P -> L
Yes


549
H -> P
Yes


608
L -> V
Yes


617
K -> E
Yes


726
P -> L
Yes


872
V -> A
Yes


907
A -> T
Yes


959
E -> D
Yes


1073
D -> G
Yes


1120
P -> L
Yes


1121
C -> S
Yes


1124
L -> I 
Yes


1125
D -> H
Yes


1176
S -> N
Yes


1207
A -> V
Yes


1210
R -> L
Yes


1286
A -> S
Yes


1317
 I -> F
Yes


1390
K -> E
No


1465
R -> 
No









Variant protein HSCOC4_PEA1_P41 (SEQ ID NO:357) is encoded by the following transcript(s): HSCOC4_PEA1_T8 (SEQ ID NO:21), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T8 (SEQ ID NO:21) is shown in bold; this coding portion starts at position 501 and ends at position 5099. The transcript also has the following SNPs as listed in Table 201 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P41 (SEQ ID NO:357) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 201







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1465
C -> 
No


1465
C -> T
No


1517
C -> T
Yes


1540
C -> A
Yes


1768
A -> 
No


1778
C -> T
Yes


1933
C -> T
Yes


1985
C -> T
Yes


2146
A -> C
Yes


2162
G -> A
Yes


2322
C -> G
Yes


2349
A -> G
Yes


2435
G -> A
Yes


2540
C -> T
No


2677
C -> T
Yes


2975
C -> T
Yes


3115
T -> C
Yes


3146
G -> T
Yes


3219
G -> A
Yes


3377
A -> C
Yes


3456
T -> C
Yes


3611
G -> T
Yes


3718
A -> G
Yes


3785
C -> A
Yes


3859
C -> T
Yes


3862
G -> C
Yes


3870
T -> A
Yes


3873
G -> C
Yes


3875
C -> T
Yes


4027
G -> A
Yes


4034
T -> C
Yes


4115
C -> G
Yes


4120
C -> T
Yes


4129
G -> T
Yes


4130
G -> C
Yes


4226
G -> A
Yes


4232
C -> G
Yes


4235
G -> A
Yes


4356
G -> T
Yes


4449
A -> T
Yes


4668
A -> G
No


4760
T -> C
Yes


4894
G -> 
No


5561
G -> A
Yes


6026
T -> G
Yes


6348
G -> C
Yes


6801
C -> G
Yes


7012
G -> C
No


7055
G -> A
Yes


7065
A -> C
Yes


7240
A -> C
Yes


7246
G -> A
Yes


7311
A -> C
Yes









Variant protein HSCOC4_PEA1_P42 (SEQ ID NO:358) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA1_T12 (SEQ ID NO:23). An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSCOC4_PEA1_P42 (SEQ ID NO:358) and CO4_HUMAN_V1 (SEQ ID NO:389):


1. An isolated chimeric polypeptide encoding for HSCOC4_PEA1_P42 (SEQ ID NO:358), comprising a first amino acid sequence being at least 90% homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSVVPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIEVTVKGHVE YTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNRRRREAPKVVEEQESRV HYTVCIW corresponding to amino acids 1-1473 of CO4_HUMAN_V1 (SEQ ID NO:389), which also corresponds to amino acids 1-1473 of HSCOC4_PEA1_P42 (SEQ ID NO:358), a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence WAPGAALGQGREGRTQAGAGLLEPAQAEPGRQLTRLHR (SEQ ID NO: 562) corresponding to amino acids 1474-1511 of HSCOC4_PEA1_P42 (SEQ ID NO:358), a third amino acid sequence being at least 90% homologous to RNGKVGLSGMAIADVTLLSGFHALRADLEK corresponding to amino acids 1474-1503 of CO4_HUMAN_V1 (SEQ ID NO:389), which also corresponds to amino acids 1512-1541 of HSCOC4_PEA1_P42 (SEQ ID NO:358), and a fourth amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence VWSATQGNPLCPRY (SEQ ID NO: 563) corresponding to amino acids 1542-1555 of HSCOC4_PEA1_P42 (SEQ ID NO:358), wherein said first amino acid sequence, second amino acid sequence, third amino acid sequence and fourth amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for an edge portion of HSCOC4_PEA1_P42 (SEQ ID NO:358), comprising an amino acid sequence being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence encoding for WAPGAALGQGREGRTQAGAGLLEPAQAEPGRQLTRLHR (SEQ ID NO: 562), corresponding to HSCOC4_PEA1_P42 (SEQ ID NO:358).


3. An isolated polypeptide encoding for a tail of HSCOC4_PEA1_P42 (SEQ ID NO:358), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VWSATQGNPLCPRY (SEQ ID NO: 563) in HSCOC4_PEA1_P42 (SEQ ID NO:358).


It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1 (SEQ ID NO:389). These changes were previously known to occur and are listed in the table below.









TABLE 202







Changes to CO4_HUMAN_V1 (SEQ ID NO:389)










SNP position(s) on




amino acid sequence
Type of change







1177
Variant



1202
Variant



1208
Variant



1211
Variant



1287
Variant










The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSCOC4_PEA1_P42 (SEQ ID NO:358) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 203, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P42 (SEQ ID NO:358) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 203







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












128
Q -> 
No


141
L -> V
Yes


183
G -> 
No


211
G -> 
No


322
A -> V
No


322
A -> 
No


347
S -> Y
Yes


423
Q -> 
No


478
P -> L
Yes


549
H -> P
Yes


608
L -> V
Yes


617
K -> E
Yes


726
P -> L
Yes


872
V -> A
Yes


907
A -> T
Yes


959
E -> D
Yes


1073
D -> G
Yes


1120
P -> L
Yes


1121
C -> S
Yes


1124
L -> I 
Yes


1125
D -> H
Yes


1176
S -> N
Yes


1207
A -> V
Yes


1210
R -> L
Yes


1286
A -> S
Yes


1317
 I -> F
Yes


1390
K -> E
No


1465
R -> 
No









Variant protein HSCOC4_PEA1_P42 (SEQ ID NO:358) is encoded by the following transcript(s): HSCOC4_PEA1_T12 (SEQ ID NO:23), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA1_T12 (SEQ ID NO:23) is shown in bold; this coding portion starts at position 501 and ends at position 5165. The transcript also has the following SNPs as listed in Table 204 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA1_P42 (SEQ ID NO:358) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 204







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












304
A -> G
Yes


884
G -> 
No


921
C -> G
Yes


1049
C -> 
No


1131
G -> 
No


1465
C -> 
No


1465
C -> T
No


1517
C -> T
Yes


1540
C -> A
Yes


1768
A -> 
No


1778
C -> T
Yes


1933
C -> T
Yes


1985
C -> T
Yes


2146
A -> C
Yes


2162
G -> A
Yes


2322
C -> G
Yes


2349
A -> G
Yes


2435
G -> A
Yes


2540
C -> T
No


2677
C -> T
Yes


2975
C -> T
Yes


3115
T -> C
Yes


3146
G -> T
Yes


3219
G -> A
Yes


3377
A -> C
Yes


3456
T -> C
Yes


3611
G -> T
Yes


3718
A -> G
Yes


3785
C -> A
Yes


3859
C -> T
Yes


3862
G -> C
Yes


3870
T -> A
Yes


3873
G -> C
Yes


3875
C -> T
Yes


4027
G -> A
Yes


4034
T -> C
Yes


4115
C -> G
Yes


4120
C -> T
Yes


4129
G -> T
Yes


4130
G -> C
Yes


4226
G -> A
Yes


4232
C -> G
Yes


4235
G -> A
Yes


4356
G -> T
Yes


4449
A -> T
Yes


4668
A -> G
No


4760
T -> C
Yes


4894
G -> 
No


5765
G -> A
Yes


6230
T -> G
Yes


6552
G -> C
Yes


7005
C -> G
Yes


7216
G -> C
No


7259
G -> A
Yes


7269
A -> C
Yes


7444
A -> C
Yes


7450
G -> A
Yes


7515
A -> C
Yes









As noted above, cluster HSCOC4 features 79 segment(s), which were listed in Table 2 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.


Segment cluster HSCOC4_PEA1_node1 (SEQ ID NO:143) according to the present invention is supported by 24 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO: 17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO: 19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO: 21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 205 below describes the starting and ending position of this segment on each transcript.









TABLE 205







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HSCOC4_PEA_1_T1 (SEQ ID
1
535


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
1
535


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
1
535


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
1
535


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
1
535


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
1
535


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
1
535


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
1
535


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
1
535


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
1
535


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
1
535


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
1
535


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
1
535


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
1
535


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
1
535


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
1
535


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
1
535


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
1
535


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
1
535


NO:33)









Segment cluster HSCOC4_PEA1_node5 (SEQ ID NO:144) according to the present invention is supported by 29 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO: 19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO: 21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 206 below describes the starting and ending position of this segment on each transcript.









TABLE 206







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HSCOC4_PEA_1_T1 (SEQ ID
566
764


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
566
764


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
566
764


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
566
764


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
566
764


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
566
764


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
566
764


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
566
764


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
566
764


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
566
764


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
566
764


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
566
764


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
566
764


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
566
764


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
566
764


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
566
764


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
566
764


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
566
764


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
566
764


NO:33)









Segment cluster HSCOC4_PEA1_node7 (SEQ ID NO:145) according to the present invention is supported by 35 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO: 19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO: 21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 207 below describes the starting and ending position of this segment on each transcript.









TABLE 207







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HSCOC4_PEA_1_T1 (SEQ ID
765
885


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
765
885


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
765
885


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
765
885


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
765
885


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
765
885


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
765
885


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
765
885


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
765
885


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
765
885


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
765
885


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
765
885


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
765
885


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
765
885


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
765
885


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
765
885


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
765
885


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
765
885


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
765
885


NO:33)









Segment cluster HSCOC4_PEA1_node30 (SEQ ID NO:146) according to the present invention is supported by 35 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO: 19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO: 21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 208 below describes the starting and ending position of this segment on each transcript.









TABLE 208







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HSCOC4_PEA_1_T1 (SEQ ID
1662
1841


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
1662
1841


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
1662
1841


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
1662
1841


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
1761
1940


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
1459
1638


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
1662
1841


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
1662
1841


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
1662
1841


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
1662
1841


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
1662
1841


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
1662
1841


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
1662
1841


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
1662
1841


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
1662
1841


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
1662
1841


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
1662
1841


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
1662
1841


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
1662
1841


NO:33)









Segment cluster HSCOC4_PEA1_node33 (SEQ ID NO:147) according to the present invention is supported by 30 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T 11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23) HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 209 below describes the starting and ending position of this segment on each transcript.









TABLE 209







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HSCOC4_PEA_1_T1 (SEQ ID
1842
2024


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
1842
2024


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
1842
2024


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
1842
2024


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
1941
2123


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
1639
1821


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
1842
2024


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
1842
2024


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
1842
2024


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
1842
2024


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
1842
2024


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
1842
2024


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
1842
2024


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
1842
2024


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
1842
2024


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
1842
2024


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
1842
2024


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
1842
2024


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
1842
2024


NO:33)









Segment cluster HSCOC4_PEA1_node35 (SEQ ID NO:148) according to the present invention is supported by 31 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T 11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29) HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 210 below describes the starting and ending position of this segment on each transcript.









TABLE 210







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HSCOC4_PEA_1_T1 (SEQ ID
2025
2210


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
2025
2210


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
2025
2210


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
2025
2210


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
2124
2309


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
1822
2007


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
2025
2210


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
2025
2210


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
2025
2210


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
2025
2210


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
2025
2210


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
2025
2210


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
2025
2210


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
2025
2210


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
2025
2210


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
2025
2210


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
2025
2210


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
2025
2210


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
2025
2210


NO:33)









Segment cluster HSCOC4_PEA1_node37 (SEQ ID NO:149) according to the present invention is supported by 33 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T 11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 211 below describes the starting and ending position of this segment on each transcript.









TABLE 211







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HSCOC4_PEA_1_T1 (SEQ ID
2211
2369


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
2211
2369


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
2211
2369


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
2211
2369


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
2310
2468


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
2008
2166


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
2211
2369


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
2211
2369


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
2211
2369


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
2211
2369


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
2211
2369


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
2211
2369


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
2211
2369


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
2211
2369


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
2211
2369


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
2211
2369


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
2211
2369


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
2211
2369


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
2211
2369


NO:33)









Segment cluster HSCOC4_PEA1_node39 (SEQ ID NO:150) according to the present invention is supported by 35 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19) HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 212 below describes the starting and ending position of this segment on each transcript.









TABLE 212







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HSCOC4_PEA_1_T1 (SEQ ID
2370
2496


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
2370
2496


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
2370
2496


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
2370
2496


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
2469
2595


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
2167
2293


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
2370
2496


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
2370
2496


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
2370
2496


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
2370
2496


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
2370
2496


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
2370
2496


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
2370
2496


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
2370
2496


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
2370
2496


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
2370
2496


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
2370
2496


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
2370
2496


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
2370
2496


NO:33)









Segment cluster HSCOC4_PEA1_node43 (SEQ ID NO:151) according to the present invention is supported by 34 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23) HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4 PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 213 below describes the starting and ending position of this segment on each transcript.









TABLE 213







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HSCOC4_PEA_1_T1 (SEQ ID
2572
2769


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
2572
2769


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
2572
2769


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
2572
2769


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
2671
2868


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
2369
2566


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
2572
2769


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
2572
2769


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
2572
2769


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
2572
2769


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
2572
2769


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
2572
2769


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
2572
2769


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
2572
2769


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
2572
2769


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
2572
2769


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
2572
2769


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
2572
2769


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
2572
2769


NO:33)









Segment cluster HSCOC4_PEA1_node48 (SEQ ID NO:152) according to the present invention is supported by 2 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T2 (SEQ ID NO:16) and HSCOC4_PEA1_T3 (SEQ ID NO:17). Table 214 below describes the starting and ending position of this segment on each transcript.









TABLE 214







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HSCOC4_PEA_1_T2 (SEQ ID
2953
3210


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
2953
3210


NO:17)









Segment cluster HSCOC4_PEA1_node49 (SEQ ID NO:153) according to the present invention is supported by 37 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:151, HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 215 below describes the starting and ending position of this segrnent on each transcript.









TABLE 215







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HSCOC4_PEA_1_T1 (SEQ ID
2953
3092


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
3211
3350


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
3211
3350


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
2953
3092


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
3052
3191


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
2750
2889


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
2953
3092


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
2953
3092


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
2953
3092


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
2953
3092


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
2953
3092


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
2953
3092


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
2953
3092


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
2953
3092


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
2953
3092


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
2953
3092


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
2953
3092


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
2953
3092


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
2953
3092


NO:33)









Segment cluster HSCOC4_PEA1_node51 (SEQ ID NO:154) according to the present invention is supported by 40 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA 11T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 216 below describes the starting and ending position of this segment on each transcript.









TABLE 216







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
3206
3415


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
3351
3560


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
3464
3673


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
3093
3302


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
3192
3401


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
2890
3099


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
3093
3302


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
3093
3302


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
3093
3302


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
3093
3302


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
3093
3302


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
3093
3302


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
3093
3302


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
3093
3302


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
3093
3302


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
3093
3302


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
3093
3302


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
3093
3302


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
3093
3302


NO:33)









Segment cluster HSCOC4_PEA1_node58 (SEQ ID NO:155) according to the present invention is supported by 52 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 217 below describes the starting and ending position of this segment on each transcript.









TABLE 217







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
3605
3767


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
3750
3912


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
3863
4025


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
3492
3654


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
3591
3753


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
3289
3451


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
3492
3654


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
3492
3654


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
3492
3654


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
3492
3654


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
3492
3654


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
3492
3654


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
3492
3654


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
3492
3654


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
3492
3654


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
3492
3654


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
3492
3654


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
3492
3654


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
3492
3654


NO:33)









Segment cluster HSCOC4_PEA1_node59 (SEQ ID NO:156) according to the present invention is supported by 8 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T4 (SEQ ID NO:18). Table 218 below describes the starting and ending position of this segment on each transcript.









TABLE 218







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T4 (SEQ ID
3655
3833


NO:18)









Segment cluster HSCOC4_PEA1_node62 (SEQ ID NO:157) according to the present invention is supported by 61 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 219 below describes the starting and ending position of this segment on each transcript.









TABLE 219







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
3844
4000


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
3989
4145


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
4102
4258


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
3910
4066


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
3830
3986


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
3528
3684


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
3731
3887


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
3731
3887


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
3731
3887


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
3731
3887


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
3731
3887


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
3731
3887


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
3731
3887


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
3731
3887


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
3731
3887


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
3731
3887


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
3731
3887


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
3731
3887


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
3731
3887


NO:33)









Segment cluster HSCOC4_PEA1_node66 (SEQ ID NO:158) according to the present invention is supported by 65 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 220 below describes the starting and ending position of this segment on each transcript.









TABLE 220







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
4118
4289


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
4263
4434


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
4376
4547


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
4184
4355


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
4104
4275


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
3802
3973


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
4005
4176


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
4005
4176


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
4005
4176


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
4005
4176


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
4005
4176


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
4005
4176


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
4005
4176


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
4005
4176


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
4005
4176


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
4005
4176


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
4005
4176


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
4005
4176


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
4005
4176


NO:33)









Segment cluster HSCOC4_PEA1_node72 (SEQ ID NO:159) according to the present invention is supported by 65 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4 PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 221 below describes the starting and ending position of this segment on each transcript.









TABLE 221







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
4392
4522


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
4537
4667


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
4650
4780


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
4458
4588


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
4378
4508


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4076
4206


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
4279
4409


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
4279
4409


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
4279
4409


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
4279
4409


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
4279
4409


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
4279
4409


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
4279
4409


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
4279
4409


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
4279
4409


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
4279
4409


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
4279
4409


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
4279
4409


NO:32)









Segment cluster HSCOC4_PEA1_node77 (SEQ ID NO:160) according to the present invention is supported by 2 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T14 (SEQ ID NO:24) and HSCOC4_PEA1_T20 (SEQ ID NO:26). Table 222 below describes the starting and ending position of this segment on each transcript.









TABLE 222







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T14 (SEQ ID
4578
4970


NO:24)


HSCOC4_PEA_1_T20 (SEQ ID
4660
5052


NO:26)









Segment cluster HSCOC4_PEA1_node79 (SEQ ID NO:161) according to the present invention is supported by 6 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T11 (SEQ ID NO:22). Table 223 below describes the starting and ending position of this segment on each transcript.









TABLE 223







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T11 (SEQ ID
4638
5686


NO:22)









Segment cluster HSCOC4_PEA1_node93 (SEQ ID NO:162) according to the present invention is supported by 25 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T12 (SEQ ID NO:23) and HSCOC4_PEA1_T21 (SEQ ID NO:27). Table 224 below describes the starting and ending position of this segment on each transcript.









TABLE 224







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T8 (SEQ ID
5085
6566


NO:21)


HSCOC4_PEA_1_T12 (SEQ ID
5289
6770


NO:23)


HSCOC4_PEA_1_T21 (SEQ ID
5085
6566


NO:27)









Segment cluster HSCOC4_PEA1_node100 (SEQ ID NO:163) according to the present invention is supported by 13 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T21 (SEQ ID NO:27). Table 225 below describes the starting and ending position of this segment on each transcript.









TABLE 225







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T21 (SEQ ID
6679
6843


NO:27)









Segment cluster HSCOC4_PEA1_node105 (SEQ ID NO:164) according to the present invention is supported by 9 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T28 (SEQ ID NO:29) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 226 below describes the starting and ending position of this segment on each transcript.









TABLE 226







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T28 (SEQ ID
5377
5558


NO:29)


HSCOC4_PEA_1_T32 (SEQ ID
5462
5643


NO:32)









Segment cluster HSCOC4_PEA1_node107 (SEQ ID NO:165) according to the present invention is supported by 27 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 227 below describes the starting and ending position of this segment on each transcript.









TABLE 227







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T25 (SEQ ID
5461
5722


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
5643
5904


NO:29)


HSCOC4_PEA_1_T32 (SEQ ID
5728
5989


NO:32)









Segment cluster HSCOC4_PEA1_node108 (SEQ ID NO:166) according to the present invention is supported by 120 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 228 below describes the starting and ending position of this segment on each transcript.









TABLE 228







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
5574
5706


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
5719
5851


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5832
5964


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
5640
5772


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
5560
5692


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
5258
5390


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
6952
7084


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
6510
6642


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
7156
7288


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5854
5986


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
5414
5546


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5936
6068


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
7117
7249


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
5723
5855


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
5905
6037


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
5358
5490


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
5546
5678


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
5990
6122


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
4499
4631


NO:33)









Segment cluster HSCOC4_PEA1_node109 (SEQ ID NO:167) according to the present invention is supported by 12 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T25 (SEQ ID NO:28) and HSCOC4_PEA1_T28 (SEQ ID NO:29). Table 229 below describes the starting and ending position of this segment on each transcript.









TABLE 229







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T25 (SEQ ID
5856
5998


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
6038
6180


NO:29)









Segment cluster HSCOC4_PEA1_node110 (SEQ ID NO:168) according to the present invention is supported by 97 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15, HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 230 below describes the starting and ending position of this segment on each transcript.









TABLE 230







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
5707
5856


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
5852
6001


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5965
6114


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
5773
5922


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
5693
5842


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
5391
5540


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
7085
7234


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
6643
6792


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
7289
7438


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5987
6136


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
5547
5696


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
6069
6218


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
7250
7399


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
5999
6148


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
6181
6330


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
5491
5640


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
5679
5828


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
6123
6272


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
4632
4781


NO:33)









Segment cluster HSCOC4_PEA1_node112 (SEQ ID NO:169) according to the present invention is supported by 71 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 231 below describes the starting and ending position of this segment on each transcript.









TABLE 231







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
5948
5989


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
6093
6134


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
6206
6247


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
6014
6055


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
5934
5975


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
5632
5673


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
7326
7367


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
6884
6925


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
7530
7571


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
6228
6269


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
5788
5829


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
6310
6351


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
7491
7532


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
6240
6619


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
6422
6801


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
5732
5773


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
5920
5961


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
6364
6743


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
4873
4914


NO:33)









Segment cluster HSCOC4_PEA1_node113 (SEQ ID NO:170) according to the present invention is supported by 19 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 232 below describes the starting and ending position of this segment on each transcript.









TABLE 232







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T25 (SEQ ID
6620
7765


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
6802
7947


NO:29)


HSCOC4_PEA_1_T32 (SEQ ID
6744
7889


NO:32)









According to an optional embodiment of the present invention, short segments related to the above cluster are also provided. These segments are up to about 120 bp in length, and so are included in a separate description.


Segment cluster HSCOC4_PEA1_node2 (SEQ ID NO:171) according to the present invention is supported by 25 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 233 below describes the starting and ending position of this segment on each transcript.









TABLE 233







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
536
565


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
536
565


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
536
565


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
536
565


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
536
565


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
536
565


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
536
565


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
536
565


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
536
565


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
536
565


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
536
565


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
536
565


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
536
565


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
536
565


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
536
565


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
536
565


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
536
565


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
536
565


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
536
565


NO:33)









Segment cluster HSCOC4_PEA1_node8 (SEQ ID NO:172) according to the present invention is supported by 35 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 234 below describes the starting and ending position of this segment on each transcript.









TABLE 234







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
886
966


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
886
966


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
886
966


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
886
966


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
886
966


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
886
966


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
886
966


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
886
966


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
886
966


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
886
966


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
886
966


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
886
966


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
886
966


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
886
966


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
886
966


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
886
966


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
886
966


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
886
966


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
886
966


NO:33)









Segment cluster HSCOC4_PEA1_node10 (SEQ ID NO:173) according to the present invention is supported by 33 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 235 below describes the starting and ending position of this segment on each transcript.









TABLE 235







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
967
1037


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
967
1037


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
967
1037


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
967
1037


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
967
1037


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
967
1037


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
967
1037


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
967
1037


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
967
1037


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
967
1037


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
967
1037


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
967
1037


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
967
1037


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
967
1037


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
967
1037


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
967
1037


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
967
1037


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
967
1037


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
967
1037


NO:33)









Segment cluster HSCOC4_PEA1_node12 (SEQ ID NO:174) according to the present invention is supported by 33 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4 PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 236 below describes the starting and ending position of this segment on each transcript.









TABLE 236







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
1038
1126


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
1038
1126


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
1038
1126


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
1038
1126


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
1038
1126


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
1038
1126


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
1038
1126


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
1038
1126


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
1038
1126


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
1038
1126


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
1038
1126


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
1038
1126


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
1038
1126


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
1038
1126


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
1038
1126


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
1038
1126


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
1038
1126


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
1038
1126


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
1038
1126


NO:33)









Segment cluster HSCOC4_PEA1_node14 (SEQ ID NO:175) according to the present invention is supported by 30 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 237 below describes the starting and ending position of this segment on each transcript.









TABLE 237







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
1127
1209


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
1127
1209


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
1127
1209


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
1127
1209


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
1127
1209


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
1127
1209


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
1127
1209


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
1127
1209


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
1127
1209


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
1127
1209


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
1127
1209


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
1127
1209


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
1127
1209


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
1127
1209


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
1127
1209


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
1127
1209


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
1127
1209


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
1127
1209


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
1127
1209


NO:33)









Segment cluster HSCOC4_PEA1_node17 (SEQ ID NO:176) according to the present invention is supported by 28 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 238 below describes the starting and ending position of this segment on each transcript.









TABLE 238







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
1210
1306


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
1210
1306


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
1210
1306


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
1210
1306


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
1210
1306


NO:19)


HSCOC4_PEA_1_T8 (SEQ ID
1210
1306


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
1210
1306


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
1210
1306


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
1210
1306


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
1210
1306


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
1210
1306


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
1210
1306


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
1210
1306


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
1210
1306


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
1210
1306


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
1210
1306


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
1210
1306


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
1210
1306


NO:33)









Segment cluster HSCOC4_PEA1_node19 (SEQ ID NO:177) according to the present invention is supported by 27 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4 PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4 PEA1_T30 (SEQ ID NO: 30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 239 below describes the starting and ending position of this segment on each transcript.









TABLE 239







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
1307
1412


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
1307
1412


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
1307
1412


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
1307
1412


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
1307
1412


NO:19)


HSCOC4_PEA_1_T8 (SEQ ID
1307
1412


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
1307
1412


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
1307
1412


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
1307
1412


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
1307
1412


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
1307
1412


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
1307
1412


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
1307
1412


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
1307
1412


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
1307
1412


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
1307
1412


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
1307
1412


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
1307
1412


NO:33)









Segment cluster HSCOC4_PEA1_node21 (SEQ ID NO:178) according to the present invention is supported by 26 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 240 below describes the starting and ending position of this segment on each transcript.









TABLE 240







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
1413
1439


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
1413
1439


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
1413
1439


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
1413
1439


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
1413
1439


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
1210
1236


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
1413
1439


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
1413
1439


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
1413
1439


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
1413
1439


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
1413
1439


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
1413
1439


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
1413
1439


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
1413
1439


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
1413
1439


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
1413
1439


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
1413
1439


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
1413
1439


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
1413
1439


NO:33)









Segment cluster HSCOC4_PEA1_node22 (SEQ ID NO:179) according to the present invention is supported by 26 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 241 below describes the starting and ending position of this segment on each transcript.









TABLE 241







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
1440
1545


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
1440
1545


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
1440
1545


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
1440
1545


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
1440
1545


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
1237
1342


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
1440
1545


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
1440
1545


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
1440
1545


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
1440
1545


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
1440
1545


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
1440
1545


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
1440
1545


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
1440
1545


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
1440
1545


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
1440
1545


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
1440
1545


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
1440
1545


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
1440
1545


NO:33)









Segment cluster HSCOC4_PEA1_node28 (SEQ ID NO:180) according to the present invention is supported by 34 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA_T40 (SEQ ID NO:33). Table 242 below describes the starting and ending position of this segment on each transcript.









TABLE 242







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
1546
1661


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
1546
1661


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
1546
1661


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
1546
1661


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
1546
1661


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
1343
1458


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
1546
1661


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
1546
1661


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
1546
1661


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
1546
1661


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
1546
1661


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
1546
1661


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
1546
1661


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
1546
1661


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
1546
1661


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
1546
1661


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
1546
1661


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
1546
1661


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
1546
1661


NO:33)









Segment cluster HSCOC4_PEA1_node29 (SEQ ID NO:181) according to the present invention is supported by 5 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T5 (SEQ ID NO:19). Table 243 below describes the starting and ending position of this segment on each transcript.









TABLE 243







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T5 (SEQ ID
1662
1760


NO:19)









Segment cluster HSCOC4_PEA1_node41 (SEQ ID NO:182) according to the present invention is supported by 32 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 244 below describes the starting and ending position of this segment on each transcript.









TABLE 244







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
2497
2571


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
2497
2571


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
2497
2571


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
2497
2571


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
2596
2670


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
2294
2368


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
2497
2571


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
2497
2571


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
2497
2571


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
2497
2571


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
2497
2571


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
2497
2571


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
2497
2571


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
2497
2571


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
2497
2571


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
2497
2571


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
2497
2571


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
2497
2571


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
2497
2571


NO:33)









Segment cluster HSCOC4_PEA1_node45 (SEQ ID NO:183) according to the present invention is supported by 31 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T 11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 245 below describes the starting and ending position of this segment on each transcript.









TABLE 245







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
2770
2881


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
2770
2881


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
2770
2881


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
2770
2881


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
2869
2980


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
2567
2678


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
2770
2881


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
2770
2881


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
2770
2881


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
2770
2881


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
2770
2881


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
2770
2881


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
2770
2881


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
2770
2881


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
2770
2881


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
2770
2881


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
2770
2881


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
2770
2881


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
2770
2881


NO:33)









Segment cluster HSCOC4_PEA1_node47 (SEQ ID NO:184) according to the present invention is supported by 32 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA 1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 246 below describes the starting and ending position of this segment on each transcript.









TABLE 246







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
2882
2952


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
2882
2952


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
2882
2952


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
2882
2952


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
2981
3051


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
2679
2749


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
2882
2952


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
2882
2952


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
2882
2952


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
2882
2952


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
2882
2952


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
2882
2952


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
2882
2952


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
2882
2952


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
2882
2952


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
2882
2952


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
2882
2952


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
2882
2952


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
2882
2952


NO:33)









Segment cluster HSCOC4_PEA1_node50 (SEQ ID NO:185) according to the present invention is supported by 5 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15) and HSCOC4_PEA1_T3 (SEQ ID NO:17). Table 247 below describes the starting and ending position of this segment on each transcript.









TABLE 247







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
3093
3205


NO:15)


HSCOC4_PEA_1_T3 (SEQ ID
3351
3463


NO:17)









Segment cluster HSCOC4_PEA1_node53 (SEQ ID NO:186) according to the present invention is supported by 38 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 248 below describes the starting and ending position of this segment on each transcript.









TABLE 248







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
3416
3467


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
3561
3612


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
3674
3725


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
3303
3354


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
3402
3453


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
3100
3151


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
3303
3354


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
3303
3354


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
3303
3354


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
3303
3354


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
3303
3354


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
3303
3354


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
3303
3354


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
3303
3354


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
3303
3354


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
3303
3354


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
3303
3354


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
3303
3354


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
3303
3354


NO:33)









Segment cluster HSCOC4_PEA1_node55 (SEQ ID NO:187) according to the present invention is supported by 40 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33).Table 249 below describes the starting and ending position of this segment on each transcript.









TABLE 249







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
3468
3557


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
3613
3702


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
3726
3815


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
3355
3444


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
3454
3543


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
3152
3241


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
3355
3444


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
3355
3444


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
3355
3444


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
3355
3444


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
3355
3444


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
3355
3444


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
3355
3444


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
3355
3444


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
3355
3444


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
3355
3444


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
3355
3444


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
3355
3444


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
3355
3444


NO:33)









Segment cluster HSCOC4_PEA1_node57 (SEQ ID NO:188) according to the present invention is supported by 42 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 250 below describes the starting and ending position of this segment on each transcript.









TABLE 250







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
3558
3604


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
3703
3749


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
3816
3862


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
3445
3491


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
3544
3590


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
3242
3288


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
3445
3491


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
3445
3491


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
3445
3491


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
3445
3491


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
3445
3491


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
3445
3491


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
3445
3491


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
3445
3491


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
3445
3491


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
3445
3491


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
3445
3491


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
3445
3491


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
3445
3491


NO:33)









Segment cluster HSCOC4_PEA1_node60 (SEQ ID NO:189) according to the present invention is supported by 50 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 251 below describes the starting and ending position of this segment on each transcript.









TABLE 251







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
3768
3843


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
3913
3988


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
4026
4101


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
3834
3909


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
3754
3829


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
3452
3527


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
3655
3730


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
3655
3730


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
3655
3730


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
3655
3730


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
3655
3730


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
3655
3730


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
3655
3730


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
3655
3730


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
3655
3730


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
3655
3730


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
3655
3730


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
3655
3730


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
3655
3730


NO:33)









Segment cluster HSCOC4_PEA1_node64 (SEQ ID NO:190) according to the present invention is supported by 65 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA 1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 252 below describes the starting and ending position of this segment on each transcript.









TABLE 252







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
4001
4117


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
4146
4262


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
4259
4375


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
4067
4183


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
3987
4103


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
3685
3801


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
3888
4004


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
3888
4004


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
3888
4004


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
3888
4004


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
3888
4004


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
3888
4004


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
3888
4004


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
3888
4004


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
3888
4004


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
3888
4004


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
3888
4004


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
3888
4004


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
3888
4004


NO:33)









Segment cluster HSCOC4_PEA1_node69 (SEQ ID NO:191) according to the present invention can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4 PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T 11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 253 below describes the starting and ending position of this segment on each transcript.









TABLE 253







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
4290
4309


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
4435
4454


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
4548
4567


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
4356
4375


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
4276
4295


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
3974
3993


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
4177
4196


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
4177
4196


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
4177
4196


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
4177
4196


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
4177
4196


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
4177
4196


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
4177
4196


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
4177
4196


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
4177
4196


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
4177
4196


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
4177
4196


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
4177
4196


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
4177
4196


NO:33)









Segment cluster HSCOC4_PEA1_node70 (SEQ ID NO:192) according to the present invention is supported by 58 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA 1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA 1_T11 (SEQ ID NO:22), HSCOC4 PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 254 below describes the starting and ending position of this segment on each transcript.









TABLE 254







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
4310
4349


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
4455
4494


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
4568
4607


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
4376
4415


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
4296
4335


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
3994
4033


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
4197
4236


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
4197
4236


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
4197
4236


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
4197
4236


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
4197
4236


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
4197
4236


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
4197
4236


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
4197
4236


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
4197
4236


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
4197
4236


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
4197
4236


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
4197
4236


NO:32)









Segment cluster HSCOC4_PEA1_node71 (SEQ ID NO:193) according to the present invention is supported by 58 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 255 below describes the starting and ending position of this segment on each transcript.









TABLE 255







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
4350
4391


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
4495
4536


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
4608
4649


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
4416
4457


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
4336
4377


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4034
4075


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
4237
4278


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
4237
4278


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
4237
4278


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
4237
4278


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
4237
4278


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
4237
4278


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
4237
4278


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
4237
4278


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
4237
4278


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
4237
4278


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
4237
4278


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
4237
4278


NO:32)









Segment cluster HSCOC4_PEA1_node73 (SEQ ID NO:194) according to the present invention is supported by 1 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T20 (SEQ ID NO:26). Table 256 below describes the starting and ending position of this segment on each transcript.









TABLE 256







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T20 (SEQ ID
4410
4491


NO:26)









Segment cluster HSCOC4_PEA1_node74 (SEQ ID NO:195) according to the present invention can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 257 below describes the starting and ending position of this segment on each transcript.









TABLE 257







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
4523
4546


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
4668
4691


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
4781
4804


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
4589
4612


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
4509
4532


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4207
4230


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
4410
4433


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
4410
4433


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
4410
4433


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
4410
4433


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
4410
4433


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
4492
4515


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
4410
4433


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
4410
4433


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
4410
4433


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
4410
4433


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
4410
4433


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
4410
4433


NO:32)









Segment cluster HSCOC4_PEA1_node75 (SEQ ID NO:196) according to the present invention is supported by 65 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA 1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA 1 T32 (SEQ ID NO:32). Table 258 below describes the starting and ending position of this segment on each transcript.









TABLE 258







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
4547
4626


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
4692
4771


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
4805
4884


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
4613
4692


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
4533
4612


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4231
4310


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
4434
4513


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
4434
4513


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
4434
4513


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
4434
4513


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
4434
4513


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
4516
4595


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
4434
4513


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
4434
4513


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
4434
4513


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
4434
4513


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
4434
4513


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
4434
4513


NO:32)









Segment cluster HSCOC4_PEA1_node76 (SEQ ID NO:197) according to the present invention is supported by 66 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4 PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 259 below describes the starting and ending position of this segment on each transcript.









TABLE 259







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
4627
4690


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
4772
4835


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
4885
4948


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
4693
4756


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
4613
4676


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4311
4374


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
4514
4577


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
4514
4577


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
4514
4577


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
4514
4577


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
4514
4577


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
4596
4659


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
4514
4577


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
4514
4577


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
4514
4577


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
4514
4577


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
4514
4577


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
4514
4577


NO:32)









Segment cluster HSCOC4_PEA1_node78 (SEQ ID NO:198) according to the present invention is supported by 71 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T 11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 260 below describes the starting and ending position of this segment on each transcript.









TABLE 260







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
4691
4750


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
4836
4895


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
4949
5008


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
4757
4816


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
4677
4736


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4375
4434


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
4578
4637


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
4578
4637


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
4578
4637


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
4971
5030


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
4578
4637


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5053
5112


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
4578
4637


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
4578
4637


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
4578
4637


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
4578
4637


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
4578
4637


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
4578
4637


NO:32)









Segment cluster HSCOC4_PEA1_node80 (SEQ ID NO:199) according to the present invention is supported by 75 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23) HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27) HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 261 below describes the starting and ending position of this segment on each transcript.









TABLE 261







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
4751
4844


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
4896
4989


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5009
5102


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
4817
4910


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
4737
4830


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4435
4528


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
4638
4731


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
5687
5780


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
4638
4731


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5031
5124


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
4638
4731


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5113
5206


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
4638
4731


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
4638
4731


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
4638
4731


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
4638
4731


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
4638
4731


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
4638
4731


NO:32)









Segment cluster HSCOC4_PEA1_node82 (SEQ ID NO:200) according to the present invention can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 262 below describes the starting and ending position of this segment on each transcript.









TABLE 262







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
4845
4855


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
4990
5000


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5103
5113


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
4911
4921


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
4831
4841


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4529
4539


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
4732
4742


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
5781
5791


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
4732
4742


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5125
5135


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
4732
4742


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5207
5217


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
4732
4742


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
4732
4742


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
4732
4742


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
4732
4742


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
4732
4742


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
4732
4742


NO:32)









Segment cluster HSCOC4_PEA1_node83 (SEQ ID NO:201) according to the present invention is supported by 77 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19) HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23) HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27) HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 263 below describes the starting and ending position of this segment on each transcript.









TABLE 263







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
4856
4971


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
5001
5116


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5114
5229


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
4922
5037


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
4842
4957


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4540
4655


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
4743
4858


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
5792
5907


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
4743
4858


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5136
5251


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
4743
4858


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5218
5333


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
4743
4858


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
4743
4858


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
4743
4858


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
4743
4858


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
4743
4858


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
4743
4858


NO:32)









Segment cluster HSCOC4_PEA1_node84 (SEQ ID NO:202) according to the present invention can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4 PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4 PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 264 below describes the starting and ending position of this segment on each transcript.









TABLE 264







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
4972
4984


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
5117
5129


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5230
5242


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
5038
5050


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
4958
4970


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4656
4668


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
4859
4871


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
5908
5920


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
4859
4871


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5252
5264


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
4859
4871


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5334
5346


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
4859
4871


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
4859
4871


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
4859
4871


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
4859
4871


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
4859
4871


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
4859
4871


NO:32)









Segment cluster HSCOC4_PEA1_node85 (SEQ ID NO:203) according to the present invention is supported by 68 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4 PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA 1 T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4 PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4 PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 265 below describes the starting and ending position of this segment on each transcript.









TABLE 265







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
4985
5031


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
5130
5176


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5243
5289


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
5051
5097


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
4971
5017


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4669
4715


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
4872
4918


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
5921
5967


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
4872
4918


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5265
5311


NO:24)


HSCOC4_PEA_1_T20 (SEQ ID
5347
5393


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
4872
4918


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
4872
4918


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
4872
4918


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
4872
4918


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
4872
4918


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
4872
4918


NO:32)









Segment cluster HSCOC4_PEA1_node86 (SEQ ID NO:204) according to the present invention is supported by 7 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T12 (SEQ ID NO:23). Table 266 below describes the starting and ending position of this segment on each transcript.









TABLE 266







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T12 (SEQ ID
4919
5032


NO:23)









Segment cluster HSCOC4_PEA1_node87 (SEQ ID NO:205) according to the present invention is supported by 74 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23) HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:261, HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 267 below describes the starting and ending position of this segment on each transcript.









TABLE 267







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
5032
5122


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
5177
5267


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5290
5380


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
5098
5188


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
5018
5108


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4716
4806


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
4919
5009


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
5968
6058


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
5033
5123


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5312
5402


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
4872
4962


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5394
5484


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
4919
5009


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
4919
5009


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
4919
5009


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
4919
5009


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
4919
5009


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
4919
5009


NO:32)









Segment cluster HSCOC4_PEA1_node88 (SEQ ID NO:206) according to the present invention is supported by 2 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T12 (SEQ ID NO:23). Table 268 below describes the starting and ending position of this segment on each transcript.









TABLE 268







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T12 (SEQ ID
5124
5213


NO:23)









Segment cluster HSCOC4_PEA1_node89 (SEQ ID NO:207) according to the present invention can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17) HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19) HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21) HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25) HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27) HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29) HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 269 below describes the starting and ending position of this segment on each transcript.









TABLE 269







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
5123
5131


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
5268
5276


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5381
5389


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
5189
5197


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
5109
5117


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4807
4815


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
5010
5018


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
6059
6067


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
5214
5222


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5403
5411


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
4963
4971


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5485
5493


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
5010
5018


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
5010
5018


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
5010
5018


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
5010
5018


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
5010
5018


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
5010
5018


NO:32)









Segment cluster HSCOC4_PEA1_node90 (SEQ ID NO:208) according to the present invention can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 270 below describes the starting and ending position of this segment on each transcript.









TABLE 270







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
5132
5142


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
5277
5287


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5390
5400


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
5198
5208


NO:18)


HSCOC4_PEA_1 T5 (SEQ ID
5118
5128


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4816
4826


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
5019
5029


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
6068
6078


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
5223
5233


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5412
5422


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
4972
4982


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5494
5504


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
5019
5029


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
5019
5029


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
5019
5029


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
5019
5029


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
5019
5029


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
5019
5029


NO:32)









Segment cluster HSCOC4_PEA1_node91 (SEQ ID NO:209) according to the present invention is supported by 78 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19) HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 271 below describes the starting and ending position of this segment on each transcript.









TABLE 271







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
5143
5179


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
5288
5324


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5401
5437


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
5209
5245


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
5129
5165


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4827
4863


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
5030
5066


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
6079
6115


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
5234
5270


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5423
5459


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
4983
5019


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5505
5541


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
5030
5066


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
5030
5066


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
5030
5066


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
5030
5066


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
5030
5066


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
5030
5066


NO:32)









Segment cluster HSCOC4_PEA1_node92 (SEQ ID NO:210) according to the present invention can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:231 HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 272 below describes the starting and ending position of this segment on each transcript.









TABLE 272







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
5180
5197


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
5325
5342


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5438
5455


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
5246
5263


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
5166
5183


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4864
4881


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
5067
5084


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
6116
6133


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
5271
5288


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5460
5477


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
5020
5037


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5542
5559


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
5067
5084


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
5067
5084


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
5067
5084


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
5067
5084


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
5067
5084


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
5067
5084


NO:32)









Segment cluster HSCOC4_PEA1_node94 (SEQ ID NO:211) according to the present invention can be found in the following transcript(s): HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T12 (SEQ ID NO:23) and HSCOC4_PEA1_T21 (SEQ ID NO:27). Table 273 below describes the starting and ending position of this segment on each transcript.









TABLE 273







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T8 (SEQ ID
6567
6575


NO:21)


HSCOC4_PEA_1_T12 (SEQ ID
6771
6779


NO:23)


HSCOC4_PEA_1_T21 (SEQ ID
6567
6575


NO:27)









Segment cluster HSCOC4_PEA1_node96 (SEQ ID NO:212) according to the present invention can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 274 below describes the starting and ending position of this segment on each transcript.









TABLE 274







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
5198
5205


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
5343
5350


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5456
5463


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
5264
5271


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
5184
5191


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4882
4889


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
6576
6583


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
6134
6141


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
6780
6787


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5478
5485


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
5038
5045


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5560
5567


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
6576
6583


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
5085
5092


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
5085
5092


NO:29)


HSCOC4_PEA_1_T31 (SEQ ID
5085
5092


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
5085
5092


NO:32)









Segment cluster HSCOC4_PEA1_node97 (SEQ ID NO:213) according to the present invention can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23) HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 275 below describes the starting and ending position of this segment on each transcript.









TABLE 275







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
5206
5222


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
5351
5367


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5464
5480


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
5272
5288


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
5192
5208


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4890
4906


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
6584
6600


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
6142
6158


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
6788
6804


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5486
5502


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
5046
5062


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5568
5584


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
6584
6600


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
5093
5109


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
5093
5109


NO:29)


HSCOC4_PEA_1_T31 (SEQ ID
5093
5109


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
5093
5109


NO:32)









Segment cluster HSCOC4_PEA1_node98 (SEQ ID NO:214) according to the present invention is supported by 93 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 276 below describes the starting and ending position of this segment on each transcript.









TABLE 276







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
5223
5271


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
5368
5416


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5481
5529


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
5289
5337


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
5209
5257


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4907
4955


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
6601
6649


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
6159
6207


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
6805
6853


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5503
5551


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
5063
5111


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5585
5633


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
6601
6649


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
5110
5158


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
5110
5158


NO:29)


HSCOC4_PEA_1_T31 (SEQ ID
5110
5158


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
5110
5158


NO:32)









Segment cluster HSCOC4_PEA1_node99 (SEQ ID NO:215) according to the present invention is supported by 93 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23) HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25) HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 277 below describes the starting and ending position of this segment on each transcript.









TABLE 277







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
5272
5300


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
5417
5445


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5530
5558


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
5338
5366


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
5258
5286


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4956
4984


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
6650
6678


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
6208
6236


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
6854
6882


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5552
5580


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
5112
5140


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5634
5662


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
6650
6678


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
5159
5187


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
5159
5187


NO:29)


HSCOC4_PEA_1_T31 (SEQ ID
5159
5187


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
5159
5187


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
4197
4225


NO:33)









Segment cluster HSCOC4_PEA1_node101 (SEQ ID NO:216) according to the present invention is supported by 116 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25) HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27) HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29) HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 278 below describes the starting and ending position of this segment on each transcript.









TABLE 278







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
5301
5390


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
5446
5535


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5559
5648


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
5367
5456


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
5287
5376


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
4985
5074


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
6679
6768


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
6237
6326


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
6883
6972


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5581
5670


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
5141
5230


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5663
5752


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
6844
6933


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
5188
5277


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
5188
5277


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
5085
5174


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
5188
5277


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
5188
5277


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
4226
4315


NO:33)









Segment cluster HSCOC4_PEA1_node102 (SEQ ID NO:217) according to the present invention is supported by 3 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T31 (SEQ ID NO:31) and HSCOC4_PEA1_T32 (SEQ ID NO:32). Table 279 below describes the starting and ending position of this segment on each transcript.









TABLE 279







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T31 (SEQ ID
5278
5362


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
5278
5362


NO:32)









Segment cluster HSCOC4_PEA1_node103 (SEQ ID NO:218) according to the present invention is supported by 106 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19) HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4 PEA1_T8 (SEQ ID NO:21) HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23) HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25) HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27) HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29) HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31) HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 280 below describes the starting and ending position of this segment on each transcript.









TABLE 280







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
5391
5463


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
5536
5608


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5649
5721


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
5457
5529


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
5377
5449


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
5075
5147


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
6769
6841


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
6327
6399


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
6973
7045


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5671
5743


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
5231
5303


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5753
5825


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
6934
7006


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
5278
5350


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
5278
5350


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
5175
5247


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
5363
5435


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
5363
5435


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
4316
4388


NO:33)









Segment cluster HSCOC4_PEA1_node104 (SEQ ID NO:219) according to the present invention is supported by 101 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4 PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 281 below describes the starting and ending position of this segment on each transcript.









TABLE 281







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
5464
5489


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
5609
5634


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5722
5747


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
5530
5555


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
5450
5475


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
5148
5173


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
6842
6867


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
6400
6425


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
7046
7071


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5744
5769


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
5304
5329


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5826
5851


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
7007
7032


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
5351
5376


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
5351
5376


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
5248
5273


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
5436
5461


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
5436
5461


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
4389
4414


NO:33)









Segment cluster HSCOC4_PEA1_node106 (SEQ ID NO:220) according to the present invention is supported by 110 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 282 below describes the starting and ending position of this segment on each transcript.









TABLE 282







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
5490
5573


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
5635
5718


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
5748
5831


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
5556
5639


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
5476
5559


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
5174
5257


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
6868
6951


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
6426
6509


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
7072
7155


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
5770
5853


NO:24)


HSCOC4_PEA 1_T15 (SEQ ID
5330
5413


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
5852
5935


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
7033
7116


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
5377
5460


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
5559
5642


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
5274
5357


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
5462
5545


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
5644
5727


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
4415
4498


NO:33)









Segment cluster HSCOC4_PEA1_node111 (SEQ ID NO:221) according to the present invention is supported by 77 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA1_T1 (SEQ ID NO:15), HSCOC4_PEA1_T2 (SEQ ID NO:16), HSCOC4_PEA1_T3 (SEQ ID NO:17), HSCOC4_PEA1_T4 (SEQ ID NO:18), HSCOC4_PEA1_T5 (SEQ ID NO:19), HSCOC4_PEA1_T7 (SEQ ID NO:20), HSCOC4_PEA1_T8 (SEQ ID NO:21), HSCOC4_PEA1_T11 (SEQ ID NO:22), HSCOC4_PEA1_T12 (SEQ ID NO:23), HSCOC4_PEA1_T14 (SEQ ID NO:24), HSCOC4_PEA1_T15 (SEQ ID NO:25), HSCOC4_PEA1_T20 (SEQ ID NO:26), HSCOC4_PEA1_T21 (SEQ ID NO:27), HSCOC4_PEA1_T25 (SEQ ID NO:28), HSCOC4_PEA1_T28 (SEQ ID NO:29), HSCOC4_PEA1_T30 (SEQ ID NO:30), HSCOC4_PEA1_T31 (SEQ ID NO:31), HSCOC4_PEA1_T32 (SEQ ID NO:32) and HSCOC4_PEA1_T40 (SEQ ID NO:33). Table 283 below describes the starting and ending position of this segment on each transcript.









TABLE 283







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSCOC4_PEA_1_T1 (SEQ ID
5857
5947


NO:15)


HSCOC4_PEA_1_T2 (SEQ ID
6002
6092


NO:16)


HSCOC4_PEA_1_T3 (SEQ ID
6115
6205


NO:17)


HSCOC4_PEA_1_T4 (SEQ ID
5923
6013


NO:18)


HSCOC4_PEA_1_T5 (SEQ ID
5843
5933


NO:19)


HSCOC4_PEA_1_T7 (SEQ ID
5541
5631


NO:20)


HSCOC4_PEA_1_T8 (SEQ ID
7235
7325


NO:21)


HSCOC4_PEA_1_T11 (SEQ ID
6793
6883


NO:22)


HSCOC4_PEA_1_T12 (SEQ ID
7439
7529


NO:23)


HSCOC4_PEA_1_T14 (SEQ ID
6137
6227


NO:24)


HSCOC4_PEA_1_T15 (SEQ ID
5697
5787


NO:25)


HSCOC4_PEA_1_T20 (SEQ ID
6219
6309


NO:26)


HSCOC4_PEA_1_T21 (SEQ ID
7400
7490


NO:27)


HSCOC4_PEA_1_T25 (SEQ ID
6149
6239


NO:28)


HSCOC4_PEA_1_T28 (SEQ ID
6331
6421


NO:29)


HSCOC4_PEA_1_T30 (SEQ ID
5641
5731


NO:30)


HSCOC4_PEA_1_T31 (SEQ ID
5829
5919


NO:31)


HSCOC4_PEA_1_T32 (SEQ ID
6273
6363


NO:32)


HSCOC4_PEA_1_T40 (SEQ ID
4782
4872


NO:33)










Variant Protein Alignment to the Previously Known Protein:














Sequence name: CO4_HUMAN


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P3 (SEQ ID NO:340) × CO4_HUMAN . . .


Alignment segment 1/1:


Quality: 8438.00


Escore: 0


Matching length: 870


Total length: 870


Matching Percent Similarity: 99.66


Matching Percent Identity: 99.66


Total Percent Similarity: 99.66


Total Percent Identity: 99.66


Gaps: 0


Alignment:












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Sequence name: CO4_HUMAN


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P5 (SEQ ID NO:341) × CO4_HUMAN . . .


Alignment segment 1/1:


Quality: 7969.00


Escore: 0


Matching length: 818


Total length: 818


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: CO4_HUMAN


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P6 (SEQ ID NO:342) × CO4_HUMAN . . .


Alignment segment 1/1:


Quality: 10211.00


Escore: 0


Matching length: 1052


Total length: 1052


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: CO4_HUMAN_V1 (SEQ ID NO:389)


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P12 (SEQ ID NO:343) × CO4_HUMAN_V1


(SEQ ID NO:389) . . .


Alignment segment 1/1:


Quality: 13367.00


Escore: 0


Matching length: 1380


Total length: 1380


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: CO4_HUMAN_V1 (SEQ ID NO:389)


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P15 (SEQ ID NO:344) × CO4_HUMAN_V1


(SEQ ID NO:389) . . .


Alignment segment 1/1:


Quality: 13174.00


Escore: 0


Matching length: 1359


Total length: 1359


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: CO4_HUMAN_V1 (SEQ ID NO:389)


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P16 (SEQ ID NO:345) × CO4_HUMAN_V1


(SEQ ID NO:389) . . .


Alignment segment 1/1:


Quality: 14137.00


Escore: 0


Matching length: 1457


Total length: 1457


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: CO4_HUMAN_V1 (SEQ ID NO:389)


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P20 (SEQ ID NO:346) × CO4_HUMAN_V1


(SEQ ID NO:389) . . .


Alignment segment 1/1:


Quality: 12641.00


Escore: 0


Matching length: 1303


Total length: 1303


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: CO4_HUMAN_V1 (SEQ ID NO:389)


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P9 (SEQ ID NO:347) × CO4_HUMAN_V1


(SEQ ID NO:389) . . .


Alignment segment 1/1:


Quality: 14831.00


Escore: 0


Matching length: 1529


Total length: 1529


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: CO4_HUMAN_V1 (SEQ ID NO:389)


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P22 (SEQ ID NO:348) × CO4_HUMAN_V1


(SEQ ID NO:389) . . .


Alignment segment 1/1:


Quality: 16066.00


Escore: 0


Matching length: 1654


Total length: 1654


Matching Percent Similarity: 100.00


Matching Percent Identity: 99.94


Total Percent Similarity: 100.00


Total Percent Identity: 99.94


Gaps: 0


Alignment:












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Sequence name: CO4_HUMAN_V1 (SEQ ID NO:389)


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P23 (SEQ ID NO:349) × CO4_HUMAN_V1


(SEQ ID NO:389) . . .


Alignment segment 1/1:


Quality: 15806.00


Escore: 0


Matching length: 1626


Total length: 1626


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: CO4_HUMAN_V1 (SEQ ID NO:389)


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P24 (SEQ ID NO:350) × CO4_HUMAN_V1


(SEQ ID NO:389) . . .


Alignment segment 1/1:


Quality: 14823.00


Escore: 0


Matching length: 1528


Total length: 1528


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: CO4_HUMAN_V1 (SEQ ID NQ:389)


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P25 (SEQ ID NO:351) × CO4_HUMAN_V1


(SEQ ID NO:389) . . .


Alignment segment 1/1:


Quality: 15464.00


Escore: 0


Matching length: 1593


Total length: 1593


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: CO4_HUMAN_V1 (SEQ ID NO:389)


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P26 (SEQ ID NO:352) × CO4_HUMAN_V1


(SEQ ID NO:389) . . .


Alignment segment 1/1:


Quality: 15464.00


Escore: 0


Matching length: 1593


Total length: 1593


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: CO4_HUMAN_V3 (SEQ ID NO:390)


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P30 (SEQ ID NO:353) × CO4_HUMAN_V3


(SEQ ID NO:390) . . .


Alignment segment 1/1:


Quality: 11940.00


Escore: 0


Matching length: 1232


Total length: 1232


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: CO4_HUMAN


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P38 (SEQ ID NO:354) × CO4_HUMAN . . .


Alignment segment 1/1:


Quality: 7969.00


Escore: 0


Matching length: 818


Total length: 818


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: CO4_HUMAN


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P39 (SEQ ID NO:355) × CO4_HUMAN . . .


Alignment segment 1/1:


Quality: 3766.00


Escore: 0


Matching length: 387


Total length: 387


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: CO4_HUMAN


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P40 (SEQ ID NO:356) × CO4_HUMAN . . .


Alignment segment 1/1:


Quality: 2309.00


Escore: 0


Matching length: 236


Total length: 236


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: CO4_HUMAN_V1 (SEQ ID NO:389)


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P41 (SEQ ID NO:357) × CO4_HUMAN_V1


(SEQ ID NO:389) . . .


Alignment segment 1/1:


Quality: 14831.00


Escore: 0


Matching length: 1529


Total length: 1529


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: CO4_HUMAN_V1 (SEQ ID NO:389)


Sequence documentation:


Alignment of: HSCOC4_PEA_1_P42 (SEQ ID NO:358) × CO4_HUMAN_V1


(SEQ ID NO:389) . . .


Alignment segment 1/1:


Quality: 14480.00


Escore: 0


Matching length: 1506


Total length: 1544


Matching Percent Similarity: 99.93


Matching Percent Identity: 99.87


Total Percent Similarity: 97.47


Total Percent Identity: 97.41


Gaps: 1


Alignment:












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Description for Cluster HSSTROL3


Cluster HSSTROL3 features 6 transcript(s) and 16 segment(s) of interest, the names for which are given in Tables 284 and 285, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 286.









TABLE 284







Transcripts of interest










Transcript Name
Sequence ID No.







HSSTROL3_T5
34



HSSTROL3_T8
35



HSSTROL3_T9
36



HSSTROL3_T10
37



HSSTROL3_T11
38



HSSTROL3_T12
39

















TABLE 285







Segments of interest










Segment Name
Sequence ID No.







HSSTROL3_node_6
222



HSSTROL3_node_10
223



HSSTROL3_node_13
224



HSSTROL3_node_15
225



HSSTROL3_node_19
226



HSSTROL3_node_21
227



HSSTROL3_node_24
228



HSSTROL3_node_25
229



HSSTROL3_node_26
230



HSSTROL3_node_28
231



HSSTROL3_node_29
232



HSSTROL3_node_11
233



HSSTROL3_node_17
234



HSSTROL3_node_18
235



HSSTROL3_node_20
236



HSSTROL3_node_27
237

















TABLE 286







Proteins of interest










Sequence










Protein Name
ID No.
Corresponding Transcript(s)












HSSTROL3_P4
359
HSSTROL3_T5 (SEQ ID NO:34)


HSSTROL3_P5
360
HSSTROL3_T8 (SEQ ID NO:35)




HSSTROL3_T9 (SEQ ID NO:36)


HSSTROL3_P7
361
HSSTROL3_T10 (SEQ ID NO:37)


HSSTROL3_P8
362
HSSTROL3_T11 (SEQ ID NO:38)


HSSTROL3_P9
363
HSSTROL3_T12 (SEQ ID NO:39)









These sequences are variants of the known protein Stromelysin-3 precursor (SEQ ID NO:391) (SwissProt accession identifier MM11_HUMAN (SEQ ID NO: 391); known also according to the synonyms EC 3.4.24.-; Matrix metalloproteinase-11; MMP-11; ST3; SL-3), SEQ ID NO: 391) referred to herein as the previously known protein.


Protein Stromelysin-3 precursor (SEQ ID NO:391) is known or believed to have the following function(s): May play an important role in the progression of epithelial malignancies. The sequence for protein Stromelysin-3 precursor (SEQ ID NO:391) is given at the end of the application, as “Stromelysin-3 precursor (SEQ ID NO:391) amino acid sequence”.


The following GO Annotation(s) apply to the previously known protein. The following annotation(s) were found: proteolysis and peptidolysis; developmental processes; morphogenesis, which are annotation(s) related to Biological Process; stromelysin 3; calcium binding; zinc binding; hydrolase, which are annotation(s) related to Molecular Function; and extracellular matrix, which are annotation(s) related to Cellular Component.


The GO assignment relies on information from one or more of the SwissProt/TremB1 Protein knowledgebase, available from expasy dot ch/sprot/; or Locuslink, available from ncbi dot nlm dot nih dot gov/projects/LocusLink/.


Cluster HSSTROL3 can be used as a diagnostic marker according to overexpression of transcripts of this cluster in cancer. Expression of such transcripts in normal tissues is also given according to the previously described methods. The term “number” in the left hand column of the table and the numbers on the y-axis of FIG. 13 refer to weighted expression of ESTs in each category, as “parts per million” (ratio of the expression of ESTs for a particular cluster to the expression of all ESTs in that category, according to parts per million).


Overall, the following results were obtained as shown with regard to the histograms in FIG. 13 and Table 287. This cluster is overexpressed (at least at a minimum level) in the following pathological conditions: transitional cell carcinoma, epithelial malignant tumors, a mixture of malignant tumors from different tissues and pancreas carcinoma.









TABLE 287







Normal tissue distribution










Name of Tissue
Number














Adrenal
0



Bladder
0



Brain
1



Colon
63



Epithelial
33



General
13



head and neck
101



Kidney
0



Lung
11



Breast
8



Ovary
14



Pancreas
0



Prostate
2



Skin
99



Thyroid
0



Uterus
181

















TABLE 288







P values and ratios for expression in cancerous tissue













Name of Tissue
P1
P2
SP1
R3
SP2
R4





Adrenal
1
4.6e−01
1
1.0
5.3e−01
1.9


Bladder
2.7e−01
3.4e−01
3.3e−03
4.9
2.1e−02
3.3


Brain
3.5e−01
2.6e−01
1
1.7
3.3e−01
2.8


Colon
7.7e−02
1.5e−01
3.1e−01
1.4
5.2e−01
1.0


Epithelial
1.2e−04
1.2e−02
1.3e−06
2.7
4.6e−02
1.4


General
5.4e−09
3.1e−05
1.8e−16
5.0
3.1e−07
2.6


head and neck
4.6e−01
4.3e−01
1
0.6
9.4e−01
0.7


Kidney
2.5e−01
3.5e−01
1.1e−01
4.0
2.4e−01
2.8


Lung
1.8e−01
4.5e−01
1.9e−01
2.7
5.1e−01
1.4


Breast
2.0e−01
3.4e−01
7.3e−02
3.3
2.5e−01
2.0


Ovary
2.6e−01
3.2e−01
2.2e−02
2.0
7.0e−02
1.6


Pancreas
9.5e−02
1.8e−01
1.8e−04
7.8
1.6e−03
5.5


Prostate
8.2e−01
7.8e−01
4.5e−01
1.8
5.6e−01
1.5


Skin
5.2e−01
5.8e−01
7.1e−01
0.8
1
0.3


Thyroid
2.9e−01
2.9e−01
1
1.1
1
1.1


Uterus
4.2e−01
8.0e−01
7.5e−01
0.6
9.9e−01
0.4









As noted above, cluster HSSTROL3 features 6 transcript(s), which were listed in Table 284 above. These transcript(s) encode for protein(s) which are variant(s) of protein Stromelysin-3 precursor (SEQ ID NO:391). A description of each variant protein according to the present invention is now provided.


Variant protein HSSTROL3_P4 (SEQ ID NO:359) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSSTROL3_T5 (SEQ ID NO:34). An alignment is given to the known protein (Stromelysin-3 precursor (SEQ ID NO:391)) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSSTROL3_P4 (SEQ ID NO:359) and MM11_HUMAN:


1. An isolated chimeric polypeptide encoding for HSSTROL3_P4 (SEQ ID NO:359) comprising a first amino acid sequence being at least 90% homologous to MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS PAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVLSGGRWEKTDLTYRILRFP WQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMIDFARYW corresponding to amino acids 1-163 of MM11_HUMAN, which also corresponds to amino acids 1-163 of HSSTROL3_P4 (SEQ ID NO:359), a bridging amino acid H corresponding to amino acid 164 of HSSTROL3_P4 (SEQ ID NO:359), a second amino acid sequence being at least 90% homologous to GDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWTIGDDQGTDLLQVAAHEFGHVLG LQHTTAAKALMSAFYTFRYPLSLSPDDCRGVQHLYGQPWPTVTSRTPALGPQAGIDTN EIAPLEPDAPPDACEASFDAVSTIRGELFFFKAGFVWRLRGGQLQPGYPALASRHWQGL PSPVDAAFEDAQGHIWFFQGAQYWVYDGEKPVLGPAPLTELGLVRFPVHAALVWGPE KNKIYFFRGRDYWRFHPSTRRVDSPVPRRATDWRGVPSEIDAAFQDADG corresponding to amino acids 165-445 of MM11_HUMAN, which also corresponds to amino acids 165-445 of HSSTROL3_P4 (SEQ ID NO:359), and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence ALGVRQLVGGGHSSRFSHLVVAGLPHACHRKSGSSSQVLCPEPSALLSVAG (SEQ ID NO: 564) corresponding to amino acids 446-496 of HSSTROL3_P4 (SEQ ID NO:359), wherein said first amino acid sequence, bridging amino acid, second amino acid sequence and third amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSSTROL3_P4 (SEQ ID NO:359) comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence ALGVRQLVGGGHSSRFSHLVVAGLPHACHRKSGSSSQVLCPEPSALLSVAG in (SEQ ID NO: 564) HSSTROL3_P4 (SEQ ID NO:359).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSSTROL3_P4 (SEQ ID NO:359) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 289, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P4 (SEQ ID NO:359) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 289







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












38
V -> A
Yes


104
R -> P
Yes


214
A -> 
No


323
Q -> H
Yes









Variant protein HSSTROL3_P4 (SEQ ID NO:359) is encoded by the following transcript(s): HSSTROL3_T5 (SEQ ID NO:34), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSSTROL3_T5 (SEQ ID NO:34) is shown in bold; this coding portion starts at position 24 and ends at position 1511. The transcript also has the following SNPs as listed in Table 290 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P4 (SEQ ID NO:359) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 290







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












136
T -> C
Yes


334
G -> C
Yes


663
G -> 
No


699
-> T 
No


992
G -> C
Yes


1528
A -> G
Yes


1710
A -> G
Yes


2251
A -> G
Yes


2392
C -> 
No


2444
C -> A
Yes


2470
A -> T
Yes


2687
-> G 
No


2696
-> G 
No


2710
C -> 
No


2729
-> A 
No


2755
T -> C
No


2813
A -> 
No


2813
A -> C
No


2963
A -> 
No


2963
A -> C
No


2993
T -> C
Yes


3140
-> T 
No









Variant protein HSSTROL3_P5 (SEQ ID NO:360) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSSTROL3_T8 (SEQ ID NO:35) and HSSTROL3_T9 (SEQ ID NO:36). An alignment is given to the known protein (Stromelysin-3 precursor (SEQ ID NO:391) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSSTROL3_P5 (SEQ ID NO:360) and MM11_HUMAN:


1. An isolated chimeric polypeptide encoding for HSSTROL3_P5 (SEQ ID NO:360) comprising a first amino acid sequence being at least 90% homologous to MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS PAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVLSGGRWEKTDLTYRILRFP WQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMIDFARYW corresponding to amino acids 1-163 of MM11_HUMAN, which also corresponds to amino acids 1-163 of HSSTROL3_P5 (SEQ ID NO:360), a bridging amino acid H corresponding to amino acid 164 of HSSTROL3_P5 (SEQ ID NO:360), a second amino acid sequence being at least 90% homologous to GDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWTIGDDQGTDLLQVAAHEFGHVLG LQHTTAAKALMSAFYTFRYPLSLSPDDCRGVQHLYGQPWPTVTSRTPALGPQAGIDTN EIAPLEPDAPPDACEASFDAVSTIRGELFFFKAGFVWRLRGGQLQPGYPALASRHWQGL PSPVDAAFEDAQGHIWFFQ corresponding to amino acids 165-358 of MM11_HUMAN, which also corresponds to amino acids 165-358 of HSSTROL3_P5 (SEQ ID NO:360), and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence ELGFPSSTGRDESLEHCRCQGLHK (SEQ ID NO: 565) corresponding to amino acids 359-382 of HSSTROL3_P5 (SEQ ID NO:360), wherein said first amino acid sequence, bridging amino acid, second amino acid sequence and third amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSSTROL3_P5 (SEQ ID NO:360) comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence ELGFPSSTGRDESLEHCRCQGLHK (SEQ ID NO: 565) in HSSTROL3_P5 (SEQ ID NO:360).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSSTROL3_P5 (SEQ ID NO:360) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 291, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P5 (SEQ ID NO:360) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 291







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












38
V -> A
Yes


104
R -> P
Yes


214
A -> 
No


323
Q -> H
Yes









Variant protein HSSTROL3_P5 (SEQ ID NO:360) is encoded by the following transcript(s): HSSTROL3_T8 (SEQ ID NO:35) and HSSTROL3_T9 (SEQ ID NO:36), for which the sequence(s) is/are given at the end of the application.


The coding portion of transcript HSSTROL3_T8 (SEQ ID NO:35) is shown in bold; this coding portion starts at position 24 and ends at position 1169. The transcript also has the following SNPs as listed in Table 292 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P5 (SEQ ID NO:360) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 292







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












136
T -> C
Yes


334
G -> C
Yes


663
G -> 
No


699
-> T 
No


992
G -> C
Yes


1903
C -> 
No


1955
C -> A
Yes


1981
A -> T
Yes


2198
-> G 
No


2207
-> G 
No


2221
C -> 
No


2240
-> A 
No


2266
T -> C
No


2324
A -> 
No


2324
A -> C
No


2474
A -> 
No


2474
A -> C
No


2504
T -> C
Yes


2651
-> T 
No









The coding portion of transcript HSSTROL3_T9 (SEQ ID NO:36) is shown in bold; this coding portion starts at position 24 and ends at position 1169. The transcript also has the following SNPs as listed in Table 293 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P5 (SEQ ID NO:360) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 293







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












136
T -> C
Yes


334
G -> C
Yes


663
G -> 
No


699
-> T 
No


992
G -> C
Yes


1666
A -> G
Yes


1848
A -> G
Yes


2389
A -> G
Yes


2530
C -> 
No


2582
C -> A
Yes


2608
A -> T
Yes


2825
-> G 
No


2834
-> G 
No


2848
C -> 
No


2867
-> A 
No


2893
T -> C
No


2951
A -> 
No


2951
A -> C
No


3101
A -> 
No


3101
A -> C
No


3131
T -> C
Yes


3278
-> T 
No









Variant protein HSSTROL3_P7 (SEQ ID NO:361) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSSTROL3_T10 (SEQ ID NO:37). An alignment is given to the known protein (Stromelysin-3 precursor (SEQ ID NO:391)) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSSTROL3_P7 (SEQ ID NO:361) and MM11_HUMAN:


1. An isolated chimeric polypeptide encoding for HSSTROL3_P7 (SEQ ID NO:361) comprising a first amino acid sequence being at least 90% homologous to MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS PAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVLSGGRWEKTDLTYRILRFP WQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMIDFARYW corresponding to amino acids 1-163 of MM11_HUMAN, which also corresponds to amino acids 1-163 of HSSTROL3_P7 (SEQ ID NO:361), a bridging amino acid H corresponding to amino acid 164 of HSSTROL3_P7 (SEQ ID NO:361), a second amino acid sequence being at least 90% homologous to GDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWTIGDDQGTDLLQVAAHEFGHVLG LQHTTAAKALMSAFYTFRYPLSLSPDDCRGVQHLYGQPWPTVTSRTPALGPQAGIDTN EIAPLEPDAPPDACEASFDAVSTIRGELFFFKAGFVWRLRGGQLQPGYPALASRHWQGL PSPVDAAFEDAQGHIWFFQG corresponding to amino acids 165-359 of MM11_HUMAN, which also corresponds to amino acids 165-359 of HSSTROL3_P7 (SEQ ID NO:361), and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence TTGVSTPAPGV (SEQ ID NO: 566) corresponding to amino acids 360-370 of HSSTROL3_P7 (SEQ ID NO:361), wherein said first amino acid sequence, bridging amino acid, second amino acid sequence and third amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSSTROL3_P7 (SEQ ID NO:361) comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TTGVSTPAPGV (SEQ ID NO: 566) in HSSTROL3_P7 (SEQ ID NO:361).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSSTROL3_P7 (SEQ ID NO:361) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 294, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P7 (SEQ ID NO:361) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 294







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












38
V -> A
Yes


104
R -> P
Yes


214
A -> 
No


323
Q -> H
Yes









Variant protein HSSTROL3_P7 (SEQ ID NO:361) is encoded by the following transcript(s): HSSTROL3_T10 (SEQ ID NO:37), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSSTROL3_T10 (SEQ ID NO:37) is shown in bold; this coding portion starts at position 24 and ends at position 1133. The transcript also has the following SNPs as listed in Table 295 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P7 (SEQ ID NO:361) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 295







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












136
T -> C
Yes


334
G -> C
Yes


663
G -> 
No


699
-> T 
No


992
G -> C
Yes


1386
A -> G
Yes


1568
A -> G
Yes


2109
A -> G
Yes


2250
C -> 
No


2302
C -> A
Yes


2328
A -> T
Yes


2545
-> G 
No


2554
-> G 
No


2568
C -> 
No


2587
-> A 
No


2613
T -> C
No


2671
A -> 
No


2671
A -> C
No


2821
A -> 
No


2821
A -> C
No


2851
T -> C
Yes


2998
-> T 
No









Variant protein HSSTROL3_P8 (SEQ ID NO:362) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSSTROL3_T11 (SEQ ID NO:38). An alignment is given to the known protein (Stromelysin-3 precursor (SEQ ID NO:391)) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSSTROL3_P8 (SEQ ID NO:362) and MM11_HUMAN:


1. An isolated chimeric polypeptide encoding for HSSTROL3_P8 (SEQ ID NO:362) comprising a first amino acid sequence being at least 90% homologous to MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS PAPAPATQEAPRPAS SLRPPRCGVPDPSDGLSARNRQKRFVLSGGRWEKTDLTYRILRFP WQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMIDFARYW corresponding to amino acids 1-163 of MM11_HUMAN, which also corresponds to amino acids 1-163 of HSSTROL3_P8 (SEQ ID NO:362), a bridging amino acid H corresponding to amino acid 164 of HSSTROL3_P8 (SEQ ID NO:362), a second amino acid sequence being at least 90% homologous to GDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWTIGDDQGTDLLQVAAHEFGHVLG LQHTTAAKALMSAFYTFRYPLSLSPDDCRGVQHLYGQPWPTVTSRTPALGPQAGIDTN EIAPLE corresponding to amino acids 165-286 of MM11_HUMAN, which also corresponds to amino acids 165-286 of HSSTROL3_P8 (SEQ ID NO:362), and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence VRPCLPVPLLLCWPL (SEQ ID NO: 567) corresponding to amino acids 287-301 of HSSTROL3_P8 (SEQ ID NO:362), wherein said first amino acid sequence, bridging amino acid, second amino acid sequence and third amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSSTROL3_P8 (SEQ ID NO:362) comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VRPCLPVPLLLCWPL (SEQ ID NO: 567) in HSSTROL3_P8 (SEQ ID NO:362).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSSTROL3_P8 (SEQ ID NO:362) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 296, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P8 (SEQ ID NO:362) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 296







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












38
V -> A
Yes


104
R -> P
Yes


214
A -> 
No









Variant protein HSSTROL3_P8 (SEQ ID NO:362) is encoded by the following transcript(s): HSSTROL3_T11 (SEQ ID NO:38), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSSTROL3_T11 (SEQ ID NO:38) is shown in bold; this coding portion starts at position 24 and ends at position 926. The transcript also has the following SNPs as listed in Table 297 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P8 (SEQ ID NO:362) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 297







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












136
T -> C
Yes


334
G -> C
Yes


663
G -> 
No


699
-> T 
No


935
G -> A
Yes


948
G -> A
Yes


1084
G -> C
Yes


1557
C -> 
No


1609
C -> A
Yes


1635
A -> T
Yes


1852
-> G 
No


1861
-> G 
No


1875
C -> 
No


1894
-> A 
No


1920
T -> C
No


1978
A -> 
No


1978
A -> C
No


2128
A -> 
No


2128
A -> C
No


2158
T -> C
Yes


2305
-> T 
No









Variant protein HSSTROL3_P9 (SEQ ID NO:363) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSSTROL3_T12 (SEQ ID NO:39). An alignment is given to the known protein (Stromelysin-3 precursor (SEQ ID NO:391) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSSTROL3_P9 (SEQ ID NO:363) and MM11_HUMAN:


1. An isolated chimeric polypeptide encoding for HSSTROL3_P9 (SEQ ID NO:363) comprising a first amino acid sequence being at least 90% homologous to MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS PAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQK corresponding to amino acids 1-96 of MM11_HUMAN, which also corresponds to amino acids 1-96 of HSSTROL3_P9 (SEQ ID NO:363), a second amino acid sequence being at least 90% homologous to RILRFPWQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMIDFARYW corresponding to amino acids 113-163 of MM11_HUMAN, which also corresponds to amino acids 97-147 of HSSTROL3_P9 (SEQ ID NO:363), a bridging amino acid H corresponding to amino acid 148 of HSSTROL3_P9 (SEQ ID NO:363), a third amino acid sequence being at least 90% homologous to GDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWTIGDDQGTDLLQVAAHEFGHVLG LQHTTAAKALMSAFYTFRYPLSLSPDDCRGVQHLYGQPWPTVTSRTPALGPQAGIDTN EIAPLEPDAPPDACEASFDAVSTIRGELFFFKAGFVWRLRGGQLQPGYPALASRHWQGL PSPVDAAFEDAQGHIWFFQG corresponding to amino acids 165-359 of MM11_HUMAN, which also corresponds to amino acids 149-343 of HSSTROL3_P9 (SEQ ID NO:363), and a fourth amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence TTGVSTPAPGV (SEQ ID NO: 566) corresponding to amino acids 344-354 of HSSTROL3_P9 (SEQ ID NO:363), wherein said first amino acid sequence, second amino acid sequence, bridging amino acid, third amino acid sequence and fourth amino acid sequence are contiguous and in a sequential order.


2. An isolated chimeric polypeptide encoding for an edge portion of HSSTROL3_P9 (SEQ ID NO:363), comprising a polypeptide having a length “n”, wherein n is at least about 10 amino acids in length, optionally at least about 20 amino acids in length, preferably at least about 30 amino acids in length, more preferably at least about 40 amino acids in length and most preferably at least about 50 amino acids in length, wherein at least two amino acids comprise KR, having a structure as follows: a sequence starting from any of amino acid numbers 96-x to 96; and ending at any of amino acid numbers 97+((n−2)−x), in which x varies from 0 to n−2.


3. An isolated polypeptide encoding for a tail of HSSTROL3_P9 (SEQ ID NO:363), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TTGVSTPAPGV (SEQ ID NO: 566) in HSSTROL3_P9 (SEQ ID NO:363).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSSTROL3_P9 (SEQ ID NO:363) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 298, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P9 (SEQ ID NO:363) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 298







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












38
V -> A
Yes


198
A -> 
 No


307
Q -> H
Yes









Variant protein HSSTROL3_P9 (SEQ ID NO:363) is encoded by the following transcript(s): HSSTROL3_T12 (SEQ ID NO:39), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSSTROL3_T12 (SEQ ID NO:39) is shown in bold; this coding portion starts at position 24 and ends at position 1085. The transcript also has the following SNPs as listed in Table 299 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P9 (SEQ ID NO:363) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 299







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












136
T -> C
Yes


615
G -> 
No


651
-> T 
No


944
G -> C
Yes


1275
C -> 
No


1327
C -> A
Yes


1353
A -> T
Yes


1570
-> G 
No


1579
-> G 
No


1593
C -> 
No


1612
-> A 
No


1638
T -> C
No


1696
A -> 
No


1696
A -> C
No


1846
A -> 
No


1846
A -> C
No


1876
T -> C
Yes


2023
-> T 
No









As noted above, cluster HSSTROL3 features 16 segment(s), which were listed in Table 2 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.


Segment cluster HSSTROL3_node6 (SEQ ID NO:222) according to the present invention is supported by 14 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5 (SEQ ID NO:34), HSSTROL3_T8 (SEQ ID NO:35), HSSTROL3_T9 (SEQ ID NO:36), HSSTROL3_T10 (SEQ ID NO:37), HSSTROL3_T11 (SEQ ID NO:38) and HSSTROL3_T12 (SEQ ID NO:39). Table 300 below describes the starting and ending position of this segment on each transcript.









TABLE 300







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSSTROL3_T5  (SEQ ID NO:34)
1
131


HSSTROL3_T8  (SEQ ID NO:35)
1
131


HSSTROL3_T9  (SEQ ID NO:36)
1
131


HSSTROL3_T10 (SEQ ID NO:37)
1
131


HSSTROL3_T11 (SEQ ID NO:38)
1
131


HSSTROL3_T12 (SEQ ID NO:39)
1
131









Segment cluster HSSTROL3_node10 (SEQ ID NO:223) according to the present invention is supported by 21 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5 (SEQ ID NO:34), HSSTROL3_T8 (SEQ ID NO:35), HSSTROL3_T9 (SEQ ID NO:36), HSSTROL3_T10 (SEQ ID NO:37), HSSTROL3_T11 (SEQ ID NO:38) and HSSTROL3_T12 (SEQ ID NO:39). Table 301 below describes the starting and ending position of this segment on each transcript.









TABLE 301







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSSTROL3_T5  (SEQ ID NO:34)
132
313


HSSTROL3_T8  (SEQ ID NO:35)
132
313


HSSTROL3_T9  (SEQ ID NO:36)
132
313


HSSTROL3_T10 (SEQ ID NO:37)
132
313


HSSTROL3_T11 (SEQ ID NO:38)
132
313


HSSTROL3_T12 (SEQ ID NO:39)
132
313









Segment cluster HSSTROL3_node13 (SEQ ID NO:224) according to the present invention is supported by 36 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5 (SEQ ID NO:34), HSSTROL3_T8 (SEQ ID NO:35), HSSTROL3_T9 (SEQ ID NO:36), HSSTROL3_T10 (SEQ ID NO:37), HSSTROL3_T11 (SEQ ID NO:38) and HSSTROL3_T12 (SEQ ID NO:39). Table 302 below describes the starting and ending position of this segment on each transcript.









TABLE 302







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSSTROL3_T5  (SEQ ID NO:34)
362
505


HSSTROL3_T8  (SEQ ID NO:35)
362
505


HSSTROL3_T9  (SEQ ID NO:36)
362
505


HSSTROL3_T10 (SEQ ID NO:37)
362
505


HSSTROL3_T11 (SEQ ID NO:38)
362
505


HSSTROL3_T12 (SEQ ID NO:39)
314
457









Segment cluster HSSTROL3_node15 (SEQ ID NO:225) according to the present invention is supported by 47 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5 (SEQ ID NO:34), HSSTROL3_T8 (SEQ ID NO:35), HSSTROL3_T9 (SEQ ID NO:36), HSSTROL3_T10 (SEQ ID NO:37), HSSTROL3_T11 (SEQ ID NO:38) and HSSTROL3_T12 (SEQ ID NO:39). Table 303 below describes the starting and ending position of this segment on each transcript.









TABLE 303







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSSTROL3_T5  (SEQ ID NO:34)
506
639


HSSTROL3_T8  (SEQ ID NO:35)
506
639


HSSTROL3_T9  (SEQ ID NO:36)
506
639


HSSTROL3_T10 (SEQ ID NO:37)
506
639


HSSTROL3_T11 (SEQ ID NO:38)
506
639


HSSTROL3_T12 (SEQ ID NO:39)
458
591









Segment cluster HSSTROL3_node19 (SEQ ID NO:226) according to the present invention is supported by 63 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5 (SEQ ID NO:34), HSSTROL3_T8 (SEQ ID NO:35), HSSTROL3_T9 (SEQ ID NO:36), HSSTROL3_T10 (SEQ ID NO:37), HSSTROL3_T11 (SEQ ID NO:38) and HSSTROL3_T12 (SEQ ID NO:39). Table 304 below describes the starting and ending position of this segment on each transcript.









TABLE 304







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSSTROL3_T5  (SEQ ID NO:34)
699
881


HSSTROL3_T8  (SEQ ID NO:35)
699
881


HSSTROL3_T9  (SEQ ID NO:36)
699
881


HSSTROL3_T10 (SEQ ID NO:37)
699
881


HSSTROL3_T11 (SEQ ID NO:38)
699
881


HSSTROL3_T12 (SEQ ID NO:39)
651
833









Segment cluster HSSTROL3_node21 (SEQ ID NO:227) according to the present invention is supported by 61 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5 (SEQ ID NO:34), HSSTROL3_T8 (SEQ ID NO:35), HSSTROL3_T9 (SEQ ID NO:36), HSSTROL3_T10 (SEQ ID NO:37), HSSTROL3_T11 (SEQ ID NO:38) and HSSTROL3_T12 (SEQ ID NO:39). Table 305 below describes the starting and ending position of this segment on each transcript.









TABLE 305







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSSTROL3_T5  (SEQ ID NO:34)
882
1098


HSSTROL3_T8  (SEQ ID NO:35)
882
1098


HSSTROL3_T9  (SEQ ID NO:36)
882
1098


HSSTROL3_T10 (SEQ ID NO:37)
882
1098


HSSTROL3_T11 (SEQ ID NO:38)
974
1190


HSSTROL3_T12 (SEQ ID NO:39)
834
1050









Segment cluster HSSTROL3_node24 (SEQ ID NO:228) according to the present invention is supported by 7 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T8 (SEQ ID NO:35) and HSSTROL3_T9 (SEQ ID NO:36). Table 306 below describes the starting and ending position of this segment on each transcript.









TABLE 306







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSSTROL3_T8 (SEQ ID NO:35)
1099
1236


HSSTROL3_T9 (SEQ ID NO:36)
1099
1236









Segment cluster HSSTROL3_node25 (SEQ ID NO:229) according to the present invention is supported by 13 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T8 (SEQ ID NO:35). Table 307 below describes the starting and ending position of this segment on each transcript.









TABLE 307







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSSTROL3_T8 (SEQ ID NO:35)
1237
1536









Segment cluster HSSTROL3_node26 (SEQ ID NO:230) according to the present invention is supported by 55 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5 (SEQ ID NO:34), HSSTROL3_T8 (SEQ ID NO:35), HSSTROL3_T9 (SEQ ID NO:36) and HSSTROL3_T 11 (SEQ ID NO:38). Table 308 below describes the starting and ending position of this segment on each transcript.









TABLE 308







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSSTROL3_T5  (SEQ ID NO:34)
1099
1240


HSSTROL3_T8  (SEQ ID NO:35)
1537
1678


HSSTROL3_T9  (SEQ ID NO:36)
1237
1378


HSSTROL3_T11 (SEQ ID NO:38)
1191
1332









Segment cluster HSSTROL3_node28 (SEQ ID NO:231) according to the present invention is supported by 10 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5 (SEQ ID NO:34), HSSTROL3_T9 (SEQ ID NO:36) and HSSTROL3_T10 (SEQ ID NO:37). Table 309 below describes the starting and ending position of this segment on each transcript.









TABLE 309







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSSTROL3_T5  (SEQ ID NO:34)
1357
2283


HSSTROL3_T9  (SEQ ID NO:36)
1495
2421


HSSTROL3_T10 (SEQ ID NO:37)
1215
2141









Segment cluster HSSTROL3_node29 (SEQ ID NO:232) according to the present invention is supported by 109 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5 (SEQ ID NO:34), HSSTROL3_T8 (SEQ ID NO:35), HSSTROL3_T9 (SEQ ID NO:36), HSSTROL3_T10 (SEQ ID NO:37), HSSTROL3_T11 (SEQ ID NO:38) and HSSTROL3_T12 (SEQ ID NO:39). Table 310 below describes the starting and ending position of this segment on each transcript.









TABLE 310







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSSTROL3_T5  (SEQ ID NO:34)
2284
3194


HSSTROL3_T8  (SEQ ID NO:35)
1795
2705


HSSTROL3_T9  (SEQ ID NO:36)
2422
3332


HSSTROL3_T10 (SEQ ID NO:37)
2142
3052


HSSTROL3_T11 (SEQ ID NO:38)
1449
2359


HSSTROL3_T12 (SEQ ID NO:39)
1167
2077









According to an optional embodiment of the present invention, short segments related to the above cluster are also provided. These segments are up to about 120 bp in length, and so are included in a separate description.


Segment cluster HSSTROL3_node11 (SEQ ID NO:233) according to the present invention is supported by 25 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5 (SEQ ID NO:34), HSSTROL3_T8 (SEQ ID NO:35), HSSTROL3_T9 (SEQ ID NO:36) HSSTROL3_T10 (SEQ ID NO:37) and HSSTROL3_T11 (SEQ ID NO:38). Table 311 below describes the starting and ending position of this segment on each transcript.









TABLE 311







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSSTROL3_T5  (SEQ ID NO:34)
314
361


HSSTROL3_T8  (SEQ ID NO:35)
314
361


HSSTROL3_T9  (SEQ ID NO:36)
314
361


HSSTROL3_T10 (SEQ ID NO:37)
314
361


HSSTROL3_T11 (SEQ ID NO:38)
314
361









Segment cluster HSSTROL3_node17 (SEQ ID NO:234) according to the present invention is supported by 45 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5 (SEQ ID NO:34), HSSTROL3_T8 (SEQ ID NO:35), HSSTROL3_T9 (SEQ ID NO:36), HSSTROL3_T10 (SEQ ID NO:37), HSSTROL3_T 11 (SEQ ID NO:38) and HSSTROL3_T12 (SEQ ID NO:39). Table 312 below describes the starting and ending position of this segment on each transcript.









TABLE 312







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSSTROL3_T5  (SEQ ID NO:34)
640
680


HSSTROL3_T8  (SEQ ID NO:35)
640
680


HSSTROL3_T9  (SEQ ID NO:36)
640
680


HSSTROL3_T10 (SEQ ID NO:37)
640
680


HSSTROL3_T11 (SEQ ID NO:38)
640
680


HSSTROL3_T12 (SEQ ID NO:39)
592
632









Segment cluster HSSTROL3_node18 (SEQ ID NO:235) according to the present invention can be found in the following transcript(s): HSSTROL3_T5 (SEQ ID NO:34) HSSTROL3_T8 (SEQ ID NO:35), HSSTROL3_T9 (SEQ ID NO:36), HSSTROL3_T10 (SEQ ID NO:37), HSSTROL3_T11 (SEQ ID NO:38) and HSSTROL3_T12 (SEQ ID NO:39). Table 313 below describes the starting and ending position of this segment on each transcript.









TABLE 313







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSSTROL3_T5  (SEQ ID NO:34)
681
698


HSSTROL3_T8  (SEQ ID NO:35)
681
698


HSSTROL3_T9  (SEQ ID NO:36)
681
698


HSSTROL3_T10 (SEQ ID NO:37)
681
698


HSSTROL3_T11 (SEQ ID NO:38)
681
698


HSSTROL3_T12 (SEQ ID NO:39)
633
650









Segment cluster HSSTROL3_node20 (SEQ ID NO:236) according to the present invention is supported by 1 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T11 (SEQ ID NO:38). Table 314 below describes the starting and ending position of this segment on each transcript.









TABLE 314







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSSTROL3_T11 (SEQ ID NO:38)
882
973









Segment cluster HSSTROL3_node27 (SEQ ID NO:237) according to the present invention is supported by 50 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5 (SEQ ID NO:34), HSSTROL3_T8 (SEQ ID NO:35), HSSTROL3_T9 (SEQ ID NO:36), HSSTROL3_T10 (SEQ ID NO:37), HSSTROL3_T11 (SEQ ID NO:38) and HSSTROL3 T12 (SEQ ID NO:39). Table 315 below describes the starting and ending position of this segment on each transcript.









TABLE 315







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSSTROL3_T5  (SEQ ID NO:34)
1241
1356


HSSTROL3_T8  (SEQ ID NO:35)
1679
1794


HSSTROL3_T9  (SEQ ID NO:36)
1379
1494


HSSTROL3_T10 (SEQ ID NO:37)
1099
1214


HSSTROL3_T11 (SEQ ID NO:38)
1333
1448


HSSTROL3_T12 (SEQ ID NO:39)
1051
1166










Variant Protein Alignment to the Previously Known Protein:














Sequence name: MM11_HUMAN


Sequence documentation:


Alignment of: HSSTROL3_P4 (SEQ ID NO:359) x MM11_HUMAN . . .


Alignment segment 1/1:








Quality:
4444.00


Escore:
0


Matching length:
445


Total length:
445


Matching Percent Similarity:
99.78


Matching Percent Identity:
99.78


Total Percent Similarity:
99.78


Total Percent Identity:
99.78


Gaps:
0







Alignment:




embedded image









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embedded image









embedded image







Sequence name: MM11_HUMAN


Sequence documentation:


Alignment of: HSSTROL3_P5 (SEQ ID NO:360) x MM11_HUMAN . . .


Alignment segment 1/1:








Quality:
3566.00


Escore:
0


Matching length:
358


Total length:
358


Matching Percent Similarity:
99.72


Matching Percent Identity:
99.72


Total Percent Similarity:
99.72


Total Percent Identity:
99.72


Gaps:
0







Alignment:




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embedded image







Sequence name: MM11_HUMAN


Sequence documentation:


Alignment of: HSSTROL3_P7 (SEQ ID NO:361) x MM11_HUMAN . . .


Alignment segment 1/1:








Quality:
3575.00


Escore:
0


Matching length:
359


Total length:
359


Matching Percent Similarity:
99.72


Matching Percent Identity:
99.72


Total Percent Similarity:
99.72


Total Percent Identity:
99.72


Gaps:
0







Alignment:




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embedded image







Seqence name: MM11_HUMAN


Sequence documentation:


Alignment of: HSSTROL3_P8 (SEQ ID NO:362) x MM11_HUMAN . . .


Alignment segment 1/1:








Quality:
2838.00


Escore:
0


Matching length:
286


Total length:
286


Matching Percent Similarity:
99.65


Matching Percent Identity:
99.65


Total Percent Similarity:
99.65


Total Percent Identity:
99.65


Gaps:
0







Alignment:




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Sequence name: MM11_HUMAN


Sequence documentation:


Alignment of: HSSTROL3_P9 (SEQ ID NO:363) x MM11_HUMAN . . .


Alignment segment 1/1:








Quality:
3316.00


Escore:
0


Matching length:
343


Total length:
359


Matching Percent Similarity:
99.71


Matching Percent Identity:
99.71


Total Percent Similarity:
95.26


Total Percent Identity:
95.26


Gaps:
1







Alignment:




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Expression of Stromelysin-3 Precursor (SEQ ID NO:391) (EC 3.4.24.-) (Matrix Metalloproteinase-11) (MMP-11) (ST3) (SL-3HSSTROL3) Transcripts Which are Detectable by Amplicon as Depicted in Sequence Name HSSTROL3 seg24 (SEQ ID NO:499) in Normal and Cancerous Prostate Tissues


Expression of Stromelysin-3 precursor (SEQ ID NO:391) (EC 3.4.24.-) (Matrix metalloproteinase-11) (MMP-11) (ST3) (SL-3) transcripts detectable by or according to seg24, HSSTROL3 seg24 (SEQ ID NO:499) amplicon(s) and HSSTROL3 seg24F (SEQ ID NO:497) and HSSTROL3 seg24R (SEQ ID NO:498) primers was measured by real time PCR. In parallel the expression of four housekeeping genes—PBGD (GenBank Accession No. BC019323 (SEQ ID NO:509); amplicon—PBGD-amplicon (SEQ ID NO:404), HPRT1 (GenBank Accession No. NM000194 (SEQ ID NO:510); amplicon—HPRT1-amplicon (SEQ ID NO:401), SDHA (GenBank Accession No. NM004168 (SEQ ID NO:508); amplicon—SDHA-amplicon (SEQ ID NO:407), and RPL19 (GenBank Accession No. NM000981 (SEQ ID NO:511); RPL19 amplicon (SEQ ID NO:410) was measured similarly. For each RT sample, the expression of the above amplicon was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal post-mortem (PM) samples (Sample Nos. 42, 48-53, 59-63, Table 1, “Tissue samples in testing panel”, above), to obtain a value of fold up-regulation for each sample relative to median of the normal PM samples.



FIG. 14 is a histogram showing over expression of the above-indicated Stromelysin-3 precursor (SEQ ID NO:391) transcripts in cancerous Prostate samples relative to the normal samples. Values represent the average of duplicate experiments. Error bars indicate the minimal and maximal values obtained.)


As is evident from FIG. 14, the expression of Stromelysin-3 precursor (SEQ ID NO:391) transcripts detectable by the above amplicon(s) in cancer samples was higher than in several non-cancerous samples (Sample Nos. 42, 48-53, 59-63, Table 1, “Tissue samples in testing panel”). Notably an over-expression of at least 3 fold was found in 4 out of 19 adenocarcinoma samples.


Statistical analysis was applied to verify the significance of these results, as described below.


The P value for the difference in the expression levels of Stromelysin-3 precursor (SEQ ID NO:391) transcripts detectable by the above amplicon(s) in Prostate cancer samples versus the normal tissue samples was determined by T test as 2.34E-03.


The above value demonstrate statistical significance of the results.


Primer pairs are also optionally and preferably encompassed within the present invention; for example, for the above experiment, the following primer pair was used as a non-limiting illustrative example only of a suitable primer pair: HSSTROL3 seg24F forward primer (SEQ ID NO:497); and HSSTROL3 seg24R reverse primer (SEQ ID NO:498).


The present invention also preferably encompasses any amplicon obtained through the use of any suitable primer pair; for example, for the above experiment, the following amplicon was obtained as a non-limiting illustrative example only of a suitable amplicon: HSSTROL seg24 (SEQ ID NO:499).









HSSTROL seg24 Forward primer (SEQ ID NO:497):


ATTTCCATCCTCAACTGGCAGA





HSSTROL seg24 Reverse primer (SEQ ID NO:498):


TGCCCTGGAACCCACG





HSSTROL seg24 Amplicon (SEQ ID NO:499):


ATTTCCATCCTCAACTGGCAGAGATGAGAGCCTGGAGCATTGCAGATGCC





AGGGACTTCAACAAATGAAGGCACAGCATGGGAAACCTGCGTGGGTTCCA





GGGCA







Expression of Stromelysin-3 Precursor (SEQ ID NO:391) Transcripts Which are Detectable by Amplicon as Depicted in Sequence Name HSSTROL3 seg24 (SEQ ID NO:499) in Different Normal Tissues


Expression of Stromelysin-3 precursor (SEQ ID NO:391) transcripts detectable by or according to HSSTROL3 seg24 (SEQ ID NO:499) amplicon(s) and HSSTROL3 seg24F (SEQ ID NO:497) and HSSTROL3 seg24R (SEQ ID NO:498) was measured by real time PCR. In parallel the expression of four housekeeping genes Ubiquitin (GenBank Accession No. BC000449 (SEQ ID NO:516); amplicon—Ubiquitin-amplicon (SEQ ID NO:519) and SDHA (GenBank Accession No. NM004168 (SEQ ID NO:508); amplicon—SDHA-amplicon (SEQ ID NO:407), RPL19 (GenBank Accession No. NM000981 (SEQ ID NO:511); RPL19 amplicon (SEQ ID NO:410)), TATA box (GenBank Accession No. NM003194 (SEQ ID NO:512); TATA amplicon (SEQ ID NO:515)) was measured similarly. For each RT sample, the expression of the above amplicon was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the lung samples (Sample Nos. 15-17, Table 2 “Tissue samples in normal panel”, above), to obtain a value of relative expression of each sample relative to median of the lung samples.


The results are shown in FIG. 15, demonstrating the expression of Stromelysin-3 transcripts which are detectable by amplicon as depicted in sequence name HSSTROL3 seg24 (SEQ ID NO:499) in different normal tissues.


Description for Cluster HUMF5A


Cluster HUMF5A features 3 transcript(s) and 33 segment(s) of interest, the names for which are given in Tables 316 and 317, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 318.









TABLE 316







Transcripts of interest










Transcript Name
Sequence ID No.







HUMF5A_PEA_1_T1
40



HUMF5A_PEA_1_T3
41



HUMF5A_PEA_1_T7
42

















TABLE 317







Segments of interest










Segment Name
Sequence ID No.







HUMF5A_PEA_1_node_0
238



HUMF5A_PEA_1_node_4
239



HUMF5A_PEA_1_node_6
240



HUMF5A_PEA_1_node_8
241



HUMF5A_PEA_1_node_10
242



HUMF5A_PEA_1_node_12
243



HUMF5A_PEA_1_node_14
244



HUMF5A_PEA_1_node_18
245



HUMF5A_PEA_1_node_21
246



HUMF5A_PEA_1_node_22
247



HUMF5A_PEA_1_node_24
248



HUMF5A_PEA_1_node_26
249



HUMF5A_PEA_1_node_27
250



HUMF5A_PEA_1_node_29
251



HUMF5A_PEA_1_node_35
252



HUMF5A_PEA_1_node_37
253



HUMF5A_PEA_1_node_39
254



HUMF5A_PEA_1_node_47
255



HUMF5A_PEA_1_node_50
256



HUMF5A_PEA_1_node_53
257



HUMF5A_PEA_1_node_56
258



HUMF5A_PEA_1_node_60
259



HUMF5A_PEA_1_node_2
260



HUMF5A_PEA_1_node_16
261



HUMF5A_PEA_1_node_31
262



HUMF5A_PEA_1_node_32
263



HUMF5A_PEA_1_node_33
264



HUMF5A_PEA_1_node_41
265



HUMF5A_PEA_1_node_43
266



HUMF5A_PEA_1_node_45
267



HUMF5A_PEA_1_node_51
268



HUMF5A_PEA_1_node_57
269



HUMF5A_PEA_1_node_59
270

















TABLE 318







Proteins of interest










Sequence ID



Protein Name
No.
Corresponding Transcript(s)





HUMF5A_PEA_1_P3
364
HUMF5A_PEA_1_T1 (SEQ




ID NO:40)


HUMF5A_PEA_1_P4
365
HUMF5A_PEA_1_T3 (SEQ




ID NO:41)


HUMF5A_PEA_1_P8
366
HUMF5A_PEA_1_T7 (SEQ




ID NO:42)









These sequences are variants of the known protein Coagulation factor V precursor (SEQ ID NO:392) (SwissProt accession identifier FA5_HUMAN (SEQ ID NO: 392); known also according to the synonyms Activated protein C cofactor), SEQ ID NO: 392, referred to herein as the previously known protein.


Protein Coagulation factor V precursor (SEQ ID NO:392) is known or believed to have the following function(s): Coagulation factor V is a cofactor that participates with factor Xa to activate prothrombin to thrombin. The sequence for protein Coagulation factor V precursor (SEQ ID NO:392) is given at the end of the application, as “Coagulation factor V precursor (SEQ ID NO:392) amino acid sequence”. Known polymorphisms for this sequence are as shown in Table 319.









TABLE 319







Amino acid mutations for Known Protein








SNP position(s)



on amino acid


sequence
Comment











107
D -> H (in dbSNP: 6019). /FTId=VAR_013886.


334
R -> G (in APCR; Hong Kong). /FTId=VAR_013620.


334
R -> T (in APCR; Cambridge). /FTId=VAR_013621.


413
M -> T (in dbSNP: 6033). /FTId=VAR_013887.


513
R -> K (in dbSNP: 6020). /FTId=VAR_013622.


534
R -> Q (in APCR; Leiden; dbSNP: 6025).



/FTId=VAR_001213.


809
P -> S (in dbSNP: 6031). /FTId=VAR_013888.


817
N -> T (in dbSNP: 6018). /FTId=VAR_013889.


858
K -> R (in dbSNP: 4524). /FTId=VAR_001214.


865
H -> R (in dbSNP: 4525). /FTId=VAR_001215.


925
K -> E (in dbSNP: 6032). /FTId=VAR_013890.


1146
H -> Q (in dbSNP: 6005). /FTId=VAR_013891.


1285
L -> I (in dbSNP: 1046712). /FTId=VAR_013892.


1327
H -> R (in dbSNP: 1800595). /FTId=VAR_013893.


1530
E -> A (in dbSNP: 6007). /FTId=VAR_013894.


1685
T -> S (in dbSNP: 6011). /FTId=VAR_013895.


1749
L -> V (in dbSNP: 6034). /FTId=VAR_013896.


1764
V -> M (in dbSNP: 6030). /FTId=VAR_013897.


1820
M -> I (in dbSNP: 6026). /FTId=VAR_013898.


2102
R -> H (in APCR). /FTId=VAR_017329.


2222
D -> G (in dbSNP: 6027). /FTId=VAR_013899.


2213
T -> A









The following GO Annotation(s) apply to the previously known protein. The following annotation(s) were found: cell adhesion; blood coagulation, which are annotation(s) related to Biological Process; and blood coagulation factor; copper binding, which are annotation(s) related to Molecular Function.


The GO assignment relies on information from one or more of the SwissProt/TremB1 Protein knowledgebase, available from expasydotch/sprot/; or Locuslink, available from ncbidotnlmdotnihgov/projects/LocusLink/.


As noted above, cluster HUMF5A features 3 transcript(s), which were listed in Table 316 above. These transcript(s) encode for protein(s) which are variant(s) of protein Coagulation factor V precursor (SEQ ID NO:392). A description of each variant protein according to the present invention is now provided.


Variant protein HUMF5A_PEA1_P3 (SEQ ID NO:364) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HUMF5A_PEA1_T1 (SEQ ID NO:40). An alignment is given to the known protein (Coagulation factor V precursor (SEQ ID NO:392)) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HUMF5A_PEA1_P3 (SEQ ID NO:364) and FA5_HUMAN_V1 (SEQ ID NO:393):


1. An isolated chimeric polypeptide encoding for HUMF5A_PEA1_P3 (SEQ ID NO:364), comprising a first amino acid sequence being at least 90% homologous to MFPGCPRLWVLVVLGTSWVGWGSQGTEAAQLRQFYVAAQGISWSYRPEPTNSSLNLS VTSFKKIVYREYEPYFKKEKPQSTISGLLGPTLYAEVGDIIKVHFKNKADKPLSIHPQGIR YSKLSEGASYLDHTFPAEKMDDAVAPGREYTYEWSISEDSGPTHDDPPCLTHIYYSHEN LIEDFNSGLIGPLLICKKGTLTEGGTQKTFDKQIVLLFAVFDESKSWSQSSSLMYTVNGY VNGTMPDITVCAHDHISWHLLGMSSGPELFSIHFNGQVLEQNHHKVSAITLVSATSTTA NMTVGPEGKWIIS SLTPKHLQAGMQAYIDIKNCPKKTRNLKKITREQRRHMKRWEYFI AAEEVIWDYAPVIPANMDKKYRSQHLDNFSNQIGKHYKKVMYTQYEDESFTKHTVNP NMKEDGILGPIIRAQVRDTLKIVFKNMASRPYSIYPHGVTFSPYEDEVNSSFTSGRNNTM IRAVQPGETYTYKWNILEFDEPTENDAQCLTRPYYSDVDIMRDIASGLIGLLLICKSRSL DRRGIQRAADIEQQAVFAVFDENKSWYLEDNINKFCENPDEVKRDDPKFYESNIMSTIN GYVPESITTLGFCFDDTVQWHFCSVGTQNEILTIHFTGHSFIYGKRHEDTLTLFPMRGES VTVTMDNVGTWMLTSMNSSPRSKKLRLKFRDVKCIPDDDEDSYEIFEPPESTVMATRK MHDRLEPEDEESDADYDYQNRLAAALGIRSFRNSSLNQEEEEFNLTALALENGTEFVSS NTDIIVGSNYSSPSNISKFTVNNLAEPQKAPSHQQATTAGSPLRHLIGKNSVLNSSTAEHS SPYSEDPIEDPLQPDVTGIRLLSLGAGEFRSQEHAKRKGPKVERDQAAKHRFSWMKLLA HKVGRHLSQDTGSPSGMRPWEDLPSQDTGSPSRMRPWKDPPSDLLLLKQSNSSKILVG RWHLASEKGSYEIIQDTDEDTAVNNWLISPQNASRAWGESTPLANKPGKQSGHPKFPR VRHKSLQVRQDGGKSRLKKSQFLIKTRKKKKEKHTHHAPLSPRTFHPLRSEAYNTFSER RLKHSLVLHKSNETSLPTDLNQTLPSMDFGWIASLPDHNQNSSNDTGQASCPPGLYQTV PPEEHYQTFPIQDPDQMHSTSDPSHRSSSPELSEMLEYDRSHKSFPTDISQMSPSSEHEV WQTVISPDLSQVTLSPELSQTNLSPDLSHTTLSPELIQRNLSPALGQMPISPDLSHTTLSPD LSHTTLSLDLSQTNLSPELSQTNLSPALGQMPLSPDLSHTTLSLDFSQTNLSPELSHMTLS PELSQTNLSPALGQMPISPDLSHTTLSLDFSQTNLSPELSQTNLSPALGQMPLSPDPSHTT LSLDLSQTNLSPELSQTNLSPDLSEMPLFADLSQIPLTPDLDQMTLSPDLGETDLSPNFGQ MSLSPDLSQVTLSPDISDTTLLPDLSQISPPPDLDQIFYPSESSQSLLLQEFNESFPYPDLGQ MPSPSSPTLNDTFLSKEFNPLVIVGLSKDGTDYIEIIPKEEVQSSEDDYAEIDYVPYDDPY KTDVRTNINSSRDPDNIAAWYLRSNNGNRRNYYIAAEEISWDYSEFVQRETDIEDSDDIP


EDTTYKK corresponding to amino acids 1-1617 of FA5_HUMAN_V1 (SEQ ID NO:393), which also corresponds to amino acids 1-1617 of HUMF5A_PEA1_P3 (SEQ ID NO:364), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence GSMKSISEFLVLLSELKWMMLSKFVLKI (SEQ ID NO: 569) corresponding to amino acids 1618-1645 of HUMF5A_PEA1_P3 (SEQ ID NO:364), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HUMF5A_PEA1_P3 (SEQ ID NO:364), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence GSMKSISEFLVLLSELKWMMLSKFVLKI (SEQ ID NO: 569) in HUMF5A_PEA1_P3 (SEQ ID NO:364).


It should be noted that the known protein sequence (FA5 HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for FA5_HUMAN_V1 (SEQ ID NO:393). These changes were previously known to occur and are listed in the table below.









TABLE 320







Changes to FA5_HUMAN_V1 (SEQ ID NO:393)










SNP position(s) on




amino acid sequence
Type of change







859
Variant



866
Variant










The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HUMF5A_PEA1_P3 (SEQ ID NO:364) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 321, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMF5A_PEA1_P3 (SEQ ID NO:364) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 321







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












15
G -> S
Yes


107
D -> H
Yes


413
M -> T
Yes


513
R -> K
Yes


534
R -> Q
Yes


781
S -> R
Yes


809
P -> S
Yes


817
N -> T
Yes


858
R -> K
Yes


865
R -> H
Yes


915
T -> S
Yes


925
K -> E
Yes


969
N -> S
Yes


980
R -> L
Yes


1146
H -> Q
Yes


1169
D -> 
No


1285
L -> I 
Yes


1327
H -> R
Yes


1397
L -> F
Yes


1404
P -> S
Yes


1530
E -> A
Yes









Variant protein HUMF5A_PEA1_P3 (SEQ ID NO:364) is encoded by the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HUMF5A_PEA1_T1 (SEQ ID NO:40) is shown in bold; this coding portion starts at position 183 and ends at position 5117. The transcript also has the following SNPs as listed in Table 322 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMF5A_PEA1_P3 (SEQ ID NO:364) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 322







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












16
C -> T
Yes


225
G -> A
Yes


419
A -> G
Yes


501
G -> C
Yes


587
G -> A
Yes


734
G -> T
Yes


746
G -> C
Yes


951
C -> T
Yes


998
C -> T
Yes


1420
T -> C
Yes


1424
A -> G
Yes


1562
C -> T
Yes


1720
G -> A
Yes


1783
G -> A
Yes


1898
G -> A
Yes


2102
C -> T
Yes


2108
C -> A
Yes


2390
T -> C
Yes


2417
C -> T
Yes


2471
A -> G
Yes


2483
G -> A
Yes


2525
T -> G
Yes


2607
C -> T
Yes


2632
A -> C
Yes


2755
G -> A
Yes


2776
G -> A
Yes


2925
A -> T
Yes


2955
A -> G
Yes


3088
A -> G
Yes


3121
G -> T
Yes


3437
A -> G
Yes


3620
C -> G
Yes


3686
A -> C
Yes


3688
A -> 
No


3689
T -> 
No


3764
C -> T
Yes


3986
T -> C
Yes


4035
C -> A
Yes


4130
C -> T
Yes


4162
A -> G
Yes


4277
C -> T
Yes


4371
C -> T
Yes


4392
C -> T
Yes


4771
A -> C
Yes


5152
A -> G
Yes


5184
C -> G
Yes


5375
C -> G
Yes


5420
G -> A
Yes


5590
G -> A
Yes


6573
T -> C
Yes


6684
A -> G
Yes


6795
A -> G
Yes









Variant protein HUMF5A_PEA1_P4 (SEQ ID NO:365) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HUMF5A_PEA1_T3 (SEQ ID NO:41). An alignment is given to the known protein (Coagulation factor V precursor (SEQ ID NO:392)) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HUMF5A_PEA1_P4 (SEQ ID NO:365) and FA5_HUMAN_V1 (SEQ ID NO:393):


1. An isolated chimeric polypeptide encoding for HUMF5A_PEA1_P4 (SEQ ID NO:365), comprising a first amino acid sequence being at least 90% homologous to MFPGCPRLWVLVVLGTSWVGWGSQGTEAAQLRQFYVAAQGISWSYRPEPTNSSLNLS VTSFKKIVYREYEPYFKKEKPQSTISGLLGPTLYAEVGDIIKVHFKNKADKPLSIHPQGIR YSKLSEGASYLDHTFPAEKMDDAVAPGREYTYEWSISEDSGPTHDDPPCLTHIYYSHEN LIEDFNSGLIGPLLICKKGTLTEGGTQKTFDKQIVLLFAVFDESKSWSQSSSLMYTVNGY VNGTMPDITVCAHDHISWHLLGMSSGPELFSIHFNGQVLEQNHHKVSAITLVSATSTTA NMTVGPEGKWIISSLTPKHLQAGMQAYIDIKNCPKKTRNLKKITREQRRHMKRWEYFI AAEEVIWDYAPVIPANMDKKYRSQHLDNFSNQIGKHYKKVMYTQYEDESFTKHTVNP NMKEDGILGPIIRAQVRDTLKIVFKNMASRPYSIYPHGVTFSPYEDEVNSSFTSGRNNTM IRAVQPGETYTYKWNILEFDEPTENDAQCLTRPYYSDVDIMRDIASGLIGLLLICKSRSL DRRGIQRAADIEQQAVFAVFDENKSWYLEDNINKFCENPDEVKRDDPKFYESNIMSTIN GYVPESITTLGFCFDDTVQWHFCSVGTQNEILTIHFTGHSFIYGKRHEDTLTLFPMRGES VTVTMDNVGTWMLTSMNSSPRSKKLRLKFRDVKClPDDDEDSYEIFEPPESTVMATRK MHDRLEPEDEESDADYDYQNRLAAALGIRSFRNSSLNQEEEEFNLTALALENGTEFVSS NTDIIVGSNYSSPSNISKFTVNNLAEPQKAPSHQQATTAGSPLRHLIGKNSVLNSSTAEHS SPYSEDPIEDPLQPDVTGIRLLSLGAGEFRSQEHAKRKGPKVERDQAAKHRFSWMKLLA HKVGRHLSQDTGSPSGMRPWEDLPSQDTGSPSRMRPWKDPPSDLLLLKQSNSSKILVG RWHLASEKGSYEIIQDTDEDTAVNNWLISPQNASRAWGESTPLANKPGKQSGHPKFPR VRHKSLQVRQDGGKSRLKKSQFLIKTRKKKKEKHTHHAPLSPRTFHPLRSEAYNTFSER RLKHSLVLHKSNETSLPTDLNQTLPSMDFGWIASLPDHNQNSSNDTGQASCPPGLYQTV PPEEHYQTFPIQDPDQMHSTSDPSHRSSSPELSEMLEYDRSHKSFPTDISQMSPSSEHEV WQTVISPDLSQVTLSPELSQTNLSPDLSHTTLSPELIQRNLSPALGQMPISPDLSHTTLSPD LSHTTLSLDLSQTNLSPELSQTNLSPALGQMPLSPDLSHTTLSLDFSQTNLSPELSHMTLS PELSQTNLSPALGQMPISPDLSHTTLSLDFSQTNLSPELSQTNLSPALGQMPLSPDPSHTT LSLDLSQTNLSPELSQTNLSPDLSEMPLFADLSQIPLTPDLDQMTLSPDLGETDLSPNFGQ MSLSPDLSQVTLSPDISDTTLLPDLSQISPPPDLDQIFYPSESSQSLLLQEFNESFPYPDLGQ MPSPSSPTLNDTFLSKEFNPLVIVGLSKDGTDYIEIIPKEEVQSSEDDYAEIDYVPYDDPY KTDVRTNINSSRDPDNIAAWYLRSNNGNRRNYYIAAEEISWDYSEFVQRETDIEDSDDIP EDTTYKKVVFRKYLDSTFTKRDPRGEYEEHLGILGPIIRAEVDDVIQVRFKNLASRPYSL HAHGLSYEKSSEGKTYEDDSPEWFKEDNAVQPNSSYTYVWHATERSGPESPGSACRA WAYYSAVNPEKDIHSGLIGPLLICQKGILHKDSNMPVDMREFVLLFMTFDEKKSWYYE KKSRSSWRLTSSEMKKSHEFHAINGMIYSLPGLKMYEQEWVRLHLLNIGGSQDIHVVH FHGQTLLENGNKQHQLGVWPLLPGSFKTLEMKASKPGWWLLNTEVGENQRAGMQTP FLIMDRDCRMPMGLSTGIISDSQIKASEFLGYWEPRLARLNNGGSYNAWSVEKLAAEFA SKPWIQVDMQKEVIITGIQTQGAKHYLKSCYTTEFYVAYSSNQINWQIFKGNSTRNVMY FNGNSDASTIKENQFDPPIVARYIRISPTRAYNRPTLRLELQGCE corresponding to amino acids 1-2062 of FA5_HUMAN_V1 (SEQ ID NO:393), which also corresponds to amino acids 1-2062 of HUMF5A_PEA1_P4 (SEQ ID NO:365), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence DVPHPWVWKMER (SEQ ID NO: 570) corresponding to amino acids 2063-2074 of HUMF5A_PEA1_P4 (SEQ ID NO:365), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HUMF5A_PEA1_P4 (SEQ ID NO:365), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DVPHPWVWKMER (SEQ ID NO: 570) in HUMF5A_PEA1_P4 (SEQ ID NO:365).


It should be noted that the known protein sequence (FA5_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for FA5_HUMAN_V1 (SEQ ID NO:393). These changes were previously known to occur and are listed in the table below.









TABLE 323







Changes to FA5_HUMAN_V1 (SEQ ID NO:393)










SNP position(s) on




amino acid sequence
Type of change














859
Variant



866.
Variant










The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HUMF5A_PEA1_P4 (SEQ ID NO:365) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 324, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMF5A_PEA1_P4 (SEQ ID NO:365) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 324







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












15
G -> S
Yes


107
D -> H
Yes


413
M -> T
Yes


513
R -> K
Yes


534
R -> Q
Yes


781
S -> R
Yes


809
P -> S
Yes


817
N -> T
Yes


858
R -> K
Yes


865
R -> H
Yes


915
T -> S
Yes


925
K -> E
Yes


969
N -> S
Yes


980
R -> L
Yes


1146
H -> Q
Yes


1169
D -> 
No


1285
L -> I 
Yes


1327
H -> R
Yes


1397
L -> F
Yes


1404
P -> S
Yes


1530
E -> A
Yes


1685
T -> S
Yes


1749
L -> V
Yes


1764
V -> M
Yes


1820
M -> I 
Yes









Variant protein HUMF5A_PEA1_P4 (SEQ ID NO:365) is encoded by the following transcript(s): HUMF5A_PEA1_T3 (SEQ ID NO:41), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HUMF5A_PEA1_T3 (SEQ ID NO:41) is shown in bold; this coding portion starts at position 183 and ends at position 6404. The transcript also has the following SNPs as listed in Table 325 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMF5A_PEA1_P4 (SEQ ID NO:365) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 325







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












16
C -> T
Yes


225
G -> A
Yes


419
A -> G
Yes


501
G -> C
Yes


587
G -> A
Yes


734
G -> T
Yes


746
G -> C
Yes


951
C -> T
Yes


998
C -> T
Yes


1420
T -> C
Yes


1424
A -> G
Yes


1562
C -> T
Yes


1720
G -> A
Yes


1783
G -> A
Yes


1898
G -> A
Yes


2102
C -> T
Yes


2108
C -> A
Yes


2390
T -> C
Yes


2417
C -> T
Yes


2471
A -> G
Yes


2483
G -> A
Yes


2525
T -> G
Yes


2607
C -> T
Yes


2632
A -> C
Yes


2755
G -> A
Yes


2776
G -> A
Yes


2925
A -> T
Yes


2955
A -> G
Yes


3088
A -> G
Yes


3121
G -> T
Yes


3437
A -> G
Yes


3620
C -> G
Yes


3686
A -> C
Yes


3688
A -> 
No


3689
T -> 
No


3764
C -> T
Yes


3986
T -> C
Yes


4035
C -> A
Yes


4130
C -> T
Yes


4162
A -> G
Yes


4277
C -> T
Yes


4371
C -> T
Yes


4392
C -> T
Yes


4771
A -> C
Yes


5204
A -> G
Yes


5236
C -> G
Yes


5427
C -> G
Yes


5472
G -> A
Yes


5642
G -> A
Yes


6618
T -> C
Yes


6729
A -> G
Yes


6840
A -> G
Yes









Variant protein HUMF5A_PEA1_P8 (SEQ ID NO:366) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HUMF5A_PEA1_T7 (SEQ ID NO:42). An alignment is given to the known protein (Coagulation factor V precursor (SEQ ID NO:392)) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HUMF5A_PEA1_P8 (SEQ ID NO:366) and FA5_HUMAN:


1. An isolated chimeric polypeptide encoding for HUMF5A_PEA1_P8 (SEQ ID NO:366), comprising a first amino acid sequence being at least 90% homologous to MFPGCPRLWVLVVLGTSWVGWGSQGTEAAQLRQFYVAAQGISWSYRPEPTNSSLNLS VTSFKKIVYREYEPYFKKEKPQSTISGLLGPTLYAEVGDIIKVHFKNKADKPLSIHPQGIR YSKLSEGASYLDHTFPAEKMDDAVAPGREYTYEWSISEDSGPTHDDPPCLTHIYYSHEN LIEDFNSGLIGPLLICKKGTLTEGGTQKTFDKQIVLLFAVFDESKSWSQSSSLMYTVNGY VNGTMPDITVCAHDHISWHLLGMSSGPELFSIHFNGQVLEQNHHKVSAITLVSATSTTA NMTVGPEGKWIISSLTPKHLQAGMQAYIDIKNCPKKTRNLKKITREQRRHMKRWEYFI AAEEVIWDYAPVIPANMDKKYRSQHLDNFSNQIGKHYKKVMYTQYEDESFTKHTVNP NMKEDGILGPIIRAQVRDTLKIVFKNMASRPYSIYPHGVTFSPYEDEVNSSFTSGRNNTM IRAVQPGETYTYKWNILEFDEPTENDAQCLTRPYYSDVDIMRDIASGLIGLLLICKSRSL DRRGIQRAADIEQQAVFAVFDENKSWYLEDNINKFCENPDEVKRDDPKFYESNIMS corresponding to amino acids 1-587 of FA5_HUMAN, which also corresponds to amino acids 1-587 of HUMF5A_PEA1_P8 (SEQ ID NO:366), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SKSEYYFCSSVFHSCG (SEQ ID NO: 571) corresponding to amino acids 588-603 of HUMF5A_PEA1_P8 (SEQ ID NO:366), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HUMF5A_PEA1_P8 (SEQ ID NO:366) comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SKSEYYFCSSVFHSCG (SEQ ID NO: 571) in HUMF5A_PEA1_P8 (SEQ ID NO:366).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HUMF5A_PEA1_P8 (SEQ ID NO:366) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 326, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMF5A_PEA1_P8 (SEQ ID NO:366) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 326







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












15
G -> S
Yes


107
D -> H
Yes


413
M -> T
Yes


513
R -> K
Yes


534
R -> Q
Yes









The glycosylation sites of variant protein HUMF5A_PEA1_P8 (SEQ ID NO:366), as compared to the known protein Coagulation factor V precursor (SEQ ID NO:392), are described in Table 327 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the glycosylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).









TABLE 327







Glycosylation site(s)









Position(s) on known
Present in
Position in


amino acid sequence
variant protein?
variant protein?












821
No



554
Yes
554


1703
No


741
No


55
Yes
55


297
Yes
297


752
No


468
Yes
468


460
Yes
460


1559
No


782
No


1479
No


938
No


776
No


760
No


1103
No


1499
No


1106
No


977
No


2010
No


239
Yes
239


1074
No


2209
No


1083
No


51
Yes
51


382
Yes
382









The phosphorylation sites of variant protein HUMF5A_PEA1_P8 (SEQ ID NO:366), as compared to the known protein Coagulation factor V precursor (SEQ ID NO:392), are described in Table 328 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the phosphorylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).









TABLE 328







Phosphorylation site(s)









Position(s) on known
Present in
Position in


amino acid sequence
variant protein?
variant protein?












724
No



726
No


1543
No


1538
No


693
No


1593
No


1522
No









Variant protein HUMF5A_PEA1_P8 (SEQ ID NO:366) is encoded by the following transcript(s): HUMF5A_PEA1_T7 (SEQ ID NO:42), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HUMF5A_PEA1_T7 (SEQ ID NO:42) is shown in bold; this coding portion starts at position 183 and ends at position 1991. The transcript also has the following SNPs as listed in Table 329 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMF5A_PEA1_P8 (SEQ ID NO:366) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 329







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












16
C -> T
Yes


225
G -> A
Yes


419
A -> G
Yes


501
G -> C
Yes


587
G -> A
Yes


734
G -> T
Yes


746
G -> C
Yes


951
C -> T
Yes


998
C -> T
Yes


1420
T -> C
Yes


1424
A -> G
Yes


1562
C -> T
Yes


1720
G -> A
Yes


1783
G -> A
Yes


1898
G -> A
Yes


2088
G -> A
Yes


2095
G -> A
Yes









As noted above, cluster HUMF5A features 33 segment(s), which were listed in Table 2 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.


Segment cluster HUMF5A_PEA1_node0 (SEQ ID NO:238) according to the present invention is supported by 9 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40), HUMF5A_PEA1_T3 (SEQ ID NO:41) and HUMF5A_PEA1_T7 (SEQ ID NO.42). Table 330 below describes the starting and ending position of this segment on each transcript.









TABLE 330







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
1
340


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
1
340


NO:41)


HUMF5A_PEA_1_T7 (SEQ ID
1
340


NO:42)









Segment cluster HUMF5A_PEA1_node4 (SEQ ID NO:239) according to the present invention is supported by 7 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40), HUMF5A_PEA1_T3 (SEQ ID NO:41) and HUMF5A_PEA1_T7 (SEQ ID NO:42). Table 331 below describes the starting and ending position of this segment on each transcript.









TABLE 331







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
433
555


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
433
555


NO:41)


HUMF5A_PEA_1_T7 (SEQ ID
433
555


NO:42)









Segment cluster HUMF5A_PEA1_node6 (SEQ ID NO:240) according to the present invention is supported by 11 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40), HUMF5A_PEA1_T3 (SEQ ID NO:41) and HUMF5A_PEA1_T7 (SEQ ID NO:42). Table 332 below describes the starting and ending position of this segment on each transcript.









TABLE 332







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
556
768


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
556
768


NO:41)


HUMF5A_PEA_1_T7 (SEQ ID
556
768


NO:42)









Segment cluster HUMF5A_PEA1_node8 (SEQ ID NO:241) according to the present invention is supported by 8 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40), HUMF5A_PEA1_T3 (SEQ ID NO:41) and HUMF5A_PEA1_T7 (SEQ ID NO:42). Table 333 below describes the starting and ending position of this segment on each transcript.









TABLE 333







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
769
912


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
769
912


NO:41)


HUMF5A_PEA_1_T7 (SEQ ID
769
912


NO:42)









Segment cluster HUMF5A_PEA1_node10 (SEQ ID NO:242) according to the present invention is supported by 7 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40), HUMF5A_PEA1_T3 (SEQ ID NO:41) and HUMF5A_PEA1_T7 (SEQ ID NO:42). Table 334 below describes the starting and ending position of this segment on each transcript.









TABLE 334







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
913
1134


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
913
1134


NO:41)


HUMF5A_PEA_1_T7 (SEQ ID
913
1134


NO:42)









Segment cluster HUMF5A_PEA1_node12 (SEQ ID NO:243) according to the present invention is supported by 10 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40), HUMF5A_PEA1_T3 (SEQ ID NO:41) and HUMF5A_PEA1_T7 (SEQ ID NO:42). Table 335 below describes the starting and ending position of this segment on each transcript.









TABLE 335







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
1135
1300


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
1135
1300


NO:41)


HUMF5A_PEA_1_T7 (SEQ ID
1135
1300


NO:42)









Segment cluster HUMF5A_PEA1_node14 (SEQ ID NO:244) according to the present invention is supported by 9 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40), HUMF5A_PEA1_T3 (SEQ ID NO:41) and HUMF5A_PEA1_T7 (SEQ ID NO:42). Table 336 below describes the starting and ending position of this segment on each transcript.









TABLE 336







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
1301
1478


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
1301
1478


NO:41)


HUMF5A_PEA_1_T7 (SEQ ID
1301
1478


NO:42)









Segment cluster HUMF5A_PEA1_node18 (SEQ ID NO:245) according to the present invention is supported by 10 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40), HUMF5A_PEA1_T3 (SEQ ID NO:41) and HUMF5A_PEA1_T7 (SEQ ID NO:42). Table 337 below describes the starting and ending position of this segment on each transcript.









TABLE 337







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
1579
1793


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
1579
1793


NO:41)


HUMF5A_PEA_1_T7 (SEQ ID
1579
1793


NO:42)









Segment cluster HUMF5A_PEA1_node21 (SEQ ID NO:246) according to the present invention is supported by 12 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40), HUMF5A_PEA1_T3 (SEQ ID NO:41) and HUMF5A_PEA1_T7 (SEQ ID NO:42). Table 338 below describes the starting and ending position of this segment on each transcript.









TABLE 338







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
1794
1944


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
1794
1944


NO:41)


HUMF5A_PEA_1_T7 (SEQ ID
1794
1944


NO:42)









Segment cluster HUMF5A_PEA1_node22 (SEQ ID NO:247 according to the present invention is supported by 1 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T7 (SEQ ID NO:42). Table 339 below describes the starting and ending position of this segment on each transcript.









TABLE 339







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T7 (SEQ ID
1945
2097


NO:42)









Segment cluster HUMF5A_PEA1_node24 (SEQ ID NO:248) according to the present invention is supported by 13 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 340 below describes the starting and ending position of this segment on each transcript.









TABLE 340







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
1945
2157


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
1945
2157


NO:41)









Segment cluster HUMF5A_PEA1_node26 (SEQ ID NO:249) according to the present invention is supported by 33 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 341 below describes the starting and ending position of this segment on each transcript.









TABLE 341







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
2158
3766


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
2158
3766


NO:41)









Segment cluster HUMF5A_PEA1_node27 (SEQ ID NO:250) according to the present invention is supported by 12 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 342 below describes the starting and ending position of this segment on each transcript.









TABLE 342







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
3767
3936


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
3767
3936


NO:41)









Segment cluster HUMF5A_PEA1_node29 (SEQ ID NO:251) according to the present invention is supported by 22 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 343 below describes the starting and ending position of this segment on each transcript.









TABLE 343







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
3937
4978


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
3937
4978


NO:41)









Segment cluster HUMF5A_PEA1_node35 (SEQ ID NO:252) according to the present invention is supported by 7 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 344 below describes the starting and ending position of this segment on each transcript.









TABLE 344







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
5102
5338


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
5154
5390


NO:41)









Segment cluster HUMF5A_PEA1_node37 (SEQ ID NO:253) according to the present invention is supported by 9 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 345 below describes the starting and ending position of this segment on each transcript.









TABLE 345







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
5339
5549


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
5391
5601


NO:41)









Segment cluster HUMF5A_PEA1_node39 (SEQ ID NO:254) according to the present invention is supported by 10 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 346 below describes the starting and ending position of this segment on each transcript.









TABLE 346







Segment location on transcripts










Segment
Segment


Transcript name
starting positon
ending position





HUMF5A_PEA_1_T1 (SEQ ID
5550
5729


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
5602
5781


NO:41)









Segment cluster HUMF5A_PEA1_node47 (SEQ ID NO:255) according to the present invention is supported by 14 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 347 below describes the starting and ending position of this segment on each transcript.









TABLE 347







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
6023
6178


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
6075
6230


NO:41)









Segment cluster HUMF5A_PEA1_node50 (SEQ ID NO:256) according to the present invention is supported by 20 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 348 below describes the starting and ending position of this segment on each transcript.









TABLE 348







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
6179
6316


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
6231
6368


NO:41)









Segment cluster HUMF5A_PEA1_node53 (SEQ ID NO:257) according to the present invention is supported by 29 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 349 below describes the starting and ending position of this segment on each transcript.









TABLE 349







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
6324
6475


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
6369
6520


NO:41)









Segment cluster HUMF5A_PEA1_node56 (SEQ ID NO:258) according to the present invention is supported by 24 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 350 below describes the starting and ending position of this segment on each transcript.









TABLE 350







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
6476
6611


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
6521
6656


NO:41)









Segment cluster HUMF5A_PEA1_node60 (SEQ ID NO:259) according to the present invention is supported by 24 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 351 below describes the starting and ending position of this segment on each transcript.









TABLE 351







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
6666
6951


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
6711
6996


NO:41)









According to an optional embodiment of the present invention, short segments related to the above cluster are also provided. These segments are up to about 120 bp in length, and so are included in a separate description.


Segment cluster HUMF5A_PEA1_node2 (SEQ ID NO:260) according to the present invention is supported by 6 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40), HUMF5A_PEA1_T3 (SEQ ID NO:41) and HUMF5A_PEA1_T7 (SEQ ID NO:42). Table 352 below describes the starting and ending position of this segment on each transcript.









TABLE 352







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
341
432


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
341
432


NO:41)


HUMF5A_PEA_1_T7 (SEQ ID
341
432


NO:42)









Segment cluster HUMF5A_PEA1_node16 (SEQ ID NO:261) according to the present invention is supported by 10 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40), HUMF5A_PEA1_T3 (SEQ ID NO:41) and HUMF5A_PEA1_T7 (SEQ ID NO:42). Table 353 below describes the starting and ending position of this segment on each transcript.









TABLE 353







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
1479
1578


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
1479
1578


NO:41)


HUMF5A_PEA_1_T7 (SEQ ID
1479
1578


NO:42)









Segment cluster HUMF5A_PEA1_node31 (SEQ ID NO:262) according to the present invention is supported by 3 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 354 below describes the starting and ending position of this segment on each transcript.









TABLE 354







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
4979
5033


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
4979
5033


NO:41)









Segment cluster HUMF5A_PEA1_node32 (SEQ ID NO:263) according to the present invention is supported by 2 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 355 below describes the starting and ending position of this segment on each transcript.









TABLE 355







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T3 (SEQ ID
5034
5085


NO:41)









Segment cluster HUMF5A_PEA1_node33 (SEQ ID NO:264) according to the present invention is supported by 4 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 356 below describes the starting and ending position of this segment on each transcript.









TABLE 356







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
5034
5101


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
5086
5153


NO:41)









Segment cluster HUMF5A_PEA1_node41 (SEQ ID NO:265) according to the present invention is supported by 8 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 357 below describes the starting and ending position of this segment on each transcript.









TABLE 357







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HUMF5A_PEA_1_T1 (SEQ ID
5730
5846


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
5782
5898


NO:41)









Segment cluster HUMF5A_PEA1_node43 (SEQ ID NO:266) according to the present invention is supported by 6 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 358 below describes the starting and ending position of this segment on each transcript.









TABLE 358







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HUMF5A_PEA_1_T1 (SEQ ID
5847
5918


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
5899
5970


NO:41)









Segment cluster HUMF5A_PEA1_node45 (SEQ ID NO:267) according to the present invention is supported by 12 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 359 below describes the starting and ending position of this segment on each transcript.









TABLE 359







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HUMF5A_PEA_1_T1 (SEQ ID
5919
6022


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
5971
6074


NO:41)









Segment cluster HUMF5A_PEA1_node51 (SEQ ID NO:268) according to the present invention can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40). Table 360 below describes the starting and ending position of this segment on each transcript.









TABLE 360







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HUMF5A_PEA_1_T1 (SEQ ID
6317
6323


NO:40)









Segment cluster HUMF5A_PEA1_node57 (SEQ ID NO:269) according to the present invention is supported by 18 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 361 below describes the starting and ending position of this segment on each transcript.









TABLE 361







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HUMF5A_PEA_1_T1 (SEQ ID
6612
6658


NO:40)


HUMF5A_PEA_1_T3 (SEQ ID
6657
6703


NO:41)









Segment cluster HUMF5A_PEA1_node59 (SEQ ID NO:270) according to the present invention can be found in the following transcript(s): HUMF5A_PEA1_T1 (SEQ ID NO:40) and HUMF5A_PEA1_T3 (SEQ ID NO:41). Table 362 below describes the starting and ending position of this segment on each transcript.









TABLE 362







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HUMF5A_PEA_1_T1 (SEQ ID
6659
6665


NO: 40)


HUMF5A_PEA_1_T3 (SEQ ID
6704
6710


NO: 41)










Variant Protein Alignment to the Previously Known Protein:














Sequence name: FA5_HUMAN_V1 (SEQ ID NO:393)


Sequence documentation:


Alignment of: HUMF5A_PEA_1_P3 (SEQ ID NO:364) × FA5_HUMAN_V1


(SEQ ID NO:393) . . .


Alignment segment 1/1:


Quality: 16060.00


Escore: 0


Matching length: 1617


Total length: 1617


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: FA5_HUMAN_V1 (SEQ ID NO:393)


Sequence documentation:


Alignment of: HUMF5A_PEA_1_P4 (SEQ ID NO:365) × FA5_HUMAN_V1


(SEQ ID NO:393) . . .


Alignment segment 1/1:


Quality: 20532.00


Escore: 0


Matching length: 2062


Total length: 2062


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: FA5_HUMAN


Sequence documentation:


Alignment of: HUMF5A_PEA_1_P8 (SEQ ID NO:366) × FA5_HUMAN . . .


Alignment segment 1/1:


Quality: 5863.00


Escore: 0


Matching length: 588


Total length: 588


Matching Percent Similarity: 100.00


Matching Percent Identity: 99.83


Total Percent Similarity: 100


Total Percent Identity: 99.83


Gaps: 0


Alignment:












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Description for Cluster Z40511

Cluster Z40511 features 1 transcript(s) and 14 segment(s) of interest, the names for which are given in Tables 363 and 364, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 365.









TABLE 363







Transcripts of interest










Transcript Name
Sequence ID No.







Z40511_T8
43

















TABLE 364







Segments of interest










Segment Name
Sequence ID No.














Z40511_node_4
271



Z40511_node_10
272



Z40511_node_11
273



Z40511_node_15
274



Z40511_node_17
275



Z40511_node_18
276



Z40511_node_19
277



Z40511_node_20
278



Z40511_node_21
279



Z40511_node_23
280



Z40511_node_25
281



Z40511_node_16
282



Z40511_node_22
283



Z40511_node_24
284

















TABLE 365







Proteins of interest









Protein Name
Sequence ID No.
Corresponding Transcript(s)





Z40511_P5
367
Z40511_T8 (SEQ ID NO:43)









These sequences are variants of the known protein Hypothetical protein (SwissProt accession identifier Q96DV8), SEQ ID NO:394, referred to herein as the previously known protein.


The sequence for protein Hypothetical protein is given at the end of the application, as “Hypothetical protein amino acid sequence”.


As noted above, cluster Z40511 features 1 transcript(s), which were listed in Table 363 above. These transcript(s) encode for protein(s) which are variant(s) of protein Hypothetical protein. A description of each variant protein according to the present invention is now provided.


Variant protein Z40511_P5 (SEQ ID NO:367) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) Z40511_T8 (SEQ ID NO:43). An alignment is given to the known protein (Hypothetical protein) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between Z40511_P5 (SEQ ID NO:367) and Q9Y4S1_V2_SEQ ID NO: 396:


1. An isolated chimeric polypeptide encoding for Z40511_P5 (SEQ ID NO:367) comprising a first amino acid sequence being at least 90% homologous to MVYKTLFALCILTAGWRVQSLPTSAPLSVSLPTNIVPPTTIWTSSPQNTDADTASPSNGT HNNSVLPVTASAPTSLLPKNISIESREEEITSPGSNWEGTNTDPSPSGFSSTSGGVHLTTTL EEHSSGTPEAGVAATLSQSAAEPPTLISPQAPASSPSSLSTSPPEVFSASVTTNHSSTVTST QPTGAPTAPESPTEESSSDHTPTSHATAEPVPQEKTPPTTVSGKVMCELIDMET corresponding to amino acids 1-238 of Q9Y4S1_V2 (SEQ ID NO:396), which also corresponds to amino acids 1-238 of Z40511_P5 (SEQ ID NO:367), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence TTTFPRVIMQEVEHALSSGIPPMEDFWTTMTTGPGETTTTLCTMTPNNGIWPGMRINCS LFISAYPVELIST (SEQ ID NO: 572) corresponding to amino acids 239-310 of Z40511_P5 (SEQ ID NO:367), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of Z40511_P5 (SEQ ID NO:367) comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TTTFPRVIMQEVEHALSSGIPPMEDFWTTMTTGPGETTTTLCTMTPNNGIWPGMRINCS LFISAYPVELIST (SEQ ID NO: 572) in Z40511_P5 (SEQ ID NO:367).


Comparison report between Z40511_P5 (SEQ ID NO:367) and Q96DV8_V1 (SEQ ID NO:395) (SEQ ID NO: 395):


1. An isolated chimeric polypeptide encoding for Z40511_P5 (SEQ ID NO:367) comprising a first amino acid sequence being at least 90% homologous to MVYKTLFALCILTAGWRVQSLPTSAPLSVSLPTNIVPPTTIWTSSPQNTDADTASPSNGT HNNSVLPVTASAPTSLLPKNISIESREEEITSPGSNWEGTNTDPSPSGFSSTSGGVHLTTTL EEHSSGTPEAGVAATLSQSAAEPPTLISPQAPASSPSSLSTSPPEVFSASVTTNHSSTVTST QPTGAPTAPESPTEESSSDHTPTSHATAEPVPQEKTPPTTVSGKVMCELIDMETTTTFPR VIMQEVEHALSSG corresponding to amino acids 1-257 of Q96DV8_V1 (SEQ ID NO:395), which also corresponds to amino acids 1-257 of Z40511_P5 (SEQ ID NO:367), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence IPPMEDFWTTMTTGPGETTTTLCTMTPNNGIWPGMRINCSLFISAYPVELIST corresponding to amino acids 258-310 of Z40511_P5 (SEQ ID NO:367), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of Z40511_P5 (SEQ ID NO:367) comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence IPPMEDFWTTMTTGPGETTTTLCTMTPNNGIWPGMRINCSLFISAYPVELIST in Z40511_P5 (SEQ ID NO:367).


It should be noted that the known protein sequence (Q96DV8) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for Q96DV8_V1 (SEQ ID NO:395). These changes were previously known to occur and are listed in the table below.









TABLE 366







Changes to Q96DV8_V1 (SEQ ID NO:395)








SNP position(s) on



amino acid sequence
Type of change





123
Public snp replace









Comparison report between Z40511_P5 (SEQ ID NO:367) and AAQ89137 (SEQ ID NO:397) (SEQ ID NO: 397):


1. An isolated chimeric polypeptide encoding for Z40511_P5 (SEQ ID NO:367) comprising a first amino acid sequence being at least 90% homologous to MVYKTLFALCILTAGWRVQSLPTSAPLSVSLPTNIVPPTTIWTSSPQNTDADTASPSNGT HNNSVLPVTASAPTSLLPKNISIESREEEITSPGSNWEGTNTDPSPSGFSSTSGGVHLTTTL EEHSSGTPEAGVAATLSQSAAEPPTLISPQAPASSPSSLSTSPPEVFSASVTTNHSSTVTST QPTGAPTAPESPTEESSSDHTPTSHATAEPVPQEKTPPTTVSGKVMCELIDMETTTTFPR VIMQEVEHALSSG corresponding to amino acids 1-257 of AAQ89137 (SEQ ID NO:397), which also corresponds to amino acids 1-257 of Z40511_P5 (SEQ ID NO:367), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence IPPMEDFWTTMTTGPGETTTTLCTMTPNNGIWPGMRINCSLFISAYPVELIST corresponding to amino acids 258-310 of Z40511_P5 (SEQ ID NO:367), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of Z40511_P5 (SEQ ID NO:367) comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence IPPMEDFWTTMTTGPGETTTTLCTMTPNNGIWPGMRINCSLFISAYPVELIST in Z40511_P5 (SEQ ID NO:367).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because, both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein Z40511_P5 (SEQ ID NO:367) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 367, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein Z40511_P5 (SEQ ID NO:367) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 367







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?





123
E -> K
Yes


127
S -> L
Yes


300
 I -> T
No









Variant protein Z40511_P5 (SEQ ID NO:367) is encoded by the following transcript(s): Z40511_T8 (SEQ ID NO:43), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript Z40511_T8 (SEQ ID NO:43) is shown in bold; this coding portion starts at position 275 and ends at position 1204. The transcript also has the following SNPs as listed in Table 368 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein Z40511_P5 (SEQ ID NO:367) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 368







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












210
G -> T
No


255
G -> C
No


328
A -> G
No


641
G -> A
Yes


654
C -> T
Yes


823
C -> T
No


862
G -> A
Yes


919
A -> G
Yes


1173
T -> C
No


1281
T -> A
No


1282
G -> A
No


1435
C -> T
Yes


1577
C -> T
Yes


1668
A -> G
Yes


1791
T -> C
Yes


2084
C -> T
Yes


2412
A -> C
Yes


2483
G -> A
Yes


2523
A -> T
Yes


2703
G -> A
Yes


3131
C -> T
Yes


3274
A -> G
Yes


3501
C -> T
Yes


3518
C -> G
Yes


3559
T -> 
Yes


3752
T -> G
No


3873
A -> G
Yes


4024
A -> G
Yes


4153
C -> A
No


4747
-> T 
No









As noted above, cluster Z40511 features 14 segment(s), which were listed in Table 2 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.


Segment cluster Z40511_node4 (SEQ ID NO:271) according to the present invention is supported by 40 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8 (SEQ ID NO:43). Table 369 below describes the starting and ending position of this segment on each transcript.









TABLE 369







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












Z40511_T8 (SEQ ID NO:43)
1
317









Segment cluster Z40511_node10 (SEQ ID NO:272) according to the present invention is supported by 49 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8 (SEQ ID NO:43). Table 370 below describes the starting and ending position of this segment on each transcript.









TABLE 370







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












Z40511_T8 (SEQ ID NO:43)
318
554









Segment cluster Z40511_node11 (SEQ ID NO:273) according to the present invention is supported by 76 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8 (SEQ ID NO:43). Table 371 below describes the starting and ending position of this segment on each transcript.









TABLE 371







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












Z40511_T8 (SEQ ID NO:43)
555
1043









Segment cluster Z40511_node15 (SEQ ID NO:274) according to the present invention is supported by 75 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8 (SEQ ID NO:43). Table 372 below describes the starting and ending position of this segment on each transcript.









TABLE 372







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












Z40511_T8 (SEQ ID NO:43)
1044
1442









Segment cluster Z40511_node17 (SEQ ID NO:275) according to the present invention is supported by 57 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8 (SEQ ID NO:43). Table 373 below describes the starting and ending position of this segment on each transcript.









TABLE 373







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












Z40511_T8 (SEQ ID NO:43)
1509
1689









Segment cluster Z40511_node18 (SEQ ID NO:276) according to the present invention is supported by 88 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8 (SEQ ID NO:43). Table 374 below describes the starting and ending position of this segment on each transcript.









TABLE 374







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












Z40511_T8 (SEQ ID NO:43)
1690
1989









Segment cluster Z40511_node19 (SEQ ID NO:277) according to the present invention is supported by 92 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8 (SEQ ID NO:43). Table 375 below describes the starting and ending position of this segment on each transcript.









TABLE 375







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












Z40511_T8 (SEQ ID NO:43)
1990
2320









Segment cluster Z40511_node20 (SEQ ID NO:278) according to the present invention is supported by 115 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8 (SEQ ID NO:43). Table 376 below describes the starting and ending position of this segment on each transcript.









TABLE 376







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












Z40511_T8 (SEQ ID NO:43)
2321
3697









Segment cluster Z40511_node21 (SEQ ID NO:279) according to the present invention is supported by 72 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8 (SEQ ID NO:43). Table 377 below describes the starting and ending position of this segment on each transcript.









TABLE 377







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












Z40511_T8 (SEQ ID NO:43)
3698
3969









Segment cluster Z40511_node23 (SEQ ID NO:280) according to the present invention is supported by 96 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8 (SEQ ID NO:43). Table 378 below describes the starting and ending position of this segment on each transcript.









TABLE 378







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





Z40511_T8 (SEQ ID NO:43)
3996
4511









Segment cluster Z40511_node25 (SEQ ID NO:281) according to the present invention is supported by 89 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8 (SEQ ID NO:43). Table 379 below describes the starting and ending position of this segment on each transcript.









TABLE 379







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





Z40511_T8 (SEQ ID NO:43)
4566
4994









According to an optional embodiment of the present invention, short segments related to the above cluster are also provided. These segments are up to about 120 bp in length, and so are included in a separate description.


Segment cluster Z40511_node16 (SEQ ID NO:282) according to the present invention is supported by 41 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8 (SEQ ID NO:43). Table 380 below describes the starting and ending position of this segment on each transcript.









TABLE 380







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





Z40511_T8 (SEQ ID NO:43)
1443
1508









Segment cluster Z40511_node22 (SEQ ID NO:283) according to the present invention is supported by 43 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8 (SEQ ID NO:43). Table 381 below describes the starting and ending position of this segment on each transcript.









TABLE 381







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





Z40511_T8 (SEQ ID NO:43)
3970
3995









Segment cluster Z40511_node24 (SEQ ID NO:284) according to the present invention is supported by 61 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8 (SEQ ID NO:43). Table 382 below describes the starting and ending position of this segment on each transcript.









TABLE 382







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





Z40511_T8 (SEQ ID NO:43)
4512
4565










Variant Protein Alignment to the Previously Known Protein:














Sequence name: Q9Y4S1_V2 (SEQ ID NO:396)


Sequence documentation:


Alignment of: Z40511_P5 (SEQ ID NO:367) × Q9Y4S1_V2 (SEQ ID NO:396) . . .


Alignment segment 1/1:


Quality: 2321.00


Escore: 0


Matching length: 243


Total length: 243


Matching Percent Similarity: 98.77


Matching Percent Identity: 98.77


Total Percent Similarity: 98.77


Total Percent Identity: 98.77


Gaps: 0


Alignment:












embedded image









embedded image









embedded image









embedded image









embedded image












Sequence name: Q96DV8_V1 (SEQ ID NO:395)


Sequence documentation:


Alignment of: Z40511_P5 (SEQ ID NO:367) × Q96DV8_V1 (SEQ ID NO:395) . . .


Alignment segment 1/1:


Quality: 2493.00


Escore: 0


Matching length: 257


Total length: 257


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












embedded image









embedded image









embedded image









embedded image









embedded image









embedded image












Sequence name: AAQ89137 (SEQ ID NO:397)


Sequence documentation:


Alignment of: Z40511_P5 (SEQ ID NO:367) × AAQ89137 (SEQ ID NO:397) . . .


Alignment segment 1/1:


Quality: 2493.00


Escore: 0


Matching length: 257


Total length: 257


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












embedded image









embedded image









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Description for Cluster H53626


Cluster H53626 features 2 transcript(s) and 20 segment(s) of interest, the names for which are given in Tables 383 and 384, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 385.









TABLE 383







Transcripts of interest










Transcript Name
Sequence ID No.







H53626_PEA_1_T15
44



H53626_PEA_1_T16
45

















TABLE 384







Segments of interest










Segment Name
Sequence ID No.














H53626_PEA_1_node_15
285



H53626_PEA_1_node_22
286



H53626_PEA_1_node_25
287



H53626_PEA_1_node_26
288



H53626_PEA_1_node_27
289



H53626_PEA_1_node_34
290



H53626_PEA_1_node_35
291



H53626_PEA_1_node_36
292



H53626_PEA_1_node_11
293



H53626_PEA_1_node_12
294



H53626_PEA_1_node_16
295



H53626_PEA_1_node_19
296



H53626_PEA_1_node_20
297



H53626_PEA_1_node_24
298



H53626_PEA_1_node_28
299



H53626_PEA_1_node_29
300



H53626_PEA_1_node_30
301



H53626_PEA_1_node_31
302



H53626_PEA_1_node_32
303



H53626_PEA_1_node_33
304

















TABLE 385







Proteins of interest










Protein Name
Sequence ID No.







H53626_PEA_1_P4
368



H53626_PEA_1_P5
369










Cluster H53626 can be used as a diagnostic marker according to overexpression of transcripts of this cluster in cancer. Expression of such transcripts in normal tissues is also given according to the previously described methods. The term “number” in the left hand column of the table and the numbers on the y-axis of FIG. 16 refer to weighted expression of ESTs in each category, as “parts per million” (ratio of the expression of ESTs for a particular cluster to the expression of all ESTs in that category, according to parts per million).


Overall, the following results were obtained as shown with regard to the histograms in FIG. 16 and Table 386. This cluster is overexpressed (at least at a minimum level) in the following pathological conditions: epithelial malignant tumors, a mixture of malignant tumors from different tissues and myosarcoma.









TABLE 386







Normal tissue distribution










Name of Tissue
Number














Adrenal
4



Bone
239



Brain
39



Colon
0



Epithelial
12



General
18



head and neck
0



Kidney
8



Lung
26



Breast
8



Muscle
0



Ovary
7



Pancreas
10



Prostate
8



Skin
0



Stomach
73



Thyroid
0



Uterus
0

















TABLE 387







P values and ratios for expression in cancerous tissue













Name of Tissue
P1
P2
SP1
R3
SP2
R4





Adrenal
6.4e−01
4.2e−01
2.1e−01
3.1
1.3e−02
4.1


Bone
5.8e−01
8.1e−01
9.8e−01
0.3
1
0.3


Brain
2.8e−01
3.3e−01
8.7e−01
0.7
9.4e−01
0.5


Colon
2.3e−01
1.4e−01
1
1.2
4.6e−01
1.9


Epithelial
7.2e−02
3.7e−03
5.8e−02
1.6
1.4e−08
4.3


General
2.7e−03
1.8e−05
7.8e−04
1.6
8.2e−13
3.0


head and neck
2.1e−01
3.3e−01
0.0e+00
0.0
0.0e+00
0.0


Kidney
7.3e−01
5.8e−01
5.8e−01
1.3
4.0e−02
2.0


Lung
8.4e−01
5.8e−01
7.9e−01
0.8
3.7e−02
2.0


Breast
6.5e−01
2.7e−01
6.9e−01
1.2
7.8e−02
1.9


Muscle
1
2.9e−01
1
1.0
3.5e−03
4.1


Ovary
6.7e−01
5.6e−01
1.5e−01
1.7
7.0e−02
2.7


Pancreas
2.3e−01
2.0e−01
3.9e−01
1.9
8.2e−02
2.3


Prostate
9.0e−01
9.0e−01
6.7e−01
1.1
1.3e−01
1.9


Skin
1
4.4e−01
1
1.0
4.1e−01
2.1


Stomach
9.0e−01
3.4e−01
1
0.3
6.1e−01
0.9


Thyroid
2.4e−01
2.4e−01
1
1.1
1
1.1


Uterus
2.1e−01
2.4e−01
2.9e−01
2.5
2.6e−01
2.2









As noted above, cluster H53626 features 2 transcript(s), which were listed in Table 1 above. A description of each variant protein according to the present invention is now provided.


Variant protein H53626_PEA1_P4 (SEQ ID NO:368) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) H53626_PEA1_T15 (SEQ ID NO:44). One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between H53626_PEA1_P4 (SEQ ID NO:368) and Q8N441 (SEQ ID NO:500):


1. An isolated chimeric polypeptide encoding for H53626_PEA1_P4 (SEQ ID NO:368), comprising a first amino acid sequence being at least 90% homologous to MTPSPLLLLLLPPLLLGAFPPAAAARGPPKMADKVVPRQVARLGRTVRLQCPVEGDPPP LTMWTKDGRTIHSGWSRFRVLPQGLKVKQVEREDAGVYVCKATNGFGSLSVNYTLVV LDDISPGKESLGPDSSSGGQEDPASQQWARPRFTQPSKMRRRVIARPVGSSVRLKCVAS GHPRPDITWMKDDQALTRPEAAEPRKKKWTLSLKNLRPEDSGKYTCRVSNRAGAINAT YKVDVIQRTRSKPVLTGTHPVNTTVDFGGTTSFQCKVRSDVKPVIQWLKRVEYGAEGR HNSTIDVGGQKFVVLPTGDVWSRPDGSYLNKLLITRARQDDAGMYICLGANTMGYSFR SAFLTVLP corresponding to amino acids 1-357 of Q8N441, which also corresponds to amino acids 1-357 of H53626_PEA1_P4 (SEQ ID NO:368), second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence GARLPRHATPCWCPDPPPGPGVPPTGWGPTLPSRAVLARSSAEGGQPRGTVSTAPGMG LGCSPGLCVGVPLPTSFPLALA (SEQ ID NO: 573) corresponding to amino acids 358-437 of H53626_PEA1_P4 (SEQ ID NO:368), and a third amino acid sequence being at least 90% homologous to DPKPPGPPVASSSSATSLPWPVVIGIPAGAVFILGTLLLWLCQAQKKPCTPAPAPPLPGH RPPGTARDRSGDKDLPSLAALSAGPGVGLCEEHGSPAAPQHLLGPGPVAGPKLYPKLY TDIHTHTHTHSHTHSHVEGKVHQHIHYQC corresponding to amino acids 358-504 of Q8N441, which also corresponds to amino acids 438-584 of H53626_PEA1_P4 (SEQ ID NO:368), wherein said first, second and third amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for an edge portion of H53626_PEA1_P4 (SEQ ID NO:368), comprising an amino acid sequence being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence encoding for GARLPRHATPCWCPDPPPGPGVPPTGWGPTLPSRAVLARSSAEGGQPRGTVSTAPGMG LGCSPGLCVGVPLPTSFPLALA (SEQ ID NO: 573), corresponding to H53626_PEA1_P4 (SEQ ID NO:368).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: membrane. The protein localization is believed to be membrane because although both signal-peptide prediction programs agree that this protein has a signal peptide, both trans-membrane region prediction programs predict that this protein has a trans-membrane region downstream of this signal peptide.


Variant protein H53626_PEA1_P4 (SEQ ID NO:368) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 388, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein H53626_PEA1_P4 (SEQ ID NO:368) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 388







Amino acid mutations









SNP position(s)




on amino acid
Alternative
Previously


sequence
amino acid(s)
known SNP?





193
R -> L
Yes


300
G -> 
No


319
Y -> H
No


442
P -> Q
Yes


504
R -> L
Yes


521
G -> 
No


544
P -> L
Yes


573
E -> G
No









Variant protein H53626_PEA1_P4 (SEQ ID NO:368) is encoded by the following transcript(s): H53626_PEA1_T 15 (SEQ ID NO:44), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript H53626_PEA1_T15 (SEQ ID NO:44) is shown in bold; this coding portion starts at position 17 and ends at position 1768. The transcript also has the following SNPs as listed in Table 389 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein H53626_PEA1_P4 (SEQ ID NO:368) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 389







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












76
G -> A
Yes


340
G -> T
No


1647
C -> T
Yes


1734
A -> G
No


1797
G -> 
No


1948
A -> G
Yes


2193
C -> T
Yes


2308
C -> T
Yes


2333
C -> G
Yes


2648
C -> T
Yes


2649
G -> A
Yes


2765
C -> T
Yes


594
G -> T
Yes


2972
G -> A
Yes


3027
C -> G
Yes


907
T -> C
Yes


916
C -> 
No


971
T -> C
No


1135
G -> A
Yes


1341
C -> A
Yes


1527
G -> T
Yes


1579
C -> 
No









Variant protein H53626_PEA1_P5 (SEQ ID NO:369) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) H53626_PEA1_T16 (SEQ ID NO:45). One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between H53626_PEA1_P5 (SEQ ID NO:369) and Q9H4D7 (SEQ ID NO:501):


1. An isolated chimeric polypeptide encoding for H53626_PEA1_P5 (SEQ ID NO:369), comprising a first amino acid sequence being at least 90% homologous to MTPSPLLLLLLPPLLLGAFPPAAAARGPPKMADKVVPRQVARLGRTVRLQCPVEGDPPP LTMWTKDGRTIHSGWSRFRVLPQGLKVKQVEREDAGVYVCKATNGFGSLSVNYTLVV LDDISPGKESLGPDSSSGGQEDPASQQWARPRFTQPSKMRRRVIARPVGSSVRLKCVAS GHPRPDITWMKDDQALTRPEAAEPRKKKWTLSLKNLRPEDSGKYTCRVSNRAGAINAT YKVDVIQRTRSKPVLTGTHPVNTTVDFGGTTSFQCK corresponding to amino acids 1-269 of Q9H4D7, which also corresponds to amino acids 1-269 of H53626_PEA1_P5 (SEQ ID NO:369), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence TQNRQGHLWPPRPRPLACRGPWSSASQPALSSSWAPCSCGFARPRRSRAPPRLPLPCLG TARRGRPATAAETRTFPRWPPSALALVWGCVRSMGLRQPPSTYWAQAQLLALSCTPNS TQTSTHTHTHTLTHTHTWRARSTSTSTISARRHRICSGHGGAGQTGRLGGWRTELQTKA GDPWRGGMASTPGSLCVRHSPWTHTHRHTHYLDACMHTHARTRAP (SEQ ID NO: 574) corresponding to amino acids 270-490 of H53626_PEA1_P5 (SEQ ID NO:369), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of H53626_PEA1_P5 (SEQ ID NO:369), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TQNRQGHLWPPRPRPLACRGPWSSASQPALSSSWAPCSCGFARPRRSRAPPRLPLPCLG TARRGRPATAAETRTFPRWPPSALALVWGCVRSMGLRQPPSTYWAQAQLLALSCTPNS TQTSTHTHTHTLTHTHTWRARSTSTSTISARRHRICSGHGGAGQTGRLGGWRTELQTKA GDPWRGGMASTPGSLCVRHSPWTHTHRHTHYLDACMHTHARTRAP (SEQ ID NO: 574) in H53626_PEA1_P5 (SEQ ID NO:369).


Comparison report between H53626_PEA1_P5 (SEQ ID NO:369) and Q8N441:


1. An isolated chimeric polypeptide encoding for H53626_PEA1_P5 (SEQ ID NO:369), comprising a first amino acid sequence being at least 90% homologous to MTPSPLLLLLLPPLLLGAFPPAAAARGPPKMADKVVPRQVARLGRTVRLQCPVEGDPPP LTMWTKDGRTIHSGWSRFRVLPQGLKVKQVEREDAGVYVCKATNGFGSLSVNYTLVV LDDISPGKESLGPDSSSGGQEDPASQQWARPRFTQPSKMRRRVIARPVGSSVRLKCVAS GHPRPDITWMKDDQALTRPEAAEPRKKKWTLSLKNLRPEDSGKYTCRVSNRAGAINAT YKVDVIQRTRSKPVLTGTHPVNTTVDFGGTTSFQCK corresponding to amino acids 1-269 of Q8N441, which also corresponds to amino acids 1-269 of H53626_PEA1_P5 (SEQ ID NO:369), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence TQNRQGHLWPPRPRPLACRGPWSSASQPALSSSWAPCSCGFARPRRSRAPPRLPLPCLG TARRGRPATAAETRTFPRWPPSALALVWGCVRSMGLRQPPSTYWAQAQLLALSCTPNS TQTSTHTHTHTLTHTHTWRARSTSTSTISARRHRICSGHGGAGQTGRLGGWRTELQTKA GDPWRGGMASTPGSLCVRHSPWTHTHRHTHYLDACMHTHARTRAP (SEQ ID NO: 574) corresponding to amino acids 270-490 of H53626_PEA1_P5 (SEQ ID NO:369), wherein said first and second amino acid sequences are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of H53626_PEA1_P5 (SEQ ID NO:369), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TQNRQGHLWPPRPRPLACRGPWSSASQPALSSSWAPCSCGFARPRRSRAPPRLPLPCLG TARRGRPATAAETRTFPRWPPSALALVWGCVRSMGLRQPPSTYWAQAQLLALSCTPNS TQTSTHTHTHTLTHTHTWRARSTSTSTISARRHRICSGHGGAGQTGRLGGWRTELQTKA GDPWRGGMASTPGSLCVRHSPWTHTHRHTHYLDACMHTHARTRAP (SEQ ID NO: 574) in H53626_PEA1_P5 (SEQ ID NO:369).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein H53626_PEA1_P5 (SEQ ID NO:369) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 390, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein H53626_PEA1_P5 (SEQ ID NO:369) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 390







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?





193
R -> L
Yes


274
Q -> K
Yes


336
A -> S
Yes


353
A -> 
No


376
Q -> * 
Yes


405
R -> G
No


426
G -> 
No


476
Y -> C
Yes









Variant protein H53626_PEA1_P5 (SEQ ID NO:369) is encoded by the following transcript(s): H53626_PEA1_T16 (SEQ ID NO:45), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript H53626_PEA1_T16 (SEQ ID NO:45) is shown in bold; this coding portion starts at position 17 and ends at position 1486. The transcript also has the following SNPs as listed in Table 391 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein H53626_PEA1_P5 (SEQ ID NO:369) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 391







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












76
G -> A
Yes


340
G -> T
No


1688
C -> T
Yes


1803
C -> T
Yes


1828
C -> G
Yes


2143
C -> T
Yes


2144
G -> A
Yes


2260
C -> T
Yes


2467
G -> A
Yes


2522
C -> G
Yes


594
G -> T
Yes


836
C -> A
Yes


1022
G -> T
Yes


1074
C -> 
No


1142
C -> T
Yes


1229
A -> G
No


1292
G -> 
No


1443
A -> G
Yes









As noted above, cluster H53626 features 20 segment(s), which were listed in Table 2 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.


Segment cluster H53626_PEA1_node15 (SEQ ID NO:285) according to the present invention is supported by 25 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA1_T15 (SEQ ID NO:44) and H53626_PEA1_T16 (SEQ ID NO:45). Table 392 below describes the starting and ending position of this segment on each transcript.









TABLE 392







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





H53626_PEA_1_T15 (SEQ ID
96
343


NO:44)


H53626_PEA_1_T16 (SEQ ID
96
343


NO:45)









Segment cluster H53626_PEA1_node22 (SEQ ID NO:286) according to the present invention is supported by 42 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA1_T 15 (SEQ ID NO:44) and H53626_PEA1_T16 (SEQ ID NO:45). Table 393 below describes the starting and ending position of this segment on each transcript.









TABLE 393







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





H53626_PEA_1_T15 (SEQ ID
450
734


NO:44)


H53626_PEA_1_T16 (SEQ ID
450
734


NO:45)









Segment cluster H53626_PEA1_node25 (SEQ ID NO:287) according to the present invention is supported by 41 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA1_T15 (SEQ ID NO:44). Table 394 below describes the starting and ending position of this segment on each transcript.









TABLE 394







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





H53626_PEA_1_T15 (SEQ ID
824
1088


NO:44)









Segment cluster H53626_PEA1_node26 (SEQ ID NO:288) according to the present invention is supported by 5 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA1_T 5 (SEQ ID NO:44). Table 395 below describes the starting and ending position of this segment on each transcript.









TABLE 395







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





H53626_PEA_1_T15 (SEQ ID
1089
1328


NO:44)









Microarray (chip) data is also available for this segment as follows. As described above with regard to the cluster itself, various oligonucleotides were tested for being differentially expressed in various disease conditions, particularly cancer. The following oligonucleotides were found to hit this segment (with regard to prostate cancer), shown in Table 396.









TABLE 396







Oligonucleotides related to this segment









Oligonucleotide name
Overexpressed in cancers
Chip reference





H53626_0_0_8391
prostate cancer
PRO









Segment cluster H53626_PEA1_node27 (SEQ ID NO:289) according to the present invention is supported by 106 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA1_T15 (SEQ ID NO:44) and H53626_PEA1_T16 (SEQ ID NO:45). Table 397 below describes the starting and ending position of this segment on each transcript.









TABLE 397







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












H53626_PEA_1_T15 (SEQ ID
1329
2228


NO:44)


H53626_PEA_1_T16 (SEQ ID
824
1723


NO:45)









Segment cluster H53626_PEA1_node34 (SEQ ID NO:290) according to the present invention is supported by 121 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA1_T15 (SEQ ID NO:44) and H53626_PEA1_T16 (SEQ ID NO:45). Table 398 below describes the starting and ending position of this segment on each transcript.









TABLE 398







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





H53626_PEA_1_T15 (SEQ ID
2507
2977


NO:44)


H53626_PEA_1_T16 (SEQ ID
2002
2472


NO:45)









Segment cluster H53626_PEA1_node35 (SEQ ID NO:291) according to the present invention is supported by 85 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA1_T15 (SEQ ID NO:44) and H53626_PEA1_T16 (SEQ ID NO:45). Table 399 below describes the starting and ending position of this segment on each transcript.









TABLE 399







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












H53626_PEA_1_T15 (SEQ ID
2978
3148


NO:44)


H53626_PEA_1_T16 (SEQ ID
2473
2643


NO:45)









Segment cluster H53626_PEA1_node36 (SEQ ID NO:292) according to the present invention is supported by 69 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA1_T 15 (SEQ ID NO:44) and H53626_PEA1_T16 (SEQ ID NO:45). Table 400 below describes the starting and ending position of this segment on each transcript.









TABLE 400







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












H53626_PEA_1_T15 (SEQ ID
3149
3322


NO:44)


H53626_PEA_1_T16 (SEQ ID
2644
2817


NO:45)









According to an optional embodiment of the present invention, short segments related to the above cluster are also provided. These segments are up to about 120 bp in length, and so are included in a separate description.


Segment cluster H53626_PEA1_node11 (SEQ ID NO:293) according to the present invention is supported by 12 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA1_T 15 (SEQ ID NO:44) and H53626_PEA1_T16 (SEQ ID NO:45). Table 401 below describes the starting and ending position of this segment on each transcript.









TABLE 401







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












H53626_PEA_1_T15 (SEQ ID
1
55


NO:44)


H53626_PEA_1_T16 (SEQ ID
1
55


NO:45)









Segment cluster H53626_PEA1_node12 (SEQ ID NO:294) according to the present invention is supported by 11 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA1_T 15 (SEQ ID NO:44) and H53626_PEA1_T16 (SEQ ID NO:45). Table 402 below describes the starting and ending position of this segment on each transcript.









TABLE 402







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












H53626_PEA_1_T15 (SEQ ID
56
95


NO:44)


H53626_PEA_1_T16 (SEQ ID
56
95


NO:45)









Segment cluster H53626_PEA1_node16 (SEQ ID NO:295) according to the present invention can be found in the following transcript(s): H53626_PEA1_T15 (SEQ ID NO:44) and H53626_PEA1_T16 (SEQ ID NO:45). Table 403 below describes the starting and ending position of this segment on each transcript.









TABLE 403







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












H53626_PEA_1_T15 (SEQ ID
344
368


NO:44)


H53626_PEA_1_T16 (SEQ ID
344
368


NO:45)









Segment cluster H53626_PEA1_node19 (SEQ ID NO:296) according to the present invention is supported by 25 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA1_T15 (SEQ ID NO:44) and H53626_PEA1_T16 (SEQ ID NO:45). Table 404 below describes the starting and ending position of this segment on each transcript.









TABLE 404







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












H53626_PEA_1_T15 (SEQ ID
369
419


NO:44)


H53626_PEA_1_T16 (SEQ ID
369
419


NO:45)









Segment cluster H53626_PEA1_node20 (SEQ ID NO:297) according to the present invention is supported by 27 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA1_T 15 (SEQ ID NO:44) and H53626_PEA1_T16 (SEQ ID NO:45). Table 405 below describes the starting and ending position of this segment on each transcript.









TABLE 405







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












H53626_PEA_1_T15 (SEQ ID
420
449


NO:44)


H53626_PEA_1_T16 (SEQ ID
420
449


NO:45)









Segment cluster H53626_PEA1_node24 (SEQ ID NO:298) according to the present invention is supported by 34 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA1_T15 (SEQ ID NO:44) and H53626_PEA1_T16 (SEQ ID NO:45). Table 406 below describes the starting and ending position of this segment on each transcript.









TABLE 406







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












H53626_PEA_1_T15 (SEQ ID
735
823


NO:44)


H53626_PEA_1_T16 (SEQ ID
735
823


NO:45)









Segment cluster H53626_PEA1_node28 (SEQ ID NO:299) according to the present invention is supported by 66 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA1_T 15 (SEQ ID NO:44) and H53626_PEA1_T16 (SEQ ID NO:45). Table 407 below describes the starting and ending position of this segment on each transcript.









TABLE 407







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












H53626_PEA_1_T15 (SEQ ID
2229
2306


NO:44)


H53626_PEA_1_T16 (SEQ ID
1724
1801


NO:45)









Segment cluster H53626_PEA1_node29 (SEQ ID NO:300) according to the present invention is supported by 73 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA1_T15 (SEQ ID NO:44) and H53626_PEA1_T16 (SEQ ID NO:45). Table 408 below describes the starting and ending position of this segment on each transcript.









TABLE 408







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












H53626_PEA_1_T15 (SEQ ID
2307
2396


NO:44)


H53626_PEA_1_T16 (SEQ ID
1802
1891


NO:45)









Segment cluster H53626_PEA1_node30 (SEQ ID NO:301) according to the present invention is supported by 71 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA1_T15 (SEQ ID NO:44) and H53626_PEA1_T16 (SEQ ID NO:45). Table 409 below describes the starting and ending position of this segment on each transcript.









TABLE 409







Segment location on transcripts










Segment starting
Segment ending


Transcript name
position
position





H53626_PEA_1_T15 (SEQ ID
2397
2442


NO:44)


H53626_PEA_1_T16 (SEQ ID
1892
1937


NO:45)









Segment cluster H53626_PEA1_node31 (SEQ ID NO:302) according to the present invention is supported by 67 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA1_T15 (SEQ ID NO:44) and H53626_PEA1_T16 (SEQ ID NO:45). Table 410 below describes the starting and ending position of this segment on each transcript.









TABLE 410







Segment location on transcripts










Segment starting
Segment ending


Transcript name
position
position





H53626_PEA_1_T15 (SEQ ID
2443
2469


NO:44)


H53626_PEA_1_T16 (SEQ ID
1938
1964


NO:45)









Segment cluster H53626_PEA1_node32 (SEQ ID NO:303) according to the present invention is supported by 65 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA1_T15 (SEQ ID NO:44) and H53626_PEA1_T16 (SEQ ID NO:45). Table 410 below describes the starting and ending position of this segment on each transcript.









TABLE 410







Segment location on transcripts










Segment starting
Segment ending


Transcript name
position
position





H53626_PEA_1_T15 (SEQ ID
2470
2498


NO:44)


H53626_PEA_1_T16 (SEQ ID
1965
1993


NO:45)









Segment cluster H53626_PEA1_node33 (SEQ ID NO:304) according to the present invention can be found in the following transcript(s): H53626_PEA1_T15 (SEQ ID NO:44) and H53626_PEA1_T16 (SEQ ID NO:45). Table 411 below describes the starting and ending position of this segment on each transcript.









TABLE 411







Segment location on transcripts










Segment starting
Segment ending


Transcript name
position
position





H53626_PEA_1_T15 (SEQ ID
2499
2506


NO:44)


H53626_PEA_1_T16 (SEQ ID
1994
2001


NO:45)









Expression of Homo Sapiens Fibroblast Growth Factor Receptor-Like 1 (FGFRL1) H53626 Transcripts Which are Detectable by Amplicon as Depicted in Sequence Name H53626 junc24-27F1R3 (SEQ ID NO:504) in Different Normal Tissues


Expression of Homo sapiens fibroblast growth factor receptor-like 1 (FGFRL1) transcripts detectable by or according to H53626 junc24-27F1R3 (SEQ ID NO:504) amplicon (s) and H53626 junc24-27F1 (SEQ ID NO:502) and H53626 junc24-27R3 (SEQ ID NO:503) was measured by real time PCR (these sequences relate to the known protein (“WT”) sequence). In parallel the expression of four housekeeping genes—RPL19 (GenBank Accession No. NM000981 (SEQ ID NO:511); RPL19 amplicon (SEQ ID NO:410)), TATA box (GenBank Accession No. NM003194 (SEQ ID NO:512); TATA amplicon (SEQ ID NO:515)), UBC (GenBank Accession No. BC000449 (SEQ ID NO:516); amplicon—Ubiquitin—(SEQ ID NO:519)) and SDHA (GenBank Accession No. NM004168 (SEQ ID NO:508); amplicon_—SDHA-amplicon (SEQ ID NO:407) was measured similarly. For each RT sample, the expression of the above amplicon was normalized to the geometric mean of the quantities of the housekeeping genes.










H53626 junc24-27 Forward primer (SEQ ID NO: 502):



GTCCTTCCAGTGCAAGACCCA





H53626 junc24-27 Reverse primer (SEQ ID NO: 503):


TGGGCCTGGCAAAGCC





H53626 junc24-27 Amplicon (SEQ ID NO: 504):


GTCCTTCCAGTGCAAGACCCAAAACCGCCAGGGCCACCTGTGGCCTCCTC





GTCCTCGGCCACTAGCCTGCCGTGGCCCGTGGTCATCGGCATCCCAGCCG





GCGCTGTCTTCATCCTGGGCACCCTGCTCCTGTGGCTTTGCCAGGCCCA






Expression of Homo Sapiens Fibroblast Growth Factor Receptor-Like 1 (FGFRL1) H53626 Transcripts, Which are Detectable by Amplicon as Depicted in Sequence Name H53626 seg25 (SEQ ID NO:507) in Different Normal Tissues.


Expression of Homo sapiens fibroblast growth factor receptor-like 1 (FGFRL1) transcripts detectable by or according to H53626 seg25 (SEQ ID NO:507) amplicon(s) and H53626 seg25F (SEQ ID NO:505) and H53626 seg25R (SEQ ID NO:506) was measured by real time PCR. In parallel the expression of four housekeeping genes: RPL19 (GenBank Accession No. NM000981 (SEQ ID NO:511); RPL19 amplicon (SEQ ID NO:410)), TATA box (GenBank Accession No. NM003194 (SEQ ID NO:512); TATA amplicon (SEQ ID NO:515)), UBC (GenBank Accession No. BC000449 (SEQ ID NO:516); amplicon—Ubiquitin-amplicon (SEQ ID NO:519)) and SDHA (GenBank Accession No. NM004168 (SEQ ID NO:508); amplicon_—SDHA-amplicon SEQ ID NO:407)) was measured similarly. For each RT sample, the expression of the above amplicon was normalized to the geometric mean of the quantities of the housekeeping genes.










H53626 seg25 Forward primer (SEQ ID NO: 505):



CCGACGGCTCCTACCTCAA





H53626 seg25 Reverse primer (SEQ ID NO: 506):


GGAAGCTGTAGCCCATGGTGT





H53626 seg25 Amplicon (SEQ ID NO: 507):


CCGACGGCTCCTACCTCAATAAGCTGCTCATCACCCGTGCCCGCCAGGAC





GATGCGGGCATGTACATCTGCCTTGGCGCCAACACCATGGGCTACAGCT





TCC







Variant Protein Alignment to the Previously Known Protein:














Sequence name: /tmp/K1Mec2ReKO/eg1EUS2AXY:Q8N441


Sequence documentation:


Alignment of: H53626_PEA_1_P4 (SEQ ID NO:368) × Q8N441 . . .


Alignment segment 1/1:


Quality: 4882.00


Escore: 0


Matching length: 504


Total length: 584


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 86.30


Total Percent Identity: 86.30


Gaps: 1


Alignment:












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Sequence name: /tmp/oSUZaRW3WK/oSh3fN5Zt0:Q9H4D7


Sequence documentation:


Alignment of: H53626_PEA_1_P5 (SEQ ID NO:369) × Q9H4D7 . . .


Alignment segment 1/1:


Quality: 2644.00


Escore: 0


Matching length: 269


Total length: 269


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Sequence name: /tmp/oSUZaRW3WK/oSh3fN5Zt0:Q8N441


Sequence documentation:


Alignment of: H53626_PEA_1_P5 (SEQ ID NO:369) × Q8N441 . . .


Alignment segment 1/1:


Quality: 2644.00


Escore: 0


Matching length: 269


Total length: 269


Matching Percent Similarity: 100.00


Matching Percent Identity: 100.00


Total Percent Similarity: 100.00


Total Percent Identity: 100.00


Gaps: 0


Alignment:












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Description for Cluster HSMUC1A


Cluster HSMUC1A features 14 transcript(s) and 22 segment(s) of interest, the names for which are given in Tables 412 and 413, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 414.









TABLE 412







Transcripts of interest










Transcript Name
Sequence ID No.







HSMUC1A_PEA_1_T12
46



HSMUC1A_PEA_1_T26
47



HSMUC1A_PEA_1_T28
48



HSMUC1A_PEA_1_T29
49



HSMUC1A_PEA_1_T30
50



HSMUC1A_PEA_1_T31
51



HSMUC1A_PEA_1_T33
52



HSMUC1A_PEA_1_T34
53



HSMUC1A_PEA_1_T35
54



HSMUC1A_PEA_1_T36
55



HSMUC1A_PEA_1_T40
56



HSMUC1A_PEA_1_T42
57



HSMUC1A_PEA_1_T43
58



HSMUC1A_PEA_1_T47
59

















TABLE 413







Segments of interest










Segment Name
Sequence ID No.







HSMUC1A_PEA_1_node_0
305



HSMUC1A_PEA_1_node_14
306



HSMUC1A_PEA_1_node_24
307



HSMUC1A_PEA_1_node_29
308



HSMUC1A_PEA_1_node_35
309



HSMUC1A_PEA_1_node_38
310



HSMUC1A_PEA_1_node_3
311



HSMUC1A_PEA_1_node_4
312



HSMUC1A_PEA_1_node_5
313



HSMUC1A_PEA_1_node_6
314



HSMUC1A_PEA_1_node_7
315



HSMUC1A_PEA_1_node_17
316



HSMUC1A_PEA_1_node_18
317



HSMUC1A_PEA_1_node_20
318



HSMUC1A_PEA_1_node_21
319



HSMUC1A_PEA_1_node_23
320



HSMUC1A_PEA_1_node_26
321



HSMUC1A_PEA_1_node_27
322



HSMUC1A_PEA_1_node_31
323



HSMUC1A_PEA_1_node_34
324



HSMUC1A_PEA_1_node_36
325



HSMUC1A_PEA_1_node_37
326

















TABLE 414







Proteins of interest










Sequence



Protein Name
ID No.
Corresponding Transcript(s)





HSMUC1A_PEA_1_P25
370
HSMUC1A_PEA_1_T26




(SEQ ID NO:47)


HSMUC1A_PEA_1_P29
371
HSMUC1A_PEA_1_T33




(SEQ ID NO:52)


HSMUC1A_PEA_1_P30
372
HSMUC1A_PEA_1_T34




(SEQ ID NO:53)


HSMUC1A_PEA_1_P32
373
HSMUC1A_PEA_1_T36




(SEQ ID NO:55)


HSMUC1A_PEA_1_P36
374
HSMUC1A_PEA_1_T40




(SEQ ID NO:56)


HSMUC1A_PEA_1_P39
375
HSMUC1A_PEA_1_T43




(SEQ ID NO:58)


HSMUC1A_PEA_1_P45
376
HSMUC1A_PEA_1_T29




(SEQ ID NO:49)


HSMUC1A_PEA_1_P49
377
HSMUC1A_PEA_1_T12




(SEQ ID NO:46)


HSMUC1A_PEA_1_P52
378
HSMUC1A_PEA_1_T30




(SEQ ID NO:50)


HSMUC1A_PEA_1_P53
379
HSMUC1A_PEA_1_T31




(SEQ ID NO:51)


HSMUC1A_PEA_1_P56
380
HSMUC1A_PEA_1_T42




(SEQ ID NO:57)


HSMUC1A_PEA_1_P58
381
HSMUC1A_PEA_1_T35




(SEQ ID NO:54)


HSMUC1A_PEA_1_P59
382
HSMUC1A_PEA_1_T28




(SEQ ID NO:48)


HSMUC1A_PEA_1_P63
383
HSMUC1A_PEA_1_T47




(SEQ ID NO:59)









These sequences are variants of the known protein Mucin 1 precursor (SEQ ID NO:398) (SwissProt accession identifier MUC1_HUMAN (SEQ ID NO: 398); known also according to the synonyms MUC-1; Polymorphic epithelial mucin; PEM; PEMT; Episialin; Tumor-associated mucin; Carcinoma-associated mucin; Tumor-associated epithelial membrane antigen; EMA; H23AG; Peanut—reactive urinary mucin; PUM; Breast carcinoma-associated antigen DF3; CD227 antigen), SEQ ID NO: 398, referred to herein as the previously known protein.


Protein Mucin 1 precursor (SEQ ID NO:398) is known or believed to have the following function(s): May play a role in adhesive functions and in cell-cell interactions, metastasis and signaling. May provide a protective layer on epithelial surfaces. Direct or indirect interaction with actin cytoskeleton; Isoform 7 behaves as a receptor and binds the secreted isoform 5. The binding induces the phosphorylation of the isoform 7, alters cellular morphology and initiates cell signaling. Can bind to GRB2 adapter protein. The sequence for protein Mucin 1 precursor (SEQ ID NO:398) is given at the end of the application, as “Mucin 1 precursor (SEQ ID NO:398) amino acid sequence”. Known polymorphisms for this sequence are as shown in Table 415.









TABLE 415







Amino acid mutations for Known Protein








SNP position(s) on



amino acid sequence
Comment











1116
D -> E: NO EFFECT ON BINDING OF



ISOFORM 7.


1116
D -> A: DRASTICALLY REDUCED BINDING



OF ISOFORM 7.


2
T -> A


134
P -> Q


154
P -> Q


1021
S -> T


1117
V -> M


1193
Q -> L


1231
K -> T


1251
A -> T









Protein Mucin 1 Precursor (SEQ ID NO:398) Localization is Believed to be Type I Membrane Protein. Two Secreted Forms (5 and 9) are Also Produced.


The previously known protein also has the following indication(s) and/or potential therapeutic use(s): Cancer, breast; Cancer, lung, non-small cell; Cancer, ovarian; Cancer, prostate; Cancer. It has been investigated for clinical/therapeutic use in humans, for example as a target for an antibody or small molecule, and/or as a direct therapeutic; available information related to these investigations is as follows. Potential pharmaceutically related or therapeutically related activity or activities of the previously known protein are as follows: CD8 agonist; DNA antagonist; Immunostimulant; Interferon gamma agonist; MUC-1 inhibitor. A therapeutic role for a protein represented by the cluster has been predicted. The cluster was assigned this field because there was information in the drug database or the public databases (e.g., described herein above) that this protein, or part thereof, is used or can be used for a potential therapeutic indication: Anticancer; Monoclonal antibody, murine; Immunotoxin; Immunostimulant; Immunoconjugate.


The following GO Annotation(s) apply to the previously known protein. The following annotation(s) were found: actin binding, which are annotation(s) related to Molecular Function; and cytoskeleton; integral plasma membrane protein, which are annotation(s) related to Cellular Component.


The GO assignment relies on information from one or more of the SwissProt/TremB1 Protein knowledgebase, available from expasydot ch/sprot/; or Locuslink, available from ncbidot nlmdot nihdot gov/projects/LocusLink/.


Cluster HSMUC1A can be used as a diagnostic marker according to overexpression of transcripts of this cluster in cancer. Expression of such transcripts in normal tissues is also given according to the previously described methods. The term “number” in the left hand column of the table and the numbers on the y-axis of FIG. 17 refer to weighted expression of ESTs in each category, as “parts per million” (ratio of the expression of ESTs for a particular cluster to the expression of all ESTs in that category, according to parts per million).


Overall, the following results were obtained as shown with regard to the histograms in FIG. 17 and Table 416. This cluster is overexpressed (at least at a minimum level) in the following pathological conditions: a mixture of malignant tumors from different tissues, breast malignant tumors, pancreas carcinoma and prostate cancer.









TABLE 416







Normal tissue distribution










Name of Tissue
Number














Bladder
41



Brain
2



Colon
66



Epithelial
96



General
36



head and neck
314



Kidney
282



Lung
200



Breast
61



Ovary
0



Pancreas
12



Prostate
24



Stomach
296



Thyroid
0



Uterus
122

















TABLE 417







P values and ratios for expression in cancerous tissue













Name of Tissue
P1
P2
SP1
R3
SP2
R4





Bladder
3.3e−01
4.5e−01
1.8e−02
2.4
8.9e−02
1.7


Brain
3.0e−02
2.6e−02
1.2e−01
4.6
1.1e−01
3.9


Colon
1.2e−01
2.4e−01
3.8e−01
1.6
5.9e−01
1.2


epithelial
5.4e−02
6.0e−01
7.3e−06
1.8
6.2e−02
1.1


General
6.5e−07
2.6e−03
4.0e−23
3.6
1.7e−12
2.3


head and neck
6.4e−01
7.2e−01
1
0.3
1
0.3


Kidney
7.8e−01
8.1e−01
1
0.3
1
0.2


Lung
7.6e−01
7.9e−01
6.7e−01
0.8
1
0.4


Breast
8.2e−02
1.3e−01
4.1e−03
3.6
7.7e−02
2.0


Ovary
3.0e−02
4.3e−02
6.9e−02
4.4
1.6e−01
3.2


Pancreas
7.2e−02
1.4e−01
9.6e−07
5.4
1.5e−05
4.5


Prostate
7.0e−01
6.0e−01
1.5e−02
1.4
6.9e−04
3.2


Stomach
3.1e−01
7.1e−01
1.5e−01
0.4
4.6e−01
0.8


Thyroid
2.9e−01
2.9e−01
4.4e−01
2.0
4.4e−01
2.0


Uterus
2.4e−01
6.5e−01
1.6e−01
1.0
7.0e−01
0.6









As noted above, cluster HSMUC1A features 14 transcript(s), which were listed in Table 1 above. These transcript(s) encode for protein(s) which are variant(s) of protein Mucin 1 precursor (SEQ ID NO:398). A description of each variant protein according to the present invention is now provided.


Variant protein HSMUC1A_PEA1_P25 (SEQ ID NO:370) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA1_T26 (SEQ ID NO:47). The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide.


Variant protein HSMUC1A_PEA1_P25 (SEQ ID NO:370) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 418, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P25 (SEQ ID NO:370) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 418







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












90
S -> N
Yes


91
D -> N
No


157
Y -> 
No


187
S -> G
No









Variant protein HSMUC1A_PEA1_P25 (SEQ ID NO:370) is encoded by the following transcript(s): HSMUC1A_PEA1_T26 (SEQ ID NO:47), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1A_PEA1_T26 (SEQ ID NO:47) is shown in bold; this coding portion starts at position 507 and ends at position 1115. The transcript also has the following SNPs as listed in Table 419 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P25 (SEQ ID NO:370) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 419







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












572
A -> G
No


775
G -> A
Yes


777
G -> A
No


977
C -> 
No


1065
A -> G
No


1073
C -> T
No


1079
C -> T
Yes


1124
C -> T
Yes


1177
C -> T
No


1197
C -> T
Yes


1303
G -> 
No


1315
G -> A
Yes


1316
C -> 
No


1316
C -> T
No


1405
A -> T
No









Variant protein HSMUC1A_PEA1_P29 (SEQ ID NO:371) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA1_T33 (SEQ ID NO:52). The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSMUC1A_PEA1_P29 (SEQ ID NO:371) is encoded by the following transcript(s): HSMUC1A_PEA1_T33 (SEQ ID NO:52), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1A_PEA1_T33 (SEQ ID NO:52) is shown in bold; this coding portion starts at position 507 and ends at position 953. The transcript also has the following SNPs as listed in Table 420 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P29 (SEQ ID NO:371) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 420







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












572
A -> G
No


964
C -> 
No


1052
A -> G
No


1060
C -> T
No


1066
C -> T
Yes


1111
C -> T
Yes


1164
C -> T
No


1184
C -> T
Yes


1290
G -> 
No


1302
G -> A
Yes


1303
C -> 
No


1303
C -> T
No


1392
A -> T
No









Variant protein HSMUC1A_PEA1_P30 (SEQ ID NO:372) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA1_T34 (SEQ ID NO:53). The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide.


Variant protein HSMUC1A_PEA1_P30 (SEQ ID NO:372) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 421, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P30 (SEQ ID NO:372) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 421







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












120
Y -> 
No


150
S -> G
No









Variant protein HSMUC1A_PEA1_P30 (SEQ ID NO:372) is encoded by the following transcript(s): HSMUC1A_PEA1_T34 (SEQ ID NO:53), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1A_PEA1_T34 (SEQ ID NO:53) is shown in bold; this coding portion starts at position 507 and ends at position 1004. The transcript also has the following SNPs as listed in Table 422 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P30 (SEQ ID NO:372) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 422







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












599
A -> G
No


866
C -> 
No


954
A -> G
No


962
C -> T
No


968
C -> T
Yes


1013
C -> T
Yes


1066
C -> T
No


1086
C -> T
Yes


1192
G -> 
No


1204
G -> A
Yes


1205
C -> 
No


1205
C -> T
No


1294
A -> T
No









Variant protein HSMUC1A_PEA1_P32 (SEQ ID NO:373) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA1_T36 (SEQ ID NO:55). The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide.


Variant protein HSMUC1A_PEA1_P32 (SEQ ID NO:373) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 423, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P32 (SEQ ID NO:373) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 423







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












111
Y -> 
No


141
S -> G
No









Variant protein HSMUC1A_PEA1_P32 (SEQ ID NO:373) is encoded by the following transcript(s): HSMUC1A_PEA1_T36 (SEQ ID NO:55), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1A_PEA1_T36 (SEQ ID NO:55) is shown in bold; this coding portion starts at position 507 and ends at position 977. The transcript also has the following SNPs as listed in Table 424 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P32 (SEQ ID NO:373) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 424







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












572
A -> G
No


839
C -> 
No


927
A -> G
No


935
C -> T
No


941
C -> T
Yes


986
C -> T
Yes


1039
C -> T
No


1059
C -> T
Yes


1165
G -> 
No


1177
G -> A
Yes


1178
C -> 
No


1178
C -> T
No


1267
A -> T
No









Variant protein HSMUC1A_PEA1_P36 (SEQ ID NO:374) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA1_T40 (SEQ ID NO:56). The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSMUC1A_PEA1_P36 (SEQ ID NO:374) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 425, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P36 (SEQ ID NO:374) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 425







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












113
Y -> 
No


143
S -> G
No









Variant protein HSMUC1A_PEA1_P36 (SEQ ID NO:374) is encoded by the following transcript(s): HSMUC1A_PEA1_T40 (SEQ ID NO:56), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1A_PEA1_T40 (SEQ ID NO:56) is shown in bold; this coding portion starts at position 507 and ends at position 983. The transcript also has the following SNPs as listed in Table 426 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P36 (SEQ ID NO:374) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 426







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












599
A -> G
No


845
C -> 
No


933
A -> G
No


941
C -> T
No


947
C -> T
Yes


992
C -> T
Yes


1045
C -> T
No


1065
C -> T
Yes


1171
G -> 
No


1183
G -> A
Yes


1184
C -> 
No


1184
C -> T
No


1273
A -> T
No









Variant protein HSMUC1A_PEA1_P39 (SEQ ID NO:375) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA1_T43 (SEQ ID NO:58). The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSMUC1A_PEA1_P39 (SEQ ID NO:375) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 427, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P39 (SEQ ID NO:375) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 427







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?












90
Y -> 
No


120
S -> G
No









Variant protein HSMUC1A_PEA1_P39 (SEQ ID NO:375) is encoded by the following transcript(s): HSMUC1A_PEA1_T43 (SEQ ID NO:58), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1A_PEA1_T43 (SEQ ID NO:58) is shown in bold; this coding portion starts at position 507 and ends at position 914. The transcript also has the following SNPs as listed in Table 428 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P39 (SEQ ID NO:375) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 428







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












599
A -> G
No


776
C -> 
No


864
A -> G
No


872
C -> T
No


878
C -> T
Yes


923
C -> T
Yes


976
C -> T
No


996
C -> T
Yes


1102
G -> 
No


1114
G -> A
Yes


1115
C -> 
No


1115
C -> T
No


1204
A -> T
No









Variant protein HSMUC1A_PEA1_P45 (SEQ ID NO:376) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA1_T29 (SEQ ID NO:49). The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSMUC1A_PEA1_P45 (SEQ ID NO:376) is encoded by the following transcript(s): HSMUC1A_PEA1_T29 (SEQ ID NO:49), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1A_PEA1_T29 (SEQ ID NO:49) is shown in bold; this coding portion starts at position 507 and ends at position 746. The transcript also has the following SNPs as listed in Table 429 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P45 (SEQ ID NO:376) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 429







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












599
A -> G
No


746
G -> A
Yes


748
G -> A
No


948
C -> 
No


1036
A -> G
No


1044
C -> T
No


1050
C -> T
Yes


1095
C -> T
Yes


1148
C -> T
No


1168
C -> T
Yes


1274
G -> 
No


1286
G -> A
Yes


1287
C -> 
No


1287
C -> T
No


1376
A -> T
No









Variant protein HSMUC1A_PEA1_P49 (SEQ ID NO:377) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA1_T12 (SEQ ID NO:46). The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSMUC1A_PEA1_P49 (SEQ ID NO:377) is encoded by the following transcript(s): HSMUC1A_PEA1_T12 (SEQ ID NO:46), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1 A_PEA1_T12 (SEQ ID NO:46) is shown in bold; this coding portion starts at position 507 and ends at position 884. The transcript also has the following SNPs as listed in Table 430 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P49 (SEQ ID NO:377) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 430







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












572
A -> G
No


704
G -> A
Yes


1012
G -> A
Yes


1088
G -> A
Yes


1090
G -> A
No


1290
C -> 
No


1378
A -> G
No


1386
C -> T
No


1392
C -> T
Yes


1437
C -> T
Yes


1490
C -> T
No


1510
C -> T
Yes


1616
G -> 
No


1628
G -> A
Yes


1629
C -> 
No


1629
C -> T
No


1718
A -> T
No









Variant protein HSMUC1A_PEA1_P52 (SEQ ID NO:378) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA1_T30 (SEQ ID NO:50). The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSMUC1A_PEA1_P52 (SEQ ID NO:378) is encoded by the following transcript(s): HSMUC1A_PEA1_T30 (SEQ ID NO:50), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1A_PEA1_T30 (SEQ ID NO:50) is shown in bold; this coding portion starts at position 507 and ends at position 719. The transcript also has the following SNPs as listed in Table 431 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P52 (SEQ ID NO:378) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 431







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












572
A -> G
No


719
G -> A
Yes


721
G -> A
No


921
C -> 
No


1009
A -> G
No


1017
C -> T
No


1023
C -> T
Yes


1068
C -> T
Yes


1121
C -> T
No


1141
C -> T
Yes


1247
G -> 
No


1259
G -> A
Yes


1260
C -> 
No


1260
C -> T
No


1349
A -> T
No









Variant protein HSMUC1A_PEA1_P53 (SEQ ID NO:379) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC 1 A_PEA1_T31 (SEQ ID NO:51). The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSMUC1A_PEA1_P53 (SEQ ID NO:379) is encoded by the following transcript(s): HSMUC1A_PEA1_T31 (SEQ ID NO:51), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1A_PEA1_T31 (SEQ ID NO:51) is shown in bold; this coding portion starts at position 507 and ends at position 665. The transcript also has the following SNPs as listed in Table 432 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P53 (SEQ ID NO:379) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 432







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












572
A -> G
No


669
G -> A
Yes


671
G -> A
No


871
C -> 
No


959
A -> G
No


967
C -> T
No


973
C -> T
Yes


1018
C -> T
Yes


1071
C -> T
No


1091
C -> T
Yes


1197
G -> 
No


1209
G -> A
Yes


1210
C -> 
No


1210
C -> T
No


1299
A -> T
No









Variant protein HSMUC1A_PEA1_P56 (SEQ ID NO:380) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA1_T42 (SEQ ID NO:57). The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSMUC1A_PEA1_P56 (SEQ ID NO:380) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 433, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P56 (SEQ ID NO:380) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 433







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?





117
P -> 
No









Variant protein HSMUC1A_PEA1_P56 (SEQ ID NO:380) is encoded by the following transcript(s): HSMUC1A_PEA1_T42 (SEQ ID NO:57), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1A_PEA1_T42 (SEQ ID NO:57) is shown in bold; this coding portion starts at position 507 and ends at position 890. The transcript also has the following SNPs as listed in Table 434 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column es whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P56 (SEQ ID NO:380) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 434







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












572
A -> G
No


855
C -> 
No


943
A -> G
No


951
C -> T
No


957
C -> T
Yes


1002
C -> T
Yes


1055
C -> T
No


1075
C -> T
Yes


1181
G -> 
No


1193
G -> A
Yes


1194
C -> 
No


1194
C -> T
No


1283
A -> T
No









Variant protein HSMUC1A_PEA1_P58 (SEQ ID NO:381) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA1_T35 (SEQ ID NO:54). The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSMUC1A_PEA1_P58 (SEQ ID NO:381) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 435, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P58 (SEQ ID NO:381) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 435







Amino acid mutations









SNP position(s) on
Alternative
Previously


amino acid sequence
amino acid(s)
known SNP?





147
P -> 
No









Variant protein HSMUC1A_PEA1_P58 (SEQ ID NO:381) is encoded by the following transcript(s): HSMUC1A_PEA1_T35 (SEQ ID NO:54), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1A_PEA1_T35 (SEQ ID NO:54) is shown in bold; this coding portion starts at position 507 and ends at position 980. The transcript also has the following SNPs as listed in Table 436 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P58 (SEQ ID NO:381) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 436







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












572
A -> G
No


945
C -> 
No


1033
A -> G
No


1041
C -> T
No


1047
C -> T
Yes


1092
C -> T
Yes


1145
C -> T
No


1165
C -> T
Yes


1271
G -> 
No


1283
G -> A
Yes


1284
C -> 
No


1284
C -> T
No


1373
A -> T
No









Variant protein HSMUC1A_PEA1_P59 (SEQ ID NO:382) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA1_T28 (SEQ ID NO:48). The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


Variant protein HSMUC1A_PEA1_P59 (SEQ ID NO:382) is encoded by the following transcript(s): HSMUC1A_PEA1_T28 (SEQ ID NO:48), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1A_PEA1_T28 (SEQ ID NO:48) is shown in bold; this coding portion starts at position 507 and ends at position 794. The transcript also has the following SNPs as listed in Table 437 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P59 (SEQ ID NO:382) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 437







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












572
A -> G
No


794
G -> A
Yes


796
G -> A
No


996
C -> 
No


1084
A -> G
No


1092
C -> T
No


1098
C -> T
Yes


1143
C -> T
Yes


1196
C -> T
No


1216
C -> T
Yes


1322
G -> 
No


1334
G -> A
Yes


1335
C -> 
No


1335
C -> T
No


1424
A -> T
No









Variant protein HSMUC1A_PEA1_P63 (SEQ ID NO:383) according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA1_T47 (SEQ ID NO:59). An alignment is given to the known protein (Mucin 1 precursor (SEQ ID NO:398)) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:


Comparison report between HSMUC1A_PEA1_P63 (SEQ ID NO:383) and MUC1_HUMAN:


1. An isolated chimeric polypeptide encoding for HSMUC1A_PEA1_P63 (SEQ ID NO:383), comprising a first amino acid sequence being at least 90% homologous to MTPGTQSPFFLLLLLTVLTVVTGSGHASSTPGGEKETSATQRSSV corresponding to amino acids 1-45 of MUCl_HUMAN, which also corresponds to amino acids 1-45 of HSMUC1A_PEA1_P63 (SEQ ID NO:383), and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence EEEVSADQVSVGASGVLGSFKEARNAPSFLSWSFSMGPSK (SEQ ID NO: 575) corresponding to amino acids 46-85 of HSMUC1A_PEA1_P63 (SEQ ID NO:383), wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.


2. An isolated polypeptide encoding for a tail of HSMUC1A_PEA1_P63 (SEQ ID NO:383), comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence EEEVSADQVSVGASGVLGSFKEARNAPSFLSWSFSMGPSK (SEQ ID NO: 575) in HSMUC1A_PEA1_P63 (SEQ ID NO:383).


The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans-membrane region.


The glycosylation sites of variant protein HSMUC1A_PEA1_P63 (SEQ ID NO:383), as compared to the known protein Mucin 1 precursor (SEQ ID NO:398), are described in Table 438 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the glycosylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).









TABLE 438







Glycosylation site(s)










Position(s) on known amino




acid sequence
Present in variant protein?














1055
No



957
No



975
No



1133
No



1029
No










Variant protein HSMUC1A_PEA1_P63 (SEQ ID NO:383) is encoded by the following transcript(s): HSMUC1A_PEA1_T47 (SEQ ID NO:59), for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1A_PEA1_T47 (SEQ ID NO:59) is shown in bold; this coding portion starts at position 507 and ends at position 761. The transcript also has the following SNPs as listed in Table 439 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA1_P63 (SEQ ID NO:383) sequence provides support for the deduced sequence of this variant protein according to the present invention).









TABLE 439







Nucleic acid SNPs









SNP position on
Alternative
Previously


nucleotide sequence
nucleic acid
known SNP?












572
A -> G
No


900
A -> 
No


904
C -> 
No


963
A -> C
Yes


1211
A -> G
No


1219
C -> T
No


1225
C -> T
Yes


1270
C -> T
Yes


1323
C -> T
No


1343
C -> T
Yes


1449
G -> 
No


1461
G -> A
Yes


1462
C -> 
No


1462
C -> T
No


1551
A -> T
No









As noted above, cluster HSMUC1A features 22 segment(s), which were listed in Table 2 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.


Segment cluster HSMUC1A_PEA1_node0 (SEQ ID NO:305) according to the present invention is supported by 31 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA1_T12 SEQ ID NO:46), HSMUC1A_PEA1_T26 (SEQ ID NO:47), HSMUC1A_PEA1_T28 (SEQ ID NO:48), HSMUC1A_PEA1_T29 (SEQ ID NO:49), HSMUC1A_PEA1_T30 (SEQ ID NO:50), HSMUC1A_PEA1_T31 (SEQ ID NO:51), HSMUC1A_PEA1_T33 (SEQ ID NO:52), HSMUC1A_PEA1_T34 (SEQ ID NO:53), HSMUC1A_PEA1_T35 (SEQ ID NO:54), HSMUC1A_PEA1_T36 (SEQ ID NO:55), HSMUC1A_PEA1_T40 (SEQ ID NO:56), HSMUC1A_PEA1_T42 (SEQ ID NO:57), HSMUC1A_PEA1_T43 (SEQ ID NO:58) and HSMUC1A_PEA1_T47 (SEQ ID NO:59). Table 440 below describes the starting and ending position of this segment on each transcript.









TABLE 440







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSMUC1A_PEA_1_T12 (SEQ ID
1
564


NO:46)


HSMUC1A_PEA_1_T26 (SEQ ID
1
564


NO:47)


HSMUC1A_PEA_1_T28 (SEQ ID
1
564


NO:48)


HSMUC1A_PEA_1_T29 (SEQ ID
1
564


NO:49)


HSMUC1A_PEA_1_T30 (SEQ ID
1
564


NO:50)


HSMUC1A_PEA_1_T31 (SEQ ID
1
564


NO:51)


HSMUC1A_PEA_1_T33 (SEQ ID
1
564


NO:52)


HSMUC1A_PEA_1_T34 (SEQ ID
1
564


NO:53)


HSMUC1A_PEA_1_T35 (SEQ ID
1
564


NO:54)


HSMUC1A_PEA_1_T36 (SEQ ID
1
564


NO:55)


HSMUC1A_PEA_1_T40 (SEQ ID
1
564


NO:56)


HSMUC1A_PEA_1_T42 (SEQ ID
1
564


NO:57)


HSMUC1A_PEA_1_T43 (SEQ ID
1
564


NO:58)


HSMUC1A_PEA_1_T47 (SEQ ID
1
564


NO:59)









Segment cluster HSMUC1A_PEA1_node14 (SEQ ID NO:306) according to the present invention is supported by 55 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA1_T12 (SEQ ID NO:46). Table 441 below describes the starting and ending position of this segment on each transcript.









TABLE 441







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSMUC1A_PEA_1_T12 (SEQ ID
666
841


NO:46)









Segment cluster HSMUC1A_PEA1_node24 (SEQ ID NO:307) according to the present invention is supported by 135 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA1_T12 (SEQ ID NO:46). Table 442 below describes the starting and ending position of this segment on each transcript.









TABLE 442







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSMUC1A_PEA_1_T12 (SEQ ID
953
1084


NO:46)









Segment cluster HSMUC1A_PEA1_node29 (SEQ ID NO:308) according to the present invention is supported by 156 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA1_T12 (SEQ ID NO:46), HSMUC1A_PEA1_T26 (SEQ ID NO:47), HSMUC1A_PEA1_T28 (SEQ ID NO:48), HSMUC1A_PEA1_T29 (SEQ ID NO:49), HSMUC1A_PEA1_T30 (SEQ ID NO:50), HSMUC1A_PEA1_T31 (SEQ ID NO:51), HSMUC1A_PEA1_T33 (SEQ ID NO:52), HSMUC1A_PEA1_T34 (SEQ ID NO:53), HSMUC1A_PEA1_T35 (SEQ ID NO:54), HSMUC1A_PEA1_T36 (SEQ ID NO:55), HSMUC1A_PEA1_T40 (SEQ ID NO:56), HSMUC1A_PEA1_T42 (SEQ ID NO:57), and HSMUC1A_PEA1_T43 (SEQ ID NO:58). Table 443 below describes the starting and ending position of this segment on each transcript.









TABLE 443







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HSMUC1A_PEA_1_T12 (SEQ ID
1207
1346


NO:46)


HSMUC1A_PEA_1_T26 (SEQ ID
894
1033


NO:47)


HSMUC1A_PEA_1_T28 (SEQ ID
913
1052


NO:48)


HSMUC1A_PEA_1_T29 (SEQ ID
865
1004


NO:49)


HSMUC1A_PEA_1_T30 (SEQ ID
838
977


NO:50)


HSMUC1A_PEA_1_T31 (SEQ ID
788
927


NO:51)


HSMUC1A_PEA_1_T33 (SEQ ID
881
1020


NO:52)


HSMUC1A_PEA_1_T34 (SEQ ID
783
922


NO:53)


HSMUC1A_PEA_1_T35 (SEQ ID
862
1001


NO:54)


HSMUC1A_PEA_1_T36 (SEQ ID
756
895


NO:55)


HSMUC1A_PEA_1_T40 (SEQ ID
762
901


NO:56)


HSMUC1A_PEA_1_T42 (SEQ ID
772
911


NO:57)


HSMUC1A_PEA_1_T43 (SEQ ID
693
832


NO:58)









Segment cluster HSMUC1A_PEA1_node35 (SEQ ID NO:309) according to the present invention is supported by 51 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA1_T47 (SEQ ID NO:59). Table 444 below describes the starting and ending position of this segment on each transcript.









TABLE 444







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSMUC1A_PEA_1_T47 (SEQ ID
666
1189


NO:59)









Segment cluster HSMUC1A_PEA1_node38 (SEQ ID NO:310) according to the present invention is supported by 140 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA1_T12 (SEQ ID NO:46), HSMUC1A_PEA1_T26 (SEQ ID NO:47), HSMUC1A_PEA1_T28 (SEQ ID NO:48), HSMUC1A_PEA1_T29 (SEQ ID NO:49), HSMUC1A_PEA1_T30 (SEQ ID NO:50), HSMUC1A_PEA1_T31 (SEQ ID NO:51), HSMUC1A_PEA1_T33 (SEQ ID NO:52), HSMUC1A_PEA1_T34 (SEQ ID NO:53), HSMUC1A_PEA1_T35 (SEQ ID NO:54), HSMUC1A_PEA1_T36 (SEQ ID NO:55), HSMUC1A_PEA1_T40 (SEQ ID NO:56), HSMUC1A_PEA1_T42 (SEQ ID NO:57), HSMUC1A_PEA1_T43 (SEQ ID NO:58) and HSMUC1A_PEA1_T47 (SEQ ID NO:59). Table 446 below describes the starting and ending position of this segment on each transcript.









TABLE 446







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HSMUC1A_PEA_1_T12 (SEQ ID
1488
1749


NO:46)


HSMUC1A_PEA_1_T26 (SEQ ID
1175
1436


NO:47)


HSMUC1A_PEA_1_T28 (SEQ ID
1194
1455


NO:48)


HSMUC1A_PEA_1_T29 (SEQ ID
1146
1407


NO:49)


HSMUC1A_PEA_1_T30 (SEQ ID
1119
1380


NO:50)


HSMUC1A_PEA_1_T31 (SEQ ID
1069
1330


NO:51)


HSMUC1A_PEA_1_T33 (SEQ ID
1162
1423


NO:52)


HSMUC1A_PEA_1_T34 (SEQ ID
1064
1325


NO:53)


HSMUC1A_PEA_1_T35 (SEQ ID
1143
1404


NO:54)


HSMUC1A_PEA_1_T36 (SEQ ID
1037
1298


NO:55)


HSMUC1A_PEA_1_T40 (SEQ ID
1043
1304


NO:56)


HSMUC1A_PEA_1_T42 (SEQ ID
1053
1314


NO:57)


HSMUC1A_PEA_1_T43 (SEQ ID
974
1235


NO:58)


HSMUC1A_PEA_1_T47 (SEQ ID
1321
1582


NO:59)









According to an optional embodiment of the present invention, short segments related to the above cluster are also provided. These segments are up to about 120 bp in length, and so are included in a separate description.


Segment cluster HSMUC1A_PEA1_node3 (SEQ ID NO:311) according to the present invention is supported by 17 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA1_T29 (SEQ ID NO:49), HSMUC1A_PEA1_T34 (SEQ ID NO:53), HSMUC1A_PEA1_T40 (SEQ ID NO:56) and HSMUC1A_PEA1_T43 (SEQ ID NO:58). Table 447 below describes the starting and ending position of this segment on each transcript.









TABLE 447







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSMUC1A_PEA_1_T29 (SEQ ID
565
591


NO:49)


HSMUC1A_PEA_1_T34 (SEQ ID
565
591


NO:53)


HSMUC1A_PEA_1_T40 (SEQ ID
565
591


NO:56)


HSMUC1A_PEA_1_T43 (SEQ ID
565
591


NO:58)









Segment cluster HSMUC1A_PEA1_node4 (SE ID NO:312) according to the present invention can be found in the following transcript(s): HSMUC1A_PEA1_T12 (SEQ ID NO:46), HSMUC1A_PEA1_T26 (SEQ ID NO:47), HSMUC1A_PEA1_T28 (SEQ ID NO:48), HSMUC1A_PEA1_T29 (SEQ ID NO:49), HSMUC1A_PEA1_T30 (SEQ ID NO:50), HSMUC1A_PEA1_T31 (SEQ ID NO:51), HSMUC1A_PEA1_T33 (SEQ ID NO:52), HSMUC1A_PEA1_T34 (SEQ ID NO:53), HSMUC1A_PEA1_T35 (SEQ ID NO:54), HSMUC1A_PEA1_T36 (SEQ ID NO:55), HSMUC1A_PEA1_T40 (SEQ ID NO:56), HSMUC1A_PEA1_T42 (SEQ ID NO:57), HSMUC1A_PEA1_T43 (SEQ ID NO:58) and HSMUC1A_PEA1_T47 (SEQ ID NO:59). Table 448 below describes the starting and ending position of this segment on each transcript.









TABLE 448







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSMUC1A_PEA_1_T12 (SEQ ID
565
573


NO:46)


HSMUC1A_PEA_1_T26 (SEQ ID
565
573


NO:47)


HSMUC1A_PEA_1_T28 (SEQ ID
565
573


NO:48)


HSMUC1A_PEA_1_T29 (SEQ ID
592
600


NO:49)


HSMUC1A_PEA_1_T30 (SEQ ID
565
573


NO:50)


HSMUC1A_PEA_1_T31 (SEQ ID
565
573


NO:51)


HSMUC1A_PEA_1_T33 (SEQ ID
565
573


NO:52)


HSMUC1A_PEA_1_T34 (SEQ ID
592
600


NO:53)


HSMUC1A_PEA_1_T35 (SEQ ID
565
573


NO:54)


HSMUC1A_PEA_1_T36 (SEQ ID
565
573


NO:55)


HSMUC1A_PEA_1_T40 (SEQ ID
592
600


NO:56)


HSMUC1A_PEA_1_T42 (SEQ ID
565
573


NO:57)


HSMUC1A_PEA_1_T43 (SEQ ID
592
600


NO:58)


HSMUC1A_PEA_1_T47 (SEQ ID
565
573


NO:59)









Segment cluster HSMUC1A_PEA1_node5 (SEQ ID NO:313) according to the present invention is supported by 34 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA1_T12 (SEQ ID NO:46), HSMUC1A_PEA1_T26 (SEQ ID NO:47), HSMUC1A_PEA1_T28 (SEQ ID NO:48), HSMUC1A_PEA1_T29 (SEQ ID NO:49), HSMUC1A_PEA1_T30 (SEQ ID NO:50), HSMUC1A_PEA1_T31 (SEQ ID NO:51), HSMUC1A_PEA1_T30 (SEQ ID NO:52), HSMUC1A_PEA1_T34 (SEQ ID NO:53), HSMUC1A_PEA1_T35 (SEQ ID NO:54), HSMUC1A_PEA1_T36 (SEQ ID NO:55), HSMUC1A_PEA1_T40 (SEQ ID NO:56), HSMUC1A_PEA1_T42 (SEQ ID NO:57), HSMUC1A_PEA1_T43 (SEQ ID NO:58) and HSMUC1A_PEA1_T47 (SEQ ID NO:59). Table 449 below describes the starting and ending position of this segment on each transcript.









TABLE 449







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSMUC1A_PEA_1_T12 (SEQ ID
574
600


NO:46)


HSMUC1A_PEA_1_T26 (SEQ ID
574
600


NO:47)


HSMUC1A_PEA_1_T28 (SEQ ID
574
600


NO:48)


HSMUC1A_PEA_1_T29 (SEQ ID
601
627


NO:49)


HSMUC1A_PEA_1_T30 (SEQ ID
574
600


NO:50)


HSMUC1A_PEA_1_T31 (SEQ ID
574
600


NO:51)


HSMUC1A_PEA_1_T33 (SEQ ID
574
600


NO:52)


HSMUC1A_PEA_1_T34 (SEQ ID
601
627


NO:53)


HSMUC1A_PEA_1_T35 (SEQ ID
574
600


NO:54)


HSMUC1A_PEA_1_T36 (SEQ ID
574
600


NO:55)


HSMUC1A_PEA_1_T40 (SEQ ID
601
627


NO:56)


HSMUC1A_PEA_1_T42 (SEQ ID
574
600


NO:57)


HSMUC1A_PEA_1_T43 (SEQ ID
601
627


NO:58)


HSMUC1A_PEA_1_T47 (SEQ ID
574
600


NO:59)









Segment cluster HSMUC1A_PEA1_node6 (SEQ ID NO:314) according to the present invention is supported by 35 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA1_T12 (SEQ ID NO:46), HSMUC1A_PEA1_T26 (SEQ ID NO:47), HSMUC1A_PEA1_T28 (SEQ ID NO:48), HSMUC1A_PEA1_T29 (SEQ ID NO:49), HSMUC1A_PEA1_T30 (SEQ ID NO:50), HSMUC1A_PEA1_T31 (SEQ ID NO:51), HSMUC1A_PEA1_T33 (SEQ ID NO:52), HSMUC1A_PEA1_T34 (SEQ ID NO:53), HSMUC1A_PEA1_T35 (SEQ ID NO:54), HSMUC1A_PEA1_T36 (SEQ ID NO:55), HSMUC1A_PEA1_T40 (SEQ ID NO:56), HSMUC1A_PEA1_T42 (SEQ ID NO:57), HSMUC1A_PEA1_T43 (SEQ ID NO:58) and HSMUC1A_PEA1_T47 (SEQ ID NO:59). Table 450 below describes the starting and ending position of this segment on each transcript.









TABLE 450







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSMUC1A_PEA_1_T12 (SEQ ID
601
638


NO:46)


HSMUC1A_PEA_1_T26 (SEQ ID
601
638


NO:47)


HSMUC1A_PEA_1_T28 (SEQ ID
601
638


NO:48)


HSMUC1A_PEA_1_T29 (SEQ ID
628
665


NO:49)


HSMUC1A_PEA_1_T30 (SEQ ID
601
638


NO:50)


HSMUC1A_PEA_1_T31 (SEQ ID
601
638


NO:51)


HSMUC1A_PEA_1_T33 (SEQ ID
601
638


NO:52)


HSMUC1A_PEA_1_T34 (SEQ ID
628
665


NO:53)


HSMUC1A_PEA_1_T35 (SEQ ID
601
638


NO:54)


HSMUC1A_PEA_1_T36 (SEQ ID
601
638


NO:55)


HSMUC1A_PEA_1_T40 (SEQ ID
628
665


NO:56)


HSMUC1A_PEA_1_T42 (SEQ ID
601
638


NO:57)


HSMUC1A_PEA_1_T43 (SEQ ID
628
665


NO:58)


HSMUC1A_PEA_1_T47 (SEQ ID
601
638


NO:59)









Segment cluster HSMUC1A_PEA1_node7 (SEQ ID NO:315) according to the present invention is supported by 32 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA1_T12 (SEQ ID NO:46), HSMUC1A_PEA1_T26 (SEQ ID NO:47), HSMUC1A_PEA1_T28 (SEQ ID NO:48), HSMUC1A_PEA1_T29 (SEQ ID NO:49), HSMUC1A_PEA1_T30 (SEQ ID NO:50), HSMUC1A_PEA1_T31 (SEQ ID NO:51), HSMUC1A_PEA1_T33 (SEQ ID NO:52), HSMUC1A_PEA1_T34(SEQ ID NO:53), HSMUC1A_PEA1—T35 (SEQ ID NO:54), HSMUC1A_PEA1_T36 (SEQ ID NO:55), HSMUC1A_PEA1_T40 (SEQ ID NO:56), HSMUC1A_PEA1_T42 (SEQ ID NO:57) and HSMUC1A_PEA1_T43 (SEQ ID NO:58). Table 451 below describes the starting and ending position of this segment on each transcript.









TABLE 451







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSMUC1A_PEA_1_T12 (SEQ ID
639
665


NO:46)


HSMUC1A_PEA_1_T26 (SEQ ID
639
665


NO:47)


HSMUC1A_PEA_1_T28 (SEQ ID
639
665


NO:48)


HSMUC1A_PEA_1_T29 (SEQ ID
666
692


NO:49)


HSMUC1A_PEA_1_T30 (SEQ ID
639
665


NO:50)


HSMUC1A_PEA_1_T31 (SEQ ID
639
665


NO:51)


HSMUC1A_PEA_1_T33 (SEQ ID
639
665


NO:52)


HSMUC1A_PEA_1_T34 (SEQ ID
666
692


NO:53)


HSMUC1A_PEA_1_T35 (SEQ ID
639
665


NO:54)


HSMUC1A_PEA_1_T36 (SEQ ID
639
665


NO:55)


HSMUC1A_PEA_1_T40 (SEQ ID
666
692


NO:56)


HSMUC1A_PEA_1_T42 (SEQ ID
639
665


NO:57)


HSMUC1A_PEA_1_T43 (SEQ ID
666
692


NO:58)









Segment cluster HSMUC1A_PEA1_node17 (SEQ ID NO:316) according to the present invention can be found in the following transcript(s): HSMUC1A_PEA1_T28 (SEQ ID NO:48), HSMUC1A_PEA1_T33 (SEQ ID NO:52) and HSMUC1A_PEA1_T40 (SEQ ID NO:56). Table 452 below describes the starting and ending position of this segment on each transcript.









TABLE 452







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSMUC1A_PEA_1_T28 (SEQ ID
666
684


NO:48)


HSMUC1A_PEA_1_T33 (SEQ ID
666
684


NO:52)


HSMUC1A_PEA_1_T40 (SEQ ID
693
711


NO:56)









Segment cluster HSMUC1A_PEA1_node18 (SEQ ID NO:317) according to the present invention is supported by 90 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA1_T12 (SEQ ID NO:46), HSMUC1A_PEA1_T26 (SEQ ID NO:47), HSMUC1A_PEA1_T28 (SEQ ID NO:48), HSMUC1A_PEA1_T29 (SEQ ID NO:49), HSMUC1A_PEA1_T30 (SEQ ID NO:50), HSMUC1A_PEA1_T33 (SEQ ID NO:52), HSMUC1A_PEA1_T35 (SEQ ID NO:54), HSMUC1A_PEA1_T40 (SEQ ID NO:56), and HSMUC1A_PEA1_T42 (SEQ ID NO:57). Table 453 below describes the starting and ending position of this segment on each transcript.









TABLE 453







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSMUC1A_PEA_1_T12 (SEQ ID
842
891


NO:46)


HSMUC1A_PEA_1_T26 (SEQ ID
666
715


NO:47)


HSMUC1A_PEA_1_T28 (SEQ ID
685
734


NO:48)


HSMUC1A_PEA_1_T29 (SEQ ID
693
742


NO:49)


HSMUC1A_PEA_1_T30 (SEQ ID
666
715


NO:50)


HSMUC1A_PEA_1_T33 (SEQ ID
685
734


NO:52)


HSMUC1A_PEA_1_T35 (SEQ ID
666
715


NO:54)


HSMUC1A_PEA_1_T40 (SEQ ID
712
761


NO:56)


HSMUC1A_PEA_1_T42 (SEQ ID
666
715


NO:57)









Segment cluster HSMUC1A_PEA1_node20 (SEQ ID NO:318) according to the present invention can be found in the following transcript(s): HSMUC1A_PEA1_T12 (SEQ ID NO:46), HSMUC1A_PEA1_T26 (SEQ ID NO:47), HSMUC1A_PEA1_T28 (SEQ ID NO:48), HSMUC1A_PEA1_T33 (SEQ ID NO:52), HSMUC1A_PEA1_T35 (SEQ ID NO:54) and HSMUC1A_PEA1_T42 (SEQ ID NO:57). Table 454 below describes the starting and ending position of this segment on each transcript.









TABLE 454







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSMUC1A_PEA_1_T12 (SEQ ID
892
900


NO:46)


HSMUC1A_PEA_1_T26 (SEQ ID
716
724


NO:47)


HSMUC1A_PEA_1_T28 (SEQ ID
735
743


NO:48)


HSMUC1A_PEA_1_T33 (SEQ ID
735
743


NO:52)


HSMUC1A_PEA_1_T35 (SEQ ID
716
724


NO:54)


HSMUC1A_PEA_1_T42 (SEQ ID
716
724


NO:57)









Segment cluster HSMUC1A_PEA1_node21 (SEQ ID NO:319) according to the present invention is supported by 97 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA1_T12 (SEQ ID NO:46), HSMUC1A_PEA1_T26 (SEQ ID NO:47), HSMUC1A_PEA1_T28 (SEQ ID NO:48), HSMUC1A_PEA1_T33 (SEQ ID NO:52), HSMUC1A_PEA1_T35 (SEQ ID NO:54) and HSMUC1A_PEA1_T42 (SEQ ID NO:57). Table 455 below describes the starting and ending position of this segment on each transcript.









TABLE 455







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSMUC1A_PEA_1_T12 (SEQ ID
901
947


NO:46)


HSMUC1A_PEA_1_T26 (SEQ ID
725
771


NO:47)


HSMUC1A_PEA_1_T28 (SEQ ID
744
790


NO:48)


HSMUC1A_PEA_1_T33 (SEQ ID
744
790


NO:52)


HSMUC1A_PEA_1_T35 (SEQ ID
725
771


NO:54)


HSMUC1A_PEA_1_T42 (SEQ ID
725
771


NO:57)









Segment cluster HSMUC1A_PEA1_node23 (SEQ ID NO:320) according to the present invention can be found in the following transcript(s): HSMUC1A_PEA1_T12 (SEQ ID NO:46). Table 456 below describes the starting and ending position of this segment on each transcript.









TABLE 456







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSMUC1A_PEA_1_T12 (SEQ ID
948
952


NO:46)









Segment cluster HSMUC1A_PEA1_node26 (SEQ ID NO:321) according to the present invention is supported by 129 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA1_T12 (SEQ ID NO:46), HSMUC1A_PEA1_T26 (SEQ ID NO:47), HSMUC1A_PEA1_T28 (SEQ ID NO:48), HSMUC1A_PEA1_T29 (SEQ ID NO:49), HSMUC1A_PEA1_T30 (SEQ ID NO:50) and HSMUC1A_PEA1_T31 (SEQ ID NO:51). Table 457 below describes the starting and ending position of this segment on each transcript.









TABLE 457







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HSMUC1A_PEA_1_T12 (SEQ ID
1085
1116


NO:46)


HSMUC1A_PEA_1_T26 (SEQ ID
772
803


NO:47)


HSMUC1A_PEA_1_T28 (SEQ ID
791
822


NO:48)


HSMUC1A_PEA_1_T29 (SEQ ID
743
774


NO:49)


HSMUC1A_PEA_1_T30 (SEQ ID
716
747


NO:50)


HSMUC1A_PEA_1_T31 (SEQ ID
666
697


NO:51)









Segment cluster HSMUC1A_PEA1_node27 (SEQ ID NO:322) according to the present invention is supported by 140 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA1_T12 (SEQ ID NO:46), HSMUC1A_PEA1_T26 (SEQ ID NO:47), HSMUC1A_PEA1_T28 (SEQ ID NO:48), HSMUC1A_PEA1_T29 (SEQ ID NO:49), HSMUC1A_PEA1_T30 (SEQ ID NO:50), HSMUC1A_PEA1_T31 (SEQ ID NO:51), HSMUC1A_PEA1_T33 (SEQ ID NO:52), HSMUC1A_PEA1_T34 (SEQ ID NO:53), HSMUC1A_PEA1_T35 (SEQ ID NO:54) and HSMUC1A_PEA1_T36 (SEQ ID NO:55). Table 458 below describes the starting and ending position of this segment on each transcript.









TABLE 458







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HSMUC1A_PEA_1_T12 (SEQ ID
1117
1206


NO:46)


HSMUC1A_PEA_1_T26 (SEQ ID
804
893


NO:47)


HSMUC1A_PEA_1_T28 (SEQ ID
823
912


NO:48)


HSMUC1A_PEA_1_T29 (SEQ ID
775
864


NO:49)


HSMUC1A_PEA_1_T30 (SEQ ID
748
837


NO:50)


HSMUC1A_PEA_1_T31 (SEQ ID
698
787


NO:51)


HSMUC1A_PEA_1_T33 (SEQ ID
791
880


NO:52)


HSMUC1A_PEA_1_T34 (SEQ ID
693
782


NO:53)


HSMUC1A_PEA_1_T35 (SEQ ID
772
861


NO:54)


HSMUC1A_PEA_1_T36 (SEQ ID
666
755


NO:55)









Segment cluster HSMUC1A_PEA1_node31 (SEQ ID NO:323) according to the present invention can be found in the following transcript(s): HSMUC1A_PEA1_T12 (SEQ ID NO:46), HSMUC1A_PEA1_T26 (SEQ ID NO:47), HSMUC1A_PEA1_T28 (SEQ ID NO:48), HSMUC1A_PEA1_T29 (SEQ ID NO:49), HSMUC1A_PEA1_T30 (SEQ ID NO:50), HSMUC1A_PEA1_T31 (SEQ ID NO:51); HSMUC1A_PEA1_T33 (SEQ ID NO:52), HSMUC1A_PEA1_T34 (SEQ ID NO:53), HSMUC1A_PEA1_T35 (SEQ ID NO:54), HSMUC1A_PEA1_T36 (SEQ ID NO:55), HSMUC1A_PEA1_T40 (SEQ ID NO:56), HSMUC1A_PEA1_T42 (SEQ ID NO:57) and HSMUC1A_PEA1_T43 (SEQ ID NO:58) Table 459 below describes the starting and ending position of this segment on each transcript.









TABLE 459







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HSMUC1A_PEA_1_T12 (SEQ ID
1347
1356


NO:46)


HSMUC1A_PEA_1_T26 (SEQ ID
1034
1043


NO:47)


HSMUC1A_PEA_1_T28 (SEQ ID
1053
1062


NO:48)


HSMUC1A_PEA_1_T29 (SEQ ID
1005
1014


NO:49)


HSMUC1A_PEA_1_T30 (SEQ ID
978
987


NO:50)


HSMUC1A_PEA_1_T31 (SEQ ID
928
937


NO:51)


HSMUC1A_PEA_1_T33 (SEQ ID
1021
1030


NO:52)


HSMUC1A_PEA_1_T34 (SEQ ID
923
932


NO:53)


HSMUC1A_PEA_1_T35 (SEQ ID
1002
1011


NO:54)


HSMUC1A_PEA_1_T36 (SEQ ID
896
905


NO:55)


HSMUC1A_PEA_1_T40 (SEQ ID
902
911


NO:56)


HSMUC1A_PEA_1_T42 (SEQ ID
912
921


NO:57)


HSMUC1A_PEA_1_T43 (SEQ ID
833
842


NO:58)









Segment cluster HSMUC1A_PEA1_node34 (SEQ ID NO:324) according to the present invention is supported by 24 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA1_T47 (SEQ ID NO:59). Table 460 below describes the starting and ending position of this segment on each transcript.









TABLE 460







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position





HSMUC1A_PEA_1_T47 (SEQ ID
639
665


NO:59)









Segment cluster HSMUC1A_PEA1_node36 (SEQ ID NO:325) according to the present invention is supported by 135 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA1_T12 (SEQ ID NO:46), HSMUC1A_PEA1_T26 (SEQ ID NO:47), HSMUC1A_PEA1_T28 (SEQ ID NO:48), HSMUC1A_PEA1_T29 (SEQ ID NO:49), HSMUC1A_PEA1_T30 (SEQ ID NO:50), HSMUC1A_PEA1_T31 (SEQ ID NO:51), HSMUC1A_PEA1_T33 (SEQ ID NO:52), HSMUC1A_PEA1_T34 (SEQ ID NO:53), HSMUC1A_PEA1_T35 (SEQ ID NO:54), HSMUC1A_PEA1_T36 (SEQ ID NO:55), HSMUC1A_PEA1_T40 (SEQ ID NO:56), HSMUC1A_PEA1_T42 (SEQ ID NO:57), HSMUC1A_PEA1_T43 (SEQ ID NO:58) and HSMUC1A_PEA1_T47 (SEQ ID NO:59). Table 461 below describes the starting and ending position of this segment on each transcript.









TABLE 461







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HSMUC1A_PEA_1_T12 (SEQ ID
1357
1388


NO:46)


HSMUC1A_PEA_1_T26 (SEQ ID
1044
1075


NO:47)


HSMUC1A_PEA_1_T28 (SEQ ID
1063
1094


NO:48)


HSMUC1A_PEA_1_T29 (SEQ ID
1015
1046


NO:49)


HSMUC1A_PEA_1_T30 (SEQ ID
988
1019


NO:50)


HSMUC1A_PEA_1_T31 (SEQ ID
938
969


NO:51)


HSMUC1A_PEA_1_T33 (SEQ ID
1031
1062


NO:52)


HSMUC1A_PEA_1_T34 (SEQ ID
933
964


NO:53)


HSMUC1A_PEA_1_T35 (SEQ ID
1012
1043


NO:54)


HSMUC1A_PEA_1_T36 (SEQ ID
906
937


NO:55)


HSMUC1A_PEA_1_T40 (SEQ ID
912
943


NO:56)


HSMUC1A_PEA_1_T42 (SEQ ID
922
953


NO:57)


HSMUC1A_PEA_1_T43 (SEQ ID
843
874


NO:58)


HSMUC1A_PEA_1_T47 (SEQ ID
1190
1221


NO:59)









Segment cluster HSMUC1A_PEA1_node37 (SEQ ID NO:326) according to the present invention is supported by 146 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA1_T12 (SEQ ID NO:46), HSMUC1A_PEA1_T26 (SEQ ID NO:47), HSMUC1A_PEA1_T28 (SEQ ID NO:48), HSMUC1A_PEA1_T29 (SEQ ID NO:49), HSMUC1A_PEA1_T30 (SEQ ID NO:50), HSMUC1A_PEA1_T31 (SEQ ID NO:51), HSMUC1A_PEA1_T33 (SEQ ID NO:52), HSMUC1A_PEA1_T34 (SEQ ID NO:53), HSMUC1A_PEA1_T35 (SEQ ID NO:54), HSMUC1A_PEA1_T36 (SEQ ID NO:55), HSMUC1A_PEA1_T40 (SEQ ID NO:56), HSMUC1A_PEA1_T42 (SEQ ID NO:57), HSMUC1A_PEA1_T43 (SEQ ID NO:58) and HSMUC1A_PEA1_T47 (SEQ ID NO:59). Table 462 below describes the starting and ending position of this segment on each transcript.









TABLE 462







Segment location on transcripts










Segment
Segment


Transcript name
starting position
ending position












HSMUC1A_PEA_1_T12 (SEQ ID
1389
1487


NO:46)


HSMUC1A_PEA_1_T26 (SEQ ID
1076
1174


NO:47)


HSMUC1A_PEA_1_T28 (SEQ ID
1095
1193


NO:48)


HSMUC1A_PEA_1_T29 (SEQ ID
1047
1145


NO:49)


HSMUC1A_PEA_1_T30 (SEQ ID
1020
1118


NO:50)


HSMUC1A_PEA_1_T31 (SEQ ID
970
1068


NO:51)


HSMUC1A_PEA_1_T33 (SEQ ID
1063
1161


NO:52)


HSMUC1A_PEA_1_T34 (SEQ ID
965
1063


NO:53)


HSMUC1A_PEA_1_T35 (SEQ ID
1044
1142


NO:54)


HSMUC1A_PEA_1_T36 (SEQ ID
938
1036


NO:55)


HSMUC1A_PEA_1_T40 (SEQ ID
944
1042


NO:56)


HSMUC1A_PEA_1_T42 (SEQ ID
954
1052


NO:57)


HSMUC1A_PEA_1_T43 (SEQ ID
875
973


NO:58)


HSMUC1A_PEA_1_T47 (SEQ ID
1222
1320


NO:59)










Variant Protein Alignment to the Previously Known Protein:














Sequence name: MUC1_HUMAN


Sequence documentation:


Alignment of: HSMUC1A_PEA_1_P63 (SEQ ID NO:383) × MUC1_HUMAN


Alignment segment 1/1:


Quality: 429.00


Escore: 0


Matching length: 59


Total length: 59


Matching Percent Similarity: 86.44


Matching Percent Identity: 81.36


Total Percent Similarity: 86.44


Total Percent Identity: 81.36


Gaps: 0


Alignment:












embedded image









embedded image












Expression of AA315457 Transcripts Which are Detectable by SEQ ID NO:413 in Normal, Benign and Cancerous Prostate Tissues


Expression of AA315457 transcripts detectable by SEQ ID NO:413 (e.g., variant no. 1 SEQ ID NO: 415) was measured by real time PCR. AA315457 is a non-limiting example of a marker according to the present invention. In parallel the expression of four housekeeping genes—PBGD (GenBank Accession No. BC019323 (SEQ ID NO:509); amplicon—SEQ ID NO:404), HPRT1 (GenBank Accession No. NM000194 (SEQ ID NO:510): amplicon (SEQ ID NO:401)—SEQ ID NO: 402), RPL19 (GenBank Accession No. NM000981 (SEQ ID NO:511); amplicon—SEQ ID NO:410) and SDHA (GenBank Accession No. NM004168 (SEQ ID NO:508); amplicon—SEQ ID NO:407), was measured similarly. For each RT sample, the expression of SEQ ID NO:413 was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal post-mortem (PM) samples (Sample Nos. 42, 48-53, 59-63, Table 2, above), to obtain a value of fold up-regulation for each sample relative to median of the normal PM samples.



FIGS. 18A and 18B are histograms showing over expression of the above-indicated AA315457 transcripts in cancerous and benign (BPH) prostate samples relative to the normal samples. The number and percentage of cancer samples that exhibit at least 3 fold over-expression, out of the total number of samples tested is indicated in the bottom.


As is evident from FIGS. 18A and 18B, the expression of AA315457 transcripts detectable by SEQ ID NO:413 in cancer samples was significantly higher than in the non-cancerous samples (Sample Nos. 33-35, 43-47—BPH samples, 40-41—normal matched samples and 42, 48-53, 59-63—normal post mortem samples, Table 2). Notably an over-expression of at least 3 fold was found in 9 out of 19 adenocarcinoma samples. However, when an additional duplicate experiment was performed, the expression of SEQ ID NO:413 was weaker so just 5 out of 19 cancer samples showed overexpression of at least 3 fold, as shown with regard to FIG. 18B.


Statistical analysis was applied to verify the significance of these results, as described below.


The P value for the difference in the expression levels of AA315457 transcripts detectable by SEQ ID NO:413 in prostate cancer samples versus the normal prostate samples was determined by T test as 7.33E-02.


Threshold of 3 fold overexpression was found to differentiate between cancer and normal samples with P value of 4.58E-03 as checked by exact fisher test.


The P value for the difference between the expression levels of AA315457 transcripts detectable by SEQ ID NO:413 in the prostate cancer samples versus the BPH prostate samples was determined by T test as 8.04E-02.


Threshold of 3 fold overexpression was found to differentiate between cancer and BPH sample with P value of 1.97E-02 as checked by exact fisher test.


The P value for the difference between the expression levels of AA315457 transcripts detectable by SEQ ID NO:413 in the prostate cancer samples versus the BPH and normal prostate samples was determined by T test as 7.60E-02.


Threshold of 3 fold overexpression was found to differentiate between cancer sample and BPH and normal sample with P value of 4.36E-04 as checked by exact fisher test.


All the above values demonstrate statistical significance of the results.


According to the present invention, AA315457 is a non-limiting example of a marker for diagnosing prostate cancer. The AA315457 marker of the present invention can be used alone or in combination, for various uses, including but not limited to, prognosis, prediction, screening, early diagnosis, therapy selection and treatment monitoring of prostate cancer. Although optionally any method may be used to detect overexpression and/or differential expression of this marker, preferably a NAT-based technology is used. Therefore, optionally and preferably, any nucleic acid molecule capable of selectively hybridizing to AA315457 as previously defined is also encompassed within the present invention. Primer pairs are also optionally and preferably encompassed within the present invention; for example, for the above experiment, the following primer pair was used as a non-limiting illustrative example only of a suitable primer pair: AA315457—forward primer (SEQ ID NO: 411): CATGGACCCCAGGCAAGTC; and AA315457—Reverse primer (SEQ ID NO: 412): CTGTTTAGGGTCGAGGCTGTG.


The present invention also preferably encompasses any amplicon obtained through the use of any suitable primer pair; for example, for the above experiment, the following amplicon was obtained as a non-limiting illustrative example only of a suitable amplicon_: AA315457 amplicon (SEQ ID NO: 413):









CATGGACCCCAGGCAAGTCCCCCCACCCACGCATTTCTAATCATCTGCCC






TGGTTTTGCCTCCTGAGTCTGTTAAGGCTGTGTGCCCCTCATCGAGGCCC





GTCACAGCCTCGACCCTAAACAG.






According to other preferred embodiments of the present invention, AA315457 or a fragment thereof comprises a biomarker for detecting prostate cancer. Optionally and more preferably, the fragment of AA315457 comprises AA315457_segment8 (SEQ ID NO: 414). Also optionally and more preferably, any suitable method may be used for detecting a fragment such as AA315457_segment8 for example. Most preferably, NAT-based technology used, such as any nucleic acid molecule capable of specifically hybridizing with the fragment. Optionally and most preferably, a primer pair is used for obtaining the fragment.


According to still other preferred embodiments, the present invention optionally and preferably encompasses any amino acid sequence or fragment thereof encoded by a nucleic acid sequence corresponding to AA315457 as described above, including but not limited to SEQ ID NOs: 414 and 415. Any oligopeptide or peptide relating to such an amino acid sequence or fragment thereof may optionally also (additionally or alternatively) be used as a biomarker. The present invention also optionally encompasses antibodies capable of recognizing, and/or being elicited by, such an oligopeptide or peptide.


The present invention also optionally and preferably encompasses any nucleic acid sequence or fragment thereof, or amino acid sequence or fragment thereof, corresponding to AA315457 as described above, optionally for any application.


Expression of Thrombospondin 1 (THBS1) Transcripts Which are Detectable by SEQ ID NO:421 in Normal, Benign and Cancerous Prostate Tissues


Expression of Thrombospondin 1 (THBS1) transcripts detectable by SEQ ID NO:421, segment 24 (e.g., variants no. 10,11 and 30; SEQ ID NOs: 441, 442, and 451) was measured by real time PCR, according to the exemplary marker HUMTHROM-segment 24 (SEQ ID NO:425). In parallel the expression of four housekeeping genes—PBGD (GenBank Accession No. BC019323 (SEQ ID NO:509); amplicon—SEQ ID NO:404), HPRT1 (GenBank Accession No. NM000194 (SEQ ID NO:510); amplicon_—SEQ ID NO:401), RPL19 (GenBank Accession No. NM000981 (SEQ ID NO:511); amplicon—SEQ ID NO:410) and SDHA (GenBank Accession No. NM004168 (SEQ ID NO:508); amplicon_—SEQ ID NO:407), was measured similarly. For each RT sample, the expression of SEQ ID NO:421 was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal post-mortem (PM) samples (Sample Nos. 42, 48-53, 59-63, Table 2, above), to obtain a value of fold up-regulation for each sample relative to median of the normal PM samples.



FIG. 19 is a histogram showing over expression of the above-indicated Thrombospondin 1 (THBS1) transcripts in cancerous and benign (BPH) prostate samples relative to the normal samples. The number and percentage of cancer samples that exhibit at least 3 fold over-expression, out of the total number of samples tested is indicated in the bottom.


As is evident from FIG. 19, the expression of Thrombospondin 1 (THBS1) transcripts detectable by SEQ ID NO:421 in cancer samples was significantly higher than in the normal PM samples (Sample Nos. 42, 48-53, 59-63, Table 2). Notably an over-expression of at least 3 fold was found in 10 out of 19 adenocarcinoma samples. Over expression of at least 3 fold was observed also in 7 out of the 8 BPH samples, and in the 2 matched normal samples. Since matched samples are histologically non-cancerous tissue that surrounds the tumor, such samples could have been contaminated with cancer or pre-cancer cells.


Statistical analysis was applied to verify the significance of these results, as described below.


The P value for the difference in the expression levels of Thrombospondin 1 (THBS1) transcripts detectable by SEQ ID NO:421 in prostate cancer samples versus the normal prostate samples was determined by T test as 9.92E-03.


Threshold of 3 fold overexpression was found to differentiate between cancer and normal samples with P value of 2.08E-03 as checked by exact fisher test.


The above value demonstrates statistical significance of the results.


According to the present invention, HUMTHROM is a non-limiting example of a marker for diagnosing prostate cancer. The HUMTHROM marker of the present invention, can be used alone or in combination, for prognosis, prediction, screening, early diagnosis, therapy selection and treatment monitoring of prostate cancer. Although optionally any method may be used to detect overexpression and/or differential expression of this marker, preferably a NAT-based technology is used. Therefore, optionally and preferably, any nucleic acid molecule capable of selectively hybridizing to HUMTHROM as previously defined is also encompassed within the present invention. Primer pairs are also optionally and preferably encompassed within the present invention; for example, for the above experiment, the following primer pair was used as a non-limiting illustrative example only of a suitable primer pair: HUMTHROM-seg24—forward (SEQ ID NO:419): CTGCAGGCTCAGCAACTTCTT; and HUMTHROM-seg24—reverse (SEQ ID NO:420): TTTCAAATCCCTCCCTTGTCA.


The present invention also preferably encompasses any amplicon obtained through the use of any suitable primer pair; for example, for the above experiment, the following amplicon was obtained as a non-limiting illustrative example only of a suitable amplicon_: Amplicon from seg 24: (SEQ ID NO:421)










CTGCAGGCTCAGCAACTTCTTTTAATGAAAAACAAACTCACCCTCTTCCC






CAGCATTCTTTCCATGTGTCAGAGAAGCAGAGGTTTCTTGAACGGGCTTA





GGAGAGTCTATGACAAGGGAGGGATTTGAAA.






According to other preferred embodiments of the present invention, HUMTHROM or a fragment thereof comprises a biomarker for detecting prostate cancer. Optionally and more preferably, the fragment of HUMTHROM comprises HUMTHROM-seg24 (SEQ ID NO:425). Also optionally and more preferably, any suitable method may be used for detecting a fragment such as HUMTHROM-seg24 for example. Most preferably, NAT-based technology used, such as any nucleic acid molecule capable of specifically hybridizing with the fragment. Optionally and most preferably, a primer pair is used for obtaining the fragment.


Optionally the HUMTHROM transcript could (additionally or alternatively) comprise any one or more of the following sequences: SEQ ID NOs: 435-440; 443-445; 447-450.


According to still other preferred embodiments, the present invention optionally and preferably encompasses any amino acid sequence or fragment thereof encoded by a nucleic acid sequence corresponding to HUMTHROM as described above or below. Any oligopeptide or peptide relating to such an amino acid sequence or fragment thereof may optionally also (additionally or alternatively) be used as a biomarker. The present invention also optionally encompasses antibodies capable of recognizing, and/or being elicited by, such an oligopeptide or peptide.


Also, optionally and preferably HUMTHROM could be detected by detection of an amino acid sequence according to any of SEQ ID NOs 452-463, for which the unique regions relating to the splice variants are given separately and additionally in SEQ ID NOs 464-472. The present invention also encompasses these amino acid sequences as a biomarker for detecting prostate cancer.


The present invention also optionally and preferably encompasses any nucleic acid sequence or fragment thereof, or amino acid sequence or fragment thereof, corresponding to HUMTHROM as described above or below, optionally for any application.


Expression of Thrombospondin 1 (THBS1) Transcripts Which are Detectable by SEQ ID NO:418 in Normal, Benign and Cancerous Prostate Tissues


Expression of Thrombospondin 1 (THBS1) transcripts detectable by SEQ ID NO:418, segment 19 (e.g., variant no. 18; SEQ ID NO: 446) was measured by real time PCR, according to the exemplary, illustrative marker HUMTHROM-segment 19 (SEQ ID NO: 423). In parallel the expression of four housekeeping genes—PBGD (GenBank Accession No. BC019323 (SEQ ID NO:509); amplicon_—SEQ ID NO:404), HPRT1 (GenBank Accession No. NM000194 (SEQ ID NO:510); amplicon—SEQ ID NO:401), RPL19 (GenBank Accession No. NM000981 (SEQ ID NO:511); amplicon—SEQ ID NO:410) and SDHA (GenBank Accession No. NM004168 (SEQ ID NO:508); amplicon—SEQ ID NO:407), was measured similarly. For each RT sample, the expression of SEQ ID NO:418 was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal post-mortem (PM) samples (Sample Nos. 42, 48-53, 59-63, Table 2, above), to obtain a value of fold up-regulation for each sample relative to median of the normal PM samples.



FIG. 20 is a histogram showing over expression of the above-indicated Thrombospondin 1 (THBS1) transcripts in cancerous and benign (BPH) prostate samples relative to the normal samples. The number and percentage of cancer samples that exhibit at least 3 fold over-expression, out of the total number of samples tested is indicated in the bottom.


As is evident from FIG. 20, the expression of Thrombospondin 1 (THBS1) transcripts detectable by SEQ ID NO: 418 in cancer samples was significantly higher than in the normal PM samples (Sample Nos. 42, 48-53, 59-63, Table 2). Notably an over-expression of at least 3 fold was found in 17 out of 19 adenocarcinoma samples. Over expression of at least 3 fold was observed also in 6 out of the 8 BPH samples, and in the 2 matched normal samples. Since matched samples are histologically non-cancerous tissue that surrounds the tumor, such samples could have been contaminated with cancer or pre-cancer cells. These samples were purchased commercially with the matching non-cancerous tissue samples, as described above.


Statistical analysis was applied to verify the significance of these results, as described below.


The P value for the difference in the expression levels of Thrombospondin 1 (THBS1) transcripts detectable by SEQ ID NO: 418 in prostate cancer samples versus the normal prostate samples was determined by T test as 1.17E-04.


Threshold of 3 fold overexpression was found to differentiate between cancer and normal samples with P value of 1.00E-05 as checked by exact fisher test.


The P value for the difference between the expression levels of Thrombospondin 1 (THBS1) transcripts detectable by SEQ ID NO: 418 in the prostate cancer samples versus the BPH and normal prostate samples was determined by T test as 7.36E-O2. Threshold of 3 fold overexpression was found to differentiate between cancer sample and BPH and normal sample with P value of 5.42E-04 as checked by exact fisher test.


All the above values demonstrate statistical significance of the results.


According to the present invention, HUMTHROM is a non-limiting example of a marker for diagnosing prostate cancer. Although optionally any method may be used to detect overexpression and/or differential expression of this marker, preferably a NAT-based technology is used. Therefore, optionally and preferably, any nucleic acid molecule capable of selectively hybridizing to HUMTHROM as previously defined is also encompassed within the present invention. Primer pairs are also optionally and preferably encompassed within the present invention; for example, for the above experiment, the following primer pair was used as a non-limiting illustrative example only of a suitable primer pair:HUMTHROM-seg19—forward (SEQ ID NO:416): AAAGCATCCGATTACCCCACT and HUMTHROM-seg 19—reverse (SEQ ID NO:417): CCGGCACAAAGTTGCAGTTA.


The present invention also preferably encompasses any amplicon obtained through the use of any suitable primer pair; for example, for the above experiment, the following amplicon was obtained as a non-limiting illustrative example only of a suitable amplicon_: Amplicon from seg 19:










AAAGGGCGAGGAGATGAATGTACGGTCTAGTTTTAGAAACGTGATTAGAA






AATCCATGGTAAATCCTGCAGGGGAAAAACAGTCTTCCATATTTAAAAAT





GCTGCTCTGGAATAAGTTGTGAGCAGATGGACTTGTAAACGCCTAGGTGC





TGAGCA.






According to other preferred embodiments of the present invention, HUMTHROM or a fragment thereof comprises a biomarker for detecting prostate cancer. Optionally and more preferably, the fragment of HUMTHROM comprises HUMTHROM-seg19 (SEQ ID NO: 423). Also optionally and more preferably, any suitable method may be used for detecting a fragment such as HUMTHROM-seg19 for example. Most preferably, NAT-based technology used, such as any nucleic acid molecule capable of specifically hybridizing with the fragment. Optionally and most preferably, a primer pair is used for obtaining the fragment.


Comparison of Expression of 3 Sequences (SEQ ID NO: 413, 418 and 421) in Normal, Benign and Cancerous Prostate Tissues


Expression of transcripts detectable by SEQ ID NO: 413, 418 and 421 was measured by real time PCR (the expression of each SEQ ID was checked separately). These transcripts correspond to markers described with Examples above. In parallel the expression of four housekeeping genes—PBGD (GenBank Accession No. BC019323 (SEQ ID NO:509); amplicon—SEQ ID NO:404), HPRT1 (GenBank Accession No. NM000194 (SEQ ID NO:510); amplicon—SEQ ID NO:401), RPL19 (GenBank Accession No. NM000981 (SEQ ID NO:511); amplicon_—SEQ ID NO:410) and SDHA (GenBank Accession No. NM004168 (SEQ ID NO:508); amplicon—SEQ ID NO:407), was measured similarly. For each RT sample, the expression was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal post-mortem (PM) samples (Sample Nos. 42, 48-53, 59-63, Table 2, above), to obtain a value of fold up-regulation for each sample relative to median of the normal PM samples.



FIG. 21 is a histogram showing over expression of the above-indicated transcripts in cancerous and benign (BPH) prostate samples relative to the normal samples. The number and percentage of cancer samples that exhibit at least 3 fold over-expression of at least one marker according to the present invention, out of the total number of samples tested, is indicated in the bottom.


As is evident from FIG. 21, over-expression of at least 3 fold of at least one of the SEQ ID NO: 413, 418 and 421 was found in 18 out of 19 adenocarcinoma samples taken from prostate tissue (almost all prostate cancers are adenocarcinomas). Overexpression of at least 3 fold of at least one marker according to the present invention was observed in 7 out of the 8 BPH samples, and in the 2 matched normal samples. Since matched samples are histologically non-cancerous tissue that surrounds the tumor, such samples could have been contaminated with cancer or pre-cancer cells. However, at least certain markers were shown to be capable of differentiating between BPH and prostate cancer, such as AA315457 for example.


Statistical analysis was applied to verify the significance of these results, as described below. Threshold of 3 fold overexpression of at least one of the amplicons as depicted in SEQ ID NO: 413, 418 and 421 was found to differentiate between cancer and normal samples with P value of 1.62E-06 as checked by exact fisher test.


Expression of DD3/PCA3 Transcript Which are Detectable by SEQ ID NO:475 in Normal, Benign and Cancerous Prostate Tissues


Expression of DD3/PCA3 transcripts detectable by the amplicon of SEQ ID NO:475 (e.g., variant no. 0; SEQ ID NO: 476; SEQ ID NO:483 is the forward primer, SEQ ID NO:474 is the reverse primer), related to cluster AA578773, segments 1 and 6, was measured by real time PCR. In parallel the expression of four housekeeping genes—PBGD (GenBank Accession No. BC019323 (SEQ ID NO:509); amplicon—SEQ ID NO:404), HPRT1 (GenBank Accession No. NM000194 (SEQ ID NO:510); amplicon—SEQ ID NO:401), RPL19 (GenBank Accession No. NM000981 (SEQ ID NO:511); amplicon—SEQ ID NO:410) and SDHA (GenBank Accession No. NM004168 (SEQ ID NO:508); amplicon—SEQ ID NO:407), was measured similarly. For each RT sample, the expression was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal post-mortem (PM) samples (Sample Nos. 42, 48-53, 59-63, Table 2, above), to obtain a value of fold up-regulation for each sample relative to median of the normal PM samples.



FIG. 22 is a histogram showing over expression of the above-indicated DD3/PCA3 transcripts in cancerous and benign (BPH) prostate samples relative to the normal samples. The number and percentage of cancer samples that exhibit at least 3 fold over-expression, out of the total number of samples tested is indicated in the bottom.


As is evident from FIG. 22, an over-expression of at least 3 fold was found in 12 out of 19 adenocarcinoma (prostate cancer) samples. Over expression of at least 3 fold was observed also in 4 out of the 12 normal PM samples.


Thus, clearly DD3 may optionally be used as a biomarker in combination with any previously described biomarker according to the present invention. The DD3 marker of the present invention, can be used alone or in combination, for prognosis, prediction, screening, early diagnosis, therapy selection and treatment monitoring of prostate cancer.


Expression of Thrombospondin 1 (THBS1) Transcripts Which are Detectable by SEQ IDs NOs:477-482 in Normal, Benign and Cancerous Prostate Tissues


Expression of Thrombospondin 1 (THBS1) transcripts detectable by SEQ ID NOs: 477-482 (e.g., variants nos. 4, 6, 8, 11, 14, 15, 26, 27, 28, 30 (SEQ ID No.: 435, 437, 439, 442, 444, 445, 448, 449, 450, 451) was measured with oligonucleotide-based micro-arrays. The results of image intensities for each feature were normalized according to the ninetieth percentile of the image intensities of all the features on the chip. Then, feature image intensities for replicates of the same oligonucleotide on the chip and replicates of the same sample were averaged. Outlying results were discarded.


For every oligonucleotide (SEQ ID NOs: 477-482) the averaged intensity determined for every sample was divided by the averaged intensity of all the normal samples (Sample Nos. 48-52, Table 2, above), to obtain a value of fold up-regulation for each sample relative to the averaged normal samples. These data are presented in a histogram in FIG. 23. As is evident from FIG. 23, the expression of Thrombospondin 1 (THBS1) transcripts detectable with oligonucleotides according to SEQ ID NOs: 477-482 in cancer samples was significantly higher than in the normal samples.


According to the present invention, Thrombospondin 1 (THBS1) transcripts detectable by oligonucleotides as depicted in SEQ ID NOs: 477-482 are non-limiting examples of markers for diagnosing lung cancer. The Thrombospondin 1 (THBS1) markers of the present invention can be used alone or in combination, for a number of uses, including but not limited to, prognosis, prediction, screening, early diagnosis, therapy selection and treatment monitoring of prostate cancer. Although optionally any method may be used to detect overexpression and/or differential expression of this marker, preferably a NAT-based technology is used. Therefore, optionally and preferably, any nucleic acid molecule capable of selectively hybridizing to Thrombospondin 1 (THBS1) transcripts as previously defined is also encompassed within the present invention. Oligonucleotides are also optionally and preferably encompassed within the present invention; for example, for the above experiment, the following oligonucleotides were used as a non-limiting illustrative example only of a suitable oligonucleotides: SEQ ID NOs: 477-482


According to other preferred embodiments of the present invention, Thrombospondin 1 (THBS1) transcripts detectable by SEQ ID NOs: 477-482, or a fragment thereof comprises biomarkers for detecting prostate cancer. Optionally and more preferably, Thrombospondin I (THBS1) splice variants, as depicted in SEQ ID NO: 435, 437, 439, 442, 444, 445, 448, 449, 450, 451 (e.g., variant no. 4, 6, 8, 11, 14, 15, 26, 27, 28, 30), or a fragment thereof comprise a biomarker for detecting prostate cancer. Optionally and more preferably, any suitable method may be used for detecting a fragment such as Thrombospondin 1 (THBS1) transcripts as depicted in SEQ ID NOs: 435, 437, 439, 442, 444, 445, 448, 449, 450, 451 or fragments thereof. Most preferably, NAT-based technology used, such as any nucleic acid molecule capable of specifically hybridizing with the fragment. Optionally and most preferably, a primer pair is used for obtaining the fragment.


According to other preferred embodiments of the present invention, Thrombospondin 1 (THBS1) splice variants containing the unique segments as depicted in SEQ ID NOs: 422, 424-427, 431-433 (unique segments), for example as these included in variants 4, 6, 8, 11, 14, 15, 26, 27, 28, 30 (SEQ ID NOs: 435, 437, 439, 442, 444, 445, 448, 449, 450, 451, respectively), are useful as biomarkers for detecting prostate cancer.


Proteins containing unique amino acid sequences are 2, 3, 4, 5, 7, 10, 16, 17, and 18. The SEQ ID Nos for those proteins are: 452-456, 458, 461-463. The amino acid unique sequences are SEQ ID NO.s: 464-472 for variants P2, P3, P4, P5, P7, P10, P16, P17 and P18 (all from the cluster HUMTHROM as described in this example). The present invention also encompasses these amino acid sequences as a biomarker for detecting prostate cancer.


The present invention also optionally and preferably encompasses any nucleic acid sequence or fragment thereof, or amino acid sequence or fragment thereof, corresponding to Thrombospondin 1 (THBS1) variants as described above, optionally for any application.


A table is provided below with additional information concerning sequences according to the present invention.
















Variant
SEQ ID NO









HUMTHROM # TAA seg_6 (ver 3.4) #len
422



822 (node 6-ver 3.6)



HUMTHROM # TAA seg_21 (ver 3.4)
424



#len 380 (node_16 ver 3.6)



HUMTHROM # TAA seg_26 (ver 3.4)
426



#len 259 (node_20 ver 3.6)



HUMTHROM # TAA seg_30 (ver 3.4)
427



#len 450 (node_24 ver 3.6)



HUMTHROM # TAA seg_33 (ver 3.4)
428



#len 310 (node_53-ver 3.6)



HUMTHROM # TAA seg_35 (ver 3.4)
429



#len 567 (node_28 ver 3.6)



HUMTHROM # TAA seg_37 (ver 3.4)
430



#len 154 (node_30 ver 3.6)



HUMTHROM # TAA seg_39 (ver 3.4)
431



#len 825 (node_32 ver 3.6)



HUMTHROM # TAA seg_50 (ver 3.4)
432



#len 169 (node_38 ver 3.6)



HUMTHROM # TAA seg_52 + 53 (ver 3.4)
433



#len 430 (node_40 ver 3.6)



HUMTHROM # TAA seg_55 (ver 3.4)
434



#len 104 (node_42 ver 3.6)



HUMTHROM # transcript_5 #len 6508
436



(contains node 35-ver 3.4/node 28-ver 3.6)



HUMTHROM # transcript_7 #len 6095
438



(contains node 37-ver 3.4/node 30-ver 3.6)



HUMTHROM # transcript_9 #len 6662
440



(contains node 35-ver 3.4/node 28-ver 3.6;



node 37-ver 3.4/node 30-ver 3.6)



HUMTHROM # transcript_12 #len 6110
443



(contains node 50-ver 3.4/node 38-ver 3.6)



HUMTHROM # transcript_20 #len 4335
447



(contains node 33-ver 3.4/node 53-ver 3.6;



node 35-ver 3.4/node 28-ver 3.6)



>HUMTHROM_P8 # trn_12; trn_15 #len
457



1000



>HUMTHROM_P12 # trn_18 #len 702
459



>HUMTHROM_P13 # trn_20 #len 345
460










Kits and Diagnostic Assays and Methods

The markers described with regard to any of Examples 1-6 above can be used alone, in combination with other markers described above, and/or with other entirely different markers (including but not limited to DD3, PSA or prostate specific membrane antigen) to aid in the diagnosis of prostate cancer, benign prostate hyperplasia or a negative diagnosis. These markers can be used in combination with other markers for a number of uses, including but not limited to, prognosis, prediction, screening, early diagnosis, therapy selection and treatment monitoring of prostate cancer, and also optionally including staging of the disease. Used together, they tend to provide more information for the diagnostician, increasing the percentage of true positive and true negative diagnoses and decreasing the percentage of false positive or false negative diagnoses, than a single marker alone.


Assays and methods according to the present invention, as described above, include but are not limited to, immunoassays, hybridization assays and NAT-based assays. The combination of the markers of the present invention with other markers described above, and/or with other entirely different markers to aid in the diagnosis of prostate cancer could be carried out as a mix of NAT-based assays, immunoassays and hybridization assays. According to preferred embodiments of the present invention, the assays are NAT-based assays, as described for example with regard to the Examples above.


In yet another aspect, the present invention provides kits for aiding a diagnosis of prostate cancer, wherein the kits can be used to detect the markers of the present invention. For example, the kits can be used to detect any one or combination of markers described above, which markers are differentially present in samples of a prostate cancer patient, BPH and normal patients. The kits of the invention have many applications. For example, the kits can be used to differentiate if a subject has prostate cancer, BPH or has a negative diagnosis, thus aiding a prostate cancer diagnosis. In another example, the kits can be used to identify compounds that modulate expression of the markers in in vitro prostate cells or in vivo animal models for prostate cancer.


In one embodiment, a kit comprises: (a) a substrate comprising an adsorbent thereon, wherein the adsorbent is suitable for binding a marker, and (b) a washing solution or instructions for making a washing solution, wherein the combination of the adsorbent and the washing solution allows detection of the marker as previously described.


Optionally, the kit can further comprise instructions for suitable operational parameters in the form of a label or a separate insert. For example, the kit may have standard instructions informing a consumer/kit user how to wash the probe after a sample of seminal plasma or other tissue sample is contacted on the probe.


In another embodiment, a kit comprises (a) an antibody that specifically binds to a marker; and (b) a detection reagent. Such kits can be prepared from the materials described above.


In either embodiment, the kit may optionally further comprise a standard or control information, and/or a control amount of material, so that the test sample can be compared with the control information standard and/or control amount to determine if the test amount of a marker detected in a sample is a diagnostic amount consistent with a diagnosis of prostate cancer.


It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.


Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

Claims
  • 1. An isolated polynucleotide consisting of the sequence of R11723_PEA—1_T5 (SEQ ID NO:9).
  • 2. The isolated polynucleotide of claim 1, comprising a node consisting of the sequence of: R11723_PEA—1_node—13 (SEQ ID NO:90).
  • 3. An amplicon consisting of the sequence of SEQ ID NO:492.
  • 4. A primer pair, comprising pair of isolated oligonucleotides to amplify said ampicon of claim 3, said pair of isolated oligonucleotides consisting of the sequences of SEQ ID NOs. 490 and 491.
CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is related to Novel Nucleotide and Amino Acid Sequences, and Assays and Methods of use thereof for Diagnosis of Prostate Cancer, and claims priority to the below U.S. provisional applications which are incorporated by reference herein: Application No. 60/620,916 filed Oct. 22, 2004—Differential Expression of Markers in Colon Cancer; Application No. 60/628,123 filed Nov. 17, 2004—Differential Expression of Markers in Colon Cancer II; Application No. 60/621,131 filed Oct. 25, 2004—Diagnostic Markers for Colon Cancer, and Assays and Methods of use thereof; Application No. 60/628,101 filed Nov. 17, 2004—Differential Expression of Markers in Breast Cancer II; Application No. 60/620,874 filed Oct. 22, 2004—Differential Expression of Markers in Ovarian Cancer; Application No. 60/628,134 filed Nov. 17, 2004—Differential Expression of Markers in Ovarian Cancer II; Application No. 60/620,853 filed Oct. 22, 2004—Differential Expression of Markers in Lung Cancer; Application No. 60/628,112 filed Nov. 17, 2004—Differential Expression of Markers in Lung Cancer II; Application No. 60/628,145 filed Nov. 17, 2004—Differential Expression of Markers in Pancreatic Cancer II; Application No. 60/620,656 filed Oct. 22, 2004—Differential Expression of Markers in Prostate Cancer; Application No. 60/628,251 filed Nov. 17, 2004—Differential Expression of Markers in Prostate Cancer II; Application No. 60/628,178 filed Nov. 17, 2004—Differential Expression of Markers in Brain Cancer II; Application No. 60/628,231 filed Nov. 17, 2004—Novel Diagnostic Serum Markers, and Assays and Methods of use thereof; Application No. 60/620,918 filed Oct. 22, 2004—Diagnostic Markers for Renal Cancer, and Assays and Methods of Use thereof. Application No. 60/628,156 filed Nov. 17, 2004—Diagnostic Markers for Renal Cancer, and Assays and Methods of Use thereof II; Application No. 60/620,677 filed Oct. 22, 2004—Differential Expression of Markers in Bladder Cancer I; Application No. 60/628,167 filed Nov. 17, 2004—Differential Expression of Markers in Bladder Cancer II; Application Ser. No. 60/628,179 filed Nov. 17, 2004—Novel Diagnostic Markers, and Assays and Methods of Use thereof. Application No. 60/539,129 filed Jan. 27, 2004—Methods and Systems for Annotating Biomolecular Sequences Application No. 60/539,128 filed Jan. 27, 2004—Evolutionary Conserved Spliced Sequences and Methods and Systems for Identifying thereof.

US Referenced Citations (1)
Number Name Date Kind
20040181048 Wang Sep 2004 A1
Related Publications (1)
Number Date Country
20060051774 A1 Mar 2006 US
Provisional Applications (20)
Number Date Country
60628251 Nov 2004 US
60628231 Nov 2004 US
60628179 Nov 2004 US
60628178 Nov 2004 US
60628167 Nov 2004 US
60628156 Nov 2004 US
60628145 Nov 2004 US
60628134 Nov 2004 US
60628123 Nov 2004 US
60628112 Nov 2004 US
60628101 Nov 2004 US
60621131 Oct 2004 US
60620918 Oct 2004 US
60620916 Oct 2004 US
60620874 Oct 2004 US
60620853 Oct 2004 US
60620677 Oct 2004 US
60620656 Oct 2004 US
60539129 Jan 2004 US
60539128 Jan 2004 US