Enzymatic nucleic acid treatment of diseases or conditions related to levels of NF-kappa B

SEQUENCE LISTING

[0003] The Sequence Listing file named “MBHB00-812D.SeqListing” submitted in duplicate on Compact Disc-Recordable (CD-R) medium (CD entitled “010518—1002”) in compliance with 37 C.F.R. §1.52(e) is incorporated herein by reference. The sequence listing file is 1,021,000 bytes in size.

FIELD OF THE INVENTION

[0004] The present invention relates to therapeutic compositions and methods for the treatment or diagnosis of diseases or conditions related to NF-kappa B (NFKB) levels, such as cancer, inflammatory, and autoimmune diseases and/or disorders.

BACKGROUND OF THE INVENTION

[0005] The following is a brief description of the physiological role of NFKB. The discussion is provided only for understanding the invention that follows. This summary is not an admission that any of the work described below is prior art to the claimed invention.

[0006] Nuclear factor kappa B (NFKB) is a multiunit transcription factor which regulates the expression of genes involved in a number of physiologic and pathologic processes. NFKB is a key component of the TNF signaling pathway. These processes include, but are not limited to: apoptosis, immune, inflammatory and acute phase responses. The REL-A gene product (a.k.a. RelA or p65), and p50 subunits of NFKB, have been implicated in the induction of inflammatory responses and cellular transformation. NFKB exists in the cytoplasm as an inactive heterodimer of the p50 and p65 subunits. NFKB is complexed with its inhibitory protein, IkappaB, until activated by the appropriate stimuli. NFKB activation can occur following stimulation of a variety of cell types by inflammatory mediators, for example TNF and IL-1, and reactive oxygen intermediates. In response to induction, NFKB can stimulate production of pro-inflammatory cytokines such as TNF-alpha, IL-1-beta, IL-6 and iNOS, thereby perpetuating a positive feedback loop. NFKB appears to play a role in a number of disease processes including: ischemia/reperfusion injury (CNS and myocardial), glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, arthritis, and cancer.

[0007] The nuclear DNA-binding protein, NFKB, was first identified as a factor that binds and activates the immunoglobulin kappa light chain enhancer in B cells. NFKB now is known to activate transcription of a variety of other cellular genes (e.g., cytokines, adhesion proteins, oncogenes and viral proteins) in response to a variety of stimuli (e.g., phorbol esters, mitogens, cytokines and oxidative stress). In addition, molecular and biochemical characterization of NFKB has shown that the activity is due to a homodimer or heterodimer of a family of DNA binding subunits. Each subunit bears a stretch of 300 amino acids that is homologous to the oncogene, v-rel. The activity first described as NFKB is a heterodimer of p49 or p50 with p65. The p49 and p50 subunits of NFKB (encoded by the NF-kappa B2 or NF kappa B1 genes, respectively) are generated from the precursors NFKB1 (p105) or NFKB2 (p100). The p65 subunit of NFKB (now termed REL-A) is encoded by the rel-A locus.

[0008] The roles of each specific transcription-activating complex now are being elucidated in cells (Perkins, et al., 1992, Proc. Natl. Acad. Sci USA, 89, 1529-1533). For instance, the heterodimer of NFKB1 and Rel A (p50/p65) activates transcription of the promoter for the adhesion molecule, VCAM-1, while NFKB2/RelA heterodimers (p49/p65) actually inhibit transcription (Shu, et al., 1993, Mol. Cell. Biol., 13, 6283-6289). Conversely, heterodimers of NFKB2/RelA (p49/p65) act with Tat-I to activate transcription of the HIV genome, while NFKB1/RelA (p50/p65) heterodimers have little effect (Liu et al., 1992, J. Virol., 66, 3883-3887). Similarly, blocking rel A gene expression with antisense oligonucleotides specifically blocks embryonic stem cell adhesion; blocking NFKB 1 gene expression with antisense oligonucleotides had no effect on cellular adhesion (Narayanan et al., 1993, Mol. Cell. Biol., 13, 3802-3810). Thus, the promiscuous role initially assigned to NFKB in transcriptional activation (Lenardo, and Baltimore, 1989, Cell, 58, 227-229) represents the sum of the activities of the rel family of DNA-binding proteins. This conclusion is supported by recent transgenic “knock-out” mice of individual members of the rel family. Such “knock-outs” show few developmental defects, suggesting that essential transcriptional activation functions can be performed by more than one member of the rel family.

[0009] A number of specific inhibitors of NFKB function in cells exist, including treatment with phosphorothioate antisense oliogonucleotide, treatment with double-stranded NFKB binding sites, and over expression of the natural inhibitor MAD-3 (an Ikappa-B family member). These agents have been used to show that NFKB is required for induction of a number of molecules involved in cancer and/or inflammation, as described below.

[0010] NFKB is required for phorbol ester-mediated induction of IL-6 (Kitajima, et al., 1992, Science, 258, 1792-5) and IL-8 (Kunsch and Rosen, 1993, Mol. Cell. Biol., 13, 6137-46).

[0011] NFKB is required for induction of the adhesion molecules ICAM-1 (Eck, et al., 1993, Mol. Cell. Biol., 13, 6530-6536), VCAM-1 (Shu et al., supra), and E-selectin (Read, et al., 1994, J. Exp. Med., 179, 503-512) on endothelial cells.

[0012] NFKB is involved in the induction of the integrin subunit, CD18, and other adhesive properties of leukocytes (Eck et al., 1993 supra).

[0013] HER2/Neu overexpression induces NFKB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IKB-alpha. Breast cancer has been shown to typify the aberrant expression of NFKB/REL factors (Pianetti et al., 2001, Oncogene, 20, 1287-1299; Sovak et al., 1999, J. Clin. Invest., 100, 2952-2960).

[0014] Inhibition of NFKB activity has been shown to induce apoptosis in murine hepatocytes (Bellas et al., 1997, Am. J. Pathol., 151, 891-896).

[0015] NFKB has been shown to regulate cyclooxygenase-2 expression and cell proliferation in human gastric cancer cells (Joo Weon et al., 2001, Laboratory Investigation, 81, 349-360).

[0016] The above studies suggest that NFKB is integrally involved in the induction of cytokines and adhesion molecules by inflammatory mediators and is involved in the transformation of cancerous cells. Two reported studies point to another connection between NFKB and inflammation: glucocorticoids may exert their anti-inflammatory effects by inhibiting NFKB. The glucocorticoid receptor and p65 both act at NFKB binding sites in the ICAM-1 promoter (van de Stolpe, et al., 1994, J. Biol. Chem., 269, 6185-6192). Glucocorticoid receptor inhibits NFKB-mediated induction of IL-6 (Ray and Prefontaine, 1994 Proc. Natl. Acad. Sci USA, 91, 752-756). Conversely, overexpression of p65 inhibits glucocorticoid induction of the mouse mammary tumor virus promoter. Finally, protein cross-linking and co-immunoprecipitation experiments demonstrated direct physical interaction between p65 and the glucocorticoid receptor.

[0017] Stinchcomb et al., U.S. Pat. No. 5,658,780, describes ribozymes targeting NFKB. Stinchcomb et al., International PCT Publication No. WO 95/23225 describe ribozymes targeting NFKB. Sullivan et al., International PCT Publication No. WO 94/02595 describe ribozymes targeting NFKB. Handel et al., International PCT Publication No. WO 01/11023, describe a specific DNAzyme motif targeting certain sites within the Rel-A subunit of NFKB.

SUMMARY OF THE INVENTION

[0018] The present invention features an enzymatic nucleic acid molecule which modulates expression of a sequence encoding a subunit of NFKB, for example REL-A, REL-B, REL, NFkappaB 1, or NFkappaB2, wherein the enzymatic nucleic acid molecule is for example in a an hammerhead, Inozyme, Zinzyme, G-cleaver, or Amberzyme configuration.

[0019] The present invention also features an enzymatic nucleic acid molecule which modulates expression of a sequence encoding a subunit of NFKB, for example REL-A, REL-B, REL, NFkappaB 1, or NFkappaB2, wherein the enzymatic nucleic acid molecule is a DNAzyme.

[0020] In one embodiment, the present invention features an enzymatic nucleic acid molecule comprising a sequence selected from the group consisting of SEQ ID NOs. 711-1420, 1717-2012, 2151-2656, 2994-3626, and 3770-3917.

[0021] In another embodiment, the present invention features an enzymatic nucleic acid molecule comprising at least one binding arm wherein one or more of said binding arms comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1-710, 1421-1716, 2013-2150, 2657-2993, and 3627-3769.

[0022] The present invention also features an antisense nucleic acid molecule comprising a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1-710, 1421-1716, 2013-2150, 2657-2993, and 3627-3769.

[0023] In one embodiment, the nucleic acid molecule of the invention, for example an enzymatic nucleic acid molecule or antisense nucleic acid molecule is adapted to treat cancer.

[0024] In another embodiment, the enzymatic nucleic acid molecule of the invention has an endonuclease activity to cleave RNA having REL-A sequence.

[0025] In a further embodiment, the enzymatic nucleic acid molecule of the invention is in a Hammerhead, Hairpin, Inozyme, Zinzyme, G-cleaver, Amberzyme, DNAzyme, or Allozyme configuration.

[0026] In one embodiment, an Inozyme of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1-710, 3752-3756, and 3660-3720. In another embodiment, an Inozyme of the invention comprises a sequence selected from the group consisting of SEQ ID NOs. 711-1420, 3898-3902, and 3806-3866.

[0027] In one embodiment, a Zinzyme of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1421-1716, 3721-3746, and 3757-3761. In another embodiment, a Zinzyme of the invention comprises a sequence selected from the group consisting of SEQ ID NOs 1717-2012, 3867-3892, and 3903-3907.

[0028] In one embodiment, an Amberzyme of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1421-1716, 2657-2993, and 3765-3769. In another embodiment, an Amberzyme of the invention comprises a sequence selected from the group consisting of SEQ ID NOs 2994-3626, and 3913-3917.

[0029] In a further embodiment, an enzymatic nucleic acid molecule of the invention comprises between 12 and 100 bases complementary to RNA sequence encoding a subunit of NFKB. In another embodiment, the enzymatic nucleic acid molecule of the invention comprises between 14 and 24 bases complementary to RNA sequence encoding a subunit of NFKB, for example REL-A, REL-B, REL, NFkappaB1, or NFkappaB2.

[0030] In one embodiment, the enzymatic nucleic acid molecule of the invention is chemically synthesized. In another embodiment, the antisense nucleic acid molecule of the invention is chemically synthesized.

[0031] In one embodiment, the enzymatic nucleic acid molecule of the invention comprises at least one 2′-sugar modification, at least one base modification, and/or at least one phosphate backbone modification. In another embodiment, the antisense nucleic acid molecule of the invention comprises at least one 2′-sugar modification, at least one base modification, and/or at least one phosphate backbone modification.

[0032] The present invention features a mammalian cell including an enzymatic nucleic acid molecule of the invention. In one embodiment, the mammalian cell of the invention is a human cell.

[0033] The present invention features a method of reducing NFKB activity in a cell, comprising contacting a cell with an enzymatic nucleic acid molecule or antisense nucleic acid molecule of the invention targeted against a subunit of NFKB, for example REL-A, REL-B, REL, NFkappaB 1, or NFkappaB2, under conditions suitable for the reduction of NFKB activity. In one embodiment, the method of the invention comprises the use of one or more drug therapies under conditions suitable for the treatment.

[0034] The present invention also features a method of treatment of a patient having a condition associated with the level of NFKB, comprising contacting cells of the patient with an enzymatic nucleic acid molecule or antisense nucleic acid molecule of the invention targeted against a subunit of NFKB, for example REL-A, REL-B, REL, NFkappaB1, or NFkappaB2, under conditions suitable for the treatment. In another embodiment, the method of the invention comprises the use of one or more drug therapies under conditions suitable for the treatment. Suitable other drug therapies contemplated by the instant invention include, for example, monoclonal antibodies, REL-A-specific inhibitors, or chemotherapy, for example paclitaxel, docetaxel, cisplatin, methotrexate, cyclophosphamide, doxorubin, fluorouracil carboplatin, edatrexate, gemcitabine, or vinorelbine.

[0035] The invention also features a method of cleaving RNA comprising a sequence of a subunit of NFKB, for example REL-A, REL-B, REL, NFkappaB1, or NFkappaB2, comprising contacting an enzymatic nucleic acid molecule of the invention with the RNA under conditions suitable for the cleavage. In one embodiment, the cleavage is carried out in the presence of a divalent cation, for example Mg2+.

[0036] In one embodiment, an enzymatic nucleic acid or antisense nucleic acid molecule of the invention comprises a cap structure, wherein the cap structure is at the 5′-end, or 3′-end, or both the 5′-end and the 3′-end. In another embodiment, the cap structure at the 5′-end, 3′-end, or both the 5′-end and the 3′-end comprises a 3′, 3′-linked or 5′,5′-linked deoxyabasic ribose derivative.

[0037] The present invention features an expression vector comprising a nucleic acid sequence encoding at least one enzymatic nucleic acid molecule of the invention, for example a hammerhead ribozyme, in a manner which allows expression of the nucleic acid molecule. In one embodiment, the invention features a mammalian cell including an expression vector of the invention, for example a human cell.

[0038] In one embodiment, an expression vector of the invention comprises a sequence for an antisense nucleic acid molecule complementary to the RNA having a sequence of a subunit of NFKB. In another embodiment, an expression vector of the invention comprises a nucleic acid sequence encoding two or more of said enzymatic nucleic acid molecules, which may be the same or different. In yet another embodiment, an expression vector of the invention comprises a sequence encoding an antisense nucleic acid molecule complementary to the RNA of a subunit of NFKB, for example REL-A, REL-B, REL, NFkappaB1, or NFkappaB2.

[0039] The present invention features a method for treatment of cancer, for example breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, esophageal cancer, stomach cancer, bladder cancer, pancreatic cancer, cervical cancer, head and neck cancer, ovarian cancer, melanoma, lymphoma, glioma, or multidrug resistant cancer, comprising administering to a patient an enzymatic nucleic acid molecule or antisense nucleic acid molecule of the invention under conditions suitable for the treatment. In one embodiment, a method of treatment contemplated by the instant invention comprises administering to a patient one or more other therapies in combination with the enzymatic nucleic acid or antisense nucleic acid molecule of the invention.

[0040] In one embodiment, a nucleic acid molecule of the invention comprises at least five ribose residues, at least ten 2′-O-methyl modifications, and/or a 3′- end modification, for example a 3′-3′ inverted abasic moiety. In anther embodiment, a nucleic acid molecule of the invention further comprises phosphorothioate linkages on at least three 5′ terminal nucleotides.

[0041] The present invention features a method for treatment of an inflammatory disease, for example rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury, glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, or infection, comprising the step of administering to a patient an enzymatic nucleic acid molecule or antisense nucleic acid molecule of the invention under conditions suitable for the treatment, with or without the use of other therapies.

[0042] The present invention also features a pharmaceutical composition comprising an enzymatic nucleic acid molecule or antisense nucleic acid molecule of the invention in a pharmaceutically acceptable carrier.

[0043] The invention also features a method of administering to a cell, such as mammalian cell (e.g. human cell), where the cell may be in culture or in a mammal, such as a human, an enzymatic nucleic acid molecule or antisense molecule of the instant invention, comprising contacting the cell with the enzymatic nucleic acid molecule or antisense molecule under conditions suitable for such administration.

DETAILED DESCRIPTION OF THE INVENTION

[0044] First the drawings will be described briefly.

DRAWINGS

[0045]
FIG. 1 shows examples of chemically stabilized ribozyme motifs. HH Rz, represents hammerhead ribozyme motif (Usman et al., 1996, Curr. Op. Struct. Bio., 1, 527); NCH Rz represents the NCH ribozyme motif (Ludwig & Sproat, International PCT Publication No. WO 98/58058); G-Cleaver, represents G-cleaver ribozyme motif (Kore et al., 1998, Nucleic Acids Research 26, 4116-4120, Eckstein et al., International PCT publication No. WO 99/16871). N or n, represent independently a nucleotide which can be same or different and have complementarity to each other; rI, represents ribo-Inosine nucleotide; arrow indicates the site of cleavage within the target. Position 4 of the HH Rz and the NCH Rz is shown as having 2′-C-allyl modification, but those skilled in the art will recognize that this position can be modified with other modifications well known in the art, so long as such modifications do not significantly inhibit the activity of the ribozyme.

[0046]
FIG. 2 shows an example of the Amberzyme ribozyme motif that is chemically stabilized (see for example Beigelman et al., International PCT publication No. WO 99/55857).

[0047]
FIG. 3 shows an example of the Zinzyme A ribozyme motif that is chemically stabilized (see for example Beigelman et al., Beigelman et al., International PCT publication No. WO 99/55857).

[0048]
FIG. 4 shows an example of a DNAzyme motif described by Santoro et al., 1997, PNAS, 94, 4262.

[0049] The invention features novel enzymatic nucleic acid molecules and methods to modulate gene expression, for example, genes encoding NF kappa-B (NFKB) and protein subunits of NFKB, such as REL-A, REL-B, REL, NFkappaB1, or NFkappaB2. In particular, the instant invention features nucleic-acid based molecules and methods to modulate the expression of the Rel-A, REL-B, REL, NFkappaB1, or NFkappaB2 subunit of NFKB.

[0050] The invention features one or more enzymatic nucleic acid-based molecules and methods that independently or in combination modulate the expression of gene(s) encoding NFKB. In particular embodiments, the invention features nucleic acid-based molecules and methods that modulate the expression of a subunit of NFKB, for example REL-A, REL-B, REL, NFkappaB 1, or NFkappaB2gene, for example (Genbank Accession No. NM—021975); REL-B gene, for example (Genbank Accession No. NM—006509), REL (c-rel), for example (Genbank Accession No. NM—003998), NFKB1 (p105/p50), for example (Genbank Accession No. NM—003998), and NFKB2 (p100/p52/p49), for example (Genbank Accession No. NM—002502).

[0051] The description below of the various aspects and embodiments is provided with reference to the exemplary NFKB subunit REL-A gene, also known as p65 or P65. However, the various aspects and embodiments are also directed to other genes which encode REL-A proteins and other subunits of NFKB, such as p49, p50, p52, p100, or p105 protein subunits (Perkins et al., 1992, Proc, Natl. Acad. Sci. USA, 89, 1529-1533; Naumann et al., 1994, EMBO J., 13, 4597-4607; Heusch et al., 1999, Oncogene, 18, 6201-6208). Those additional genes can be analyzed for target sites using the methods described for REL-A. Thus, the inhibition and the effects of such inhibition of the other genes can be performed as described herein.

[0052] In one embodiment, the invention features the use of an enzymatic nucleic acid molecule, preferably in the hammerhead, NCH, G-cleaver, amberzyme, zinzyme and/or DNAzyme motif, to down-regulate the expression of REL-A genes.

[0053] By “inhibit” or “down-regulate” it is meant that the expression of the gene, or level of RNAs or equivalent RNAs encoding one or more protein subunits, or activity of one or more protein subunits, such as REL-A subunit(s), is reduced below that observed in the absence of the nucleic acid molecules of the invention. In one embodiment, inhibition or down-regulation with enzymatic nucleic acid molecule preferably is below that level observed in the presence of an enzymatically inactive or attenuated molecule that is able to bind to the same site on the target RNA, but is unable to cleave that RNA. In another embodiment, inhibition or down-regulation with antisense oligonucleotides is preferably below that level observed in the presence of, for example, an oligonucleotide with scrambled sequence or with mismatches. In another embodiment, inhibition or down-regulation of REL-A with the nucleic acid molecule of the instant invention is greater in the presence of the nucleic acid molecule than in its absence.

[0054] By “up-regulate” is meant that the expression of the gene, or level of RNAs or equivalent RNAs encoding one or more protein subunits, or activity of one or more protein subunits, such as REL-A subunit(s), is greater than that observed in the absence of the nucleic acid molecules of the invention. For example, the expression of a gene, such as REL-A gene, can be increased in order to treat, prevent, ameliorate, or modulate a pathological condition caused or exacerbated by an absence or low level of gene expression.

[0055] By “modulate” is meant that the expression of the gene, or level of RNAs or equivalent RNAs encoding one or more protein subunits, or activity of one or more protein subunit(s) is up-regulated or down-regulated, such that the expression, level, or activity is greater than or less than that observed in the absence of the nucleic acid molecules of the invention.

[0056] By “enzymatic nucleic acid molecule” it is meant a nucleic acid molecule which has complementarity in a substrate binding region to a specified gene target, and also has an enzymatic activity which is active to specifically cleave target RNA. That is, the enzymatic nucleic acid molecule is able to intermolecularly cleave RNA and thereby inactivate a target RNA molecule. These complementary regions allow sufficient hybridization of the enzymatic nucleic acid molecule to the target RNA and thus permit cleavage. One hundred percent complementarity is preferred, but complementarity as low as 50-75% can also be useful in this invention (see for example Werner and Uhlenbeck, 1995, Nucleic Acids Research, 23, 2092-2096; Hammann et al., 1999, Antisense and Nucleic Acid Drug Dev., 9, 25-31). The nucleic acids can be modified at the base, sugar, and/or phosphate groups. The term enzymatic nucleic acid is used interchangeably with phrases such as ribozymes, catalytic RNA, enzymatic RNA, catalytic DNA, aptazyme or aptamer-binding ribozyme, regulatable ribozyme, catalytic oligonucleotides, nucleozyme, DNAzyme, RNA enzyme, endoribonuclease, endonuclease, minizyme, leadzyme, oligozyme or DNA enzyme. All of these terminologies describe nucleic acid molecules with enzymatic activity. The specific enzymatic nucleic acid molecules described in the instant application are not limiting in the invention and those skilled in the art will recognize that all that is important in an enzymatic nucleic acid molecule of this invention is that it has a specific substrate binding site which is complementary to one or more of the target nucleic acid regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart a nucleic acid cleaving and/or ligation activity to the molecule (Cech et al., U.S. Pat. No. 4,987,071; Cech et al., 1988, 260 JAMA 3030).

[0057] By “nucleic acid molecule” as used herein is meant a molecule having nucleotides. The nucleic acid can be single, double, or multiple stranded and can comprise modified or unmodified nucleotides or non-nucleotides or various mixtures and combinations thereof.

[0058] By “enzymatic portion” or “catalytic domain” is meant that portion/region of the enzymatic nucleic acid molecule essential for cleavage of a nucleic acid substrate (for example see FIGS. 1-4).

[0059] By “substrate binding arm” or “substrate binding domain” is meant that portion/region of a enzymatic nucleic acid which is able to interact, for example via complementarity (i.e., able to base-pair with), with a portion of its substrate. Preferably, such complementarity is 100%, but can be less if desired. For example, as few as 10 bases out of 14 can be base-paired (see for example Werner and Uhlenbeck, 1995, Nucleic Acids Research, 23, 2092-2096; Hammann et al., 1999, Antisense and Nucleic Acid Drug Dev., 9, 25-31). Examples of such arms are shown generally in FIGS. 1-4. That is, these arms contain sequences within a enzymatic nucleic acid which are intended to bring enzymatic nucleic acid and target RNA together through complementary base-pairing interactions. The enzymatic nucleic acid of the invention can have binding arms that are contiguous or non-contiguous and may be of varying lengths. The length of the binding arm(s) are preferably greater than or equal to three nucleotides and of sufficient length to stably interact with the target RNA; preferably 12-100 nucleotides; more preferably 14-24 nucleotides long (see for example Werner and Uhlenbeck, supra; Hammann et al., supra; Hampel et al., EP0360257; Berzal-Herranz et al., 1993, EMBO J., 12, 2567-73). If two binding arms are chosen, the design is such that the length of the binding arms are symmetrical (i.e., each of the binding arms is of the same length; e.g., five and five nucleotides, or six and six nucleotides, or seven and seven nucleotides long) or asymmetrical (i.e., the binding arms are of different length; e.g., six and three nucleotides; three and six nucleotides long; four and five nucleotides long; four and six nucleotides long; four and seven nucleotides long; and the like).

[0060] By “Inozyme” or “NCH” motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described as NCH Rz in FIG. 1. Inozymes possess endonuclease activity to cleave RNA substrates having a cleavage triplet NCH/, where N is a nucleotide, C is cytidine and H is adenosine, uridine or cytidine, and/represents the cleavage site. H is used interchangeably with X. Inozymes can also possess endonuclease activity to cleave RNA substrates having a cleavage triplet NCN/, where N is a nucleotide, C is cytidine, and/represents the cleavage site. “I” in FIG. 1 represents an Inosine nucleotide, preferably a ribo-Inosine or xylo-Inosine nucleoside.

[0061] By “G-cleaver” motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described as G-cleaver Rz in FIG. 1. G-cleavers possess endonuclease activity to cleave RNA substrates having a cleavage triplet NYN/, where N is a nucleotide, Y is uridine or cytidine and/represents the cleavage site. G-cleavers can be chemically modified as is generally shown in FIG. 1.

[0062] By “amberzyme” motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described in FIG. 2. Amberzymes possess endonuclease activity to cleave RNA substrates having a cleavage triplet NG/N, where N is a nucleotide, G is guanosine, and/represents the cleavage site. Amberzymes can be chemically modified to increase nuclease stability through substitutions as are generally shown in FIG. 2. In addition, differing nucleoside and/or non-nucleoside linkers can be used to substitute the 5′-gaaa-3′ loops shown in the figure. Amberzymes represent a non-limiting example of an enzymatic nucleic acid molecule that does not require a ribonucleotide (2′-OH) group within its own nucleic acid sequence for activity.

[0063] By “zinzyme” motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described in FIG. 3. Zinzymes possess endonuclease activity to cleave RNA substrates having a cleavage triplet including but not limited to YG/Y, where Y is uridine or cytidine, and G is guanosine and/represents the cleavage site. Zinzymes can be chemically modified to increase nuclease stability through substitutions as are generally shown in FIG. 3, including substituting 2′-O-methyl guanosine nucleotides for guanosine nucleotides. In addition, differing nucleotide and/or non-nucleotide linkers can be used to substitute the 5′-gaaa-2′ loop shown in the figure. Zinzymes represent a non-limiting example of an enzymatic nucleic acid molecule that does not require a ribonucleotide (2′-OH) group within its own nucleic acid sequence for activity.

[0064] By ‘DNAzyme’ is meant, an enzymatic nucleic acid molecule that does not require the presence of a 2′-OH group within its own nucleic acid sequence for activity. In particular embodiments the enzymatic nucleic acid molecule can have an attached linker(s) or other attached or associated groups, moieties, or chains containing one or more nucleotides with 2′-OH groups. DNAzymes can be synthesized chemically or expressed endogenously in vivo, by means of a single stranded DNA vector or equivalent thereof. An example of a DNAzyme is shown in FIG. 4 and is generally reviewed in Usman et al., U.S. Pat. No., 6,159,714; Chartrand et al., 1995, NAR 23, 4092; Breaker et al., 1995, Chem. Bio. 2, 655; Santoro et al., 1997, PNAS 94, 4262; Breaker, 1999, Nature Biotechnology, 17, 422-423; and Santoro et. al., 2000, J. Am. Chem. Soc., 122, 2433-39. Additional DNAzyme motifs can be selected for using techniques similar to those described in these references, and hence, are within the scope of the present invention.

[0065] By “sufficient length” is meant an oligonucleotide of greater than or equal to 3 nucleotides that is of a length great enough to provide the intended function under the expected condition. For example, for binding arms of enzymatic nucleic acid “sufficient length” means that the binding arm sequence is long enough to provide stable binding to a target site under the expected binding conditions. Preferably, the binding arms are not so long as to prevent useful turnover of the nucleic acid molecule.

[0066] By “stably interact” is meant interaction of the oligonucleotides with target nucleic acid (e.g., by forming hydrogen bonds with complementary nucleotides in the target under physiological conditions) that is sufficient to the intended purpose (e.g., cleavage of target RNA by an enzyme).

[0067] By “equivalent” or “related” RNA to NFKB is meant to include those naturally occurring RNA molecules having homology (partial or complete) to NFKB proteins or encoding for proteins with similar function as NFKB proteins in various organisms, including human, rodent, primate, rabbit, pig, protozoans, fungi, plants, and other microorganisms and parasites. The equivalent RNA sequence also includes in addition to the coding region, regions such as 5′-untranslated region, 3′-untranslated region, introns, intron-exon junction and the like.

[0068] By “homology” is meant the nucleotide sequence of two or more nucleic acid molecules is partially or completely identical.

[0069] By “antisense nucleic acid”, it is meant a non-enzymatic nucleic acid molecule that binds to target RNA by means of RNA-RNA or RNA-DNA or RNA-PNA (protein nucleic acid; Egholm et al., 1993 Nature 365, 566) interactions and alters the activity of the target RNA (for a review, see Stein and Cheng, 1993 Science 261, 1004 and Woolf et al., U.S. Pat. No. 5,849,902). Typically, antisense molecules are complementary to a target sequence along a single contiguous sequence of the antisense molecule. However, in certain embodiments, an antisense molecule can bind to substrate such that the substrate molecule forms a loop, and/or an antisense molecule can bind such that the antisense molecule forms a loop. Thus, the antisense molecule can be complementary to two (or even more) non-contiguous substrate sequences or two (or even more) non-contiguous sequence portions of an antisense molecule can be complementary to a target sequence or both. For a review of current antisense strategies, see Schmajuk et al., 1999, J. Biol. Chem., 274, 21783-21789, Delihas et al., 1997, Nature, 15, 751-753, Stein et al., 1997, Antisense N. A. Drug Dev., 7, 151, Crooke, 2000, Methods Enzymol., 313, 3-45; Crooke, 1998, Biotech. Genet. Eng. Rev., 15, 121-157, Crooke, 1997, Ad. Pharmacol., 40, 1-49. In addition, antisense DNA can be used to target RNA by means of DNA-RNA interactions, thereby activating RNase H, which digests the target RNA in the duplex. The antisense oligonucleotides can comprise one or more RNAse H activating region, which is capable of activating RNAse H cleavage of a target RNA. Antisense DNA can be synthesized chemically or expressed via the use of a single stranded DNA expression vector or equivalent thereof.

[0070] By “RNase H activating region” is meant a region (generally greater than or equal to 4-25 nucleotides in length, preferably from 5-11 nucleotides in length) of a nucleic acid molecule capable of binding to a target RNA to form a non-covalent complex that is recognized by cellular RNase H enzyme (see for example Arrow et al., U.S. Pat. No. 5,849,902; Arrow et al., U.S. Pat. No. 5,989,912). The RNase H enzyme binds to the nucleic acid molecule-target RNA complex and cleaves the target RNA sequence. The RNase H activating region comprises, for example, phosphodiester, phosphorothioate (preferably at least four of the nucleotides are phosphorothiote substitutions; more specifically, 4-11 of the nucleotides are phosphorothiote substitutions); phosphorodithioate, 5′-thiophosphate, or methylphosphonate backbone chemistry or a combination thereof. In addition to one or more backbone chemistries described above, the RNase H activating region can also comprise a variety of sugar chemistries. For example, the RNase H activating region can comprise deoxyribose, arabino, fluoroarabino or a combination thereof, nucleotide sugar chemistry. Those skilled in the art will recognize that the foregoing are non-limiting examples and that any combination of phosphate, sugar and base chemistry of a nucleic acid that supports the activity of RNase H enzyme is within the scope of the definition of the RNase H activating region and the instant invention.

[0071] By “gene” it is meant a nucleic acid that encodes an RNA, for example, nucleic acid sequences including but not limited to structural genes encoding a polypeptide.

[0072] “Complementarity” refers to the ability of a nucleic acid to form hydrogen bond(s) with another RNA sequence by either traditional Watson-Crick or other non-traditional types. In reference to the nucleic molecules of the present invention, the binding free energy for a nucleic acid molecule with its target or complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., enzymatic nucleic acid cleavage, antisense or triple helix inhibition. Determination of binding free energies for nucleic acid molecules is well known in the art (see, e.g., Turner et al., 1987, CSH Symp. Quant. Biol. LII pp.123-133; Frier et al., 1986, Proc. Nat. Acad. Sci. USA 83:9373-9377; Turner et al., 1987, J. Am. Chem. Soc. 109:3783-3785). A percent complementarity indicates the percentage of contiguous residues in a nucleic acid molecule which can form hydrogen bonds (e.g., Watson-Crick base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, 10 out of 10 being 50%, 60%, 70%, 80%, 90% and 100% complementary). “Perfectly complementary” means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence.

[0073] By “RNA” is meant a molecule comprising at least one ribonucleotide residue. By “ribonucleotide” or “2′-OH” is meant a nucleotide with a hydroxyl group at the 2′position of a β-D-ribo-furanose moiety.

[0074] By “decoy RNA” is meant an RNA molecule or aptamer that is designed to preferentially bind to a predetermined ligand. Such binding can result in the inhibition or activation of a target molecule. The decoy RNA or aptamer can compete with a naturally occurring binding target for the binding of a specific ligand. For example, it has been shown that over-expression of HIV trans-activation response (TAR) RNA can act as a “decoy” and efficiently binds HIV tat protein, thereby preventing it from binding to TAR sequences encoded in the HIV RNA (Sullenger et al., 1990, Cell, 63, 601-608). This is but a specific example and those in the art will recognize that other embodiments can be readily generated using techniques generally known in the art, see for example Gold et al., 1995, Annu. Rev. Biochem., 64, 763; Brody and Gold, 2000, J. Biotechnol., 74, 5; Sun, 2000, Curr. Opin. Mol. Ther., 2, 100; Kusser, 2000, J. Biotechnol., 74, 27; Hermann and Patel, 2000, Science, 287, 820; and Jayasena, 1999, Clinical Chemistry, 45, 1628. Similarly, a decoy RNA can be designed to bind to REL-A and block the binding of REL-A or a decoy RNA can be designed to bind to REL-A and prevent interaction with the REL-A protein.

[0075] Several varieties of enzymatic RNAs are known presently. Each can catalyze the hydrolysis of RNA phosphodiester bonds in trans (and thus can cleave other RNA molecules) under physiological conditions. Table I summarizes some of the characteristics of these ribozymes. In general, enzymatic nucleic acids act by first binding to a target RNA. Such binding occurs through the target binding portion of a enzymatic nucleic acid which is held in close proximity to an enzymatic portion of the molecule that acts to cleave the target RNA. Thus, the enzymatic nucleic acid first recognizes and then binds a target RNA through complementary base-pairing, and once bound to the correct site, acts enzymatically to cut the target RNA. Strategic cleavage of such a target RNA will destroy its ability to direct synthesis of an encoded protein. After an enzymatic nucleic acid has bound and cleaved its RNA target, it is released from that RNA to search for another target and can repeatedly bind and cleave new targets. Thus, a single ribozyme molecule is able to cleave many molecules of target RNA. In addition, the ribozyme is a highly specific inhibitor of gene expression, with the specificity of inhibition depending not only on the base-pairing mechanism of binding to the target RNA, but also on the mechanism of target RNA cleavage. Single mismatches, or base-substitutions, near the site of cleavage can completely eliminate catalytic activity of a ribozyme.

[0076] The enzymatic nucleic acid molecule that cleave the specified sites in NFKB-specific RNAs represent a therapeutic approach to treat a variety of inflammatory diseases and conditions, including but not limited to rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, and any other inflammatory disease or condition which respond to the modulation of REL-A NFKB function.

[0077] The enzymatic nucleic acid molecule that cleave the specified sites in NFKB-specific RNAs also represent a therapeutic approach to treat a variety of cancers, including but not limited to breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidrug resistant cancers, and/or other cancers which respond to the modulation of NFKB function.

[0078] In one embodiment of the inventions described herein, the enzymatic nucleic acid molecule is formed in a hammerhead or hairpin motif, but can also be formed in the motif of a hepatitis delta virus, group I intron, group II intron or RNase P RNA (in association with an RNA guide sequence), Neurospora VS RNA, DNAzymes, NCH cleaving motifs, or G-cleavers. Examples of such hammerhead motifs are described by Dreyfus, supra, Rossi et al., 1992, AIDS Research and Human Retroviruses 8, 183; of hairpin motifs by Hampel et al., EP0360257, Hampel and Tritz, 1989 Biochemistry 28, 4929, Feldstein et al., 1989, Gene 82, 53, Haseloff and Gerlach, 1989, Gene, 82, 43, and Hampel et al., 1990 Nucleic Acids Res. 18, 299; Chowrira & McSwiggen, U.S. Pat. No. 5,631,359; of the hepatitis delta virus motif is described by Perrotta and Been, 1992 Biochemistry 31, 16; of the RNase P motif by Guerrier-Takada et al., 1983 Cell 35, 849; Forster and Altman, 1990, Science 249, 783; Li and Altman, 1996, Nucleic Acids Res. 24, 835; Neurospora VS RNA ribozyme motif is described by Collins (Saville and Collins, 1990 Cell 61, 685-696; Saville and Collins, 1991 Proc. Natl. Acad. Sci. USA 88, 8826-8830; Collins and Olive, 1993 Biochemistry 32, 2795-2799; Guo and Collins, 1995, EMBO. J. 14, 363); Group II introns are described by Griffin et al., 1995, Chem. Biol. 2, 761; Michels and Pyle, 1995, Biochemistry 34, 2965; Pyle et al., International PCT Publication No. WO 96/22689; of the Group I intron by Cech et al., U.S. Pat. No. 4,987,071 and of DNAzymes by Usman et al., International PCT Publication No. WO 95/11304; Chartrand et al., 1995, NAR 23, 4092; Breaker et al., 1995, Chem. Bio. 2, 655; Santoro et al., 1997, PNAS 94, 4262, and Beigelman et al., International PCT publication No. WO 99/55857. NCH cleaving motifs are described in Ludwig & Sproat, International PCT Publication No. WO 98/58058; and G-cleavers are described in Kore et al., 1998, Nucleic Acids Research 26, 4116-4120 and Eckstein et al., International PCT Publication No. WO 99/16871. Additional motifs such as the Aptazyme (Breaker et al., WO 98/43993), Amberzyme (Class I motif; FIG. 2; Beigelman et al., U.S. Ser. No. 09/301,511) and Zinzyme (FIG. 3) (Beigelman et al., U.S. Ser. No. 09/301,511), all included by reference herein including drawings, can also be used in the present invention. These specific motifs or configurations are not limiting in the invention and those skilled in the art will recognize that all that is important in an enzymatic nucleic acid molecule of this invention is that it has a specific substrate binding site which is complementary to one or more of the target gene RNA regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart an RNA cleaving activity to the molecule (Cech et al., U.S. Pat. No. 4,987,071).

[0079] In one embodiment of the present invention, a nucleic acid molecule of the instant invention can be between about 10 and 100 nucleotides in length. Exemplary enzymatic nucleic acid molecules of the invention are shown in Tables III to VII. For example, enzymatic nucleic acid molecules of the invention are preferably between about 15 and 50 nucleotides in length, more preferably between about 25 and 40 nucleotides in length, e.g., 34, 36, or 38 nucleotides in length (for example see Jarvis et al., 1996, J. Biol. Chem., 271, 29107-29112). Exemplary DNAzymes of the invention are preferably between about 15 and 40 nucleotides in length, more preferably between about 25 and 35 nucleotides in length, e.g., 29, 30, 31, or 32 nucleotides in length (see for example Santoro et al., 1998, Biochemistry, 37, 13330-13342; Chartrand et al., 1995, Nucleic Acids Research, 23, 4092-4096). Exemplary antisense molecules of the invention are preferably between about 15 and 75 nucleotides in length, more preferably between about 20 and 35 nucleotides in length, e.g., 25, 26, 27, or 28 nucleotides in length (see for example Woolf et al., 1992, PNAS., 89, 7305-7309; Milner et al., 1997, Nature Biotechnology, 15, 537-541). Exemplary triplex forming oligonucleotide molecules of the invention are preferably between about 10 and 40 nucleotides in length, more preferably between about 12 and 25 nucleotides in length, e.g., 18, 19, 20, or 21 nucleotides in length (see for example Maher et al., 1990, Biochemistry, 29, 8820-8826; Strobel and Dervan, 1990, Science, 249, 73-75). Those skilled in the art will recognize that all that is required is that the nucleic acid molecule be of sufficient length and suitable conformation for the nucleic acid molecule to interact with its target and/or catalyze a reaction contemplated herein. The length of the nucleic acid molecules of the instant invention are not limiting within the general limits stated.

[0080] Preferably, a nucleic acid molecule that modulates, for example, down-regulates REL-A expression comprises between 12 and 100 bases complementary to a RNA molecule of REL-A. Even more preferably, a nucleic acid molecule that modulates, for example REL-A expression comprises between 14 and 24 bases complementary to a RNA molecule of REL-A.

[0081] The invention provides a method for producing a class of nucleic acid-based gene modulating agents which exhibit a high degree of specificity for the RNA of a desired target. For example, the enzymatic nucleic acid molecule is preferably targeted to a highly conserved sequence region of target RNAs encoding REL-A (specifically REL-A genes) such that specific treatment of a disease or condition can be provided with either one or several nucleic acid molecules of the invention. Such nucleic acid molecules can be delivered exogenously to specific tissue or cellular targets as required. Alternatively, the nucleic acid molecules (e.g., ribozymes and antisense) can be expressed from DNA and/or RNA vectors that are delivered to specific cells.

[0082] As used in herein “cell” is used in its usual biological sense, and does not refer to an entire multicellular organism. The cell can, for example, be in vitro, e.g., in cell culture, or present in a multicellular organism, including, e.g., birds, plants and mammals such as humans, cows, sheep, apes, monkeys, swine, dogs, and cats. The cell may be prokaryotic (e.g., bacterial cell) or eukaryotic (e.g., mammalian or plant cell).

[0083] By “REL-A proteins” is meant, a peptide or protein comprising a REL-A or p65 subunit of NFKB, for example a subunit involved in transcriptional activation activity.

[0084] By “highly conserved sequence region” is meant, a nucleotide sequence of one or more regions in a target gene does not vary significantly from one generation to the other or from one biological system to the other.

[0085] Nucleic acid-based inhibitors of NFKB function are useful for the prevention and/or treatment of cancers and cancerous conditions such as breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidrug resistant cancers, and any other diseases or conditions that are related to or will respond to the levels of NFKB in a cell or tissue, alone or in combination with other therapies.

[0086] Nucleic acid-based inhibitors of NFKB function are also useful for the prevention and/or treatment of inflammatory diseases and conditions, including but not limited to rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, and any other inflammatory disease or condition which respond to the modulation of NFKB function.

[0087] The nucleic acid-based inhibitors of the invention are added directly, or can be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to target cells or tissues. The nucleic acid or nucleic acid complexes can be locally administered to relevant tissues ex vivo, or in vivo through injection or infusion pump, with or without their incorporation in biopolymers. In preferred embodiments, the enzymatic nucleic acid inhibitors comprise sequences, which are complementary to the substrate sequences in Tables III to VII. Examples of such enzymatic nucleic acid molecules also are shown in Tables III to VII. Examples of such enzymatic nucleic acid molecules consist essentially of sequences defined in these tables.

[0088] In another embodiment, the invention features antisense nucleic acid molecules and 2-5A chimera including sequences complementary to the substrate sequences shown in Tables III to VII. Such nucleic acid molecules can include sequences as shown for the binding arms of the enzymatic nucleic acid molecules in Tables III to VII. Similarly, triplex molecules can be provided targeted to the corresponding DNA target regions, and containing the DNA equivalent of a target sequence or a sequence complementary to the specified target (substrate) sequence. Typically, antisense molecules are complementary to a target sequence along a single contiguous sequence of the antisense molecule. However, in certain embodiments, an antisense molecule can bind to substrate such that the substrate molecule forms a loop, and/or an antisense molecule can bind such that the antisense molecule forms a loop. Thus, the antisense molecule can be complementary to two (or even more) non-contiguous substrate sequences or two (or even more) non-contiguous sequence portions of an antisense molecule can be complementary to a target sequence or both.

[0089] By “consists essentially of” is meant that the active nucleic acid molecule of the invention, for example, an enzymatic nucleic acid molecule, contains an enzymatic center or core equivalent to those in the examples, and binding arms able to bind RNA such that cleavage at the target site occurs. Other sequences can be present which do not interfere with such cleavage. Thus, a core region can, for example, include one or more loop, stem-loop structure, or linker which does not prevent enzymatic activity. Thus, the underlined regions in the sequences in Table III can be such a loop, stem-loop, nucleotide linker, and/or non-nucleotide linker and can be represented generally as sequence “X”. For example, a core sequence for a hammerhead enzymatic nucleic acid can comprise a conserved sequence, such as 5′-CUGAUGAG-3′ and 5′-CGAA-3′ connected by “X”, where X is 5′-GCCGUUAGGC-3′ (SEQ ID NO 3929), or any other Stem II region known in the art, or a nucleotide and/or non-nucleotide linker. Similarly, for other nucleic acid molecules of the instant invention, such as Inozyme, G-cleaver, amberzyme, zinzyme, DNAzyme, antisense, 2-5A antisense, triplex forming nucleic acid, and decoy nucleic acids, other sequences or non-nucleotide linkers can be present that do not interfere with the function of the nucleic acid molecule.

[0090] Sequence X can be a linker of >2 nucleotides in length, preferably 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 26, 30, where the nucleotides can preferably be internally base-paired to form a stem of preferably≧2 base pairs. In yet another embodiment, the nucleotide linker X can be a nucleic acid aptamer, such as an ATP aptamer, HIV Rev aptamer (RRE), HIV Tat aptamer (TAR) and others (for a review see Gold et al., 1995, Annu. Rev. Biochem., 64, 763; and Szostak & Ellington, 1993, in The RNA World, ed. Gesteland and Atkins, pp. 511, CSH Laboratory Press). A “nucleic acid aptamer” as used herein is meant to indicate a nucleic acid sequence capable of interacting with a ligand. The ligand can be any natural or a synthetic molecule, including but not limited to a resin, metabolites, nucleosides, nucleotides, drugs, toxins, transition state analogs, peptides, lipids, proteins, amino acids, nucleic acid molecules, hormones, carbohydrates, receptors, cells, viruses, bacteria and others.

[0091] In yet another embodiment, alternatively or in addition, sequence X can be a non-nucleotide linker. Non-nucleotides as can include abasic nucleotide, polyether, polyamine, polyamide, peptide, carbohydrate, lipid, or polyhydrocarbon compounds. Specific examples include those described by Seela and Kaiser, Nucleic Acids Res. 1990, 18:6353 and Nucleic Acids Res. 1987, 15:3113; Cload and Schepartz, J. Am. Chem. Soc. 1991, 113:6324; Richardson and Schepartz, J. Am. Chem. Soc. 1991, 113:5109; Ma et al., Nucleic Acids Res. 1993, 21:2585 and Biochemistry 1993, 32:1751; Durand et al., Nucleic Acids Res. 1990, 18:6353; McCurdy et al., Nucleosides & Nucleotides 1991, 10:287; Jschke et al., Tetrahedron Lett. 1993, 34:301; Ono et al., Biochemistry 1991, 30:9914; Arnold et al., International Publication No. WO 89/02439; Usman et al., International Publication No. WO 95/06731; Dudycz et al., International Publication No. WO 95/11910 and Ferentz and Verdine, J. Am. Chem. Soc. 1991, 113:4000, all hereby incorporated by reference herein. A “non-nucleotide” further means any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound can be abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine. Thus, in a preferred embodiment, the invention features an enzymatic nucleic acid molecule having one or more non-nucleotide moieties, and having enzymatic activity to cleave an RNA or DNA molecule.

[0092] In another aspect of the invention, enzymatic nucleic acid molecules or antisense molecules that interact with target RNA molecules and down-regulate REL-A (specifically REL-A gene) activity are expressed from transcription units inserted into DNA or RNA vectors. The recombinant vectors are preferably DNA plasmids or viral vectors. Enzymatic nucleic acid molecule or antisense expressing viral vectors can be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. Preferably, the recombinant vectors capable of expressing the enzymatic nucleic acid molecules or antisense are delivered as described above, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of enzymatic nucleic acid molecules or antisense. Such vectors can be repeatedly administered as necessary. Once expressed, the enzymatic nucleic acid molecules or antisense bind to the target RNA and down-regulate its function or expression. Delivery of enzymatic nucleic acid molecule or antisense expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that would allow for introduction into the desired target cell. Antisense DNA can be expressed via the use of a single stranded DNA intracellular expression vector.

[0093] By “vectors” is meant any nucleic acid- and/or viral-based technique used to deliver a desired nucleic acid.

[0094] By “patient” is meant an organism, which is a donor or recipient of explanted cells or the cells themselves. “Patient” also refers to an organism to which the nucleic acid molecules of the invention can be administered. Preferably, a patient is a mammal or mammalian cells. More preferably, a patient is a human or human cells.

[0095] By “enhanced enzymatic activity” is meant to include activity measured in cells and/or in vivo where the activity is a reflection of both the catalytic activity and the stability of the nucleic 30 acid molecules of the invention. In this invention, the product of these properties can be increased in vivo compared to an all RNA enzymatic nucleic acid or all DNA enzyme. In some cases, the activity or stability of the nucleic acid molecule can be decreased (i.e., less than ten- fold), but the overall activity of the nucleic acid molecule is enhanced, in vivo.

[0096] The nucleic acid molecules of the instant invention, individually, or in combination or in conjunction with other drugs, can be used to treat diseases or conditions discussed above. For example, to treat a disease or condition associated with the levels of REL-A, the patient can be treated, or other appropriate cells can be treated, as is evident to those skilled in the art, individually or in combination with one or more drugs under conditions suitable for the treatment.

[0097] In a further embodiment, the described molecules, such as antisense or ribozymes, can be used in combination with other known treatments to treat conditions or diseases discussed above. For example, the described molecules can be used in combination with one or more known therapeutic agents to treat breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidrug resistant cancers, rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, and any other cancerous disease or inflammatory disease or condition which respond to the modulation of REL-A expression.

[0098] In another embodiment, the invention features nucleic acid-based inhibitors (e.g., enzymatic nucleic acid molecules (eg; ribozymes), antisense nucleic acids, 2-5A antisense chimeras, triplex DNA, antisense nucleic acids containing RNA cleaving chemical groups) and methods for their use to down regulate or inhibit the expression of genes (e.g., REL-A) capable of progression and/or maintenance of cancer, inflammatory diseases, and/or other disease states which respond to the modulation of REL-A expression.

[0099] By “comprising” is meant including, but not limited to, whatever follows the word “comprising”. Thus, use of the term “comprising” indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present. By “consisting of” is meant including, and limited to, whatever follows the phrase “consisting of”. Thus, the phrase “consisting of⇄ indicates that the listed elements are required or mandatory, and that no other elements may be present.

[0100] Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims.

[0101] Mechanism of Action of Nucleic Acid Molecules of the Invention as Proposed in the Art

[0102] Antisense: Antisense molecules can be modified or unmodified RNA, DNA, or mixed polymer oligonucleotides and primarily function by specifically binding to matching sequences resulting in inhibition of peptide synthesis (Wu-Pong, Nov. 1994, BioPharm, 20-33). The antisense oligonucleotide binds to target RNA by Watson Crick base-pairing and blocks gene expression by preventing ribosomal translation of the bound sequences either by steric blocking or by activating RNase H enzyme. Antisense molecules can also alter protein synthesis by interfering with RNA processing or transport from the nucleus into the cytoplasm (Mukhopadhyay & Roth, 1996, Crit. Rev. in Oncogenesis 7, 151-190).

[0103] In addition, binding of single stranded DNA to RNA can result in nuclease degradation of the heteroduplex (Wu-Pong, supra; Crooke, supra). To date, the only backbone modified DNA chemistry which act as substrates for RNase H are phosphorothioates, phosphorodithioates, and borontrifluoridates. Recently it has been reported that 2′-arabino and 2′-fluoro arabino-containing oligos can also activate RNase H activity.

[0104] A number of antisense molecules have been described that utilize novel configurations of chemically modified nucleotides, secondary structure, and/or RNase H substrate domains (Woolf et al., International PCT Publication No. WO 98/13526; Thompson et al., International PCT Publication No. WO 99/54459; Hartmann et al., U.S. Ser. No. 60/101,174 which was filed on Sep. 21, 1998) all of these are incorporated by reference herein in their entirety.

[0105] In addition, antisense deoxyoligoribonucleotides can be used to target RNA by means of DNA-RNA interactions, thereby activating RNase H, which digests the target RNA in the duplex. Antisense DNA can be expressed via the use of a single stranded DNA intracellular expression vector or equivalents and variations thereof.

[0106] Enzymatic Nucleic Acid: Several varieties of enzymatic RNAs are presently known. In addition, several in vitro selection (evolution) strategies (Orgel, 1979, Proc. R. Soc. London, B 205, 435) have been used to evolve new nucleic acid catalysts capable of catalyzing cleavage and ligation of phosphodiester linkages (Joyce, 1989, Gene, 82, 83-87; Beaudry et al., 1992, Science 257, 635-641; Joyce, 1992, Scientific American 267, 90-97; Breaker et al., 1994, TIBTECH 12, 268; Bartel et al., 1993, Science 261:1411-1418; Szostak, 1993, TIBS 17, 89-93; Kumar et al., 1995, FASEB J., 9, 1183; Breaker, 1996, Curr. Op. Biotech., 7, 442; Santoro et al., 1997, Proc. Natl. Acad. Sci., 94, 4262; Tang et al., 1997, RNA 3, 914; Nakamaye & Eckstein, 1994, supra; Long & Uhlenbeck, 1994, supra; Ishizaka et al., 1995, supra; Vaish et al., 1997, Biochemistry 36, 6495; all of these are incorporated by reference herein). Each can catalyze a series of reactions including the hydrolysis of phosphodiester bonds in trans (and thus can cleave other RNA molecules) under physiological conditions.

[0107] Nucleic acid molecules of this invention will block to some extent REL-A and/or NFKB protein expression and can be used to treat disease or diagnose disease associated with the levels of REL-A and/or NFKB. Enzymatic nucleic acid sequences targeting REL-A RNA and sequences that can be targeted with nucleic acid molecules of the invention to down-regulate REL-A expression are shown in Tables III to VII.

[0108] The enzymatic nature of an enzymatic nucleic acid molecule can allow the concentration of enzymatic nucleic acid molecule necessary to affect a therapeutic treatment to be lower. This reflects the ability of the enzymatic nucleic acid molecule to act enzymatically. Thus, a single enzymatic nucleic acid molecule is able to cleave many molecules of target RNA. In addition, the enzymatic nucleic acid molecule is a highly specific inhibitor, with the specificity of inhibition depending not only on the base-pairing mechanism of binding to the target RNA, but also on the mechanism of target RNA cleavage. Single mismatches, or base-substitutions, near the site of cleavage can be chosen to greatly attenuate the catalytic activity of a enzymatic nucleic acid molecule.

[0109] Nucleic acid molecules having an endonuclease enzymatic activity are able to repeatedly cleave other separate RNA molecules in a nucleotide base sequence-specific manner. Such enzymatic nucleic acid molecules can be targeted to virtually any RNA transcript, and achieve efficient cleavage in vitro (Zaug et al., 324, Nature 429 1986; Uhlenbeck, 1987 Nature 328, 596; Kim et al., 84 Proc. Natl. Acad. Sci. USA 8788, 1987; Dreyfus, 1988, Einstein Quart. J. Bio. Med., 6, 92; Haseloff and Gerlach, 334 Nature 585, 1988; Cech, 260 JAMA 3030, 1988; and Jefferies et al., 17 Nucleic Acids Research 1371, 1989; Santoro et al., 1997 supra).

[0110] Because of their sequence specificity, trans-cleaving enzymatic nucleic acid molecules can be used as therapeutic agents for human disease (Usman & McSwiggen, 1995 Ann. Rep. Med. Chem. 30, 285-294; Christoffersen and Marr, 1995 J. Med. Chem. 38, 2023-2037). Enzymatic nucleic acid molecules can be designed to cleave specific RNA targets within the background of cellular RNA. Such a cleavage event renders the RNA non-functional and abrogates protein expression from that RNA. In this manner, synthesis of a protein associated with a disease state can be selectively inhibited (Warashina et al., 1999, Chemistry and Biology., 6, 237-250).

[0111] Enzymatic nucleic acid molecules of the invention that are allosterically regulated (“allozymes”) can be used to modulate NFKB expression. These allosteric enzymatic nucleic acids or allozymes (see for example George et al., U.S. Pat. Nos. 5,834,186 and 5,741,679, Shih et al., U.S. Pat. No. 5,589,332, Nathan et al., U.S. Pat. No 5,871,914, Nathan and Ellington, International PCT publication No. WO 00/24931, Breaker et al., International PCT Publication Nos. WO 00/26226 and 98/27104, and Sullenger et al., International PCT publication No. WO 99/29842) are designed to respond to a signaling agent, for example, mutant REL-A protein, wild-type REL-A protein, mutant REL-A RNA, wild-type REL-A RNA, other proteins and/or RNAs involved in NFKB activity, compounds, metals, polymers, molecules and/or drugs that are targeted to NFKB or NFKB subunit, such as REL-A, expressing cells etc., which in turn modulates the activity of the enzymatic nucleic acid molecule. In response to interaction with a predetermined signaling agent, the allosteric enzymatic nucleic acid molecule's activity is activated or inhibited such that the expression of a particular target is selectively down-regulated. The target can comprise wild-type REL-A, mutant REL-A, a component of NFKB, and/or a predetermined cellular component that modulates REL-A/NFKB activity. In a specific example, allosteric enzymatic nucleic acid molecules that are activated by interaction with a RNA encoding a mutant REL-A protein are used as therapeutic agents in vivo. The presence of RNA encoding the mutant REL-A protein activates the allosteric enzymatic nucleic acid molecule that subsequently cleaves the RNA encoding a mutant REL-A protein resulting in the inhibition of mutant REL-A protein expression. In this manner, cells that express the mutant form of the REL-A protein are selectively targeted.

[0112] In another non-limiting example, an allozyme can be activated by a REL-A protein, peptide, or mutant polypeptide that caused the allozyme to inhibit the expression of REL-A gene, by, for example, cleaving RNA encoded by REL-A gene. In this non-limiting example, the allozyme acts as a decoy to inhibit the function of REL-A and also inhibit the expression of REL-A once activated by the REL-A protein.

[0113] The nucleic acid molecules of the instant invention are also referred to as GeneBloc reagents, which are essentially nucleic acid molecules (eg; ribozymes, antisense) capable of down-regulating gene expression.

[0114] Target Sites

[0115] Targets for useful enzymatic nucleic acid molecules and antisense nucleic acids can be determined as disclosed in Draper et al., WO 93/23569; Sullivan et al., WO 93/23057; Thompson et al., WO 94/02595; Draper et al., WO 95/04818; McSwiggen et al., U.S. Pat. No. 5,525,468, and hereby incorporated by reference herein in totality. Other examples include the following PCT applications, which concern inactivation of expression of disease-related genes: WO 95/23225, WO 95/13380, WO 94/02595, incorporated by reference herein. Rather than repeat the guidance provided in those documents here, below are provided specific examples of such methods, not limiting to those in the art. Enzymatic nucleic acid molecules and antisense to such targets are designed as described in those applications and synthesized to be tested in vitro and in vivo, as also described. The sequences of human REL-A RNAs were screened for optimal enzymatic nucleic acid and antisense target sites using a computer-folding algorithm. Antisense, hammerhead, DNAzyme, NCH, amberzyme, zinzyme, or G-Cleaver enzymatic nucleic acid molecule binding/cleavage sites were identified. These sites are shown in Tables III to VII (all sequences are 5′ to 3′ in the tables; underlined regions can be any sequence “X” or linker X, the actual sequence is not relevant here). The nucleotide base position is noted in the Tables as that site to be cleaved by the designated type of enzymatic nucleic acid molecule. While human sequences can be screened and enzymatic nucleic acid molecule and/or antisense thereafter designed, as discussed in Stinchcomb et al., WO 95/23225, mouse targeted enzymatic nucleic acid molecules can be useful to test efficacy of action of the enzymatic nucleic acid molecule and/or antisense prior to testing in humans.

[0116] Antisense, hammerhead, DNAzyme, NCH, amberzyme, zinzyme or G-Cleaver enzymatic nucleic acid molecule binding/cleavage sites were identified. The nucleic acid molecules are individually analyzed by computer folding (Jaeger et al., 1989 Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whether the sequences fold into the appropriate secondary structure. Those nucleic acid molecules with unfavorable intramolecular interactions such as between the binding arms and the catalytic core are eliminated from consideration. Varying binding arm lengths can be chosen to optimize activity.

[0117] Antisense, hammerhead, DNAzyme, NCH, amberzyme, zinzyme or G-Cleaver enzymatic nucleic acid molecule binding/cleavage sites were identified and were designed to anneal to various sites in the RNA target. The binding arms are complementary to the target site sequences described above. The nucleic acid molecules were chemically synthesized. The method of synthesis used follows the procedure for normal DNA/RNA synthesis as described below and in Usman et al., 1987 J. Am. Chem. Soc., 109, 7845; Scaringe et al., 1990 Nucleic Acids Res., 18, 5433; and Wincott et al., 1995 Nucleic Acids Res. 23, 2677-2684; Caruthers et al., 1992, Methods in Enzymology 211,3-19.

[0118] Synthesis of Nucleic Acid Molecules

[0119] Synthesis of nucleic acids greater than 100 nucleotides in length can be difficult using automated methods, and the therapeutic cost of such molecules can be prohibitive. In this invention, small nucleic acid motifs (” small refers to nucleic acid motifs less than about 100 nucleotides in length, preferably less than about 80 nucleotides in length, and more preferably less than about 50 nucleotides in length; e.g., antisense oligonucleotides, hammerhead or the NCH ribozymes) are preferably used for exogenous delivery. The simple structure of these molecules increases the ability of the nucleic acid to invade targeted regions of RNA structure. Exemplary molecules of the instant invention are chemically synthesized, and others can similarly be synthesized.

[0120] Oligonucleotides (eg; antisense, GeneBlocs) are synthesized using protocols known in the art as described in Caruthers et al., 1992, Methods in Enzymology 211, 3-19, Thompson et al., International PCT Publication No. WO 99/54459, Wincott et al., 1995, Nucleic Acids Res. 23, 2677-2684, Wincott et al., 1997, Methods Mol. Bio., 74, 59, Brennan et al., 1998, Biotechnol Bioeng., 61, 33-45, and Brennan, U.S. Pat. No. 6,001,311. All of these references are incorporated herein by reference. The synthesis of oligonucleotides makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end. In a non-limiting example, small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 μmol scale protocol with a 2.5 min coupling step for 2′-O-methylated nucleotides and a 45 sec coupling step for 2′-deoxy nucleotides. Table II outlines the amounts and the contact times of the reagents used in the synthesis cycle. Alternatively, syntheses at the 0.2 μmol scale can be performed on a 96-well plate synthesizer, such as the instrument produced by Protogene (Palo Alto, Calif.) with minimal modification to the cycle. A 33-fold excess (60 μL of 0.11 M=6.6 μmol) of 2′-O-methyl phosphoramidite and a 105-fold excess of S-ethyl tetrazole (60 μL of 0.25 M=15 μmol) can be used in each coupling cycle of 2′-O-methyl residues relative to polymer-bound 5′-hydroxyl. A 22-fold excess (40 μL of 0.11 M=4.4 μmol) of deoxy phosphoramidite and a 70-fold excess of S-ethyl tetrazole (40 μL of 0.25 M=10 μmol) can be used in each coupling cycle of deoxy residues relative to polymer-bound 5′-hydroxyl. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation of the trityl fractions, are typically 97.5-99%. Other oligonucleotide synthesis reagents for the 394 Applied Biosystems, Inc. synthesizer include; detritylation solution is 3% TCA in methylene chloride (ABI); capping is performed with 16% N-methyl imidazole in THF (ABI) and 10% acetic anhydride/10% 2,6-lutidine in THF (ABI); and oxidation solution is 16.9 mM I2, 49 mM pyridine, 9% water in THF (PERSEPTIVE™). Burdick & Jackson Synthesis Grade acetonitrile is used directly from the reagent bottle. S-Ethyltetrazole solution (0.25 M in acetonitrile) is made up from the solid obtained from American International Chemical, Inc. Alternately, for the introduction of phosphorothioate linkages, Beaucage reagent (3H-1,2-Benzodithiol-3-one 1,1-dioxide, 0.05 M in acetonitrile) is used.

[0121] Deprotection of the antisense oligonucleotides is performed as follows: the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65° C. for 10 min. After cooling to −20 ° C., the supernatant is removed from the polymer support. The support is washed three times with 1.0 mL of EtOH:MeCN:H2O/3:1:1, vortexed and the supernatant is then added to the first supernatant. The combined supernatants, containing the oligoribonucleotide, are dried to a white powder.

[0122] The method of synthesis used for RNA and chemically modified RNA including certain enzymatic nucleic acid molecules follows the procedure as described in Usman et al., 1987, J. Am. Chem. Soc., 109, 7845; Scaringe et al., 1990, Nucleic Acids Res., 18, 5433; and Wincott et al., 1995, Nucleic Acids Res. 23, 2677-2684 Wincott et al., 1997, Methods Mol. Bio., 74, 59, and makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end. In a non-limiting example, small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 μmol scale protocol with a 7.5 min coupling step for alkylsilyl protected nucleotides and a 2.5 min coupling step for 2′-O-methylated nucleotides. Table II outlines the amounts and the contact times of the reagents used in the synthesis cycle. Alternatively, syntheses at the 0.2 μmol scale can be done on a 96-well plate synthesizer, such as the instrument produced by Protogene (Palo Alto, Calif.) with minimal modification to the cycle. A 33-fold excess (60 μL of 0.11 M=6.6 μmol) of 2′-O-methyl phosphoramidite and a 75-fold excess of S-ethyl tetrazole (60 μL of 0.25 M=15 μmol) can be used in each coupling cycle of 2′-O-methyl residues relative to polymer-bound 5′-hydroxyl. A 66-fold excess (120 μL of 0.11 M=13.2 μmol) of alkylsilyl (ribo) protected phosphoramidite and a 150-fold excess of S-ethyl tetrazole (120 μL of 0.25 M=30 μmol) can be used in each coupling cycle of ribo residues relative to polymer-bound 5′-hydroxyl. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation of the trityl fractions, are typically 97.5-99%. Other oligonucleotide synthesis reagents for the 394 Applied Biosystems, Inc. synthesizer include; detritylation solution is 3% TCA in methylene chloride (ABI); capping is performed with 16% N-methyl imidazole in THF (ABI) and 10% acetic anhydride/10% 2,6-lutidine in THF (ABI); oxidation solution is 16.9 mM I2, 49 mM pyridine, 9% water in THF (PERSEPTIVE™). Burdick & Jackson Synthesis Grade acetonitrile is used directly from the reagent bottle. S-Ethyltetrazole solution (0.25 M in acetonitrile) is made up from the solid obtained from American International Chemical, Inc. Alternately, for the introduction of phosphorothioate linkages, Beaucage reagent (3H-1,2-Benzodithiol-3-one 1,1-dioxide 0.05 M in acetonitrile) is used.

[0123] Deprotection of the RNA is performed using either a two-pot or one-pot protocol. For the two-pot protocol, the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65° C. for 10 min. After cooling to −20 ° C., the supernatant is removed from the polymer support. The support is washed three times with 1.0 mL of EtOH:MeCN:H2O/3:1:1, vortexed and the supernatant is then added to the first supernatant. The combined supernatants, containing the oligoribonucleotide, are dried to a white powder. The base deprotected oligoribonucleotide is resuspended in anhydrous TEA/HF/NMP solution (300 μL of a solution of 1.5 mL N-methylpyrrolidinone, 750 μL TEA and 1 mL TEA.3HF to provide a 1.4 M HF concentration) and heated to 65° C. After 1.5 h, the oligomer is quenched with 1.5 M NH4HCO3.

[0124] Alternatively, for the one-pot protocol, the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 33% ethanolic methylamine/DMSO: 1/1 (0.8 mL) at 65° C. for 15 min. The vial is brought to r.t. TEA3HF (0.1 mL) is added and the vial is heated at 65° C. for 15 min. The sample is cooled at −20° C. and then quenched with 1.5 M NH4HCO3.

[0125] For purification of the trityl-on oligomers, the quenched NH4HCO3 solution is loaded onto a C-18 containing cartridge that had been prewashed with acetonitrile followed by 50 mM TEAA. After washing the loaded cartridge with water, the RNA is detritylated with 0.5% TFA for 13 min. The cartridge is then washed again with water, salt exchanged with 1 M NaCl and washed with water again. The oligonucleotide is then eluted with 30% acetonitrile.

[0126] Inactive hammerhead ribozymes or binding attenuated control (BAC) oligonucleotides can be synthesized by substituting a U for G5 and a U for A14 (numbering from Hertel, K. J., et al., 1992, Nucleic Acids Res., 20, 3252). Similarly, one or more nucleotide substitutions can be introduced in other enzymatic nucleic acid molecules to inactivate the molecule and such molecules can serve as a negative control.

[0127] The average stepwise coupling yields are typically >98% (Wincott et al., 1995 Nucleic Acids Res. 23, 2677-2684). Those of ordinary skill in the art will recognize that the scale of synthesis can be adapted to be larger or smaller than the example described above including but not limited to 96 well format, with the ratio of chemicals being used in the reaction adjusted accordingly.

[0128] Alternatively, the nucleic acid molecules of the present invention can be synthesized separately and joined together post-synthetically, for example by ligation (Moore et al., 1992, Science 256, 9923; Draper et al., International PCT publication No. WO 93/23569; Shabarova et al., 1991, Nucleic Acids Research 19, 4247; Bellon et al., 1997, Nucleosides & Nucleotides, 16, 951; Bellon et al., 1997, Bioconjugate Chem. 8, 204).

[0129] The nucleic acid molecules of the present invention are modified extensively to enhance stability by modification with nuclease resistant groups, for example, 2′-amino, 2′-C-allyl, 2′-flouro, 2′-O-methyl, 2′-H (for a review see Usman and Cedergren, 1992, TIBS 17, 34; Usman et al., 1994, Nucleic Acids Symp. Ser. 31, 163). Ribozymes are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al., Supra, the totality of which is hereby incorporated herein by reference) and are re-suspended in water.

[0130] The sequences of the nucleic acid molecules, including enzymatic nucleic acid molecules and antisense, that are chemically synthesized, are shown in Table VII. The sequences of the enzymatic nucleic acid and antisense constructs that are chemically synthesized, are complementary to the Substrate sequences shown in Table VII. Those in the art will recognize that these sequences are representative only of many more such sequences where the enzymatic portion of the ribozyme (all but the binding arms) is altered to affect activity. The enzymatic nucleic acid and antisense construct sequences listed in Tables III to VII can be formed of ribonucleotides or other nucleotides or non-nucleotides. Such enzymatic nucleic acid molecules with enzymatic activity are equivalent to the enzymatic nucleic acid molecules described specifically in the Tables.

[0131] Optimizing Activity of the Nucleic Acid Molecule of the Invention

[0132] Chemically synthesizing nucleic acid molecules with modifications (base, sugar and/or phosphate) that prevent their degradation by serum ribonucleases can increase their potency (see e.g., Eckstein et al., International Publication No. WO 92/07065; Perrault et al., 1990 Nature 344, 565; Pieken et al., 1991, Science 253, 314; Usman and Cedergren, 1992, Trends in Biochem. Sci. 17, 334; Usman et al., International Publication No. WO 93/15187; and Rossi et al., International Publication No. WO 91/03162; Sproat, U.S. Pat. No. 5,334,711; and Burgin et al., supra; all of these describe various chemical modifications that can be made to the base, phosphate and/or sugar moieties of the nucleic acid molecules herein). Modifications which enhance their efficacy in cells, and removal of bases from nucleic acid molecules to shorten oligonucleotide synthesis times and reduce chemical requirements are desired. (All these publications are hereby incorporated by reference herein).

[0133] There are several examples in the art describing sugar, base and phosphate modifications that can be introduced into nucleic acid molecules with significant enhancement in their nuclease stability and efficacy. For example, oligonucleotides are modified to enhance stability and/or enhance biological activity by modification with nuclease resistant groups, for example, 2′-amino, 2′-C-allyl, 2′-flouro, 2′-O-methyl, 2′-H, nucleotide base modifications (for a review see Usman and Cedergren, 1992, TIBS. 17, 34; Usman et al., 1994, Nucleic Acids Symp. Ser. 31, 163; Burgin et al., 1996, Biochemistry , 35, 14090). Sugar modification of nucleic acid molecules have been extensively described in the art (see Eckstein et al., International Publication PCT No. WO 92/07065; Perrault et al. Nature, 1990, 344, 565-568; Pieken et al. Science, 1991, 253, 314-317; Usman and Cedergren, Trends in Biochem. Sci. , 1992, 17, 334-339; Usman et al. International Publication PCT No. WO 93/15187; Sproat, U.S. Pat. No. 5,334,711 and Beigelman et al., 1995, J. Biol. Chem., 270, 25702; Beigelman et al., International PCT publication No. WO 97/26270; Beigelman et al., U.S. Pat. No. 5,716,824; Usman et al., U.S. Pat. No. 5,627,053; Woolf et al., International PCT Publication No. WO 98/13526; Thompson et al., U.S. Ser. No. 60/082,404 which was filed on Apr. 20, 1998; Karpeisky et al., 1998, Tetrahedron Lett., 39, 1131; Earnshaw and Gait, 1998, Biopolymers (Nucleic acid Sciences), 48, 39-55; Verma and Eckstein, 1998, Annu. Rev. Biochem., 67, 99-134; and Burlina et al., 1997, Bioorg. Med. Chem., 5, 1999-2010; all of the references are hereby incorporated in their totality by reference herein). Such publications describe general methods and strategies to determine the location of incorporation of sugar, base and/or phosphate modifications and the like into ribozymes without inhibiting catalysis, and are incorporated by reference herein. In view of such teachings, similar modifications can be used as described herein to modify the nucleic acid molecules of the instant invention.

[0134] While chemical modification of oligonucleotide internucleotide linkages with phosphorothioate, phosphorothioate, and/or 5′-methylphosphonate linkages improves stability, too many of these modifications can cause some toxicity. Therefore when designing nucleic acid molecules the amount of these internucleotide linkages should be minimized. The reduction in the concentration of these linkages should lower toxicity resulting in increased efficacy and higher specificity of these molecules.

[0135] Nucleic acid molecules having chemical modifications that maintain or enhance activity are provided. Such nucleic acid is also generally more resistant to nucleases than unmodified nucleic acid. Thus, in a cell and/or in vivo the activity may not be significantly lowered. Therapeutic nucleic acid molecules delivered exogenously are optimally stable within cells until translation of the target RNA has been inhibited long enough to reduce the levels of the undesirable protein. This period of time varies between hours to days depending upon the disease state. Nucleic acid molecules are preferably resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of RNA and DNA (Wincott et al., 1995 Nucleic Acids Res. 23, 2677; Caruthers et al., 1992, Methods in Enzymology 211,3-19 (incorporated by reference herein) have expanded the ability to modify nucleic acid molecules by introducing nucleotide modifications to enhance their nuclease stability as described above.

[0136] Use of the nucleic acid-based molecules of the invention can lead to better treatment of the disease progression by affording the possibility of combination therapies (e.g., multiple antisense or enzymatic nucleic acid molecules targeted to different genes, nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of molecules (including different motifs) and/or other chemical or biological molecules). The treatment of patients with nucleic acid molecules can also include combinations of different types of nucleic acid molecules.

[0137] Therapeutic nucleic acid molecules (e.g., enzymatic nucleic acid molecules and antisense nucleic acid molecules) delivered exogenously are optimally stable within cells until translation of the target RNA has been inhibited long enough to reduce the levels of the undesirable protein. This period of time varies between hours to days depending upon the disease state. These nucleic acid molecules should be resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of nucleic acid molecules described in the instant invention and in the art have expanded the ability to modify nucleic acid molecules by introducing nucleotide modifications to enhance their nuclease stability as described above.

[0138] In one embodiment, nucleic acid catalysts having chemical modifications that maintain or enhance enzymatic activity are provided. Such nucleic acids are also generally more resistant to nucleases than unmodified nucleic acid. Thus, in a cell and/or in vivo the activity of the nucleic acid may not be significantly lowered. As exemplified herein such enzymatic nucleic acids are useful in a cell and/or in vivo even if activity over all is reduced about 10 fold (Burgin et al., 1996, Biochemistry, 35, 14090). Such enzymatic nucleic acids herein are said to “maintain” the enzymatic activity of an all RNA ribozyme or all DNA DNAzyme.

[0139] In another aspect the nucleic acid molecules comprise a 5′ and/or a 3′-cap structure.

[0140] By “cap structure” is meant chemical modifications, which have been incorporated at either terminus of the oligonucleotide (see for example Wincott et al., WO 97/26270, incorporated by reference herein). These terminal modifications protect the nucleic acid molecule from exonuclease degradation, and can help in delivery and/or localization within a cell. The cap can be present at the 5′-terminus (5′-cap) or at the 3′-terminus (3′-cap) or can be present on both terminus. In non-limiting examples, the 5′-cap includes inverted abasic residue (moiety), 4′,5′-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide, 4′-thio nucleotide, carbocyclic nucleotide; 1,5-anhydrohexitol nucleotide; L-nucleotides; alpha-nucleotides; modified base nucleotide; phosphorodithioate linkage; threo-pentofuranosyl nucleotide; acyclic 3′,4′-seco nucleotide; acyclic 3,4-dihydroxybutyl nucleotide; acyclic 3,5-dihydroxypentyl nucleotide, 3′-3′inverted nucleotide moiety; 3′-3′-inverted abasic moiety; 3′-2′-inverted nucleotide moiety; 3′-2′-inverted abasic moiety; 1,4-butanediol phosphate; 3′-phosphoramidate; hexylphosphate; aminohexyl phosphate; 3′-phosphate; 3′-phosphorothioate; phosphorodithioate; or bridging or non-bridging methylphosphonate moiety (for more details see Wincott et al., International PCT publication No. WO 97/26270, incorporated by reference herein).

[0141] In another embodiment the 3′-cap includes, for example 4′,5′-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide; 4′-thio nucleotide, carbocyclic nucleotide; 5′-amino-alkyl phosphate; 1,3-diamino-2-propyl phosphate, 3-aminopropyl phosphate; 6-aminohexyl phosphate; 1,2-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitol nucleotide; L-nucleotide; alpha-nucleotide; modified base nucleotide; phosphorodithioate; threo-pentofuranosyl nucleotide; acyclic 3′,4′-seco nucleotide; 3,4-dihydroxybutyl nucleotide; 3,5-dihydroxypentyl nucleotide, 5′-5′-inverted nucleotide moiety; 5′-5′-inverted abasic moiety; 5′-phosphoramidate; 5′-phosphorothioate; 1,4-butanediol phosphate; 5′-amino; bridging and/or non-bridging 5′-phosphoramidate, phosphorothioate and/or phosphorodithioate, bridging or non bridging methylphosphonate and 5′-mercapto moieties (for more details see Beaucage and Iyer, 1993, Tetrahedron 49, 1925; incorporated by reference herein).

[0142] By the term “non-nucleotide” is meant any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound is abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine.

[0143] The term “alkyl” as used herein refers to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain “isoalkyl”, and cyclic alkyl groups. The term “alkyl” also comprises alkoxy, alkyl-thio, alkyl-thio-alkyl, alkoxyalkyl, alkylamino, alkenyl, alkynyl, alkoxy, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, C1-C6 hydrocarbyl, aryl or substituted aryl groups. Preferably, the alkyl group has 1 to 12 carbons. More preferably it is a lower alkyl of from about 1 to 7 carbons, more preferably about 1 to 4 carbons. The alkyl group can be substituted or unsubstituted. When substituted the substituted group(s) preferably comprise hydroxy, oxy, thio, amino, nitro, cyano, alkoxy, alkyl-thio, alkyl-thio-alkyl, alkoxyalkyl, alkylamino, silyl, alkenyl, alkynyl, alkoxy, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, C1-C6 hydrocarbyl, aryl or substituted aryl groups. The term “alkyl” also includes alkenyl groups containing at least one carbon-carbon double bond, including straight-chain, branched-chain, and cyclic groups. Preferably, the alkenyl group has about 2 to 12 carbons. More preferably it is a lower alkenyl of from about 2 to 7 carbons, more preferably about 2 to 4 carbons. The alkenyl group can be substituted or unsubstituted. When substituted the substituted group(s) preferably comprise hydroxy, oxy, thio, amino, nitro, cyano, alkoxy, alkyl-thio, alkyl-thio-alkyl, alkoxyalkyl, alkylamino, silyl, alkenyl, alkynyl, alkoxy, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, C1-C6 hydrocarbyl, aryl or substituted aryl groups. The term “alkyl” also includes alkynyl groups containing at least one carbon-carbon triple bond, including straight-chain, branched-chain, and cyclic groups. Preferably, the alkynyl group has about 2 to 12 carbons. More preferably it is a lower alkynyl of from about 2 to 7 carbons, more preferably about 2 to 4 carbons. The alkynyl group can be substituted or unsubstituted. When substituted the substituted group(s) preferably comprise hydroxy, oxy, thio, amino, nitro, cyano, alkoxy, alkyl-thio, alkyl-thio-alkyl, alkoxyalkyl, alkylamino, silyl, alkenyl, alkynyl, alkoxy, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, C1-C6 hydrocarbyl, aryl or substituted aryl groups. Alkyl groups or moieties of the invention can also include aryl, alkylaryl, carbocyclic aryl, heterocyclic aryl, amide and ester groups. The preferred substituent(s) of aryl groups are halogen, trihalomethyl, hydroxyl, SH, OH, cyano, alkoxy, alkyl, alkenyl, alkynyl, and amino groups. An “alkylaryl” group refers to an alkyl group (as described above) covalently joined to an aryl group (as described above). Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are all carbon atoms. The carbon atoms are optionally substituted. Heterocyclic aryl groups are groups having from about 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen, and include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like, all optionally substituted. An “amide” refers to an —C(O)—NH—R, where R is either alkyl, aryl, alkylaryl or hydrogen. An “ester” refers to an —C(O)—OR′, where R is either alkyl, aryl, alkylaryl or hydrogen.

[0144] The term “alkoxyalkyl” as used herein refers to an alkyl-O-alkyl ether, for example methoxyethyl or ethoxymethyl.

[0145] The term “alkyl-thio-alkyl” as used herein refers to an alkyl-S-alkyl thioether, for example methylthiomethyl or methylthioethyl.

[0146] The term “amino” as used herein refers to a nitrogen containing group as is known in the art derived from ammonia by the replacement of one or more hydrogen radicals by organic radicals. For example, the terms “aminoacyl” and “aminoalkyl” refer to specific N-substituted organic radicals with acyl and alkyl substituent groups respectively.

[0147] The term “amination” as used herein refers to a process in which an amino group or substituted amine is introduced into an organic molecule.

[0148] The term “exocyclic amine protecting moiety” as used herein refers to a nucleobase amino protecting group compatible with oligonucleotide synthesis, for example an acyl or amide group.

[0149] The term “alkenyl” as used herein refers to a straight or branched hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon double bond. Examples of “alkenyl” include vinyl, allyl, and 2-methyl-3-heptene.

[0150] The term “alkoxy” as used herein refers to an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge. Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy and isopropoxy.

[0151] The term “alkynyl” as used herein refers to a straight or branched hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon triple bond. Examples of “alkynyl” include propargyl, propyne, and 3-hexyne.

[0152] The term “aryl” as used herein refers to an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring can optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Examples of aryl groups include, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene and biphenyl. Preferred examples of aryl groups include phenyl and naphthyl.

[0153] The term “cycloalkenyl” as used herein refers to a C3-C8 cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.

[0154] The term “cycloalkyl” as used herein refers to a C3-C8 cyclic hydrocarbon. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0155] The term “cycloalkylalkyl,” as used herein, refers to a C3-C7 cycloalkyl group attached to the parent molecular moiety through an alkyl group, as defined above. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.

[0156] The terms “halogen” or “halo” as used herein refers to indicate fluorine, chlorine, bromine, and iodine.

[0157] The term “heterocycloalkyl,” as used herein refers to a non-aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl ring can be optionally fused to or otherwise attached to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings. Preferred heterocycloalkyl groups have from 3 to 7 members. Examples of heterocycloalkyl groups include, for example, piperazine, morpholine, piperidine, tetrahydrofuran, pyrrolidine, and pyrazole. Preferred heterocycloalkyl groups include piperidinyl, piperazinyl, morpholinyl, and pyrolidinyl.

[0158] The term “heteroaryl” as used herein refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The heteroaryl ring can be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings. Examples of heteroaryl groups include, for example, pyridine, furan, thiophene, 5,6,7,8-tetrahydroisoquinoline and pyrimidine. Preferred examples of heteroaryl groups include thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl.

[0159] The term “C1-C6 hydrocarbyl” as used herein refers to straight, branched, or cyclic alkyl groups having 1-6 carbon atoms, optionally containing one or more carbon-carbon double or triple bonds. Examples of hydrocarbyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, vinyl, 2-pentene, cyclopropylmethyl, cyclopropyl, cyclohexylmethyl, cyclohexyl and propargyl. When reference is made herein to C1-C6 hydrocarbyl containing one or two double or triple bonds it is understood that at least two carbons are present in the alkyl for one double or triple bond, and at least four carbons for two double or triple bonds.

[0160] By “nucleotide” is meant a heterocyclic nitrogenous base in N-glycosidic linkage with a phosphorylated sugar. Nucleotides are recognized in the art to include natural bases (standard), and modified bases well known in the art. Such bases are generally located at the 1′ position of a nucleotide sugar moiety. Nucleotides generally comprise a base, sugar and a phosphate group. The nucleotides can be unmodified or modified at the sugar, phosphate and/or base moiety, (also referred to interchangeably as nucleotide analogs, modified nucleotides, non-natural nucleotides, non-standard nucleotides and other; see for example, Usman and McSwiggen, supra; Eckstein et al., International PCT Publication No. WO 92/07065; Usman et al., International PCT Publication No. WO 93/15187; Uhlman & Peyman, supra all are hereby incorporated by reference herein). There are several examples of modified nucleic acid bases known in the art as summarized by Limbach et al., 1994, Nucleic Acids Res. 22, 2183. Some of the non-limiting examples of chemically modified and other natural nucleic acid bases that can be introduced into nucleic acids include, for example, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2,4,6-trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines (e.g. 6-methyluridine), propyne, quesosine, 2-thiouridine, 4-thiouridine, wybutosine, wybutoxosine, 4-acetylcytidine, 5-(carboxyhydroxymethyl)uridine, 5′-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluridine, beta-D-galactosylqueosine, 1-methyladenosine, 1-methylinosine, 2,2-dimethylguanosine, 3-methylcytidine, 2-methyladenosine, 2-methylguanosine, N6-methyladenosine, 7-methylguanosine, 5-methoxyaminomethyl-2-thiouridine, 5-methylaminomethyluridine, 5-methylcarbonylmethyluridine, 5-methyloxyuridine, 5-methyl-2-thiouridine, 2-methylthio-N6-isopentenyladenosine, beta-D-mannosylqueosine, uridine-5-oxyacetic acid, 2-thiocytidine, threonine derivatives and others (Burgin et al., 1996, Biochemistry, 35, 14090; Uhlman & Peyman, supra). By “modified bases” in this aspect is meant nucleotide bases other than adenine, guanine, cytosine and uracil at 1′ position or their equivalents; such bases can be used at any position, for example, within the catalytic core of an enzymatic nucleic acid molecule and/or in the substrate-binding regions of the nucleic acid molecule.

[0161] By “nucleoside” is meant a heterocyclic nitrogenous base in N-glycosidic linkage with a sugar. Nucleosides are recognized in the art to include natural bases (standard), and modified bases well known in the art. Such bases are generally located at the 1′ position of a nucleoside sugar moiety. Nucleosides generally comprise a base and sugar group. The nucleosides can be unmodified or modified at the sugar, and/or base moiety, (also referred to interchangeably as nucleoside analogs, modified nucleosides, non-natural nucleosides, non-standard nucleosides and other; see for example, Usman and McSwiggen, supra; Eckstein et al., International PCT Publication No. WO 92/07065; Usman et al., International PCT Publication No. WO 93/15187; Uhlman & Peyman, supra all are hereby incorporated by reference herein). There are several examples of modified nucleic acid bases known in the art as summarized by Limbach et al., 1994, Nucleic Acids Res. 22, 2183. Some of the non-limiting examples of chemically modified and other natural nucleic acid bases that can be introduced into nucleic acids include, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2, 4, 6-trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines (e.g. 6-methyluridine), propyne, quesosine, 2-thiouridine, 4-thiouridine, wybutosine, wybutoxosine, 4-acetylcytidine, 5-(carboxyhydroxymethyl)uridine, 5′-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluridine, beta-D-galactosylqueosine, 1-methyladenosine, 1-methylinosine, 2,2-dimethylguanosine, 3-methylcytidine, 2-methyladenosine, 2-methylguanosine, N6-methyladenosine, 7-methylguanosine, 5-methoxyaminomethyl-2-thiouridine, 5-methylaminomethyluridine, 5-methylcarbonylmethyluridine, 5-methyloxyuridine, 5-methyl-2-thiouridine, 2-methylthio-N6-isopentenyladenosine, beta-D-mannosylqueosine, uridine-5-oxyacetic acid, 2-thiocytidine, threonine derivatives and others (Burgin et al., 1996, Biochemistry, 35, 14090; Uhlman & Peyman, supra). By “modified bases” in this aspect is meant nucleoside bases other than adenine, guanine, cytosine and uracil at 1′ position or their equivalents; such bases can be used at any position, for example, within the catalytic core of an enzymatic nucleic acid molecule and/or in the substrate-binding regions of the nucleic acid molecule.

[0162] In one embodiment, the invention features modified enzymatic nucleic acid molecules with phosphate backbone modifications comprising one or more phosphorothioate, phosphorodithioate, methylphosphonate, morpholino, amidate carbamate, carboxymethyl, acetamidate, polyamide, sulfonate, sulfonamide, sulfamate, formacetal, thioformacetal, and/or alkylsilyl, substitutions. For a review of oligonucleotide backbone modifications see Hunziker and Leumann, 1995, Nucleic Acid Analogues: Synthesis and Properties, in Modern Synthetic Methods, VCH, 331-417, and Mesmaeker et al., 1994, Novel Backbone Replacements for Oligonucleotides, in Carbohydrate Modifications in Antisense Research, ACS, 24-39. These references are hereby incorporated by reference herein.

[0163] By “abasic” is meant sugar moieties lacking a base or having other chemical groups in place of a base at the 1′ position, for example a 3′,3′-linked or 5′,5′-linked deoxyabasic ribose derivative (for more details see Wincott et al., International PCT publication No. WO 97/26270).

[0164] By “unmodified nucleoside” is meant one of the bases adenine, cytosine, guanine, thymine, uracil joined to the 1′carbon of β-D-ribo-furanose.

[0165] By “modified nucleoside” is meant any nucleotide base which contains a modification in the chemical structure of an unmodified nucleotide base, sugar and/or phosphate.

[0166] In connection with 2′-modified nucleotides as described for the present invention, by “amino” is meant 2′-NH2 or 2′-O-NH2, which can be modified or unmodified. Such modified groups are described, for example, in Eckstein et al., U.S. Pat. No. 5,672,695 and Matulic-Adamic et al., WO 98/28317, respectively, which are both incorporated by reference in their entireties.

[0167] Various modifications to nucleic acid (e.g., antisense and ribozyme) structure can be made to enhance the utility of these molecules. For example, such modifications can enhance shelf-life, half-life in vitro, stability, and ease of introduction of such oligonucleotides to the target site, including e.g., enhancing penetration of cellular membranes and conferring the ability to recognize and bind to targeted cells.

[0168] Use of these molecules can lead to better treatment of the disease progression by affording the possibility of combination therapies (e.g., multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules (including different enzymatic nucleic acid molecule motifs) and/or other chemical or biological molecules). The treatment of patients with nucleic acid molecules can also include combinations of different types of nucleic acid molecules. Therapies can be devised which include a mixture of enzymatic nucleic acid molecules (including different enzymatic nucleic acid molecule motifs), antisense and/or 2-5A chimera molecules to one or more targets to alleviate symptoms of a disease.

[0169] Administration of Nucleic Acid Molecules

[0170] Methods for the delivery of nucleic acid molecules are described in Akhtar et al., 1992, Trends Cell Bio., 2, 139; and Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed. Akhtar, 1995 which are both incorporated herein by reference. Sullivan et al., PCT WO 94/02595, further describes the general methods for delivery of enzymatic RNA molecules. These protocols can be utilized for the delivery of virtually any nucleic acid molecule. Nucleic acid molecules can be administered to cells by a variety of methods known to those familiar to the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as hydrogels, cyclodextrins, biodegradable nanocapsules, and bioadhesive microspheres. Alternatively, the nucleic acid/vehicle combination is locally delivered by direct injection or by use of an infusion pump. Other routes of delivery include, but are not limited to oral (tablet or pill form) and/or intrathecal delivery (Gold, 1997, Neuroscience, 76, 1153-1158). Other approaches include the use of various transport and carrier systems, for example, through the use of conjugates and biodegradable polymers. For a comprehensive review on drug delivery strategies including CNS delivery, see Ho et al., 1999, Curr. Opin. Mol. Ther., 1, 336-343 and Jain, Drug Delivery Systems: Technologies and Commercial Opportunities, Decision Resources, 1998 and Groothuis et al., 1997, J. NeuroVirol., 3, 387-400. More detailed descriptions of nucleic acid delivery and administration are provided in Sullivan et al., supra, Draper et al., PCT WO93/23569, Beigelman et al., PCT WO99/05094, and Klimuk et al., PCT WO99/04819 all of which have been incorporated by reference herein.

[0171] The molecules of the instant invention can be used as pharmaceutical agents. Pharmaceutical agents prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state in a patient.

[0172] The negatively charged polynucleotides of the invention can be administered (e.g., RNA, DNA or protein) and introduced into a patient by any standard means, with or without stabilizers, buffers, and the like, to form a pharmaceutical composition. When it is desired to use a liposome delivery mechanism, standard protocols for formation of liposomes can be followed. The compositions of the present invention can also be formulated and used as tablets, capsules or elixirs for oral administration; suppositories for rectal administration; sterile solutions; suspensions for injectable administration; and the other compositions known in the art.

[0173] The present invention also includes pharmaceutically acceptable formulations of the compounds described. These formulations include salts of the above compounds, e.g., acid addition salts, for example, salts of hydrochloric, hydrobromic, acetic acid, and benzene sulfonic acid.

[0174] A pharmacological composition or formulation refers to a composition or formulation in a form suitable for administration, e.g., systemic administration, into a cell or patient, preferably a human. Suitable forms, in part, depend upon the use or the route of entry, for example oral, transdermal, or by injection. Such forms should not prevent the composition or formulation from reaching a target cell (i.e., a cell to which the negatively charged polymer is desired to be delivered to). For example, pharmacological compositions injected into the blood stream should be soluble. Other factors are known in the art, and include considerations such as toxicity and forms which prevent the composition or formulation from exerting its effect.

[0175] By “systemic administration” is meant in vivo systemic absorption or accumulation of drugs in the blood stream followed by distribution throughout the entire body. Administration routes which lead to systemic absorption include, without limitations: intravenous, subcutaneous, intraperitoneal, inhalation, oral, intrapulmonary and intramuscular. Each of these administration routes expose the desired negatively charged polymers, e.g., nucleic acids, to an accessible diseased tissue. The rate of entry of a drug into the circulation has been shown to be a function of molecular weight or size. The use of a liposome or other drug carrier comprising the compounds of the instant invention can potentially localize the drug, for example, in certain tissue types, such as the tissues of the reticular endothelial system (RES). A liposome formulation which can facilitate the association of drug with the surface of cells, such as, lymphocytes and macrophages is also useful. This approach can provide enhanced delivery of the drug to target cells by taking advantage of the specificity of macrophage and lymphocyte immune recognition of abnormal cells, such as cancer cells.

[0176] By pharmaceutically acceptable formulation is meant, a composition or formulation that allows for the effective distribution of the nucleic acid molecules of the instant invention in the physical location most suitable for their desired activity. Non-limiting examples of agents suitable for formulation with the nucleic acid molecules of the instant invention include: PEG conjugated nucleic acids, phospholipid conjugated nucleic acids, nucleic acids containing lipophilic moieties, phosphorothioates, P-glycoprotein inhibitors (such as Pluronic P85) which can enhance entry of drugs into various tissues, for example the CNS (Jolliet-Riant and Tillement, 1999, Fundam. Clin. Pharmacol., 13, 16-26); biodegradable polymers, such as poly (DL-lactide-coglycolide) microspheres for sustained release delivery after implantation (Emerich, D F et al., 1999, Cell Transplant, 8, 47-58) Alkermes, Inc. Cambridge, Mass.; and loaded nanoparticles, such as those made of polybutylcyanoacrylate, which can deliver drugs across the blood brain barrier and can alter neuronal uptake mechanisms (Prog Neuropsychopharmacol Biol Psychiatry, 23, 941-949, 1999). Other non-limiting examples of delivery strategies, including CNS delivery of the nucleic acid molecules of the instant invention include material described in Boado et al., 1998, J. Pharm. Sci., 87, 1308-1315; Tyler et al., 1999, FEBS Lett., 421, 280-284; Pardridge et al., 1995, PNAS USA., 92, 5592-5596; Boado, 1995, Adv. Drug Delivery Rev., 15, 73-107; Aldrian-Herrada et al., 1998, Nucleic Acids Res., 26, 4910-4916; and Tyler et al., 1999, PNAS USA., 96, 7053-7058. All these references are hereby incorporated herein by reference.

[0177] The invention also features the use of the composition comprising surface-modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or long-circulating liposomes or stealth liposomes). Nucleic acid molecules of the invention can also comprise covalently attached PEG molecules of various molecular weights. These formulations offer a method for increasing the accumulation of drugs in target tissues. This class of drug carriers resists opsonization and elimination by the mononuclear phagocytic system (MPS or RES), thereby enabling longer blood circulation times and enhanced tissue exposure for the encapsulated drug (Lasic et al. Chem. Rev. 1995, 95, 2601-2627; Ishiwata et al., Chem. Pharm. Bull. 1995, 43, 1005-1011). Such liposomes have been shown to accumulate selectively in tumors, presumably by extravasation and capture in the neovascularized target tissues (Lasic et al., Science 1995, 267, 1275-1276; Oku et al.,1995, Biochim. Biophys. Acta, 1238, 86-90). The long-circulating liposomes enhance the pharmacokinetics and pharmacodynamics of DNA and RNA, particularly compared to conventional cationic liposomes which are known to accumulate in tissues of the MPS (Liu et al., J. Biol. Chem. 1995, 42, 24864-24870; Choi et al., International PCT Publication No. WO 96/10391; Ansell et al., International PCT Publication No. WO 96/10390; Holland et al., International PCT Publication No. WO 96/10392; all of which are incorporated by reference herein). Long-circulating liposomes are also likely to protect drugs from nuclease degradation to a greater extent compared to cationic liposomes, based on their ability to avoid accumulation in metabolically aggressive MPS tissues such as the liver and spleen. All of these references are incorporated by reference herein.

[0178] The present invention also includes compositions prepared for storage or administration which include a pharmaceutically effective amount of the desired compounds in a pharmaceutically acceptable carrier or diluent. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985) hereby incorporated by reference herein. For example, preservatives, stabilizers, dyes and flavoring agents can be provided. These include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. In addition, antioxidants and suspending agents can be used.

[0179] A pharmaceutically effective dose is that dose required to prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state. The pharmaceutically effective dose depends on the type of disease, the composition used, the route of administration, the type of mammal being treated, the physical characteristics of the specific mammal under consideration, concurrent medication, and other factors which those skilled in the medical arts will recognize. Generally, an amount between 0.1 mg/kg and 100 mg/kg body weight/day of active ingredients is administered dependent upon potency of the negatively charged polymer.

[0180] The nucleic acid molecules of the invention and formulations thereof can be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like. In addition, there is provided a pharmaceutical formulation comprising a nucleic acid molecule of the invention and a pharmaceutically acceptable carrier. One or more nucleic acid molecules of the invention can be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired other active ingredients. The pharmaceutical compositions containing nucleic acid molecules of the invention can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

[0181] Compositions intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more such sweetening agents, flavoring agents, coloring agents or preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques. In some cases such coatings can be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate can be employed.

[0182] Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

[0183] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions can also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0184] Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents can be added to provide palatable oral preparations. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.

[0185] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.

[0186] Pharmaceutical compositions of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents can be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening and flavoring agents.

[0187] Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations can also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0188] The nucleic acid molecules of the invention can also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

[0189] Nucleic acid molecules of the invention can be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

[0190] Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration. Dosage unit forms generally contain between from about 1 mg to about 500 mg of an active ingredient.

[0191] It is understood that the specific dose level for any particular patient depends upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

[0192] For administration to non-human animals, the composition can also be added to the animal feed or drinking water. It can be convenient to formulate the animal feed and drinking water compositions so that the animal takes in a therapeutically appropriate quantity of the composition along with its diet. It can also be convenient to present the composition as a premix for addition to the feed or drinking water.

[0193] The nucleic acid molecules of the present invention can also be administered to a patient in combination with other therapeutic compounds to increase the overall therapeutic effect. The use of multiple compounds to treat an indication can increase the beneficial effects while reducing the presence of side effects.

[0194] Alternatively, certain of the nucleic acid molecules of the instant invention can be expressed within cells from eukaryotic promoters (e.g., Izant and Weintraub, 1985, Science, 229, 345; McGarry and Lindquist, 1986, Proc. Natl. Acad. Sci., USA 83, 399; Scanlon et al., 1991, Proc. Natl. Acad. Sci. USA, 88, 10591-5; Kashani-Sabet et al., 1992, Antisense Res. Dev., 2,3-15; Dropulic et al., 1992, J. Virol., 66, 1432-41; Weerasinghe et al., 1991, J. Virol., 65, 5531-4; Ojwang et al., 1992, Proc. Natl. Acad. Sci. USA, 89, 10802-6; Chen et al., 1992, Nucleic Acids Res., 20, 4581-9; Sarver et al., 1990 Science, 247, 1222-1225; Thompson et al., 1995, Nucleic Acids Res., 23, 2259; Good et al., 1997, Gene Therapy, 4, 45; all of these references are hereby incorporated in their totalities by reference herein). Those skilled in the art realize that any nucleic acid can be expressed in eukaryotic cells from the appropriate DNA/RNA vector. The activity of such nucleic acids can be augmented by their release from the primary transcript by a enzymatic nucleic acid (Draper et al., PCT WO 93/23569, and Sullivan et al., PCT WO 94/02595; Ohkawa et al., 1992, Nucleic Acids Symp. Ser., 27, 15-6; Taira et al., 1991, Nucleic Acids Res., 19, 5125-30; Ventura et al., 1993, Nucleic Acids Res., 21, 3249-55; Chowrira et al., 1994, J. Biol. Chem., 269, 25856; all of these references are hereby incorporated in their totalities by reference herein). Gene therapy approaches specific to the CNS are described by Blesch et al., 2000, Drug News Perspect., 13, 269-280; Peterson et al. 2000, Cent. Nerv. Syst. Dis., 485-508; Peel and Klein, 2000, J. Neurosci. Methods, 98, 95-104; Hagihara et al., 2000, Gene Ther., 7, 759-763; and Herrlinger et al., 2000, Methods Mol. Med., 35, 287-312. AAV-mediated delivery of nucleic acid to cells of the nervous system is further described by Kaplitt et al., U.S. Pat. No. 6,180,613.

[0195] In another aspect of the invention, RNA molecules of the present invention are preferably expressed from transcription units (see for example Couture et al., 1996, TIG., 12, 510) inserted into DNA or RNA vectors. The recombinant vectors are preferably DNA plasmids or viral vectors. Ribozyme expressing viral vectors can be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. Preferably, the recombinant vectors capable of expressing the nucleic acid molecules are delivered as described above, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of nucleic acid molecules. Such vectors can be repeatedly administered as necessary. Once expressed, the nucleic acid molecule binds to the target mRNA. Delivery of nucleic acid molecule expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that would allow for introduction into the desired target cell (for a review see Couture et al., 1996, TIG., 12, 510).

[0196] In one aspect the invention features an expression vector comprising a nucleic acid sequence encoding at least one of the nucleic acid molecules of the instant invention is disclosed. The nucleic acid sequence encoding the nucleic acid molecule of the instant invention is operable linked in a manner which allows expression of that nucleic acid molecule.

[0197] In another aspect the invention features an expression vector comprising: a) a transcription initiation region (e.g., eukaryotic pol I, II or III initiation region); b) a transcription termination region (e.g., eukaryotic pol I, II or III termination region); c) a nucleic acid sequence encoding at least one of the nucleic acid catalyst of the instant invention; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. The vector can optionally include an open reading frame (ORF) for a protein operably linked on the 5′ side or the 3′-side of the sequence encoding the nucleic acid catalyst of the invention; and/or an intron (intervening sequences).

[0198] Transcription of the nucleic acid molecule sequences are driven from a promoter for eukaryotic RNA polymerase I (pol I), RNA polymerase II (pol II), or RNA polymerase III (pol III). Transcripts from pol II or pol III promoters are expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type depends on the nature of the gene regulatory sequences (enhancers, silencers, etc.) present nearby. Prokaryotic RNA polymerase promoters are also used, providing that the prokaryotic RNA polymerase enzyme is expressed in the appropriate cells (Elroy-Stein and Moss, 1990, Proc. Natl. Acad. Sci. U S A, 87, 6743-7; Gao and Huang 1993, Nucleic Acids Res., 21, 2867-72; Lieber et al., 1993, Methods Enzymol., 217, 47-66; Zhou et al., 1990, Mol. Cell. Biol., 10, 4529-37). All of these references are incorporated by reference herein. Several investigators have demonstrated that nucleic acid molecules, such as ribozymes expressed from such promoters can function in mammalian cells (e.g. Kashani-Sabet et al., 1992, Antisense Res. Dev., 2, 3-15; Ojwang et al., 1992, Proc. Natl. Acad. Sci. U S A, 89, 10802-6; Chen et al., 1992, Nucleic Acids Res., 20, 4581-9; Yu et al., 1993, Proc. Natl. Acad. Sci. U S A, 90, 6340-4; L'Huillier et al., 1992, EMBO J., 11, 4411-8; Lisziewicz et al., 1993, Proc. Natl. Acad. Sci. U. S. A, 90, 8000-4; Thompson et al., 1995, Nucleic Acids Res., 23, 2259; Sullenger & Cech, 1993, Science, 262, 1566). More specifically, transcription units such as the ones derived from genes encoding U6 small nuclear (snRNA), transfer RNA (tRNA) and adenovirus VA RNA are useful in generating high concentrations of desired RNA molecules such as ribozymes in cells (Thompson et al., supra; Couture and Stinchcomb, 1996, supra; Noonberg et al., 1994, Nucleic Acid Res., 22, 2830; Noonberg et al., U.S. Pat. No. 5,624,803; Good et al., 1997, Gene Ther., 4,45; Beigelman et al., International PCT Publication No. WO 96/18736; all of these publications are incorporated by reference herein. The above ribozyme transcription units can be incorporated into a variety of vectors for introduction into mammalian cells, including but not restricted to, plasmid DNA vectors, viral DNA vectors (such as adenovirus or adeno-associated virus vectors), or viral RNA vectors (such as retroviral or alphavirus vectors) (for a review see Couture and Stinchcomb, 1996, supra).

[0199] In another aspect the invention features an expression vector comprising nucleic acid sequence encoding at least one of the nucleic acid molecules of the invention, in a manner which allows expression of that nucleic acid molecule. The expression vector comprises in one embodiment; a) a transcription initiation region; b) a transcription termination region; c) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

[0200] In another embodiment the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an open reading frame; d) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said sequence is operably linked to the 3′-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. In yet another embodiment the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region, said intron and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

[0201] In another embodiment, the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) an open reading frame; e) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said sequence is operably linked to the 3′-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said intron, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

EXAMPLES

[0202] The following are non-limiting examples showing the selection, isolation, synthesis and activity of nucleic acids of the instant invention.

[0203] The following examples demonstrate the selection and design of Antisense, hammerhead, DNAzyme, NCH, Amberzyme, Zinzyme, or G-Cleaver ribozyme molecules and binding/cleavage sites within REL-A RNA.

Example 1

Identification of Potential Target Sites in Human REL-A RNA

[0204] The sequence of human REL-A genes are screened for accessible sites using a computer-folding algorithm. Regions of the RNA that do not form secondary folding structures and contained potential enzymatic nucleic acid molecule and/or antisense binding/cleavage sites are identified. The sequences of these binding/cleavage sites are shown in Tables III-VII.

Example 2

Selection of Enzymatic Nucleic Acid Cleavage Sites in Human REL-A RNA

[0205] Enzymatic nucleic acid molecule target sites are chosen by analyzing sequences of Human REL-A (Genbank accession No: NM—005228) and prioritizing the sites on the basis of folding. Enzymatic nucleic acid molecules are designed that can bind each target and are individually analyzed by computer folding (Christoffersen et al., 1994 J. Mol. Struc. Theochem, 311, 273; Jaeger et al., 1989, Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whether the enzymatic nucleic acid molecule sequences fold into the appropriate secondary structure. Those enzymatic nucleic acid molecules with unfavorable intramolecular interactions between the binding arms and the catalytic core are eliminated from consideration. As noted below, varying binding arm lengths can be chosen to optimize activity. Generally, at least 5 bases on each arm are able to bind to, or otherwise interact with, the target RNA.

Example 3

Chemical Synthesis and Purification of Ribozymes and Antisense for Efficient Cleavage and/or blocking of REL-A RNA

[0206] Enzymatic nucleic acid molecules and antisense constructs are designed to anneal to various sites in the RNA message. The binding arms of the enzymatic nucleic acid molecules are complementary to the target site sequences described above, while the antisense constructs are fully complementary to the target site sequences described above. The enzymatic nucleic acid molecules and antisense constructs were chemically synthesized. The method of synthesis used followed the procedure for normal RNA synthesis as described above and in Usman et al., (1987 J. Am. Chem. Soc., 109, 7845), Scaringe et al., (1990 Nucleic Acids Res., 18, 5433) and Wincott et al., supra, and made use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end. The average stepwise coupling yields were typically >98%.

[0207] Enzymatic nucleic acid molecules and antisense constructs are also synthesized from DNA templates using bacteriophage T7 RNA polymerase (Milligan and Uhlenbeck, 1989, Methods Enzymol. 180, 51). Enzymatic nucleic acid molecules and antisense constructs are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al., supra; the totality of which is hereby incorporated herein by reference) and are resuspended in water. The sequences of the chemically synthesized enzymatic nucleic acid molecules used in this study are shown below in Table VII. The sequences of the chemically synthesized antisense constructs used in this study are complementary sequences to the Substrate sequences shown below as in Tables III to VII.

Example 4

Enzymatic Nucleic Acid Molecule Cleavage of REL-A RNA Target in Vitro

[0208] Enzymatic nucleic acid molecules targeted to the human REL-A RNA are designed and synthesized as described above. These enzymatic nucleic acid molecules can be tested for cleavage activity in vitro, for example, using the following procedure. The target sequences and the nucleotide location within the REL-A RNA are given in Tables III-VII.

[0209] Cleavage Reactions: Full-length or partially full-length, internally-labeled target RNA for enzymatic nucleic acid molecule cleavage assay is prepared by in vitro transcription in the presence of [a-32P] CTP, passed over a G 50 Sephadex column by spin chromatography and used as substrate RNA without further purification. Alternately, substrates are 5′-32P-end labeled using T4 polynucleotide kinase enzyme. Assays are performed by pre-warming a 2× concentration of purified enzymatic nucleic acid molecule in enzymatic nucleic acid molecule cleavage buffer (50 mM Tris-HCl, pH 7.5 at 37° C., 10 mM MgCl2) and the cleavage reaction was initiated by adding the 2× enzymatic nucleic acid molecule mix to an equal volume of substrate RNA (maximum of 1-5 nM) that was also pre-warmed in cleavage buffer. As an initial screen, assays are carried out for 1 hour at 37° C. using a final concentration of either 40 nM or 1 mM enzymatic nucleic acid molecule, i.e., enzymatic nucleic acid molecule excess. The reaction is quenched by the addition of an equal volume of 95% formamide, 20 mM EDTA, 0.05% bromophenol blue and 0.05% xylene cyanol after which the sample is heated to 95° C. for 2 minutes, quick chilled and loaded onto a denaturing polyacrylamide gel. Substrate RNA and the specific RNA cleavage products generated by enzymatic nucleic acid molecule cleavage are visualized on an autoradiograph of the gel. The percentage of cleavage is determined by Phosphor Imager® quantitation of bands representing the intact substrate and the cleavage products.

Example 5

Nucleic Acid Down-regulation of REL-A target RNA in vivo

[0210] Nucleic acid molecules targeted to the human REL-A RNA are designed and synthesized as described above. These nucleic acid molecules can be tested for cleavage activity in vivo, for example using the procedures described below. The target sequences and the nucleotide location within the REL-A RNA are given in Tables III-VII.

Example 6

In vivo Models used to Evaluate the Down-regulation of REL-A Gene Expression

[0211] A variety of endpoints have been used in cell culture models to evaluate REL-A-mediated effects after treatment with anti-REL-A agents. Phenotypic endpoints include inhibition of cell proliferation, apoptosis assays and reduction of REL-A protein expression. Because overexpression of REL-A is directly associated with increased proliferation of tumor cells, a proliferation endpoint for cell culture assays is preferably used as a primary screen. There are several methods by which this endpoint can be measured. Following treatment of cells with nucleic acid molecules, cells are allowed to grow (typically 5 days) after which either the cell viability, the incorporation of [3H] thymidine into cellular DNA and/or the cell density can be measured. The assay of cell density is very straightforward and can be performed in a 96-well format using commercially available fluorescent nucleic acid stains (such as Syto® 13 or CyQuant®). The assay using CyQuant® is described herein

[0212] As a secondary, confirmatory endpoint a nucleic acid-mediated decrease in the level of REL-A RNA and/or REL-A protein expression can be evaluated.

[0213] Cell Culture

[0214] Cell types that express/over-express NFKB include HeLa, macrophages, peripheral blood lymphocytes, hepatocytes, fibroblasts, endothelial cells and epithelial cells. In culture, these cells can be stimulated to express/over-express NFKB by addition of TNF-alpha PMA or IL-1-beta to the culture medium. Some of these cell types also may respond with a similar activation of NFKB following LPS treatment. Activation of NFKB in cultured cells can be evaluated by electrophoretic mobility shift assay (EMSA). Delineation of alterations in the subunits can be determined by Western blot.

[0215] Primary Screen

[0216] A usefult cell culture system is human colonic epithelial cells. One suitable cell line is SW620 colon carcinoma cells (CCL227). These cells respond to stimulation with TNF-alpha, LPS and/or IL-1-beta with an increase in NFKB activation. SW620 cells are grown in MEM supplemented with 10% heat-inactivated FBS and glutamine (2 mmol/L).

[0217] TNF-alpha dose-response curves in these cells are determined by incubating cells with various concentrations of recombinant human TNF-alpha (Sigma Chemical Co.). Maximal DNA binding activity induction can occur with 150 U/ml TNF-alpha in the culture medium. Induction is typically evident within 10 minutes of treatment with TNF-alpha reaches a peak at one hour post-treatment and persists for up to 4 hours post-treatment. The primary readout can be NFKB DNA activity in nuclear extracts of SW620 cells as determined by electrophoretic mobility shift assays (EMSA). Once the appropriate TNF-alpha dose/response profile has been determined, inhibition of NFKB activation is evaluated using specific and non-specific inhibitors of activation, sultasalazine and steroids, respectively. Cells are incubated with inhibitors or control media for 30 minutes prior to stimulation with TNF-alpha Nuclear extracts are prepared and evaluated for DNA binding activity by EMSA. Once the activity of positive controls has been established, enzymatic nucleic acids targeting the REL-A subunit of NFKB are evaluated in this system. Supershift assays using polyclonal antibodies against the NFKB protein subunits can be performed to confirm down-regulation of the REL-A component of the heterodimer.

[0218] Secondary Screens

[0219] SW620 cells can be transfected with the 3xIg-kappa-B-Luc reporter construct 18 hours before challenge with TNF-alpha, LPS or PMA. The readout for this assay is luciferase activity. Test compounds are applied 17.5 hours after transfection (30 minutes before challenge). Cells are harvested 24 hours after challenge and relative changes in luciferase activity is used as the endpoint. Lastly, the activation of NFKB can be visualized fluorescently. Inactive NFKB heterodimers are held in the cytoplasm by inhibitory proteins. Once activated, the free heterodimers translocate to the nucleus. Thus, the relative change in cytoplasmic versus nuclear fluorescence can indicate the degree of NFKB activation. Cells can be grown on chamber slides, treated with TNF-alpha with and without test compounds), and the location of the REL-A subunit can be determined by immunofluorescence using a FITC-labeled antibody to REL-A.

[0220] Animal Models

[0221] Evaluating the efficacy of anti-REL-A/NFKB agents in animal models is an important prerequisite to human clinical trials. Studies have shown that human breast carcinoma cell lines express high levels of REL-A/NFKB (Sovak et al., 1997, J. Clin. Invest., 100, 2952-2960). High levels of REL-A/NFKB have also been observed in carcinogen-induced primary rat mammary tumors and in human breast cancer specimins. Additionally, HER2/neu overexpression has been shown to activate NFKB (Pianetti et al., 2001, Oncogene, 20, 1287-1299). As such, xenografts of cell lines that over-express NFKB can be used in animal models of tumorigenesis and/or inflammation to study the inhibition of REL-A/NFKB.

[0222] Oncology Animal Model Development

[0223] Tumor cell lines are characterized to establish their growth curves in mice. These cell lines are implanted into both nude and SCID mice and primary tumor volumes are measured 3 times per week. Growth characteristics of these tumor lines using a Matrigel implantation format can also be established. The use of other cell lines that have been engineered to express high levels of REL-A can also be used in the described studies. The tumor cell line(s) and implantation method that supports the most consistent and reliable tumor growth is used in animal studies testing the lead REL-A nucleic acid(s). Nucleic acids are administered by daily subcutaneous injection or by continuous subcutaneous infusion from Alzet mini osmotic pumps beginning 3 days after tumor implantation and continuing for the duration of the study. Group sizes of at least 10 animals are employed. Efficacy is determined by statistical comparison of tumor volume of nucleic acid-treated animals to a control group of animals treated with saline alone. Because the growth of these tumors is generally slow (45-60 days), an initial endpoint is the time in days it takes to establish an easily measurable primary tumor (i.e. 50-100 mm3) in the presence or absence of nucleic acid treatment.

[0224] Inflammation Animal Model Development

[0225] Chronic, sublethal administration of indomethacin to outbred rats produces an enteropathy characterized by thickening of the small intestine and mesentery, ulcerations, granulomatous inflammation, crypt abcesses and adhesions. These lesions are similar to those that are characteristic findings in human patients with Crohn's disease (CD). Thus, any beneficial therapeutic effects revealed using this model can be extrapolated to potential benefit for patients with CD.

[0226] Male Sprague-Dawley rats (200-275 g) are utilized for these studies. Chronic intestinal inflammation is induced by two subcutaneous injections of indomethacin (7.5 mg/kg in 5% NaHCO3) administered on subsequent days (Day-0 and Day-1). Animals are followed for four days following the first indomethacin injection. The mortality rate associated with this model is typically less than 10%. On the last day of the study, animals are euthanized by CO2 asphyxiation, small intestines excised and gross pathologic findings ranked according to the following criteria: 0, normal ; 1, minimal abnormalities, slight thickening of the small intestine, no adhesions; 2, obvious thickening of small intestine with 1 adhesion; 3, obvious thickening of small intestine with 2 or 3 adhesions; 4, massive adhesions to the extent that the intestine cannot be separated, contents primarily fluid; 5, severe peritonitis resulting in death. A 10-cm portion of the most affected region of the small intestine is weighed, placed in 10% neutral buffered formalin and submitted for histopathologic evaluation.

[0227] The 10 cm portion of gut from each animal is cut into five equal sections. Transverse and longitudinal sections of each portion are cut and stained with hematoxylin and eosin. All slides are read in a blinded fashion and each section is scored for necrosis (% area of involvement) and inflammatory response according to the following scale:

[0228] Necrosis 1, 10%; 2, 10-25%; 3, 25-50%; 4, 50-75%; 5, 75-100%;

[0229] Inflammation

[0230] 1=minimal in mesentery and muscle or lesion

[0231] 2=mild in mesentery and muscle or lesion

[0232] 3=moderate in mesentery and muscle or lesion

[0233] 4=marked in lesion

[0234] 5=severe in lesion

[0235] The scores for each of the five sections are averaged for necrosis and for inflammation.

[0236] REL-A Protein Levels for Patient Screening and as a Potential Endpoint

[0237] Because elevated REL-A levels can be detected in cancers, cancer patients can be pre-screened for elevated REL-A prior to admission to initial clinical trials testing an anti-REL-A nucleic acid. Initial REL-A levels can be determined (by ELISA) from tumor biopsies or resected tumor samples. During clinical trials, it may be possible to monitor circulating REL-A protein by ELISA. Evaluation of serial blood/serum samples over the course of the anti-REL-A nucleic acid treatment period could be useful in determining early indications of efficacy.

Example 7

Activity of Nucleic Acid Molecules used to Down-regulate REL-A Gene Expression

[0238] Applicant has designed and synthesized several nucleic acid molecules targeted against REL-A RNA. These nucleic acid molecules can be tested in cell proliferation and RNA reduction assays described herein.

[0239] Proliferation Assay

[0240] The model proliferation assay used in the study requires a cell-plating density of 2,000-10,000 cells/well in 96-well plates and at least 2 cell doublings over a 5-day treatment period. Cells used in proliferation studies were either lung or ovarian cancer cells (A549 and SKOV-3 cells respectively). To calculate cell density for proliferation assays, the FIPS (fluoro-imaging processing system) method known in the art was used. This method allows for cell density measurements after nucleic acids are stained with CyQuant® dye, and has the advantage of accurately measuring cell densities over a very wide range 1,000-100,000 cells/well in 96-well format. Enzymatic nucleic acid molecules (50-200 nM) are delivered in the presence of cationic lipid at 2.5-5.0 μg/mL and inhibition of proliferation was determined on day 5 post-treatment.

[0241] RNA Assay

[0242] RNA is harvested 24 hours post-treatment using the Qiagen RNeasy® 96 procedure. Real time RT-PCR (TaqMan® assay) is performed on purified RNA samples using separate primer/probe sets specific for target REL-A RNA.

[0243] Indications

[0244] Particular degenerative and disease states that can be associated with REL-A expression modulation include but are not limited to cancerous and/or inflammatory diseases and conditions such as breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidrug resistant cancers, rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, and any other diseases or conditions that are related to or respond to the levels of REL-A in a cell or tissue. The present body of knowledge in REL-A research indicates the need for methods to assay REL-A activity and for compounds that can regulate REL-A expression for research, diagnostic, and therapeutic use.

[0245] The use of monoclonal antibodies, chemotherapy, radiation therapy, analgesics, and/or anti-inflammatory compounds, are all non-limiting examples of a methods that can be combined with or used in conjunction with the nucleic acid molecules (e.g. ribozymes and antisense molecules) of the instant invention. Common chemotherapies that can be combined with nucleic acid molecules of the instant invention include various combinations of cytotoxic drugs to kill cancer cells. These drugs include but are not limited to paclitaxel (Taxol), docetaxel, cisplatin, methotrexate, cyclophosphamide, doxorubin, fluorouracil carboplatin, edatrexate, gemcitabine, vinorelbine etc. Those skilled in the art will recognize that other drug compounds and therapies can be similarly be readily combined with the nucleic acid molecules of the instant invention (e.g. ribozymes and antisense molecules) are hence within the scope of the instant invention.

[0246] Diagnostic Uses

[0247] The nucleic acid molecules of this invention (e.g., enzymatic nucleic acid molecules) can be used as diagnostic tools to examine genetic drift and mutations within diseased cells or to detect the presence of REL-A RNA in a cell. The close relationship between enzymatic nucleic acid molecule activity and the structure of the target RNA allows the detection of mutations in any region of the molecule which alters the base-pairing and three-dimensional structure of the target RNA. By using multiple enzymatic nucleic acid molecules described in this invention, one can map nucleotide changes which are important to RNA structure and function in vitro, as well as in cells and tissues. Cleavage of target RNAs with enzymatic nucleic acid molecules can be used to inhibit gene expression and define the role (essentially) of specified gene products in the progression of disease. In this manner, other genetic targets can be defined as important mediators of the disease. These experiments can lead to better treatment of the disease progression by affording the possibility of combinational therapies (e.g., multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules and/or other chemical or biological molecules). Other in vitro uses of enzymatic nucleic acid molecules of this invention are well known in the art, and include detection of the presence of mRNAs associated with REL-A-related condition. Such RNA is detected by determining the presence of a cleavage product after treatment with an enzymatic nucleic acid molecule using standard methodology.

[0248] In a specific example, enzymatic nucleic acid molecules which cleave only wild-type or mutant forms of the target RNA are used for the assay. The first enzymatic nucleic acid molecule is used to identify wild-type RNA present in the sample and the second enzymatic nucleic acid molecule is used to identify mutant RNA in the sample. As reaction controls, synthetic substrates of both wild-type and mutant RNA are cleaved by both enzymatic nucleic acid molecules to demonstrate the relative enzymatic nucleic acid molecule efficiencies in the reactions and the absence of cleavage of the “non-targeted” RNA species. The cleavage products from the synthetic substrates also serve to generate size markers for the analysis of wild-type and mutant RNAs in the sample population. Thus each analysis requires two enzymatic nucleic acid molecules, two substrates and one unknown sample which is combined into six reactions. The presence of cleavage products is determined using an RNAse protection assay so that full-length and cleavage fragments of each RNA can be analyzed in one lane of a polyacrylamide gel. It is not absolutely required to quantify the results to gain insight into the expression of mutant RNAs and putative risk of the desired phenotypic changes in target cells. The expression of mRNA whose protein product is implicated in the development of the phenotype (i.e., REL-A) is adequate to establish risk. If probes of comparable specific activity are used for both transcripts, then a qualitative comparison of RNA levels will be adequate and will decrease the cost of the initial diagnosis. Higher mutant form to wild-type ratios are correlated with higher risk whether RNA levels are compared qualitatively or quantitatively. The use of enzymatic nucleic acid molecules in diagnostic applications contemplated by the instant invention is more fully described in George et al., U.S. Pat. Nos. 5,834,186 and 5,741,679, Shih et al., U.S. Pat. No. 5,589,332, Nathan et al., U.S. Pat. No. 5,871,914, Nathan and Ellington, International PCT publication No. WO 00/24931, Breaker et al., International PCT Publication Nos. WO 00/26226 and 98/27104, and Sullenger et al., International PCT publication No. WO 99/29842.

[0249] Additional Uses

[0250] Potential uses of sequence-specific enzymatic nucleic acid molecules of the instant invention can have many of the same applications for the study of RNA that DNA restriction endonucleases have for the study of DNA (Nathans et al., 1975 Ann. Rev. Biochem. 44:273). For example, the pattern of restriction fragments can be used to establish sequence relationships between two related RNAs, and large RNAs can be specifically cleaved to fragments of a size more useful for study. The ability to engineer sequence specificity of the enzymatic nucleic acid molecule is ideal for cleavage of RNAs of unknown sequence. Applicant has described the use of nucleic acid molecules to down-regulate gene expression of target genes in bacterial, microbial, fungal, viral, and eukaryotic systems including plant, or mammalian cells.

[0251] All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains. All references cited in this disclosure are incorporated by reference to the same extent as if each reference had been incorporated by reference in its entirety individually.

[0252] One skilled in the art would readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The methods and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims.

[0253] It will be readily apparent to one skilled in the art that varying substitutions and modifications can be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, such additional embodiments are within the scope of the present invention and the following claims.

[0254] The invention illustratively described herein suitably can be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising”, “consisting essentially of” and “consisting of” may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments, optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the description and the appended claims.

[0255] In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group.

[0256] Other embodiment are within the claims that follow.

1TABLE ICharacteristics of naturally occurring ribozymesGroup I IntronsSize: ˜150 to >1000 nucleotides.Requires a U in the target sequence immediately 5′ of the cleavage site.Binds 4-6 nucleotides at the 5-side of the cleavage site.Reaction mechanism: attack by the 3′-OH of guanosine to generatecleavage products with 3′-OH and 5′-guanosine.Additional protein cofactors required in some cases to help folding andmaintenance of the active structure.Over 300 known members of this class. Found as an intervening sequencein Tetrahymena thermophila rRNA, fungal mitochondria, chloroplasts,phage T4, blue-green algae, and others.Major structural features largely established through phylogeneticcomparisons, mutagenesis, and biochemical studies [i,ii].Complete kinetic framework established for one ribozyme [iii,iv,v,vi].Studies of ribozyme folding and substrate docking underway [vii,viii,ix].Chemical modification investigation of important residues well established[x,xi].The small (4-6 nt) binding site may make this ribozyme too non-specificfor targeted RNA cleavage, however, the Tetrahymena group I intron hasbeen used to repair a “defective” β-galactosidase message by theligation of new galactosidase sequences onto the defective message [xii].RNAse P RNA (M1 RNA)Size: ˜290 to 400 nucleotides.RNA portion of a ubiquitous ribonucleoprotein enzyme.Cleaves tRNA precursors to form mature tRNA [xiii].Reaction mechanism: possible attack by M2+ -OH to generate cleavageproducts with 3′-OH and 5′-phosphate.RNAse P is found throughout the prokaryotes and eukaryotes. The RNAsubunit has been sequenced from bacteria, yeast, rodents, and primates.Recruitment of endogenous RNAse P for therapeutic applications ispossible through hybridization of an External Guide Sequence (EGS)to the target RNA [xiv,xv]Important phosphate and 2′ OH contacts recently identified [xvi,xvii]Group II IntronsSize: >1000 nucleotides.Trans cleavage of target RNAs recently demonstrated [xviii,xix].Sequence requirements not fully determined.Reaction mechanism: 2′-OH of an internal adenosine generates cleavageproducts with 3′-OH and a “lariat” RNA containing a 3′-5′ and a2′-5′ branch point.Only natural ribozyme with demonstrated participation in DNA cleavage[xx,xxi] in addition to RNA cleavage and ligation.Major structural features largely established through phylogeneticcomparisons [xxii].Important 2′ OH contacts beginning to be identified [xxiii]Kinetic framework under development [xxiv]Neurospora VS RNASize: ˜144 nucleotides.Trans cleavage of hairpin target RNAs recently demonstrated [xxv].Sequence requirements not fully determined.Reaction mechanism: attack by 2′-OH 5′ to the scissile bond togenerate cleavage products with 2′,3′-cyclic phosphate and 5′-OH ends.Binding sites and structural requirements not fully determined.Only 1 known member of this class. Found in Neurospora VS RNA.Hammerhead Ribozyme(see text for references)Size: ˜13 to 40 nucleotides.Requires the target sequence UH immediately 5′ of the cleavage site.Binds a variable number nucleotides on both sides of the cleavage site.Reaction mechanism: attack by 2′-OH 5′ to the scissile bond togenerate cleavage products with 2′,3′-cyclic phosphate and 5′-OH ends.14 known members of this class. Found in a number of plant pathogens(virusoids) that use RNA as the infectious agent.Essential structural features largely defined, including 2 crystal structures[xxvi,xxvii]Minimal ligation activity demonstrated (for engineering through in vitroselection) [xxviii]Complete kinetic framework established for two or more ribozymes [xxix].Chemical modification investigation of important residues well established[xxx].Hairpin RibozymeSize: ˜50 nucleotides.Requires the target sequence GUC immediately 3′ of the cleavage site.Binds 4-6 nucleotides at the 5-side of the cleavage site and a variablenumber to the 3′-side of the cleavage site.Reaction mechanism: attack by 2′-OH 5′ to the scissile bond to generatecleavage products with 2′,3′-cyclic phosphate and 5′-OH ends.3 known members of this class. Found in three plant pathogen (satelliteRNAs of the tobacco ringspot virus, arabis mosaic virus and chicoryyellow mottle virus) which uses RNA as the infectious agent.Essential structural features largely defined [xxxi,xxxii,xxxiii,xxxiv]Ligation activity (in addition to cleavage activity) makes ribozymeamenable to engineering through in vitro selection [xxxv]Complete kinetic framework established for one ribozyme [xxxvi].Chemical modification investigation of important residues begun[xxxvii,xxxviii].Hepatitis Delta Virus (HDV) RibozymeSize: ˜60 nucleotides.Trans cleavage of target RNAs demonstrated [xxxix].Binding sites and structural requirements not fully determined, although nosequences 5′ of cleavage site are required. Folded ribozyme contains apseudoknot structure [xl]Reaction mechanism: attack by 2′-OH 5′ to the scissile bond to generatecleavage products with 2′,3′-cyclic phosphate and 5′-OH ends.Only 2 known members of this class. Found in human HDV.Circular form of HDV is active and shows increased nuclease stability [xli][i], Michel, Francois; Westhof, Eric. Slippery substrates. Nat. Struct. Biol. (1994), 1(1), 5-7. [ii], Lisacek, Frederique; Diaz, Yolande; Michel, Francois. Automatic identification of group I intron cores in genomic DNA sequences. J. Mol. Biol. (1994), 235(4), 1206-17. [iii], Herschlag, Daniel; Cech, Thomas R.. Catalysis of RNA cleavage by the Tetrahymena thermophila ribozyme. 1. Kinetic description of the reaction of an RNA substrate complementary to the active site. Biochemistry (1990), 29(44), 10159-71. [iv], Herschlag, Daniel; Cech, Thomas R.. Catalysis of RNA cleavage by the Tetrahymena thermophila ribozyme. 2. Kinetic description of the reaction of an RNA substrate that forms a mismatch at the active site. Biochemistry (1990), 29(44), 10172-80. [v], Knitt, Deborah S.; Herschlag, Daniel. pH Dependencies of the Tetrahymena Ribozyme Reveal an Unconventional Origin of an Apparent pKa. Biochemistry (1996), 35(5), 1560-70. [vi], Bevilacqua, Philip C.; Sugimoto, Naoki; Turner, Douglas H.. A mechanistic framework for the second step of splicing catalyzed by the Tetrahymena ribozyme. Biochemistry (1996), 35(2), 648-58. [vii], Li, Yi; Bevilacqua, Philip C.; Mathews, David; Turner, Douglas H.. Thermodynamic and activation parameters for binding of a pyrene-labeled substrate by the Tetrahymena ribozyme: docking is not diffusion-controlled and is driven by a favorable entropy change. Biochemistry (1995), 34(44), 14394-9. [viii], Banerjee, Aloke Raj; Turner, Douglas H.. The time dependence of chemical modification reveals slow steps in the folding of a group I ribozyme. Biochemistry (1995), 34(19), 6504-12. [ix], Zarrinkar, Patrick P.; Williamson, James R.. The P9.1-P9.2 peripheral extension helps guide folding of the Tetrahymena ribozyme. Nucleic Acids Res. (1996), 24(5), 854-8. [x], Strobel, Scott A.; Cech, Thomas R.. Minor groove recognition of the conserved G.cntdot.U pair at the Tetrahymena ribozyme reaction site. Science (Washington, D. C.) (1995), 267(5198), 675-9. [xi], Strobel, Scott A.; Cech, Thomas R.. Exocydic Amine of the Conserved G.cntdot.U Pair at the Cleavage Site of the Tetrahymena Ribozyme Contributes to 5′-Splice Site Selection and Transition State Stabilization. Biochemistry (1996), 35(4), 1201-11. [xii], Sullenger, Bruce A.; Cech, Thomas R.. Ribozyme-mediated repair of defective mRNA by targeted trans-splicing. Nature (London) (1994), 371(6498), 619-22. [xiii], Robertson, H. D.; Altman, S.; Smith, J. D. J. Biol. Chem., 247, 5243-5251 (1972). [xiv], Forster, Anthony C.; Altman, Sidney. External guide sequences for an RNA enzyme. Science (Washington, D. C., 1883-) (1990), 249(4970), 783-6. [xv], Yuan, Y.; Hwang, E. S.; Altman, S. Targeted cleavage of mRNA by human RNase P. Proc. Natl. Acad. Sci. USA (1992) 89, 8006-10. [xvi], Harris, Michael E.; Pace, Norman R.. Identification of phosphates involved in catalysis by the ribozyme RNase P RNA. RNA (1995), 1(2), 210-18. [xvii], Pan, Tao; Loria, Andrew; Zhong, Kun. Probing of tertiary interactions in RNA: 2-hydroxyl-base contacts between the RNase P RNA and pre-tRNA. Proc. Natl. Acad. Sci. U.S.A. (1995), 92(26), 12510-14. [xviii], Pyle, Anna Marie; Green, Justin B.. Building a Kinetic Framework for Group II Intron Ribozyme Activity: Quantitation of Interdomain Binding and Reaction Rate. Biochemistry (1994), 33(9), 2716-25. [xix], Michels, William J. Jr.; Pyle, Anna Marie. Conversion of a Group II Intron into a New Multiple-Turnover Ribozyme that Selectively Cleaves Oligonucleotides: Elucidation of Reaction Mechanism and Structure/Function Relationships. Biochemistry (1995), 34(9), 296-77. [xx], Zimmerly, Steven; Guo, Huatao; Eskes, Robert; Yang, Jian; Perlman, Philip S.; Lambowitz, Alan M.. A group II intron RNA is a catalytic component of a DNA endonuclease involved in intron mobility. Cell (Cambridge, Mass.) (1995), 83(4), 529-38. [xxi], Griffin, Edmund A., Jr.; Qin, Zhifeng; Michels, Williams J., Jr.; Pyle, Anna Marie. Group II intron ribozymes that cleave DNA and RNA linkages with similar efficiency, and lack contacts with substrate 2′-hydroxyl groups. Chem. Biol. (1995), 2(11), 761-70. [xxii], Michel, Francois; Ferat, Jean Luc. Structure and activities of group II introns. Annu. Rev. Biochem. (1995), 64, 435-61. [xxiii], Abramovitz, Dana L.; Friedman, Richard A.; Pyle, Anna Marie. Catalytic role of 2′-hydroxyl groups within a group II intron active site. Science (Washington, D. C.) (1996), 271(5254), 1410-13. [xxiv], Daniels, Danette L.; Michels, William J., Jr.; Pyle, Anna Marie. Two competing pathways for self-splicing by group II introns: a quantitative analysis of in vitro reaction rates and products. J. Mol. Biol. (1996), 256(1), 31-49. [xxv], Guo, Hans C. T.; Collins, Richard A.. Efficient trans-cleavage of a stem-loop RNA substrate by a ribozyme derived from Neurospora VS RNA. EMBO J. (1995), 14(2), 368-76. [xxvi], Scott, W. G., Finch, J. T., Aaron, K. The crystal structure of an all RNA hammerhead ribozyme: A proposed mechanism for RNA catalytic cleavage. Cell, (1995), 81, 991-1002. [xxvii], McKay, Structure and function of the hammerhead ribozyme: an unfinished story. RNA, (1996), 2, 395-403. [xxviii], Long, D., Uhlenbeck, O., Hertel, K. Ligation with hammerhead ribozymes. U.S. Pat. No. 5,633,133. [xxix], Hertel, K. J., Herschlag, D., Uhlenbeck, O. A kinetic and thermodynamic framework for the hammerhead ribozyme reaction. Biochemistry, (1994) 33, 3374-3385. Beigelman, L., et al., Chemical modifications of hammerhead ribozymes. J. Biol. Chem., (1995) 270, 25702-25708. [xxx], Beigelman, L., et al, Chemical modifications of hammerhead ribozymes. J. Biol. Chem., (1995) 270, 25702-25708. [xxxi], Hampel, Arnold; Tritz, Richard; Hicks, Margaret; Cruz, Philip. ′Hairpin′ catalytic RNA model: evidence for helixes and sequence requirement for substrate RNA. Nucleic Acids Res. (1990), 18(2), 299-304. [xxxii], Chowrira, Bharat M.; Berzal-Herranz, Alfredo; Burke, John M.. Novel guanosine requirement for catalysis by the hairpin ribozyme. Nature (London) (1991), 354(6351), 320-2. [xxxiii], Berzal-Herranz, Alfredo; Joseph, Simpson; Chowrira, Bharat M.; Butcher, Samuel E.; Burke, John M.. Essential nucleotide sequences and secondary structure elements of the hairpin ribozyme. EMBO J.(1993), 12(6), 2567-73. [xxxiv], Joseph, Simpson; Berzal-Herranz, Alfredo; Chowrira, Bharat M.; Butcher, Samuel E.. Substrate selection rules for the hairpin ribozyme determined by in vitro selection, mutation, and analysis of mismatched substrates. Genes Dev. (1993), 7(1), 130-8. [xxxv], Berzal-Herranz, Alfredo; Joseph, Simpson; Burke, John M.. In vitro selection of active hairpin ribozymes by sequential RNA-catalyzed cleavage and ligation reactions. Genes Dev. (1992), 6(1), 129-34. [xxxvi], Hegg, Lisa A.; Fedor, Martha J.. Kinetics and Thermodynamics of Intermolecular Catalysis by Hairpin Ribozymes. Biochemistry (1995), 34(48), 15813-28. [xxxvii], Grasby, Jane A.; Mersmann, Karin; Singh, Mohinder; Gait, Michael I.. Purine Functional Groups in Essential Residues of the Hairpin Ribozyme Required for Catalytic Cleavage of RNA. Biochemistry (1995), 34(12), 4068-76. [xxxviii], Schmidt, Sabine; Beigelman, Leonid; Karpeisky, Alexander; Usman, Nassim; Sorensen, Ulrik S.; Gait, Michael J.. Base and sugar requirements for RNA cleavage of essential nucleoside residues in internal loop B of the hairpin ribozyme: implications for secondary structure. Nucleic Acids Res. (1996), 24(4), 573-81. [xxxix], Perrotta, Anne T.; Been, Michael D.. Cleavage of oligoribonucleotides by a ribozyme derived from the hepatitis .delta. virus RNA sequence. Biochemistry (1992), 31(1), 16-21. [xl], Perrotta, Anne T.; Been, Michael D.. A pseudoknot-like structure required for efficient self-cleavage of hepatitis delta virus RNA. Nature (London) (1991), 350(6317), 434-6. [xli], Puttaraju, M.; Perrotta, Anne T.; Been, Michael D.. A circular trans-acting hepatitis delta virus ribozyme. Nucleic Acids Res. (1993), 21(18), 4253-8.

[0257]

2

TABLE II

A. 2.5 μmol Synthesis Cycle ABI 394 Instrument

Reagent
Equivalents
Amount
Wait Time* DNA
Wait Time* 2′-O-methyl
Wait Time*RNA

Phosphoramidites
6.5
163
μL
45 sec
2.5
min
7.5
min

S-Ethyl Tetrazole
23.8
238
μL
45 sec
2.5
min
7.5
min

Acetic Anhydride
100
233
μL
5 sec
5
sec
5
sec

N-Methyl
186
233
μL
5 sec
5
sec
5
sec

Imidazole

TCA
176
2.3
mL
21 sec
21
sec
21
sec

Iodine
11.2
1.7
mL
45 sec
45
sec
45
sec

Beaucage
12.9
645
μL
100 sec
300
sec
300
sec

Acetonitrile
NA
6.67
mL
NA
NA
NA

B. 0.2 μmol Synthesis Cycle ABI 394 Instrument

Reagent
Equivalents
Amount
Wait Time* DNA
Wait Time* 2′-O-methyl
Wait Time*RNA

Phosphoramidites
15
31
μL
45 sec
233
sec
465 sec

S-Ethyl Tetrazole
38.7
31
μL
45 sec
233
min
465 sec

Acetic Anhydride
655
124
μL
5 sec
5
sec
5 sec

N-Methyl
1245
124
μL
5 sec
5
sec
5 sec

Imidazole

TCA
700
732
μL
10 sec
10
sec
10 sec

Iodine
20.6
244
μL
15 sec
15
sec
15 sec

Beaucage
7.7
232
μL
100 sec
300
sec
300 sec

Acetonitrile
NA
2.64
mL
NA
NA
NA

C. 0.2 μmol Synthesis Cycle 96 well Instrument

Equivalents:

DNA/2′-O-
Amount: DNA/2′-O-

Wait Time* 2′-O-

Reagent
methyl/Ribo
methyl/Ribo
Wait Time* DNA
methyl
Wait Time* Ribo

Phosphoramidites
22/33/66
40/60/120
μL
60 sec
180
sec
360 sec

S-Ethyl Tetrazole
70/105/210
40/60/120
μL
60 sec
180
min
360 sec

Acetic Anhydride
265/265/265
50/50/50
μL
10 sec
10
sec
10 sec

N-Methyl
502/502/502
50/50/50
μL
10 sec
10
sec
10 sec

Imidazole

TCA
238/475/475
250/500/500
μL
15 sec
15
sec
15 sec

Iodine
6.8/6.8/6.8
80/80/80
μL
30 sec
30
sec
30 sec

Beaucage
34/51/51
80/120/120

100 sec
200
sec
200 sec

Acetonitrile
NA
1150/1150/1150
μL
NA
NA

NA

*Wait time does not include contact time during delivery.

[0258]

3

TABLE III

Human REL-A Inozyme and Substrate Sequence

Seq

Seq

Pos
Substrate
ID
Inozyme
ID

16
GGCGGGGC C GGGUCGCA
1
UGCGACCC CUGAUGAGGCCGUUAGGCCGAA ICCCCGCC
711

24
CGGGUCGC A GCUGGGCC
2
GGCCCAGC CUGAUGAGGCCGUUAGGCCGAA ICCACCCG
712

27
GUCCCAGC U GGGCCCGC
3
GCGGGCCC CUGAUGAGGCCGUUAGGCCGAA ICUGCGAC
713

32
AGCUGGGC C CGCGGCAU
4
AUGCCGCG CUGAUGAGGCCGUUAGGCCGAA ICCCAGCU
714

33
GCUGGGCC C GCGGCAUG
5
CAUGCCGC CUGAUGAGGCCGUUAGGCCGAA IGCCCAGC
715

39
CCCGCGGC A UGGACGAA
6
UUCGUCCA CUGAUGAGGCCGUUAGGCCGAA ICCGCGGG
716

49
GGACGAAC U GUUCCCCC
7
GGGGGAAC CUGAUGAGGCCGUUAGGCCGAA IUUCGUCC
717

54
AACUGUUC C CCCUCAUC
8
GAUGAGGG CUGAUGAGGCCGUUAGGCCGAA IAACAGUU
718

55
ACUGUUCC C CCUCAUCU
9
AGAUGAGG CUGAUGAGGCCGUUAGGCCGAA IGAACAGU
719

56
CUGUUCCC C CUCAUCUU
10
AAGAUGAG CUGAUGAGGCCGUUAGGCCGAA IGGAACAG
720

57
UGUUCCCC C UCAUCUUC
11
GAAGAUGA CUGAUGAGGCCGUUAGGCCGAA IGGGAACA
721

58
GUUCCCCC U CAUCUUCC
12
GGAAGAUG CUGAUGAGGCCGUUAGGCCGAA IGGGGAAC
722

60
UCCCCCUC A UCUUCCCG
13
CCGGAAGA CUGAUGAGGCCGUUAGGCCGAA IAGGGGGA
723

63
COCUCAUC U UCCCGCCA
14
UGCCGGGA CUGAUGAGGCCGUUAGGCCGAA IAUGAGGG
724

66
UCAUCUUC C CGGCAGAG
15
CUCUGCCG CUGAUGAGGCCGUUAGGCCGAA IAAGAUGA
725

67
CAUCUUCC C GGCAGAGC
16
GCUCUGCC CUGAUGAGGCCGUUAGGCCGAA IGAAGAUG
726

71
UUCCCGGC A GAGCAGCC
17
GGCUGCUC CUGAUGAGGCCGUUAGGCCGAA ICCGGGAA
727

76
GGCAGAGC A GCCCAAGC
18
GCUUGGGC CUGAUGAGGCCGUUAGGCCGAA ICUCUGCC
728

79
AGAGCAGC C CAAGCAGC
19
GCUGCUUG CUGAUGAGGCCGUUAGGCCGAA ICUGCUCU
729

80
GAGCAGCC C AAGCAGCG
20
CGCUGCUU CUGAUGAGGCCGUUAGGCCGAA IGCUGCUC
730

81
AGCAGCCC A AGCAGCGG
21
CCGCUGCU CUGAUGAGGCCGUUAGGCCGAA IGGCUGCU
731

85
GCCCAAGC A GCGGGGCA
22
UGCCCCGC CUGAUGAGGCCGUUAGGCCGAA ICUUGGGC
732

93
AGCGGGGC A UGCGCUUC
23
GAAGCGCA CUGAUGAGGCCGUUAGGCCGAA ICCCCGCU
733

99
GCAUGCGC U UCCGCUAC
24
GUAGCGGA CUGAUGAGGCCGUUAGGCCGAA ICGCAUGC
734

102
UGCGCUUC C GCUACAAG
25
CUUGUAGC CUGAUGAGGCCGUUAGGCCGAA IAAGCGCA
735

105
GCUUCCGC U ACAAGUGC
26
GCACUUGU CUGAUGAGGCCGUUAGGCCGAA ICGGAAGC
736

108
UCCGCUAC A AGUGCGAG
27
CUCGCACU CUGAUGAGGCCGUUAGGCCGAA IUAGCGGA
737

123
AGGGGCGC U CCGCGGGC
28
GCCCGCGG CUGAUGAGGCCGUUAGGCCGAA ICGCCCCU
738

125
GGGCGCUC C GCGGGCAG
29
CUGCCCGC CUGAUGAGGCCGUUAGGCCGAA IAGCGCCC
739

132
CCCCGGGC A GCAUCCCA
30
UGGGAUGC CUGAUGAGGCCGUUAGGCCGAA ICCCGCGG
740

135
CGGGCAGC A UCCCAGGC
31
GCCUGGGA CUGAUGAGGCCGUUAGGCCGAA ICUGCCCG
741

138
GCAGCAUC C CAGGCGAG
32
CUCGCCUG CUGAUGAGGCCGUUAGGCCGAA IAUGCUGC
742

139
CAGCAUCC C AGGCGAGA
33
UCUCGCCU CUGAUGAGGCCGUUAGGCCGAA IGAUGCUG
743

140
AGCAUCCC A GGCGAGAG
34
CUCUCGCC CUGAUGAGGCCGUUAGGCCGAA IGGAUGCU
744

153
AGAGGAGC A CAGAUACC
35
GGUAUCUG CUGAUGAGGCCGUUAGGCCGAA ICUCCUCU
745

155
AGGAGCAC A GAUACCAC
36
GUGGUAUC CUGAUGAGGCCGUUAGGCCGAA IUGCUCCU
746

161
ACAGAUAC C ACCAAGAC
37
GUCUUGGU CUGAUGAGGCCGUUAGGCCGAA IUAUCUGU
747

162
CAGAUACC A CCAAGACC
38
GGUCUUGG CUGAUCAGGCCGUUAGGCCGAA IGUAUCUG
748

164
GAUACCAC C AAGACCCA
39
UGCCUCUU CUGAUGAGGCCGUUAGGCCGAA IUGGUAUC
749

165
AUACCACC A AGACCCAC
40
GUGGGUCU CUGAUGAGGCCGUUAGGCCGAA IGUGGUAU
750

170
ACCAAGAC C CACCCCAC
41
GUGGGGUG CUGAUGAGGCCGUUAGGCCGAA IUCUUGGU
751

171
CCAAGACC C ACCCCACC
42
GGUGGGGU CUGAUGAGGCCGUUAGGCCGAA ICUCUUGG
752

172
CAAGACCC A CCCCACCA
43
UGGUGGGG CUGAUGAGGCCGUUAGGCCGAA IGGUCUUG
753

174
AGACCCAC C CCACCAUC
44
GAUGGUGG CUGAUGAGGCCGUUAGGCCGAA IUGGGUCU
754

175
GACCCACC C CACCAUCA
45
UGAUGGUG CUGAUGAGGCCGUUAGGCCGAA IGUGGGUC
755

176
ACCCACCC C ACCAUCAA
46
UUGAUGGU CUGAUGAGGCCGUUAGGCCGAA IGGUGGGU
756

177
CCCACCCC A CCAUCAAG
47
CUUGAUGG CUGAUGAGGCCGUUAGGCCGAA IGGGUGGG
757

179
CACCCCAC C AUCAAGAU
48
AUCUUGAU CUGAUGAGGCCGUUAGGCCGAA IUGGGGUG
758

180
ACCCCACC A UCAAGAUC
49
GAUCUUGA CUGAUGAGGCCGUUAGGCCGAA IGUGCGGU
759

183
CCACCAUC A AGAUCAAU
50
AUUGAUCU CUGAUGAGGCCGUUAGGCCGAA IAUGGUGG
760

189
UCAAGAUC A AUGGCUAC
51
GUAGCCAU CUGAUGAGGCCGUUAGGCCGAA IAUCUUGA
761

195
UCAAUGGC U ACACAGGA
52
UCCUGUGU CUGAUGAGGCCGUUAGGCCGAA ICCAUUGA
762

198
AUGGCUAC A CAGGACCA
53
UGGUCCUG CUGAUGAGGCCGUUAGGCCGAA IUAGCCAU
763

200
GGCUACAC A GGACCAGG
54
CCUGGUCC CUGAUGAGGCCGUUAGGCCGAA IUGUAGCC
764

205
CACAGGAC C AGGGACAG
55
CUGUCCCU CUGAUGAGGCCGUUAGGCCGAA IUCCUGUG
765

206
ACAGGACC A GGGACAGU
56
ACUGUCCC CUGAUGAGGCCGUUAGGCCGAA IGUCCUGU
766

212
CCAGGGAC A GUGCGCAU
57
AUGCGCAC CUGAUGAGGCCGUUAGGCCGAA IUCCCUGG
767

219
CAGUGCGC A UCUCCCUG
58
CAGGGAGA CUGAUGAGGCCGUUAGGCCGAA ICGCACUG
768

222
UGCGCAUC U CCCUGGUC
59
GACCAGGG CUGAUGAGGCCGUUAGGCCGAA IAUGCGCA
769

224
CGCAUCUC C CUGGUCAC
60
GUGACCAG CUGAUGAGGCCGUUAGGCCGAA IAGAUGCG
770

225
GCAUCUCC C UGGUCACC
61
GGUGACCA CUGAUGAGGCCGUUAGGCCGAA IGAGAUGC
771

226
CAUCUCCC U GGUCACCA
62
UGGUGACC CUGAUGAGGCCGUUAGGCCGAA IGGAGAUG
772

231
CCCUGGUC A CCAAGGAC
63
GUCCUUGG CUGAUGAGGCCGUUAGGCCGAA IACCAGGG
773

233
CUGGUCAC C AAGGACCC
64
GGGUCCUU CUGAUGAGGCCGUUAGGCCGAA IUGACCAG
774

234
UGGUCACC A AGGACCCU
65
AGGGUCCU CUGAUGAGGCCGUUAGGCCGAA IGUGACCA
775

240
CCAAGGAC C CUCCUCAC
66
GUGAGGAG CUGAUGAGGCCGUUAGGCCGAA IUCCUUGG
776

241
CAAGGACC C UCCUCACC
67
GGUGAGGA CUGAUGAGGCCGUUAGGCCGAA IGUCCUUG
777

242
AAGGACCC U CCUCACCG
68
CGGUGAGG CUGAUGAGGCCGUUAGGCCGAA IGGUCCUU
778

244
GGACCCUC C UCACCGGC
69
GCCGGUGA CUGAUGAGGCCGUUAGGCCGAA IAGGGUCC
779

245
GACCCUCC U CACCGGCC
70
GGCCGGUG CUGAUGAGGCCGUUAGGCCGAA IGAGGGUC
780

247
CCCUCCUC A CCGGCCUC
71
GAGGCCGG CUGAUGAGGCCGUUAGGCCGAA IAGGAGGG
781

249
CUCCUCAC C GGCCUCAC
72
GUGAGGCC CUGAUGAGGCCGUUAGGCCGAA IUGAGGAG
782

253
UCACCGGC C UCACCCCC
73
GGGGGUGA CUGAUGAGGCCGUUAGGCCGAA ICCUGUGA
783

254
CACCGGCC U CACCCCCA
74
UGGGGGUG CUGAUGAGGCCGUUAGGCCGAA IGOOGGUG
784

256
CCGGCCUC A CCCCCACG
75
CGUGGGGG CUGAUGAGGCCGUUAGGCCGAA IAGGCCGG
785

258
GGCCUCAC C CCCACGAG
76
CUCGUGGG CUGAUGAGGCCGUUAGGCCGAA IUGAGGCC
786

259
GCCUCACC C CCACGAGC
77
GCUCGUGG CUGAUGAGGCCGUUAGGCCGAA IGUGAGGC
787

260
CCUCACCC C CACGAGCU
78
AGCUCGUG CUGAUGAGGCCGUUAGGCCGAA IGGUGAGG
788

261
CUCACCCC C ACGAGCUU
79
AAGCUCGU CUGAUGAGGCCGUUAGGCCGAA IGGGUGAG
789

262
UCACCCCC A CGAGCUUG
80
CAAGCUCG CUGAUGAGGCCGUUAGGCCGAA IGGGGUGA
790

268
CCACGAGC U UGUAGGAA
81
UUCCUACA CUGAUGAGGCCGUUAGGCCGAA ICUCGUGG
791

282
GAAAGGAC U GCCGGGAU
82
AUCCCGGC CUGAUGAGGCCGUUAGGCCGAA IUCCUUUC
792

285
AGGACUGC C GGGAUGGC
83
GCCAUCCC CUGAUGAGGCCGUUAGGCCGAA ICAGUCCU
793

294
GGGAUGGC U UCUAUGAG
84
CUCAUAGA CUGAUGAGGCCGUUAGGCCGAA ICCAUCCC
794

297
AUGGCUUC U AUGAGGCU
85
AGCCUCAU CUGAUGAGGCCGUUAGGCCGAA IAAGCCAU
795

305
UAUGAGGC U GAGCUCUG
86
CAGAGCUC CUGAUGAGGCCGUUAGGCCGAA ICCUCAUA
796

310
GGCUGAGC U CUGCCCGG
87
CCGGGCAG CUGAUGAGGCCGUUAGGCCGAA ICUCAGCC
797

312
CUGAGCUC U GCCCGGAC
88
GUCCGGGC CUGAUGAGGCCGUUAGGCCGAA IAGCUCAG
798

315
AGCUCUGC C CGGACCGC
89
GCGGUCCG CUGAUGAGGCCGUUAGGCCGAA ICAGAGCU
799

316
GCUCUGCC C GGACCGCU
90
AGCGGUCC CUGAUGAGGCCGUUAGGCCGAA IGCAGAGC
800

321
GCCCGGAC C GCUGCAUC
91
GAUGCAGC CUGAUGAGGCCGUUAGGCCGAA IUCCGGGC
801

324
CGGACCGC U GCAUCCAC
92
GUGGAUGC CUGAUGAGGCCGUUAGGCCGAA ICGGUCCG
802

327
ACCGCUGC A UCCACAGU
93
ACUGUGGA CUGAUGAGGCCGUUAGGCCGAA ICAGCGGU
803

330
GCUGCAUC C ACAGUUUC
94
GAAACUGU CUGAUGAGGCCGUUAGGCCGAA IAUGCAGC
804

331
CUGCAUCC A CAGUUUCC
95
GGAAACUG CUGAUGAGGCCGUUAGGCCGAA IGAUGCAG
805

333
UCAUCCAC A GUUUCCAG
96
CUGGAAAC CUGAUGAGGCCGUUAGGCCGAA IUGGAUGC
806

339
ACAGUUUC C AGAACCUG
97
CAGGUUCU CUGAUGAGGCCGUUAGGCCGAA IAAACUGU
807

340
CAGUUUCC A GAACCUGG
98
CCAGGUUC CUGAUGAGGCCGUUAGGCCGAA IGAAACUG
808

345
UCCAGAAC C UGGGAAUC
99
GAUUCCCA CUGAUGAGGCCGUUAGGCCGAA IUUCUGGA
809

346
CCAGAACC U GGGAAUCC
100
GGAUUCCC CUGAUGAGGCCGUUAGGCCGAA IGUUCUGG
810

354
UGGGAAUC C AGUGUGUG
101
CACACACU CUGAUGAGGCCGUUAGGCCGAA IAUUCCCA
811

355
GGGAAUCC A GUGUGUGA
102
UCACACAC CUGAUGAGGCCGUUAGGCCGAA IGAUUCCC
812

375
AGCGGGAC C UGGAGCAG
103
CUGCUCCA CUGAUGAGGCCGUUAGGCCGAA IUCCCGCU
813

376
GCGGGACC U GGAGCAGG
104
CCUGCUCC CUGAUGAGGCCGUUAGGCCGAA IGUCCCGC
814

382
CCUGGAGC A GGCUAUCA
105
UGAUAGCC CUGAUGAGGCCGUUAGGCCGAA ICUCCAGG
815

386
GAGCAGGC U AUCAGUCA
106
UGACUGAU CUGAUGAGGCCGUUAGGCCGAA ICCUGCUC
816

390
AGGCUAUC A GUCAGCGC
107
GCGCUGAC CUGAUGAGGCCGUUAGGCCGAA IAUAGCCU
817

394
UAUCAGUC A GCGCAUCC
108
GGAUGCGC CUGAUGAGGCCGUUAGGCCGAA IACUGAUA
818

399
GUCAGCGC A UCCAGACC
109
GGUCUGGA CUGAUGAGGCCGUUAGGCCGAA ICGCUGAC
819

402
AGCGCAUC C AGACCAAC
110
GUUGGUCU CUGAUGAGGCCGUUAGGCCGAA IAUGCGCU
820

403
GCGCAUCC A GACCAACA
111
UGUUGGUC CUGAUGAGGCCGUUAGGCCGAA IGAUGCGC
821

407
AUCCAGAC C AACAACAA
112
UUGUUGUU CUGAUGAGGCCGUUAGGCCGAA IUCUGGAU
822

408
UCCAGACC A ACAACAAC
113
GUUGUUGU CUGAUGAGGCCGUUAGGCCGAA IGUCUGGA
823

411
AGACCAAC A ACAACCCC
114
GGGGUUGU CUGAUGAGGCCGUUAGGCCGAA IUUGGUCU
824

414
CCAACAAC A ACCCCUUC
115
GAAGGGGU CUGAUGAGGCCGUUAGGCCGAA IUUGUUGG
825

417
ACAACAAC C CCUUCCAA
116
UUGGAAGG CUGAUGAGGCCGUUAGGCCGAA IUUGUUGU
826

418
CAACAACC C CUUCCAAG
117
CUUGGAAG CUGAUGAGGCCGUUAGGCCGAA IGUUGUUG
827

419
AACAACCC C UUCCAAGU
118
ACUUGGAA CUGAUGAGGCCGUUAGGCCGAA IGGUUGUU
828

420
ACAACCCC U UCCAAGUU
119
AACUUGGA CUGAUGAGGCCGUUAGGCCGAA IGGGUUGU
829

423
ACCCCUUC C AAGUUCCU
120
AGGAACUU CUGAUGAGGCCGUUAGGCCGAA IAAGGGGU
830

424
CCCCUUCC A AGUUCCUA
121
UAGGAACU CUGAUGAGGCCGUUAGGCCGAA IGAAGGGG
831

430
CCAAGUUC C UAUAGAAG
122
CUUCUAUA CUGAUGAGGCCGUUAGGCCGAA IAACUUGG
832

431
CAAGUUCC U AUAGAAGA
123
UCUUCUAU CUGAUGAGGCCGUUAGGCCGAA IGAACUUG
833

442
AGAAGAGC A GCGUGGGG
124
CCCCACGC CUGAUGAGGCCGUUAGGCCGAA ICUCUUCU
834

453
GUGGGGAC U ACGACCUG
125
CAGGUCGU CUGAUGAGGCCGUUAGGCCGAA IUCCCCAC
835

459
ACUACGAC C UGAAUGCU
126
AGCAUUCA CUGAUGAGGCCGUUAGGCCGAA IUCGUAGU
836

460
CUACGACC U GAAUGCUG
127
CAGCAUUC CUGAUGAGGCCGUUAGGCCGAA IGUCGUAG
837

467
CUGAAUGC U GUGCGGCU
128
AGCCGCAC CUGAUGAGGCCGUUAGGCCGAA ICAUUCAG
838

475
UGUGCGGC U CUGCUUCC
129
GGAAGCAG CUGAUGAGGCCGUUAGGCCGAA ICCGCACA
839

477
UGCGGCUC U GCUUCCAG
130
CUGGAAGC CUGAUGAGGCCGUUAGGCCGAA IAGCCGCA
840

480
GGCUCUGC U UCCAGGUG
131
CACCUGGA CUGAUGAGGCCGUUAGGCCGAA ICAGAGCC
841

483
UCUGCUUC C AGGUGACA
132
UGUCACCU CUGAUGAGGCCGUUAGGCCGAA IAAGCAGA
842

484
CUGCUUCC A GGUGACAG
133
CUGUCACC CUGAUGAGGCCGUUAGGCCGAA IGAAGCAG
843

491
CAGGUGAC A GUGCGGGA
134
UCCCGCAC CUGAUGAGGCCGUUAGGCCGAA IUCACCUG
844

501
UGCGGGAC C CAUCAGGC
135
GCCUGAUG CUGAUGAGGCCGUUAGGCCGAA IUCCCGCA
845

502
GCGGGACC C AUCAGGCA
136
UGCCUGAU CUGAUGAGGCCGUUAGGCCGAA IGUCCCGC
846

503
CGGGACCC A UCAGGCAG
137
CUGCCUGA CUGAUGAGGCCGUUAGGCCGAA IGGUCCCG
847

506
GACCCAUC A GGCAGGCC
138
GGCCUGCC CUGAUGAGGCCGUUAGGCCGAA IAUGGGUC
848

510
CAUCAGGC A GGCCCCUC
139
GAGGGGCC CUGAUGAGGCCGUUAGGCCGAA ICCUGAUG
849

514
AGGCAGGC C CCUCCGCC
140
GGCGGAGG CUGAUGAGGCCGUUAGGCCGAA ICCUGCCU
850

515
GGCAGGCC C CUCCGCCU
141
AGGCGGAG CUGAUGAGGCCGUUAGGCCGAA IGCCUGCC
851

516
GCAGGCCC C UCCGCCUG
142
CAGGCGGA CUGAUGAGGCCGUUAGGCCGAA IGGCCUGC
852

517
CAGGCCCC U CCGCCUGC
143
GCAGGCGG CUGAUGAGGCCGUUAGGCCGAA IGGGCCUG
853

519
GGCCCCUC C GCCUGCCG
144
CGGCAGGC CUGAUGAGGCCGUUAGGCCGAA IAGGGGCC
854

522
CCCUCCGC C UGCCGCCU
145
AGGCGGCA CUGAUGAGGCCGUUAGGCCGAA ICGGAGGG
855

523
CCUCCGCC U GCCGCCUG
146
CAGGCGGC CUGAUGAGGCCGUUAGGCCGAA IGCGGAGG
856

526
CCGCCUGC C GCCUGUCC
147
GGACAGGC CUGAUGAGGCCGUUAGGCCGAA ICAGGCGG
857

529
CCUGCCGC C UGUCCUUU
148
AAAGGACA CUGAUGAGGCCGUUAGGCCGAA ICGGCAGG
858

530
CUGCCGCC U GUCCUUUC
149
GAAAGGAC CUGAUGAGGCCGUUAGGCCGAA IGCGGCAG
859

534
CGCCUGUC C UUUCUCAU
150
AUGAGAAA CUGAUGAGGCCGUUAGGCCGAA IACAGGCG
860

535
GCCUGUCC U UUCUCAUC
151
GAUGAGAA CUGAUGAGGCCGUUAGGCCGAA IGACAGGC
861

539
GUCCUUUC U CAUCCCAU
152
AUGGGAUG CUGAUGAGGCCGUUAGGCCGAA IAAAGGAC
862

541
CCUUUCUC A UCCCAUCU
153
AGAUGGGA CUGAUGAGGCCGUUAGGCCGAA IAGAAAGG
863

544
UUCUCAUC C CAUCUUUG
154
CAAAGAUG CUGAUGAGGCCGUUAGGCCGAA IAUGACAA
864

545
UCUCAUCC C AUCUUUGA
155
UCAAAGAU CUGAUGAGGCCGUUAGGCCGAP IGAUGAGA
865

546
CUCAUCCC A UCUUUGAC
156
GUCAAAGA CUGAUGAGGCCGUUAGGCCGAA IGGAUGAG
866

549
AUCCCAUC U UUGACAAU
157
AUUGUCAA CUGAUGAGGCCGUUAGGCCGAA IAUGGGAU
867

555
UCUUUGAC A AUCGUGCC
158
GGCACGAU CUGAUGAGGCCGUUAGGCCGAA IUCAAAGA
868

563
AAUCGUGC C CCCAACAC
159
GUGUUGGG CUGAUGAGGCCGUUAGGCCGAA ICACGAUU
869

564
AUCGUGCC C CCAACACU
160
AGUGUUGG CUGAUGAGGCCGUUAGGCCGAA IGCACGAU
870

565
UCGUGCCC C CAACACUG
161
CAGUGUUG CUGAUGAGGCCGUUAGGCCGAA IGGCACGA
871

566
CGUGCCCC C AACACUGC
162
GCAGUGUU CUGAUGAGGCCGUUAGGCCGAA IGGGCACG
872

567
GUGCCCCC A ACACUGCC
163
GGCAGUGU CUGAUGAGGCCGUUAGGCCGAA IGGGGCAC
873

570
CCCCCAAC A CUGCCGAG
164
CUCGGCAG CUGAUGAGGCCGUUAGGCCGAA IUUGGGGG
874

572
CCCAACAC U GCCGAGCU
165
AGCUCGGC CUGAUGAGGCCGUUAGGCCGAA IUGUUGGG
875

575
AACACUGC C GAGCUCAA
166
UUGAGCUC CUGAUGAGGCCGUUAGGCCGAA ICAGUGUU
876

580
UGCCGAGC U CAAGAUCU
167
AGAUCUUG CUGAUGAGGCCGUUAGGCCGAA ICUCGGCA
877

582
CCGAGCUC A AGAUCUGC
168
GCAGAUCU CUGAUGAGGCCGUUAGGCCGAA IAGCUCGG
878

588
UCAAGAUC U GCCGAGUG
169
CACUCGGC CUGAUGAGGCCGUUAGGCCGAA IAUCUUGA
879

591
AGAUCUGC C GAGUGAAC
170
GUUCACUC CUGAUGAGGCCGUUAGGCCGAA ICAGAUCU
880

600
GAGUGAAC C GAAACUCU
171
AGAGUUUC CUGAUGAGGCCGUUAGGCCGAA IUUCACUC
881

606
ACCGAAAC U CUGGCAGC
172
GCUGCCAG CUGAUGAGGCCGUUAGGCCGAA IUUUCGGU
882

608
CGAAACUC U GGCAGCUG
173
CAGCUGCC CUGAUGAGGCCGUUAGGCCGAA IAGUUUCG
883

612
ACUCUGGC A GCUGCCUC
174
GAGGCAGC CUGAUGAGGCCGUUAGGCCGAA ICCAGAGU
884

615
CUGGCAGC U GCCUCGGU
175
ACCGAGGC CUGAUGAGGCCGUUAGGCCGAA ICUGCCAG
885

618
GCAGCUGC C UCGGUGGG
176
CCCACCGA CUGAUGAGGCCGUUAGGCCGAA ICAGCUGC
886

619
CAGCUGCC U CGGUGGGG
177
CCCCACCG CUGAUGAGGCCGUUAGGCCGAA IGCAGCUG
887

636
AUGAGAUC U UCCUACUG
178
CAGUAGGA CUGAUGAGGCCGUUAGGCCGAA IAUCUCAU
888

639
AGAUCUUC C UACUGUGU
179
ACACAGUA CUGAUGAGGCCGUUAGGCCGAA IAAGAUCU
889

640
GAUCUUCC U ACUGUGUG
180
CACACAGU CUGAUGAGGCCGUUAGGCCGAA IGAAGAUC
890

643
CUUCCUAC U GUGUGACA
181
UGUCACAC CUGAUGAGGCCGUUAGGCCGAA IUAGGAAG
891

651
UGUGUGAC A AGGUGCAG
182
CUGCACCU CUGAUGAGGCCGUUAGGCCGAA IUCACACA
892

658
CAAGGUGC A GAAAGAGG
183
CCUCUUUC CUGAUGAGGCCGUUAGGCCGAA ICACCUUG
893

669
AAGAGGAC A UUGAGGUG
184
CACCUCAA CUGAUGAGGCCGUUAGGCCGAA IUCCUCUU
894

684
UGUAUUUC A CGGGACCA
185
UGGUCCCG CUGAUGAGGCCGUUAGGCCGAA IAAAUACA
895

691
CACGGGAC C AGGCUGGG
186
CCCAGCCU CUGAUGAGGCCGUUAGGCCGAA IUCCCGUG
896

692
ACGGGACC A GGCUGGGA
187
UCCCAGCC CUGAUGAGGCCGUUAGGCCGAA IGUCCCGU
897

696
GACCAGGC U GGGAGGCC
188
GGCCUCCC CUGAUGAGGCCGUUAGGCCGAA ICCUGGUC
898

704
UGGGAGGC C CGAGGCUC
189
GAGCCUCG CUGAUGAGGCCGUUAGGCCGAA ICCUCCCA
899

705
GGGAGGCC C GAGGCUCC
190
GGAGCCUC CUGAUGAGGCCGUUAGGCCGAA IGCCUCCC
900

711
CCCGAGGC U CCUUUUCG
191
CGAAAAGG CUGAUGAGGCCGUUAGGCCGAA ICCUCGGG
901

713
CGAGGCUC C UUUUCGCA
192
UGCGAAAA CUGAUGAGGCCGUUAGGCCGAA IAGCCUCG
902

714
GAGGCUCC U UUUCGCAA
193
UUGCGAAA CUGAUGAGGCCGUUAGGCCGAA IGAGCCUC
903

721
CUUUUCGC A AGCUGAUG
194
CAUCAGCU CUGAUGAGGCCGUUAGGCCGAA ICGAAAAG
904

725
UCGCAAGC U GAUGUGCA
195
UGCACAUC CUGAUGAGGCCGUUAGGCCGAA ICUUGCGA
905

733
UGAUGUOC A CCGACAAG
196
CUUGUCGG CUGAUGAGGCCGUUAGGCCGAA ICACAUCA
906

735
AUGUGCAC C GACAAGUG
197
CACUUGUC CUGAUGAGGCCGUUAGGCCGAA IUGCACAU
907

739
GCACCGAC A AGUGGCCA
198
UGGCCACU CUGAUGAGGCCGUUAGGCCGAA IUCGGUGC
908

746
CAAGUGGC C AUUGUGUU
199
AACACAAU CUGAUGAGGCCGUUAGGCCGAA ICCACUUG
909

747
AAGUGGCC A UUGUGUUC
200
GAACACAA CUGAUGAGGCCGUUAGGCCGAA IGCCACUU
910

756
UUGUGUUC C GGACCCCU
201
ACGGGUCC CUGAUGAGGCCGUUAGGCCGAA IAACACAA
911

761
UUCCGGAC C CCUCCCUA
202
UAGGGAGG CUGAUGAGGCCGUUAGGCCGAA IUCCGGAA
912

762
UCCGGACC C CUCCCUAC
203
GUAGGGAG CUGAUGAGGCCGUUAGGCCGAA IGUCCGGA
913

763
CCGGACCC C UCCCUACG
204
CGUAGGGA CUGAUGAGGCCGUUAGGCCGAA ICGUCCGG
914

764
CGGACCCC U CCCUACGC
205
GCGUAGGG CUGAUGAGGCCGUUAGGCCGAA IGGGLICCG
915

766
GACCCCUC C CUACGCAG
206
CUGCGUAG CUGAUGAGGCCGUUAGGCCGAA IAGGGGUC
916

767
ACCCCUCC C UACGCAGA
207
UCUGCGUA CUGAUGAGGCCGUUAGGCCGAA IGAGGGGU
917

768
CCCCUCCC U ACGCAGAC
208
GUCUGCGU CUGAUGAGGCCGUUAGGCCGAA IGGAGGGG
918

773
CCCUACGC A GACCCCAG
209
CUGGGGUC CUGAUGAGGCCGUUAGGCCGAA ICGUAGGG
919

777
ACGCAGAC C CCAGCCUG
210
CAGGCUGG CUGAUGAGGCCGUUAGGCCGAA IUCUGCGU
920

778
CGCAGACC C CAGCCUGC
211
GCAGGCUG CUGAUGAGGCCGUUAGGCCGAA IGUCUGCG
921

779
GCAGACCC C AGCCUGCA
212
UGCAGGCU CUGAUGAGGCCGUUAGGCCGAA IGGUCUGC
922

780
CAGACCCC A GCCUGCAG
213
CUGCAGGC CUGAUCAGGCCGUUAGGCCGAA IGGGUCUG
923

783
ACCCCAGC C UGCAGGCU
214
AGCCUGCA CUGAUGAGGCCGUUAGGCCGAA ICUGGGGU
924

784
CCCCAGCC U GCAGGCUC
215
GAGCCUGC CUGAUGAGGCCGUUAGGCCGAA IGCUGGGG
925

787
CAGCCUGC A GCCUCCUG
216
CAGGAGCC CUGAUGAGGCCGUUAGGCCGAA ICAGGCUG
926

791
CUGCACGC U CCUGUGCG
217
CGCACAGG CUGAUGAGGCCGUUAGGCCGAA ICCUGCAG
927

793
GCAGGCUC C UGUGCGUG
218
CACGCACA CUGAUGAGGCCGUUAGGCCGAA IAGCCUGC
928

794
CAGGCUCC U GUGCGUGU
219
ACACGCAC CUGAUGAGGCCGUUAGGCCGAA IGAGCCUG
929

804
UGCGUGUC U CCAUGCAG
220
CUGCAUGG CUGAUGAGGCCGUUAGGCCGAA IACACGCA
930

806
CGUGUCUC C AUGCAGCU
221
AGCUGCAU CUGAUGAGGCCGUUAGGCCGAA IAGACACG
931

807
GUGUCUCC A UGCAGCUG
222
CAGCUGCA CUGAUGAGGCCGUUAGGCCGAA IGAGACAC
932

811
CUCCAUGC A GCUGCGGC
223
GCCGCAGC CUGAUGAGGCCGUUAGGCCGAA ICAUGGAG
933

814
CAUGCAGC U GCGGCGGC
224
GCCGCCGC CUGAUGAGGCCGUUAGGCCGAA ICUGCAUG
934

823
GCGGCGGC C UUCCGACC
225
GGUCGGAA CUGAUGAGGCCGUUAGGCCGAA ICCGCCGC
935

824
CGGCGGCC U UCCGACCG
226
CGGUCGGA CUGAUGAGGCCGUUAGGCCGAA IGCCGCCG
936

827
CGGCCUUC C GACCGGGA
227
UCCCGGUC CUGAUGAGGCCGUUAGGCCGAA IAAGGCCG
937

831
CUUCCGAC C GGGAGCUC
228
GAGCUCCC CUGAUGAGGCCGUUAGGCCGAA IUCGGAAG
938

838
CCGGGAGC U CAGUGAGC
229
GCUCACUG CUGAUGAGGCCGUUAGGCCGAA ICUCCCGG
939

840
GGGAGCUC A GUGAGCCC
230
GGGCUCAC CUGAUGAGGCCGUUAGGCCGAA IAGCUCCC
940

847
CAGUGAGC C CAUGGAAU
231
AUUCCAUG CUGAUGAGGCCGUUAGGCCGAA ICUCACUG
941

848
AGUGAGCC C AUGGAAUU
232
AAUUCCAU CUGAUGAGGCCGUUAGGCCGAA IGCUCACU
942

849
GUGAGCCC A UGGAAUUC
233
GAAUUCCA CUGAUGAGGCCGUUAGGCCGAA IGGCUCAC
943

858
UGGAAUUC C AGUACCUG
234
CAGGUACU CUGAUGAGGCCGUUAGGCCGAA IAAUUCCA
944

859
GGAAUUCC A GUACCUGC
235
GCAGGUAC CUGAUGAGGCCGUUAGGCCGAA IGAAUUCC
945

864
UCCAGUAC C UGCCAGAU
236
AUCUGGCA CUGAUGAGGCCGUUAGGCCGAA IUACUGGA
946

865
CCAGUACC U GCCAGAUA
237
UAUCUGGC CUGAUGAGGCCGUUAGGCCGAA IGUACUGG
947

868
GUACCUGC C AGAUACAG
238
CUGUAUCU CUGAUGGAGCCGUUAGGCCGAA ICAGGUAC
948

869
UACCUGCC A GAUACAGA
239
UCUGUAUC CUGAUGAGGCCGUUAGGCCGAA IGCAGGUA
949

875
CCAGAUAC A GACGAUCG
240
CGAUCGUC CUGAUGAGGCCGUUAGGCCGAA IUAUCUGG
950

886
CGAUCGUC A CCGGAUUG
241
CAAUCCGG CUGAUGAGGCCGUUAGGCCGAA IACGAUCG
951

888
AUCGUCAC C GGAUUGAG
242
CUCAAUCC CUGAUGAGGCCGUUAGGCCGAA IUGACGAU
952

914
AAAAGGAC A UAUGAGAC
243
GUCUCAUA CUGAUGAGGCCGUUAGGCCGAA IUCCUUUU
953

923
UAUGAGAC C UUAAAGAG
244
CUCUUGAA CUGAUGAGGCCGUUAGGCCGAA IUCUCAUA
954

924
AUGAGACC U UCAAGAGC
245
GCUCUUGA CUGAUGAGGCCGUUAGGCCGAA IGUCUCAU
955

927
AGACCUUC A AGAGCAUC
246
GAUGCUCU CUGAUGAGGCCGUUAGGCCGAA IAAGGUCU
956

933
UCAAGAGC A UCAUGAAG
247
CUUCAUGA CUGAUGAGGCCGUUAGGCCGAA ICUCUUGA
957

936
AGAGCAUC A UGAAGAAG
248
CUUCUUCA CUGAUGAGGCCGUUAGGCCGAA IAUGCUCU
958

949
GAAGAGUC C UUUCAGCG
249
CGCUGAAA CUGAUGAGGCCGUUAGGCCGAA IACUCUUC
959

950
AAGAGUCC U UUCAGCGG
250
CCGCUGAA CUGAUGAGGCCGUUAGGCCGAA IGACUCUU
960

954
GUCCUUUC A GCGGACCC
251
GGGUCCGC CUGAUGAGGCCGUUAGGCCGAA IAAAGGAC
961

961
CAGCGGAC C CACCGACC
252
GGUCGGUG CUGAUGAGGCCGUUAGGCCGAA IUCCGCUG
962

962
AGCGGACC C ACCGACCC
253
GGGUCGGU CUGAUGAGGCCGUUAGGCCGAA IGUCCGCU
963

963
GCGGACCC A CCGACCCC
254
GGGGUCGG CUGAUGAGGCCGUUAGGCCGAA IGGUCCGC
964

965
GGACCCAC C GACCCCCG
255
CGGGGGUC CUGAUGAGGCCGUUAGGCCGAA IUGGGUCC
965

969
CCACCGAC C CCCGGCCU
256
AGGCCGGG CUGAUGAGGCCGUUAGGCCGAA IUCGGUGG
966

970
CACCGACC C CCGGCCUC
257
GAGGCCGG CUGAUGAGGCCGUUAGGCCGAA IGUCGGUG
967

971
ACCGACCC C CGGCCUCC
258
GGAGGCCG CUGAUGAGGCCGUUAGGCCGAA IGGUCGGU
968

972
CCGACCCC C GGCCUCCA
259
UGGAGGCC CUGAUGAGGCCGUUAGGCCGAA IGGGUCGG
969

976
CCCCCGGC C UCCACCUC
260
GAGGUGGA CUGAUGAGGCCGUUAGGCCGAA ICCGGGGG
970

977
CCCCGGCC U CCACCUCG
261
CGAGGUGG CUGAUGAGGCCGUUAGGCCGAA IGCCGGGG
971

979
CCGGCCUC C ACCUCGAC
262
GUCGAGGU CUGAUGAGGCCGUUAGGCCGAA IAGGCCGG
972

980
CGGCCUCC A CCUCGACG
263
CGUCGAGG CUGAUGAGGCCGUUAGGCCGAA IGAGGCCG
973

982
GCCUCCAC C UCGACGCA
264
UGCGUCGA CUGAUGAGGCCGUUAGGCCGAA IUGGAGGC
974

983
CCUCCACC U CGACGCAU
265
AUGCGUCG CUGAUGAGGCCGUUAGGCCGAA IGUGGAGG
975

990
CUCGACGC A UUGCUGUG
266
CACAGCAA CUGAUGAGGCCGUUAGGCCGAA ICGUCGAG
976

995
CGCAUUGC U GUGCCUUC
267
GAAGGCAC CUGAUGAGGCCGUUAGGCCGAA ICAAUGCG
977

1000
UGCUGUGC C UUCCCGCA
268
UGCGGGAA CUGAUGAGGCCGUUAGGCCGAA ICACAGCA
978

1001
GCUGUGCC U UCCCGCAG
269
CUGCGGGA CUGAUGAGGCCGUUAGGCCGAA IGCACAGC
979

1004
GUGCCUUC C CGCAGCUC
270
GAGCUGCG CUGAUGAGGCCGUUAGGCCGAA IAAGGCAC
980

1005
UGCCUUCC C GCAGCUCA
271
UGAGCUGC CUGAUGAGGCCGUUAGGCCGAA IGAAGGCA
981

1008
CUUCCCGC A GCUCAGCU
272
AGCUGAGC CUGAUGAGGCCGUUAGGCCGAA ICGGGAAG
982

1011
CCCGCAGC U CAGCUUCU
273
AGAAGCUG CUGAUGAGGCCGUUAGGCCGAA ICUGCGGG
983

1013
CGCAGCUC A GCUUCUGU
274
ACAGAAGC CUGAUGAGGCCGUUAGGCCGAA IAGCUGCG
984

1016
AGCUCAGC U UCUGUCCC
275
GGGACAGA CUGAUGAGGCCGUUAGGCCGAA ICUGAGCU
985

1019
UCAGCUUC U GUCCCCAA
276
UUGGGGAC CUGAUGAGGCCGUUAGGCCGAA IAAGCUGA
986

1023
CUUCUGUC C CCAAGCCA
277
UGGCUUGG CUGAUGAGGCCGUUAGGCCGAA IACAGAAG
987

1024
UUCUGUCC C CAAGCCAG
278
CUGGCUUG CUGAUGAGGCCGUUAGGCCGAA IGACAGAA
988

1025
UCUGUCCC C AAGCCAGC
279
GCUGGCUU CUGAUGAGGCCGUUAGGCCGAA IGGACAGA
989

1026
CUGUCCCC A AGCCAGCA
280
UGCUGGCU CUGAUGAGGCCGUUAGGCCGAA IGGGACAG
990

1030
CCCCAAGC C AGCACCCC
281
GGGGUGCU CUGAUGAGGCCGUUAGGCCGAA ICUUGGGG
991

1031
CCCAAGCC A GCACCCCA
282
UGGGGUGC CUGAUGAGGCCGUUAGGCCGAA IGCUUGGG
992

1034
AAGCCAGC A CCCCAGCC
283
GGCUGGGG CUGAUGAGGCCGUUAGGCCGAA ICUGGCUU
993

1036
GCCAGCAC C CCAGCCCU
284
AGGGCUGG CUGAUGAGGCCGUUAGGCCGAA IUGCUGGC
994

1037
CCAGCACC C CAGCCCUA
285
UAGGGCUG CUGAUGAGGCCGUUAGGCCGAA IGUGCUGG
995

1038
CAGCACCC C AGCCCUAU
286
AUAGGGCU CUGAUGAGGCCGUUAGGCCGAA IGGUGCUG
996

1039
AGCACCCC A GCCCUAUC
287
GAUAGGGC CUGAUGAGGCCGUUAGGCCGAA IGGGUGCU
997

1042
ACCCCAGC C CUAUCCCU
288
AGGGAUAG CUGAUGAGGCCGUUAGGCCGAA ICUGGGGU
998

1043
CCCCAGCC C UAUCCCUU
289
AAGGGAUA CUGAUGAGGCCGUUAGGCCGAA IGCUGGGG
999

1044
CCCAGCCC U AUCCCUUU
290
AAAGGGAU CUGAUGAGGCCGUUAGGCCGAA IGGCUGGG
1000

1048
GCCCUAUC C CUUUACGU
291
ACGUAAAG CUGAUGAGGCCGUUAGGCCGAA IAUAGGGC
1001

1049
CCCUAUCC C UUUACGUC
292
GACGUAAA CUGAUGAGGCCGUUAGGCCGAA IGAUAGGG
1002

1050
CCUAUCCC U UUACGUCA
293
UGACGUAA CUGAUGAGGCCGUUAGGCCGAA IGGAUAGG
1003

1058
UUUACGUC A UCCCUGAG
294
CUCAGGGA CUGAUGAGGCCGUUAGGCCGAA IACGUAAA
1004

1061
ACGUCAUC C CUGAGCAC
295
GUGCUCAG CUGAUGAGGCCGUUAGGCCGAA IAUGACGU
1005

1062
CGUCAUCC C UGAGCACC
296
GGUGCUCA CUGAUGAGGCCGUUAGGCCGAA IGAUGACG
1006

1063
GUCAUCCC U GAGCACCA
297
UGGUGCUC CUGAUGAGGCCGUUAGGCCGAA IGGAUGAC
1007

1068
CCCUGAGC A CCAUCAAC
298
GUUGAUGG CUGAUGAGGCCGUUAGGCCGAA ICUCAGGG
1008

1070
CUGAGCAC C AUCAACUA
299
UAGUUGAU CUGAUGAGGCCGUUAGGCCGAA IUGCUCAG
1009

1071
UGAGCACC A UCAACUAU
300
AUAGUUGA CUGAUGAGGCCGUUAGGCCGAA IGUGCUCA
1010

1074
GCACCAUC A ACUAUGAU
301
AUCAUAGU CUGAUGAGGCCGUUAGGCCGAA IAUGGUGC
1011

1077
CCAUCAAC U AUGAUGAG
302
CUCAUCAU CUGAUGAGGCCGUUAGGCCGAA IUUGAUGG
1012

1090
UGAGUUUC C CACCAUGG
303
CCAUGGUG CUGAUGAGGCCGUUAGGCCGAA IAAACUCA
1013

1091
GAGUUUCC C ACCAUGGU
304
ACCAUGGU CUGAUGAGGCCGUUAGGCCGAA IGAAACUC
1014

1092
AGUUUCCC A CCAUGGUG
305
CACCAUGG CUGAUGAGGCCGUUAGGCCGAA IGGAAACU
1015

1094
UUUCCCAC C AUGGUGUU
306
AACACCAU CUGAUGAGGCCGUUAGGCCGAA IUGGGAAA
1016

1095
UUCCCACC A UGGUGUUU
307
AAACACCA CUGAUGAGGCCGUUAGGCCGAA IGUGGGAA
1017

1105
GGUGUUUC C UUCUGGGC
308
GCCCAGAA CUGAUGAGGCCGUUAGGCCGAA IAAACACC
1018

1106
GUGUUUCC U UCUGGGCA
309
UGCCCAGA CUGAUGAGGCCGUUAGGCCGAA IGAAACAC
1019

1109
UUUCCUUC U GGGCAGAU
310
AUCUGCCC CUGAUGAGGCCGUUAGGCCGAA IAAGGAAA
1020

1114
UUCUGGGC A GAUCAGCC
311
GGCUGAUC CUGAUGAGGCCGUUAGGCCGAA ICCCAGAA
1021

1119
GGCAGAUC A GCCAGGCC
312
GGCCUGGC CUGAUGAGGCCGUUAGGCCGAA IAUCUGCC
1022

1122
AGAUCAGC C AGGCCUCG
313
CGAGGCCU CUGAUGAGGCCGUUAGGCCGAA ICUGAUCU
1023

1123
GAUCAGCC A GGCCUCGG
314
CCGAGGCC CUGAUGAGGCCGUUAGGCCGAA IGCUGAUC
1024

1127
AGCCAGGC C UCGGCCUU
315
AAGGCCGA CUGAUGAGGCCGUUAGGCCGAA ICCUGGCU
1025

1128
GCCAGGCC U CGGCCUUG
316
CAAGGCCG CUGAUGAGGCCGUUAGGCCGAA IGCCUGGC
1026

1133
GCCUCGGC C UUGGCCCC
317
GGGGCCAA CUGAUGAGGCCGUUAGGCCGAA ICCGAGGC
1027

1134
CCUCGGCC U UGGCCCCG
318
CGCGGCCA CUGAUGAGGCCGUUAGGCCGAA ICCCGAGG
1028

1139
GCCUUGGC C CCGGCCCC
319
GGGGCCGG CUGAUGAGGCCGUUAGGCCGAA ICCAAGGC
1029

1140
CCUUGGCC C CGGCCCCU
320
ACGGGCCG CUGAUGAGGCCGUUAGGCCGAA IGCCAAGG
1030

1141
CUUGGCCC C GGCCCCUC
321
GAGGGGCC CUGAUGAGGCCGUUAGGCCGAA IGGCCAAG
1031

1145
GCCCCGGC C CCUCCCCA
322
UGGGGAGG CUGAUGAGGCCGUUAGGCCGAA ICCGGGGC
1032

1146
CCCCGGCC C CUCCCCAA
323
UUGGGGAG CUGAUGAGGCCGUUAGGCCGAA IGCCGGGG
1033

1147
CCCGGCCC C UCCCCAAG
324
CUUGGGGA CUGAUGAGGCCGUUAGGCCGAA IGGCCGGG
1034

1148
CCGGCCCC U CCCCAAGU
325
ACUUCGGG CUGAUGAGGCCGUUAGGCCGAA IGGGCCGG
1035

1150
GGCCCCUC C CCAAGUCC
326
GGACUUGG CUGAUGAGGCCGUUAGGCCGAA IAGGGCCC
1036

1151
GCCCCUCC C CAAGUCCU
327
AGGACUUG CUGAUGAGGCCGUUAGGCCGAA IGAGGGGC
1037

1152
CCCCUCCC C AAGUCCUG
328
CAGGACUU CUGAUGAGGCCGUUAGGCCGAA IGGAGGGG
1038

1153
CCCUCCCC A ACUCCUGC
329
GCAGGACU CUGAUGAGGCCGUUAGGCCGAA IGGGAGGG
1039

1158
CCCAAGUC C UGCCCCAG
330
CUGGGGCA CUGAUGAGGCCGUUAGGCCGAA IACUUGGG
1040

1159
CCAAGUCC U GCCCCAGG
331
CCUGGGGC CUGAUGAGGCCGUUAGGCCGAA IGACUUGG
1041

1162
AGUCCUGC C CCAGGCUC
332
GAGCCUGG CUGAUGAGGCCGUUAGGCCGAA ICAGGACU
1042

1163
GUCCUCCC C CAGGCUCC
333
GGAGCCUG CUGAUGAGGCCGUUAGGCCGAA IGCAGGAC
1043

1164
UCCUGCCC C AGGCUCCA
334
UGGAGCCU CUGAUGAGGCCGUUAGGCCGAA IGGCAGGA
1044

1165
CCUGCCCC A GGCUCCAG
335
CUGGAGCC CUGAUGAGGCCGUUAGGCCGAA IGGGCAGG
1045

1169
CCCCAGGC U CCAGCCCC
336
GGGGCUGG CUGAUGAGGCCGUUAGGCCGAA ICCUGGGG
1046

1171
CCAGGCUC C AGCCCCUG
337
CAGGGGCU CUGAUGAGGCCGUUAGGCCGAA IAGCCUGG
1047

1172
CAGGCUCC A GCCCCUGC
338
GCAGGGGC CUGAUGAGGCCGUUAGGCCGAA IGAGCCUG
1048

1175
GCUCCAGC C CCUGCCCC
339
GGGGCAGG CUGAUGAGGCCGUUAGGCCGAA ICUGGAGC
1049

1176
CUCCAGCC C CUGCCCCU
340
AGGGGCAG CUGAUGAGGCCGUUAGGCCGAA IGCUGGAG
1050

1177
UCCAGCCC C UGCCCCUG
341
CAGGGGCA CUGAUGAGGCCGUUAGGCCGAA IGGCUGGA
1051

1178
CCAGCCCC U GCCCCUGC
342
GCAGGGGC CUGAUGAGGCCGUUAGGCCGAA IGGGCUGG
1052

1181
GCCCCUGC C CCUGCUCC
343
GGAGCAGG CUGAUGAGGCCGUUAGGCCGAA ICAGGGGC
1053

1182
CCCCUGCC C CUGCUCCA
344
UGGAGCAG CUGAUGAGGCCGUUAGGCCGAA IGCAGGGG
1054

1183
CCCUGCCC C UGCUCCAG
345
CUGGAGCA CUGAUGAGGCCGUUAGGCCGAA IGGCAGGG
1055

1184
CCUGCCCC U GCUCCAGC
346
GCUGGAGC CUGAUGAGGCCGUUAGGCCGAA IGGGCAGG
1056

1187
GCCCCUCC U CCAGCCAU
347
AUGGCUGG CUGAUGAGGCCGUUAGGCCGAA ICAGGGGC
1057

1189
CCCUGCUC C AGCCAUGG
348
CCAUGGCU CUGAUGAGGCCGUUAGGCCGAA IAGCAGGG
1058

1190
CCUGCUCC A GCCAUGGU
349
ACCAUGGC CUGAUGAGGCCGUUAGGCCGAA IGAGCAGG
1059

1193
GCUCCAGC C AUGGUAUC
350
GAUACCAU CUGAUGAGGCCOUUAGGCCGAA ICUGGAGC
1060

1194
CUCCAGCC A UGGUAUCA
351
UGAUACCA CUGAUGAGGCCGUUAGGCCGAA IGCUGGAG
1061

1202
AUGGUAUC A GCUCUGGC
352
GCCAGAGC CUGAUGAGGCCGUUAGGCCGAA IAUACCAU
1062

1205
GUAUCAGC U CUGGCCCA
353
UGGGCCAG CUGAUGAGGCCGUUAGGCCGAA ICUGAUAC
1063

1207
AUCAGOUC U GGCCCAGG
354
CCUGGGCC CUGAUGAGGCCGUUAGGCCGAA IAGCUGAU
1064

1211
GCUCUGGC C CAGGCCCC
355
GGGGCCUG CUGAUGAGGCCGUUAGGCCGAA ICCAGAGC
1065

1212
CUCUGGCC C AGGCCCCA
356
UGGGGCCU CUGAUGAGGCCGUUAGGCCGAA IGCCAGAG
1066

1213
UCUGGCCC A GGCCCCAG
357
CUGGGGCC CUGAUGAGGCCGUUAGGCCGAA IGGCCAGA
1067

1217
GCCCAGGC C CCAGCCCC
358
GGGGCUGG CUGAUGAGGCCGUUAGGCCGAA ICCUGGGC
1068

1218
CCCAGGCC C CAGCCCCU
359
AGGGGCUG CUGAUGAGGCCGUUAGGCCGAA IGCCUGGG
1069

1219
CCAGGCCC C AGCCCCUG
360
CAGGGGCU CUGAUGAGGCCGUUAGGCCGAA IGGCCUGG
1070

1220
CAGGCCCC A GCCCCUGU
361
ACAGGGGC CUGAUGAGGCCGUUAGGCCGAA IGGGCCUG
1071

1223
GCCCCAGC C CCUGUCCC
362
GGGACAGG CUGAUGAGGCCGUUAGGCCGAA ICUGGGGC
1072

1224
CCCCAGCC C CUGUCCCA
363
UGGGACAG CUGAUGAGGCCGUUAGGCCGAA IGCUGGGG
1073

1225
CCCAGCCC C UGUCCCAG
364
CUGGGACA CUGAUGAGGCCGUUAGGCCGAA IGGCUGGG
1074

1226
CCAGCCCC U GUCCCAGU
365
ACUGGGAC CUGAUGAGGCCGUUAGGCCGAA IGGGCUGG
1075

1230
CCCCUGUC C CAGUCCUA
366
UAGGACUG CUGAUGAGGCCGUUAGGCCGAA IACAGGGG
1076

1231
CCCUGUCC C AGUCCUAG
367
CUAGGACU CUGAUGAGGCCGUUAGGCCGAA IGACAGGG
1077

1232
CCUGUCCC A GUCCUAGC
368
GCUAGGAC CUGAUGAGGCCGUUAGGCCGAA IGGACAGG
1078

1236
UCCCAGUC C UAGCCCCA
369
UGGGGCUA CUGAUGAGGCCGUUAGGCCGAA IACUGGGA
1079

1237
CCCAGUCC U AGCCCCAG
370
CUGGGGCU CUGAUGAGGCCGUUAGGCCGAA IGACUGGG
1080

1241
GUCCUAGC C CCAGGCCC
371
GGGCCUGG CUGAUGAGGCCGUUAGGCCGAA ICUAGGAC
1081

1242
UCCUAGCC C CAGGCCCU
372
AGGGCCUG CUGAUGAGGCCGUUAGGCCGAA IGCUAGGA
1082

1243
CCUAGCCC C AGGCCCUC
373
GAGGGCCU CUGAUGAGGCCGUUAGGCCGAA IGGCUAGG
1083

1244
CUAGCCCC A GGCCCUCC
374
GGAGGGCC CUGAUGAGGCCGUUAGGCCGAA IGGGCUAG
1084

1248
CCCCAGGC C CUCCUCAG
375
CUGAGGAG CUGAUGAGGCCGUUAGGCCGAA ICCUGGGG
1085

1249
CCCAGGCC C UCCUCAGG
376
CCUGAGGA CUGAUGAGGCCGUUAGGCCGAA IGCCUGGG
1086

1250
CCAGGCCC U CCUCAGGC
377
GCCUGAGG CUGAUGAGGCCGUUAGGCCGAA IGGCCUGG
1087

1252
AGGCCCUC C UCAGGCUG
378
CAGCCUGA CUGAUGAGGCCGUUAGGCCGAA IAGGGCCU
1088

1253
GGCCCUCC U CAGGCUGU
379
ACAGCCUG CUGAUGAGGCCGUUAGGCCGAA IGAGGGCC
1089

1255
CCCUCCUC A GGCUGUGG
380
CCACAGCC CUGAUGAGGCCGUUAGGCCGAA IAGGAGGG
1090

1259
CCUCAGGC U GUGGCCCC
381
GGGGCCAC CUGAUGAGGCCGUUAGGCCGAA ICCUGAGG
1091

1265
GCUGUGGC C CCACCUGC
382
GCAGGUGG CUGAUGAGGCCGUUAGGCCGAA ICCACAGC
1092

1266
CUGUGGCC C CACCUGCC
383
GGCAGGUG CUGAUGAGGCCGUUAGGCCGAA IGCCACAG
1093

1267
UGUGGCCC C ACCUGCCC
384
GGGCAGGU CUGAUGAGGCCGUUAGGCCGAA IGOCCACA
1094

1268
GUGGCCCC A CCUGCCCC
385
GGGGCAGG CUGAUGAGGCCGUUAGGCCGAA IGGGCCAC
1095

1270
GGCCCCAC C UGCCCCCA
386
UGGGGGCA CUGAUGAGGCCGUUAGGCCGAA IUGGGGCC
1096

1271
GCCCCACC U GCCCCCAA
387
UUGGGGGC CUGAUGAGGCCGUUAGGCCGAA IGUGGGGC
1097

1274
CCACCUGC C CCCAAGCC
388
GGCUUGGG CUGAUGAGGCCGUUAGGCCGAA ICAGGUGC
1098

1275
CACCUGCC C CCAAGCCC
389
GGGCUUGG CUGAUGAGGCCGUUAGGCCGAA IGCAGGUG
1099

1276
ACCUGCCC C CAAGCCCA
390
UGGGCUUG CUGAUGAGGCCGUUAGGCCGAA IGGCAGGU
1100

1277
CCUGCCCC C AAGCCCAC
391
GUGGGCUU CUGAUGAGGCCGUUAGGCCGAA IGGGCAGG
1101

1278
CUGCCCCC A AGCCCACC
392
GGUGGGCU CUGAUGAGGCCGUUAGGCCGAA IGGGGCAG
1102

1282
CCCCAAGC C CACCCAGG
393
CCUGGGUG CUGAUGAGGCCGUUAGGCCGAA ICUUGGGG
1103

1283
CCCAAGCC C ACCCAGGC
394
GCCUGGGU CUGAUGAGGCCGUUAGGCCGAA IGCUUGGG
1104

1284
CCAAGCCC A CCCAGGCU
395
AGCCUGGG CUGAUGAGGCCGUUAGGCCGAA IGGCUUGG
1105

1286
AAGCCCAC C CAGGCUGG
396
CCAGCCUG CUGAUGAGGCCGUUAGGCCGAA IUGGGCUU
1106

1287
AGCCCACC C AGGCUGGG
397
CCCAGCCU CUGAUGAGGCCGUUAGGCCGAA IGUGGGCU
1107

1288
GCCCACCC A GGCUGGGG
398
CCCCAGCC CUGAUGAGGCCGUUAGGCCGAA IGGUGGGC
1108

1292
ACCCAGGC U GGGGAAGG
399
CCUUCCCC CUGAUGAGGCCGUUAGGCCGAA ICCUGGGU
1109

1306
AGGAACGC U GUCAGAGG
400
CCUCUGAC CUGAUGAGGCCGUUAGGCCGAA ICGUUCCU
1110

1310
ACGCUGUC A GAGGCCCU
401
AGGGCCUC CUGAUGAGGCCGUUAGGCCGAA IACAGCGU
1111

1316
UCAGAGGC C CUGCUGCA
402
UGCAGCAG CUGAUGAGGCCGUUAGGCCGAA ICCUCUGA
1112

1317
CAGAGGCC C UGCUGCAG
403
CUGCAGCA CUGAUGAGGCCGUUAGGCCGAA IGCCUCUG
1113

1318
AGAGGCCC U GCUGCAGC
404
GCUGCAGC CUGAUGAGGCCGUUAGGCCGAA IGGCCUCU
1114

1321
GGCCCUGC U GCAGCUGC
405
GCAGCUGC CUGAUGAGGCCGUUAGGCCGAA ICAGGGCC
1115

1324
CCUGCUGC A GCUGCAGU
406
ACUGCAGC CUGAUGAGGCCGUUAGGCCGAA ICAGCAGG
1116

1327
GCUGCAGC U GCAGUUUG
407
CAAACUGC CUGAUGAGGCCGUUAGGCCGAA ICUGCAGC
1117

1330
GCAGCUGC A GUUUGAUG
408
CAUCAAAC CUGAUGAGGCCGUUAGGCCGAA ICAGCUGC
1118

1347
AUGAAGAC C UGGGGGCC
409
GCCCCCCA CUGAUGAGGCCGUUAGGCCGAA IUCUUCAU
1119

1348
UGAAGACC U GGGGGCCU
410
ACGCCCCC CUGAUGAGGCCGUUAGGCCGAA IGUCUUCA
1120

1355
CUGGGGGC C UUGCUUGG
411
CCAAGCAA CUGAUGAGGCCGUUAGGCCGAA ICCCCCAG
1121

1356
UGGGGGCC U UGCUUGGC
412
GCCAAGCA CUGAUGAGGCCGUUAGGCCGAA IGCCCCCA
1122

1360
GGCCUUGC U UGGCAACA
413
UCUUGCCA CUGAUGAGGCCGUUAGGCCGAA ICAAGGCC
1123

1365
UGCUUGGC A ACAGCACA
414
UGUGCUGU CUGAUGAGGCCGUUAGGCCGAA ICCAACCA
1124

1368
UUGGCAAC A GCACAGAC
415
GUCUGUGC CUGAUGAGGCCGUUAGGCCGAA IUUGCCAA
1125

1371
GCAACAGC A CAGACCCA
416
UGGGUCUG CUGAUGAGGCCGUUAGGCCGAA ICUGUUGC
1126

1373
AACAGCAC A GACCCAGC
417
GCUGGGUC CUGAUGAGGCCGUUAGGCCGAA IUGCUGUU
1127

1377
GOACAGAC C CAGCUGUG
418
CACAGCUG CUGAUGAGGCCGUUAGGCCGAA IUCUGUGC
1128

1378
CACAGACC C AGCUGUGU
419
ACACAGCU CUGAUGAGGCCGUUAGGCCGAA IGUCUGUG
1129

1379
ACAGACCC A GCUGUGUU
420
AACACAGC CUGAUGAGGCCGUUAGGCCGAA IGGUCUGU
1130

1382
GACCCAGC U GUGUUCAC
421
GUGAACAC CUGAUGAGGCCGUUAGGCCGAA ICUGGGUC
1131

1389
CUGUGUUC A CAGACCUG
422
CAGGUCUG CUGAUGAGGCCGUUAGGCCGAA IAACACAG
1132

1391
GUGGUCAC A GACCUGGC
423
GCCAGGUC CUGAUGAGGCCGUUAGGCCGAA IUGAACAC
1133

1395
UCACAGAC C UGGCAUCC
424
GGAUGCCA CUGAUGAGGCCGUUAGGCCGAA IUCUGUGA
1134

1396
CACAGACC U GGCAUCCG
425
CGGAUGCC CUGAUGAGGCCGUUAGGCCGAA IGUCUGUG
1135

1400
GACCUGGC A UCCGUCGA
426
UCGACGGA CUGAUGAGGCCGUUAGGCCGAA ICCAGGUC
1136

1403
CUGGCAUC C GUCGACAA
427
UUGUCGAC CUGAUGAGGCCGUUAGGCCGAA IAUGCCAG
1137

1410
CCGUCGAC A ACUCCGAG
428
CUCGGAGU CUGAUGAGGCCGUUAGGCCGAA IUCGACGG
1138

1413
UCGACAAC U CCGAGUIJU
429
AAACUCGG CUGAUGAGGCCGUUAGGCCGAA IUUGUCGA
1139

1415
GACAACUC C GAGUUUCA
430
UGAAACUC CUGAUGAGGCCGUUAGGCCGAA IAGUUGUC
1140

1423
CGAGUUUC A GCAGCUGC
431
GCAGCUGC CUGAUGAGGCCGUUAGGCCGAA IAAACUCG
1141

1426
GUU1ICAGC A GCUGCUGA
432
UCAGCAGC CUGAUGAGGCCGUUAGGCCGAA ICUGAAAC
1142

1429
UCAGCAGC U GCUGAACC
433
GGUUCAGC CUGAUGAGGCCGUUAGGCCGAA ICUGCUGA
1143

1432
GCAGCUGC U GAACCAGG
434
CCUGGUUC CUGAUGAGGCCGUUAGGCCGAA ICAGCUGC
1144

1437
UGCUGAAC C AGGGCAUA
435
UAUGCCCU CUGAUGAGGCCGUUAGGCCGAA IUUCAGCA
1145

1438
GCUGAACC A GGGCAUAC
436
GUAUGCCC CUGAUGAGGCCGUUAGGCCGAA IGUUCAGC
1146

1443
ACCAGGGC A UACCUGUG
437
CACAGGUA CUGAUGAGGCCGUUAGGCCGAA ICCCUGGU
1147

1447
GGGCAUAC C UGUGGCCC
438
GGGCCACA CUGAUGAGGCCGUUAGGCCGAA IUAUGCCC
1148

1448
GGCAUACC U GUGGCCCC
439
GGGGCCAC CUGAUGAGGCCGUUAGGCCGAA IGUAUGCC
1149

1454
CCUGUGGC C CCCCACAC
440
GUGUGGGG CUGAUGAGGCCGUUAGGCCGAA ICCACAGG
1150

1455
CUGUGGCC C CCCACACA
441
UGUGUGGG CUGAUGAGGCCGUUAGGCCGAA IGCCACAG
1151

1455
UGUGGCCC C CCACACAA
442
UUGUGUGG CUGAUGAGGCCGUUAGGCCGAA IGGCCACA
1152

1457
GUGGCCCC C CACACAAC
443
GUUGUGUG CUGAUGAGGCCGUUAGGCCGAA IGGGCCAC
1153

1458
UGGCCCCC C ACACAACU
444
AGUUGUGU CUGAUGAGGCCGUUAGGCCGAA IGGGGCCA
1154

1459
GGCCCCCC A CACAACUG
445
CAGUUGUG CUGAUGAGGCCGUUAGGCCGAA IGGGGGCC
1155

1461
CCCCCCAC A CAACUGAG
446
CUCAGUUG CUGAUGAGGCCGUUAGGCCGAA IUGGGGGG
1156

1463
CCCCACAC A ACUGAGCC
447
GGCUCAGU CUGAUGAGGCCGUUAGGCCGAA IUGUGGGG
1157

1466
CACACAAC U GAGCCCAU
448
AUGGGCUC CUGAUGAGGCCGUUAGGCCGAA IUUGUGUG
1158

1471
AACUGAGC C CAUGCUGA
449
UCAGCAUG CUGAUGAGGCCGUUAGGCCGAA ICUCAGUU
1159

1472
ACUGAGCC C AUGCUGAU
450
AUCAGCAU CUGAUGAGGCCGUUAGGCCGAA IGCUCAGU
1160

1473
CUGAGCCC A UGCUGAUG
451
CAUCAGCA CUGAUGAGGCCGUUAGGCCGAA IGGCUCAG
1161

1477
GCCCAUGC U GAUGGAGU
452
ACUCCAUC CUGAUGAGGCCGUUAGGCCGAA ICAUGGGC
1162

1488
UGGAGUAC C CUGAGGCU
453
AGCCUCAG CUGAUGAGGCCGUUAGGCCGAA IUACUCCA
1163

1489
GGAGUACC C UGAGGCUA
454
UAGCCUCA CUGAUGAGGCCGUUAGGCCGAA IGUACUCC
1164

1490
GAGUACCC U GAGGCUAU
455
AUAGCCUC CUGAUGAGGCCGUUAGGCCGAA IGGUACUC
1165

1496
CCUGAGGC U AUAACUCG
456
CGAGUUAU CUGAUGAGGCCGUUAGGCCGAA ICCUCAGG
1166

1502
GCUAUAAC U CGCCUAGU
457
ACUAGGCG CUGAUGAGGCCGUUAGGCCGAA IUUAUAGC
1167

1506
UAACUCGC C UAGUGACA
458
UGUCACUA CUGAUGAGGCCGUUAGGCCGAA ICGAGUUA
1168

1507
AACUCGCC U AGUGACAG
459
CUGUCACU CUGAUGAGGCCGUUAGGCCGAA IGCGAGUU
1169

1514
CUAGUGAC A GCCCAGAG
460
CUCUGGGC CUGAUGAGGCCGUUAGGCCGAA IUCACUAG
1170

1517
GUGACAGC C CAGAGGCC
461
GGCCUCUG CUGAUGAGGCCGUUAGGCCGAA ICUGUCAC
1171

1518
UGACAGCC C AGAGGCCC
462
GGGCCUCU CUGAUGAGGCCGUUAGGCCGAA ICCUGUCA
1172

1519
GACAGCCC A GAGGCCCC
463
GGGGCCUC CUGAUGAGGCCGUUAGGCCGAA IGGCUGUC
1173

1525
CCAGAGGC C CCCCGACC
464
GGUCGGGG CUGAUGAGGCCGUUAGGCCGAA ICCUCUGG
1174

1526
CAGAGGCC C CCCGACCC
465
GGGUCGGG CUGAUGAGGCCGUUAGGCCGAA IGCCUCUG
1175

1527
AGAGGCCC C CCGACCCA
466
UGGGUCGG CUGAUGAGGCCGUUAGGCCGAA IGGCCUCU
1176

1528
GAGGCCCC C CGACCCAG
467
CUGGGUCG CUGAUGAGGCCGUUAGGCCGAA IGGGCCUC
1177

1529
AGGCCCCC C GACCCAGC
468
GCUGGGUC CUGAUGAGGCCGUUAGGCCGAA IGGGGCCU
1178

1533
CCCCCGAC C CAGCUCCU
469
AGGAGCUG CUGAUGAGGCCGUUAGGCCGAA IUCGGGGG
1179

1534
CCCCGACC C AGCUCCUG
470
CAGGAGCU CUGAUGAGGCCGUUAGGCCGAA IGUCGGGG
1180

1535
CCCGACCC A GCUCCUGC
471
GCAGGAGC CUGAUGAGGCCGUUAGGCCGAA IGGUCGGG
1181

1538
GACCCAGC U CCUGCUCC
472
GGAGCAGG CUGAUGAGGCCGUUAGGCCGAA ICUGGGUC
1182

1540
CCCAGCUC C UGCUCCAC
473
GUGGAGCA CUGAUGAGGCCGUUAGGCCGAA IAGCUGGG
1183

1541
CCAGCUCC U GCUCCACU
474
AGUGGAGC CUGAUGAGGCCGUUAGGCCGAA IGAGCUGG
1184

1544
GCUCCUGC U CCACUGGG
475
CCCAGUGG CUGAUGAGGCCGUUAGGCCGAA ICAGGAGC
1185

1546
UCCUGCUC C ACUGGGGG
476
CCCCCAGU CUGAUGAGGCCGUUAGGCCGAA IAGCAGGA
1186

1547
CCUGCUCC A CUGGGGGC
477
GCCCCCAG CUGAUGAGGCCGUUAGGCCGAA IGAGCAGG
1187

1549
UGCUCCAC U GGGGGCCC
478
GGGCCCCC CUGAUGAGGCCGUUAGGCCGAA IUGGAGCA
1188

1556
CUGGGGGC C CCGGGGCU
479
AGCCCCGG CUGAUGAGGCCGUUAGGCCGAA ICCCCCAG
1189

1557
UGGGGGCC C CGGGGCUC
480
GAGCCCCG CUGAUGAGGCCGUUAGGCCGAA IGCCCCCA
1190

1558
GGGGGCCC C GGGGCUCC
481
GGAGCCCC CUGAUGAGGCCGUUAGGCCGAA IGGCCCCC
1191

1564
CCCGGGGC U CCCCPAUG
482
CAUUGGGG CUGAUGAGGCCGUUAGGCCGAA ICCCCGGG
1192

1566
CGGGGCUC C CCAAUGGC
483
GCCAUUGG CUGAUGAGGCCGUUAGGCCGAA IAGCCCCG
1193

1567
GGGGCUCC C CAAUGGCC
484
GGCCAUUG CUGAUGAGGCCGUUAGGCCGAA IGAGCCCC
1194

1568
GGGCUCCC C AAUGGCCU
485
AGGCCAUU CUGAUGAGGCCGUUAGGCCGAA IGGAGCCC
1195

1569
GGCUCCCC A AUGGCCUC
486
GAGGCCAU CUGAUGAGGCCGUUAGGCCGAA IGGGAGCC
1196

1575
CCAAUGGC C UCCUUUCA
487
UGAAAGGA CUGAUGAGGCCGUUAGGCCGAA ICCAUUGG
1197

1576
CAAUGGCC U CCUUUCAG
488
CUGAAAGG CUGAUGAGGCCGUUAGGCCGAA IGCCAUUG
1198

1578
AUGOCCUC C UUUCAGGA
489
UCCUGAAA CUGAUGAGGCCGUUAGGCCGAA IAGGCCAU
1199

1579
UGGCCUCC U UUCAGGAG
490
CUCCUGAA CUGAUGAGGCCGUUAGGCCGAA IGAGCCCA
1200

1583
CUCCUUUC A GGAGAUGA
491
UCAUCUCC CUGAUGAGGCCGUUAGGCCGAA IAAAGGAG
1201

1596
AUGAAGAC U UCUCCUCC
492
GGAGGAGA CUGAUGAGGCCGUUAGGCCGAA IUCUUCAU
1202

1599
AAGACUUC U CCUCCAUU
493
AAUGGAGG CUGAUGAGGCCGUUAGGCCGAA IAAGUCUU
1203

1601
GACUUCUC C UCCAUUGC
494
GCAAUGGA CUGAUGAGGCCGUUAGGCCGAA IAGAAGUC
1204

1602
ACUUCUCC U CCAUUGCG
495
CGCAAUGG CUGAUGAGGCCGUUAGGCCGAA IGAGAAGU
1205

1604
UUCUCCUC C AUUGCGGA
496
UCCGCAAU CUGAUGAGGCCGUUAGGCCGAA IAGGAGAA
1206

1605
UCUCCUCC A UUGCGGAC
497
GUCCGCAA CUGAUGAGGCCGUUAGGCCGAA IGAGGAGA
1207

1614
UUGCGGAC A UGGACUUC
498
GAAGUCCA CUGAUGAGGCCGUUAGGCCGAA IUCCGCAA
1208

1620
ACAUGGAC U UCUCAGCC
499
GGCUGAGA CUGAUGAGGCCGUUAGGCCGAA IUCCAUGU
1209

1623
UGGACUUC U CAGCCCUG
500
CAGGGCUG CUGAUGAGGCCGUUAGGCCGAA IAAGUCCA
1210

1625
GACUUCUC A GCCCUGCU
501
AGCAGGGC CUGAUGAGGCCGUUAGGCCGAA IAGAAGUC
1211

1628
UUCUCAGC C CUGCUGAG
502
CUCAGCAG CUGAUGAGGCCGUUAGGCCGAA ICUGAGAA
1212

1629
UCUCAGCC C UGCUGAGU
503
ACUCAGCA CUGAUGAGGCCGUUAGGCCGAA IGCUGAGA
1213

1630
CUCAGCCC U GCUGAGUC
504
GACUCAGC CUGAUGAGGCCGUUAGGCCGAA IGGCUGAG
1214

1633
AGCCCUGC U GAGUCAGA
505
UCUGACUC CUGAUGAGGCCGUUAGGCCGAA ICAGGGCU
1215

1639
GCUGAGUC A GAUCAGCU
506
AGCUGAUC CUGAUGAGGCCGUUAGGCCGAA IACUCAGC
1216

1644
GUCAGAUC A GCUCCUAA
507
UUAGGAGC CUGAUGAGGCCGUUAGGCCGAA IAUCUGAC
1217

1647
AGAUCAGC U CCUAAGGG
508
CCCUUAGG CUGAUGAGGCCGUUAGGCCGAA ICUGAUCU
1218

1649
AUCAGCUC C UAAGGGGG
509
CCCCCUUA CUGAUGAGGCCGUUAGGCCGAA IAGCUGAU
1219

1650
UCAGCUCC U AAGGGGGU
510
ACCCCCUU CUGAUGAGGCCGUUAGGCCGAA IGAGCUGA
1220

1664
GGUGACGC C UGCCCUCC
511
GGAGGGCA CUGAUGAGGCCGUUAGGCCGAA ICGUCACC
1221

1665
GUGACGCC U GCCCUCCC
512
GGGAGGGC CUGAUGAGGCCGUUAGGCCGAA IGCGUCAC
1222

1668
ACGCCUGC C CUCCCCAG
513
CUGGGGAG CUGAUGAGGCCGUUAGGCCGAA ICAGGCGU
1223

1669
CGCCUGCC C UCCCCAGA
514
UCUGGGGA CUGAUGAGGCCGUUAGGCCGAA IGCAGGCG
1224

1670
GCCUGCCC U CCCCAGAG
515
CUCUGGGG CUGAUGAGGCCGUUAGGCCGAA IGGCAGGC
1225

1672
CUGCCCUC C CCAGAGCA
516
UGCUCUGG CUGAUGAGGCCGUUAGGCCGAA IAGGGCAG
1226

1673
UGCCCUCC C CAGAGCAC
517
GUGCUCUG CUGAUGAGGCCGUUAGGCCGAA IGAGGGCA
1227

1674
GCCCUCCC C AGAGCACU
518
AGUGCUCU CUGAUGAGGCCGUUAGGCCGAA IGGAGGGC
1228

1675
CCCUCCCC A GAGCACUG
519
CAGUGCUC CUGAUGAGGCCGUUAGGCCGAA IGGGAGGG
1229

1680
CCCAGAGC A CUGGUUGC
520
GCAACCAG CUGAUGAGGCCGUUAGGCCGAA ICUCUGGG
1230

1682
CAGAGCAC U GGUUGCAG
521
CUGCAACC CUGAUGAGGCCGUUAGGCCGAA IUGCUCUG
1231

1689
CUGGUUGC A GGGGAUUG
522
CAAUCCCC CUGAUGAGGCCGUUAGGCCGAA ICAACCAG
1232

1702
AUUGAAGC C CUCCAAAA
523
UUUUGGAG CUGAUGAGGCCGUUAGGCCGAA ICUUCAAU
1233

1703
UUGAAGCC C UCCAAAAG
524
CUUUUGGA CUGAUGAGGCCGUUAGGCCGAA IGCUUCAA
1234

1704
UGAAGCCC U CCAAAAGC
525
GCUUUUGG CUGAUGAGGCCGUUAGGCCGAA IGGCUUCA
1235

1706
AAGCCCUC C AAAAGCAC
526
GUGCUUUU CUGAUGAGGCCGUUAGGCCGAA IAGGGCUU
1236

1707
AGCCCUCC A AAAGCACU
527
AGUGCUUU CUGAUGAGGCCGUUAGGCCGAA IGAGGGCU
1237

1713
CCAAAAGC A CUUACGGA
528
UCCGUAAG CUGAUGAGGCCGUUAGGCCGAA ICUUUUGG
1238

1715
AAAAGCAC U UACGGAUU
529
AAUCCGUA CUGAUGAGGCCGUUAGGCCGAA IUGCUUUU
1239

1725
ACGGAUUC U GGUGGGGU
530
ACCCCACC CUGAUGAGGCCGUUAGGCCGAA IAAUCCGU
1240

1740
GUGUGUUC C AACUGCCC
531
GGGCAGUU CUGAUGAGGCCGUUAGGCCGAA IAACACAC
1241

1741
UGUGUUCC A ACUGCCCC
532
GGGGCAGU CUGAUGAGGCCGUUAGGCCGAA IGAACACA
1242

1744
GUUCCAAC U GCCCCCAA
533
UUGGGGGC CUGAUGAGGCCGUUAGGCCGAA IUUGGAAC
1243

1747
CCAACUGC C CCCAACUU
534
AAGUUGGG CUGAUGAGGCCGUUAGGCCGAA ICAGUUGG
1244

1748
CAACUGCC C CCAACUUU
535
AAAGUUGG CUGAUGAGGCCGUUAGGCCGAA IGCAGUUG
1245

1749
AACUGCCC C CAACUUUG
536
CAAAGUUG CUGAUGAGGCCGUUAGGCCGAA IGGCAGUU
1246

1750
ACUGCCCC C AACUUUGU
537
ACAAAGUU CUGAUGAGGCCGUUAGGCCGAA IGGGCAGU
1247

1751
CUGCCCCC A ACUUUGUG
538
CACAAAGU CUGAUGAGGCCGUUAGGCCGAA IGGGGCAG
1248

1754
CCCCCAAC U UUGUGGAU
539
AUCCACAA CUGAUGAGGCCGUUAGGCCGAA IUUGGGGG
1249

1766
UGGAUGUC U UCCUUGGA
540
UCCAAGGA CUGAUGAGGCCGUUAGGCCGAA IACAUCCA
1250

1769
AUGUCUUC C UUGGAGGG
541
CCCUCCAA CUGAUGAGGCCGUUAGGCCGAA IAAGACAU
1251

1770
UGUCUUCC U UGGAGGGG
542
CCCCUCCA CUGAUGAGGCCGUUAGGCCGAA IGAAGACA
1252

1784
GGGGGAGC C AUAUUUUA
543
UAAAAUAU CUGAUGAGGCCGUUAGGCCGAA ICUCCCCC
1253

1785
GGGGAGCC A UAUUUUAU
544
AUAAAAUA CUGAUGAGGCCGUUAGGCCGAA IGCUCCCC
1254

1796
UUUUAUUC U UUUAUUGU
545
ACAAUAAA CUGAUGAGGCCGUUAGGCCGAA IAAUAAAA
1255

1806
UUAUUGUC A GUAUCUGU
546
ACAGAUAC CUGAUGAGGCCGUUAGGCCGAA IACAAUAA
1256

1812
UCAGUAUC U GUAUCUCU
547
AGAGAUAC CUGAUGAGGCCGUUAGGCCGAA IAUACUGA
1257

1818
UCUGUAUC U CUCUCUCU
548
AGAGAGAG CUGAUGAGGCCGUUAGGCCGAA IAUACAGA
1258

1820
UGUAUCUC U CUCUCUUU
549
AAAGAGAG CUGAUGAGGCCGUUAGGCCGAA IAGAUACA
1259

1822
UAUCUCUC U CUCUUUUU
550
AAAAAGAG CUGAUGAGGCCGUUAGGCCGAA IAGAGAUA
1260

1824
UCUCUCUC U CUUUUUGG
551
CCAAAAAG CUGAUGAGGCCGUUAGGCCGAA IAGAGAGA
1261

1826
UCUCUCUC U UUUUGGAG
552
CUCCAAAA CUGAUGAGGCCGUUAGGCCGAA IAGAGAGA
1262

1839
GGAGGUGC U UAAGCAGA
553
UCUGCUUA CUGAUGAGGCCGUUAGGCCGAA ICACCUCC
1263

1845
GCUUAAGC A GAAGCAUU
554
AAUGCUUC CUGAUGAGGCCGUUAGGCCGAA ICUUAAGC
1264

1851
GCAGAAGC A UUAACUUC
555
GAAGUUAA CUGAUGAGGCCGUUAGGCCGAA ICUUCUGC
1265

1857
GCAUUAAC U UCUCUGGA
556
UCCAGAGA CUGAUGAGGCCGUUAGGCCGAA IUUAAUGC
1266

1860
UUAACUUC U CUGGAAAG
557
CUUUCCAG CUGAUGAGGCCGUUAGGCCGAA IAAGUUAA
1267

1862
AACUUCUC U GGAAAGGG
558
CCCUUUCC CUGAUGAGGCCGUUAGGCCGAA IAGAAGUU
1268

1877
GGGGGAGC U GGGGAAAC
559
GUUUCCCC CUGAUGAGGCCGUUAGGCCGAA ICUCCCCC
1269

1886
GGGGAAAC U CAAACUUU
560
AAAGUUUG CUGAUGAGGCCGUUAGGCCGAA IUUUCCCC
1270

1888
GGAAACUC A AACUUUUC
561
GAAAAGUU CUGAUGAGGCCGUUAGGCCGAA IAGUUUCC
1271

1892
ACUCAAAC U UUUCCCCU
562
AGGGGAAA CUGAUGAGGCCGUUAGGCCGAA IUUUGAGU
1272

1897
AACUUUUC C CCUGUCCU
563
AGGACAGG CUGAUGAGGCCGUUAGGCCGAA IAAAAGUU
1273

1898
ACUUUUCC C CUGUCCUG
564
CAGGACAG CUGAUGAGGCCGUUAGGCCGAA IGAAAAGU
1274

1899
CUUUUCCC C UGUCCUGA
565
UCAGGACA CUGAUGAGGCCGUUAGGCCGAA IGGAAAAG
1275

1900
UUUUCCCC U GUCCUGAU
566
AUCAGGAC CUGAUGAGGCCGUUAGGCCGAA IGGGAAAA
1276

1904
CCCCUGUC C UGAUGGUC
567
GACCAUCA CUGAUGAGGCCGUUAGGCCGAA IACAGGGG
1277

1905
CCCUGUCC U GAUGGUCA
568
UGACCAUC CUGAUGAGGCCGUUAGGCCGAA IGACAGGG
1278

1913
UGAUGGUC A GCUCCCUU
569
AAGGGAGC CUGAUGAGGCCGUUAGGCCGAA IACCAUCA
1279

1916
UGGUCAUC U CCCUUCUC
570
GAGAAGGG CUGAUGAGGCCGUUAGGCCGAA ICUGACCA
1280

1918
GUCAGCUC C CUUCUCUG
571
CAGAGAAG CUGAUGAGGCCGUUAGGCCGAA IAGCUGAC
1281

1919
UCAGCUCC C UUCUCUGU
572
ACAGAGAA CUGAUGAGGCCGUUAGGCCGAA IGAGCUGA
1282

1920
CAGCUCCC U UCUCUGUA
573
UACAGAGA CUGAUGAGGCCGUUAGGCCGAA IGGAGCUG
1283

1923
CUCCCUUC U CUGUAGGG
574
CCCUACAG CUGAUGAGGCCGUUAGGCCGAA IAAGGGAG
1284

1925
CCCUUCUC U GUAGGGAA
575
UUCCCUAC CUGAUGAGGCCGUUAGGCCGAA IAGAAGGG
1285

1935
UAGGGAAC U GUGGGGUC
576
GACCCCAC CUGAUGAGGCCGUUAGGCCGAA IUUCCCUA
1286

1944
GUGGGGUC C CCCAUCCC
577
GGGAUGGG CUGAUGAGGCCGUUAGGCCGAA IACCCCAC
1287

1945
UGGGGUCC C CCAUCCCC
578
GGGGAUGG CUGAUGAGGCCGUUAGGCCGAA IGACCCCA
1288

1946
GGGGUCCC C CAUCCCCA
579
UGGGGAUG CUGAUGAGGCCGUUAGGCCGAA IGGACCCC
1289

1947
GGGUCCCC C AUCCCCAU
580
AUGGGGAU CUGAUGAGGCCGUUAGGCCGAA IGGGACCC
1290

1948
GGUCCCCC A UCCCCAUC
581
GAUGGGGA CUGAUGAGGCCGUUAGGCCGAA IGGGGACC
1291

1951
CCCCCAUC C CCAUCCUC
582
GAGGAUGG CUGAUGAGGCCGUUAGGCCGAA IAUGGGGG
1292

1952
CCCCAUCC C CAUCCUCC
583
GGAGGAUG CUGAUGAGGCCGUUAGGCCGAA IGAUGGGG
1293

1953
CCCAUCCC C AUCCUCCA
584
UGGAGGAU CUGAUGAGGCCGUUAGGCCGAA IGGAUGGG
1294

1954
CCAUCCCC A UCCUCCAG
585
CUGGAGGA CUGAUGAGGCCGUUAGGCCGAA IGGGAUGG
1295

1957
UCCCCAUC C UCCAGCUU
586
AGCUGGAA CUGAUGAGGCCGUUAGGCCGAA IAUGGGGA
1296

1958
CCCCAUCC U CCAGCUUC
587
GAAGCUGG CUGAUGAGGCCGUUAGGCCGAA IGAUGGGG
1297

1960
CCAUCCUC C AGCUUCUG
588
CAGAAGCU CUGAUGAGGCCGUUAGGCCGAA IAGGAUGG
1298

1961
CAUCCUCC A GCUUCUGG
589
CCAGAAGC CUGAUGAGGCCGUUAGGCCGAA IGAGGAUG
1299

1964
CCUCCAGC U UCUGGUAC
590
GUACCAGA CUGAUGAGGCCGUUAGGCCGAA ICUGGAGG
1300

1967
CCAGCUUC U GGUACUCU
591
AGAGUACC CUGAUGAGGCCGUUAGGCCGAA IAAGCUGG
1301

1973
UCUGGUAC U CUCCUAGA
592
UCUAGGAG CUGAUGAGGCCGUUAGGCCGAA IUACCAGA
1302

1975
UGGUACUC U CCUAGAGA
593
UCUCUAGG CUGAUGAGGCCGUUAGGCCGAA IAGUACCA
1303

1977
GUACUCUC C UAGAGACA
594
UGUCUCUA CUGAUGAGGCCGUUAGGCCGAA IAGAGUAC
1304

1978
UACUCUCC U AGAGACAG
595
CUGUCUCU CUGAUGAGGCCGUUAGGCCGAA IGAGAGUA
1305

1985
CUAGAGAC A GAAGCAGG
596
CCUGCUUC CUGAUGAGGCCGUUAGGCCGAA IUCUCUAG
1306

1991
ACAGAAGC A GGCUGGAG
597
CUCCAGCC CUGAUGAGGCCGUUAGGCCGAA ICUUCUGU
1307

1995
AAGCAGGC U GGAGGUAA
598
UUACCUCC CUGAUGAGGCCGUUAGGCCGAA ICCUGCUU
1308

2007
GGUAAGGC C UUUGAGCC
599
GGCUCAAA CUGAUGAGGCCGUUAGGCCGAA ICCUUACC
1309

2008
GUAAGGCC U UUGAGCCC
600
GGGCUCAA CUGAUGAGGCCGUUAGGCCGAA IGCCUUAC
1310

2015
CUUUGAGC C CACAAAGC
601
GCUUUGUG CUGAUGAGGCCGUUAGGCCGAA ICUCAAAG
1311

2016
UUUGAGCC C ACAAAGCC
602
GGCUUUGU CUGAUGAGGCCGUUAGGCCGAA IGCUCAAA
1312

2017
UUGAGCCC A CAAAGCCU
603
AGGCUUUG CUGAUGAGGCCGUUAGGCCGAA IGGCUCAA
1313

2019
GAGCCCAC A AAGCCUUA
604
UAAGGCUU CUGAUGAGGCCGUUAGGCCGAA IUGGGCUC
1314

2024
CACAAAGC C UUAUCAAG
605
CUUGAUAA CUGAUGAGGCCGUUAGGCCGAA ICUCUGUG
1315

2025
ACAAAGCC U UAUCAAGU
606
ACUUGAUA CUGAUGAGGCCGUUAGGCCGAA IGCUUUGU
1316

2030
GCCUUAUC A AGUGUCUU
607
AAGACACU CUGAUGAGGCCGUUAGGCCGAA IAUAAGGC
1317

2037
CAAGUGUC U UCCAUCAU
608
AUGAUGGA CUGAUGAGGCCGUUAGGCCGAA IACACUUG
1318

2040
GUGUCUUC C AUCAUGGA
609
UCCAUGAU CUGAUGAGGCCGUUAGGCCGAA IAAGACAC
1319

2041
UGUCUUCC A UCAUGGAU
610
AUCCAUGA CUGAUGAGGCCGUUAGGCCGAA IGAAGACA
1320

2044
CUUCCAUC A UGGAUUCA
611
UGAAUCCA CUGAUGAGGCCGUUAGGCCGAA IAUGGAAG
1321

2052
AUGGAUUC A UUACAGCU
612
AGCUGUAA CUGAUGAGGCCGUUAGGCCGAA IAAUCCAU
1322

2057
UUCAUUAC A GCUUAAUC
613
GAUUAAGC CUGAUGAGGCCGUUAGGCCGAA IUAAUGAA
1323

2060
AUUACAGC U UAAUCAAA
614
UUUGAUUA CUGAUGAGGCCGUUAGGCCGAA ICUGUAAU
1324

2066
GCUUAAUC A AAAUAACG
615
CGUUAUUU CUGAUGAGGCCGUUAGGCCGAA IAUUAAGC
1325

2076
AAUAACGC C CCAGAUAC
616
GUAUCUGG CUGAUGAGGCCGUUAGGCCGAA ICGUUAUU
1326

2077
AUAACGCC C CAGAUACC
617
GGUAUCUG CUGAUGAGGCCGUUAGGCCGAA IGCGUUAU
1327

2078
UAACGCCC C AGAUACCA
618
UGGUAUCU CUGAUGAGGCCGUUAGGCCGAA IGGCGUUA
1328

2079
AACGCCCC A GAUACCAG
619
CUGGUAUC CUGAUGAGGCCGUUAGGCCGAA IGGGCGUU
1329

2085
CCAGAUAC C AGCCCCUG
620
CAGGGGCU CUGAUGAGGCCGUUAGGCCGAA IUAUCUGG
1330

2086
CAGAUACC A GCCCCUGU
621
ACAGGGGC CUGAUGAGGCCGUUAGGCCGAA IGUAUCUG
1331

2089
AUACCAGC C CCUGUAUG
622
CAUACAGG CUGAUGAGGCCGUUAGGCCGAA ICUGGUAU
1332

2090
UACCAGCC C CUGUAUGG
623
CCAUACAG CUGAUGAGGCCGUUAGGCCGAA IGCUGGUA
1333

2091
ACCAGCCC C UGUAUGGC
624
GCCAUACA CUGAUGAGGCCGUUAGGCCGAA IGGCUGGU
1334

2092
CCAGCCCC U GUAUGGCA
625
UGCCAUAC CUGAUGAGGCCGUUAGGCCGAA IGGGCUGG
1335

2100
UGUAUGGC A CUGGCAUU
626
AAUGCCAG CUGAUGAGGCCGUUAGGCCGAA ICCAUACA
1336

2102
UAUGGCAC U GGCAUUGU
627
ACAAUGCC CUGAUGAGGCCGUUAGGCCGAA IUGCCAUA
1337

2106
GCACUGGC A UUGUCCCU
628
AGGGACAA CUGAUGAGGCCGUUAGGCCGAA ICCAGUGC
1338

2112
GCAUUGUC C CUGUGCCU
629
AGGCACAG CUGAUGAGGCCGUUAGGCCGAA IACAAUGC
1339

2113
CAUUGUCC C UGUGCCUA
630
UAGGCACA CUGAUGAGGCCGUUAGGCCGAA IGACAAUG
1340

2114
AUUGUCCC U GUGCCUAA
631
UUAGGCAC CUGAUGAGGCCGUUAGGCCGAA IGGACAAU
1341

2119
CCCUGUGC C UAACACCA
632
UGGUGUUA CUGAUGAGGCCGUUAGGCCGAA ICACAGGG
1342

2120
CCUGUGCC U AACACCAG
633
CUGGUGUU CUGAUGAGGCCGUUAGGCCGAA IGCACAGG
1343

2124
UGCCUAAC A CCAGCGUU
634
AACGCUGG CUGAUGAGGCCGUUAGGCCGAA IUUAGGCA
1344

2126
CCUAACAC C AGCGUUUG
635
CAAACGCU CUGAUGAGGCCGUUAGGCCGAA IUGUUAGG
1345

2127
CUAACACC A GCGUUUGA
636
UCAAACGC CUGAUGAGGCCGUUAGGCCGAA IGUGUUAG
1346

2141
UGAGGGGC U GCCUUCCU
637
AGGAAGGC CUGAUGAGGCCGUUAGGCCGAA ICCCCUCA
1347

2144
GGGGCUGC C UUCCUGCC
638
GGCAGGAA CUGAUGAGGCCGUUAGGCCGAA ICAGCCCC
1348

2145
GGGCUGCC U UCCUGCCC
639
GGGCAGGA CUGAUGAGGCCGUUAGGCCGAA IGCAGCCC
1349

2148
CUGCCUUC C UGCCCUAC
640
GUAGGGCA CUGAUGAGGCCGUUAGGCCGAA IAAGGCAG
1350

2149
UGCCUUCC U GCCCUACA
641
UGUAGGGC CUGAUGAGGCCGUUAGGCCGAA IGAAGGCA
1351

2152
CUUCCUGC C CUACAGAG
642
CUCUGUAG CUGAUGAGGCCGUUAGGCCGAA ICAGGAAG
1352

2153
UUCCUGCC C UACAGAGG
643
CCUCUGUA CUGAUGAGGCCGUUAGGCCGAA IGCAGGAA
1353

2154
UCCUGCCC U ACAGAGGU
644
ACCUCUGU CUGAUGAGGCCGUUAGGCCGAA IGGCAGGA
1354

2157
UGCCCUAC A GAGGUCUC
645
GAGACCUC CUGAUGAGGCCGUUAGGCCGAA IUAGGGCA
1355

2164
CAGAGGUC U CUGCCGGC
646
GCCGGCAG CUGAUGAGGCCGUUAGGCCGAA IACCUCUG
1356

2166
GAGGUCUC U GCCGGCUC
647
GAGCCGGC CUGAUGAGGCCGUUAGGCCGAA IAGACCUC
1357

2169
GUCUCUGC C GGCUCUUU
648
AAAGAGCC CUGAUGAGGCCGUUAGGCCGAA ICAGAGAC
1358

2173
CUGCCGGC U CUUUCCUU
649
AAGGAAAG CUGAUGAGGCCGUUAGGCCGAA ICCGGCAG
1359

2175
GCCGGCUC U UUCCUUGC
650
GCAAGGAA CUGAUGAGGCCGUUAGGCCGAA IAGCCGGC
1360

2179
GCUCUUUC C UUGCUCAA
651
UUGAGCAA CUGAUGAGGCCGUUAGGCCGAA IAAAGAGC
1361

2180
CUCUUUCC U UGCUCAAC
652
GUUGAGCA CUGAUGAGGCCGUUAGGCCGAA IGAAAGAG
1362

2184
UUCCUUGC U CAACCAUG
653
CAUGGUUG CUGAUGAGGCCGUUAGGCCGAA ICAAGGAA
1363

2186
CCUUGCUC A ACCAUGGC
654
GCCAUGGU CUGAUGAGGCCGUUAGGCCGAA IAGCAAGG
1364

2189
UGCUCAAC C AUGGCUGA
655
UCAGCCAU CUGAUGAGGCCGUUAGGCCGAA IUUGAGCA
1365

2190
GCUCAACC A UGGCUGAA
656
UUCAGCCA CUGAUGAGGCCGUUAGGCCGAA IGUUGAGC
1366

2195
ACCAUGGC U GAAGGAAA
657
UUUCCUUC CUGAUGAGGCCGUUAGGCCGAA ICCAUGGU
1367

2205
AAGGAAAC A GUGCAACA
658
UGUUGCAC CUGAUGAGGCCGUUAGGCCGAA IUUUCCUU
1368

2210
AACAGUGC A ACAGCACU
659
AGUGCUGU CUGAUGAGGCCGUUAGGCCGAA ICACUGUU
1369

2213
AGUGCAAC A GCACUGGC
660
GCCAGUGC CUGAUGAGGCCGUUAGGCCGAA IUUGCACU
1370

2216
GCAACAGC A CUGGCUCU
661
AGAGCCAG CUCAUGAGGCCGUUAGGCCGAA ICUGUUGC
1371

2218
AACAGCAC U GGCUCUCU
662
AGAGAGCC CUGAUGAGGCCGUUAGGCCGAA IUGCUGUU
1372

2222
GCACUGGC U CUCUCCAG
663
CUGGAGAG CUGAUGAGGCCGUUAGGCCGAA ICCAGUOC
1373

2224
ACUGGCUC U CUCCAGGA
664
UCCUGGAG CUGAUGAGGCCGUUAGGCCGAA IAGCCAGU
1374

2226
UGGCUCUC U CCAGGAUC
663
GAUCCUGG CUGAUGAGGCCGUUAGGCCGAA IAGAGCCA
1375

2228
GCUCUCUC C AGGAUCCA
666
UGGAUCCU CUGAUGAGGCCGUUAGGCCGAA IAGAGAGC
1376

2229
CUCUCUCC A GGAUCCAG
667
CUGGAUCC CUGAUGAGGCCGUUAGGCCGAA IGAGAGAG
1377

2235
CCAGGAUC C AGAAGGGG
668
CCCCUUCU CUGAUGAGGCCGUUAGGCCGAA IAUCCUGG
1378

2236
CAGGAUCC A GAAGGGGU
669
ACCCCUUC CUGAUGAGGCCGUUAGGCCGAA IGAUCCUG
1379

2251
GUUUGGUC U GGACUUCC
670
GGAAGUCC CUGAUGAGGCCGUUAGGCCGAA IACCAAAC
1380

2256
GUCUGGAC U UCCUUGCU
671
AGCAAGGA CUGAUGAGGCCGUUAGGCCGAA IUCCAGAC
1381

2259
UGGACUUC C UUGCUCUC
672
GAGAGCAA CUGAUGAGGCCGUUAGGCCGAA IAAGUCCA
1382

2260
GGACUUCC U UGCUCUCC
673
GGAGAGCA CUGAUGAGGCCGUUAGGCCGAA IGAAGUCC
1383

2264
UUCCUUGC U CUCCCCUC
674
GAGGGGAC CUGAUGAGGCCGUUAGGCCGAA ICAAGGAA
1384

2266
CCUUGCUC U CCCCUCUU
675
AAGAGGGG CUGAUGAGGCCGUUAGGCCGAA IAGCAAGG
1385

2268
UUGCUCUC C CCUCUUCU
676
AGAAGAGG CUGAUGAGGCCGUUAGGCCGAA IAGAGCAA
1386

2269
UGCUCUCC C CUCUUCUC
677
GAGAAGAG CUGAUGAGGCCGUUAGGCCGAA IGAGAGCA
1387

2270
GCUCUCCC C UCUUCUCA
678
UGAGAAGA CUGAUGAGGCCGUUAGGCCGAA IGGAGAGC
1388

2271
CUCUCCCC U CUUCUCAA
679
UUGAGAAG CUGAUGAGGCCGUUAGGCCGAA IGGGAGAG
1389

2273
CUCCCCUC U UCUCAAGU
680
ACUUGAGA CUGAUGAGGCCGUUAGGCCGAA IAGGGGAG
1390

2276
CCCUCUUC U CAAGUGCC
681
GGCACUUG CUGAUGAGGCCGUUAGGCCGAA IAAGAGGG
1391

2278
CUCUUCUC A AGUGCCUU
682
AACGCACU CUGAUGAGGCCGUUAGGCCGAA IAGAAGAG
1392

2284
UCAAGUGC C UUAAUAGU
683
ACUAUUAA CUGAUGAGGCCGUUAGGCCGAA ICACUUGA
1393

2285
CAAGUGCC U UAAUAGUA
684
UACUAUUA CUGAUGAGGCCGUUAGGCCGAA IGCACUUG
1394

2322
GGGAGAGC A GGCUGGCA
685
UGCCAGCC CUGAUGAGGCCGUUAGGCCGAA ICUCUCCC
1395

2326
GAGCAGGC U GGCAGCUC
686
GAGCUGCC CUGAUGAGGCCGUUAGGCCGAA ICCUGCUC
1396

2330
AGGCUGGC A GCUCUCCA
687
UGGAGAGC CUGAUGAGGCCGUUAGGCCGAA ICCAGCCU
1397

2333
CUGGCAGC U CUCCAGUC
688
GACUGGAG CUGAUGAGGCCGUUAGGCCGAA ICUGCCAG
1398

2335
GGCAGCUC U CCAGUCAG
689
CUGACUGO CUGAUGAGGCCGUUAGGCCGAA IAGCUGCC
1399

2337
CAGCUCUC C AGUCAGGA
690
UCCUGACU CUGAUGAGGCCGUUAGGCCGAA IAGAGCUG
1400

2338
AGCUCUCC A GUCACGAG
691
CUCCUGAC CUGAUGAGGCCGUUAGGCCGAA IGAGAGCU
1401

2342
CUCCAGUC A GGAGGCAU
692
AUGCCUCC CUGAUGAGGCCGUUAGGCCGAA IACUGGAG
1402

2349
CAGGAGCC A UAGUUUUU
693
AAAAACUA CUGAUGAGGCCGUUAGGCCGAA ICCUCCUG
1403

2365
UAGUGAAC A AUCAAAGC
694
GCUUUGAU CUGAUGAGGCCGUUAGGCCGAA IUUCACUA
1404

2369
GAACAAUC A AAGCACUU
695
AAGUGCUU CUGAUGAGGCCGUUAGGCCGAA IAUUGUUC
1405

2374
AUCAAAGC A CUUGGACU
696
AGUCCAAG CUGAUGAGGCCGUUAGGCCGAA ICUUUGAU
1406

2376
CAAAGCAC U UGGACUCU
697
AGAGUCCA CUGAUGAGGCCGUUAGGCCGAA IUGCUUUG
1407

2382
ACUUGGAC U CUUGCUCU
698
AGAGCAAG CUGAUGAGGCCGUUAGGCCGAA IUCCAAGU
1408

2384
UUGGACUC U UGCUCUUU
699
AAAGAGCA CUGAUGAGGCCGUUAGGCCGAA IAGUCCAA
1409

2388
ACUCUUGC U CUUUCUAC
700
GUAGAAAG CUGAUGAGGCCGUUAGGCCGAA ICAAGAGU
1410

2390
UCUUGCUC U UUCUACUC
701
GAGUAGAA CUGAUGAGGCCGUUAGGCCGAA IAGCAAGA
1411

2394
GCUCUUUC U ACUCUGAA
702
UUCAGAGU CUGAUGAGGCCGUUAGGCCGAA IAAAGAGC
1412

2397
CUUUCUAC U CUGAACUA
703
UAGUUCAG CUGAUGAGGCCGUUAGGCCGAA IUAGAAAG
1413

2399
UUCUACUC U GAACUAAU
704
AUUAGUUC CUGAUGAGGCCGUUAGGCCGAA IAGUAGAA
1414

2404
CUCUGAAC U AAUAAAGC
705
GCUUUAUU CUGAUGAGGCCGUUAGGCCGAA IUUCAGAG
1415

2413
AAUAAAGC U GUUGCCAA
706
UUGGCAAC CUGAUGAGGCCGUUAGGCCGAA ICUUUAUU
1416

2419
GCUGUUGC C AAGCUGGA
707
UCCAGCUU CUGAUGAGGCCGUUAGGCCGAA ICAACAGC
1417

2420
CUGUUGCC A AGCUGGAC
708
GUCCAGCU CUGAUGAGGCCGUUAGGCCGAA IGCAACAG
1418

2424
UGCCAAGC U GGACGGCA
709
UGCCGUCC CUGAUGAGGCCGUUAGGCCGAA ICUUGGCA
1419

2432
UGGACGGC A CGAGCUCG
710
CGAGCUCG CUGAUGAGGCCGUUAGGCCGAA ICCGUCCA
1420

Input Sequence = NM_021975. Cut Site = CH/.

Arm Length = 8. Core Sequence = CUGAUGAG GCCGUUAGGC CGAA

NM_021975 (Homo sapiens p65 RelA (NFKB), mRNA; 2444 bp)

[0259]

4

TABLE IV

Human REL-A Zinzyme and Substrate Sequence

Seq

Seq

Pos
Substrate
ID
Zinzyme
ID

9
GGCACGAG G CGGGGCCG
1421
CGGCCCCG GCCGAAAGGCGAGUGAGGUCU CUCGUGCC
1717

14
GAGGCGGG G CCGGGUCG
1422
CGACCCGG GCCGAAAGGCGAGUGAGGUCU CCCGCCUC
1718

19
GGGGCCGG G UCGCAGCU
1423
AGCUGCGA GCCGAAAGGCGAGUGAGGUCU CCGGCCCC
1719

22
GCCGGGUC G CAGCUGGG
1424
CCCAGCUG GCCGAAAGGCGAGUGAGGUCU GACCCGGC
1720

25
GGGUCGCA G CUGGGCCC
1425
GGCCCCAG GCCGAAAGGCGAGUGAGGUCU UGCGACCC
1721

30
GCAGCUGG G CCCGCGGC
1426
GCCGCGGG GCCGAAAGGCGAGUGAGGUCU CCAGCUGC
1722

34
CUGGGCCC G CGGCAUGG
1427
CCAUGCCG GCCGAAAGGCGAGUGAGGUCU GGGCCCAG
1723

37
GGCCCGCG G CAUGGACG
1428
CGUCCAUG GCCGAAAGGCGAGUGAGGUCU CGCGGGCC
1724

50
GACGAACU G UUCCCCCU
1429
AGGGGGAA GCCGAAAGGCGAGUGAGGUCU AGUUCGUC
1725

69
UCUUCCCG G CACAGCAG
1430
CUGCUCUG GCCGAAAGGCGAGUGAGCUCU CGGGAAGA
1726

74
CCGGCAGA G CAGCCCAA
1431
UUGGGCUG GCCGAAAGGCGAGUGAGGUCU UCUGCCGG
1727

77
GCAGAGCA G CCCAAGCA
1432
UGCUUGGG GCCGAAAGGCGAGUGAGGUCU UGCUCUGC
1728

83
CAGCCCAA G CAGCGGGG
1433
CCCCGCUG GCCGAAAGGCGAGUGAGGUCU UUGGGCUG
1729

86
CCCAAGCA G CGGGGCAU
1434
AUGCCCCG GCCGAAAGGCGAGUGAGGUCU UGCUUGGG
1730

91
GCAGCGGG G CAUGCGCU
1435
AGCGCAUG GCCGAAAGGCGAGUGAGGUCU CCCGCUGC
1731

95
CGGGGCAU G CGCUUCCG
1436
CGGAAGCG GCCGAAAGGCGAGUGAGGUCU AUGCCCCG
1732

97
GGGCAUGC G CUUCCGCU
1437
AGCGGAAG GCCGAAAGGCGAGUGAGGUCU GCAUGCCC
1733

103
GCGCUUCC G CUACAAGU
1438
ACUUGUAG GCCGAAAGGCGAGUGAGGUCU GGAAGCGC
1734

110
CGCUACAA G UGCGAGGG
1439
CCCUCGCA GCCGAAAGGCGAGUGAGGUCU UUGUAGCG
1735

112
CUACAAGU G CGAGGGGC
1440
GCCCCUCG GCCGAAAGGCGAGUGACGUCU ACUUGUAG
1736

119
UGCGAGGG G CGCUCCGC
1441
GCGGAGCG GCCGAAAGGCGAGUGAGGUCU CCCUCGCA
1737

121
CGAGGGGC G CUCCGCGG
1442
CCGCGGAG GCCGAAAGGCCAGUGAGGUCU GCCCCUCG
1738

126
GGCGCUCC G CGGGCAGC
1443
GCUGCCCG GCCGAAAGGCGAGUGAGGUCU GGAGCGCC
1739

130
CUCCGCGG C CACCAUCC
1444
GGAUGCUG CCCGAAAGGCGAGUGAGGUCU CCGCGGAG
1740

133
CGCGGGCA G CAUCCCAG
1445
CUGGGAUG GCCGAAAGGCGAGUGAGGUCU UGCCCGCG
1741

142
CAUCCCAG G CGAGAGGA
1446
UCCUCUCG GCCGAAACGCGAGUGAGGUCU CUGGCAUG
1742

151
OGAGAGGA C CACAGAUA
1447
UAUCUGUG GCCGAAAGGCGAGUGAGGUCU UCCUCUCG
1743

193
GAUCAAUG C CUACACAG
1448
CUGUGUAG GCCGAAAGGCGAGUGAGGUCU CAUUGAUC
1744

213
CAGGGACA C UGCGCAUC
1449
GAUGCGCA GCCGAAAGGCGAGUGAGGUCU UGUCCCUG
1745

215
GGGACAGU G CGCAUCUC
1450
GAGAUGCG GCCGAAAGGCGAGUGAGGUCU ACUGUCCC
1746

217
GACAGUGC C CAUCUCCC
1451
GGGAGAUG GCCGAAAGGCGAGUGAGGUCU GCACUGUC
1747

228
UCUCCCUG G UCACCAAG
1452
CUUGGUGA GCCGAAAGGCGAGUGAGGUCU CAGGGAGA
1748

251
CCUCACCG C CCUCACCC
1453
GGGUGAGG GCCGAAAGGCGAGUGAGGUCU CGGUGAGG
1749

266
CCCCACGA G CUUGUAGG
1454
CCUACAAG GCCGAAAGGCGAGUGAGGUCU UCCUCGGG
1750

270
ACGAGCUU C UAGGAAAG
1455
CUUUCCUA GCCGAAAGGCGAGUGAGGUCU AAGCUCGU
1751

283
AAAGGACU G CCGGGAUG
1456
CAUCCCGG GCCGAAAGGCGAGUGAGGUCU AGUCCUUU
1752

292
CCGCGAUG G CUUCUAUG
1457
CAUAGAAG GCCCAAAGGCGAGUGAGGUCU CAUCCCGG
1753

303
UCUAUGAG C CUGAGCUC
1458
GACCUCAG CCCGAAACGCGAGUGAGGUCU CUCAUAGA
1754

308
GAGGCUGA C CUCUGCCC
1459
GCCCAGAG GCCGAAAGGCGAGUCACGUCU UCAGCCUC
1755

313
UCAGCUCU G CCCCGACC
1460
GGUCCGGG GCCGAAAGGCGAGUCAGGUCU AGACCUCA
1756

322
CCCGGACC G CUGCAUCC
1461
GGAUGCAC GCCGAAAGGCGAGUGAGGUCU GGUCCGGG
1757

325
GGACCGCU G CAUCCACA
1462
UGUGGAUG GCCGAAAGGCGAGUGAGGUCU AGCGGUCC
1758

334
CAUCCACA C UUUCCACA
1463
UCUCCAAA GCCCAAAGGCGACUCAGGUCU UGUGGAUG
1759

356
GGAAUCCA G UGUGUGAA
1464
UUCACACA GCCGAAAGGCGAGUGAGGUCU UGGAUUCC
1760

358
AAUCCACU C UCUCAAGA
1465
UCUUCACA GCCCAAAGGCGAGUGAGGUCU ACUCCAUU
1761

360
UCCAGUGU C UGAAGAAG
1466
CUUCUUCA GCCGAAAGGCGAGUCAGGUCU ACACUCCA
1762

368
GUGAACAA G CGGGACCU
1467
AGGUCCCC CCCGAAAGGCGAGUCACCUCU UUCUUCAC
1763

380
CACCUGGA G CAGGCUAU
1468
AUAGCCUG GCCGAAAGGCGAGUGAGGUCU UCCAGGUC
1764

384
UGGACCAG G CUAUCAGU
1469
ACUGAUAG GCCGAAAGGCGAGUGAGGUCU CUGCUCCA
1765

391
GGCUAUCA G UCAGCGCA
1470
UGCGCUGA GCCGAAAGGCGAGUGAGGUCU UGAUAGCC
1766

395
AUCAGUCA G CGCAUCCA
1471
UGGAUGCG GCCGAAAGGCCAGUGAGCUCU UGACUGAU
1767

397
CAGUCAGC G CAUCCAGA
1472
UCUGGAUG GCCGAAAGGCGAGUGAGGUCU GCUGACUG
1768

426
CCUUCCAA G UUCCUAUA
1473
UAUAGGAA GCCGAAAGGCGAGUGAGGUCU UUCGAAGG
1769

440
AUAGAACA C CAGCGUGG
1474
CCACGCUG GCCGAAAGGCGAGUGAGGUCU UCUUCUAU
1770

443
CAACACCA C COUGGOGA
1475
UCCCCACG GCCCAAAGGCGAGUGAGGUCU UGCUCUUC
1771

445
AGAGCAGC G UGGGGACU
1476
ACUCCCCA GCCGAAAGGCGAGUGAGGUCU GCUGCUCU
1772

465
ACCUCAAU C CUGUCCCG
1477
CCGCACAG GCCGPAAGGCGAGUGAGGUCU AUUCAGGU
1773

468
UGAAUGCU C UGCGGCUC
1478
GAGCCGCA GCCCAAAGGCGAGUGAGGUCU AGCAUUCA
1774

470
AAUGCUGU C CGGCUCUG
1479
CAGAGCCG CCCGAAAGGCGAGUGAGCUCU ACAGCAUU
1775

473
GCUGUGCG G CUCUGCUU
1480
AAGCAGAG GCCGAAAGGCGAGUGAGGUCU CGCACAGC
1776

478
GCGGCUCU G CUUCCAGC
1481
CCUGGAAG GCCGAAAGGCGACUGAGGUCU AGAGCCGC
1777

486
GCUUCCAG G UCACAGUG
1482
CACUGUCA GCCCAAAGGCGAGUGAGCUCU CUGGAAGC
1778

492
AGGUGACA C UGCGCGAC
1483
CUCCCGCA GCCGAAAGGCGAGUGAGGUCU UGUCACCU
1779

494
GUGACAGU G CCGCACCC
1484
CCCUCCCG CCCCAAAGGCCAGUGAGGUCU ACUGUCAC
1780

508
CCCAUCAG G CAGGCCCC
1485
CCCCCCUG GCCGAAAGGCCAGUGACCUCU CUCAUGGG
1781

512
UCAGCCAG G CCCCUCCC
1486
CCGAGCGG GCCGAAAGGCCACUGACGUCU CUGCCUGA
1782

520
GCCCCUCC G CCUGCCCC
1487
GCGCCAGG GCCGAAAGGCGAGUGAGGUCU CCACGCCC
1783

524
CUCCGCCU C CCGCCUGU
1488
ACACGCCG GCCGAAAGGCGACUGAGCUCU AGCCGGAG
1784

527
CGCCUGCC C CCUGUCCU
1489
ACGACACC CCCGAAAGGCGAGUGAGGUCU GGCAGCCC
1785

531
UGCCGCCU G UCCUUUCU
1490
AGAAAGGA CCCGAAAGGCCAGUGAGGUCU ACGCGGCA
1786

559
UGACAAUC G UGCCCCCA
1491
UCCGGGCA GCCGAAAGGCGAGUGAGGUCU CAUUGUCA
1787

561
ACAAUCGU C CCCCCAAC
1492
GUUCGCGG GCCGAAAGGCGAGUCACGUCU ACGAUUGU
1788

573
CCAACACU C CCGAGCUC
1493
GAGCUCGC CCCGAAAGGCGAGUGAGGUCU AGUGUUCG
1789

578
ACUGCCCA C CUCAAGAU
1494
AUCUUGAG GCCCAAAGCCGAGUCACCUCU UCCGCAGU
1790

589
CAAGAUCU C CCCACUGA
1495
UCACUCCC CCCGAAAGGCGACUGAGGUCU AGAUCUUG
1791

594
UCUCCCGA C UCAACCGA
1496
UCGGUUCA CCCGAAAGGCCACUGAGGUCU UCGGCACA
1792

610
AAACUCUG C CAGCUGCC
1497
GGCAGCUC GCCCAAAGGCGAGUGACGUCU CAGAGUUU
1793

613
CUCUGCCA C CUGCCUCC
1498
CCACGCAC GCCGAAAGCCCACUGAGGUCU UGCCACAC
1794

616
UGGCAGCU C CCUCGGUG
1499
CACCGAGG GCCCAAAGGCCAGUCACCUCU AGCUGCCA
1795

622
CUCCCUCC C UCGCCAUC
1500
CAUCCCCA GCCCAAAGCCCACUCACGUCU CGAGCCAC
1796

644
UUCCUACU C UCUGACAA
1501
UUGUCACA GCCGAAAGGCGACUCACCUCU ACUACCAA
1797

646
CCUACUCU G UCACAAGC
1502
CCUUGUCA CCCCAAAGCCGACUGACCUCU ACAGUAGC
1798

654
GUCACAAG G UGCAGAAA
1503
UUUCUGCA GCCGAAAGGCGAGUGAGGUCU CUUCUCAC
1799

656
GACAACGU C CACAAACA
1504
UCUUUCUC CCCCAAAGCCCAGUCACGUCU ACCUUGUC
1800

675
ACAUUGAG C UCUAUUUC
1505
CAAAUACA GCCCUAAGGCCAGUGAGGUCU CUCAAUGU
1801

677
AUUGAGGU C UAUUUCAC
1506
GUCAAAUA CCCCAAACCCCACUCACCUCU ACCUCAAU
1802

694
CCCACCAG C CUGGCAGG
1507
CCUCCCAG CCCCAAAGCCCAGUGACCUCU CUGGUCCC
1803

702
GCUCCGAG C CCCGACCC
1508
GCCUCGGC GCCGAAAGGCCAGUGAGGUCU CUCCCACC
1804

709
GGCCCCAG C CUCCUUUU
1509
AAAAGCAC CCCGAAAGGCGACUGACCUCU CUCCCCCC
1805

719
UCCUUUUC C CAACCUGA
1510
UCAGCUUG GCCCAAAGCCGACUGACCUCU GAAAAGCA
1806

723
UUUCCCAA C CUGAUGUC
1511
CACAUCAC CCCCAAACCCCACUGAGGUCU UUGCGAAA
1807

729
AACCUGAU C UCCACCCA
1512
UCCCUCCA CCCGAAAGCCCACUCACCUCU AUCAGCUU
1808

731
GCUCAUCU C CACCCACA
1513
UGUCGGUG CCCCAAACCCCACUCACCUCU ACAUCACC
1809

741
ACCCACAA C UCGCCAUU
1514
AAUCGCCA CCCCAAAGGCCACUCACGUCU UUCUCGGU
1810

744
CACAACUG C CCAUUCUC
1515
CACAAUCC CCCCAAAGCCCACUCACCUCU CACUUGUC
1811

750
UCGCCAUU C UCUUCCCC
1516
CCCCAACA GCCGAAAGGCCAGUGACCUCU AAUGCCCA
1812

752
GCCAUUCU C UUCCCCAC
1517
CUCCGCAA CCCCAAAGCCGACUCACCUCU ACAAUGCC
1813

771
CUCCCUAC C CAGACCCC
1518
CCCCUCUC CCCCAAAGGCCACUCACCUCU CUAGCGAC
1814

781
AGACCCCA G CCUGCAGG
1519
CCUGCAGG GCCGAAAGGCGAGUGAGGUCU UGGGGUCU
1815

785
CCCAGCCU G CAGGCUCC
1520
GGAGCCUG GCCGAAAGGCGAGUGAGGUCU AGGCUGGG
1816

789
GCCUGCAG G CUCCUGUG
1521
CACAGGAG GCCGAAAGGCGAGUGAGGUCU CUGCAGGC
1817

795
AGGCUCCU G UGCGUGUC
1522
GACACGCA GCCGAAAGGCGAGUGAGGUCU AGGAGCCU
1818

797
GCUCCUGU G CGUGUCUC
1523
GAGACACG GCCGAAAGGCGAGUGAGGUCU ACAGGAGC
1819

799
UCCUGUGC G UGUCUCCA
1524
UGGAGACA GCCGAAAGGCGAGUGAGGUCU GCACAGGA
1820

801
CUGUGCGU G UCUCCAUG
1525
CAUGGAGA GCCGAAAGGCGAGUGAGGUCU ACGCACAG
1821

809
GUCUCCAU G CAGCUGCG
1526
CGCAGCUG GCCGAAAGGCGAGUGAGGUCU AUGGAGAC
1822

812
UCCAUGCA G CUGCGGCG
1527
CGCCGCAG GCCGAAAGGCGAGUGAGGUCU UGCAUGGA
1823

815
AUGCAGCU G CGGCGGCC
1528
GGCCGCCG GCCGAAAGGCGAGUGAGGUCU AGCUGCAU
1824

818
CAGCUGCG G CGGCCUUC
1529
GAAGGCCG GCCGAAAGGCGAGUGAGGUCU CGCAGCUG
1825

821
CUGCGGCG G CCUUCCGA
1530
UCGGAAGG GCCGAAAGGCGAGUGAGGUCU CGCCGCAG
1826

836
GACCGGGA G CUCAGUGA
1531
UCACUGAG GCCGAAAGGCGAGUGAGGUCU UCCCGGUC
1827

841
GGAGCUCA G UGAGCCCA
1532
UGGGCUCA GCCGAAAGGCGAGUGAGGUCU UGAGCUCC
1828

845
CUCAGUGA G CCCAUGGA
1533
UCCAUGGG GCCGAAAGGCGAGUGAGGUCU UCACUGAG
1829

860
GAAUUCCA G UACCUGCC
1534
GGCAGGUA GCCGAAAGGCGAGUGAGGUCU UGGAAUUC
1830

866
CAGUACCU G CCAGAUAC
1535
GUAUCUGG GCCGAAAGGCGAGUGAGGUCU AGGUACUG
1831

883
AGACGAUC G UCACOGGA
1536
UCCGGUGA GCCGAAAGGCGAGUGAGGUCU GAUCGUCU
1832

904
GGAGAAAC G UAAAAGGA
1537
UCCUUUUA GCCGAAAGGCGAGUGAGGUCU GUUUCUCC
1833

931
CUUCAAGA G CAUCAUGA
1538
UCAUGAUG GCCGAAAGGCGAGUGAGGUCU UCUUGAAG
1834

946
GAAGAAGA G UCCUUUCA
1539
UGAAAGGA GCCGAAAGGCGAGUGAGGUCU UCUUCUUC
1835

955
UCCUUUCA G CGGACCCA
1540
UGGGUCCG GCCGAAAGGCGAGUGAGGUCU UGAAAGGA
1836

974
GACCCCCG G CCUCCACC
1541
GGUGGAGG GCCGAAAGGCGAGUGAGGUCU CGGGGGUC
1837

988
ACCUCGAC G CAUUGCUG
1542
CAGCAAUG GCCGAAAGGCGAGUGAGGUCU GUCGAGGU
1838

993
GACGCAUU G CUGUGCCU
1543
AGGCACAG GCCGAAAGGCGAGUGAGGUCU AAUGCGUC
1839

996
GCAUUGCU G UGCCUUCC
1544
GGAAGGCA GCCGAAAGGCGAGUGAGGUCU AGCAAUGC
1840

998
AUUGCUGU G CCUUCCCG
1545
CGGGAAGG GCCGAAAGGCGAGUGAGGUCU ACAGCAAU
1841

1006
GCCUUCCC G CAGCUCAG
1546
CUGAGCUG GCCGAAAGGCGAGUGAGGUCU GGGAAGGC
1842

1009
UUCCCGCA G CUCAGCUU
1547
AAGCUGAG GCCGAAAGGCGAGUGAGGUCU UGCGGGAA
1843

1014
GCAGCUCA G CUUCUGUC
1548
GACAGAAG GCCGAAAGGCGAGUGAGGUCU UGAGCUGC
1844

1020
CAGCUUCU G UCCCCAAG
1549
CUUGGGGA GCCGAAAGGCGAGUGAGGUCU AGAAGCUG
1845

1028
GUCCCCAA G CCAGCACC
1550
GGUGCUGG GCCGAAAGGCGAGUGAGGUCU UUGGGGAC
1846

1032
CCAAGCCA G CACCCCAG
1551
CUGGGGUG GCCGAAAGGCGAGUGAGGUCU UGGCUUGG
1847

1040
GCACCCCA G CCCUAUCC
1552
GGAUAGGG GCCGAAAGGCGAGUGAGGUCU UGGGGUGC
1848

1055
CCCUUUAC G UCAUCCCU
1553
AGGGAUGA GCCGAAAGGCGAGUGAGGUCU GUAAAGGG
1849

1066
AUCCCUGA G CACCAUCA
1554
UGAUGGUG GCCGAAAGGCGAGUGAGGUCU UCAGGGAU
1850

1085
UAUGAUGA G UUUCCCAC
1555
GUGGGAAA GCCGAAAGGCGAGUGAGGUCU UCAUCAUA
1851

1098
CCACCAUG G UGUUUCCU
1556
AGGAAACA GCCGAAAGGCGAGUGAGGUCU CAUGGUGG
1852

1100
ACCAUGGU G UUUCCUUC
1557
GAAGGAAA GCCGAAAGGCGAGUGAGGUCU ACCAUGGU
1853

1112
CCUUCUGG G CAGAUCAG
1558
CUGAUCUG GCCGAAAGGCGAGUGAGGUCU CCAGAAGG
1854

1120
GCAGAUCA G CCAGGCCU
1559
AGGCCUGG GCCGAAAGGCGAGUGAGGUCU UGAUCUGC
1855

1125
UCAUCCAG G CCUCGGCC
1560
GGCCGAGG GCCGAAAGGCGAGUGAGGUCU CUGGCUGA
1856

1131
AGGCCUCG G CCUUGGCC
1561
GGCCAAGG GCCGAAAGGCGAGUGAGGUCU CGAGGCCU
1857

1137
CGGCCUUG G CCCCGGCC
1562
GGCCGGGG GCCGAAAGGCGAGUGAGGUCU CAAGGCCG
1858

1143
UGGCCCCG G CCCCUCCC
1563
GGGAGGGG GCCGAAAGGCGAGUGAGGUCU CGGGGCCA
1859

1155
CUCCCCAA G UCCUGCCC
1564
GGGCAGGA GCCGAAAGGCGAGUGAGGUCU UUGGGGAG
1860

1160
CAAGUCCU G CCCCAGGC
1565
GCCUGGGG GCCGAAAGGCGAGUGAGGUCU AGGACUUG
1861

1167
UGCCCCAG G CUCCAGCC
1566
GGCUGGAG GCCGAAAGGCGAGUGAGGUCU CUGGGGCA
1862

1173
AGGCUCCA G CCCCUGCC
1567
GGCAGGGG GCCGAAAGGCGAGUGAGGUCU UGGAGCCU
1863

1179
CAGCCCCU G CCCCUGCU
1568
AGCAGGGG GCCGAAAGGCGAGUGAGGUCU AGGGGCUG
1864

1185
CUGCCCCU G CUCCAGCC
1569
GGCUGGAG GCCGAAAGGCGAGUGAGGUCU AGGGGCAG
1865

1191
CUCCUCCA G CCAUGGUA
1570
UACCAUGG GCCGAAAGGCGAGUGAGGUCU UGGAGCAG
1866

1197
CAGCCAUG G UAUCAGCU
1571
AGCUGAUA GCCGAAAGGCGAGUGACGUCU CAUGCCUG
1867

1203
UGGUAUCA G CUCUGGCC
1572
CGCCAGAG GCCGAAAGGCGAGUGAGGUCU UGAUACCA
1868

1209
CAGCUCUG G CCCAAGCC
1573
GGCCUGGG GCCGAAAGGCGAAUGAGGUCU CAGAGCUG
1869

1215
UGGCCCAG G CCCCAGCC
1574
GGCUGGGG GCCGAAAGGCGAGUGAGGUCU CUGGGCCA
1870

1221
AGGCCCCA C CCCCUGUC
1575
GACAGCGG CCCGAAAGGCGAGUCAGGUCU UGGGGCCU
1871

1227
CACCCCCU G UCCCAGUC
1576
GACUGGGA GCCGAAAGGCGAGUGAGGUCU AGGGGCUG
1872

1233
CUGUCCCA G UCCUAGCC
1577
CGCUAGGA GCCGAAAGGCGAGUGAGGUCU UGGGACAG
1873

1239
CAGUCCUA C CCCCAGGC
1578
GCCUGGCG CCCGAAACGCGACUGAGGUCU UAGCACUG
1874

1246
AGCCCCAG G CCCUCCUC
1579
CAGGACGG CCCGAAAGGCGACUGAGGUCU CUGGGGCU
1875

1257
CUCCUCAG G CUGUCGCC
1580
GGCCACAG GCCGAAAGGCGAGUGAGGUCU CUGAGGAG
1876

1260
CUCAGGCU G UGGCCCCA
1581
UGGGGCCA GCCGAAAGGCGAGUGAGGUCU AGCCUGAG
1877

1263
AGGCUGUG G CCCCACCU
1582
AGGUGGGG GCCGAAAGGCGAGUGAGGUCU CACAGCCU
1878

1272
CCCCACCU G CCCCCAAC
1583
CUUCGGGG GCCGAAAGGCGAGUGAGGUCU AGGUGGGG
1879

1280
GCCCCCAA G CCCACCCA
1584
UGGCUGGG GCCGAAAGGCGAGUGAGGUCU UUGGGGGC
1880

1290
CCACCCAG G CUGGGGAA
1585
UUCCCCAG GCCGAAAGGCGAGUGAGCUCU CUGOGUOG
1881

1304
GAAGGAAC G CUGUCAGA
1586
UCUGACAG GCCGAAAGGCGAGUGAGGUCU GUUCCUUC
1882

1307
GGAACGCU G UCAGAGGC
1587
GCCUCUGA GCCGAAAGGCGAGUGAGGUCU AGCGUUCC
1883

1314
UGUCAGAG C CCCUGCUG
1588
CAGCAGGG GCCGAAAGGCGAGUGAGGUCU CUCUGACA
1884

1319
GAGGCCCU G CUGCAGCU
1589
AGCUGCAG GCCGAAAGGCCAGUGAGGUCU AGGGCCUC
1885

1322
CCCCUGCU G CACCUCCA
1590
UGCAGCUG GCCGAAAGGCGAGUGAGGUCU AGCAGGGC
1886

1325
CUGCUGCA G CUGCAGUU
1591
AACUGCAG GCCGAAACGCGAGUGAGGUCU UGCAGCAG
1887

1328
CUGCAGCU G CAGUUUGA
1592
UCAAACUG GCCGAAAGGCGAGUGAGGUCU AGCUCCAG
1888

1331
CAGCUGCA G UUUGAUGA
1593
UCAUCAAA GCCGAAACGCCAGUGAGGUCU UGCAGCUG
1889

1353
ACCUGGGG C CCUUGCUU
1594
AAGCAAGG CCCGAAAGGCGAGUGAGGUCU CCCCAGGU
1890

1358
GGGGCCUU C CUUGGCAA
1595
UUGCCAAG GCCGAAAGGCGAGUGAGGUCU AAGGCCCC
1891

1363
CUUGCUUG C CAACAGCA
1596
UGCUGUUG GCCGAAAGGCGAGUGAGGUCU CAAGCAAG
1892

1369
UGGCAACA C CACAGACC
1597
GCUCUGUC GCCGAAACGCGAGUGAGGUCU UGUUGCCA
1893

1380
CAGACCCA G CUGUGGUC
1598
GAACACAG GCCGAAACGCGAGUGAGGUCU UGGGUCUG
1894

1383
ACCCAGCU G UGUUCACA
1599
UGUGAACA GCCGAAAGGCGAGUGAGGUCU AGCUGGGU
1895

1385
CCAGCUGU C UUCACAGA
1600
UCUGUGAA GCCGAAAGGCGAGUGAGCUCU ACAGCUCG
1896

1398
CAGACCUG C CAUCCCUC
1601
GACGGAUG GCCGAAAGGCGAGUGAGGUCU CAGGUCUG
1897

1404
UGGCAUCC C UCCACAAC
1602
GUUGUCCA GCCCAAAGCCGAGUGAGGUCU GCAUCCCA
1898

1418
AACUCCGA C UUUCAGCA
1603
UGCUGAAA GCCGAAAGGCGAGUGAGGUCU UCGGAGUU
1899

1424
GAGUUUCA C CAGCUGCU
1604
ACCACCUG CCCGAAACGCGAGUGAGGUCU UGAAACUC
1900

1427
UUUCAGCA C CUGCUGAA
1605
UUCAGCAG GCCCAAAGGCGACUGAGGUCU UCCUCAAA
1901

1430
CAGCAGCU C CUGAACCA
1606
UGGUUCAG GCCGAAAGGCGAGUGACGUCU ACCUCCUG
1902

1441
CAACCAGG C CAUACCUG
1607
CAGGUAUG GCCGAAAGGCGAGUGAGGUCU CCUGGUUC
1903

1449
GCAUACCU C UCGCCCCC
1608
GGGGGCCA GCCGAAAGGCGAGUGAGGUCU AGCUAUGC
1904

1452
UACCUCUG C CCCCCCAC
1609
CUGCGGCG GCCGAAAGGCGAGUGAGGUCU CACAGGUA
1905

1469
ACAACUCA C CCCAUGCU
1610
AGCAUGGG GCCGAAAGGCGAGUGAGGUCU UCAGUUCU
1906

1475
GAGCCCAU C CUGAUGGA
1611
UCCAUCAC GCCCAAACGCCAGUGAGCUCU AUCGGCUC
1907

1484
CUGAUGGA C UACCCUGA
1612
UCAGGCUA GCCGAAACCCGAGUGACGUCU UCCAUCAC
1908

1494
ACCCUCAG C CUAUAACU
1613
AGUUAUAG GCCGAAAGGCGAGUGAGGUCU CUCAGGGU
1909

1504
UAUAACUC C CCUACUGA
1614
UCACUAGC CCCCAAACGCGACUGACGUCU GAGUUAUA
1910

1509
CUCGCCUA C UGACAGCC
1615
CGCUGUCA GCCGAAAGGCGAGUGAGGUCU UAGGCGAG
1911

1515
UACUGACA C CCCACACC
1616
CCUCUCCG GCCCAAACGCGACUGACCUCU UGUCACUA
1912

1523
CCCCACAG C CCCCCCGA
1617
UCGGCGCC CCCGAAAGGCGAGUGAGGUCU CUCUCGCC
1913

1536
CCGACCCA C CUCCUGCU
1618
ACCAGGAG CCCCAAACCCCAGUCACGUCU UCCGUCGG
1914

1542
CAGCUCCU C CUCCACUG
1619
CAGUGGAG GCCGAAAGCCGAGUGACGUCU AGGACCUC
1915

1554
CACUGGGC C CCCCCGGG
1620
CCCCGGCG GCCGAAAGGCGAGUGAGCUCU CCCCAGUC
1916

1562
GCCCCGGG G CUCCCCAA
1621
UUGGGGAG GCCGAAAGGCGAGUGAGGUCU CCCGGGAAC
1917

1573
CCCCAAUG G CCUCCUUU
1622
AAAGGAGG GCCGAAAGGCGAGUGAGGUCU CAUUGGGG
1918

1608
CCUCCAUU G OGGACAUG
1623
CAUGUCCG GCCGAAAGGCGAGUGAGGUCU AAUGGAGG
1919

1626
ACUUCUCA G CCCUGCUG
1624
CAGCAGGG GCCGAAAGGCGAGUGAGGUCU UGAGAAGU
1920

1631
UCAGCCCU G CUGAGUCA
1625
UGACUCAG GCCGAAAGGCGAGUGAGGUCU AGGGCUGA
1921

1636
CCUGCUGA G UCAGAUCA
1626
UGAUCUGA GCCGAAAGGCGAGUGAGGUCU UCAGCAGG
1922

1645
UCAGAUCA C CUCCUAAG
1627
CUCAGGAG GCCGAAAGGCGAGUGAGGUCU UGAUCUGA
1923

1657
CUAAGGGG G UGACGCCU
1628
AGGCGUCA GCCGAAAGGCGAGUGAGGUCU CCCCUUAG
1924

1662
GGGGUGAC G CCUGCCCU
1629
AGGGCAGG GCCGAAAGGCGAGUGAGGUCU GUCACCOC
1925

1666
UGACGCCU G CCCUCCCC
1630
GGGGAGGG GCCGAAAGGCGAGUGAGGUCU AGGCGUCA
1926

1678
UCCCCAGA G CACUGGUC
1631
AACCAGUG GCCGAAAGGCGAGUGAGGUCU UCUGGGGA
1927

1684
GACCACUG G UUGCAGGG
1632
CCCUGCAA GCCGAAAGGCGAGUGAGGUCU CAGUGCUC
1928

1687
CACUGGUC G CAGGGGAU
1633
AUCCCCUG GCCGAAAGGCGAGUGAGGUCU AACCAGUG
1929

1700
GGAUUGAA G CCCUCCAA
1634
UUGGAGGG GCCGAAAGGCGAGUGAGGUCU UUCAAUCC
1930

1711
CUCCAAAA C CACUUACG
1635
CGUAAGUG GCCGAAAGGCGAGUGAGGUCU UUUUGGAG
1931

1727
GGAUUCUG G UGGGGUGU
1636
ACACCCCA GCCGAAAGGCGAGUGAGGUCU CAGAAUCC
1932

1732
CUGGUGGG G UGUGUUCC
1637
GGAACACA GCCGAAAGGCGAGUGAGGUCU CCCACCAG
1933

1734
GGUGGGGU G UGUUCCAA
1638
UUGGAACA GCCGAAAGGCGAGUGAGGUCU ACCCCACC
1934

1736
UGGGGUGU C UUCCAACU
1639
AGUUGGAA GCCGAAAGGCGAGUGAGGUCU ACACCCCA
1935

1745
UUCCAACU G CCCCCAAC
1640
GUUGGGGG GCCGAAAGGCGAGUGAGGUCU AGUUGGAA
1936

1757
CCAACUUU G UGGAUGUC
1641
GACAUCCA GCCGAAAGGCGAGUGAGGUCU AAAGUUGG
1937

1763
UUGUGGAU G UCUUCCUC
1642
AAGGAAGA GCCGAAAGGCGAGUGAGGUCU AUCCACAA
1938

1782
AGGGGGGA G CCAUAUUU
1643
AAAUAUGG GCCGAAAGGCGAGUGAGGUCU UCCCCCCU
1939

1803
CUUUUAUU G UCAGUAUC
1644
GAUACUGA GCCGAAAGGCGAGUGAGGUCU AAUAAAAG
1940

1807
UAUUGUCA C UAUCUGUA
1645
UACAGAUA GCCGAAAGGCGAGUGAGGUCU UGACAAUA
1941

1813
CAGUAUCU C UAUCUCUC
1646
GAGAGAUA GCCGAAAGGCGAGUGAGGUCU AGAUACUG
1942

1835
UUUUGGAG C UGCUUAAG
1647
CUUAAGCA GCCGAAAGGCGAGUGAGGUCU CUCCAAAA
1943

1837
UUGGAGGU C CUUAAGCA
1648
UGCUUAAG GCCGAAAGGCGAGUGAGGUCU ACCUCCAA
1944

1843
GUGCUUAA C CAGAAGCA
1649
UGCUUCUG GCCGAAAGGCGAGUGAGGUCU UUAAGCAC
1945

1849
AAGCAGAA C CAUUAACU
1650
AGUUAAUG GCCGAAAGGCGAGUGAGGUCU UUCUGCUU
1946

1875
AGCGCCCA C CUGGGGAA
1651
UUCCCCAG CCCGAAAGGCGAGUGAGGUCU UCCCCCCU
1947

1901
UUUCCCCU C UCCUGAUG
1652
CAUCAGGA GCCGAAAGGCGAGUGAGGUCU AGGGGAAA
1948

1910
UCCUCAUC C UCACCUCC
1653
COACCUCA GCCGAAAGGCGAGUGAGGUCU CAUCACCA
1949

1914
GAUCCUCA C CUCCCUUC
1654
GAAGGGAG GCCGAAAGGCGAGUGAGGUCU UCACCAUC
1950

1926
CCUUCUCU C UAGGGAAC
1655
GUUCCCUA GCCGAAAGGCGAGUGAGGUCU AGAGAAGG
1951

1936
AGGGAACU C UCGGGUCC
1656
CCACCCCA GCCGAAAGGCGAGUGAGGUCU AGUUCCCU
1952

1941
ACUGUGGG C UCCCCCAU
1657
AUGGGGCA GCCGAAACGCGAGUGAGGUCU CCCACACU
1953

1962
AUCCUCCA C CUUCUGGU
1658
ACCAGAAG GCCGAAAGGCGAGUGAGGUCU UGCACGAU
1954

1969
AGCUUCUG C UACUCUCC
1659
GGAGAGUA GCCGAAAGGCGAGUGAGGUCU CAGAAGCU
1955

1989
AGACAGAA C CACCCUCC
1660
CCACCCUC GCCGAAACGCGACUGAGGUCU UUCUGUCU
1956

1993
AGAAGCAG C CUCCAGCU
1661
ACCUCCAG GCCGAAAGGCGAGUGAGGUCU CUGCUUCU
1957

2000
GGCUCGAC C UAAGGCCU
1662
AGGCCUUA GCCGAAAGGCGAGUGAGCUCU CUCCAGCC
1958

2005
GAGGUAAG C CCUUUGAG
1663
CUCAAAGG CCCGAAACCCGAGUCAGCUCU CUCACCUC
1959

2013
GCCUUUGA C CCCACAAA
1664
UUUGUGGG GCCCAAAGCCCACUGACCUCU UCAAAGGC
1960

2022
CCCACAAA C CCUUAUCA
1665
UCAUAAGC CCCGAAACGCGACUGAGGUCU UUUCUGGG
1961

2032
CUUAUCAA C UCUCUUCC
1666
GGAAGACA GCCGAAAGGCGAGUGAGGUCU UUGAUAAG
1962

2034
UAUCAAGU C UCUUCCAU
1667
AUCCAAGA CCCGAAACCCGACUCACCUCU ACUUCAUA
1963

2058
UCAUUACA C CUUAAUCA
1668
UCAUUAAC CCCGAAAGGCGACUGACGUCU UGUAAUGA
1964

2074
AAAAUAAC C CCCCACAU
1669
AUCUCCGC CCCCAAACCCCAGUCACCUCU CUUAUUUU
1965

2087
AGAUACCA C CCCCUGUA
1670
UACAGCGG CCCGAAAGGCGAGUGAGGUCU UCGUAUCU
1966

2093
CAGCCCCU C UAUGGCAC
1671
GUCCCAUA CCCGAAAGCCGACUCACCUCU ACCCCCUC
1967

2098
CCUGUAUG G CACUGGCA
1672
UGCCAGUG GCCGAAAGGCGAGUGAGGUCU CAUACAGG
1968

2104
UGGCACUG G CAUUGUCC
1673
GGACAAUG GCCGAAAGGCGAGUGAGGUCU CAGUGCCA
1969

2109
CUGGCAUU G UCCCUGUG
1674
CACAGGGA GCCGAAAGGCGAGUGAGGUCU AAUCCCAG
1970

2115
UUGUCCCU G UCCCUAAC
1675
GUUAGGCA GCCGAAAGGCGAGUGAGCUCU AGCGACAA
1971

2117
GUCCCUGU C CCUAACAC
1676
GUGUUAGG GCCGAAAGGCGAGUGAGGUCU ACAGGGAC
1972

2128
UAACACCA G CGUUUGAG
1677
CUCAAACG GCCGAAAGGCGAGUGAGGUCU UGGUGUUA
1973

2130
ACACCAGC G UUUGAGGG
1678
CCCUCAAA GCCGAAAGGCGAGUGAGGUCU GCUGGUGU
1974

2139
UUUGAGCG G CUGCCUUC
1679
GAAGGCAG GCCGAAAGGCGAGUGAGGUCU CCCUCAAA
1975

2142
GAGGGGCU G CCUUCCUG
1680
CAGGAAGG GCCGAAAGGCGAGUGAGGUCU AGCCCCUC
1976

2150
GCCUUCCU G CCCUACAG
1681
CUGUAGGG GCCGAAAGGCCACUGAGGUCU AGGAAGGC
1977

2161
CUACAGAG C UCUCUGCC
1682
GCCAGACA GCCGAAAGGCGAGUGAGGUCU CUCUGUAG
1978

2167
AGGUCUCU G CCGGCUCU
1683
AGAGCCGG GCCGAAAGGCGAGUGAGGUCU AGAGACCU
1979

2171
CUCUGCCG G CUCUUUCC
1684
GGAAAGAG GCCGAAAGGCGAGUGAGGUCU CGGCAGAG
1980

2182
CUUUCCUU G CUCAACCA
1685
UGGUUGAG GCCGAAAGGCGAGUGAGGUCU AAGGAAAG
1981

2193
CAACCAUG G CUGAAGGA
1686
UCCUUCAG GCCGAAAGGCGAGUGAGGUCU CAUGGUUG
1982

2206
AGGAAACA G UCCAACAG
1687
CUGUUGCA GCCGAAAGGCCAGUGAGGUCU UGUUUCCU
1983

2208
GAAACAGU G CAACAGCA
1688
UGCUGUUG GCCGAAAGGCGAGUGAGGUCU ACUGUUUC
1984

2214
GUGCAACA G CACUGGCU
1689
AGCCAGUG GCCGAAAGGCGAGUGAGGUCU UGUUGCAC
1985

2220
CACCACUG G CUCUCUCC
1690
GGAGACAG GCCGAAACCCCAGUGAGGUCU CAGUGCUC
1986

2243
CAGAAGGG G UUUGGUCU
1691
AGACCAAA GCCGAAAGGCGAGUGAGGUCU CCCUUCUG
1987

2248
GGGGUUUG G UCUGGACU
1692
AGUCCAGA GCCGAAAGCCGAGUGAGGUCU CAAACCCC
1988

2262
ACUUCCUU C CUCUCCCC
1693
GGGGAGAG GCCGAAAGGCGAGUGAGGUCU AAGGAAGU
1989

2280
CUUCUCAA C UGCCUUAA
1694
UUAAGGCA GCCGAAAGGCGAGUGAGCUCU UUGAGAAG
1990

2282
UCUCAAGU G CCUUAAUA
1695
UAUUAAGG CCCGAAAGGCGACUGAGGUCU ACUGGAGA
1991

2291
CCUUAAUA G UACGGUAA
1696
UUACCCUA GCCGAAAGGCGAGUGAGGUCU UAUUAAGG
1992

2296
AUAGUAGG C UAAGUUGU
1697
ACAACUUA GCCGAAAGGCGAGUCAGGUCU CCUACUAU
1993

2300
UAGGGUAA G UUGUUAAG
1698
CUUAACAA GCCGAAAGGCGAGUGAGGUCU UUACCCUA
1994

2303
GGUAAGUU C UUAAGAGU
1699
ACUCUUAA GCCGAAACGCGAGUGAGCUCU AACUUACC
1995

2310
UGUUAAGA G UGGGGGAG
1700
CUCCCCCA GCCGAAAGGCGAGUGAGGUCU UCUUAACA
1996

2320
GGGGGAGA G CAGCCUGG
1701
CCAGCCUG GCCGAAAGGCGAGUGAGGUCU UCUCCCCC
1997

2324
GAGACCAC C CUGGCAGC
1702
GCUGCCAC GCCGAAAGGCCACUGAGGUCU CUGCUCUC
1998

2328
GCAGGCUG C CAGCUCUC
1703
GAGAGCUG GCCGAAAGGCGAGUGAGGUCU CAGCCUGC
1999

2331
CGCUGGCA C CUCUCCAG
1704
CUGGAGAG GCCCAAAGGCGAGUGAGGUCU UGCCAGCC
2000

2339
GCUCUCCA G UCAGGAGG
1705
CCUCCUGA GCCGAAAGGCGAGUGAGGUCU UGGAGAGC
2001

2347
GUCAGGAG C CAUAGUUU
1706
AAACUAUG GCCGAAAGGCGAGUGAGGUCU CUCCUGAC
2002

2352
GAGGCAUA G UUUUUAGU
1707
ACUAAAAA GCCGAAAGGCGAGUGAGGUCU UAUGCCUC
2003

2359
AGUUUUUA G UGAACAAU
1708
AUUGUUCA GCCGAAACGCGAGUGAGGUCU UAAAAACU
2004

2372
CAAUCAAA C CACUUGGA
1709
UCCAACUG GCCGAAAGGCGAGUGAGGUCU UUUGAUUG
2005

2386
GGACUCUU C CUCUUUCU
1710
ACAAACAG GCCGAAAGGCGAGUGACGUCU AAGAGUCC
2006

2411
CUAAUAAA C CUGUUCCC
1711
GCCAACAC GCCGAAAGGCGAGUGACCUCU UUUAUUAG
2007

2414
AUAAAGCU G UUCCCAAG
1712
CUUGGCAA CCCGAAAGGCGAGUGACCUCU AGCUUUAU
2008

2417
AAGCUGUU C CCAAGCUG
1713
CAGCUUGG GCCGAAAGGCGAGUGAGCUCU AACAGCUU
2009

2422
CUUGCCAA G CUGGACGG
1714
CCGUCCAC GCCCAAAGGCGACUGAGGUCU UUGGCAAC
2010

2430
GCUGGACG C CACGAGCU
1715
AGCUCCUC CCCGAAAGCCCACUGAGGUCU CCUCCACC
2011

2436
CGCCACCA C CUCCUGCC
1716
GCCACGAG GCCGAAAGGCCAGUCAGGUCU UCCUGCCG
2012

Input Sequence = NM_021975. Cut Site = G/Y

Arm Length = 8. Core Sequence = GCcgaaagGCGaGUCaaGGUCU

NM_021975 (Homo sapiens p65 RelA (NFKB), mRNA; 2444 bp)

[0260]

5

TABLE V

Human REL-A DNAzyme and Substrate Sequence

Seq

Seq

Pos
Substrate
ID
DNAzyzme
ID

9
GGCACGAG G CGGGGCCG
1421
CGGCCCCG GGCTAGCTACAACGA CTCGTGCC
2151

14
GAGGCGGG G CCGGGUCG
1422
CGACCCGG GGCTAGCTACAACGA CCCGCCTC
2152

19
GGGGCCGG G UCGCAGCU
1423
AGCTGCGA GGCTAGCTACAACGA CCGGCCCC
2153

22
GCCGGGUC G CAGCUGGG
1424
CCCAGCTG GGCTAGCTACAACGA GACCCGGC
2154

25
GGGUCGCA G CUGGGCCC
1425
GGGCCCAG GGCTAGCTACAACGA TGCGACCC
2155

30
GCAGCUGG G CCCGCGGC
1426
GCCGCGGG GGCTAGCTACAACGA CCAGCTGC
2156

34
CUGGGCCC G CGGCAUGG
1427
CCATGCCG GGCTAGCTACAACGA GGGCCCAG
2157

37
GGCCCGCG G CAUGGACG
1428
CGTCCATG GGCTAGCTACAACGA CGCGGGCC
2158

39
CCCGCGGC A UGGACGAA
6
TTCGTCCA GGCTAGCTACAACGA GCCGCGGG
2159

43
CGGCAUGG A CGAACUGU
2013
ACAGTTCG GGCTAGCTACAACGA CCATGCCG
2160

47
AUGGACGA A CUGUUCCC
2014
GGGAACAG GGCTAGCTACAACGA TCGTCCAT
2161

50
GACGAACU G UUCCCCCU
1429
AGGGGGAA GGCTAGCTACAACGA AGTTCGTC
2162

60
UCCCCCUC A UCUUCCCG
13
CGGGAAGA GGCTAGCTACAACGA GAGGGGGA
2163

69
UCUUCCCG G CAGAGCAG
1430
CTGCTCTG GGCTAGCTACAACGA CGGGAAGA
2164

74
CCGGCAGA G CAGCCCAA
1431
TTGGGCTG GGCTAGCTACAACGA TCTGCCGG
2165

77
GCAGAGCA G CCCAAGCA
1432
TGCTTGGG GGCTAGCTACAACGA TGCTCTGC
2166

83
CAGCCCAA G CAGCGGGG
1433
CCCCGCTG GGCTAGCTACAACGA TTGGGCTG
2167

86
CCCAAGCA G CGGGGCAU
1434
ATGCCCCG GGCTAGCTACAACGA TGCTTGGG
2168

91
GCAGCGGG G CAUGCGCU
1435
AGCGCATG GGCTAGCTACAACGA CCCGCTGC
2169

93
AGCGGGGC A UGCGCUUC
23
GAAGCGCA GGCTAGCTACAACGA GCCCCGCT
2170

95
CGGGGCAU G CGCUUCCG
1436
CGGAAGCG GGCTAGCTACAACGA ATGCCCCG
2171

97
GGGCAUGC G CUUCCGCU
1437
AGCGGAAG GGCTAGCTACAACGA GCATGCCC
2172

103
GCGCUUCC G CUACAAGU
1438
ACTTGTAG GGCTAGCTACAACGA GGAAGCGC
2173

106
CUUCCGCU A CAAGUGCG
2015
CGCACTTG GGCTAGCTACAACGA AGCGGAAG
2174

110
CGCUACAA G UGCGAGGG
1439
CCCTCGCA GGCTAGCTACAACGA TTGTAGCG
2175

112
CUACAAGU G CGAGGGGC
1440
GCCCCTCG GGCTAGCTACAACGA ACTTGTAG
2176

119
UGCGAGGG G CGCUCCGC
1441
GCGGAGCG GGCTAGCTACAACGA CCCTCGCA
2177

121
CGAGGCGC G CUCCGCGG
1442
CCGCGGAG GGCTAGCTACAACGA GCCCCTCG
2178

126
GGCGCUCC G CGGGCAGC
1443
GCTGCCCG GGCTAGCTACAACGA GGAGCGCC
2179

130
CUCCGCGG G CAGCAUCC
1444
GGATGCTG GGCTAGCTACAACGA CCGCGGAG
2180

133
CGCGGGCA G CAUCCCAG
1445
CTGGGATG GGCTAGCTACAACGA TGCCCGCG
2181

135
CGGGCAGC A UCCCAGGC
31
GCCTGGGA GGCTAGCTACAACGA GCTGCCCG
2182

142
CAUCCCAG G CGAGAGGA
1446
TCCTCTCG GGCTAGCTACAACGA CTGGGATG
2183

151
CGAGAGGA G CACAGAUA
1447
TATCTGTG GGCTAGCTACAACGA TCCTCTCG
2184

153
AGAGGAGC A CAGAUACC
35
GGTATCTG GGCTAGCTACAACGA GCTCCTCT
2185

157
GAGCACAG A UACCACCA
2016
TGGTGGTA GGCTAGCTACAACGA CTGTGCTC
2186

159
GCACAGAU A CCACCAAG
2017
CTTGGTGG GGCTAGCTACAACGA ATCTGTGC
2187

162
CAGAUACC A CCAAGACC
38
GGTCTTGG GGCTAGCTACAACGA GGTATCTG
2188

168
CCACCAAG A CCCACCCC
2018
GGGGTGGG GGCTAGCTACAACGA CTTGGTGG
2189

172
CAAGACCC A CCCCACCA
43
TGGTGGGG GGCTAGCTACAACGA GGGTCTTG
2190

177
CCCACCCC A CCAUCAAG
47
CTTGATGG GGCTAGCTACAACGA GGGGTGGG
2191

180
ACCCCACC A UCAAGAUC
49
GATCTTGA GGCTAGCTACAACGA GGTGGGGT
2192

186
CCAUCAAG A UCAAUGGC
2019
GCCATTGA GGCTAGCTACAACGA CTTGATGG
2193

190
CAAGAUCA A UGGCUACA
2020
TGTAGCCA GGCTAGCTACAACGA TGATCTTG
2194

193
GAUCAAUG G CUACACAG
1448
CTGTGTAG GGCTAGCTACAACGA CATTGATC
2195

196
CAAUGGCU A CACAGGAC
2021
GTCCTGTG GGCTAGCTACAACGA AGCCATTG
2196

198
AUGGCUAC A CAGGACCA
53
TGGTCCTG GGCTAGCTACAACGA GTAGCCAT
2197

203
UACACAGG A CCAGGGAC
2022
GTCCCTGG GGCTAGCTACAACGA CCTGTGTA
2198

210
GACCAGGG A CAGUGCGC
2023
GCGCACTG GGCTAGCTACAACGA CCCTGGTC
2199

213
CAGGGACA G UGCGCAUC
1449
GATGCGCA GGCTAGCTACAACGA TGTCCCTG
2200

215
GGGACAGU G CGCAUCUC
1450
GAGATGCG GGCTAGCTACAACGA ACTGTCCC
2201

217
GACAGUGC G CAUCUCCC
1451
GGGAGATG GGCTAGCTACAACGA GCACTGTC
2202

219
CAGUGCGC A UCUCCCUG
58
CAGGGAGA GGCTAGCTACAACGA GCGCACTG
2203

228
UCUCCCUG G UCACCAAG
1452
CTTGGTGA GGCTAGCTACAACGA CAGGGAGA
2204

231
CCCUGGUC A CCAAGGAC
63
GTCCTTGG GGCTAGCTACAACGA GACCAGGG
2205

238
CACCAAGG A CCCUCCUC
2024
GAGGAGGG GGCTAGCTACAACGA CCTTGGTG
2206

247
CCCUCCUC A CCGGCCUC
71
GAGGCCGG GGCTAGCTACAACGA GAGGAGGG
2207

251
CCUCACCG G CCUCACCC
1453
GGGTGAGG GGCTAGCTACAACGA CGGTGAGG
2208

256
CCGGCCUC A CCCCCACG
75
CGTGGGGG GGCTAGCTACAACGA GAGGCCGG
2209

262
UCACCCCC A CGAGCUUG
80
CAAGCTCG GGCTAGCTACAACGA GGGGGTGA
2210

266
CCCCACGA G CUUGUAGG
1454
CCTACAAG GGCTAGCTACAACGA TCGTGGGG
2211

270
ACGAGCUU G UAGGAAAG
1455
CTTTCCTA GGCTAGCTACAACGA AAGCTCGT
2212

280
AGCAAAGG A CUGCCGGG
2025
CCCGGCAG GGCTAGCTACAACGA CCTTTCCT
2213

283
AAAGGACU G CCGGGAUG
1456
CATCCCGG GGCTAGCTACAACGA AGTCCTTT
2214

289
CUGCCGGG A UGGCUUCU
2026
AGAAGCCA GGCTAGCTACAACGA CCCGGCAG
2215

292
CCGGGAUG G CUUCUAUG
1457
CATAGAAG GGCTAGCTACAACGA CATCCCGG
2216

298
UGGCUUCU A UGAGGCUG
2027
CAGCCTCA GGCTAGCTACAACGA AGAAGCCA
2217

303
UCUAUGAG G CUGAGCUC
1458
GAGCTCAG GGCTAGCTACAACGA CTCATAGA
2218

308
GAGGCUGA G CUCUGCCC
1459
GGGCAGAG GGCTAGCTACAACGA TCAGCCTC
2219

313
UGAGCUCU G CCCGGACC
1460
GGTCCGGG GGCTAGCTACAACGA AGAGCTCA
2220

319
CUGCCCGG A CCGCUGCA
2028
TGCAGCGG GGCTAGCTACAACGA CCGGGCAG
2221

322
CCCGGACC G CUGCAUCC
1461
GGATGCAG GGCTAGCTACAACGA GGTCCGGG
2222

325
GGACCGCU G CAUCCACA
1462
TGTGGATG GGCTAGCTACAACGA AGCGGTCC
2223

327
ACCGCUGC A UCCACAGU
93
ACTGTGGA GGCTAGCTACAACGA GCAGCGGT
2224

331
CUGCAUCC A CAGUUUCC
95
GGAAACTG GGCTAGCTACAACGA GGATGCAG
2225

334
CAUCCACA G UUUCCAGA
1463
TCTGGAAA GGCTAGCTACAACGA TGTGGATG
2226

343
UUUCCAGA A CCUGGGAA
2029
TTCCCAGG GGCTAGCTACAACGA TCTGGAAA
2227

351
ACCUGGGA A UCCAGUGU
2030
ACACTGGA GGCTAGCTACAACGA TCCCAGGT
2228

356
GGAAUCCA G UGUGUGAA
1464
TTCACACA GGCTAGCTACAACGA TGGATTCC
2229

358
AAUCCAGU G UGUGAAGA
1465
TCTTCACA GGCTAGCTACAACGA ACTGGATT
2230

360
UCCAGUGU G UGAAGAAG
1466
CTTCTTCA GGCTAGCTACAACGA ACACTGGA
2231

368
GUGAAGAA G CGGGACCU
1467
AGGTCCCG GGCTAGCTACAACGA TTCTTCAC
2232

373
GAAGCGGG A CCUGGAGC
2031
GCTCCAGG GGCTAGCTACAACGA CCCGCTTC
2233

380
GACCUGGA G CAGGCUAU
1468
ATAGCCTG GGCTAGCTACAACGA TCCAGGTC
2234

384
UGGAGCAG G CUAUCAGU
1469
ACTGATAG GGCTAGCTACAACGA CTGCTCCA
2235

387
AGCAGGCU A UCAGUCAG
2032
CTGACTGA GGCTAGCTACAACGA AGCCTGCT
2236

391
GGCUAUCA G UCAGCGCA
1470
TGCGCTGA GGCTAGCTACAACGA TGATAGCC
2237

395
AUCAGUCA G CGCAUCCA
1471
TGGATGCG GGCTAGCTACAACGA TGACTGAT
2238

397
CAGUCAGC G CAUCCAGA
1472
TCTGGATG GGCTAGCTACAACGA GCTGACTG
2239

399
GUCAGCGC A UCCAGACC
109
GGTCTGGA GGCTAGCTACAACGA GCGCTGAC
2240

405
GCAUCCAG A CCAACAAC
2033
GTTGTTGG GGCTAGCTACAACGA CTGGATGC
2241

409
CCAGACCA A CAACAACC
2034
GGTTGTTG GGCTAGCTACAACGA TGGTCTGG
2242

412
GACCAACA A CAACCCCU
2035
AGGGGTTG GGCTAGCTACAACGA TGTTGGTC
2243

415
CAACAACA A CCCCUUCC
2036
GGAAGGGG GGCTAGCTACAACGA TGTTGTTG
2244

426
CCUUCCAA G UUCCUAUA
1473
TATAGGAA GGCTAGCTACAACGA TTGGAAGG
2245

432
AAGUUCCU A UAGAAGAG
2037
CTCTTCTA GGCTAGCTACAACGA AGGAACTT
2246

440
AUAGAAGA G CAGCGUGG
1474
CCACGCTG GGCTAGCTACAACGA TCTTCTAT
2247

443
GAAGAGCA G CGUGGGGA
1475
TCCCCACG GGCTAGCTACAACGA TGCTCTTC
2248

445
AGAGCAGC G UGGGGACU
1476
AGTCCCCA GGCTAGCTACAACGA GCTGCTCT
2249

451
GCGUGGGG A CUACGACC
2038
GGTCGTAG GGCTAGCTACAACGA CCCCACGC
2250

454
UGGGGACU A CGACCUGA
2039
TCAGGTCG GGCTAGCTACAACGA AGTCCCCA
2251

457
GGACUACG A CCUGAAUG
2040
CATTCAGG GGCTAGCTACAACGA CGTAGTCC
2252

463
CGACCUGA A UGCUGUGC
2041
GCACAGCA GGCTAGCTACAACGA TCAGGTCG
2253

465
ACCUCAAU G CUGUGCGG
1477
CCGCACAG GGCTAGCTACAACGA ATTCAGGT
2254

468
UGAAUGCU G UGCGGCUC
1478
GAGCCGCA GGCTAGCTACAACGA AGCATTCA
2255

470
AAUGCUGU G CGGCUCUG
1479
CAGAGCCG GGCTAGCTACAACGA ACAGCATT
2256

473
GCUGUGCG G CUCUGCUU
1480
AAGCAGAG GGCTAGCTACAACGA CGCACAGC
2257

478
GCGGCUCU G CUUCCAGG
1481
CCTGGAAG GGCTAGCTACAACGA AGAGCCGC
2258

486
GCUUCCAG G UGACAGUG
1482
CACTGTCA GGCTAGCTACAACGA CTGGAAGC
2259

489
UCCAGGUG A CAGUGCGG
2042
CCGCACTG GGCTAGCTACAACGA CACCTGGA
2260

492
AGGUGACA G UGCGGGAC
1483
GTCCCGCA GGCTAGCTACAACGA TGTCACCT
2261

494
GUGACAGU G CGGGACCC
1484
GGGTCCCG GGCTAGCTACAACGA ACTGTCAC
2262

499
AGUGCGGG A CCCAUCAG
2043
CTGATGGG GGCTAGCTACAACGA CCCGCACT
2263

503
CGGGACCC A UCAGGCAG
137
CTGCCTGA GGCTAGCTACAACGA GGGTCCCG
2264

508
CCCAUCAG G CAGGCCCC
1485
GGGGCCTG GGCTAGCTACAACGA CTGATGGG
2265

512
UCAGGCAG G CCCCUCCG
1486
CGGAGGGG GGCTAGCTACAACGA CTGCCTGA
2266

520
GCCCCUCC G CCUGCCGC
1487
GCGGCAGG GGCTAGCTACAACGA GGAGGGGC
2267

524
CUCCGCCU G CCGCCUGU
1488
ACAGGCGG GGCTAGCTACAACGA AGGCGGAG
2268

527
CGCCUGCC G CCUGUCCU
1489
AGGACAGG GGCTAGCTACAACGA GGCAGGCG
2269

531
UGCCGCCU G UCCUUUCU
1490
AGAAAGGA GGCTAGCTACAACGA AGGCGGCA
2270

541
CCUUUCUC A UCCCAUCU
153
AGATGGGA GGCTAGCTACAACGA GAGAAAGG
2271

546
CUCAUCCC A UCUUUGAC
156
GTCAAAGA GGCTAGCTACAACGA GGGATGAG
2272

553
CAUCUUUG A CAAUCGUG
2044
CACGATTG GGCTAGCTACAACGA CAAAGATG
2273

556
CUUUGACA A UCGUGCCC
2045
GGGCACGA GGCTAGCTACAACGA TGTCAAAG
2274

559
UGACAAUC G UGCCCCCA
1491
TGGGGGCA GGCTAGCTACAACGA GATTGTCA
2275

561
ACAAUCGU G CCCCCAAC
1492
GTTGGGGG GGCTAGCTACAACGA ACGATTGT
2276

568
UGCCCCCA A CACUGCCG
2046
CGGCAGTG GGCTAGCTACAACGA TGGGGGCA
2277

570
CCCCCAAC A CUGCCGAG
164
CTCGGCAG GGCTAGCTACAACGA GTTGGGGG
2278

573
CCAACACU G CCGAGCUC
1493
GAGCTCGG GGCTAGCTACAACGA AGTGTTGG
2279

578
ACUGCCGA G CUCAAGAU
1494
ATCTTGAG GGCTAGCTACAACGA TCGGCAGT
2280

585
AGCUCAAG A UCUGCCGA
2047
TCGGCAGA GGCTAGCTACAACGA CTTGAGCT
2281

589
CAAGAUCU G CCGAGUGA
1495
TCACTCGG GGCTAGCTACAACGA AGATCTTG
2282

594
UCUGCCGA G UGAACCGA
1496
TCGGTTCA GGCTAGCTACAACGA TCGGCAGA
2283

598
CCGAGUGA A CCGAAACU
2048
AGTTTCGG GGCTAGCTACAACGA TCACTCGG
2284

604
GAACCGAA A CUCUGGCA
2049
TGCCAGAG GGCTAGCTACAACGA TTCGGTTC
2285

610
AAACUCUG G CAGCUGCC
1497
GGCAGCTG GGCTAGCTACAACGA CAGAGTTT
2286

613
CUCUGGCA G CUGCCUCG
1498
CGAGGCAG GGCTAGCTACAACGA TGCCAGAG
2287

616
UGGCAGCU G CCUCGGUG
1499
CACCGAGG GGCTAGCTACAACGA AGCTGCCA
2288

622
CUGCCUCG G UGGGGAUG
1500
CATCCCCA GGCTAGCTACAACGA CGAGGCAG
2289

628
CGGUGGGG A UGAGAUCU
2050
AGATCTCA GGCTAGCTACAACGA CCCCACCG
2290

633
GGGAUGAG A UCUUCCUA
2051
TAGGAAGA GGCTAGCTACAACGA CTCATCCC
2291

641
AUCUUCCU A CUGUGUGA
2052
TCACACAG GGCTAGCTACAACGA AGGAAGAT
2292

644
UUCCUACU G UGUGACAA
1501
TTGTCACA GGCTAGCTACAACGA AGTAGGAA
2293

646
CCUACUGU G UGACAAGG
1502
CCTTGTCA GGCTAGCTACAACGA ACAGTAGG
2294

649
ACUGUGUG A CAAGGUGC
2053
GCACCTTG GGCTAGCTACAACGA CACACAGT
2295

654
GUGACAAG G UGCAGAAA
1503
TTTCTGCA GGCTAGCTACAACGA CTTGTCAC
2296

656
GACAAGGU G CAGAAAGA
1504
TCTTTCTG GGCTAGCTACAACGA ACCTTGTC
2297

667
GAAAGAGG A CAUUGAGG
2054
CCTCAATG GGCTAGCTACAACGA CCTCTTTC
2298

669
AAGAGGAC A UUGAGGUG
184
CACCTCAA GGCTAGCTACAACGA GTCCTCTT
2299

675
ACAUUGAG G UGUAUUUC
1505
GAAATACA GGCTAGCTACAACGA CTCAATGT
2300

677
AUUGAGGU G UAUUUCAC
1506
GTGAAATA GGCTAGCTACAACGA ACCTCAAT
2301

679
UGAGGUGU A UUUCACGG
2055
CCGTGAAA GGCTAGCTACAACGA ACACCTCA
2302

684
UGUAUUUC A CGGGACCA
185
TGGTCCCG GGCTAGCTACAACGA GAAATACA
2303

689
UUCACGGG A CCAGGCUG
2056
CAGCCTGG GGCTAGCTACAACGA CCCGTGAA
2304

694
GGGACCAG G CUGGGAGG
1507
CCTCCCAG GGCTAGCTACAACGA CTGGTCCC
2305

702
GCUGGGAG G CCCGAGGC
1508
GCCTCGGG GGCTAGCTACAACGA CTCCCAGC
2306

709
GGCCCGAG G CUCCUUUU
1509
AAAAGGAG GGCTAGCTACAACGA CTCGGGCC
2307

719
UCCUUUUC G CAAGCUGA
1510
TCAGCTTG GGCTAGCTACAACGA GAAAAGGA
2308

723
UUUCGCAA G CUGAUGUG
1511
CACATCAG GGCTAGCTACAACGA TTGCGAAA
2309

727
GCAAGCUG A UGUGCACC
2057
GGTGCACA GGCTAGCTACAACGA CAGCTTGC
2310

729
AAGCUGAU G UGCACCGA
1512
TCGGTGCA GGCTAGCTACAACGA ATCAGCTT
2311

731
GCUGAUGU G CACCGACA
1513
TGTCGGTG GGCTAGCTACAACGA ACATCAGC
2312

733
UGAUGUGC A CCGACAAG
196
CTTGTCGG GGCTAGCTACAACGA GCACATCA
2313

737
GUGCACCG A CAAGUGGC
2058
GCCACTTG GGCTAGCTACAACGA CGGTGCAC
2314

741
ACCGACAA G UGGCCAUU
1514
AATGGCCA GGCTAGCTACAACGA TTGTCGGT
2315

744
GACAAGUG G CCAUUGUG
1515
CACAATGG GGCTAGCTACAACGA CACTTGTC
2316

747
AAGUGGCC A UUGUGUUC
200
GAACACAA GGCTAGCTACAACGA GGCCACTT
2317

750
UGGCCAUU G UGUUCCGG
1516
CCGGAACA GGCTAGCTACAACGA AATGGCCA
2318

752
GCCAUUGU G UUCCGGAC
1517
GTCCGGAA GGCTAGCTACAACGA ACAATGGC
2319

759
UGUUCCGG A CCCCUCCC
2059
GGGAGGGG GGCTAGCTACAACGA CCGGAACA
2320

769
CCCUCCCU A CGCAGACC
2060
GGTCTGCG GGCTAGCTACAACGA AGGGAGGG
2321

771
CUCCCUAC G CAGACCCC
1518
GGGGTCTG GGCTAGCTACAACGA GTAGGGAG
2322

775
CUACGCAG A CCCCAGCC
2061
GGCTGGGG GGCTAGCTACAACGA CTGCGTAG
2323

781
AGACCCCA G CCUGCAGG
1519
CCTGCAGG GGCTAGCTACAACGA TGGGGTCT
2324

785
CCCAGCCU G CAGGCUCC
1520
GGAGCCTG GGCTAGCTACAACGA AGGCTGGG
2325

789
GCCUGCAG G CUCCUGUG
1521
CACAGGAG GGCTAGCTACAACGA CTGCAGGC
2326

795
AGGCUCCU G UGCGUGUC
1522
GACACGCA GGCTAGCTACAACGA AGGAGCCT
2327

797
GCUCCUGU G CGUGUCUC
1523
GAGACACG GGCTAGCTACAACGA ACAGGAGC
2328

799
UCCUGUGC G UGUCUCCA
1524
TGGAGACA GGCTAGCTACAACGA GCACAGGA
2329

801
CUGUGCGU G UCUCCAUG
1525
CATGGAGA GGCTAGCTACAACGA ACGCACAG
2330

807
GUGUCUCC A UGCAGCUG
222
CAGCTGCA GGCTAGCTACAACGA GGAGACAC
2331

809
GUCUCCAU G CAGCUGCG
1526
CGCAGCTG GGCTAGCTACAACGA ATGGAGAC
2332

812
UCCAUGCA G CUGCGGCG
1527
CGCCGCAG GGCTAGCTACAACGA TGCATGGA
2333

815
AUGCAGCU G CCGCGGCC
1528
GGCCGCCG GGCTAGCTACAACGA AGCTGCAT
2334

818
CAGCUGCG G CGGCCUUC
1529
GAAGGCCG GGCTAGCTACAACGA CGCAGCTG
2335

821
CUGCGGCG G CCUUCCGA
1530
TCGGAAGG GGCTAGCTACAACGA CGCCGCAG
2336

829
GCCUUCCG A CCGGGAGC
2062
GCTCCCGG GGCTAGCTACAACGA CGGAAGGC
2337

836
GACCGGGA G CUCAGUGA
1531
TCACTGAG GGCTAGCTACAACGA TCCCGGTC
2338

841
GGAGCUCA G UGAGCCCA
1532
TGGGCTCA GGCTAGCTACAACGA TGAGCTCC
2339

845
CUCAGUGA G CCCAUGGA
1533
TCCATGGG GGCTAGCTACAACGA TCACTGAG
2340

849
GUGAGCCC A UGGAAUUC
233
GAATTCCA GGCTAGCTACAACGA GGGCTCAC
2341

854
CCCAUGGA A UUCCAGUA
2063
TACTGGAA GGCTAGCTACAACGA TCCATGGG
2342

860
GAAUUCCA G UACCUGCC
1534
GGCAGGTA GGCTAGCTACAACGA TGGAATTC
2343

862
AUUCCAGU A CCUGCCAG
2064
CTGGCAGG GGCTAGCTACAACGA ACTGGAAT
2344

866
CAGUACCU G CCAGAUAC
1535
GTATCTGG GGCTAGCTACAACGA AGGTACTG
2345

871
CCUGCCAG A UACAGACG
2065
CGTCTGTA GGCTAGCTACAACGA CTGGCAGG
2346

873
UGCCAGAU A CAGACGAU
2066
ATCGTCTG GGCTAGCTACAACGA ATCTGGCA
2347

877
AGAUACAG A CGAUCGUC
2067
GACGATCG GGCTAGCTACAACGA CTGTATCT
2348

880
UACAGACG A UCGUCACC
2068
GGTGACGA GGCTAGCTACAACGA CGTCTGTA
2349

883
AGACCAUC G UCACCGGA
1536
TCCGGTGA GGCTAGCTACAACGA GATCCTCT
2350

886
CGAUCGUC A CCGGAUUG
241
CAATCCGG GGCTAGCTACAACGA GACGATCG
2351

891
GUCACCGG A UUGAGGAG
2069
CTCCTCAA GGCTAGCTACAACGA CCGGTGAC
2352

902
GAGGAGAA A CGUAAAAG
2070
CTTTTACG GGCTAGCTACAACGA TTCTCCTC
2353

904
GGAGAAAC G UAAAAGGA
1537
TCCTTTTA GGCTAGCTACAACGA GTTTCTCC
2354

912
GUAAAAGG A CAUAUGAG
2071
CTCATATG GGCTAGCTACAACGA CCTTTTAC
2355

914
AAAAGGAC A UAUGAGAC
243
GTCTCATA GGCTAGCTACAACGA GTCCTTTT
2356

916
AAGGACAU A UGAGACCU
2072
AGGTCTCA GGCTAGCTACAACGA ATGTCCTT
2357

921
CAUAUGAG A CCUUCAAG
2073
CTTGAAGG GGCTAGCTACAACGA CTCATATG
2358

931
CUUCAAGA G CAUCAUGA
1538
TCATGATG GGCTAGCTACAACGA TCTTGAAG
2359

933
UCAAGAGC A UCAUGAAG
247
CTTCATGA GGCTAGCTACAACGA GCTCTTGA
2360

936
AGAGCAUC A UGAAGAAG
248
CTTCTTCA GGCTAGCTACAACGA GATGCTCT
2361

946
GAAGAAGA G UCCUUUCA
1539
TGAAAGGA GGCTAGCTACAACGA TCTTCTTC
2362

955
UCCUUUCA G CGGACCCA
1540
TGGGTCCG GGCTAGCTACAACGA TGAAAGGA
2363

959
UUCAGCGG A CCCACCGA
2074
TCGGTGGG GGCTAGCTACAACGA CCGCTGAA
2364

963
GCGGACCC A CCGACCCC
254
GGGGTCGG GGCTAGCTACAACGA GGGTCCGC
2365

967
ACCCACCG A CCCCCGGC
2075
GCCGGGGG GGCTAGCTACAACGA CGGTGGGT
2366

974
GACCCCCG G CCUCCACC
1541
GGTGGAGG GGCTAGCTACAACGA CGGGGGTC
2367

980
CGGCCUCC A CCUCGACG
263
CGTCGAGG GGCTAGCTACAACGA GGAGGCCG
2368

986
CCACCUCG A CGCAUUGC
2076
GCAATGCG GGCTAGCTACAACGA CGAGGTGG
2369

988
ACCUCGAC G CAUUGCUG
1542
CAGCAATG GGCTAGCTACAACGA GTCGAGGT
2370

990
CUCGACGC A UUGCUGUG
266
CACAGCAA GGCTAGCTACAACGA GCGTCGAG
2371

993
GACGCAUU G CUGUGCCU
1543
AGGCACAG GGCTAGCTACAACGA AATGCGTC
2372

996
GCAUUGCU G UGCCUUCC
1544
GGAAGGCA GGCTAGCTACAACGA AGCAATGC
2373

998
AUUGCUGU G CCUUCCCG
1545
CGGGAAGG GGCTAGCTACAACGA ACAGCAAT
2374

1006
GCCUUCCC G CAGCUCAG
1546
CTGAGCTG GGCTAGCTACAACGA GGGAAGGC
2375

1009
UUCCCGCA G CUCAGCUU
1547
AAGCTGAG GGCTAGCTACAACGA TGCGGGAA
2376

1014
GCAGCUCA G CUUCUGUC
1548
GACAGAAG GGCTAGCTACAACGA TGAGCTGC
2377

1020
CAGCUUCU G UCCCCAAG
1549
CTTGGGGA GGCTAGCTACAACGA AGAAGCTG
2378

1028
GUCCCCAA G CCAGCACC
1550
GGTGCTGG GGCTAGCTACAACGA TTGGGGAC
2379

1032
CCAAGCCA G CACCCCAG
1551
CTGGGGTG GGCTAGCTACAACGA TGGCTTGG
2380

1034
AAGCCAGC A CCCCAGCC
283
GGCTGGGG GGCTAGCTACAACGA GCTGGCTT
2381

1040
GCACCCCA G CCCUAUCC
1552
GGATAGGG GGCTAGCTACAACGA TGGGGTGC
2382

1045
CCAGCCCU A UCCCUUUA
2077
TAAAGGGA GGCTAGCTACAACGA AGGGCTGG
2383

1053
AUCCCUUU A CGUCAUCC
2078
GGATGACG GGCTAGCTACAACGA AAAGGGAT
2384

1055
CCCUUUAC G UCAUCCCU
1553
AGGGATGA GGCTAGCTACAACGA GTAAAGGG
2385

1058
UUUACGUC A UCCCUGAG
294
CTCAGGGA GGCTAGCTACAACGA GACGTAAA
2386

1066
AUCCCUGA G CACCAUCA
1554
TGATGGTG GGCTAGCTACAACGA TCAGGGAT
2387

1068
CCCUGAGC A CCAUCAAC
298
GTTGATGG GGCTAGCTACAACGA GCTCAGGG
2388

1071
UGAGCACC A UCAACUAU
300
ATAGTTGA GGCTAGCTACAACGA GGTGCTCA
2389

1075
CACCAUCA A CUAUGAUG
2079
CATCATAG GGCTAGCTACAACGA TGATGGTG
2390

1078
CAUCAACU A UGAUGAGU
2080
ACTCATCA GGCTAGCTACAACGA AGTTGATG
2391

1081
CAACUAUG A UGAGUUUC
2081
GAAACTCA GGCTAGCTACAACGA CATAGTTG
2392

1085
UAUGAUGA G UUUCCCAC
1555
GTGGGAAA GGCTAGCTACAACGA TCATCATA
2393

1092
AGUUUCCC A CCAUGGUG
305
CACCATGG GGCTAGCTACAACGA GGGAAACT
2394

1095
UUCCCACC A UGGUGUUU
307
AAACACCA GGCTAGCTACAACGA GGTGGGAA
2395

1098
CCACCAUG G UGUUUCCU
1556
AGGAAACA GGCTAGCTACAACGA CATGGTGG
2396

1100
ACCAUGGU G UUUCCUUC
1557
GAAGGAAA GGCTAGCTACAACGA ACCATGGT
2397

1112
CCUUCUGG G CAGAUCAG
1558
CTGATCTG GGCTAGCTACAACGA CCAGAAGG
2398

1116
CUGGGCAG A UCAGCCAG
2082
CTGGCTGA GGCTAGCTACAACGA CTGCCCAG
2399

1120
GCAGAUCA G CCAGGCCU
1559
AGGCCTGG GGCTAGCTACAACGA TGATCTGC
2400

1125
UCAGCCAG G CCUCGGCC
1560
GGCCGAGG GGCTAGCTACAACGA CTGGCTGA
2401

1131
AGGCCUCG G CCUUGGCC
1561
GGCCAAGG GGCTAGCTACAACGA CGAGGCCT
2402

1137
CGGCCUUG G CCCCGGCC
1562
GGCCGGGG GGCTAGCTACAACGA CAAGGCCG
2403

1143
UGGCCCCG G CCCCUCCC
1563
GGGAGGGG GGCTAGCTACAACGA CGGGGCCA
2404

1155
CUCCCCAA G UCCUGCCC
1564
GGGCAGGA GGCTAGCTACAACGA TTGGGGAG
2405

1160
CAAGUCCU G CCCCAGGC
1565
GCCTGGGG GGCTAGCTACAACGA AGGACTTG
2406

1167
UGCCCCAG G CUCCAGCC
1566
GGCTGGAG GGCTAGCTACAACGA CTGGGGCA
2407

1173
AGGCUCCA G CCCCUGCC
1567
GGCAGGGG GGCTAGCTACAACGA TGGAGCCT
2408

1179
CAGCCCCU G CCCCUGCU
1568
AGCAGGGG GGCTAGCTACAACGA AGGGGCTG
2409

1185
CUGCCCCU G CUCCAGCC
1569
GGCTGGAG GGCTAGCTACAACGA AGGCGCAG
2410

1191
CUGCUCCA G CCAUGGUA
1570
TACCATGG GGCTAGCTACAACGA TGGAGCAG
2411

1194
CUCCAGCC A UGGUAUCA
351
TGATACCA GGCTAGCTACAACGA GGCTGGAG
2412

1197
CAGCCAUG G UAUCAGCU
1571
AGCTGATA GGCTAGCTACAACGA CATGGCTG
2413

1199
GCCAUGGU A UCAGCUCU
2083
AGAGCTGA GGCTAGCTACAACGA ACCATGGC
2414

1203
UGGUAUCA G CUCUGGCC
1572
GGCCAGAG GGCTAGCTACAACGA TGATACCA
2415

1209
CAGCUCUG G CCCAGGCC
1573
GGCCTGGG GGCTAGCTACAACGA CAGAGCTG
2416

1215
UGGCCCAG G CCCCAGCC
1574
GGCTGGGG GGCTAGCTACAACGA CTGGGCCA
2417

1221
AGGCCCCA G CCCCUGUC
1575
GACAGGGG GGCTAGCTACAACGA TGGGGCCT
2418

1227
CAGCCCCU G UCCCAGUC
1576
GACTGGGA GGCTAGCTACAACGA AGGGGCTG
2419

1233
CUGUCCCA G UCCUAGCC
1577
GGCTAGGA GGCTAGCTACAACGA TGGGACAG
2420

1239
CAGUCCUA G CCCCAGGC
1578
GCCTGGGG GGCTAGCTACAACGA TAGGACTG
2421

1246
AGCCCCAG G CCCUCCUC
1579
CAGGAGGG GGCTAGCTACAACGA CTGCGGCT
2422

1257
CUCCUCAG G CUGUGGCC
1580
GGCCACAG GGCTAGCTACAACGA CTGAGGAG
2423

1260
CUCAGGCU G UGGCCCCA
1581
TGGGGCCA GGCTAGCTACAACGA AGCCTGAG
2424

1263
AGGCUGUG G CCCCACCU
1582
AGGTGGGG GGCTAGCTACAACGA CACAGCCT
2425

1268
GUGGCCCC A CCUGCCCC
385
GGGGCAGG GGCTAGCTACAACGA GGGGCCAC
2426

1272
CCCCACCU G CCCCCAAG
1583
CTTGGGGG GGCTAGCTACAACGA AGGTGGGG
2427

1280
GCCCCCAA G CCCACCCA
1584
TGGGTGGG GGCTAGCTACAACGA TTGGGGGC
2428

1284
CCAAGCCC A CCCAGGCU
395
AGCCTGGG GGCTAGCTACAACGA GGGCTTGG
2429

1290
CCACCCAG G CUGGGGAA
1585
TTCCCCAG GGCTAGCTACAACGA CTGGGTGG
2430

1302
GGGAAGGA A CGCUGUCA
2084
TGACAGCG GGCTAGCTACAACGA TCCTTCCC
2431

1304
GAAGGAAC G CUGUCAGA
1586
TCTGACAG GGCTAGCTACAACGA GTTCCTTC
2432

1307
GGAACGCU G UCAGAGGC
1587
GCCTCTGA GGCTAGCTACAACGA AGCGTTCC
2433

1314
UGUCAGAG G CCCUGCUG
1588
CAGCAGGG GGCTAGCTACAACGA CTCTGACA
2434

1319
GAGGCCCU G CUGCAGCU
1589
AGCTGCAG GGCTAGCTACAACGA AGGGCCTC
2435

1322
GCCCUGCU G CAGCUGCA
1590
TGCAGCTG GGCTAGCTACAACGA AGCAGGGC
2436

1325
CUGCUGCA G CUGCAGUU
1591
AACTGCAG GGCTAGCTACAACGA TGCAGCAG
2437

1328
CUGCAGCU G CAGUUUGA
1592
TCAAACTG GGCTAGCTACAACGA AGCTGCAG
2438

1331
CAGCUGCA G UUUGAUGA
1593
TCATCAAA GGCTAGCTACAACGA TGCAGCTG
2439

1336
GCAGUUUG A UGAUGAAG
2085
CTTCATCA GGCTAGCTACAACGA CAAACTGC
2440

1339
GUUUGAUG A UGAAGACC
2086
GGTCTTCA GGCTAGCTACAACGA CATCAAAC
2441

1345
UGAUGAAG A CCUGGGGG
2087
CCCCCAGG GGCTAGCTACAACGA CTTCATCA
2442

1353
ACCUGGGG G CCUUGCUU
1594
AAGCAAGG GGCTAGCTACAACGA CCCCAGGT
2443

1358
GGGGCCUU G CUUGGCAA
1595
TTGCCAAG GGCTAGCTACAACGA AAGGCCCC
2444

1363
CUUGCUUG G CAACAGCA
1596
TGCTGTTG GGCTAGCTACAACGA CAAGCAAG
2445

1366
GCUUGGCA A CAGCACAG
2088
CTGTGCTG GGCTAGCTACAACGA TGCCAAGC
2446

1369
UGGCAACA G CACAGACC
1597
GGTCTGTG GGCTAGCTACAACGA TGTTGCCA
2447

1371
GCAACAGC A CAGACCCA
416
TGGGTCTG GGCTAGCTACAACGA GCTGTTGC
2448

1375
CAGCACAG A CCCAGCUG
2089
CAGCTGGG GGCTAGCTACAACGA CTGTGCTG
2449

1380
CAGACCCA G CUGUGUUC
1598
GAACACAG GGCTAGCTACAACGA TGGGTCTG
2450

1383
ACCCAGCU G UGUUCACA
1599
TGTGAACA GGCTAGCTACAACGA AGCTGGGT
2451

1385
CCAGCUGU G UUCACAGA
1600
TCTGTGAA GGCTAGCTACAACGA ACAGCTGG
2452

1389
CUGUGUUC A CAGACCUG
422
CAGGTCTG GGCTAGCTACAACGA GAACACAG
2453

1393
GUUCACAG A CCUGGCAU
2090
ATGCCAGG GGCTAGCTACAACGA CTGTGAAC
2454

1398
CAGACCUG G CAUCCGUC
1601
GACGGATG GGCTAGCTACAACGA CAGGTCTG
2455

1400
GACCUGGC A UCCGUCGA
426
TCGACGGA GGCTAGCTACAACGA GCCAGGTC
2456

1404
UGGCAUCC G UCGACAAC
1602
GTTGTCGA GGCTAGCTACAACGA GGATGCCA
2457

1408
AUCCGUCG A CAACUCCG
2091
CGGAGTTG GGCTAGCTACAACGA CGACGGAT
2458

1411
CGUCGACA A CUCCGAGU
2092
ACTCGGAG GGCTAGCTACAACGA TGTCGACG
2459

1418
AACUCCGA G UUUCAGCA
1603
TGCTGAAA GGCTAGCTACAACGA TCGGAGTT
2460

1424
GAGUUUCA G CAGCUGCU
1604
AGCAGCTG GGCTAGCTACAACGA TGAAACTC
2461

1427
UUUCAGCA G CUGCUGAA
1605
TTCAGCAG GGCTAGCTACAACGA TGCTGAAA
2462

1430
CAGCAGCU G CUGAACCA
1606
TGGTTCAG GGCTAGCTACAACGA AGCTGCTG
2463

1435
GCUGCUGA A CCAGGGCA
2093
TGCCCTGG GGCTAGCTACAACGA TCAGCAGC
2464

1441
GAACCAGG G CAUACCUG
1607
CAGGTATG GGCTAGCTACAACGA CCTGGTTC
2465

1443
ACCAGGGC A UACCUGUG
437
CACAGGTA GGCTAGCTACAACGA GCCCTGGT
2466

1445
CAGGGCAU A CCUGUGGC
2094
GCCACAGG GGCTAGCTACAACGA ATGCCCTG
2467

1449
GCAUACCU G UGGCCCCC
1608
GGGGGCCA GGCTAGCTACAACGA AGGTATGC
2468

1452
UACCUGUG G CCCCCCAC
1609
GTGGGGGG GGCTAGCTACAACGA CACAGGTA
2469

1459
GGCCCCCC A CACAACUG
445
CAGTTGTG GGCTAGCTACAACGA GGGGGGCC
2470

1461
CCCCCCAC A CAACUGAG
446
CTCAGTTG GGCTAGCTACAACGA GTGGGGGG
2471

1464
CCCACACA A CUGAGCCC
2095
GGGCTCAG GGCTAGCTACAACGA TGTGTGGG
2472

1469
ACAACUGA G CCCAUGCU
1610
AGCATGGG GGCTAGCTACAACGA TCAGTTGT
2473

1473
CUGAGCCC A UGCUGAUG
451
CATCAGCA GGCTAGCTACAACGA GGGCTCAG
2474

1475
GAGCCCAU G CUGAUGGA
1611
TCCATCAG GGCTAGCTACAACGA ATGGGCTC
2475

1479
CCAUGCUG A UGGAGUAC
2096
GTACTCCA GGCTAGCTACAACGA CAGCATGG
2476

1484
CUGAUGGA G UACCCUGA
1612
TCAGGGTA GGCTAGCTACAACGA TCCATCAG
2477

1486
GAUGGAGU A CCCUGAGG
2097
CCTCAGGG GGCTAGCTACAACGA ACTCCATC
2478

1494
ACCCUGAG G CUAUAACU
1613
AGTTATAG GGCTAGCTACAACGA CTCAGGGT
2479

1497
CUGAGGCU A UAACUCGC
2098
GCGAGTTA GGCTAGCTACAACGA AGCCTCAG
2480

1500
AGGCUAUA A CUCGCCUA
2099
TAGGCGAG GGCTAGCTACAACGA TATAGCCT
2481

1504
UAUAACUC G CCUAGUGA
1614
TCACTAGG GGCTAGCTACAACGA GAGTTATA
2482

1509
CUCGCCUA G UGACAGCC
1615
GGCTGTCA GGCTAGCTACAACGA TAGGCGAG
2483

1512
GCCUAGUG A CAGCCCAG
2100
CTGGGCTG GGCTAGCTACAACGA CACTAGGC
2484

1515
UAGUGACA G CCCAGAGG
1616
CCTCTGGG GGCTAGCTACAACGA TGTCACTA
2485

1523
GCCCAGAG G CCCCCCGA
1617
TCGGGGGG GGCTAGCTACAACGA CTCTGGGC
2486

1531
GCCCCCCG A CCCAGCUC
2101
GAGCTGGG GGCTAGCTACAACGA CGGGGGGC
2487

1536
CCGACCCA G CUCCUGCU
1618
AGCAGGAG GGCTAGCTACAACGA TGGGTCGG
2488

1542
CAGCUCCU G CUCCACUG
1619
CAGTGGAG GGCTAGCTACAACGA AGGAGCTG
2489

1547
CCUGCUCC A CUGGGGGC
477
GCCCCCAG GGCTAGCTACAACGA GGAGCAGG
2490

1554
CACUGGGG G CCCCGGGG
1620
CCCCGGGG GGCTAGCTACAACGA CCCCAGTG
2491

1562
GCCCCCGG G CUCCCCAA
1621
TTCGGGAG GGCTAGCTACAACGA CCCGGGGC
2492

1570
CCUCCCCA A UGGCCUCC
2102
GGAGGCCA GGCTAGCTACAACGA TGGGGAGC
2493

1573
CCCCAAUG G CCUCCUUU
1622
AAAGGAGG GGCTAGCTACAACGA CATTGGGG
2494

1588
UUCAGGAG A UGAAGACU
2103
AGTCTTCA GGCTAGCTACAACGA CTCCTGAA
2495

1594
AGAUGAAG A CUUCUCCU
2104
AGGAGAAG GGCTAGCTACAACGA CTTCATCT
2496

1605
UCUCCUCC A UUGCGGAC
497
GTCCGCAA GGCTAGCTACAACGA GGAGGAGA
2497

1608
CCUCCAUU G CGGACAUG
1623
CATGTCCG GGCTAGCTACAACGA AATGGAGG
2498

1612
CAUUGCGG A CAUGGACU
2105
AGTCCATG GGCTAGCTACAACGA CCGCAATG
2499

1614
UUGCGGAC A UGGACUUC
498
GAAGTCCA GGCTAGCTACAACGA GTCCGCAA
2500

1618
CGACAUGG A CUUCUCAG
2106
CTGAGAAG GGCTAGCTACAACGA CCATGTCC
2501

1626
ACUUCUCA G CCCUGCUG
1624
CAGCAGGG GGCTAGCTACAACGA TGAGAAGT
2502

1631
UCAGCCCU G CUGAGUCA
1625
TGACTCAG GGCTAGCTACAACGA AGGGCTGA
2503

1636
CCUGCUGA G UCAGAUCA
1626
TGATCTGA GGCTAGCTACAACGA TCAGCAGG
2504

1641
UGAGUCAG A UCAGCUCC
2107
GGAGCTGA GGCTAGCTACAACGA CTGACTCA
2505

1645
UCAGAUCA G CUCCUAAG
1627
CTTAGGAG GGCTAGCTACAACGA TGATCTGA
2506

1657
CUAAGGGG G UGACGCCU
1628
AGGCGTCA GGCTAGCTACAACGA CCCCTTAG
2507

1660
AGGGGGUG A CGCCUGCC
2108
GGCAGGCG GGCTAGCTACAACGA CACCCCCT
2508

1662
GGGGUGAC G CCUGCCCU
1629
AGGGCAGG GGCTAGCTACAACGA GTCACCCC
2509

1666
UGACGCCU G CCCUCCCC
1630
GGGGAGGG GGCTAGCTACAACGA AGGCGTCA
2510

1678
UCCCCAGA G CACUGGUU
1631
AACCAGTG GGCTAGCTACAACGA TCTGGGGA
2511

1680
CCCAGAGC A CUGGUUGC
520
GCAACCAG GGCTAGCTACAACGA GCTCTGGG
2512

1684
GAGCACUG G UUGCAGGG
1632
CCCTGCAA GGCTAGCTACAACGA CAGTGCTC
2513

1687
CACUGGUU G CAGGGGAU
1633
ATCCCCTG GGCTAGCTACAACGA AACCAGTG
2514

1694
UGCAGGGG A UUGAAGCC
2109
GGCTTCAA GGCTAGCTACAACGA CCCCTGCA
2515

1700
GGAUUGAA G CCCUCCAA
1634
TTGGAGGG GGCTAGCTACAACGA TTCAATCC
2516

1711
CUCCAAAA G CACUUACG
1635
CGTAAGTG GGCTAGCTACAACGA TTTTGGAG
2517

1713
CCAAAAGC A CUUACGGA
528
TCCGTAAG GGCTAGCTACAACGA GCTTTTGG
2518

1717
AAGCACUU A CGGAUUCU
2110
AGAATCCG GGCTAGCTACAACGA AAGTGCTT
2519

1721
ACUUACGG A UUCUGGUG
2111
CACCAGAA GGCTAGCTACAACGA CCGTAAGT
2520

1727
GGAUUCUG G UGGGGUGU
1636
ACACCCCA GGCTAGCTACAACGA CAGAATCC
2521

1732
CUGGUGGG G UGUGUUCC
1637
GGAACACA GGCTAGCTACAACGA CCCACCAG
2522

1734
GGUGGGGU G UGUUCCAA
1638
TTGGAACA GGCTAGCTACAACGA ACCCCACC
2523

1736
UGGGGUGU G UUCCAACU
1639
AGTTGGAA GGCTAGCTACAACGA ACACCCCA
2524

1742
GUGUUCCA A CUGCCCCC
2112
GGGGGCAG GGCTAGCTACAACGA TGGAACAC
2525

1745
UUCCAACU G CCCCCAAC
1640
GTTGGGGG GGCTAGCTACAACGA AGTTGGAA
2526

1752
UGCCCCCA A CUUUGUGG
2113
CCACAAAG GGCTAGCTACAACGA TGGGGGCA
2527

1757
CCAACUUU G UGGAUGUC
1641
GACATCCA GGCTAGCTACAACGA AAAGTTGG
2528

1761
CUUUGUGG A UGUCUUCC
2114
GGAAGACA GGCTAGCTACAACGA CCACAAAG
2529

1763
UUGUGGAU G UCUUCCUU
1642
AAGGAAGA GGCTAGCTACAACGA ATCCACAA
2530

1782
AGGGGGGA G CCAUAUUU
1643
AAATATGG GGCTAGCTACAACGA TCCCCCCT
2531

1785
GGGGAGCC A UAUUUUAU
544
ATAAAATA GGCTAGCTACAACGA GGCTCCCC
2532

1787
GGAGCCAU A UUUUAUUC
2115
GAATAAAA GGCTAGCTACAACGA ATGGCTCC
2533

1792
CAUAUUUU A UUCUUUUA
2116
TAAAAGAA GGCTAGCTACAACGA AAAATATG
2534

1800
AUUCUUUU A UUGUCAGU
2117
ACTGACAA GGCTAGCTACAACGA AAAAGAAT
2535

1803
CUUUUAUU G UCAGUAUC
1644
GATACTGA GGCTAGCTACAACGA AATAAAAG
2536

1807
UAUUGUCA G UAUCUGUA
1645
TACAGATA GGCTAGCTACAACGA TGACAATA
2537

1809
UUGUCAGU A UCUGUAUC
2118
GATACAGA GGCTAGCTACAACGA ACTGACAA
2538

1813
CAGUAUCU G UAUCUCUC
1646
GAGAGATA GGCTAGCTACAACGA AGATACTG
2539

1815
GUAUCUGU A UCUCUCUC
2119
GAGAGAGA GGCTAGCTACAACGA ACAGATAC
2540

1835
UUUUGGAG G UGCUUAAG
1647
CTTAAGCA GGCTAGCTACAACGA CTCCAAAA
2541

1837
UUGGAGGU G CUUAAGCA
1648
TGCTTAAG GGCTAGCTACAACGA ACCTCCAA
2542

1843
GUGCUUAA G CAGAAGCA
1649
TGCTTCTG GGCTAGCTACAACGA TTAAGCAC
2543

1849
AAGCAGAA G CAUUAACU
1650
AGTTAATG GGCTAGCTACAACGA TTCTGCTT
2544

1851
GCAGAAGC A UUAACUUC
555
GAAGTTAA GGCTAGCTACAACGA GCTTCTGC
2545

1855
AAGCAUUA A CUUCUCUG
2120
CAGAGAAG GGCTAGCTACAACGA TAATGCTT
2546

1875
AGGGGGGA G CUGGGGAA
1651
TTCCCCAG GGCTAGCTACAACGA TCCCCCCT
2547

1884
CUGGGGAA A CUCAAACU
2121
AGTTTGAG GGCTAGCTACAACGA TTCCCCAG
2548

1890
AAACUCAA A CUUUUCCC
2122
GGGAAAAG GGCTAGCTACAACGA TTGAGTTT
2549

1901
UUUCCCCU G UCCUGAUG
1652
CATCAGGA GGCTAGCTACAACGA AGGGGAAA
2550

1907
CUGUCCUG A UGGUCAGC
2123
GCTGACCA GGCTAGCTACAACGA CAGGACAG
2551

1910
UCCUGAUG G UCAGCUCC
1653
GGAGCTGA GGCTAGCTACAACGA CATCAGGA
2552

1914
GAUGGUCA G CUCCCUUC
1654
GAAGGGAG GGCTAGCTACAACGA TGACCATC
2553

1926
CCUUCUCU G UAGGGAAC
1655
GTTCCCTA GGCTAGCTACAACGA AGAGAAGG
2554

1933
UGUAGGGA A CUGUGGGG
2124
CCCCACAG GGCTAGCTACAACGA TCCCTACA
2555

1936
AGGGAACU G UGGGGUCC
1656
GGACCCCA GGCTAGCTACAACGA AGTTCCCT
2556

1941
ACUGUGGG G UCCCCCAU
1657
ATGGGGGA GGCTAGCTACAACGA CCCACAGT
2557

1948
GGUCCCCC A UCCCCAUC
581
GATGGGGA GGCTAGCTACAACGA GGGGGACC
2558

1954
CCAUCCCC A UCCUCCAG
585
CTGGAGGA GGCTAGCTACAACGA GGGGATGG
2559

1962
AUCCUCCA G CUUCUGGU
1658
ACCAGAAG GGCTAGCTACAACGA TGGAGGAT
2560

1969
AGCUUCUG G UACUCUCC
1659
GGAGAGTA GGCTAGCTACAACGA CAGAAGCT
2561

1971
CUUCUGGU A CUCUCCUA
2125
TAGGAGAG GGCTAGCTACAACGA ACCAGAAG
2562

1983
UCCUAGAG A CAGAAGCA
2126
TGCTTCTG GGCTAGCTACAACGA CTCTAGGA
2563

1989
AGACAGAA G CAGGCUGG
1660
CCAGCCTG GGCTAGCTACAACGA TTCTGTCT
2564

1993
AGAAGCAG G CUGGAGGU
1661
ACCTCCAG GGCTAGCTACAACGA CTGCTTCT
2565

2000
GGCUGGAG G UAAGGCCU
1662
AGGCCTTA GGCTAGCTACAACGA CTCCAGCC
2566

2005
GAGGUAAG G CCUUUGAG
1663
CTCAAAGG GGCTAGCTACAACGA CTTACCTC
2567

2013
GCCUUUGA G CCCACAAA
1664
TTTGTGGG GGCTAGCTACAACGA TCAAAGGC
2568

2017
UUGAGCCC A CAAAGCCU
603
AGGCTTTG GGCTAGCTACAACGA GGGCTCAA
2569

2022
CCCACAAA G CCUUAUCA
1665
TGATAAGG GGCTAGCTACAACGA TTTGTGGG
2570

2027
AAAGCCUU A UCAAGUGU
2127
ACACTTGA GGCTAGCTACAACGA AAGGCTTT
2571

2032
CUUAUCAA G UGUCUUCC
1666
GGAAGACA GGCTAGCTACAACGA TTGATAAG
2572

2034
UAUCAAGU G UCUUCCAU
1667
ATGGAAGA GGCTAGCTACAACGA ACTTGATA
2573

2041
UGUCUUCC A UCAUGGAU
610
ATCCATGA GGCTAGCTACAACGA GGAAGACA
2574

2044
CUUCCAUC A UGGAUUCA
611
TGAATCCA GGCTAGCTACAACGA GATGGAAG
2575

2048
CAUCAUGG A UUCAUUAC
2128
GTAATGAA GGCTAGCTACAACGA CCATGATG
2576

2052
AUGGAUUC A UUACAGCU
612
AGCTGTAA GGCTAGCTACAACGA GAATCCAT
2577

2055
GAUUCAUU A CAGCUUAA
2129
TTAAGCTG GGCTAGCTACAACGA AATGAATC
2578

2058
UCAUUACA G CUUAAUCA
1668
TGATTAAG GGCTAGCTACAACGA TGTAATGA
2579

2063
ACAGCUUA A UCAAAAUA
2130
TATTTTGA GGCTAGCTACAACGA TAAGCTGT
2580

2069
UAAUCAAA A UAACGCCC
2131
GGGCGTTA GGCTAGCTACAACGA TTTGATTA
2581

2072
UCAAAAUA A CGCCCCAG
2132
CTGGGGCG GGCTAGCTACAACGA TATTTTGA
2582

2074
AAAAUAAC G CCCCAGAU
1669
ATCTGGGG GGCTAGCTACAACGA GTTATTTT
2583

2081
CGCCCCAG A UACCAGCC
2133
GGCTGGTA GGCTAGCTACAACGA CTGGGGCG
2584

2083
CCCCAGAU A CCAGCCCC
2134
GGGGCTGG GGCTAGCTACAACGA ATCTGGGG
2585

2087
AGAUACCA G CCCCUGUA
1670
TACAGGGG GGCTAGCTACAACGA TGGTATCT
2586

2093
CAGCCCCU G UAUGGCAC
1671
GTGCCATA GGCTAGCTACAACGA AGGGGCTG
2587

2095
GCCCCUGU A UGGCACUG
2135
CAGTGCCA GGCTAGCTACAACGA ACAGGGGC
2588

2098
CCUGUAUG G CACUGGCA
1672
TGCCAGTG GGCTAGCTACAACGA CATACAGG
2589

2100
UGUAUGGC A CUGGCAUU
626
AATGCCAG GGCTAGCTACAACGA GCCATACA
2590

2104
UGGCACUG G CAUUGUCC
1673
GGACAATG GGCTAGCTACAACGA CAGTGCCA
2591

2106
GCACUGGC A UUGUCCCU
628
AGGGACAA GGCTAGCTACAACGA GCCAGTGC
2592

2109
CUGGCAUU G UCCCUGUG
1674
CACAGGGA GGCTAGCTACAACGA AATGCCAG
2593

2115
UUGUCCCU G UGCCUAAC
1675
GTTAGGCA GGCTAGCTACAACGA AGGGACAA
2594

2117
GUCCCUGU G CCUAACAC
1676
GTGTTAGG GGCTAGCTACAACGA ACAGGGAC
2595

2122
UGUGCCUA A CACCAGCG
2136
CGCTGGTG GGCTAGCTACAACGA TAGGCACA
2596

2124
UGCCUAAC A CCAGCGUU
634
AACGCTGG GGCTAGCTACAACGA GTTAGGCA
2597

2128
UAACACCA G CGUUUGAG
1677
CTCAAACG GGCTAGCTACAACGA TGGTGTTA
2598

2130
ACACCAGC G UUUGAGGG
1678
CCCTCAAA GGCTAGCTACAACGA GCTGGTGT
2599

2139
UUUGAGGG G CUGCCUUC
1679
GAAGGCAG GGCTAGCTACAACGA CCCTCAAA
2600

2142
GAGGGGCU G CCUUCCUG
1680
CAGGAAGG GGCTAGCTACAACGA AGCCCCTC
2601

2150
GCCUUCCU G CCCUACAG
1681
CTGTAGGG GGCTAGCTACAACGA AGGAAGGC
2602

2155
CCUGCCCU A CAGAGGUC
2137
GACCTCTG GGCTAGCTACAACGA AGGGCAGG
2603

2161
CUACAGAG G UCUCUGCC
1682
GGCAGAGA GGCTAGCTACAACGA CTCTGTAG
2604

2167
AGGUCUCU G CCGGCUCU
1683
AGAGCCGG GGCTAGCTACAACGA AGAGACCT
2605

2171
CUCUGCCG G CUCUUUCC
1684
GGAAAGAG GGCTAGCTACAACGA CGGCAGAG
2606

2182
CUUUCCUU G CUCAACCA
1685
TGGTTGAG GGCTAGCTACAACGA AAGGAAAG
2607

2187
CUUGCUCA A CCAUGGCU
2138
AGCCATGG GGCTAGCTACAACGA TGAGCAAG
2608

2190
GCUCAACC A UGGCUGAA
656
TTCAGCCA GGCTAGCTACAACGA GGTTGAGC
2609

2193
CAACCAUG G CUGAAGGA
1686
TCCTTCAG GGCTAGCTACAACGA CATGGTTG
2610

2203
UGAAGGAA A CAGUGCAA
2139
TTGCACTG GGCTAGCTACAACGA TTCCTTCA
2611

2206
AGGAAACA G UGCAACAG
1687
CTGTTGCA GGCTAGCTACAACGA TGTTTCCT
2612

2208
GAAACAGU G CAACAGCA
1688
TGCTGTTG GGCTAGCTACAACGA ACTGTTTC
2613

2211
ACAGUGCA A CAGCACUG
2140
CAGTGCTG GGCTAGCTACAACGA TGCACTGT
2614

2214
GUGCAACA G CACUGGCU
1689
AGCCAGTG GGCTAGCTACAACGA TGTTGCAC
2615

2216
GCAACAGC A CUGGCUCU
661
AGAGCCAG GGCTAGCTACAACGA GCTGTTGC
2616

2220
CAGCACUG G CUCUCUCC
1690
GGAGAGAG GGCTAGCTACAACGA CAGTGCTG
2617

2232
UCUCCAGG A UCCAGAAG
2141
CTTCTGGA GGCTAGCTACAACGA CCTGGAGA
2618

2243
CAGAAGGG G UUUGGUCU
1691
AGACCAAA GGCTAGCTACAACGA CCCTTCTG
2619

2248
GGGGUUUG G UCUGGACU
1692
AGTCCAGA GGCTAGCTACAACGA CAAACCCC
2620

2254
UGGUCUGG A CUUCCUUG
2142
CAAGGAAG GGCTAGCTACAACGA CCAGACCA
2621

2262
ACUUCCUU G CUCUCCCC
1693
GUGGAGAG GGCTAGCTACAACGA AAGGAAGT
2622

2280
CUUCUCAA G UGCCUUAA
1694
TTAAGGCA GGCTAGCTACAACGA TTGAGAAG
2623

2282
UCUCAAGU G CCUUAAUA
1695
TATTAAGG GGCTAGCTACAACGA ACTTGAGA
2624

2288
GUGCCUUA A UAGUAGGG
2143
CCCTACTA GGCTAGCTACAACGA TAAGGCAC
2625

2291
CCUUAAUA G UAGGGUAA
1696
TTACCCTA GGCTAGCTACAACGA TATTAAGG
2626

2296
AUAGUAGG G UAAGUUGU
1697
ACAACTTA GGCTAGCTACAACGA CCTACTAT
2627

2300
UAGGGUAA G UUGUUAAG
1698
CTTAACAA GGCTAGCTACAACGA TTACCCTA
2628

2303
GGUAAGUU G UUAAGAGU
1699
ACTCTTAA GGCTAGCTACAACGA AACTTACC
2629

2310
UGUUAAGA G UGGGGGAG
1700
CTCCCCCA GGCTAGCTACAACGA TCTTAACA
2630

2320
GGGGGAGA G CAGGCUGG
1701
CCAGCCTG GGCTAGCTACAACGA TCTCCCCC
2631

2324
GAGAGCAG G CUGGCAGC
1702
GCTGCCAG GGCTAGCTACAACGA CTGCTCTC
2632

2328
GCAGGCUG G CAGCUCUC
1703
GAGAGCTG GGCTAGCTACAACGA CAGCCTGC
2633

2331
GGCUGGCA G CUCUCCAG
1704
CTGGAGAG GGCTAGCTACAACGA TGCCAGCC
2634

2339
GCUCUCCA G UCAGGAGG
1705
CCTCCTGA GGCTAGCTACAACGA TGGAGAGC
2635

2347
GUCAGGAG G CAUAGUUU
1706
AAACTATG GGCTAGCTACAACGA CTCCTGAC
2636

2349
CAGGAGGC A UAGUUUUU
693
AAAAACTA GGCTAGCTACAACGA GCCTCCTG
2637

2352
GAGGCAUA G UUUUUAGU
1707
ACTAAAAA GGCTAGCTACAACGA TATGCCTC
2638

2359
AGUUUUUA G UGAACAAU
1708
ATTGTTCA GGCTAGCTACAACGA TAAAAACT
2639

2363
UUUAGUGA A CAAUCAAA
2144
TTTGATTG GGCTAGCTACAACGA TCACTAAA
2640

2366
AGUGAACA A UCAAAGCA
2145
TGCTTTGA GGCTAGCTACAACGA TGTTCACT
2641

2372
CAAUCAAA G CACUUGGA
1709
TCCAAGTG GGCTAGCTACAACGA TTTGATTG
2642

2374
AUCAAAGC A CUUGGACU
696
AGTCCAAG GGCTAGCTACAACGA GCTTTGAT
2643

2380
GCACUUGG A CUCUUGCU
2146
AGCAAGAG GGCTAGCTACAACGA CCAAGTGC
2644

2386
GGACUCUU G CUCUUUCU
1710
AGAAAGAG GGCTAGCTACAACGA AAGAGTCC
2645

2395
CUCUUUCU A CUCUGAAC
2147
GTTCAGAG GGCTAGCTACAACGA AGAAAGAC
2646

2402
UACUCUGA A CUAAUAAA
2148
TTTATTAG GGCTAGCTACAACGA TCAGAGTA
2647

2406
CUGAACUA A UAAAGCUG
2149
CAGCTTTA GGCTAGCTACAACGA TAGTTCAG
2648

2411
CUAAUAAA G CUGUUGCC
1711
GGCAACAG GGCTAGCTACAACGA TTTATTAG
2649

2414
AUAAAGCU G UUGCCAAG
1712
CTTGGCAA GGCTAGCTACAACGA AGCTTTAT
2650

2417
AAGCUGUU G CCAAGCUG
1713
CAGCTTGG GGCTAGCTACAACGA AACAGCTT
2651

2422
GUUGCCAA G CUGGACGG
1714
CCGTCCAG GGCTAGCTACAACGA TTGGCAAC
2652

2427
CAAGCUGG A CGGCACGA
2150
TCGTGCCG GGCTAGCTACAACGA CCAGCTTG
2653

2430
GCUGGACG G CACGAGCU
1715
AGCTCGTG GGCTAGCTACAACGA CGTCCAGC
2654

2432
UGGACGGC A CGAGCUCG
710
CGAGCTCG GGCTAGCTACAACGA GCCGTCCA
2655

2436
CGGCACGA G CUCGUGCC
1716
GGCACGAG GGCTAGCTACAACGA TCGTGCCG
2656

Input Sequence = NM_021975. Cut Site = R/Y Arm Length = 8. Core Sequence = GGCTAGCTACAACGA NM_021975 (Homo sapiens p65 RelA (NFKB), mRNA; 2444 bp)

[0261]

6

TABLE VI

Human REL-A Amberzyme and Substrate Sequence

Seq

Seq

Pos
Substrate
ID
Amberzyme
ID

9
GGCACGAG G CGGGGCCG
1421
CGGCCCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGUGCC
2994

11
CACGAGGC G GGGCCGGG
2657
CCCGGCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCUCGUG
2995

12
ACGAGGCG G GGCCGGGU
2658
ACCCGGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCUCGU
2996

13
CGAGGCGG G GCCGGGUC
2659
GACCCGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGCCUCG
2997

14
GAGGCGGG G CCGGGUCG
1422
CGACCCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCGCCUC
2998

17
GCGGGGCC G GGUCGCAG
2660
CUGCGACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCCCCGC
2999

18
CGGGGCCG G GUCGCAGC
2661
GCUGCGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGCCCCG
3000

19
GGGGCCGG G UCGCAGCU
1423
AGCUGCGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGGCCCC
3001

22
GCCGGGUC G CAGCUGGG
1424
CCCAGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GACCCGGC
3002

25
GGGUCGCA G CUGGGCCC
1425
GGGCCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCGACCC
3003

28
UCGCAGCU G GGCCCGCG
2662
CGCGGGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUGCGA
3004

29
CGCAGCUG G GCCCGCGG
2663
CCGCGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCUGCG
3005

30
GCAGCUGG G CCCGCGGC
1426
GCCGCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGCUGC
3006

34
CUGGGCCC G CGGCAUGG
1427
CCAUGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCCCAG
3007

36
GGGCCCGC G GCAUGGAC
2664
GUCCAUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGGGCCC
3008

37
GGCCCGCG G CAUGGACG
1428
CGUCCAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCGGGCC
3009

41
CGCGGCAU G GACGAACU
2665
AGUUCGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGCCGCG
3010

42
GCGGCAUG G ACGAACUG
2666
CAGUUCGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGCCGC
3011

45
GCAUCGAC G AACUGUUC
2667
GAACAGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCAUGC
3012

50
GACGAACU G UUCCCCCU
1429
AGGGGGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUUCGUC
3013

68
AUCUUCCC G GCAGAGCA
2668
UGCUCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGAAGAU
3014

69
UCUUCCCG G CAGAGCAG
1430
CUGCUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGGAAGA
3015

72
UCCCCGCA G AGCAGCCC
2669
GGGCUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCGCGA
3016

74
CCGGCAGA G CAGCCCAA
1431
UUGGGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGCCGG
3017

77
GCAGACCA G CCCAAGCA
1432
UGCUUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUCUGC
3018

83
CAGCCCAA G CAGCGGGG
1433
CCCCGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGGCUG
3019

86
CCCAAGCA G CGGGGCAU
1434
AUGCCCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUUGGG
3020

88
CAAGCAGC G GGGCAUGC
2670
GCAUGCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGCUUG
3021

89
AAGCAGCG G GGCAUGCG
2671
CGCAUGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCUGCUU
3022

90
AGCAGCGG G GCAUGCGC
2672
GCGCAUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGCUGCU
3023

91
GCAGCGGG G CAUGCGCU
1435
AGCGCAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCGCUGC
3024

95
CGGGGCAU G CGCUUCCG
1436
CGGAAGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGCCCCG
3025

97
GGGCAUGC G CUUCCGCU
1437
GCAUGCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAUGCCC
3026

103
GCGCUUCC G CUACAAGU
1438
GGAAGCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAAGCGC
3027

110
CGCUACAA G UGCGAGGG
1439
UUGUAGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGUAGCG
3028

112
CUACAAGU G CGAGGGGC
1440
ACUUGUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUUGUAG
3029

114
ACAAGUGC G AGGGGCGC
2673
GCACUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCACUUGU
3030

116
AAGUGCGA G GGGCGCUC
2674
UCGCACUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGCACUU
3031

117
AGUGCGAG G GGCGCUCC
2675
CUCGCACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGCACU
3032

118
GUGCGAGG G GCGCUCCG
2676
CCUCGCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUCGCAC
3033

119
UGCGAGGG G CGCUCCGC
1441
CCCUCGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCUCGCA
3034

121
CGAGGGGC G CUCCGCGG
1442
GCCCCUCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCCCUCG
3035

126
GGCGCUCC G CGGGCAGC
1443
GGAGCGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAGCGCC
3036

128
CGCUCCGC G GGCAGCAU
2677
GCGGAGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGGAGCG
3037

129
GCUCCGCG G GCAGCAUC
2678
CGCGCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCGGAGC
3038

130
CUCCGCGG G CAGCAUCC
1444
GGAUGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGCGGAG
3039

133
CGCGGGCA G CAUCCCAG
1445
CUGGGAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCCGCG
3040

141
GCAUCCCA G GCGAGAGG
2679
CCUCUCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGAUGC
3041

142
CAUCCCAG G CGAGAGGA
1446
UCCUCUCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGGAUG
3042

144
UCCCAGGC G AGAGGAGC
2680
GCUCCUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCUGGGA
3043

146
CCAGGCGA G AGGAGCAC
2681
GUGCUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGCCUGG
3044

148
AGGCGAGA G GAGCACAG
2682
CUGUGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUCGCCU
3045

149
GGCGAGAG G AGCACAGA
2683
UCUGUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUCGCC
3046

151
CGAGAGGA G CACAGAUA
1447
UAUCUGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCUCG
3047

156
GGAGCACA G AUACCACC
2684
GGUGGUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGCUCC
3048

167
ACCACCAA G ACCCACCC
2685
GGGUGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGUGGU
3049

185
ACCAUCAA G AUCAAUGG
2686
CCAUUGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGAUGGU
3050

192
AGAUCAAU G GCUACACA
2687
UGUGUAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUGAUCU
3051

193
GAUCAAUG G CUACACAG
1448
CUGUGUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUUGAUC
3052

201
GCUACACA G GACCAGGG
2688
CCCUGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGUAGC
3053

202
CUACACAG G ACCAGGGA
2689
UCCCUGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUGUAG
3054

207
CAGGACCA G GGACAGUG
2690
CACUGUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUCCUG
3055

208
AGGACCAG G GACAGUGC
2691
GCACUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGUCCU
3056

209
GGACCAGG G ACAGUGCG
2692
CGCACUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUGGUCC
3057

213
CAGGGACA G UGCGCAUC
1449
GAUGCGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUCCCUG
3058

215
GGGACAGU G GGCAUCUC
1450
GAGAUGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGUCCC
3059

217
GACAGUGC G CAUCUCCC
1451
GGGAGAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCACUGUC
3060

227
AUCUCCCU G CUCACCAA
2693
UUGGUGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGAGAU
3061

228
UCUCCCUG G UCACCAAG
1452
CUUGGUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGGAGA
3062

236
GUCACCAA G GACCCUCC
2694
GGAGGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGUGAC
3063

237
UCACCAAG G ACCCUCCU
2695
AGGAGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUGGUGA
3064

250
UCCUCACC G GCCUCACC
2696
GGUCAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUGAGGA
3065

251
CCUCACCG G CCUCACCC
1453
GGGUGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGUGAGG
3066

264
ACCCCCAC G AGCUUGUA
2697
UACAAGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUGGGGGU
3067

266
CCCCACGA G CUUGUAGG
1454
CCUACAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGUGGGG
3068

270
ACGAGCUU G UAGGAAAG
1455
CUUUCCUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGCUCGU
3069

273
AGCUUGUA G GAAAGGAC
2698
GUCCUUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UACAAGCU
3070

274
GCUUGUAG G AAAGGACU
2699
AGUCCUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUACAAGC
3071

278
GUAGGAAA G GACUGCCG
2700
CGGCAGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUCCUAC
3072

279
UAGGAAAG G ACUGCCGG
2701
CCGGCAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUUCCUA
3073

283
AAAGGACU G CCGGGAUG
1456
CAUCCCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUCCUUU
3074

286
GGACUGCC G GGAUGGCU
2702
AGCCAUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCAGUCC
3075

287
GACUGCCG G GAUGGCUU
2703
AAGCCAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGCAGUC
3076

288
ACUGCCGG G AUGGCUUC
2704
GAAGCCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGGCAGU
3077

291
GCCGGGAU G GCUUCUAU
2705
AUAGAAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCCGGC
3078

292
CCGGGAUG G CUUCUAUG
1457
CAUAGAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCCCGG
3079

300
GCUUCUAU G AGGCUGAG
2706
CUCAGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAGAAGC
3080

302
UUCUAUGA G GCUGAGCU
2707
AGCUCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAUAGAA
3081

303
UCUAUGAG G CUGAGCUC
1458
GAGCUCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCAUAGA
3082

306
AUGAGGCU G AGCUCUGC
2708
GCAGAGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCUCAU
3083

308
GAGGCUGA G CUCUGCCC
1459
GGGCAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAGCCUC
3084

313
UGAGCUCU G CCCGGACC
1460
GGUCCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGCUCA
3085

317
CUCUGCCC G GACCGCUG
2709
CAGCGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCAGAG
3086

318
UCUGCCCG G ACCGCUGC
2710
GCAGCGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGGCAGA
3087

322
CCCGGACC G CUGCAUCC
1461
GGAUGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUCCGGG
3088

325
GGACCGCU G CAUCCACA
1462
UGUGGAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGGUCC
3089

334
CAUCCACA G UUUCCAGA
1463
UCUGGAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGGAUG
3090

341
AGUUUCCA G AACCUGGG
2711
CCCAGGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAAACU
3091

347
CAGAACCU G GGAAUCCA
2712
UGGAUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUUCUG
3092

348
AGAACCUG G GAAUCCAG
2713
CUGGAUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGUUCU
3093

349
GAACCUGG G AAUCCAGU
2714
ACUGGAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGGUUC
3094

356
GGAAUCCA G UGUGUGAA
1464
UUCACACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAUUCC
3095

358
AAUCCAGU G UGUGAAGA
1465
UCUUCACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGGAUU
3096

360
UCCAGUGU G UGAAGAAG
1466
CUUCUUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACACUGGA
3097

362
CAGUGUGU G AAGAAGCG
2715
CGCUUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACACACUG
3098

365
UGUGUGAA G AAGCGGGA
2716
UCCCGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCACACA
3099

368
GUGAAGAA G CGGGACCU
1467
AGGUCCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUUCAC
3100

370
GAAGAAGC G GGACCUGG
2717
CCAGGUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUUCUUC
3101

371
AAGAAGCG G GACCUGGA
2718
UCCAGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCUUCUU
3102

372
AGAAGCGG G ACCUGGAG
2719
CUCCAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGCUUCU
3103

377
CGGGACCU G GAGCAGGC
2720
GCCUGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUCCCG
3104

378
GGGACCUG G AGCAGGCU
2721
AGCCUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGUCCC
3105

380
GACCUGGA G CAGGCUAU
1468
AUAGCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAGGUC
3106

383
CUGGAGCA G GCUAUCAG
2722
CUGAUAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUCCAG
3107

384
UGGAGCAG G CUAUCAGU
1469
ACUGAUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCUCCA
3108

391
GGCUAUCA G UCAGCGCA
1470
UGCGCUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAUAGCC
3109

395
AUCAGUCA G CGCAUCCA
1471
UGGAUGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGACUGAU
3110

397
CAGUCAGC G CAUCCAGA
1472
UCUGGAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGACUG
3111

404
CGCAUCCA G ACCAACAA
2723
UUGUUGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAUGCG
3112

426
CCUUCCAA G UUCCUAUA
1473
UAUAGGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGAAGG
3113

435
UUCCUAUA G AAGAGCAG
2724
CUGCUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUAGGAA
3114

438
CUAUAGAA G AGCAGCGU
2725
ACGCUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUAUAG
3115

440
AUAGAAGA G CAGCGUGG
1474
CCACGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUCUAU
3116

443
GAAGAGCA G CGUGGGGA
1475
UCCCCACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUCUUC
3117

445
AGAGCAGC G UGGGGACU
1476
AGUCCCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGCUCU
3118

447
AGCAGCGU G GGGACUAC
2726
GUAGUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGCUGCU
3119

448
GCAGCGUG G GGACUACG
2727
CGUAGUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACGCUGC
3120

449
CAGCGUGG G GACUACGA
2728
UCGUAGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCACGCUG
3121

450
AGCGUGGG G ACUACGAC
2729
GUCGUAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCACGCU
3122

456
GGGACUAC G ACCUGAAU
2730
AUUCAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUAGUCCC
3123

461
UACGACCU G AAUGCUGU
2731
ACAGCAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUCGUA
3124

465
ACCUGAAU G CUGUGCGG
1477
CCGCACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUCAGGU
3125

468
UGAAUGCU G UGCGGCUC
1478
GAGCCGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAUUCA
3126

470
AAUGCUGU G CGGCUCUG
1479
CAGAGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGCAUU
3127

472
UGCUGUGC G GCUCUGCU
2732
AGCAGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCACAGCA
3128

473
GCUGUGCG G CUCUGCUU
1480
AAGCAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCACAGC
3129

478
GCGGCUCU G CUUCCAGG
1481
CCUGGAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGCCGC
3130

485
UGCUUCCA G GUGACAGU
2733
ACUGUCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAAGCA
3131

486
GCUUCCAG G UGACAGUG
1482
CACUGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGAAGC
3132

488
UUCCAGGU G ACAGUGCG
2734
CGCACUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUGGAA
3133

492
AGGUGACA G UGCGGGAC
1483
GUCCCGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUCACCU
3134

494
GUGACAGU G CGGGACCC
1484
GGGUCCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGUCAC
3135

496
GACAGUGC G GGACCCAU
2735
AUGGGUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCACUGUC
3136

497
ACAGUGCG G GACCCAUC
2736
GAUGGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCACUGU
3137

498
CAGUGCGG G ACCCAUCA
2737
UGAUGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGCACUG
3138

507
ACCCAUCA G GCAGGCCC
2738
CGGCCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAUGCCU
3139

508
CCCAUCAG G CAGGCCCC
1485
CGGGCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGAUGGG
3140

511
AUCAGGCA G GCCCCUCC
2739
GGAGGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCUGAU
3141

512
UCAGGCAG G CCCCUCCG
1486
CCGAGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCCUGA
3142

520
GCCCCUCC G CCUGCCGC
1487
GCGGCAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAGGGGC
3143

524
CUCCGCCU G CCGCCUGU
1488
ACAGGCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGCGGAG
3144

527
CGCCUGCC G CCUGUCCU
1489
AGGACAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCAGGCG
3145

531
UGCCGCCU G UCCUUUCU
1490
AGAAAGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGCGGCA
3146

552
CCAUCUUU G ACAAUCGU
2740
ACGAUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGAUGG
3147

559
UGACAAUC G UGCCCCCA
1491
UGGGGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAUUGUCA
3148

561
ACAAUCGU G CCCCCAAC
1492
GUUGGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGAUUGU
3149

573
CCAACACU G CCGAGCUC
1493
GAGCUCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUGUUGG
3150

576
ACACUGCC G AGCUCAAG
2741
CUUGAGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCAGUGU
3151

578
ACUGCCGA G CUCAAGAU
1494
AUCUUGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGGCAGU
3152

584
GAGCUCAA G AUCUGCCG
2742
CGGCAGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGAGCUC
3153

589
CAAGAUCU G CCGAGUGA
1495
UCACUCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAUCUUG
3154

592
GAUCUGCC G AGUGAACC
2743
GGUUCACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCAGAUC
3155

594
UCUGCCGA G UGAACCGA
1496
UCGGUUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGGCAGA
3156

596
UGCCGAGU G AACCCAAA
2744
UUUCGGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUCGGCA
3157

601
AGUGAACC G AAACUCUG
2745
CAGAGUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUUCACU
3158

609
GAAACUCU G CCAGCUGC
2746
GCAGCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGUUUC
3159

610
AAACUCUG G CAGCUGCC
1497
GGCAGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGAGUUU
3160

613
CUCUGGCA G CUGCCUCG
1498
CGAGGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCAGAG
3161

616
UGGCAGCU G CCUCGGUG
1499
CACCGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUGCCA
3162

621
GCUGCCUC G GUGGGGAU
2747
AUCCCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGGCAGC
3163

622
CUGCCUCG G UGGGGAUG
1500
CAUCCCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGAGGCAG
3164

624
GCCUCGGU G GGGAUGAG
2748
CUCAUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCGAGGC
3165

625
CCUCGGUG G GGAUGAGA
2749
UCUCAUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCGAGG
3166

626
CUCGGUGG G GAUGAGAU
2750
AUCUCAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCACCGAG
3167

627
UCGGUGGG G AUGAGAUC
2751
GAUCUCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCACCGA
3168

630
GUGGGGAU G AGAUCUUC
2752
GAAGAUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCCCAC
3169

632
GGGGAUGA G AUCUUCCU
2753
AGGAAGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAUCCCC
3170

644
UUCCUACU G UGUGACAA
1501
UUGUCACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUAGGAA
3171

646
CCUACUGU G UGACAAGG
1502
CCUUGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGUAGG
3172

648
UACUGUGU C ACAAGGUG
2754
CACCUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACACAGUA
3173

653
UGUGACAA G GUGCAGAA
2755
UUCUGCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGUCACA
3174

654
GUGACAAG G UGCAGAAA
1503
UUUCUGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUGUCAC
3175

656
GACAAGGU G CAGAAAGA
1504
UCUUUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUUGUC
3176

659
AAGGUGCA G AAAGAGGA
2756
UCCUCUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCACCUU
3177

663
UGCAGAAA G AGGACAUU
2757
AAUGUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUCUGCA
3178

665
CAGAAAGA G GACAUUGA
2758
UCAAUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUUCUG
3179

666
AGAAAGAG G ACAUUGAG
2759
CUCAAUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUUUCU
3180

672
AGGACAUU G AGGUGUAU
2760
AUACACCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUGUCCU
3181

674
GACAUUGA G GUGUAUUU
2761
AAAUACAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAAUGUC
3182

675
ACAUUGAG G UGUAUUUC
1505
GAAAUACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCAAUGU
3183

677
AUUGAGGU G UAUUUCAC
1506
GUGAAAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUCAAU
3184

686
UAUUUCAC G GGACCAGG
2762
CCUGGUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUGAAAUA
3185

687
AUUUCACG G GACCAGGC
2763
GCCUGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUGAAAU
3186

688
UUUCACGG G ACCAGGCU
2764
AGCCUGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGUGAAA
3187

693
CGGGACCA G GCUGGGAG
2765
CUCCCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUCCCG
3188

694
GGGACCAG G CUGGGAGG
1507
CCUCCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGUCCC
3189

697
ACCAGGCU G GGAGGCCC
2766
GGGCCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCUGGU
3190

698
CCAGGCUG G GAGGCCCG
2767
CGGGCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCCUGG
3191

699
CAGGCUGG G AGGCCCGA
2768
UCGGGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGCCUG
3192

701
GGCUGGGA G GCCCGAGG
2769
CCUCGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCAGCC
3193

702
GCUGGGAG G CCCGAGGC
1508
GCCUCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCCAGC
3194

706
GGAGGCCC G AGGCUCCU
2770
AGGAGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCCUCC
3195

708
AGGCCCGA G GCUCCUUU
2771
AAAGGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGGGCCU
3196

709
GGCCCGAG G CUCCUUUU
1509
AAAAGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGGGCC
3197

719
UCCUUUUC G CAAGCUGA
1510
UCAGCUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAAAAGGA
3198

723
UUUCGCAA G CUGAUGUG
1511
CACAUCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGCGAAA
3199

726
CGCAAGCU G AUGUGCAC
2772
GUGCACAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUUUGCG
3200

729
AAGCUGAU G UGCACCGA
1512
UCGGUGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCAGCUU
3201

731
GCUGAUGU G CACCGACA
1513
UGUCGGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAUCAGC
3202

736
UGUGCACC G ACAAGUGG
2773
CCACUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUGCACA
3203

741
ACCGACAA G UGGCCAUU
1514
AAUGGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGUCGGU
3204

743
CGACAAGU G GCCAUUGU
2774
ACAAUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUUGUCG
3205

744
GACAAGUG G CCAUUGUG
1515
CACAAUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACUUGUC
3206

750
UGGCCAUU G UGUUCCGG
1516
CCGGAACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUGGCCA
3207

752
GCCAUUGU G UUCCGGAC
1517
GUCCGGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAAUGGC
3208

757
UGUGUUCC G GACCCCUC
2775
GAGGGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAACACA
3209

758
GUGUUCCG G ACCCCUCC
2776
GGAGGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGAACAC
3210

771
CUCCCUAC G CAGACCCC
1518
GGGGUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUAGGGAG
3211

774
CCUACGCA G ACCCCAGC
2777
GCUGGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCGUAGG
3212

781
AGACCCCA G CCUGCAGG
1519
CCUGCAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGGUCU
3213

785
CCCAGCCU G CAGGCUCC
1520
GGAGCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGCUGGG
3214

788
AGCCUGCA G GCUCCUGU
2778
ACAGGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAGGCU
3215

789
GCCUGCAG G CUCCUGUG
1521
CACAGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCAGGC
3216

795
AGGCUCCU G UGCGUGUC
1522
GACACGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAGCCU
3217

797
GCUCCUGU G CGUGUCUC
1523
GAGACACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGGAGC
3218

799
UCCUGUGC G UGUCUCCA
1524
UGGAGACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCACAGGA
3219

801
CUGUGCGU G UCUCCAUG
1525
CAUGGAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGCACAG
3220

809
GUCUCCAU G CAGCUGCG
1526
CGCAGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGGAGAC
3221

812
UCCAUGCA G CUGCGGCG
1527
CGCCGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAUGGA
3222

815
AUGCAGCU G CGGCGGCC
1528
GGCCGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUGCAU
3223

817
GCAGCUGC G GCGGCCUU
2779
AAGGCCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAGCUGC
3224

818
CAGCUGCG G CGGCCUUC
1529
GAAGGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCAGCUG
3225

820
GCUGCGGC G GCCUUCCG
2780
CGGAAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCGCAGC
3226

821
CUGCGGCG G CCUUCCGA
1530
UCGGAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCGCAG
3227

828
GGCCUUCC G ACCGGGAG
2781
CUCCCGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAAGGCC
3228

832
UUCCGACC G GGAGCUCA
2782
UGAGCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUCGGAA
3229

833
UCCGACCG G GAGCUCAG
2783
CUGAGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGUCGGA
3230

834
CCGACCGG G AGCUCAGU
2784
ACUGAGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGGUCGG
3231

836
GACCGGGA G CUCAGUGA
1531
UCACUGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCGGUC
3232

841
GGAGCUCA G UGAGCCCA
1532
UGGGCUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGCUCC
3233

843
AGCUCAGU G AGCCCAUG
2785
CAUGGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGAGCU
3234

845
CUCAGUGA G CCCAUGGA
1533
UCCAUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCACUGAG
3235

851
GAGCCCAU G GAAUUCCA
2786
UGGAAUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGGGCUC
3236

852
AGCCCAUG G AAUUCCAG
2787
CUGGAAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGGGCU
3237

860
GAAUUCCA G UACCUGCC
1534
GGCAGGUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAAUUC
3238

866
CAGUACCU G CCAGAUAC
1535
GUAUCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUACUG
3239

870
ACCUGCCA G AUACAGAC
2788
GUCUGUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCAGGU
3240

876
CAGAUACA G ACGAUCGU
2789
ACGAUCGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUAUCUG
3241

879
AUACAGAC G AUCGUCAC
2790
GUGACGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUCUGUAU
3242

883
AGACGAUC G UCACCGGA
1536
UCCGGUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAUCGUCU
3243

889
UCGUCACC G GAUUGAGG
2791
CCUCAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUGACGA
3244

890
CGUCACCG G AUUGAGGA
2792
UCCUCAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGUGACG
3245

894
ACCGGAUU G AGGAGAAA
2793
UUUCUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUCCGGU
3246

896
CGGAUUGA G GAGAAACG
2794
CGUUUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAAUCCG
3247

897
GGAUUGAG G AGAAACGU
2795
ACGUUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCAAUCC
3248

899
AUUGAGGA G AAACGUAA
2796
UUACGUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCAAU
3249

904
GGAGAAAC G UAAAAGGA
1537
UCCUUUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUUUCUCC
3250

910
ACGUAAAA G GACAUAUG
2797
CAUAUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUACGU
3251

911
CGUAAAAG G ACAUAUGA
2798
UCAUAUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUUUACG
3252

918
GGACAUAU G AGACCUUC
2799
GAAGGUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAUGUCC
3253

920
ACAUAUGA G ACCUUCAA
2800
UUGAAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAUAUGU
3254

929
ACCUUCAA G AGCAUCAU
2801
AUGAUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGAAGGU
3255

931
CUUCAAGA G CAUCAUGA
1538
UCAUGAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUGAAG
3256

938
AGCAUCAU G AAGAAGAG
2802
CUCUUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGAUGCU
3257

941
AUCAUGAA G AAGAGUCC
2803
GGACUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAUGAU
3258

944
AUGAAGAA G AGUCCUUU
2804
AAAGGACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUUCAU
3259

946
GAAGAAGA G UCCUUUCA
1539
UGAAAGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUCUUC
3260

955
UCCUUUCA G CGGACCCA
1540
UGGGUCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAAGGA
3261

957
CUUUCAGC G GACCCACC
2805
GGUGGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGAAAG
3262

958
UUUCAGCG G ACCCACCG
2806
CGGUGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCUGAAA
3263

966
GACCCACC G ACCCCCGG
2807
CCGGGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUGGGUC
3264

973
CGACCCCC G GCCUCCAC
2808
GUGGAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGGGUCG
3265

974
GACCCCCG G CCUCCACC
1541
GGUGGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGGGGUC
3266

985
UCCACCUC G ACGCAUUG
2809
CAAUGCGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGGUGGA
3267

988
ACCUCGAC G CAUUGCUG
1542
CAGCAAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUCGAGGU
3268

993
GACGCAUU G CUGUGCCU
1543
AGGCACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUGCGUC
3269

996
GCAUUGCU G UGCCUUCC
1544
GGAAGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAAUGC
3270

998
AUUGCUGU G CCUUCCCG
1545
CGGGAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGCAAU
3271

1006
GCCUUCCC G CAGCUCAG
1546
CUGAGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGAAGGC
3272

1009
UUCCCGCA G CUCAGCUU
1547
AAGCUGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCGGGAA
3273

1014
GCAGCUCA G CUUCUGUC
1548
GACAGAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGCUGC
3274

1020
CAGCUUCU G UCCCCAAG
1549
CUUGGGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAGCUG
3275

1028
GUCCCCAA G CCAGCACC
1550
GGUGCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGGGAC
3276

1032
CCAAGCCA G CACCCCAG
1551
CUGGGGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCUUGG
3277

1040
GCACCCCA G CCCUAUCC
1552
GGAUAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGGUGC
3278

1055
CCCUUUAC G UCAUCCCU
1553
AGGGAUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUAAAGGG
3279

1064
UCAUCCCU G AGCACCAU
2810
AUGGUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGAUGA
3280

1066
AUCCCUGA G CACCAUCA
1554
UGAUGGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAGGGAU
3281

1080
UCAACUAU G AUGAGUUU
2811
AAACUCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAGUUGA
3282

1083
ACUAUGAU G AGUUUCCC
2812
GGGAAACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCAUAGU
3283

1085
UAUGAUGA G UUUCCCAC
1555
GUGGGAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAUCAUA
3284

1097
CCCACCAU G GUGUUUCC
2813
GGAAACAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGGUGGG
3285

1098
CCACCAUG G UGUUUCCU
1556
AGGAAACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGGUGG
3286

1100
ACCAUGGU G UUUCCUUC
1557
GAAGGAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCAUGGU
3287

1110
UUCCUUCU G GGCAGAUC
2814
GAUCUGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAGGAA
3288

1111
UCCUUCUG G GCAGAUCA
2815
UGAUCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGAAGGA
3289

1112
CCUUCUGG G CAGAUCAG
1558
CUGAUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGAAGG
3290

1115
UCUGGGCA G AUCAGCCA
2816
UGGCUGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCCAGA
3291

1120
GCAGAUCA G CCAGGCCU
1559
AGGCCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAUCUGC
3292

1124
AUCAGCCA G GCCUCGGC
2817
GCCGAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCUGAU
3293

1125
UCAGCCAG G CCUCGGCC
1560
GGCCGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGCUGA
3294

1130
CAGGCCUC G GCCUUGGC
2818
GCCAAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGGCCUG
3295

1131
AGGCCUCG G CCUUGGCC
1561
GGCCAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGAGGCCU
3296

1136
UCGGCCUU G GCCCCGGC
2819
GCCGGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGCCGA
3297

1137
CGGCCUUG G CCCCGGCC
1562
GGCCGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAGGCCG
3298

1142
UUGGCCCC G GCCCCUCC
2820
GGAGGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGGCCAA
3299

1143
UGGCCCCG G CCCCUCCC
1563
GGGAGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGGGCCA
3300

1155
CUCCCCAA G UCCUGCCC
1564
GGGCAGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGGGAG
3301

1160
CAAGUCCU G CCCCAGGC
1565
GCCUGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGACUUG
3302

1166
CUGCCCCA G GCUCCAGC
2821
GCUGGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGGCAG
3303

1167
UGCCCCAG G CUCCAGCC
1566
GGCUGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGGGCA
3304

1173
AGGCUCCA G CCCCUGCC
1567
GGCAGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAGCCU
3305

1179
CAGCCCCU G CCCCUGCU
1568
AGCAGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGGCUG
3306

1185
CUGCCCCU G CUCCAGCC
1569
GUCUGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGGCAG
3307

1191
CUGCUCCA G CCAUGGUA
1570
UACCAUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAGCAG
3308

1196
CCAGCCAU G GUAUCAGC
2822
GCUGAUAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGGCUGG
3309

1197
CAGCCAUG G UAUCAGCU
1571
AGCUGAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGGCUG
3310

1203
UGGUAUCA G CUCUGGCC
1572
GUCCAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAUACCA
3311

1208
UCAGCUCU G GCCCAGGC
2823
UCCUUUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGCUGA
3312

1209
CAUCUCUG G CCCAGGCC
1573
GGCCUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGAGCUG
3313

1214
CUGGCCCA G GCCCCAGC
2824
UCUGGUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCCAG
3314

1215
UGGCCCAG G CCCCAGCC
1574
GGCUGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGGCCA
3315

1221
AUGCCCCA G CCCCUGUC
1575
GACAUGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGGCCU
3316

1227
CAGCCCCU G UCCCAGUC
1576
GACUGGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGGCUG
3317

1233
CUGUCCCA G UCCUAGCC
1577
GUCUAGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGACAG
3318

1239
CAGUCCUA G CCCCAGGC
1578
GCCUGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAGGACUG
3319

1245
UAGCCCCA G GCCCUCCU
2825
AUGAUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGGCUA
3320

1246
AGCCCCAG G CCCUCCUC
1579
GAUGAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGGGCU
3321

1256
CCUCCUCA G GCUGUGGC
2826
GCCACAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGGAGG
3322

1257
CUCCUCAG G CUGUGGCC
1380
GGCCACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGAGGAG
3323

1260
CUCAGGCU G UGGCCCCA
1581
UGGGGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCUGAG
3324

1262
CAGGCUGU G GCCCCACC
2827
GGUGGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAUCCUG
3325

1263
AGGCUGUG G CCCCACCU
1582
AGGUGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACAGCCU
3326

1272
CCCCACCU G CCCCCAAG
1583
CUUGGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUGGGG
3327

1280
GCCCCCAA G CCCACCCA
1584
UGGGUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGGGGC
3328

1289
CCCACCCA G GCUGGGGA
2828
UCCCCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGUGGG
3329

1290
CCACCCAG G CUGGGGAA
1585
UUCCCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGGUGG
3330

1293
CCCAGGCU G GGGAAGGA
2829
UCCUUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCUGGG
3331

1294
CCAGGCUG G GGAAGGAA
2830
UUCCUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCCUGG
3332

1295
CAGGCUGG G GAAGGAAC
2831
GUUCCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGCCUG
3333

1296
AGGCUGGG G AAGGAACG
2832
CGUUCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAGCCU
3334

1299
CUGGGGAA G GAACGCUG
2833
CAGCGUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCCCAG
3335

1300
UGGGGAAG G AACGCUGU
2834
ACAGCGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCCCCA
3336

1304
GAAGGAAC G CUGUCAGA
1586
UCUGACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUUCCUUC
3337

1307
GGAACGCU G UCAGAGGC
1587
GCCUCUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGUUCC
3338

1311
CGCUGUCA G AGGCCCUG
2835
CAGGGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGACAGCG
3339

1313
CUGUCAGA G GCCCUGCU
2836
AGCAGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGACAG
3340

1314
UGUCAGAG G CCCUGCUG
1588
CAGCAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUGACA
3341

1319
GAGGCCCU G CUGCAGCU
1589
AGCUGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGCCUC
3342

1322
GCCCUGCU G CAGCUGCA
1590
UGCAGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAGGGC
3343

1325
CUGCUGCA G CUGCAGUU
1591
AACUGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAGCAG
3344

1328
CUGCAGCU G CAGUUUGA
1592
UCAAACUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUGCAG
3345

1331
CAGCUGCA G UUUGAUGA
1593
UCAUCAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAGCUG
3346

1335
UGCAGUUU G AUGAUGAA
2837
UUCAUCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAACUGCA
3347

1338
AGUUUGAU G AUGAAGAC
2838
GUCUUCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCAAACU
3348

1341
UUGAUGAU G AAGACCUG
2839
CAGGUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCAUCAA
3349

1344
AUGAUGAA G ACCUGGGG
2840
CCCCAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAUCAU
3350

1349
GAAGACCU G GGGGCCUU
2841
AAGGCCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUCUUC
3351

1350
AAGACCUG G GGGCCUUG
2842
CAAGGCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGUCUU
3352

1351
AGACCUGG G GGCCUUGC
2843
GCAAGGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGGUCU
3353

1352
GACCUGGG G GCCUUGCU
2844
AGCAAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAGGUC
3354

1353
ACCUGGGG G CCUUGCUU
1594
AAGCAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCCAGGU
3355

1358
GGGGCCUU G CUUGGCAA
1595
UUGCCAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGCCCC
3356

1362
CCUUGCUU G GCAACAGC
2845
GCUGUUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGCAAGG
3357

1363
CUUGCUUG G CAACAGCA
1596
UGCUGUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAGCAAG
3358

1369
UGGCAACA G CACAGACC
1597
GGUCUGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUGCCA
3359

1374
ACAGCACA G ACCCAGCU
2846
AGCUGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGCUGU
3360

1380
CAGACCCA G CUGUGUUC
1598
GAACACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGUCUG
3361

1383
ACCCAGCU G UGUUCACA
1599
UGUGAACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUGGGU
3362

1385
CCAGCUGU G UUCACAGA
1600
UCUGUGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGCUGG
3363

1392
UGUUCACA G ACCUGGCA
2847
UGCCAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGAACA
3364

1397
ACAGACCU G GCAUCCGU
2848
ACGGAUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUCUGU
3365

1398
CAGACCUG G CAUCCGUC
1601
GACGGAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGUCUG
3366

1404
UGGCAUCC G UCGACAAC
1602
GUUGUCGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAUGCCA
3367

1407
CAUCCGUC G ACAACUCC
2849
GGAGUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GACGGAUG
3368

1416
ACAACUCC G AGUUUCAG
2850
CUGAAACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAGUUGU
3369

1418
AACUCCGA G UUUCAGCA
1603
UGCUGAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGGAGUU
3370

1424
GAGUUUCA G CAGCUGCU
1604
AGCAGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAACUC
3371

1427
UUUCAGCA G CUGCUGAA
1605
UUCAGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUGAAA
3372

1430
CAGCAGCU G CUGAACCA
1606
UGGUUCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUGCUG
3373

1433
CAGCUGCU G AACCAGGG
2851
CCCUGGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAGCUG
3374

1439
CUGAACCA G GGCAUACC
2852
GGUAUGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUUCAG
3375

1440
UGAACCAG G GCAUACCU
2853
AGGUAUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGUUCA
3376

1441
GAACCAGG G CAUACCUG
1607
CAGGUAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUGGUUC
3377

1449
GCAUACCU G UGGCCCCC
1608
GGGGGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUAUGC
3378

1451
AUACCUGU G GCCCCCCA
2854
UGGGGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGGUAU
3379

1452
UACCUGUG G CCCCCCAC
1609
GUGGGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACAGGUA
3380

1467
ACACAACU G AGCCCAUG
2855
CAUGGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUUGUGU
3381

1469
ACAACUGA G CCCAUGCU
1610
AGCAUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAGUUGU
3382

1475
GAGCCCAU G CUGAUGGA
1611
UCCAUCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGGGCUC
3383

1478
CCCAUGCU G AUGGAGUA
2856
UACUCCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAUGGG
3384

1481
AUGCUGAU G GAGUACCC
2857
GGGUACUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCAGCAU
3385

1482
UGCUGAUG G AGUACCCU
2858
AGGGUACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCAGCA
3386

1484
CUGAUGGA G UACCCUGA
1612
UCAGGGUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAUCAG
3387

1491
AGUACCCU G AGGCUAUA
2859
UAUAGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGUACU
3388

1493
UACCCUGA G GCUAUAAC
2860
GUUAUAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAGGUUA
3389

1494
ACCCUGAG G CUAUAACU
1613
AGUUAUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCAGGGU
3390

1504
UAUAACUC G CCUAGUGA
1614
UCACUAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGUUAUA
3391

1509
CUCGCCUA G UGACAGCC
1615
GGCUGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAGGCGAG
3392

1511
CGCCUAGU G ACAGCCCA
2861
UGGGCUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUAUGCG
3393

1515
UAGUGACA G CCCAGAGG
1616
CCUCUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUCACUA
3394

1520
ACAGCCCA G AGGCCCCC
2862
GGGGGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCUGU
3395

1522
AGCCCAGA G GCCCCCCG
2863
CGGGGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGGGCU
3396

1523
GCCCAGAG G CCCCCCGA
1617
UCGGGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUGGGC
3397

1530
GGCCCCCC G ACCCAGCU
2864
AGCUGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGGGGCC
3398

1536
CCGACCCA G CUCCUGCU
1618
AGCAGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGUCGG
3399

1542
CAGCUCCU G CUCCACUG
1619
CAGUGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAGCUG
3400

1550
GCUCCACU G GGGGCCCC
2865
GGGGCCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUGGAGC
3401

1551
CUCCACUG G GGGCCCCG
2866
CGGGGCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGUGGAG
3402

1552
UCCACUGG G GGCCCCGG
2867
CCGGGGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGUGGA
3403

1553
CCACUGGG G GCCCCGGG
2868
CCCGGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAGUGG
3404

1554
CACUGGGG G CCCCGGGG
1620
CCCCGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCCAGUG
3405

1559
GGGGCCCC G GGGCUCCC
2869
GGGAGCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGGCCCC
3406

1560
GGGCCCCG G GGCUCCCC
2870
GGGGAGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGGGCCC
3407

1561
GGCCCCGG G GCUCCCCA
2871
UGGGGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGGGGCC
3408

1562
GCCCCCGG G CUCCCCAA
1621
UUGGGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCGGGGC
3409

1572
UCCCCAAU G GCCUCCUU
2872
AAGGAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUGGGGA
3410

1573
CCCCAAUG G CCUCCUUU
1622
AAAGGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUUGGGG
3411

1584
UCCUUUCA G GAGAUGAA
2873
UUCAUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAAGGA
3412

1585
CCUUUCAG G AGAUGAAG
2874
CUUCAUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGAAAGG
3413

1587
UGUCAGGA G AUGAAGAC
2875
GUCUUCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUGAAA
3414

1590
CAGGAGAU G AAGACUUC
2876
GAAGUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCUCCUG
3415

1593
GAGAUGAA G ACUUCUCC
2877
GGAGAAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAUCUC
3416

1608
CCUCCAUU G CGGACAUG
1623
CAUGUCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUGGAGG
3417

1610
UCCAUUGC G GACAUGGA
2878
UCCAUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAAUGGA
3418

1611
CCAUUGCG G ACAUGGAC
2879
GUCCAUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCAAUGG
3419

1616
GCGGACAU G GACUUCUC
2880
GAGAAGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGUCCGC
3420

1617
CGGACAUG G ACUUCUCA
2881
UGAGAAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGUCCG
3421

1626
ACUUCUCA G CCCUGCUG
1624
CAGCAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGACAAGU
3422

1631
UCAGCCCU G CUGAGUCA
1625
UGACUCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGCUGA
3423

1634
GCCCUGCU G AGUCAGAU
2882
AUCUGACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAGGGC
3424

1636
CCUGCUGA G UCAGAUCA
1626
UGAUCUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAGCAGG
3425

1640
CUGAGUCA G AUCAGCUC
2883
GAGCUGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGACUCAG
3426

1645
UCAGAUCA G CUCCUAAG
1627
CUUAGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAUCUGA
3427

1653
GCUCCUAA G GGGGUGAC
2884
GUCACCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUAGGAGC
3428

1654
CUCCUAAG G GGGUGACG
2885
CGUCACCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUAGGAG
3429

1655
UCCUAAGG G GGUGACGC
2886
GCGUCACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUUAGGA
3430

1656
CCUAAGGG G GUGACGCC
2887
GGCCUCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCUUAGG
3431

1657
CUAAGGGG G UGACGCCU
1628
AGGCGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCCUUAG
3432

1659
AAGGGCGU G ACGCCUGC
2888
GCAGGCGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCCCCUU
3433

1662
GGGGUGAC G CCUGCCCU
1629
AGGGCAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUCACCCC
3434

1666
UGACGCCU G CCCUCCCC
1630
GGGGAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGCGUCA
3435

1676
CCUCCCCA G AGCACUGG
2889
CCAGUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGGCAGG
3436

1678
UCCCCAGA G CACUGGUU
1631
AACCAGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGGGGA
3437

1683
AGAGCACU G GUUGCAGG
2890
CCUGCAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUGCUCU
3438

1684
GAGCACUG G UUGCAGGG
1632
CCCUGCAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGUGCUC
3439

1687
CACUGGUU G CAGGGGAU
1633
AUCCCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AACCAGUG
3440

1690
UGGUUGCA G GGGAUUGA
2891
UCAAUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAACCA
3441

1691
GGUUGCAG G GGAUUGAA
2892
UUCAAUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCAACC
3442

1692
GUUGCAGG G GAUUGAAG
2893
CUUCAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUGCAAC
3443

1693
UUGCAGGG G AUUGAAGC
2894
GCUUCAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCUGCAA
3444

1697
AGGGGAUU G AAGCCCUC
2895
GAGGGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUCCCCU
3445

1700
GGAUUGAA G CCCUCCAA
1634
UUGGAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAAUCC
3446

1711
CUCCAAAA G CACUUACG
1635
CGUAAGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUGGAG
3447

1719
GCACUUAC G GAUUCUGG
2896
CCAGAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUAAGUGC
3448

1720
CACUUACG G AUUCUGGU
2897
ACCAGAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUAAGUG
3449

1726
CGGAUUCU G CUGGGGUG
2898
CACCCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAUCCG
3450

1727
GGAUUCUG G UGGGGUGU
1636
ACACCCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGAAUCC
3451

1729
AUUCUGGU G GGGUGUGU
2899
ACACACCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCAGAAU
3452

1730
UUCUGGUG G GGUGUGUU
2900
AACACACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCAGAA
3453

1731
UCUGGUGG G GUGUGUUC
2901
GAACACAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCACCAGA
3454

1732
CUGGUGGG G UGUGUUCC
1637
GGAACACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCACCAG
3455

1734
GGUGGGGU G UGUUCCAA
1638
UUGGAACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCCCACC
3456

1736
UGGGGUGU G UUCCAACU
1639
AGUUGGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACACCCCA
3457

1745
UUCCAACU G CCCCCAAC
1640
GUUGGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUUGGAA
3458

1757
CCAACUUU G UGGAUCUC
1641
GACAUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGUUGG
3459

1759
AACUUUGU G GAUGUCUU
2902
AAGACAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAAAGUU
3460

1760
ACUUUGUG G AUGUCUUC
2903
GAAGACAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACAAAGU
3461

1763
UUGUGGAU G UCUUCCUU
1642
AAGGAAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCACAA
3462

1772
UCUUCCUU G GAGGGGGG
2904
CCCCCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGAAGA
3463

1773
CUUCCUUG G AGGGGGGA
2905
UCCCCCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAGGAAG
3464

1775
UCCUUGGA G GGGGGAGC
2906
GCUCCCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAAGGA
3465

1776
CCUUCGAG G GGGGAGCC
2907
GGCUCCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCAAGG
3466

1777
CUUGGAGG G GGGAGCCA
2908
UGGCUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUCCAAG
3467

1778
UUGGAGGG G GGAGCCAU
2909
AUGGCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCUCCAA
3468

1779
UGGAGGGG G GAGCCAUA
2910
UAUGGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCCUCCA
3469

1780
GGAGGGGG G AGCCAUAU
2911
AUAUGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCCCUCC
3470

1782
AGGGGGGA G CCAUAUUU
1643
AAAUAUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCCCCU
3471

1803
CUUUUAUU G UCAGUAUC
1644
GAUACUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUAAAAG
3472

1807
UAUUGUCA G UAUCUGUA
1645
UACAGAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGACAAUA
3473

1813
CAGUAUCU G UAUCUCUC
1646
GAGAGAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAUACUG
3474

1831
CUCUUUUU G GAGGUGCU
2912
AGCACCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAAAGAG
3475

1832
UCUUUUUG G AGGUGCUU
2913
AAGCACCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAAAAGA
3476

1834
UUUUUGGA G GUGCUUAA
2914
UUAAGCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAAAAA
3477

1835
UUUUGGAG G UGCUUAAG
1647
CUUAAGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCAAAA
3478

1837
UUGGAGGU G CUUAAGCA
1648
UGCUUAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUCCAA
3479

1843
GUGCUUAA G CAGAAGCA
1649
UGCUUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUAAGCAC
3480

1846
CUUAAGCA G AAGCAUUA
2915
UAAUGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUUAAG
3481

1849
AAGCAGAA G CAUUAACU
1650
AGUUAAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUGCUU
3482

1863
ACUUCUCU G GAAAGGGG
2916
CCCCUUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGAAGU
3483

1864
CUUCUCUG G AAAGGGGG
2917
CCCCCUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGAGAAG
3484

1868
UCUGGAAA G GGGGGAGC
2918
GCUCCCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUCCAGA
3485

1869
CUGGAAAG G GGGGAGCU
2919
AGCUCCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUUCCAG
3486

1870
UGGAAAGG G GGGAGCUG
2920
CAGCUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUUUCCA
3487

1871
GGAAAGGG G GGAGCUGG
2921
CCAGCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCUUUCC
3488

1872
GAAAGGGG G GAGCUGGG
2922
CCCAGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCCUUUC
3489

1873
AAAGGGGG G AGCUGGGG
2923
CCCCAGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCCCUUU
3490

1875
AGGGGGGA G CUGGGGAA
1651
UUCCCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCCCCU
3491

1878
GGGGAGCU G GGGAAACU
2924
AGUUUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUCCCC
3492

1879
GGGAGCUG G GGAAACUC
2925
GAGUUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCUCCC
3493

1880
GGAGCUGG G GAAACUCA
2926
UGAGUUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGCUCC
3494

1881
GAGCUGGG G AAACUCAA
2927
UUGAGUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAGCUC
3495

1901
UUUCCCCU G UCCUGAUG
1652
CAUCAGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGGAAA
3496

1906
CCUGUCCU G AUGGUCAG
2928
CUGACCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGACAGG
3497

1909
GUCCUGAU G GUCAGCUC
2929
GAGCUGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCAGGAC
3498

1910
UCCUGAUG G UCAGCUCC
1653
GGAGCUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCAGGA
3499

1914
GAUGGUCA G CUCCCUUC
1654
GAAGGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGACCAUC
3500

1926
CCUUCUCU G UAGGGAAC
1655
GUUCCCUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGAAGG
3501

1929
UCUCUGUA G GGAACUGU
2930
ACAGUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UACAGAGA
3502

1930
CUCUGUAG G GAACUGUG
2931
CACAGUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUACAGAG
3503

1931
UCUGUAGG G AACUGUGG
2932
CCACAGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUACAGA
3504

1936
AGGGAACU G UGGGGUCC
1656
GGACCCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUUCCCU
3505

1938
GGAACUGU G GGGUCCCC
2933
GGGGACCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGUUCC
3506

1939
GAACUGUG G GGUCCCCC
2934
GGGGGACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACAGUUC
3507

1940
AACUGUGG G GUCCCCCA
2935
UGGGGGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCACAGUU
3508

1941
ACUGUGGG G UCCCCCAU
1657
AUGGGGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCACAGU
3509

1962
AUCCUCCA G CUUCUGGU
1658
ACCAGAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAGGAU
3510

1968
CAGCUUCU G GUACUCUC
2936
GAGAGUAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAGCUG
3511

1969
AGCUUCUG G UACUCUCC
1659
GGAGAGUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGAAGCU
3512

1980
CUCUCCUA G AGACAGAA
2937
UUCUGUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAGGAGAG
3513

1982
CUCCUAGA G ACAGAAGC
2938
GCUUCUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUAGGAG
3514

1986
UAGAGACA G AAGCAGGC
2939
GCCUGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUCUCUA
3515

1989
AGACAGAA G CAGGCUGG
1660
CCAGCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUGUCU
3516

1992
CAGAAGCA G GCUGGAGG
2940
CCUCCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUUCUG
3517

1993
AGAAGCAG G CUGGAGGU
1661
ACCUCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCUUCU
3518

1996
AGCAGGCU G GAGGUAAG
2941
CUUACCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCUGCU
3519

1997
GCAGGCUG G AGGUAAGG
2942
CCUUACCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCCUGC
3520

1999
AGGCUGGA G GUAAGGCC
2943
GGCCUUAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAGCCU
3521

2000
GGCUGGAG G UAAGGCCU
1662
AGGCCUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCAGCC
3522

2004
GGAGGUAA G GCCUUUGA
2944
UCAAAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUACCUCC
3523

2005
GAGGUAAG G CCUUUGAG
1663
CUCAAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUACCUC
3524

2011
AGGCCUUU G AGCCCACA
2945
UGUGGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGGCCU
3525

2013
GCCUUUGA G CCCACAAA
1664
UUUGUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAAAGGC
3526

2022
CCCACAAA G CCUUAUCA
1665
UGAUAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGUGGG
3527

2032
CUUAUCAA G UGUCUUCC
1666
GGAAGACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGAUAAG
3528

2034
UAUCAAGU G UCUUCCAU
1667
AUGGAAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUUGAUA
3529

2046
UCCAUCAU G GAUUCAUU
2946
AAUGAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGAUGGA
3530

2047
CCAUCAUG G AUUCAUUA
2947
UAAUGAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGAUGG
3531

2058
UCAUUACA G CUUAAUCA
1668
UGAUUAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUAAUGA
3532

2074
AAAAUAAC G CCCCAGAU
1669
AUCUGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUUAUUUU
3533

2080
ACGCCCCA G AUACCAGC
2948
GCUGGUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGGCGU
3534

2087
AGAUACCA G CCCCUGUA
1670
UACAGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUAUCU
3535

2093
CAGCCCCU G UAUGGCAC
1671
GUGCCAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGGCUG
3536

2097
CCCUGUAU G GCACUGGC
2949
GCCAGUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUACAGGG
3537

2098
CCUGUAUG G CACUGGCA
1672
UGCCAGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUACAGG
3538

2103
AUGGCACU G GCAUUGUC
2950
GACAAUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUGCCAU
3539

2104
UGGCACUG G CAUUGUCC
1673
GGACAAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGUGCCA
3540

2109
CUGGCAUU G UCCCUGUG
1674
CACAGGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUGCCAG
3541

2115
UUGUCCCU G UGCCUAAC
1675
GUUAGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGACAA
3542

2117
GUCCCUGU G CCUAACAC
1676
GUGUUAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGGGAC
3543

2128
UAACACCA G CGUUUGAG
1677
CUCAAACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUGUUA
3544

2130
ACACCAGC G UUUGAGGG
1678
CCCUCAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGGUGU
3545

2134
CAGCGUUU G AGGGGCUG
2951
CAGCCCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAACGCUG
3546

2136
GCGUUUGA G GGGCUGCC
2952
GGCAGCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAAACGC
3547

2137
CGUUUGAG G GGCUGCCU
2953
AGGCAGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCAAACG
3548

2138
GUUUGAGG G GCUGCCUU
2954
AAGGCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUCAAAC
3549

2139
UUUGAGGG G CUGCCUUC
1679
GAAGGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCUCAAA
3550

2142
GAGGGGCU G CCUUCCUG
1680
CAGGAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCCCUC
3551

2150
GCCUUCCU G CCCUACAG
1681
CUGUAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAAGGC
3552

2158
GCCCUACA G AGGUCUCU
2955
AGAGACCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUAGGGC
3553

2160
CCUACAGA G GUCUCUGC
2956
GCAGAGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGUAGG
3554

2161
CUACAGAG G UCUCUGCC
1682
GGCAGAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUGUAG
3555

2167
AGGUCUCU G CCGGCUCU
1683
AGAGCCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGACCU
3556

2170
UCUCUGCC G GCUCUUUC
2957
GAAAGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCAGAGA
3557

2171
CUCUGCCG G CUCUUUCC
1684
GGAAAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGCAGAG
3558

2182
CUUUCCUU G CUCAACCA
1685
UGGUUGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGAAAG
3559

2192
UCAACCAU G GCUGAAGG
2958
CCUUCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGGUUGA
3560

2193
CAACCAUG G CUGAAGGA
1686
UCCUUCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGGUUG
3561

2196
CCAUGGCU G AAGGAAAC
2959
CUUUCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCAUGG
3562

2199
UGGCUGAA G GAAACAGU
2960
ACUGUUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAGCCA
3563

2200
GGCUGAAG G AAACAGUG
2961
CACUGUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCAGCC
3564

2206
AGGAAACA G UGCAACAG
1687
CUGUUGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUUCCU
3565

2208
GAAACAGU G CAACAGCA
1688
UGCUGUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGUUUC
3566

2214
GUGCAACA G CACUGGCU
1689
AGCCAGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUGCAC
3567

2219
ACAGCACU G GCUCUCUC
2962
GAGAGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUGCUGU
3568

2220
CAGCACUG G CUCUCUCC
1690
GGAGAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGUGCUG
3569

2230
UCUCUCCA G GAUCCAGA
2963
UCUGGAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAGAGA
3570

2231
CUCUCCAG G AUCCAGAA
2964
UUCUGGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGAGAG
3571

2237
AGGAUCCA G AAGGGGUU
2965
AACCCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAUCCU
3572

2240
AUCCAGAA G GGGUUUGG
2966
CCAAACCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUGGAU
3573

2241
UCCAGAAG G GGUUUGGU
2967
ACCAAACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCUGGA
3574

2242
CCAGAAGG G GUUUGGUC
2968
GACCAAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUUCUGG
3575

2243
CAGAAGGG G UUUGGUCU
1691
AGACCAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCUUCUG
3576

2247
AGGGGUUU G GUCUGGAC
2969
GUCCAGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAACCCCU
3577

2248
GGGGUUUG G UCUGGACU
1692
AGUCCAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAACCCC
3578

2252
UUUGGUCU G GACUUCCU
2970
AGGAAGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGACCAAA
3579

2253
UUGGUCUG G ACUUCCUU
2971
AAGGAAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGACCAA
3580

2262
ACUUCCUU G CUCUCCCC
1693
GGGGAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGAAGU
3581

2280
CUUCUCAA G UGCCUUAA
1694
UUAAGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGAGAAG
3582

2282
UCUCAAGU G CCUUAAUA
1695
UAUUAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUUGAGA
3583

2291
CCUUAAUA G UAGGGUAA
1696
UUACCCUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUUAAGG
3584

2294
UAAUAGUA G GGUAAGUU
2972
AACUUACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UACUAUUA
3585

2295
AAUAGUAG G GUAAGUUG
2973
CAACUUAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUACUAUU
3586

2296
AUAGUAGG G UAAGUUGU
1697
ACAACUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUACUAU
3587

2300
UAGGGUAA G UUGUUAAG
1698
CUUAACAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUACCCUA
3588

2303
GGUAAGUU G UUAAGAGU
1699
ACUCUUAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AACUUACC
3589

2308
GUUGUUAA G AGUGGGGG
2974
CCCCCACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUAACAAC
3590

2310
UGUUAAGA G UGGGGGAG
1700
CUCCCCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUAACA
3591

2312
UUAAGAGU G GGGGAGAC
2975
CUCUCCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUCUUAA
3592

2313
UAAGAGUG G GGGAGAGC
2976
GCUCUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACUCUUA
3593

2314
AAGAGUGG G GGAGAGCA
2977
UGCUCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCACUCUU
3594

2315
AGAGUGGG G GAGAGCAG
2978
CUGCUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCACUCU
3595

2316
GAGUGGGG G AGAGCAGG
2979
CCUGCUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCCACUC
3596

2318
GUGGGGGA G AGCAGGCU
2980
AGCCUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCCCAC
3597

2320
GGGGGAGA G CAGGCUGG
1701
CCAGCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUCCCCC
3598

2323
GGAGAGCA G GCUGGCAG
2981
CUGCCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUCUCC
3599

2324
GAGAGCAG G CUGGCAGC
1702
GCUGCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCUCUC
3600

2327
AGCAGGCU G GCAGCUCU
2982
AGAGCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCUGCU
3601

2328
GCAGGCUG G CAGCUCUC
1703
GAGAGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCCUGC
3602

2331
GGCUGGCA G CUCUCCAG
1704
CUGGAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCAGCC
3603

2339
GCUCUCCA G UCAGGAGG
1705
CCUCCUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAGAGC
3604

2343
UCCAGUCA G GAGGCAUA
2983
UAUGCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGACUGGA
3605

2344
CCAGUCAG G AGGCAUAG
2984
CUAUGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGACUGG
3606

2346
AGUCAGGA G GCAUAGUU
2985
AACUAUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUGACU
3607

2347
GUCAGGAG G CAUAGUUU
1706
AAACUAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCUGAC
3608

2352
GAGGCAUA G UUUUUAGU
1707
ACUAAAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUGCCUC
3609

2359
AGUUUUUA G UGAACAAU
1708
AUUGUUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAAAAACU
3610

2361
UUUUUAGU G AACAAUCA
2986
UGAUUGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUAAAAA
3611

2372
CAAUCAAA G CACUUGGA
1709
UCCAAGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGAUUG
3612

2378
AAGCACUU G GACUCUUG
2987
CAAGAGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGUGCUU
3613

2379
AGCACUUG G ACUCUUGC
2988
GCAAGAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAGUGCU
3614

2386
GGACUCUU G CUCUUUCU
1710
AGAAAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGAGUCC
3615

2400
UCUACUCU G AACUAAUA
2989
UAUUAGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGUAGA
3616

2411
CUAAUAAA G CUGUUGCC
1711
GGCAACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUAUUAG
3617

2414
AUAAAGCU G UUGCCAAG
1712
CUUGGCAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUUUAU
3618

2417
AAGCUGUU G CCAAGCUG
1713
CAGCUUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AACAGCUU
3619

2422
GUUGCCAA G CUGGACGG
1714
CCGUCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGCAAC
3620

2425
GCCAAGCU G GACGGCAC
2990
GUGCCGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUUGGC
3621

2426
CCAAGCUG G ACGGCACG
2991
CGUGCCGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCUUGG
3622

2429
AGCUGGAC G GCACGAGC
2992
GCUCGUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUCCAGCU
3623

2430
GCUGGACG G CACGAGCU
1715
AGCUCGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUCCAGC
3624

2434
GACGGCAC G AGCUCGUG
2993
CACGAGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUGCCGUC
3625

2436
CGGCACGA G CUCGUGCC
1716
GGCACGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGUGCCG
3626

Input Sequence = NM_021975. Cut Site = G/. Arm Length = 8. Core Sequence = GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG NM_021975 (Homo sapiens p65 RelA (NFKB), mRNA; 2444 bp)

[0262]

7

TABLE VII

Human REL-A Nucleic Acid and Target molecules

Pos
Target
Seq ID
RPI#
Enzymatic Nucleic Acid
Seq ID
Alias

262
CCACCAUCAAGAUCA
3627
6167
UGAUCUUCUGAUGAGGCCG
3770
NFKB-262 Rz-7

AAAGGCCGAAAUGGUGG

303
GCAUCUCCCUGGU
3628
6168
ACCAGGCUGAUGAGGCCGA
3772
NFKB-303 Rz-6

AAGGCCGAAAGAUGC

508
CCAAGUUCCUAUA
3629
6169
UAUAGGCUGAUGAGGCCGA
3772
NFKB-508 Rz-6

AAGGCCGAAACUUGG

661
CGAGCUCAAGAUC
3630
6170
GAUCUUCUGAUGAGGCCGA
3773
NFKB-661 Rz-6

AAGGCCGAAAGCUCG

759
AGGUGUAUUUCAC
3631
6171
GUGAAACUGAUGAGGCCGA
3774
NFKB-759 Rz-6

AAGGCCGAAACACCU

883
CGUGUCUCCAU
3632
6172
AUGGACUGAUGAGGCCGAA
3775
NFKB-883 Rz-5

AGGCCGAAACACG

1028
AAGAGUCCUUUCA
3633
6173
UGAAAGCUGAUGAGGCCGA
3776
NFKB-1028 Rz-6

AAGGCCGAAACUCUU

1579
GCUAUAACUCG
3634
6174
CGAGUCUGAUGAGGCCGAA
3777
NFKB-1579 Rz-5

AGGCCGAAAUAGC

1683
ACUUCUCOUCCAU
3635
6175
AUGGAGCUGAUGAGGCCGA
3778
NFKB-1683 Rz-6

AAGGCCGAAAGAAGU

1726
GUCAGAUCAGCUCCU
3636
6176
AGGAGCUCUGAUGAGGCCG
3779
NFKB-1726 Rz-7

AAAGGCCGAAAUCUGAC

413
CCACAGUUUCCAGA
3637
6178
UCUGGAAGAAGUGGACCAGAGAAAC
3780
NFKB-413 HP-4/6

ACACGUUGUGGUACAUUACCUGGUA

159
ACAGAUACCACCA
3638
24047
usgsgsusggcUGAuGagg
3781
NFKB-159 Rz-6 allyl stab1

ccguuaggccGaaAucuguB

159
CACAGAUACCACCAA
3639
24048
ususgsgsuggcUGAuGag
3782
NFKB-159 Rz-7 allyl stab1

gccguuaggccGaaAucugugB

196
AUGGCUACACAGG
3640
24049
cscsusgsugcUGAuGagg
3783
NFKB-196 Rz-6 allyl stab1

ccguuaggccGaaAgccauB

581
CGAGCUCAAGAUC
3630
24050
gsasuscsuucUGAuGagg
3784
NFK8-581 Rz-6 allyl stab1

ccguuaggccGaaAgcucgB

581
CCGAGCUCAAGAUCU
3641
24051
asgsasuscuucUGAuGag
3785
NFKB-581 Rz-7 allyl stab1

gccguuaggccGaaAgcucggB

679
AGGUGUAUUUCAC
3631
24052
gsusgsasaacUGAuGaggccg
3786
NFKB-679 Rz-6 allyl stab1

uuaggccGaaAcaccuB

682
UGUAUUUCACGGG
3642
24053
cscscsgsugcUGAuGaggccg
3787
NFKB-682 Rz-6 allyl stab1

uuaggccGaaAauacaB

682
GUGUAUUUCACGGGA
3643
24054
uscscscsgugcUGAuGaggcc
3788
NFKB-682 Rz-7 allyl stab1

guuaggccGaaAauacacB

683
UGUAUUUCACGGGAC
3644
24055
gsuscscscgucUGAuGaggcc
3789
NFKB-683 Rz-7 allyl stab1

guuaggccGaaAaauacaB

712
GAGGCUCCUUUUC
3645
24056
gsasasasagcUGAuGaggccg
3790
NFKB-712 Rz-6 allyl stab1

uuaggccGaaAgccucB

754
UUGUGUUCCGGAC
3646
24057
gsuscscsggcUGAuGaggccg
3791
NFKB-754 Rz-6 allyl stab1

uuaggccGaaAcacaaB

925
AGACCUUCAAGAG
3647
24058
csuscsusugcUGAuGaggcog
3792
NFKB-925 Rz-6 allyl stab1

uuaggccGaaAggucuB

1022
UUCUGUCCCCAAG
3648
24059
csususgsggcUGAuGaggccg
3793
NFKB-1022 Rz-6 allyl stab1

uuaggccGaaAcagaaB

1022
CUUCUGUCCCCAAGC
3649
24060
gscsususgggcUGAuGaggcc
3794
NFKB-1022 Rz-7 allyl stab1

guuaggccGaaAcagaagB

1486
UGGAGUACOCUGA
3650
24061
uscsasgsggcUGAuGaggccg
3795
NFKB-1486 Rz-6 allyl stab1

uuaggccGaaAcuccaB

1600
GACUUCUCCUCCAUU
3651
24062
asasusgsgagcUGAUGaggcc
3796
NFkB-1600 Rz-7 allyl stab1

guuaggccGaaAgaagucB

1603
UUCUCCUCCAUUGCG
3652
24063
csgscsasaugcUGAuGaggccg
3797
NFKB-1603 Rz-7 allyl stab1

uuaggccGaaAggagaaB

1643
GUCAGAUCAGCUCCU
3636
24064
asgsgsasgcucuGAuGaggccg
3798
NFKB-1643 Rz-7 allyl stab1

uuaggccGaaAucugacB

2383
UGGACUCUUGCUC
3653
24065
gsasgscsaacuGAuGaggccgu
3799
NFKB-2383 Rz-6 allyl stab1

uaggccGaaAguccaB

2383
UUGGACUCUUGCUCU
3654
24066
asgsasgscaacUGAuGaggccg
3800
NFKB-2383 Rz-7 allyl stab1

uuaggccGaaAguccaaB

2385
GACUCUUGCUCUU
3655
24067
asasgsasgccUGAuGaggccgu
3801
NFKB-2385 Rz-6 allyl stab1

uaggccGaaAgagucB

2385
GGACUCUUGCUCUUU
3656
24068
asasasgsagccUGAuGaggccg
3802
NFKB-2385 Rz-7 allyl stab1

uuaggccGaaAgaguccB

2389
CUUGCUCUUUCUA
3657
24069
usasgsasaacUGAuGaggccgu
3803
NFKB-2389 Rz-6 allyl stab1

uaggccGaaAgcaagB

control
ACGACUCGUUCGA
3658
24070
uscsgsasaccUAGuGacgcc
3804
NFKB-CtrI Rz-6 allyl (SAC)

guuaggcgGaaAgucguB

control
AGCCUGUAUACCGCG
3659
24071
csgsosgsguacUAGUGacg
3805
NFKB-CtrI Rz-7 allyl (SAC)

ccguuaggcgGaaAcaggcuB

162
GAUACCACCAAGA
3660
24092
uscsususggcUGAuGaggccg
3806
NFKB-162 CHz-6 allyl stab1

uUaggccGaaIguaucB

162
AGAUACCACCAAGAC
3661
24093
gsuscsusuggoUGAUGaggc
3807
NFKB-162 CHz-7 allyl stab1

cguuaggccGaaIguaucuB

180
CCCACCAUCAAGA
3662
24094
uscsususgacUGAuGaggcc
3808
NFKB-180 CHz-6 allyl stab1

guuaggccGaaIgugggB

183
ACCAUCAAGAUCA
3663
24095
usgsasuscucUGAuGaggcc
3809
NFKB-183 CHz-6 allyl stab1

guuaggccGaaIaugguB

183
CACCAUCAAGAUCAA
3664
24096
ususgsasuoucUGAuGaggc
3810
NFKB-183 CHz-7 allyl stab1

cguuaggcoGaaIauggugB

189
AAGAUCAAUGGCU
3665
24097
asgscscsaucUGAuGaggccg
3811
NFKB-189 CHz-6 allyl stab1

uuagccGaaIaucuuB

189
CAAGAUCAAUGGCUA
3666
24098
usasgscscaucUGAuGaggc
3812
NFKB-189 CHz-7 allyl stab1

cguuaggccGaaIaucuugB

195
AAUGGCUACACAG
3667
24099
csusgsusgucUGAuGaggcc
3813
NFKB-195 CHz-6 allyl stab1

guuaggccGaaIccauuB

195
CAAUGGCUACACAGG
3668
24100
cscsusgsugucUGAuGaggcc
3814
NFKB-195 CHz-7 allyl stab1

guuaggccGaaIccauugB

285
GACUGCCGGGAUG
3669
24101
csasuscscccUGAuGaggcc
3815
NFKB-285 CHz-6 allyl stab1

guuaggccGaaIcagucB

480
CUCUGCUUCCAGG
3670
24102
cscsusgsgacUGAuGaggcc
3816
NFKB-480 CHz-6 allyl stab1

guuaggocGaalcagagB

491
GGUGACAGUGCGG
3671
24103
cscsgscsaccUGAuGaggcc
3817
NFKB-491 CHz-6 allyl stab1

guuaggccGaaIucaccB

491
AGGUGACAGUGCGGG
3672
24104
cscscsgscaccUGAUGaggcc
3818
NFKB-491 CHz-7 allyl stab1

guuaggccGaaIucaccuB

575
CACUGCCGAGCUC
3673
24105
gsasgscsuccUGAuGaggcc
3819
NFKB-575 CHz-6 allyl stab1

guuaggccGaaIcagugB

575
ACACUGCCGAGCUCA
3674
24106
usgsasgscuccUGAuGaggcc
3820
NFKB-575 CHz-7 allyl stab1

guuaggccGaaIcaguguB

580
CCGAGCUCAAGAU
3675
24107
asuscsusugcUGAUGaggcc
3821
NFKB-580 CHz-6 allyl stab1

guuaggccGaaIcucggB

582
GAGCUCAAGAUCU
3676
24108
asgsasuscuoUGAuGaggccg
3822
NFKB-582 CHz-6 allyl stab1

uuaggccGaaIagcucB

658
AGGUGCAGAAAGA
3677
24109
uscsususuccUGAuGaggcc
3823
NFKB-658 CHz-6 allyl stab1

guuaggccGaaIcaccuB

684
GUAUUUCACGGGACC
3678
24110
gsgsuscsccgcUGAuGaggcc
3824
NFKB-684 CHz-7 allyl stab1

guuaggcoGaaIaaauaaB

692
GGGACCAGGCUGG
3679
24111
cscsasgscccUGAuGaggcc
3825
NFKB-692 CHz-6 allyl stab1

guuaggccGaaIgucccB

746
AGUGGCCAUUGUG
3680
24112
csascsasaucUGAuGaggcc
3826
NFkB-746 CHz-6 allyl stab1

guuaggcoGaaIccacuB

746
AAGUGGCCAUUGUGU
3681
24113
as0sascsaucUGAuGaggccg
3827
NFKB-746 CHz-7 allyl stab1

uuaggccGaaIccacuuB

747
GUGGCCAUUGUGU
3682
24114
ascsascsaacUGAuGaggcc
3828
NFKB-747 CHz-6 allyl stab1

guuaggccGaaIgccacB

747
AGUGGCCAUUGUGUU
3683
24115
assscsascaacUGAuGaggc
3829
NFkB-747 CHz-7 allyl stab1

cguuaggccGaaIgccacuB

807
GUCUCCAUGOAGO
3684
24116
gscsusgscacUGAuGaggcc
3830
NFKB-807 CHz-6 allyl stab1

guuaggccGaalgagacB

847
GUGAGCCCAUGGA
3685
24117
uscscsasugcUGAuGaggcc
3831
NFKB-847 CHz-6 allyl stab1

guuaggccGaaIcucacB

864
CAGUACCUGOCAG
3686
24118
csusgsgscacUGAuGaggccg
3832
NFKB-864 cHz-6 allyl stab1

uuaggcCGaaIUaCUgB

864
CCAGUACCUGCCAGA
3687
24119
uscsusgsgcacUGAuGaggcc
3833
NFKB-864 CHz-7 allyl stab1

guuaggccGaaIuacuggB

914
AAGGACAUAUGAG
3688
24120
csuscsasuacUGAuGaggccg
3834
NFKB-914 CHz-6 allyl stab1

uuaggccGaaIuccuuB

914
AAAGGACAUAUGAGA
3689
24121
uscsuscsauacUGAuGaggcc
3835
NFKB-914 CHz-7 allyl stab1

guuaggccGaaIuccuuuB

1023
UCUGUCCCCAAGC
3690
24122
gscsususggcUGAuGaggccg
3836
NFKB-1023 CHz-6 allyl stab1

uuaggccGaaIacagaB

1024
CUGUCCCCAAGCC
3691
24123
gsgsosusugcUGAUGaggccg
3837
NFKB-1024 CHz-6 allyl stab1

uuaggccGaaIgacagB

1024
UCUGUCCCCAAGCCA
3692
24124
usgsgscsuugcUGAuGaggcc
3838
NFKB-1024 CHz-7 allyl stab1

guuaggccGaaIgacagaB

1071
AGCACCAUCAACU
3693
24125
asgsususgacUGAuGaggccg
3839
NFKB-1071 CHz-6 allyl stab1

uuaggccGaaIgugcuB

1347
GAAGACCUGGGGG
3694
24126
cscscscscacUGAuGaggccg
3840
NFKB-1347 CHz-6 allyl stab1

uuaggccGaaIucuucB

1347
UGAAGACCUGGGGGC
3695
24127
gscscscsccacUGAuGaggcc
3841
NFKB-1347 CHz-7 allyl stab1

guuaggccGaaIucuucaB

1371
AACAGCACAGACC
3696
24128
gsgsuscsugcUGAuGaggccg
3842
NFKB-1371 CHz-6 allyl stab1

uuaggccGaaIcuguuB

1371
CAACAGCACAGACCC
3697
24129
gsgsgsusCugCUGAUGaggcc
3843
NFKB-1371 CHz-7 allyl stab1

guuaggccGaaIcuguugB

1373
CAGCACAGACCCA
3698
24130
usgsgsgsuccUGAuGaggccg
3844
NFKB-1373 CHz-6 allyl stab1

uuaggccGaaIugcugB

1373
ACAGCACAGACCCAG
3699
24131
csusgsgsguccUGAuGaggcc
3845
NFKB-1373 CHz-7 allyl stab1

guuaggccGaaIugcuguB

1389
GUGUUCACAGACC
3700
24132
gsgsuscsugcUGAUGaggccg
3846
NFKB-1389 CHz-6 allyl stab1

uuaggccGaaIaacacB

1391
GUUCACAGACCUG
3701
24133
csasgsgsuccUGALIGaggcc
3847
NFKB-1391 CHz-6 allyl stab1

guuaggccGaaIugaacB

1391
UGUUCACAGACCUGG
3702
24134
cscsasgsguccUGAuGaggcc
3848
NFKB-1391 CHz-7 allyl stab1

guuaggccGaaIugaacaB

1395
ACAGACCUGGCAU
3703
24135
asusgscscacUGAuGaggccg
3849
NFKB-1395 CHz-6 allyl stab1

uuaggccGaaIucuguB

1395
CACAGACCUGGCAUC
3704
24136
gsasusgsccacUGAuGaggcc
3850
NFKB-1395 CHz-7 allyl stab1

guuaggccGaaIucugugB

1396
CAGACCUGGCAUC
3705
24137
gsasusgscccUGAuGaggccg
3851
NFKB-1396 CHz-6 allyl stab1

uuaggccGaaIgucugB

1601
ACUUCUCCUCCAUUG
3706
24138
csasasusggacUGAuGaggcc
3852
NFKB-1 601 CHz-7 allyl stab1

guuaggccGaaIagaaguB

1602
CUUCUCCUCCAUUGC
3707
24139
gsosasasuggcUGAuGaggcc
3853
NFKB-1602 CHz-7 allyl stab1

guuaggccGaalgagaagB

1604
UCUCCUCCAUUGCGG
3708
24140
cscsgscsaaucUGAuGaggcc
3854
NFKB-1604 CHz-7 allyl stab1

guuaggccGaalaggagaB

1605
UCCUCCAUUGCGG
3709
24141
cscsgscsaacUGAuGaggccg
3855
NFKB-1605 CHz-6 allyl stab1

uuaggccGaalgaggaB

1614
GCGGACAUGGACU
3710
24142
asgsuscscacUGAuGaggccg
3856
NFKB-1614 CHz-6 allyl stab1

uuaggccGaaIuccgcB

1614
UGCGGACAUGGACUU
3711
24143
asasgsusccacUGAuGaggcc
3857
NFKB-1614 CHz-7 allyl stab1

guuaggccGaaIuccgcaB

1644
CAGAUCAGCUCCU
3712
24144
asgsgsasgccUGAUGaggccg
3858
NFKB-1644 CHz-6 allyl stab1

uuaggccGaaIaucugB

1644
UCAGAUCAGCUCCUA
3713
24145
usasgsgsagCcUGALIGaggc
3859
NFKB-1644 CHz-7 allyl stab1

cguuaggccGaaIaucugaB

2382
UUGGACUCUUGCU
3714
24146
asgscsasagcUGAuGaggccg
3860
NFKB-2382 CHz-6 allyl stab1

uuaggccGaaluccaaB

2384
GGACUCUUGCUCU
3715
24147
asgsasgscacUGAuGaggccg
3861
NFKB-2384 CHz-6 allyl stab1

uuaggccGaaIaguccB

2384
UGGACUCUUGCUCUU
3716
24148
asasgsasgcacUGAuGaggcc
3862
NFKB-2384 CHz-7 allyl stab1

guuaggccGaaIaguccaB

2388
UCUUGOUCUUUCU
3717
24149
asgsasasagcUGAuGaggccg
3863
NFKB-2388 CHz-6 allyl stab1

uuaggccGaaIcaagaB

2388
CUCUUGCUCUUUCUA
3718
24150
usasgsasaagcUGAuGaggcc
3864
NFKB-2388 CHz-7 allyl stab1

guuaggccGaalcaagagB

Control
CUAUGCUACGGCA
3719
24151
usgscscsgucUAGuGacgcc
3865
NFKB-Ctrl CHz-6 allyl (SAC)

guuaggCgGaaIGauagB

Control
AUGCUCCCGGGUCAA
3720
24152
ususgsasccccUAGuGacgc
3866
NFKB-Ctrl CHz-7 allyl (SAC)

cguuaggcgGaaIgagcauB

193
AUCAAUGGCUACACA
3721
24184
usgsusgsuaggccgaaa
3867
NFKB-193 Zin.Rz-7 amino

ggCgagugaGguCucauugauB

358
UCOAGUGUGUGAA
3722
24185
ususcsascagccgaaa
3868
NFKB-358 Zin.Rz-6 amino

ggCgagUgaGguCuacuggaB

358
AUCCAGUGUGUGAAG
3723
24186
csususcsacagccgaaa
3869
NFKB-358 Zin.Rz-7 amino

ggCgagugaGguCuacuggauB

360
CCAGUGUGUGAAGAA
3724
24187
ususcsusucagccgaaa
3870
NFKB-360 Zin.Rz-7 amino

ggCgagugaGguCuacacuggB

486
UUCCAGGUGACAG
3725
24188
csusgsuscagccgaaa
3871
NFKB-486 Zin.Rz-6 amino

ggCgagugaGguCucuggaaB

486
cuuCCAGGUGACAGU
3726
24189
ascsusgsucagccgaaa
3872
NFKB-486 Zin.Rz-7 amino

ggCgagugaGguCucuggaagB

492
GUGACAGUGCGGG
3727
24190
cscscsgscagccgaaa
3873
NFKB-492 Zin.Rz-6 amino

ggCgagugaGguCuugucacB

492
GGUGACAGUGCGGGA
3728
24191
uscscscsgcagccgaaa
3874
NFKB-492 Zin.Rz-7 amino

ggCgagugaGguCuugucaccB

494
GACAGUGCGGGAC
3729
24192
gsuscscscggccgaaa
3875
NFKB-494 Zin.Rz-6 amino

ggCgagugaGguCuacugucB

494
UGACAGUGCGGGACC
3730
24193
gsgsuscsccggccgaaa
3876
NFKB-494 Zin.Rz-7 amino

ggCgagugaGguCuacugucaB

573
AACACUGCCGAGC
3731
24194
gscsuscsgggccgaaag
3877
NFKB-573 Zin.Rz-6 amino

ggCgagugaGguCuagugggB

573
CAACACUGCCGAGCU
3732
24195
asgscsuscgggccgaaa
3878
NFKB-573 Zin.Rz-7 amino

ggCgagugaGguguaguguugB

578
UGCCGAGCUCAAG
3733
24196
csususgsaggccgaaa
3879
NFKB-578 Zin.Rz-6 amino

ggCgagugaGguCuucggcaB

578
CUGCCGAGCUCAAGA
3734
24197
uscsususgaggccgaaa
3880
NFKB-578 Zin.Rz-7 amino

ggCgagugaGguCuucggcagB

654
GACAAGGUGCAGA
3735
24198
uscsusgscagccgaaa
3881
NFKB-654 Zin.Rz-6 amino

C
gggagugaGguCucuugucB

656
ACAAGGUGCAGAAAG
3736
24199
csusususcuggccgaaa
3882
NFKB-656 Zin.Rz-7 amino

ggCgagugaGguCuaccuuguB

677
UGAGGUGUAUUUC
3737
24200
gsasasasuagccgaaa
3883
NFKB-677 Zin.Rz-6 amino

ggCgagugaGguCuaccucaB

750
GCCAUUGUGUUCC
3738
24201
gsgsasascagccgaaa
3884
NFKB-750 Zin.Rz-6 amino

ggCgagugaGguCuaauggcB

750
GGCCAUUGUGUUCCG
3739
24202
csgsgsasacagccgaaa
3885
NFKB-750 Zin.Rz-7 amino

ggCgagugaGguCuaauggccB

752
CCAUUGUGUUCCGGA
3740
24203
uscscsgsgaagccgaaa
3886
NFKB-752 Zin.Rz-7 amino

ggCgagugaGguCuaCaauggB

1475
GCCCAUGCUGAUG
3741
24204
csasuscsaggccgaaa
3887
NFKB-1 475 Zin.Rz-6 amino

ggCgagugaGguCuaugggcB

1645
CAGAUCAGCUCCUAA 3742
24205
ususasgsgaggccgaaa
3888
NFKB-1 645 Zin.Rz-7 amino

ggCgagugaGguCuugaucugB

2386
ACUCUUGCUCUUU
3743
24206
asasasgsaggccgaaa
3889
NFKB-2386 Zin.Rz-6 amino

ggCgagugaGguCuaagaguB

2386
GACUCUUGCUCUUUC 3744
24207
gsasasasgaggccgaaa
3890
NFKB-2386 Zin.Rz-7 amino

ggCgagugaGguCuaagagucB

Control
UCCGACGCGAAUU
3745
24208
asasususcggccgaaa
3891
NFKB-ctrl Zin. Rz-6 (SAC)

ggCuCugGagugaggucggaB

Control
ACAUGACGUCCGUGC
3746
24209
gscsascsggagccgaaa
3892
NFKB-ctrl Zin.Rz-7 (SAC)

ggCuCugGagugaggucauguB

269
ACGAGCUUGUAGGAA
3747
24367
uuccuaccUGAUGAggc
3893
NFKB-269 Rz-7 Ome stab1

cguuaggccGAAAgcucguB

536
CUGUCCUUUCUCAUC
3748
24368
gaugagaoUGAUGAggc
3894
NFKB-536 Rz-7 Ome stab1

cguuaggcoGAAAggacagB

671
AGGACAUUGAGGUGU
3749
24369
acaccuccUGAUGAggc
3895
NFKB-671 Rz-7 Ome stab1

cguuaggccGAAAuguccuB

951
GAGUCCUUUCAGCGG
3750
24370
ccgcugacUGAUGAggcc
3896
NFKB-951 Rz-7 Ome stab1

guuaggccGAAAggacucB

2391
UUGCUCUUUCUACUC
3751
24371
gaguagacUGAUGAggccg
3897
NFKB-2391 Rz-7 Ome stab1

uuaggccGAAAgagcaaB

327
CCGCUGCAUCCACAG
3752
24372
cuguggacUGAUGAggccg
3898
NFKB-327 CHz-7 Ome stab1

uuaggccGAAIcagcggB

535
CCUGUCCUUUCUCAU
3753
24373
augagaacUGAUGAggccg
3899
NFKB-535 CHz-7 Ome stab1

uuaggccGMIgacaggB

1062
GUCAUCOCUGAGOAC
3754
24374
gugcucacUGAuGAggccg
3900
NFKB-1062 CHz-7 Ome stab1

uuaggccGpAIgaugacB

1114
UCUGGGCAGAUCAGC
3755
24375
gcugauccUGAUGAggccg
3901
NFKB-1114 CHz-7 Ome stab1

uuaggccGMIcccagaB

1231
CCUGUCCCAGUCCUA
3756
24376
uaggacucUGAUGAggccg
3902
NFKB-1231 CHz-7 Ome stab1

uuaggccGMIgacaggB

325
GACCGCUGCAUCCAC
3757
24377
guggauggccgaaaggC
3903
NFKB-325 Zin.Rz-7 amino

gagugaGGuCuagcggucB

368
UGAAGAAGCGGGAcC
3758
24378
ggucocggccgaaaggC
3904
NFKB-368 Zin.Rz-7 amino

gagugaGGuCuuucuucaB

799
CCUGUGCGUGUCUCC
3759
24379
ggagacagccgaaaggC
3905
NFKB-799 Zin.Rz-7 amino

gagugaGGuCugcacaggB

801
UGUGCGUGUCUCCAU
3760
24380
auggagagccgaaaggC
3906
NFKB-801 Zin.Rz-7 amino

gagugaGGuCuacgcacaB

1233
UGUCCCAGUCCUAGC
3761
24381
gcuaggagccgaaaggC
3907
NFKB-1233 Zin.Rz-7 amino

gagugaGGuCuugggacaB

157
AGCACAGAUACCACC
3762
24382
ggugguaGGcTAGcTAc
3908
NFKB-1 57 Dz-7

AAcGAcugugcuB

190
AAGAUCAAUGGCUAC
3763
24383
guagccaGGcTAGcTAc
3909
NFKB-1 90 Dz-7

AAcGAugaucuuB

399
UCAGCGCAUCCAGAC
3764
24384
gucuggaGGcTAGcTAc
3910
NFKB-399 Dz-7

AAcGAgcgcugaB

799
CCUGUGCGUGUCUCC
3759
24385
ggagacaGGcTAGcTAc
3911
NFKB-799 Dz-7

AAcGAgcacaggB

1614
UGCGGACAUGGACUU
3711
24386
aaGUccaGGcTAGcTAc
3912
NFKB-1614 Dz-7

AAcGAgUccgcaB

156
GAGCACAGAUACCAC
3765
24387
gugguauGgaggaaacucCCUUCaa
3913
NFKB-156 Amb.Rz-7

ggacaucgucCGGGugugcucB

896
GGAUUGAGGAGAAAC
3766
24388
guuucucGgaggaaacucCCUUCaa
3914
NFKB-896 Amb.Rz-7

ggacaucgucCGGGucaauccB

1341
UGAUGAUGAAGACCU
3767
24389
aggucuuGgaggaaacucCCUUCaa
3915
NFKB-1 341 Amb.Rz-7

ggacaucgucCGGGaucaucaB

2314
AGAGUGGGGGAGAGC
3768
24390
gcucuccGgaggaaacucCCUUCaa
3916
NFKB-2314 Amb.Rz-7

ggacaucgucCGGGccacucuB

2318
UGGGGGAGAGCAGGC
3769
24391
gccugcuGgaggaaacucCCUUCaa
3917
NFKB-2318 Amb.Rz-7

ggacaucgucCGGGucccccaB

A, G, C, U = Ribo

A, G, C, T (italic) = deoxy

lower case = 2′-O-methyl

s = phosphorothioate 3′-internucleotide linkage

U = 2′-deoxy-2′-C-allyl uridine

U
= 2′-deoxy-2′-Amino uridine

C
= 2′-deoxy-2′-Amino cytidine

I = Inosine

B = inverted deoxyabasic derivative

[0263]

	Number	Date	Country
Parent	08291932	Aug 1994	US
Child	08777916	Dec 1996	US

	Number	Date	Country
Parent	08777916	Dec 1996	US
Child	09864785	May 2001	US
Parent	08245466	May 1994	US
Child	08291932	Aug 1994	US
Parent	07987132	Dec 1992	US
Child	08245466	May 1994	US

Enzymatic nucleic acid treatment of diseases or conditions related to levels of NF-kappa B

Information

Publication Number

Date Filed

Date Published

Inventors

CPC

US Classifications

International Classifications

Abstract

Description

Claims

Parent Case Info

Continuations (1)

Continuation in Parts (3)