ENDOGENOUS RETROVIRUSES UP-REGULATED IN PROSTATE CANCER

Abstract

uses of the HML-2 family show up-regulated expression in prostate tumors. This finding can be used in prostate cancer screening, diagnosis and therapy.

Description

[0001]All documents cited herein are incorporated by reference in their entirety.

CROSS-REFERENCE TO RELATED APPLICATION

[0002]This application is a continuation of U.S. application Ser. No. 10/016,604 filed Dec. 7, 2001, now allowed, which claims the benefit of priority of U.S. Provisional Patent Application No. 60/251,830, filed Dec. 7, 2000. Each of these applications is incorporated herein by reference in its entirety.

TECHNICAL FIELD

[0003]The present invention relates to the diagnosis of cancer, particularly prostate cancer. In particular, it relates to a subgroup of human endogenous retroviruses (HERVs) which show up-regulated expression in tumors, particularly prostate tumors.

BACKGROUND ART

[0004]Prostate cancer is the most common type of cancer in men in the USA. Benign prostatic hyperplasia (BPH) is the abnormal growth of benign prostate cells in which the prostate grows and pushes against the urethra and bladder, blocking the normal flow of urine. More than half of the men in the USA between the ages of 60 and 70 and as many as 90 percent between the ages of 70 and 90 have symptoms of BPH. Although this condition is seldom a threat to life, it may require treatment to relieve symptoms.

[0005]Cancer that begins in the prostate is called primary prostate cancer (or prostatic cancer). Prostate cancer may remain in the prostate gland, or it may spread to nearby lymph nodes and may also spread to the bones, bladder, rectum, and other organs. Prostate cancer is diagnosed by measuring the levels of prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) in the blood. The level of PSA in blood may rise in men who have prostate cancer, BPH, or an infection in the prostate. The level of PAP rises above normal in many prostate cancer patients, especially if the cancer has spread beyond the prostate. However, one cannot diagnose prostate cancer with these tests alone because elevated PSA or PAP levels may also indicate other, non-cancerous problems.

[0006]In order to help determine whether conditions of the prostate are benign or malignant further tests such as transrectal ultrasonography, intravenous pyelogram, and cystoscopy are usually performed. If these test results suggest that cancer may be present, the patient must undergo a biopsy as the only sure way to diagnose prostate cancer. Consequently, it is desirable to provide a simple and direct test for the early detection and diagnosis of prostate cancer without having to undergo multiple rounds of cumbersome testing procedures. It is also desirable and necessary to provide compositions and methods for the prevention and/or treatment of prostate cancer.

[0007]It is an object of the invention to provide materials that can be used in the prevention, treatment and diagnosis of prostate cancer. It is a further object to provide improvements in the prevention, treatment and diagnosis of prostate cancer.

DISCLOSURE OF THE INVENTION

[0008]It has been found that human endogenous retroviruses (HERVs) of the HML-2 subgroup of the HERV-K family show up-regulated expression in prostate tumors. This finding can be used in prostate cancer screening, diagnosis and therapy.

[0009]The invention provides a method for diagnosing cancer, especially prostate cancer, the method comprising the step of detecting the presence or absence of an expression product of a HML-2 endogenous retrovirus in a patient sample. Higher levels of expression product relative to normal tissue indicate that the patient from whom the sample was taken has cancer.

[0010]The HML-2 expression product which is detected is either a mRNA transcript or a polypeptide translated from such a transcript. These expression products may be detected directly or indirectly. A direct test uses an assay which detects HML-2 RNA or polypeptide in a patient sample. An indirect test uses an assay which detects biomolecules which are not directly expressed in vivo from HML-2 e.g. an assay to detect cDNA which has been reverse-transcribed from a HML-2 mRNA, or an assay to detect an antibody which has been raised in response to a HML-2 polypeptide.

[0011]A--The Patient Sample

[0012]Where the diagnostic method of the invention is based on HML-2 mRNA, the patient sample will generally comprise cells, preferably, prostate cells. These may be present in a sample of tissue, preferably, prostate tissue, or may be cells, preferably, prostate cells which have escaped into circulation (e.g. during metastasis). Instead of or as well as comprising prostate cells, the sample may comprise virions which contain mRNA from HML-2.

[0013]Where the diagnostic method of the invention is based on Hml-2 polypeptides, the patient sample may comprise cells, preferably, prostate cells and/or virions (as described above for mRNA), or may comprise antibodies which recognize HML-2 polypeptides. Such antibodies will typically be present in circulation.

[0014]In general, therefore, the patient sample is tissue sample (e.g. a biopsy), preferably, a prostate sample (e.g. a biopsy) or a blood sample.

[0015]The patient is generally a human, preferably human male, and more preferably an adult human male.

[0016]Expression products may be detected in the patient sample itself, or it may be detected in material derived from the sample (e.g. the supernatant of a cell lysate, or a RNA extract, or cDNA generated from a RNA extract, or polypeptides translated from a RNA extract, or cells derived from culture of cells extracted from a patient etc.). These are still considered to be "patient samples" within the meaning of the invention.

[0017]Methods of the invention can be conducted in vitro or in vivo.

[0018]Other possible sources of patient samples include isolated cells, whole tissues, or bodily fluids (e.g. blood, plasma, serum, urine, pleural effusions, cerebro-spinal fluid, etc.)

[0019]B--The mRNA Expression Product

[0020]Where the diagnostic method of the invention is based on mRNA detection, it typically involves detecting a RNA comprising six basic regions. From 5' to 3', these are:

[0021]1. A sequence which has at least 75% identity to SEQ ID NO:155 (e.g. 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% identity); or a sequence which has at least 50% identity to SEQ ID NO:155 (e.g. 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% identity) and is expressed at least 1.5 fold (e.g. 2, 2.5, 5, 10, 20, 50, etc., fold) higher level relative to expression in a normal (i.e., non cancerous) cell with at least a 95% confidence level; or a sequence which has at least 80% identity (e.g. 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% identity) to at least a 20 contiguous nucleotide fragment (e.g. 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 125, 130, 135, 140, 145, etc., contiguous nucleotides) of SEQ ID NO:155; or a sequence which has at least 80% identity (e.g. 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% identity) to at least a 20 contiguous nucleotide fragment (e.g. 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 125, 130, 135, 140, 145, etc., contiguous nucleotides) of SEQ ID NO:155 and is expressed at least 1.5 fold (e.g. 2, 2.5, 5, 10, 20, 50, etc., fold) higher level relative to expression in a normal (i.e., non cancerous) cell with at least a 95% confidence level. This sequence will typically be at the 5' end of the RNA. SEQ ID NO:155 is the nucleotide sequence of the start of R region in the LTR of the `ERVK6` HML-2 virus [ref 1]. This portion of the R region is found in all full-length HML-2 transcripts.

[0022]2. A downstream region comprising a sequence which has at least 75% sequence identity to SEQ ID NO:156 (e.g. 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% identity); or a sequence which has at least 50% identity to SEQ ID NO:156 (e.g. 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% identity) and is expressed at least 1.5 fold (e.g. 2, 2.5, 5, 10, 20, 50, etc., fold) higher level relative to expression in a normal (i.e., non cancerous) cell with at least a 95% confidence level; or a sequence which has at least 80% identity (e.g. 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% identity) to at least a 20 contiguous nucleotide fragment (e.g. 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, etc., contiguous nucleotides) of SEQ ID NO:156; or a sequence which has at least 80% identity (e.g. 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% identity) to at least a 20 contiguous nucleotide fragment (e.g. 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, etc., contiguous nucleotides) of SEQ ID NO:156 and is expressed at least 1.5 fold (e.g. 2, 2.5, 5, 10, 20, 50, etc., fold) higher level relative to expression in a normal (i.e., non cancerous) cell with at least a 95% confidence level. SEQ ID NO:156 is the nucleotide sequence of the RU5 region downstream of SEQ ID NO:155 in the ERVK6 LTR. This region is found in full-length HML-2 transcripts, but may not be present in all mRNAs transcribed from a HML-2 LTR promoter.

[0023]3. A downstream region comprising a sequence which has at least 75% sequence identity to SEQ ID NO:6 (e.g. 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% identity); or a sequence which has at least 50% identity to SEQ ID NO:6 (e.g. 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% identity) and is expressed at least 1.5 fold (e.g. 2, 2.5, 5, 10, 20, 50, etc., fold) higher level relative to expression in a normal (i.e., non cancerous) cell with at least a 95% confidence level; or a sequence which has at least 80% identity (e.g. 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% identity) to at least a 20 contiguous nucleotide fragment (e.g. 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, etc., contiguous nucleotides) of SEQ ID NO:6; or a sequence which has at least 80% identity (e.g. 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% identity) to at least a 20 contiguous nucleotide fragment (e.g. 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, etc., contiguous nucleotides) of SEQ ID NO:6 and is expressed at least 1.5 fold (e.g. 2, 2.5, 5, 10, 20, 50, etc., fold) higher level relative to expression in a normal (i.e., non cancerous) cell with at least a 95% confidence level. SEQ ID NO:6 is the nucleotide sequence of the region of the ERVK6 virus between the U5 region and the first 5' splice site. This region is found in full-length HML-2 transcripts, but has been lost by some variants and, like region 2 above, may not be present in all mRNAs transcribed from a HML-2 LTR promoter.

[0024]4. A downstream region comprising any RNA sequence. This region will typically comprise the coding sequence of one or more HML-2 polypeptides, but may alternatively comprise: a mutant viral coding sequence; a viral or non-viral non-coding sequence; or a non-viral coding sequence. Transcription of any of these sequences can come under the control of a HML-2 LTR.

[0025]5. A downstream region comprising a sequence which has at least 75% sequence identity to SEQ ID NO:5 (e.g. 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% identity); or a sequence which has at least 50% identity to SEQ ID NO:5 (e.g. 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% identity) and is expressed at least 1.5 fold (e.g. 2, 2.5, 5, 10, 20, 50, etc., fold) higher level relative to expression in a normal (i.e., non cancerous) cell with at least a 95% confidence level; or a sequence which has at least 80% identity (e.g. 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% identity) to at least a 20 contiguous nucleotide fragment (e.g. 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, etc., contiguous nucleotides) of SEQ ID NO:5; or a sequence which has at least 80% identity (e.g. 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% identity) to at least a 20 contiguous nucleotide fragment (e.g. 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, etc., contiguous nucleotides) of SEQ ID NO:5 and is expressed at least 1.5 fold (e.g. 2, 2.5, 5, 10, 20, 50, etc., fold) higher level relative to expression in a normal (i.e., non cancerous) cell with at least a 95% confidence level. SEQ ID NO:5 is the nucleotide sequence of the U3R region in the 3' end of ERVK6. This sequence will typically be near the 3' end of the RNA, immediately preceding any polyA tail.

[0026]6. A 3' polyA tail.

[0027]The percent identity of the sequences described above are determined by the Smith-Waterman algorithm using the default parameters: open gap penalty=-20 and extension penalty=-5.

[0028]These mRNA molecules are referred to below as "PCA-mRNA" molecules ("prostate cancer associated mRNA"), and endogenous viruses which express these PCA-mRNAs are referred to as PCAVs ("prostate cancer associated viruses"). Nevertheless, said PCAVs may also be associated with other types of cancer.

[0029]Although some PCA-mRNAs include all six of these regions, most HERVs are defective in that they have accumulated multiple stop codons, frameshifts, or larger deletions etc. This means that many PCA-mRNAs do not include all six regions. As all PCA-mRNAs are transcribed under the control of the same group of LTRs, however, transcription of all PCA-mRNAs is up-regulated in prostate tumors even though the mRNA may not encode functional polypeptides.

[0030]Where a mRNA to be detected is driven by 5' LTR of HML-2 in genomic DNA, the first of these regions will always be present, but the remaining five are optional. Conversely, where a mRNA to be detected is controlled by 3' LTR of HML-2, the fifth of these regions will always be present, but the remaining five are optional.

[0031]In general, therefore, the mRNA to be detected has the formula N₁--N₂--N₃--N₄N₅--polyA, wherein: [0032]N1 has at least 75% sequence identity to SEQ ID NO:155; or has at least 50% identity to SEQ ID NO:155 and is expressed at least 1.5 fold higher relative to expression in a normal (i.e., non cancerous) cell with at least a 95% confidence level; or has at least 80% identity to at least a 20 contiguous nucleotide fragment of SEQ ID NO:155; or has at least 80% identity to at least a 20 contiguous nucleotide fragment of SEQ ID NO:155 and is expressed at least 1.5 fold higher relative to expression in a normal (i.e., non cancerous) cell with at least a 95% confidence level; [0033]N2 has at least 75% sequence identity to SEQ ID NO:156; or has at least 50% identity to SEQ ID NO:156 and is expressed at least 1.5 fold higher relative to expression in a normal (i.e., non cancerous) cell with at least a 95% confidence level; or has at least 80% identity to SEQ ID NO:156 and is expressed at least 1.5 fold higher relative to expression in a normal (i.e., non cancerous) cell with at least a 95% confidence level; or has at least 80% identity to at least a 20 contiguous nucleotide fragment of SEQ ID NO:156; or has at least 80% identity to at least a 20 contiguous nucleotide fragment of SEQ ID NO:156 and is expressed at least 1.5 fold higher relative to expression in a normal (i.e., non cancerous) cell with at least a 95% confidence level; [0034]N3 has at least 75% sequence identity to SEQ ID NO:6; or has at least 50% identity to SEQ ID NO:6 and is expressed at least 1.5 fold higher relative to expression in a normal (i.e., non cancerous) cell with at least a 95% confidence level; or has at least 80% identity to at least a 20 contiguous nucleotide fragment of SEQ ID NO:6; or has at least 80% identity to at least a 20 contiguous nucleotide fragment of SEQ ID NO:6 and is expressed at least 1.5 fold higher relative to expression in a normal (i.e., non cancerous) cell with at least a 95% confidence level; [0035]N4 comprises any RNA sequence; [0036]N5 has at least 75% sequence identity to SEQ ID NO:5; or has at least 50% identity to SEQ ID NO:5 and is expressed at least 1.5 fold higher relative to expression in a normal (i.e., non cancerous) cell with at least a 95% confidence level; or has at least 80% identity to at least a 20 contiguous nucleotide fragment of SEQ ID NO:5; or has at least 80% identity to at least a 20 contiguous nucleotide fragment of SEQ ID NO:5 and is expressed at least 1.5 fold higher relative to expression in a normal (i.e., non cancerous) cell with at least a 95% confidence level; and [0037]at least one of N₁, N₂, N₃, N₄ or N₅ is present, but polyA is optional.

[0038]Although only at least one of N₁, N₂, N₃, N₄ or N₅ needs to be present, it is preferred that two, three, four or five of these regions are present. It is preferred that at least one of N₁ and/or N₅ is present.

[0039]N₁ is preferably present in the mRNA to be detected (i.e. the invention is preferably based on the detection of mRNA driven by a 5' LTR). More preferably, at least N₁--N₂ is present.

[0040]Where N₁ is present, it is preferably at the 5' end of the mRNA (i.e. 5'-N₁-- . . . ).

[0041]Where N₅ is present, it is preferably immediately before a 3' polyA tail (i.e. . . . --N₅-polyA-3').

[0042]Where N₄ is present, it preferably comprises a polypeptide-coding sequence (e.g. encoding a HML-2 polypeptide). Examples of HML-2 polypeptide-coding sequences are described below.

[0043]The RNA will generally have a 5' cap.

[0044]B.1--Enriching RNA in a Sample

[0045]Where diagnosis is based on mRNA detection, the method of the invention preferably comprises an initial step of: (a) extracting RNA (e.g. mRNA) from a patient sample; (b) removing DNA from a patient sample without removing mRNA; and/or (c) removing or disrupting DNA which comprises SEQ ID NO:4, but not RNA which comprises SEQ ID NO:4, from a patient sample. This is necessary because the genomes of both normal and cancerous prostate cells contain multiple PCAV DNA templates, whereas increased PCA-mRNA levels are only found in cancerous cells. As an alternative, a RNA-specific assay can be used which is not affected by the presence of homologous DNA.

[0046]Methods for extracting RNA from biological samples are well known [e.g. refs. 2 & 8] and include methods based on guanidinium buffers, lithium chloride, SDS/potassium acetate etc. After total cellular RNA has been extracted, mRNA may be enriched e.g. using oligo-dT techniques.

[0047]Methods for removing DNA from biological samples without removing mRNA are well known [e.g. appendix C of ref. 2] and include DNase digestion.

[0048]Methods for removing DNA, but not RNA, comprising PCA-mRNA sequences will use a reagent which is specific to a sequence within a PCA-mRNA e.g. a restriction enzyme which recognizes a DNA sequence within SEQ ID NO:4, but which does not cleave the corresponding RNA sequence.

[0049]Methods for specifically purifying PCA-mRNAs from a sample may also be used. One such method uses an affinity support which binds to PCA-mRNAs. The affinity support may include a polypeptide sequence which binds to the PCAV-mRNA e.g. the cORF polypeptide, which binds to the LTR of HERV-K mRNAs in a sequence-specific manner, or HIV Rev protein, which has been shown to recognize the HERV-K LTR [3].

[0050]B.2--Direct Detection of RNA

[0051]Various techniques are available for detecting the presence or absence of a particular RNA sequence in a sample [e.g. refs. 2 & 8]. If a sample contains genomic PCAV DNA, the detection technique will generally be RNA-specific; if the sample contains no PCAV DNA, the detection technique may or may not be RNA-specific.

[0052]Hybridization-based detection techniques may be used, in which a polynucleotide probe complementary to a region of PCA-mRNA is contacted with a RNA-containing sample under hybridizing conditions. Detection of hybridization indicates that nucleic acid complementary to the probe is present. Hybridization techniques for use with RNA include Northern blots, in situ hybridization and arrays.

[0053]Sequencing may also be used, in which the sequence(s) of RNA molecules in a sample are obtained. These techniques reveal directly whether a sequence of interest is present in a sample. Sequence determination of the 5' end of a RNA corresponding to N₁ will generally be adequate.

[0054]Amplification-based techniques may also be used. These include PCR, SDA, SSSR, LCR, TMA, NASBA, T7 amplification etc. The technique preferably gives exponential amplification. A preferred technique for use with RNA is RT-PCR [e.g. see chapter 15 of ref. 2]. RT-PCR of mRNA from prostate cells is reported in references 4, 5, 6 & 7.

[0055]B.3--Indirect Detection of RNA

[0056]Rather than detect RNA directly, it may be preferred to detect molecules which are derived from RNA (i.e. indirect detection of RNA). A typical indirect method of detecting mRNA is to prepare cDNA by reverse transcription and then to directly detect the cDNA. Direct detection of cDNA will generally use the same techniques as described above for direct detection of RNA (but it will be appreciated that methods such as RT-PCR are not suitable for DNA detection and that cDNA is double-stranded, so detection techniques can be based on a sequence, on its complement, or on the double-stranded molecule).

[0057]B.4--Polynucleotide Materials

[0058]The invention provides polynucleotide materials for use in the detection of PCAV nucleic acids.

[0059]The invention provides an isolated polynucleotide comprising: (a) the nucleotide sequence N₁--N₂--N₃--N₄--N₅-polyA as defined above; (b) a fragment of at least x nucleotides of nucleotide sequence N₁--N₂--N₃--N₄--N₅ as defined above; (c) a nucleotide sequence having at least s % identity to nucleotide sequence N₁--N₂--N₃--N₄--N₅ as defined above; or (d) the complement of (a), (b) or (c). These polynucleotides include variants of nucleotide sequence N₁--N₂--N₃--N₄--N₅-polyA (e.g. degenerate variants, allelic variants, homologs, orthologs, mutants etc.).

[0060]Fragment (b) is preferably a fragment of N₁.

[0061]The value of x is at least 7 (e.g. at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, 100 etc.). The value ofx may be less than 2000 (e.g. less than 1000, 500, 100, or 50).

[0062]The value of s is preferably at least 50 (e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 99.9 etc.).

[0063]The invention also provides an isolated polynucleotide having formula 5'-A-B-C-3', wherein: -A- is a nucleotide sequence consisting of a nucleotides; -C- is a nucleotide sequence consisting of c nucleotides; -B- is a nucleotide sequence consisting of either (a) a fragment of b nucleotides of nucleotide sequence N₁--N₂--N₃--N₄--N₅ as defined above or (b) the complement of a fragment of b nucleotides of nucleotide sequence N₁--N₂--N₃--N₄--N₅ as defined above; and said polynucleotide is neither (a) a fragment of nucleotide sequence N₁--N₂--N₃--N₄--N₅ or (b) the complement of a fragment of nucleotide sequence N₁--N₂--N₃--N₄--N₅.

[0064]The -B- moiety is preferably a fragment of N₁--N₂, and more preferably a fragment of N₁. The -A- and/or -C- moieties may comprise a promoter sequence (or its complement) e.g. for use in TMA.

[0065]The value of a+c is at least 1 (e.g. at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 etc.). The value of b is at least 7 (e.g. at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 etc.). It is preferred that the value of a+b+c is at least 9 (e.g. at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 etc.). It is preferred that the value of a+b+c is at most 500 (e.g. at most 450, 400, 350, 300, 250, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60, 50, 40, 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9).

[0066]Where -B- is a fragment of N₁--N₂--N₃--N₄--N₅, the nucleotide sequence of -A- typically shares less than n % sequence identity to the a nucleotides which are 5' of sequence -B- in N₁--N₂--N₃--N₄--N₅ and/or the nucleotide sequence of --C-- typically shares less than n % sequence identity to the c nucleotides which are 3' of sequence -C- in N₁--N₂--N₃--N₄--N₅. Similarly, where -B- is the complement of a fragment of N₁--N₂--N₃--N₄--N₅, the nucleotide sequence of -A- typically shares less than n % sequence identity to the complement of the a nucleotides which are 5' of the complement of sequence -B- in N₁--N₂--N₃--N₄--N₅ and/or the nucleotide sequence of -C- typically shares less than n % sequence identity to the complement of the c nucleotides which are 3' of the complement of sequence -C- in N₁--N₂--N₃--N₄--N₅. The value of n is generally 60 or less (e.g. 50, 40, 30, 20, 10 or less).

[0067]The invention also provides an isolated polynucleotide which selectively hybridizes to a nucleic acid having nucleotide sequence N₁--N₂--N₃--N₄--N₅ as defined above or to a nucleic acid having the complement of nucleotide sequence N₁--N₂--N₃--N₄--N₅ as defined above. The polynucleotide preferably hybridizes to at least N₁.

[0068]Hybridization reactions can be performed under conditions of different "stringency". Conditions that increase stringency of a hybridization reaction of widely known and published in the art [e.g. page 7.52 of reference 8]. Examples of relevant conditions include (in order of increasing stringency): incubation temperatures of 25° C., 37° C., 50° C., 55° C. and 68° C.; buffer concentrations of 10×SSC, 6×SSC, 1×SSC, 0.1×SSC (where SSC is 0.15 M NaCl and 15 mM citrate buffer) and their equivalents using other buffer systems; formamide concentrations of 0%, 25%, 50%, and 75%; incubation times from 5 minutes to 24 hours; 1, 2, or more washing steps; wash incubation times of 1, 2, or 15 minutes; and wash solutions of 6×SSC, 1×SSC, 0.1×SSC, or de-ionized water. Hybridization techniques are well known in the art [e.g. see references 2, 8, 9, 10, 11 etc.]. Depending upon the particular polynucleotide sequence and the particular domain encoded by that polynucleotide sequence, hybridization conditions upon which to compare a polynucleotide of the invention to a known polynucleotide may differ, as will be understood by the skilled artisan.

[0069]In some embodiments, the isolated polynucleotide of the invention selectively hybridizes under low stringency conditions; in other embodiments it selectively hybridizes under intermediate stringency conditions; in other embodiments, it selectively hybridizes under high stringency conditions. An exemplary set of low stringency hybridization conditions is 50° C. and 10×SSC. An exemplary set of intermediate stringency hybridization conditions is 55° C. and 1×SSC. An exemplary set of high stringent hybridization conditions is 68° C. and 0.1×SSC.

[0070]The polynucleotides of the invention are particularly useful as probes and/or as primers for use in hybridization and/or amplification reactions.

[0071]More than one polynucleotide of the invention can hybridize to the same nucleic acid target (e.g. more than one can hybridize to a single RNA).

[0072]References to a percentage sequence identity between two nucleic acid sequences mean that, when aligned, that percentage of bases are the same in comparing the two sequences. This alignment and the percent homology or sequence identity can be determined using software programs known in the art, for example those described in section 7.7.18 of reference 11. A preferred alignment program is GCG Gap (Genetics Computer Group, Wisconsin, Suite Version 10.1), preferably using default parameters, which are as follows: open gap=3; extend gap=1.

[0073]Polynucleotides of the invention may take various forms e.g. single-stranded, double-stranded, linear, circular, vectors, primers, probes etc.

[0074]Polynucleotides of the invention can be prepared in many ways e.g. by chemical synthesis (at least in part), by digesting longer polynucleotides using restriction enzymes, from genomic or cDNA libraries, from the organism itself etc.

[0075]Polynucleotides of the invention may be attached to a solid support (e.g. a bead, plate, filter, film, slide, resin, etc.)

[0076]Polynucleotides of the invention may include a detectable label (e.g. a radioactive or fluorescent label, or a biotin label). This is particularly useful where the polynucleotide is to be used in nucleic acid detection techniques e.g. where the nucleic acid is a primer or as a probe for use in techniques such as PCR, LCR, TMA, NASBA, bDNA etc.

[0077]The term "polynucleotide" in general means a polymeric form of nucleotides of any length, which contain deoxyribonucleotides, ribonucleotides, and/or their analogs. It includes DNA, RNA, DNA/RNA hybrids, and DNA or RNA analogs, such as those containing modified backbones or bases, and also peptide nucleic acids (PNA) etc. The term "polynucleotide" is not intended to be limiting as to the length or structure of a nucleic acid unless specifically indicated, and the following are non-limiting examples of polynucleotides: a gene or gene fragment, exons, introns, mRNA, tRNA, rRNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, any isolated DNA from any source, any isolated RNA from any sequence, nucleic acid probes, and primers. Polynucleotides may have any three-dimensional structure, and may perform any function, known or unknown. Unless otherwise specified or required, any embodiment of the invention that includes a polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to make up the double stranded form.

[0078]Polynucleotides of the invention may be isolated and obtained in substantial purity, generally as other than an intact chromosome. Usually, the polynucleotides will be obtained substantially free of other naturally-occurring nucleic acid sequences, generally being at least about 50% (by weight) pure, usually at least about 90% pure.

[0079]Polynucleotides of the invention (particularly DNA) are typically "recombinant" e.g. flanked by one or more nucleotides with which it is not normally associated on a naturally-occurring chromosome.

[0080]The polynucleotides can be used, for example: to produce polypeptides; as probes for the detection of nucleic acid in biological samples; to generate additional copies of the polynucleotides; to generate ribozymes or antisense oligonucleotides; and as single-stranded DNA probes or as triple-strand forming oligonucleotides. The polynucleotides are preferably uses to detect PCA-mRNAs.

[0081]A "vector" is a polynucleotide construct designed for transduction/transfection of one or more cell types. Vectors may be, for example, "cloning vectors" which are designed for isolation, propagation and replication of inserted nucleotides, "expression vectors" which are designed for expression of a nucleotide sequence in a host cell, "viral vectors" which is designed to result in the production of a recombinant virus or virus-like particle, or "shuttle vectors", which comprise the attributes of more than one type of vector.

[0082]A "host cell" includes an individual cell or cell culture which can be or has been a recipient of exogenous polynucleotides. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in total DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation and/or change. A host cell includes cells transfected or infected in vivo or in vitro with a polynucleotide of this invention.

[0083]B.5--Nucleic Acid Detection Kits

[0084]The invention provides a kit comprising primers (e.g. PCR primers) for amplifying a template sequence contained within a PCAV nucleic acid, the kit comprising a first primer and a second primer, wherein the first primer is substantially complementary to said template sequence and the second primer is substantially complementary to a complement of said template sequence, wherein the parts of said primers which have substantial complementarity define the termini of the template sequence to be amplified. The first primer and/or the second primer may include a detectable label.

[0085]The invention also provides a kit comprising first and second single-stranded oligonucleotides which allow amplification of a PCAV template nucleic acid sequence contained in a single- or double-stranded nucleic acid (or mixture thereof), wherein: (a) the first oligonucleotide comprises a primer sequence which is substantially complementary to said template nucleic acid sequence; (b) the second oligonucleotide comprises a primer sequence which is substantially complementary to the complement of said template nucleic acid sequence; (c) the first oligonucleotide and/or the second oligonucleotide comprise(s) sequence which is not complementary to said template nucleic acid; and (d) said primer sequences define the termini of the template sequence to be amplified. The non-complementary sequence(s) of feature (c) are preferably upstream of (i.e. 5' to) the primer sequences. One or both of the (c) sequences may comprise a restriction site [12] or promoter sequence [13]. The first and/or the second oligonucleotide may include a detectable label.

[0086]The kit of the invention may also comprise a labeled polynucleotide which comprises a fragment of the template sequence (or its complement). This can be used in a hybridization technique to detect amplified template.

[0087]The primers and probes used in these kits are preferably polynucleotides as described in section B.4.

[0088]The template is preferably a sequence as defined in section B.1 above.

[0089]C--Polypeptide Expression Product

[0090]Where the method is based on polypeptide detection, it will involve detecting expression of a polypeptide encoded by a PCAV-mRNA. This will typically involve detecting one or more of the following HML-2 polypeptides: gag, prt, pol, env, cORF. Although some PCA-mRNAs encode all of these polypeptides (e.g. ERVK6 [1]), the polypeptide-coding regions of most HERVs (including PCAVs) contain mutations which mean that one or more coding-regions in the mRNA transcript are either mutated or absent. Thus not all PCAVs have the ability to encode all HML-2 polypeptides.

[0091]The transcripts which encode HML-2 polypeptides are generated by alternative splicing of the full-length mRNA copy of the endogenous genome [e.g. FIG. 4 of ref. 143].

[0092]HML-2 gag polypeptide is encoded by the first long ORF in a complete HML-2 genome [140]. Full-length gag polypeptide is proteolytically cleaved.

[0093]Examples of gag nucleotide sequences are: SEQ ID NOS:7, 8, 9 & 11 [HERV-K(CH)]; SEQ ID NO:85 [HERV-K108]; SEQ ID NO:91 [HERV-K(C7)]; SEQ ID NO:97 [HERV-K(II)]; SEQ ID NO:102 [HERV-K10].

[0094]Examples of gag polypeptide sequences are: SEQ ID NOS:46, 47, 48, 49, 56 & 57 [HERV-K(CH)]; SEQ ID NO:92 [HERV-K(C7)]; SEQ ID NO:98 [HERV-K(II)]; SEQ ID NOS:103 & 104 [HERV-K10]; SEQ ID NO:146 [`ERVK6`].

[0095]An alignment of gag polypeptide sequences is shown in FIG. 7.

[0096]HML-2 prt polypeptide is encoded by the second long ORF in a complete HML-2 genome. It is translated as a gag-prt fusion polypeptide. The fusion polypeptide is proteolytically cleaved to

[0097]Examples of prt nucleotide sequences are: SEQ ID NO:86 [HERV-K(108)]; SEQ ID NO:99 [HERV-K(II)]; SEQ ID NO:105 [HERV-K10].

[0098]Examples of prt polypeptide sequences are: SEQ ID NO:106 [HERV-K10]; SEQ ID NO:147 [`ERVK6`].

[0099]HML-2 pol polypeptide is encoded by the third long ORF in a complete HML-2 genome. It is translated as a gag-prt-pol fusion polypeptide. The fusion polypeptide is proteolytically cleaved to give three pol products--reverse transcriptase, endonuclease and integrase [14].

[0100]Examples of pol nucleotide sequences are: SEQ ID NO:87 [HERV-K(108)]; SEQ ID NO:93 [HERV-K(C7)]; SEQ ID NO:100 [HERV-K(II)]; SEQ ID NO:107 [HERV-K10].

[0101]Examples of pol polypeptide sequences are: SEQ ID NO:94 [HERV-K(C7)]; SEQ ID NO:108 [HERV-K10]; SEQ ID NO:148 [`ERVK6`].

[0102]An alignment of pol polypeptide sequences is shown in FIG. 8.

[0103]HML-2 env polypeptide is encoded by the fourth long ORF in a complete HML-2 genome. The translated polypeptide is proteolytically cleaved.

[0104]Examples of env nucleotide sequences are: SEQ ID NO:88 [HERV-K(108)]; SEQ ID NO:95 [HERV-K(C7)]; SEQ ID NO:101 [HERV-K(II)]; SEQ ID NO:107 [HERV-K10].

[0105]Examples of env polypeptide sequences are: SEQ ID NO:96 [HERV-K(C7)]; SEQ ID NO:108 [HERV-K10]; SEQ ID NO:149 [`ERVK6`].

[0106]Alignments of env polynucleotide and polypeptide sequences are shown in FIGS. 6 and 9.

[0107]HML-2 cORF polypeptide is encoded by an ORF which shares the same 5' region and start codon as env. After amino acid 87, a splicing event removes env-coding sequences and the cORF-coding sequence continues in the reading frame +1 relative to that of env [15, 16; see below]. cORF has also been called Rec [17].

[0108]Examples of cORF nucleotide sequences are: SEQ ID NO:89 and SEQ ID NO:90 [HERV-K(108)].

[0109]Examples of cORF polypeptide sequences are SEQ ID NO:109.

[0110]C.1--Direct Detection of HML-2 Polypeptides

[0111]Various techniques are available for detecting the presence or absence of a particular polypeptides in a sample. These are generally immunoassay techniques which are based on the specific interaction between an antibody and an antigenic amino acid sequence in the polypeptide. Suitable techniques include standard immunohistological methods, immunoprecipitation, immunofluorescence, ELISA, RIA, FIA, etc.

[0112]In general, therefore, the invention provides a method for detecting the presence of and/or measuring a level of a polypeptide of the invention in a biological sample, wherein the method uses an antibody specific for the polypeptide. The method generally comprises the steps of: a) contacting the sample with an antibody specific for the polypeptide; and b) detecting binding between the antibody and polypeptides in the sample.

[0113]Polypeptides of the invention can also be detected by functional assays e.g. assays to detect binding activity or enzymatic activity. For instance, a functional assay for cORF is disclosed in references 16, 129 & 130. A functional assay for the protease is disclosed in reference 140.

[0114]Another way for detecting polypeptides of the invention is to use standard proteomics techniques e.g. purify or separate polypeptides and then use peptide sequencing. For example, polypeptides can be separated using 2D-PAGE and polypeptide spots can be sequenced (e.g. by mass spectroscopy) in order to identify if a sequence is present in a target polypeptide.

[0115]Detection methods may be adapted for use in vivo (e.g. to locate or identify sites where cancer cells are present). In these embodiments, an antibody specific for a target polypeptide is administered to an individual (e.g. by injection) and the antibody is located using standard imaging techniques (e.g. magnetic resonance imaging, computed tomography scanning, etc.). Appropriate labels (e.g. spin labels etc.) will be used. Using these techniques, cancer cells are differentially labeled.

[0116]An immunofluorescence assay can be easily performed on cells without the need for purification of the target polypeptide. The cells are first fixed onto a solid support, such as a microscope slide or microtiter well. The membranes of the cells are then permeablized in order to permit entry of polypeptide-specific antibody (NB: fixing and permeabilization can be achieved together). Next, the fixed cells are exposed to an antibody which is specific for the encoded polypeptideand which is fluorescently labeled. The presence of this label (e.g. visualized under a microscope) identifies cells which express the target PCAV polypeptide. To increase the sensitivity of the assay, it is possible to use a second antibody to bind to the anti-PCAV antibody, with the label being carried by the second antibody. [18]

[0117]C.2--Indirect Detection of HML-2 Polypeptides

[0118]Rather than detect polypeptides directly, it may be preferred to detect molecules which are produced by the body in response to a polypeptide (i.e. indirect detection of a polypeptide). This will typically involve the detection of antibodies, so the patient sample will generally be a blood sample. Antibodies can be detected by conventional immunoassay techniques e.g. using PCAV polypeptides of the invention, which will typically be immobilized.

[0119]Antibodies against HERV-K polypeptides have been detected in humans [143].

[0120]C.3--Polypeptide Materials

[0121]The invention provides polypeptides for use in the detection methods of the invention. In general, these polypeptides will be encoded by PCA-mRNAs e.g. by sequence(s) in the --N₄-- region.

[0122]The invention provides an isolated polypeptide comprising: (a) an amino acid sequence selected from the group consisting of SEQ ID NOS:109 (cORF), 146 (gag), 147 (prt), 148 (pol), 149 (env); (b) a fragment of at least x amino acids of (a); or (c) a polypeptide sequence having at least s % identity to (a). These polypeptides include variants (e.g. allelic variants, homologs, orthologs, mutants etc.).

[0123]The value of x is at least 5 (e.g. at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, 100 etc.). The value of x may be less than 2000 (e.g. less than 1000, 500, 100, or 50).

[0124]The value of s is preferably at least 50 (e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 99.9 etc.).

[0125]The invention also provides an isolated polypeptide having formula NH2-A-B-C-COOH, wherein: A is a polypeptide sequence consisting of a amino acids; C is a polypeptide sequence consisting of c amino acids; B is a polypeptide sequence consisting of a fragment of b amino acids of an amino acid sequence selected from the group consisting of SEQ ID NOS:109, 146, 147, 148, 149; and said polypeptide is not a fragment of polypeptide sequence SEQ ID NO:109, 146, 147, 148 or 149.

[0126]The value of a+c is at least 1 (e.g. at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 etc.). The value of b is at least 5 (e.g. at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 etc.). It is preferred that the value of a+b+c is at least 9 (e.g. at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 etc.). It is preferred that the value of a+b+c is at most 500 (e.g. at most 450, 400, 350, 300, 250, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60, 50, 40, 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9).

[0127]The amino acid sequence of -A- typically shares less than n % sequence identity to the a amino acids which are N-terminal of sequence -B- in SEQ ID NO:109, 146, 147, 148 or 149 and the amino acid sequence of -C- typically shares less than n % sequence identity to the c amino acids which are C-terminal of sequence -B- in SEQ ID NO:109, 146, 147, 148 or 149. The value of n is generally 60 or less (e.g. 50, 40, 30, 20, 10 or less).

[0128]The fragment of (b) may comprise a T-cell or, preferably, a B-cell epitope of SEQ ID NO:109, 146, 147, 148 or 149. T- and B-cell epitopes can be identified empirically (e.g. using the PEPSCAN method [19, 20] or similar methods), or they can be predicted (e.g. using the Jameson-Wolf antigenic index [21], matrix-based approaches [22], TEPITOPE [23], neural networks [24], OptiMer & EpiMer [25, 26], ADEPT [27], Tsites [28], hydrophilicity [29], antigenic index [30] or the methods disclosed in reference 31 etc.).

[0129]References to a percentage sequence identity between two amino acid sequences means that, when aligned, that percentage of amino acids are the same in comparing the two sequences. This alignment and the percent homology or sequence identity can be determined using software programs known in the art, for example those described in section 7.7.18 of reference 11. A preferred alignment is determined by the Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 2, BLOSUM matrix of 62. The Smith-Waterman homology search algorithm is taught in reference 32.

[0130]Polypeptides of the invention can be prepared in many ways e.g. by chemical synthesis (at least in part), by digesting longer polypeptides using proteases, by translation from RNA, by purification from cell culture (e.g. from recombinant expression), from the organism itself (e.g. isolation from prostate tissue), from a cell line source etc.

[0131]Polypeptides of the invention can be prepared in various forms (e.g. native, fusions, glycosylated, non-glycosylated etc.).

[0132]Polypeptides of the invention may be attached to a solid support.

[0133]Polypeptides of the invention may comprise a detectable label (e.g. a radioactive or fluorescent label, or a biotin label).

[0134]In general, the polypeptides of the subject invention are provided in a non-naturally occurring environment e.g. they are separated from their naturally-occurring environment. In certain embodiments, the subject polypeptide is present in a composition that is enriched for the polypeptide as compared to a control. As such, purified polypeptide is provided, whereby purified is meant that the polypeptide is present in a composition that is substantially free of other expressed polypeptides, where by substantially free is meant that less than 90%, usually less than 60% and more usually less than 50% of the composition is made up of other expressed polypeptides.

[0135]The term "polypeptide" refers to amino acid polymers of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art. Polypeptides can occur as single chains or associated chains. Polypeptides of the invention can be naturally or non-naturally glycosylated (i.e. the polypeptide has a glycosylation pattern that differs from the glycosylation pattern found in the corresponding naturally occurring polypeptide).

[0136]Mutants can include amino acid substitutions, additions or deletions. The amino acid substitutions can be conservative amino acid substitutions or substitutions to eliminate non-essential amino acids, such as to alter a glycosylation site, a phosphorylation site or an acetylation site, or to minimize misfolding by substitution or deletion of one or more cysteine residues that are not necessary for function. Conservative amino acid substitutions are those that preserve the general charge, hydrophobicity/hydrophilicity, and/or steric bulk of the amino acid substituted. Variants can be designed so as to retain or have enhanced biological activity of a particular region of the polypeptide (e.g. a functional domain and/or, where the polypeptide is a member of a polypeptide family, a region associated with a consensus sequence). Selection of amino acid alterations for production of variants can be based upon the accessibility (interior vs. exterior) of the amino acid (e.g. ref. 33), the thermostability of the variant polypeptide (e.g. ref. 34), desired glycosylation sites (e.g. ref. 35), desired disulfide bridges (e.g. refs. 36 & 37), desired metal binding sites (e.g. refs. 38 & 39), and desired substitutions with in proline loops (e.g. ref. 40). Cysteine-depleted muteins can be produced as disclosed in reference 41.

[0137]C.4--Antibody Materials

[0138]The invention also provides isolated antibodies, or antigen-binding fragments thereof, that bind to a polypeptide of the invention. The invention also provides isolated antibodies or antigen binding fragments thereof, that bind to a polypeptide encoded by a polynucleotide of the invention.

[0139]Antibodies of the invention may be polyclonal or monoclonal and may be produced by any suitable means (e.g. by recombinant expression).

[0140]Antibodies of the invention may include a label. The label may be detectable directly, such as a radioactive or fluorescent label. Alternatively, the label may be detectable indirectly, such as an enzyme whose products are detectable (e.g. luciferase, β-galactosidase, peroxidase etc.).

[0141]Antibodies of the invention may be attached to a solid support.

[0142]Antibodies of the invention may be prepared by administering (e.g. injecting) a polypeptide of the invention to an appropriate animal (e.g. a rabbit, hamster, mouse or other rodent).

[0143]Antigen-binding fragments of antibodies include Fv, scFv, Fc, Fab, F(ab')₂ etc.

[0144]To increase compatibility with the human immune system, the antibodies may be chimeric or humanized [e.g. refs. 42 & 43], or fully human antibodies may be used. Because humanized antibodies are far less immunogenic in humans than the original non-human monoclonal antibodies, they can be used for the treatment of humans with far less risk of anaphylaxis. Thus, these antibodies may be preferred in therapeutic applications that involve in vivo administration to a human such as, use as radiation sensitizers for the treatment of neoplastic disease or use in methods to reduce the side effects of cancer therapy.

[0145]Humanized antibodies may be achieved by a variety of methods including, for example: (1) grafting non-human complementarity determining regions (CDRs) onto a human framework and constant region ("humanizing"), with the optional transfer of one or more framework residues from the non-human antibody; (2) transplanting entire non-human variable domains, but "cloaking" them with a human-like surface by replacement of surface residues ("veneering"). In the present invention, humanized antibodies will include both "humanized" and "veneered" antibodies. [44, 45, 46, 47, 48, 49, 50].

[0146]CDRs are amino acid sequences which together define the binding affinity and specificity of a Fv region of a native immunoglobulin binding site [e.g. refs. 51 & 52].

[0147]The phrase "constant region" refers to the portion of the antibody molecule that confers effector functions. In chimeric antibodies, mouse constant regions are substituted by human constant regions. The constant regions of humanized antibodies are derived from human immunoglobulins. The heavy chain-constant region can be selected from any of the 5 isotypes: alpha, delta, epsilon, gamma or mu.

[0148]One method of humanizing antibodies comprises aligning the heavy and light chain sequences of a non-human antibody to human heavy and light chain sequences, replacing the non-human framework residues with human framework residues based on such alignment, molecular modeling of the conformation of the humanized sequence in comparison to the conformation of the non-human parent antibody, and repeated back mutation of residues in the framework region which disturb the structure of the non-human CDRs until the predicted conformation of the CDRs in the humanized sequence model closely approximates the conformation of the non-human CDRs of the parent non-human antibody. Such humanized antibodies may be further derivatized to facilitate uptake and clearance e.g, via Ashwell receptors. [refs. 53 & 54]

[0149]Humanized or fully-human antibodies can also be produced using transgenic animals that are engineered to contain human immunoglobulin loci. For example, ref. 55 discloses transgenic animals having a human Ig locus wherein the animals do not produce functional endogenous immunoglobulins due to the inactivation of endogenous heavy and light chain loci. Ref. 56 also discloses transgenic non-primate mammalian hosts capable of mounting an immune response to an immunogen, wherein the antibodies have primate constant and/or variable regions, and wherein the endogenous immunoglobulin-encoding loci are substituted or inactivated. Ref. 57 discloses the use of the Cre/Lox system to modify the immunoglobulin locus in a mammal, such as to replace all or a portion of the constant or variable region to form a modified antibody molecule. Ref. 58 discloses non-human mammalian hosts having inactivated endogenous Ig loci and functional human Ig loci. Ref. 59 discloses methods of making transgenic mice in which the mice lack endogenous heavy claims, and express an exogenous immunoglobulin locus comprising one or more xenogeneic constant regions.

[0150]Using a transgenic animal described above, an immune response can be produced to a PCAV polypeptide, and antibody-producing cells can be removed from the animal and used to produce hybridomas that secrete human monoclonal antibodies. Immunization protocols, adjuvants, and the like are known in the art, and are used in immunization of, for example, a transgenic mouse as described in ref. 60. The monoclonal antibodies can be tested for the ability to inhibit or neutralize the biological activity or physiological effect of the corresponding polypeptide.

[0151]D--Comparison with Control Samples

[0152]D.1--The Control

[0153]HML-2 transcripts are up-regulated in tumors, including prostate tumors. To detect such up-regulation, a reference point is needed i.e. a control. Analysis of the control sample gives a standard level of RNA and/or protein expression against which a patient sample can be compared.

[0154]A negative control gives a background or basal level of expression against which a patient sample can be compared. Higher levels of expression product relative to a negative control indicate that the patient from whom the sample was taken has, for example, prostate cancer. Typically, for prostate cancer, for example, negative controls would include lifetime baseline levels of expression or the expression level observed in pooled normals. Conversely, equivalent levels of expression product indicate that the patient does not have a HML-2-related cancer such as prostate cancer.

[0155]A positive control gives a level of expression against which a patient sample can be compared. Equivalent or higher levels of expression product relative to a positive control indicate that the patient from whom the sample was taken has cancer such as prostate cancer. Conversely, lower levels of expression product indicate that the patient does not have a HML-2 related cancer such as prostate cancer.

[0156]For direct or indirect RNA measurement, or for direct polypeptide measurement, a negative control will generally comprise cells which are not from a tumor cell, e.g. a prostate tumor cell. For indirect polypeptide measurement, a negative control will generally be a blood sample from a patient who does not have a prostate tumor. The negative control could be a sample from the same patient as the patient sample, but from a tissue in which HML-2 expression is not up-regulated e.g. a non-tumor non-prostate cell. The negative control could be a prostate cell from the same patient as the patient sample, but taken at an earlier stage in the patient's life. The negative control could be a cell from a patient without a prostate tumor. This cell may or may not be a prostate cell. The negative control cell could be a prostate cell from a patient with BPH.

[0157]For direct or indirect RNA measurement, or for direct polypeptide measurement, a positive control will generally comprise cells from a tumor cell e.g. a prostate tumor. For indirect polypeptide measurement, a positive control will generally be a blood sample from a patient who has a prostate tumor. The positive control could be a prostate tumor cell from the same patient as the patient sample, but taken at an earlier stage in the patient's life (e.g. to monitor remission). The positive control could be a cell from another patient with a prostate tumor. The positive control could be a prostate cell line.

[0158]Other suitable positive and negative controls will be apparent to the skilled person.

[0159]HML-2 expression in the control can be assessed at the same time as expression in the patient sample. Alternatively, HML-2 expression in the control can be assessed separately (earlier or later).

[0160]Rather than actually compare two samples, however, the control may be an absolute value i.e. a level of expression which has been empirically determined from samples taken from prostate tumor patients (e.g. under standard conditions).

[0161]D. 2--Degree of Up-Regulation

[0162]The up-regulation relative to the control (100%) will usually be at least 150% (e.g. 200%, 250%, 300%, 400%, 500%, 600% or more).

[0163]D.3--Diagnosis

[0164]The invention provides a method for diagnosing prostate cancer. It will be appreciated that "diagnosis" according to the invention can range from a definite clinical diagnosis of disease to an indication that the patient should undergo further testing which may lead to a definite diagnosis. For example, the method of the invention can be used as part of a screening process, with positive samples being subjected to further analysis.

[0165]Furthermore, diagnosis includes monitoring the progress of cancer in a patient already known to have the cancer. Cancer can also be staged by the methods of the invention. Preferably, the cancer is prostate cancer.

[0166]The efficacy of a treatment regimen (therametrics) of a cancer associated can also monitored by the method of the invention e.g. to determine its efficacy.

[0167]Susceptibility to a cancer can also be detected e.g. where up-regulation of expression has occurred, but before cancer has developed. Prognostic methods are also encompassed.

[0168]All of these techniques fall within the general meaning of "diagnosis" in the present invention.

[0169]E--Pharmaceutical Compositions

[0170]The invention provides a pharmaceutical composition comprising polynucleotide, polypeptide, or antibody as defined above. The invention also provides their use as medicaments, and their use in the manufacture of medicaments for treating prostate cancer. The invention also provides a method for raising an immune response, comprising administering an immunogenic dose of polynucleotide or polypeptide of the invention to an animal.

[0171]Pharmaceutical compositions encompassed by the present invention include as active agent, the polynucleotides, polypeptides, or antibodies of the invention disclosed herein in a therapeutically effective amount. An "effective amount" is an amount sufficient to effect beneficial or desired results, including clinical results. An effective amount can be administered in one or more administrations. For purposes of this invention, an effective amount is an amount that is sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the symptoms and/or progression of prostate cancer.

[0172]The compositions can be used to treat cancer as well as metastases of primary cancer. In addition, the pharmaceutical compositions can be used in conjunction with conventional methods of cancer treatment, e.g. to sensitize tumors to radiation or conventional chemotherapy. The terms "treatment", "treating", "treat" and the like are used herein to generally refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or adverse effect attributable to the disease. "Treatment" as used herein covers any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, i.e. arresting its development; or (c) relieving the disease symptom, i.e. causing regression of the disease or symptom.

[0173]Where the pharmaceutical composition comprises an antibody that specifically binds to a gene product encoded by a differentially expressed polynucleotide, the antibody can be coupled to a drug for delivery to a treatment site or coupled to a detectable label to facilitate imaging of a site comprising cancer cells, such as prostate cancer cells. Methods for coupling antibodies to drugs and detectable labels are well known in the art, as are methods for imaging using detectable labels.

[0174]The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a detectable therapeutic or preventative effect. The effect can be detected by, for example, chemical markers or antigen levels. Therapeutic effects also include reduction in physical symptoms. The precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition, and the therapeutics or combination of therapeutics selected for administration. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician. For purposes of the present invention, an effective dose will generally be from about 0.01 mg/kg to about 5 mg/kg, or about 0.01 mg/kg to about 50 mg/kg or about 0.05 mg/kg to about 10 mg/kg of the compositions of the present invention in the individual to which it is administered.

[0175]A pharmaceutical composition can also contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to a carrier for administration of a therapeutic agent, such as antibodies or a polypeptide, genes, and other therapeutic agents. The term refers to any pharmaceutical carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which can be administered without undue toxicity. Suitable carriers can be large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles. Such carriers are well known to those of ordinary skill in the art. Pharmaceutically acceptable carriers in therapeutic compositions can include liquids such as water, saline, glycerol and ethanol. Auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, can also be present in such vehicles. Typically, the therapeutic compositions are prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared. Liposomes are included within the definition of a pharmaceutically acceptable carrier. Pharmaceutically acceptable salts can also be present in the pharmaceutical composition, e.g. mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like. A thorough discussion of pharmaceutically acceptable excipients is available in Remington: The Science and Practice of Pharmacy (1995) Alfonso Gennaro, Lippincott, Williams, & Wilkins.

[0176]The composition is preferably sterile and/or pyrogen-free. It will typically be buffered around pH 7.

[0177]Once formulated, the compositions contemplated by the invention can be (1) administered directly to the subject (e.g. as polynucleotide, polypeptides, small molecule agonists or antagonists, and the like); or (2) delivered ex vivo, to cells derived from the subject (e.g. as in ex vivo gene therapy). Direct delivery of the compositions will generally be accomplished by parenteral injection, e.g. subcutaneously, intraperitoneally, intravenously or intramuscularly, intratumoral or to the interstitial space of a tissue. Other modes of administration include oral and pulmonary administration, suppositories, and transdermal applications, needles, and gene guns or hyposprays. Dosage treatment can be a single dose schedule or a multiple dose schedule.

[0178]Methods for the ex vivo delivery and reimplantation of transformed cells into a subject are known in the art [e.g. ref. 61]. Examples of cells useful in ex vivo applications include, for example, stem cells, particularly hematopoetic, lymph cells, macrophages, dendritic cells, or tumor cells.

[0179]Generally, delivery of nucleic acids for both ex vivo and in vitro applications can be accomplished by, for example, dextran-mediated transfection, calcium phosphate precipitation, polybrene mediated transfection, protoplast fusion, electroporation, encapsulation of the polynucleotide(s) in liposomes, and direct microinjection of the DNA into nuclei, all well known in the art.

[0180]Differential expression PCAV polynucleotides has been found to correlate with prostate tumors. The tumor can be amenable to treatment by administration of a therapeutic agent based on the provided polynucleotide, corresponding polypeptide or other corresponding molecule (e.g. antisense, ribozyme, etc.). In other embodiments, the disorder can be amenable to treatment by administration of a small molecule drug that, for example, serves as an inhibitor (antagonist) of the function of the encoded gene product of a gene having increased expression in cancerous cells relative to normal cells or as an agonist for gene products that are decreased in expression in cancerous cells (e.g. to promote the activity of gene products that act as tumor suppressors).

[0181]The dose and the means of administration of the inventive pharmaceutical compositions are determined based on the specific qualities of the therapeutic composition, the condition, age, and weight of the patient, the progression of the disease, and other relevant factors. For example, administration of polynucleotide therapeutic compositions agents includes local or systemic administration, including injection, oral administration, particle gun or catheterized administration, and topical administration. Preferably, the therapeutic polynucleotide composition contains an expression construct comprising a promoter operably linked to a polynucleotide of the invention. Various methods can be used to administer the therapeutic composition directly to a specific site in the body. For example, a small metastatic lesion is located and the therapeutic composition injected several times in several different locations within the body of tumor. Alternatively, arteries which serve a tumor are identified, and the therapeutic composition injected into such an artery, in order to deliver the composition directly into the tumor. A tumor that has a necrotic center is aspirated and the composition injected directly into the now empty center of the tumor. An antisense composition is directly administered to the surface of the tumor, for example, by topical application of the composition. X-ray imaging is used to assist in certain of the above delivery methods.

[0182]Targeted delivery of therapeutic compositions containing an antisense polynucleotide, subgenomic polynucleotides, or antibodies to specific tissues can also be used. Receptor-mediated DNA delivery techniques are described in, for example, references 62 to 67. Therapeutic compositions containing a polynucleotide are administered in a range of about 100 ng to about 200 mg of DNA for local administration in a gene therapy protocol. Concentration ranges of about 500 ng to about 50 mg, about 1 μg to about 2 mg, about 5 μg to about 500 and about 20 μg to about 100 μg of DNA can also be used during a gene therapy protocol. Factors such as method of action (e.g. for enhancing or inhibiting levels of the encoded gene product) and efficacy of transformation and expression are considerations which will affect the dosage required for ultimate efficacy of the antisense subgenomic polynucleotides. Where greater expression is desired over a larger area of tissue, larger amounts of antisense subgenomic polynucleotides or the same amounts re-administered in a successive protocol of administrations, or several administrations to different adjacent or close tissue portions of, for example, a tumor site, may be required to effect a positive therapeutic outcome. In all cases, routine experimentation in clinical trials will determine specific ranges for optimal therapeutic effect.

[0183]The therapeutic polynucleotides and polypeptides of the present invention can be delivered using gene delivery vehicles. The gene delivery vehicle can be of viral or non-viral origin (see generally references 68, 69, 70 and 71). Expression of such coding sequences can be induced using endogenous mammalian or heterologous promoters. Expression of the coding sequence can be either constitutive or regulated.

[0184]Viral-based vectors for delivery of a desired polynucleotide and expression in a desired cell are well known in the art. Exemplary viral-based vehicles include, but are not limited to, recombinant retroviruses (e.g. references 72 to 82), alphavirus-based vectors (e.g. Sindbis virus vectors, Semliki forest virus (ATCC VR-67; ATCC VR-1247), Ross River virus (ATCC VR-373; ATCC VR-1246) and Venezuelan equine encephalitis virus (ATCC VR-923; ATCC VR-1250; ATCC VR 1249; ATCC VR-532)), adenovirus vectors, and adeno-associated virus (AAV) vectors (e.g. see refs. 83 to 88). Administration of DNA linked to killed adenovirus [89] can also be employed.

[0185]Non-viral delivery vehicles and methods can also be employed, including, but not limited to, polycationic condensed DNA linked or unlinked to killed adenovirus alone [e.g. 89], ligand-linked DNA [90], eukaryotic cell delivery vehicles cells [e.g. refs. 91 to 95] and nucleic charge neutralization or fusion with cell membranes. Naked DNA can also be employed. Exemplary naked DNA introduction methods are described in refs. 96 and 97. Liposomes that can act as gene delivery vehicles are described in refs. 98 to 102. Additional approaches are described in refs. 103 & 104.

[0186]Further non-viral delivery suitable for use includes mechanical delivery systems such as the approach described in ref. 104. Moreover, the coding sequence and the product of expression of such can be delivered through deposition of photopolymerized hydrogel materials or use of ionizing radiation [e.g. refs. 105 & 106]. Other conventional methods for gene delivery that can be used for delivery of the coding sequence include, for example, use of hand-held gene transfer particle gun [107] or use of ionizing radiation for activating transferred gene [108 & 109].

[0187]Vaccine Compositions

[0188]The invention provides a composition comprising a polypeptide or polynucleotide of the invention and a pharmaceutically acceptable carrier.

[0189]The composition may additionally comprise an adjuvant. For example, the composition may comprise one or more of the following adjuvants: (1) oil-in-water emulsion formulations (with or without other specific immunostimulating agents such as muramyl peptides (see below) or bacterial cell wall components), such as for example (a) MF59® [110; Chapter 10 in ref. 111], containing 5% Squalene, 0.5% Tween 80, and 0.5% Span 85 (optionally containing MTP-PE) formulated into submicron particles using a microfluidizer, (b) SAF, containing 10% Squalane, 0.4% Tween 80, 5% pluronic-blocked polymer L121, and thr-MDP either microfluidized into a submicron emulsion or vortexed to generate a larger particle size emulsion, and (c) Ribi® adjuvant system (RAS), (Ribi Immunochem, Hamilton, Mont.) containing 2% Squalene, 0.2% Tween 80, and one or more bacterial cell wall components from the group consisting of monophosphorylipid A (MPL), trehalose dimycolate (TDM), and cell wall skeleton (CWS), preferably MPL+CWS (Detox®); (2) saponin adjuvants, such as QS21 or Stimulon® (Cambridge Bioscience, Worcester, Mass.) may be used or particles generated therefrom such as ISCOMs (immunostimulating complexes), which ISCOMS may be devoid of additional detergent [112]; (3) Complete Freund's Adjuvant (CFA) and Incomplete Freund's Adjuvant (IFA); (4) cytokines, such as interleukins (e.g. IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-12 etc.), interferons (e.g. gamma interferon), macrophage colony stimulating factor (M-CSF), tumor necrosis factor (TNF), etc.; (5) monophosphoryl lipid A (MPL) or 3-O-deacylated MPL (3dMPL) [e.g. 113, 114]; (6) combinations of 3dMPL with, for example, QS21 and/or oil-in-water emulsions [e.g. 115, 116, 117]; (7) oligonucleotides comprising CpG motifs i.e. containing at least one CG dinucleotide, with 5-methylcytosine optionally being used in place of cytosine; (8) a polyoxyethylene ether or a polyoxyethylene ester [118]; (9) a polyoxyethylene sorbitan ester surfactant in combination with an octoxynol [119] or a polyoxyethylene alkyl ether or ester surfactant in combination with at least one additional non-ionic surfactant such as an octoxynol [120]; (10) an immunostimulatory oligonucleotide (e.g. a CpG oligonucleotide) and a saponin [121]; (11) an immunostimulant and a particle of metal salt [122]; (12) a saponin and an oil-in-water emulsion [123]; (13) a saponin (e.g. QS21)+3dMPL+IL-12 (optionally+a sterol) [124]; (14) aluminum salts, preferably hydroxide or phosphate, but any other suitable salt may also be used (e.g. hydroxyphosphate, oxyhydroxide, orthophosphate, sulphate etc. [chapters 8 & 9 of ref. 111]). Mixtures of different aluminum salts may also be used. The salt may take any suitable form (e.g. gel, crystalline, amorphous etc.); (15) chitosan; (16) cholera toxin or E. coli heat labile toxin, or detoxified mutants thereof [125]; (17) microparticles of poly(α-hydroxy)acids, such as PLG; (18) other substances that act as immunostimulating agents to enhance the efficacy of the composition. Aluminum salts and/or MF59® are preferred.

[0190]The composition is preferably sterile and/or pyrogen-free. It will typically be buffered around pH 7.

[0191]The composition is preferably an immunogenic composition and is more preferably a vaccine composition. The composition can be used to raise antibodies in a mammal (e.g. a human).

[0192]Vaccines of the invention may be prophylactic (i.e. to prevent disease) or therapeutic (i.e. to reduce or eliminate the symptoms of a disease).

[0193]Efficacy can be tested by monitoring expression of polynucleotides and/or polypeptides of the invention after administration of the composition of the invention.

[0194]F--Screening Methods and Drug Design

[0195]The invention provides methods of screening for compounds with activity against cancer, comprising: contacting a test compound with a tissue sample derived from a cell in which HML-2 expression is up-regulated; or a cell line; and monitoring HML-2 expression in the sample. A decrease in expression indicates potential anti-cancer efficacy of the test compound.

[0196]The invention also provides methods of screening for compounds with activity against prostate cancer, comprising: contacting a test compound with a polynucleotide or polypeptide of the invention; and detecting a binding interaction between the test compound and the polynucleotide/polypeptide. A binding interaction indicates potential anti-cancer efficacy of the test compound.

[0197]The invention also provides methods of screening for compounds with activity against prostate cancer, comprising: contacting a test compound with a polypeptide of the invention; and assaying the function of the polypeptide. Inhibition of the polypeptide's function (e.g. loss of protease activity, loss of RNA export, loss of reverse transcriptase activity, loss of endonuclease activity, loss of integrase activity etc.) indicates potential anti-cancer efficacy of the test compound.

[0198]Typical test compounds include, but are not restricted to, peptides, peptoids, proteins, lipids, metals, nucleotides, nucleosides, small organic molecules, antibiotics, polyamines, and combinations and derivatives thereof. Small organic molecules have a molecular weight of more than 50 and less than about 2,500 daltons, and most preferably between about 300 and about 800 daltons. Complex mixtures of substances, such as extracts containing natural products, or the products of mixed combinatorial syntheses, can also be tested and the component that binds to the target RNA can be purified from the mixture in a subsequent step.

[0199]Test compounds may be derived from large libraries of synthetic or natural compounds. For instance, synthetic compound libraries are commercially available from Maybridge Chemical Co. (Trevillet, Cornwall, UK) or Aldrich (Milwaukee, Wis.). Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts may be used. Additionally, test compounds may be synthetically produced using combinatorial chemistry either as individual compounds or as mixtures.

[0200]Agonists or antagonists of the polypeptides of the invention can be screened using any available method known in the art, such as signal transduction, antibody binding, receptor binding, mitogenic assays, chemotaxis assays, etc. The assay conditions ideally should resemble the conditions under which the native activity is exhibited in vivo, that is, under physiologic pH, temperature, and ionic strength. Suitable agonists or antagonists will exhibit strong inhibition or enhancement of the native activity at concentrations that do not cause toxic side effects in the subject. Agonists or antagonists that compete for binding to the native polypeptide can require concentrations equal to or greater than the native concentration, while inhibitors capable of binding irreversibly to the polypeptide can be added in concentrations on the order of the native concentration.

[0201]Such screening and experimentation can lead to identification of an agonist or antagonist of a HML-2 polypeptide. Such agonists and antagonists can be used to modulate, enhance, or inhibit HML-2 expression and/or function. [126]

[0202]The present invention relates to methods of using the polypeptides of the invention (e.g. recombinantly produced HML-2 polypeptides) to screen compounds for their ability to bind or otherwise modulate, such as, inhibit, the activity of HML-2 polypeptides, and thus to identify compounds that can serve, for example, as agonists or antagonists of the HML-2 polypeptides. In one screening assay, the HML-2 polypeptide is incubated with cells susceptible to the growth stimulatory activity of HML-2, in the presence and absence of a test compound. The HML-2 activity altering or binding potential of the test compound is measured. Growth of the cells is then determined. A reduction in cell growth in the test sample indicates that the test compound binds to and thereby inactivates the HML-2 polypeptide, or otherwise inhibits the HML-2 polypeptide activity.

[0203]Transgenic animals (e.g. rodents) that have been transformed to over-express HML-2 genes can be used to screen compounds in vivo for the ability to inhibit development of tumors resulting from HML-2 over-expression or to treat such tumors once developed. Transgenic animals that have prostate tumors of increased invasive or malignant potential can be used to screen compounds, including antibodies or peptides, for their ability to inhibit the effect of HML-2 polypeptides. Such animals can be produced, for example, as described in the examples herein.

[0204]Screening procedures such as those described above are useful for identifying agents for their potential use in pharmacological intervention strategies in prostate cancer treatment. Additionally, polynucleotide sequences corresponding to HML-2, including LTRs, may be used to assay for inhibitors of elevated gene expression.

[0205]Potent inhibitors of HERV-K protease are already known [127]. Inhibition of HERV-K protease by HIV-1 protease inhibitors has also been reported [128]. These compounds can be studied for use in prostate cancer therapy, and are also useful lead compounds for drug design.

[0206]Transdominant negative mutants of cORF have also been reported [129,130]. Transdominant cORF mutants can be studied for use in prostate cancer therapy.

[0207]Antisense oligonucleotides complementary to HML-2 mRNA can be used to selectively diminish or oblate the expression of the polypeptide. More specifically, antisense constructs or antisense oligonucleotides can be used to inhibit the production of HML-2 polypeptide(s) in prostate tumor cells. Antisense mRNA can be produced by transfecting into target cancer cells an expression vector with a HML-2 polynucleotide of the invention oriented in an antisense direction relative to the direction of PCAV-mRNA transcription. Appropriate vectors include viral vectors, including retroviral vectors, as well as non-viral vectors. Alternately, antisense oligonucleotides can be introduced directly into target cells to achieve the same goal. Oligonucleotides can be selected/designed to achieve the highest level of specificity and, for example, to bind to a PCAV-mRNA at the initiator ATG.

[0208]Monoclonal antibodies to HML-2 polypeptides can be used to block the action of the polypeptides and thereby control growth of cancer cells. This can be accomplished by infusion of antibodies that bind to HML-2 polypeptides and block their action.

[0209]The invention also provides high-throughput screening methods for identifying compounds that bind to a polynucleotide or polypeptide of the invention. Preferably, all the biochemical steps for this assay are performed in a single solution in, for instance, a test tube or microtitre plate, and the test compounds are analyzed initially at a single compound concentration. for the purposes of high throughput screening, the experimental conditions are adjusted to achieve a proportion of test compounds identified as "positive" compounds from amongst the total compounds screened. The assay is preferably set to identify compounds with an appreciable affinity towards the target e.g., when 0.1% to 1% of the total test compounds from a large compound library are shown to bind to a given target with a K_i of 10 μM or less (e.g. 1 μM, 100 nM, 10 nM, or less)

[0210]G--The HML-2 Family of Human Endogenous Retroviruses

[0211]Genomes of all eukaryotes contain multiple copies of sequences related to infectious retroviruses. These endogenous retroviruses have been well studied in mice where both true infectious forms and thousands of defective retrovirus-like elements (e.g. the TAP and Etn sequence families) exist. Some members of the IAP and Etn families are "active" retrotransposons since insertions of these elements have been documented which cause germ line mutations or oncogenic transformation.

[0212]Endogenous retroviruses were identified in human genomic DNA by their homology to retroviruses of other vertebrates [131, 132]. It is believed that the human genome probably contains numerous copies of endogenous proviral DNAs, but little is known about their function. Most HERV families have relatively few members (1-50) but one family (HERV-H) consists of ˜1000 copies per haploid genome distributed on all chromosomes. The large numbers and general transcriptional activity of HERVs in embryonic and tumor cell lines suggest that they could act as disease-causing insertional mutagens or affect adjacent gene expression in a neutral or beneficial way.

[0213]The K family of human endogenous retroviruses (HERV-K) is well known [133]. It is related to the mouse mammary tumor virus (MMTV) and is present in the genomes of humans, apes and old world monkeys, but several human HERV-K proviruses are unique to humans [134]. The HERV-K family is present at 30-50 full-length copies per haploid human genome and possesses long open reading frames that potentially are translated into viral proteins [135, 136]. Two types of proviral genomes are known, which differ by the presence (type 2) or absence (type 1) of a stretch of 292 nucleotides in the overlapping boundary of the pol and env genes [137]. Some members of the HERV-K family are known to code for the gag protein and retroviral particles, which are both detectable in germ cell tumors and derived cell lines [138]. Analysis of the RNA expression pattern of full-length HERV-K has also identified a doubly-spliced RNA that encodes a 105 amino acid protein termed central ORF (`cORF`) which is a sequence-specific nuclear RNA export factor that is functionally equivalent to the Rev protein of HW [139]. HERV-K10 has been shown to encode a full-length gag homologous 73 kDa protein and a functional protease [140].

[0214]Patients suffering from germ cell tumors show high antibody titers against HERV-K gag and env proteins at the time of tumor detection [141]. In normal testis and testicular tumors the HERV-K transmembrane envelope protein has been detected both in germ cells and tumor cells, but not in the surrounding tissue. In the case of testicular tumor, correlations between the expression of the env-specific mRNA, the presence of the transmembrane env, cORF and gag proteins and antibodies against HERV-K specific peptides in the serum of the patients, have been reported. Reference 142 reports that HERV-K10 gag and/or env proteins are synthesized in seminoma cells and that patients with those tumors exhibit relatively high antibody titers against gag and/or env.

[0215]Gag proteins released in form of particles from HERV-K have been identified in the cell culture supernatant of the teratocarcinoma derived cell line Tera 1. These retrovirus-like particles (termed "human teratocarcinoma derived virus" or HTDV) have been shown to have a 90% sequence homology to the HERV-K10 genome [138, 143].

[0216]While the HERV-K family is present in the genome of every human cell, a high level of expression of mRNAs, proteins and particles is observed only in human teratocarcinoma cell lines [144]. In other tissues and cell lines, only a basal level of expression of mRNA has been demonstrated even using very sensitive methods. The expression of retroviral proviruses is generally regulated by elements of the 5' long terminal repeat (LTR). Furthermore, the activation of expression of an endogenous retrovirus may trigger the expression of a downstream gene that triggers a neoplastic effect.

[0217]The sequence of HERV-K(II), which locates to chromosome 3, has been disclosed [145].

[0218]HML-2 is a subgroup of the HERV-K family [146]. HERV isolates which are members of the HML-2 subgroup include HERV-K10 [137,142], the 27 HML-2 viruses shown in FIG. 4 of reference 147, HERV-K(C7) [148], HERV-K(II) [145], HERV-K(CH) Table 11 provides a list of all known members of the HML-2 subgroup of the HERV-K family as determined by searching the DoubleTwist database containing all genomic contigs with the sequence AF074086 using the Smith-Waterman algorithm with the default parameters: open gap penalty=-20 and extension penalty=-5.

[0219]The invention is based on the finding that HML-2 mRNA expression is up-regulated in prostate tumors. Because HML-2 is a well-recognized family, the skilled person will be able to determine without difficulty whether any particular endogenous retroviruses is or is not a HML-2. Preferred members of the HML-2 family for use in accordance with the present invention are those whose proviral genome has an LTR which has at least 75% sequence identity to SEQ ID NO:150 (the LTR sequence from HML-2.HOM [1]). Example LTRs include SEQ ID NOS:151-154.

[0220]H--HERV-K(CH)

[0221]The present invention is based on the discovery of elevated levels of multiple HML-2 polynucleotides in prostate tumor samples as compared to normal prostate tissue. One particular HML-2 whose mRNA was found to be up-regulated is designated herein as `HERV-K(CH)`.

[0222]Sequences from HERV-K(CH) are shown in SEQ ID NOS:14-39 and have been deposited with the ATCC (see Table 7). The skilled person will be able to classify any further HERV as HERV-K(CH) or not based on sequence identity to these HERV-K(CH) polynucleotides. Preferably such a comparison is to one or more, or all, of the polynucleotide sequences disclosed herein or of the polynucleotide inserts in the ATCC-deposited isolates. Alternatively, the skilled artisan can determine the sequence identity based on a comparison to any one or more, or all, of the sequences in SEQ ID NOS:7-10 and SEQ ID NOS:14-39 taking into consideration the spontaneous mutation rate associated with retroviral replication. Thus, it will be apparent when the differences in the sequences are consistent with a HERV-K(CH) isolate or consistent with another HERV.

[0223]HERV-K(CH) is therefore a specific member of the HML-2 subgroup which can be used in the invention as described above. It can also be used in methods previously described in relation to HERV-K e.g. the diagnosis of testicular cancer [142], autoimmune diseases, multiple sclerosis [149], insulin-dependent diabetes mellitus (IDDM) [150] etc.

[0224]H.1--HERV-K(CH) Nucleic Acids

[0225]H.1.1-HERV-K(CH) Genomic Sequences

[0226]The invention provides an isolated polynucleotide comprising: (a) the nucleotide sequence of any of SEQ ID NOS:7-10; (b) the nucleotide sequence of any of SEQ ID NOS:27-39; (c) the complement of a nucleotide sequence of any of SEQ ID NOS:7-10; or (d) the complement of the nucleotide sequence of any of SEQ ID NOS:27-39.0

[0227]H.1.2--HERV-K(CH) Fragments

[0228]The invention also provides an isolated polynucleotide comprising a fragment of: (a) a nucleotide sequence shown in SEQ ID NOS:7-10; (b) the nucleotide sequence shown in any of SEQ ID NOS:27-39; (c) the complement of a nucleotide sequence shown in SEQ ID NOS:7-10; or (d) the complement of the nucleotide sequence shown in any of SEQ ID NOS:27-39.

[0229]The fragment is preferably at least x nucleotides in length, wherein x is at least 7 (e.g. at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, 100 etc.). The value of x may be between about 150 and about 200 or be between about 250 and about 300. The value of x may be about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, or about 750. The value of x may be less than 2000 (e.g. less than 1000, 500, 100, or 50).

[0230]The fragment is preferably neither one of the following sequences nor a fragment of one of the following sequences: (i) the nucleotide sequence shown in SEQ ID NO:42; (ii) the nucleotide sequence shown in SEQ ID NO:43; (iii) the nucleotide sequence shown in SEQ ID NO:44; (iv) the nucleotide sequence shown in SEQ ID NO:45; (v) a known polynucleotide; or (vi) a polynucleotide known as of 7 Dec. 2000 (e.g. a polynucleotide available in a public database such as GenBank of GeneSeq before 7 Dec. 2000).

[0231]The fragment is preferably a contiguous sequence of one of polynucleotides of (a), (b), (c) or (d) that remains unmasked following application of a masking program for masking low complexity (e.g. XBLAST) to the sequence (i.e. one would select an unmasked region, as indicated by the polynucleotides outside the poly-n stretches of the masked sequence produced by the masking program).

[0232]These polynucleotides are particularly useful as probes. In general, a probe in which x=15 represents sufficient sequence for unique identification. Probes can be used, for example, to determine the presence or absence of a polynucleotide of the invention (or variants thereof) in a sample. By using probes, particularly labeled probes of DNA sequences, one can isolate homologous or related genes. The source of homologous genes can be any species e.g. primate species, particularly human; rodents, such as rats and mice; canines; felines; bovines; ovines; equines; yeast; nematodes; etc.

[0233]Probes from more than one polynucleotide sequence of the invention can hybridize with the same nucleic acid if the nucleic acid from which they were derived corresponds to a single sequence (e.g. more than one can hybridize to a single cDNA derived from the same mRNA).

[0234]Preferred fragments (e.g. for the identification of HERV-K(CH) polynucleotides associated with cancer) which do not correspond identically in their entirety to any portion of the sequence(s) shown in SEQ ID NOS:42-45 are: SEQ ID NO:59 (from gag region), SEQ ID NOS:60-70 (from pol region) and SEQ ID NOS:71-82 (from 3' pol region).

[0235]Preferred fragments (e.g. for the simultaneous identification of HERV-K(CH) polynucleotides, HERV-KII polynucleotides and/or HERV-K10 polynucleotides) which do correspond identically in their entirety to any portion of the sequence(s) shown in SEQ ID NOS:44 & 45 are SEQ ID NOS:83 & 84 (from gag region).

[0236]Polynucleotide probes unique to HERV-K(CH), HERV-KII and HERV-K10 gag regions are provided in Table 1; polynucleotide probes unique to HERV-K(CH), HERV-KII, and HERV-K10 protease 3' and polymerase 5' regions are provided in Table 2; polynucleotide probes unique to HERV-K(CH), HERV-KII, and HERV-K10 3' pol only regions are provided in Table 3.

[0237]H.1.3--HERV-K(CH) Fragments Plus Heterologous Sequences

[0238]The invention also provides an isolated polynucleotide comprising (a) a segment that is a fragment of the sequence shown in SEQ ID NOS:7-10 or SEQ ID NOS:27-39, wherein (i) said fragment is at least 10 nucleotides in length and (ii) corresponds identically in its entirety to a portion of SEQ ID NO:44 and/or 45; and, optionally, (b) one or more segments flanking the segment defined in (a), wherein the presence of said optional segment(s) causes said polynucleotide to not correspond identically to any portion of a sequence shown in SEQ ID NOS:7-10 or SEQ ID NOS:27-39. In some embodiments, the optional flanking segments share less than 40% sequence identity to the nucleic acid sequences shown in SEQ ID NOS:7-10, SEQ ID NO:44 and/or SEQ ID NO:45. In other embodiments, the optional flanking segments have no contiguous sequence of 10, 12, 15 or 20 nucleotides in common with SEQ ID NOS:7-10, SEQ ID NO:44 and/or SEQ ID NO:45. In yet other embodiments, the optional flanking segment is not present. In further embodiments, a fragment of the polynucleotide sequence is up to at least 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 1000, or 1500 nucleotides in length.

[0239]The invention also provides an isolated polynucleotide having formula 5'-A-B-C-3', wherein: A is a nucleotide sequence consisting of a nucleotides; B is a nucleotide sequence consisting of a fragment of b nucleotides from (i) the nucleotide sequence shown in SEQ ID NOS:7-10, (ii) the nucleotide sequence shown in any of SEQ ID NOS:27-39, (iii) the complement of the nucleotide sequence shown in SEQ ID NOS:7-10, or (iv) the complement of the nucleotide sequence shown in any of SEQ ID NOS:27-39; C is a nucleotide sequence consisting of c nucleotides; and wherein said polynucleotide is not a fragment of (i) the nucleotide sequence shown in SEQ ID NOS:7-10, (ii) the nucleotide sequence shown in any of SEQ ID NOS:27-39, (iii) the complement of the nucleotide sequence shown in SEQ ID NOS:7-10, or (iv) the complement of the nucleotide sequence shown in any of SEQ ID NOS:27-39.

[0240]In this polynucleotide, a+c is at least 1 (e.g. at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 etc.) and b is at least 7 (e.g. at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 etc.). It is preferred that the value of a+b+c is at least 9 (e.g. at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 etc.). It is preferred that the value of a+b+c is at most 200 (e.g. at most 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60, 50, 40, 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9).

[0241]A and/or C may comprise a promoter sequence (or its complement).

[0242]H.1.4--Homologous Sequences

[0243]The invention provides a polynucleotide having at least s % identity to: (a) SEQ ID NOS:7-10; (b) a fragment of x nucleotides of SEQ ID NOS:7-10; (c) SEQ ID NOS:11-13; (b) a fragment of x nucleotides of SEQ ID NOS:11-13. The value of s is at least 50 (e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 99.9 etc.). The value of x is at least 7 (e.g. 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 etc.).

[0244]These polynucleotides include naturally-occurring variants (e.g. degenerate variants, allelic variants, etc.), homologs, orthologs, and functional mutants.

[0245]Variants can be identified by hybridization of putative variants with the polynucleotide sequences disclosed in SEQ ID NOS:14-39 herein, preferably by hybridization under stringent conditions. For example, by using appropriate wash conditions, variants can be identified where the allelic variant exhibits at most about 25-30% base pair (bp) mismatches relative to the selected polynucleotide probe. In general, allelic variants contain 15-25% bp mismatches, and can contain as little as even 5-15%, or 2-5%, or 1-2% bp mismatches, as well as a single bp mismatch.

[0246]The invention also encompasses homologs corresponding to any one of the polynucleotide sequences provided herein, where the source of homologous genes can be any mammalian species (e.g. primate species, particularly human; rodents, such as rats, etc.). Between mammalian species (e.g. human and primate), homologs generally have substantial sequence similarity (e.g. at least 75% sequence identity, usually at least 90%, more usually at least 95%) between nucleotide sequences. Sequence similarity is calculated based on a reference sequence, which may be a subset of a larger sequence, such as a conserved motif, coding region, flanking region, domain, etc. A reference sequence will usually be at least about 18 contiguous nt long, more usually at least about 30 nt long, and may extend to the complete sequence that is being compared. Algorithms for sequence analysis are known in the art.

[0247]A preferred HERV-K(CH) isolate is an isolate sequence which is shown in SEQ ID NOS:7-10. Another preferred class of HERV-K(CH) isolates are those having a nucleotide sequence identity of at least 90%, preferably at least 95% to the 3' polymerase region shown in SEQ ID NO:13 which relates to integrase, as measured by the alignment program GCG Gap (Suite Version 10.1) using the default parameters: open gap=3 and extend gap=1. Another preferred class of HERV-K(CH) isolates are those having a nucleotide sequence identity of at least 98%, more preferably at least 99% to the 5' polymerase region shown in SEQ ID NO:12 which relates to reverse transcriptase, as measured by the alignment program GCG Gap (Suite Version 10.1) using the default parameters: open gap=3 and extend gap=1. Another typical classification of the relationship of retroviruses is based on the amino acid sequence similarities in the reverse transcriptase protein. Thus, an even more preferred class of HERV-K(CH) isolates are those having an amino acid sequence identity of at least 90%, more preferably 95% to the 5' polymerase region encoded by the nucleotide sequence shown in SEQ ID NO:12, as determined by the Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 2, BLOSUM matrix of 62. Thus, these prostate cancer-associated polynucleotide sequences define a class of human endogenous retroviruses, designated herein as HERV-K(CH), whose members comprise variations which, without wanted to be bound by theory, may be due to the presence of polymorphisms or allelic variations.

[0248]H.1.5--HERV-K(CH) Hybridizable Sequences

[0249]The invention provides an isolated polynucleotide comprising a polynucleotide that selectively hybridizes, relative to a known polynucleotide, to: (a) the nucleotide sequence shown in SEQ ID NOS:7-10; (b) the nucleotide sequence shown in any of SEQ ID NOS:27-39; (c) the complement of the nucleotide sequence shown in SEQ ID NOS:7-10; (d) the complement of the nucleotide sequence shown in any of SEQ ID NOS:27-39; (e) a fragment of the nucleotide sequence shown in SEQ ID NOS:7-10; (f) a fragment of the nucleotide sequence shown in any of SEQ ID NOS:27-39; (g) the complement of a fragment of the nucleotide sequence shown in SEQ r ID NOS:7-10; (h) the complement of a fragment of the nucleotide sequence shown in any of SEQ ID NOS:27-39; (j) a nucleotide sequence shown in SEQ ID NOS:14-39; or (k) polynucleotides found in ATCC deposits having ATCC accession numbers given in Table 7. The fragment of (e), (f), (g) or (h) is preferably at least x nucleotides in length, wherein x is as defined in H.1.2 above, and is preferably not one of the sequences (i), (ii), (iii), (iv), (v) or (vi) as defined H.1.2 above.

[0250]Hybridization reactions can be performed under conditions of different "stringency", as described in B.4 above. In some embodiments, the polynucleotide hybridizes under low stringency conditions; in other embodiments it hybridizes under intermediate stringency conditions; in other embodiments, it hybridizes under high stringency conditions.

[0251]H.1.6--Deposited HERV-K Sequences

[0252]The invention also provides an isolated polynucleotide comprising: (a) a HERV-K(CH) cDNA insert as deposited at the ATCC and having an ATCC accession number given in Table 7; (b) a HERV-K(CH) sequence as shown in any one of SEQ ID NOS:14-26; (c) a HERV-K(CH) sequence as shown in any one of SEQ ID NOS:27-39; or (d) a fragment of (a), (b) or (c). The fragment of (d) is preferably at least x nucleotides in length, wherein x is at least 7 (e.g. at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 etc.).

[0253]H.1.7--Preferred HERV-K(CH) Sequences

[0254]Preferred polynucleotides of the invention are those having a sequence set forth in any one of the polynucleotide sequences SEQ ID NOS:7-10 and SEQ ID NOS:14-39 provided herein; polynucleotides obtained from the biological materials described herein, in particular, polynucleotide sequences present in the isolates deposited with the ATCC and having ATCC accession numbers given in Table 7 or other biological sources (particularly human sources) or by hybridization to the above mentioned sequences under stringent conditions (particularly conditions of high stringency); genes corresponding to the provided polynucleotides; variants of the provided polynucleotides and their corresponding genes particularly those variants that retain a biological activity of the encoded gene product (e.g. a biological activity ascribed to a gene product corresponding to the provided polynucleotides as a result of the assignment of the gene product to a protein family(ies) and/or identification of a functional domain present in the gene product). Other polynucleotides and polynucleotide compositions contemplated by and within the scope of the present invention will be readily apparent to one of ordinary skill in the art when provided with the disclosure here.

[0255]H.1.8--General Features of Polynucleotides of the Invention

[0256]General features of the polynucleotides described in this section H.1 are the same as those described in section B.4 above.

[0257]The isolated polynucleotides preferably comprise a polynucleotide having a HERV-K(CH) sequence.

[0258]A polynucleotide of the invention can encode all or a part of a polypeptide, such as the gag region, 5' pol region or 3' pol region of a human endogenous retrovirus. Double or single stranded fragments can be obtained from the DNA sequence by chemically synthesizing oligonucleotides in accordance with conventional methods, by restriction enzyme digestion, by PCR amplification, etc.

[0259]Polynucleotides of the invention can be cDNAs or genomic DNAs, as well as fragments thereof, particularly fragments that encode a biologically active gene product and/or are useful in the methods disclosed herein (e.g. in diagnosis, as a unique identifier of a differentially expressed gene of interest, etc.). The term "cDNA" as used herein is intended to include all nucleic acids that share the arrangement of sequence elements found in native mature mRNA species, where sequence elements are exons and 3' and 5' non-coding regions. Normally mRNA species have contiguous exons, with the intervening introns, when present, being removed by nuclear RNA splicing, to create a continuous open reading frame encoding a polypeptide. mRNA species can also exist with both exons and introns, where the introns may be removed by alternative splicing. Furthermore it should be noted that different species of mRNAs encoded by the same genomic sequence can exist at varying levels in a cell, and detection of these various levels of mRNA species can be indicative of differential expression of the encoded gene product in the cell.

[0260]A genomic sequence of interest comprises the nucleic acid present between the initiation codon and the stop codon, as defined in the listed sequences, including all of the introns that are normally present in a native chromosome. It can further include the 3' and 5' untranslated regions found in the mature mRNA. It can further include specific transcriptional and translational regulatory sequences, such as promoters, enhancers, etc., including about 1 kb, but possibly more, of flanking genomic DNA at either the 5' and 3' end of the transcribed region. The genomic DNA can be isolated as a fragment of 100 kbp or smaller; and substantially free of flanking chromosomal sequence. The genomic DNA flanking the coding region, either 3' and 5', or internal regulatory sequences as sometimes found in introns, contains sequences required for proper tissue, stage-specific, or disease-state specific expression.

[0261]Polynucleotides of the invention can be provided as linear molecules or within circular molecules, and can be provided within autonomously replicating molecules (vectors) or within molecules without replication sequences. Expression of the polynucleotides can be regulated by their own or by other regulatory sequences known in the art. The polynucleotides can be introduced into suitable host cells using a variety of techniques available in the art, such as transferrin polycation-mediated DNA transfer, transfection with naked or encapsulated nucleic acids, liposome-mediated DNA transfer, intracellular transportation of DNA-coated latex beads, protoplast fusion, viral infection, electroporation, gene gun, calcium phosphate-mediated transfection, and the like.

[0262]A polynucleotide sequence that is "shown in" or "depicted in" a SEQ ID NO or Figure means that the sequence is present as an identical contiguous sequence in the SEQ ID NO or Figure. The term encompasses portions, or regions of the SEQ ID NO or Figure as well as the entire sequence contained within the SEQ ID NO or Figure.

[0263]H.2--HERV-K(CH) Polypeptides

[0264]H.2.1--HERV-K(CH) Open Reading Frames

[0265]The invention provides an isolated polypeptide: (a) encoded within a HERV-K(CH) open reading frame; (b) encoded by a polynucleotide shown in SEQ ID NO:11, 12 or 13; or (c) comprising an amino acid sequence as shown in any one of SEQ ID NOS:46-49, 50-55, 56-57 or 58.

[0266]Deduced polypeptides encoded by the HERV-K(CH) polynucleotides of the invention include the gag translations shown in SEQ IDS 46-49 and the 3' pol translations shown in SEQ ID NOS:50-55. A polypeptide sequence encoded by the polynucleotide having the sequence shown in SEQ ID NO:15 is provided in SEQ ID NO:56; a polypeptide sequence encoded by the polynucleotide having the sequence shown in SEQ ID NO:14, is shown in SEQ ID NO:57. A consensus 3' pol polypeptide sequence encoded by the polynucleotides having the sequence shown in SEQ ID NOS:21-27, inclusive, is provided in SEQ ID NO:58.

[0267]The polypeptides encompassed by the present invention include those encoded by polynucleotides of the invention, e.g. SEQ ID NOS:7-10 and SEQ ID NOS:14-39, as well as polynucleotides deposited with the ATCC as disclosed herein, as well as nucleic acids that, by virtue of the degeneracy of the genetic code, are not identical in sequence to the disclosed polynucleotides and encode the polypeptides. Thus, the invention includes within its scope a polypeptide encoded by a polynucleotide having the sequence of any one of the polynucleotide sequences provided herein, or a variant thereof.

[0268]While the over-expression of the polynucleotides associated with prostate tumor is observed, elevated levels of expression of the polypeptides encoded by these polynucleotides may likely play a role in prostate tumors.

[0269]Typically, in retroviruses, a single large gag polypeptide is synthesized (e.g. a 73 kDa gag protein in HERV-K10) which is subsequently cleaved into multiple functional peptides by a functional protease encoded by the pol or protease region of the genome. Overexpression of sequences corresponding to both gag and pol domains of the HERV-K(CH) suggest such a mechanism. Sequences corresponding to the env and the nuclear RNA transport protein cORF region of the HERV-K(CH) genome may also be overexpressed. The polypeptides encoded by the open reading frames within the over-expressed polynucleotide sequences may play a significant role in the progression of prostate tumors.

[0270]The detection of these polypeptides by antibodies or other reagents that specifically recognize them may aid in the early diagnosis of prostate tumor or any other cancers associated with the overexpression of these HERV-K(CH) sequences.

[0271]Furthermore, inhibition of the function of these polypeptides may suggest means for therapy and treatment of prostatic or other HERV-K(CH) sequence related cancers. One method of accomplishing such inhibition is by administration of vaccines as a preventative therapy or antibody-mediated drug therapy as a post-neoplasia regimen for treatment of such cancers.

[0272]H.2.2--HERV-K(CH) Fragments

[0273]The invention provides an isolated polypeptide comprising a fragment of: (a) a polypeptide sequence encoded within a HERV-K(CH) open reading frame; (b) a polypeptide sequence encoded by a polynucleotide shown in SEQ ID NO:11, 12 or 13; or (c) an amino acid sequence as shown in any one of SEQ ID NOS:46-49, 50-55, 56-57 or 58.

[0274]The fragment is preferably at least x amino acids in length, wherein x is at least 5 (e.g. at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, 100, 125, 150, 200, 300, 400, 500 or more etc.). The value ofx will typically not exceed 1000.

[0275]The fragment may include an epitope e.g. an epitope of the amino acid sequence shown in SEQ ID NOS:56, 57 or 58.

[0276]SEQ ID NOS:46-49 provide a translation of the HERV-K(CH) polynucleotides having a sequence shown in SEQ ID NOS:14, 15, 16 and 40 (the sequence of SEQ ID NO:40 is from a polynucleotide found in a normal prostate library) corresponding to polynucleotides encoding the gag region. SEQ ID NOS:50-55 provide a translation of the HERV-K(CH) polynucleotides having a sequence shown in SEQ ID NOS:21-26, inclusive, corresponding to the 3' region of pol. SEQ ID NOS:56 & 57 provide translations of the HERV-K(CH) polynucleotide of SEQ ID NO:15 and SEQ ID NO:14, respectively. SEQ ID NO:58 provides a consensus translation of the polynucleotide from the 3' pol region (SEQ ID NOS:21-26, inclusive). Encompassed with the present invention are polypeptide fragments, such as, epitopes, of at least 5 amino acids, at least 6 amino acids, at least 8 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids and at least 15 amino acids of the translations shown in SEQ ID NOS:46-49 and 50-55. In a preferred embodiment, the HERV-K(CH) epitopes of the amino acid sequence as shown in SEQ ID NOS:56-58 were determined by the Jameson-Wolf antigenic index [21].

[0277]The following regions in 3' pol (SEQ ID NO:58) were determined to be antigenic by Jameson-Wolf algorithm: amino acids: 1-10; 15-35; 45-55; 60-85; 100-115; 125-140; 170-190; 195-215; 230-268. Additional epitope-containing fragments include amino acids 1-8; 2-10; 1-15; 5-15; 7-15; 10-20; 12-20; 15-23; 20-28; 28-35; 15-30; 15-40; 20-30; 45-52; 48-55; 60-68; 60-70; 65-73; 70-78; 75-83; 70-80; 65-75; 68-75; 75-85; 78-85; 65-85; 60-75; 100-108; 103-110; 105-113; 108-115; 125-133; 128-135; 132-140; 170-178; 175-182; 180-187; 182-190; 195-202; 200-208; 205-212; 208-215; 230-237; 235-242; 240-247; 245-252; 250-257; 255-262; 260-268; 230-250; 235-255; 240-260; 245-268; 230-245; 235-245; 235-250; 240-255; 245-260; 250-268; 15-55; 170-215; 45-85.

[0278]The following regions in gag (SEQ ID NO:56) were determined to be antigenic by Jameson-Wolf algorithm: amino acids: 1-40; 45-60; 80-105; 130-145; 147-183; 186-220; 245-253; 255-288. Additional epitope-containing fragments include amino acids 1-8; 2-10; 1-15; 5-15; 7-15; 10-20; 12-20; 15-23; 20-28; 28-35; 30-37; 33-40; 1-20; 20-40; 1-15; 15-30; 15-40; 45-52; 50-57; 55-62; 50-60; 1-60; 80-87; 85-92; 80-90; 90-97; 95-102; 98-105; 85-100; 90-105; 80-100; 85-105; 130-137; 135-142; 140-147; 145-152; 150-157; 155-162; 160-167; 165-172; 170-177; 175-183; 180-187; 185-192; 190-197; 195-202; 200-207; 205-212; 210-217; 213-220; 185-220; 190-220; 195-220; 200-220; 205-220; 255-262; 260-267; 265-272; 270-277; 275-282; 280-288; 245-288; 250-288; 260-288; 265-288; 270-288.

[0279]The following regions in gag (SEQ ID NO:57) were determined to be antigenic by Jameson-Wolf algorithm: amino acids: 1-40; 80-105; 145-180; 185-225; 240-335. Additional epitope-containing fragments include amino acids 1-8; 2-10; 1-15; 5-15; 7-15; 10-20; 12-20; 15-23; 20-28; 28-35; 30-37; 33-40; 1-20; 20-40; 1-15; 15-30; 15-40; 80-87; 85-92; 80-90; 90-97; 95-102; 98-1-05; 85-100; 90-105; 80-100; 85-105; 145-152; 150-157; 155-162; 160-167; 165-172; 170-177; 175-182; 180-187; 185-192; 190-197; 195-202; 200-207; 205-212; 210-217; 215-212; 218-225; 145-160; 150-165; 155-170; 160-175; 170-185; 180-225; 185-225; 190-225; 195-225; 200-225; 205-225; 210-225; 215-225; 240-247; 245-252; 250-257; 255-262; 260-267; 265-272; 270-277; 275-282; 280-287; 285-292; 290-297; 295-302; 300-307; 305-312; 310-317; 315-322; 320-327; 325-332; 328-335; 245-285; 250-285; 260-285; 265-285; 270-295; 275-300; 280-305; 285-310; 295-315; 300-320; 305-325; 325-335; 245-335; 250-335; 255-335; 260-335; 270-335; 275-335; 280-335; 285-335; 290-335; 295-335; 305-335; 310-335; 315-335; 320-335.

[0280]H.2.3--HERV-K(CH) Fragments Plus Heterologous Sequences

[0281]The invention also provides an isolated polypeptide having formula 5'-A-B-C-3', wherein: A is an amino acid sequence consisting of a amino acids; B is an amino acid sequence consisting of a fragment of b amino acids from (i) the amino acid sequence encoded by a polynucleotide shown in SEQ ID NO:11, 12 or 13; (ii) any one of SEQ ID NOS:46-49, 50-55, 56-57 or 58; C is an amino acid sequence consisting of c amino acids; and wherein said polypeptide is not a fragment of the amino acid sequence defined in (i) or (ii).

[0282]In this polypeptide, a+c is at least 1 (e.g. at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 etc.) and b is at least 7 (e.g. at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 etc.). It is preferred that the value of a+b+c is at least 9 (e.g. at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 etc.). It is preferred that the value of a+b+c is at most 200 (e.g. at most 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60, 50, 40, 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9).

[0283]H.2.4--Homologous Sequences

[0284]The invention provides a polypeptide having at least s % identity to: (a) the polypeptide sequences encoded by SEQ ID NOS:7-45; (b) a fragment of x amino acids of the polypeptide sequences encoded by SEQ ID NOS:7-45; (c) the polypeptide sequences SEQ ID NOS:46-58; (d) a fragment of x amino acids of the polypeptide sequences SEQ ID NOS:46-58. The value of s is at least 35 (e.g. at least 40, 45, 50, 55, 60, 65, 70, 75, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 99.9 etc.). The value of x is at least 7 (e.g. 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100.

[0285]These polypeptides include naturally-occurring variants (e.g. allelic variants, etc.), homologs, orthologs, and functional mutants.

[0286]The invention thus encompasses variants of the naturally-occurring polypeptides, wherein such variants are homologous or substantially similar to the naturally occurring polypeptide, and can be of an origin of the same or different species as the naturally occurring polypeptide (e.g. human, murine, or some other species that naturally expresses the recited polypeptide, usually a mammalian species). These polypeptide variants are encoded by polynucleotides that are within the scope of the invention, and the genetic code can be used to select appropriate codons to construct the corresponding variants.

[0287]H.2.5--Preferred HERV-K(CH) Sequences

[0288]The invention provides polypeptides, such as those shown in SEQ ID NOS:46-58, encoded by HERV-K(CH) polynucleotides that are differentially expressed in prostate cancer cells. Such polypeptides are referred to herein as "polypeptides associated with prostate cancer" or "HERV-K(CH) polypeptides". The polypeptides can be used to generate antibodies specific for a polypeptide associated with prostate cancer, which antibodies are in turn useful in diagnostic methods, prognostic methods, therametric methods, and the like as discussed in more detail herein. Polypeptides are also useful as targets for therapeutic intervention, as discussed in more detail herein.

[0289]Preferred polypeptides are encoded by polynucleotides of the invention.

[0290]H.2.6--General Features of Polypeptides of the Invention

[0291]General features of the polypeptides described in this section H.2 are the same as those described in section C.3 above.

[0292]The isolated polypeptides of the invention preferably comprise a polypeptide having a HERV-K(CH) sequence.

[0293]Polypeptides, such as polypeptides of the gag regions or polypeptides of the pol regions, encoded by the polynucleotides disclosed herein, such as polynucleotides having the sequences as shown in SEQ ID NOS:7-10 and SEQ ID NOS:14-39, and in isolates deposited with the ATCC and having ATCC accession numbers given in Table 7 and/or their corresponding full length genes, can be used to screen peptide libraries to identify binding partners, such as receptors, from among the encoded polypeptides. Peptide libraries can be synthesized according to methods known in the art (e.g. see refs. 151 & 152).

[0294]In general, the term "polypeptide" as used herein refers to both the full length polypeptide encoded by the recited polynucleotide, the polypeptide encoded by the gene represented by the recited polynucleotide, as well as portions or fragments thereof.

[0295]A polypeptide sequence that is "shown in" or "depicted in" a SEQ ID NO or Figure means that the sequence is present as an identical contiguous sequence in the SEQ ID NO or Figure. The term encompasses portions, or regions of the SEQ ID NO or Figure as well as the entire sequence contained within the SEQ ID NO or Figure.

[0296]H.3--Anti-HERV-K(CH) Antibodies

[0297]The present invention also provides isolated antibodies or antigen binding fragments thereof, that bind to a polypeptide of the present invention. The present invention also provides isolated antibodies or antigen binding fragments thereof, that bind to a polypeptide encoded by a polynucleotide of the present invention. The present invention also provides isolated antibodies that bind to a polypeptide of the invention, or antigen binding fragment thereof, encoded by a polynucleotide made by the method comprising the following steps i) immunizing a host animal with a composition comprising said polypeptide of the present invention, or antigen binding fragment thereof, and ii) collecting cells from said host expressing antibodies against the antigen or antigen binding fragment thereof. The present invention also provides isolated antibodies that bind to a polypeptide, or antigen binding fragment thereof, encoded by a polynucleotide of the present invention made by the method comprising the following steps: providing a cell line producing an antibody, wherein said antibody binds to a polypeptide of the present invention, or antigen binding fragment thereof, encoded by a polynucleotide of the present invention and culturing said cell line under conditions wherein said antibodies are produced. In additional embodiments, the antibodies are collected and monoclonal antibodies are produced using the collected host cells or genetic material derived from the collected host cells. In additional embodiments, the antibody is a polyclonal antibody. In a further embodiment, the antibody is attached to a solid surface or further comprises a detectable label.

[0298]The present invention further provides antibodies, which may be isolated antibodies, that bind a polypeptide encoded by a polynucleotide described herein. Antibodies can be provided in a composition comprising the antibody and a buffer and/or a pharmaceutically acceptable excipient. Antibodies specific for a polypeptide associated with cancer are useful in a variety of diagnostic and therapeutic methods, as discussed in detail herein.

[0299]Expression products of a polynucleotide described herein, as well as the corresponding mRNA (particularly mRNAs having distinct secondary and/or tertiary structures), cDNA, or complete gene, or fragments of said expression products can be prepared and used for raising antibodies for experimental, diagnostic, and therapeutic purposes. For polynucleotides to which a corresponding gene has not been assigned, this provides an additional method of identifying the corresponding gene. The polynucleotide or related cDNA is expressed as described above, and antibodies are prepared. These antibodies are specific to an epitope on the polypeptide encoded by the polynucleotide, and can precipitate or bind to the corresponding native polypeptide in a cell or tissue preparation or in a cell-free extract of an in vitro expression system.

[0300]Polyclonal or monoclonal antibodies to the HERV-K(CH) polypeptides or an epitope thereof can be made for use in immunoassays by any of a number of methods known in the art. By epitope reference is made to an antigenic determinant of a polypeptide. The presence of an epitope is demonstrated by the ability of an antibody to bind a polypeptide with specificity. Two antibodies are considered to be directed to the same epitope if they cross block each others binding to the same polypeptide.

[0301]One approach for preparing antibodies to a polypeptide is the selection and preparation of an amino acid sequence of all or part of the polypeptide, chemically synthesizing the sequence and injecting it into an appropriate animal, typically a rabbit, hamster or a mouse.

[0302]Oligopeptides can be selected as candidates for the production of an antibody to the HERV-K(CH) polypeptide based upon the oligopeptides lying in hydrophilic regions, which are thus likely to be exposed in the mature polypeptide. Additional oligopeptides can be determined using, for example, the Antigenicity Index [30].

[0303]In other embodiments of the present invention, humanized monoclonal antibodies are provided, wherein the antibodies are specific for HERV-K(CH) polypeptides and do not appreciably bind other HERV polypeptides. The phrase "humanized antibody" refers to an antibody derived from a non-human antibody, typically a mouse monoclonal antibody. Alternatively, a humanized antibody may be derived from a chimeric antibody that retains or substantially retains the antigen-binding properties of the parental, non-human, antibody but which exhibits diminished immunogenicity in humans as compared to the parental antibody. The phrase "chimeric antibody," as used herein, refers to an antibody containing sequence derived from two different antibodies (see, e.g. ref. 153) which typically originate from different species. Most typically, chimeric antibodies comprise human and murine antibody fragments, generally human constant and mouse variable regions.

[0304]In the present invention, HERV-K(CH) polypeptides of the invention and variants thereof are used to immunize a transgenic animal as described above. Monoclonal antibodies are made using methods known in the art, and the specificity of the antibodies is tested using isolated HERV-K(CH) polypeptides.

[0305]Methods for preparation of the human or primate HERV-K(CH) or an epitope thereof include, but are not limited to chemical synthesis, recombinant DNA techniques or isolation from biological samples. Chemical synthesis of a peptide can be performed, for example, by the classical Merrifeld method of solid phase peptide synthesis [154] or the FMOC strategy on a Rapid Automated Multiple Peptide Synthesis system (E. I. du Pont de Nemours Company, Wilmington, Del.) [155].

[0306]Polyclonal antibodies can be prepared by immunizing rabbits or other animals by injecting antigen followed by subsequent boosts at appropriate intervals. The animals are bled and sera assayed against purified HERV-K(CH) usually by ELISA or by bioassay based upon the ability to block the action of HERV-K(CH). When using avian species, e.g. chicken, turkey and the like, the antibody can be isolated from the yolk of the egg. Monoclonal antibodies can be prepared after the method of Milstein and Kohler by fusing splenocytes from immunized mice with continuously replicating tumor cells such as myeloma or lymphoma cells. [156, 157, 158]. The hybridoma cells so formed are then cloned by limiting dilution methods and supernates assayed for antibody production by ELISA, RIA or bioassay.

[0307]The unique ability of antibodies to recognize and specifically bind to target polypeptides provides an approach for treating an overexpression of the polypeptide. Thus, another aspect of the present invention provides for a method for preventing or treating diseases involving overexpression of a HERV-K(CH) polypeptide by treatment of a patient with specific antibodies to the HERV-K(CH) polypeptide.

[0308]Specific antibodies, either polyclonal or monoclonal, to the HERV-K(CH) polypeptides can be produced by any suitable method known in the art as discussed above. For example, murine or human monoclonal antibodies can be produced by hybridoma technology or, alternatively, the HERV-K(CH) polypeptides, or an immunologically active fragment thereof, or an anti-idiotypic antibody, or fragment thereof can be administered to an animal to elicit the production of antibodies capable of recognizing and binding to the HERV-K(CH) polypeptides. Such antibodies can be from any class of antibodies including, but not limited to IgG, IgA, IgM, IgD, and IgE or in the case of avian species, IgY and from any subclass of antibodies.

[0309]H.4--HER V-K(CH) Vectors and Host Cells

[0310]The present invention also encompasses vectors and host cells comprising an isolated polynucleotide of the present invention.

[0311]H.5--HERV-K(CH) Kits, Libraries and Arrays

[0312]The invention provides kits, electronic libraries and arrays comprising polynucleotides of the invention, for use in diagnosing the presence of cancer in a test sample.

[0313]In general, a library of polynucleotides is a collection of sequence information, which information is provided in either biochemical form (e.g. as a collection of polynucleotide molecules), or in electronic form (e.g. as a collection of polynucleotide sequences stored in a computer-readable form, as in a computer system and/or as part of a computer program). The sequence information of the polynucleotides can be used in a variety of ways, e.g. as a resource for gene discovery, as a representation of sequences expressed in a selected cell type (e.g. cell type markers), and/or as markers of a given disease or disease state. In general, a disease marker is a representation of a gene product that is present in all cells affected by disease either at an increased or decreased level relative to a normal cell (e.g. a cell of the same or similar type that is not substantially affected by disease). For example, a polynucleotide sequence in a library can be a polynucleotide that represents an mRNA, polypeptide, or other gene product encoded by the polynucleotide, that is either over-expressed or under-expressed in a tissue affected by cancer, such as prostate cancer relative to a normal (i.e. substantially disease-free) tissue, such as normal prostate tissue.

[0314]The nucleotide sequence information of the library can be embodied in any suitable form, e.g. electronic or biochemical forms. For example, a library of sequence information embodied in electronic form comprises an accessible computer data file (or, in biochemical form, a collection of nucleic acid molecules) that contains the representative nucleotide sequences of genes that are differentially expressed (e.g. over-expressed or under-expressed) as between, for example, i) a cancerous cell and a normal cell; ii) a cancerous cell and a dysplastic cell; iii) a cancerous cell and a cell affected by a disease or condition other than cancer; iv) a metastatic cancerous cell and a normal cell and/or non-metastatic cancerous cell; v) a malignant cancerous cell and a non-malignant cancerous cell (or a normal cell) and/or vi) a dysplastic cell relative to a normal cell. Other combinations and comparisons of cells affected by various diseases or stages of disease will be readily apparent to the ordinarily skilled artisan. Biochemical embodiments of the library include a collection of nucleic acids that have the sequences of the genes in the library, where the nucleic acids can correspond to the entire gene in the library or to a fragment thereof, as described in greater detail below.

[0315]The polynucleotide libraries of the subject invention generally comprise sequence information of a plurality of polynucleotide sequences, where at least one of the polynucleotides has a sequence of any of sequence described herein. By plurality is meant at least 2, usually at least 3 and can include up to all of the sequences described herein. The length and number of polynucleotides in the library will vary with the nature of the library, e.g. if the library is an oligonucleotide array, a cDNA array, a computer database of the sequence information, etc.

[0316]Where the library is an electronic library, the nucleic acid sequence information can be present in a variety of media. "Media" refers to a manufacture, other than an isolated nucleic acid molecule, that contains the sequence information of the present invention. Such a manufacture provides the genome sequence or a subset thereof in a form that can be examined by means not directly applicable to the sequence as it exists in a nucleic acid. For example, the nucleotide sequence of the present invention, e.g. the nucleic acid sequences of any of the polynucleotides of the sequences described herein, can be recorded on computer readable media, e.g. any medium that can be read and accessed directly by a computer. Such media include, but are not limited to: magnetic storage media, such as a floppy disc, a hard disc storage medium, and a magnetic tape; optical storage media such as CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media. One of skill in the art can readily appreciate how any of the presently known computer readable mediums can be used to create a manufacture comprising a recording of the present sequence information. "Recorded" refers to a process for storing information on computer readable medium, using any such methods as known in the art. Any convenient data storage structure can be chosen, based on the means used to access the stored information. A variety of data processor programs and formats can be used for storage, e.g. word processing text file, database format, etc. In addition to the sequence information, electronic versions of libraries comprising one or more sequence described herein can be provided in conjunction or connection with other computer-readable information and/or other types of computer-readable files (e.g. searchable files, executable files, etc, including, but not limited to, for example, search program software, etc.).

[0317]By providing the nucleotide sequence in computer readable form, the information can be accessed for a variety of purposes. Computer software to access sequence information is publicly available. For example, the gapped BLAST [159] and BLAZE [160] search algorithms on a Sybase system can be used to identify open reading frames (ORFs) within the genome that contain homology to ORFS from other organisms.

[0318]As used herein, "a computer-based system" refers to the hardware means, software means, and data storage means used to analyze the nucleotide sequence information of the present invention. The minimum hardware of the computer-based systems of the present invention comprises a central processing unit (CPU), input means, output means, and data storage means. A skilled artisan can readily appreciate that any one of the currently available computer-based system are suitable for use in the present invention. The data storage means can comprise any manufacture comprising a recording of the present sequence information as described above, or a memory access means that can access such a manufacture.

[0319]"Search means" refers to one or more programs implemented on the computer-based system, to compare a target sequence or target structural motif, or expression, levels of a polynucleotide in a sample, with the stored sequence information. Search means can be used to identify fragments or regions of the genome that match a particular target sequence or target motif. A variety of known algorithms are publicly known and commercially available, e.g. MacPattern (EMBL), BLASTN and BLASTX (NCBI). A "target sequence" can be any polynucleotide or amino acid sequence of six or more contiguous nucleotides or two or more amino acids, preferably from about 10 to 100 amino acids or from about 30 to 300 nt A variety of comparing means can be used to accomplish comparison of sequence information from a sample (e.g. to analyze target sequences, target motifs, or relative expression levels) with the data storage means. A skilled artisan can readily recognize that any one of the publicly available homology search programs can be used as the search means for the computer based systems of the present invention to accomplish comparison of target sequences and motifs. Computer programs to analyze expression levels in a sample and in controls are also known in the art.

[0320]A "target structural motif," or "target motif," refers to any rationally selected sequence or combination of sequences in which the sequence(s) are chosen based on a three-dimensional configuration that is formed upon the folding of the target motif, or on consensus sequences of regulatory or active sites. There are a variety of target motifs known in the art. Protein target motifs include, but are not limited to, enzyme active sites and signal sequences. Nucleic acid target motifs include, but are not limited to, hairpin structures, promoter sequences and other expression elements such as binding sites for transcription factors.

[0321]A variety of structural formats for the input and output means can be used to input and output the information in the computer-based systems of the present invention. One format for an output means ranks the relative expression levels of different polynucleotides. Such presentation provides a skilled artisan with a ranking of relative expression levels to determine a gene expression profile.

[0322]As discussed above, the "library" as used herein also encompasses biochemical libraries of the polynucleotides of the sequences described herein, e.g. collections of nucleic acids representing the provided polynucleotides. The biochemical libraries can take a variety of forms, e.g. a solution of cDNAs, a pattern of probe nucleic acids stably associated with a surface of a solid support (i.e. an array) and the like. Of particular interest are nucleic acid arrays in which one or more of the genes described herein is represented by a sequence on the array. By array is meant an article of manufacture that has at least a substrate with at least two distinct nucleic acid targets on one of its surfaces, where the number of distinct nucleic acids can be considerably higher, typically being at least 10 nt, usually at least 20 nt and often at least 25 nt. A variety of different array formats have been developed and are known to those of skill in the art. The arrays of the subject invention find use in a variety of applications, including gene expression analysis, drug screening, mutation analysis and the like, as disclosed in the above-listed exemplary patent documents.

[0323]In addition to the above nucleic acid libraries, analogous libraries of polypeptides are also provided, where the where the polypeptides of the library will represent at least a portion of the polypeptides encoded by a gene corresponding to a sequence described herein.

[0324]Polynucleotide arrays provide a high throughput technique that can assay a large number of polynucleotides or polypeptides in a sample. This technology can be used as a tool to test for differential expression. A variety of methods of producing arrays, as well as variations of these methods, are known in the art and contemplated for use in the invention. For example, arrays can be created by spotting polynucleotide probes onto a substrate (e.g. glass, nitrocellulose, etc.) in a two-dimensional matrix or array having bound probes. The probes can be bound to the substrate by either covalent bonds or by non-specific interactions, such as hydrophobic interactions. Samples of polynucleotides can be detectably labeled (e.g. using radioactive or fluorescent labels) and then hybridized to the probes. Double stranded polynucleotides, comprising the labeled sample polynucleotides bound to probe polynucleotides, can be detected once the unbound portion of the sample is washed away. Alternatively, the polynucleotides of the test sample can be immobilized on the array, and the probes detectably labeled. Techniques for constructing arrays and methods of using these arrays are described in, for example, references 161 to 177.

[0325]Arrays can be used to, for example, examine differential expression of genes and can be used to determine gene function. For example, arrays can be used to detect differential expression of a gene corresponding to a polynucleotide described herein, where expression is compared between a test cell and control cell (e.g. cancer cells and normal cells). For example, high expression of a particular message in a cancer cell, which is not observed in a corresponding normal cell, can indicate a cancer specific gene product. Exemplary uses of arrays are further described in, for example, references 178 and 179. Furthermore, many variations on methods of detection using arrays are well within the skill in the art and within the scope of the present invention. For example, rather than immobilizing the probe to a solid support, the test sample can be immobilized on a solid support which is then contacted with the probe.

[0326]A gene or polynucleotide that is differentially expressed in a cancer cell when the polynucleotide is detected at higher or lower levels in cancer compared with a cell of the same cell type that is not cancerous. Typically, screening for polynucleotides differentially expressed focuses on a polynucleotide that is expressed such that, for example, mRNA is found at levels at least about 25%, at least about 50% to about 75%, at least about 90%, preferably at least about 2-fold, more preferably at least about 5-fold, at least about 10-fold, or at least about 50-fold or more, higher (e.g. overexpressed) or lower (e.g. underexpressed) in a cancer cell when compared with a cell of the same cell type that is not cancerous. The comparison can be made between two tissues, for example, if one is using in situ hybridization or another assay method that allows some degree of discrimination among cell types in the tissue. The comparison may also be made between cells removed from their tissue source. Thus, a polypeptide encoded by a polynucleotide that is differentially expressed in a cancer cell would be of clinical significance with respect to cancer.

[0327]In one preferred embodiment of the present invention, an array comprises at least two polynucleotides, each having a sequence selected from the group consisting of SEQ ID NOS:14-39 and polynucleotides present in isolates deposited with the ATCC and having ATCC accession numbers PTA-2561, PTA-2572, PTA-2566, PTA-2571, PTA-2562, PTA-2573, PTA-2560, PTA-2565, PTA-2568, PTA-2564, PTA-2569, PTA-2567, PTA-2559, PTA-2563, PTA-2570. In another preferred embodiment, an array comprises at least one polynucleotide having a sequence selected from the group consisting of SEQ ID NOS:14-39 and polynucleotides present in isolates deposited with the ATCC and having ATCC accession numbers PTA-2561, PTA-2572, PTA-2566, PTA-2571, PTA-2562, PTA-2573, PTA-2560, PTA-2565, PTA-2568, PTA-2564, PTA-2569, PTA-2567, PTA-2559, PTA-2563, PTA-2570 and at least one of a polynucleotide having a sequence shown in SEQ ID NO:42 or 43.

[0328]The polynucleotides described herein, as well as their gene products, are of particular interest as genetic or biochemical markers (e.g. in blood or tissues) that will detect the earliest changes along the carcinogenesis pathway and/or to monitor the efficacy of various therapies and preventive interventions. For example, the level of expression of certain polynucleotides can be indicative of a poorer prognosis, and therefore warrant more aggressive chemo- or radio-therapy for a patient or vice versa. The correlation of novel surrogate tumor specific features with response to treatment and outcome in patients can define prognostic indicators that allow the design of tailored therapy based on the molecular profile of the tumor. These therapies include antibody targeting, antagonists (e.g. small molecules), and gene therapy. Determining expression of certain polynucleotides and comparison of a patients profile with known expression in normal tissue and variants of the disease allows a determination of the best possible treatment for a patient, both in terms of specificity of treatment and in terms of comfort level of the patient. Polynucleotide expression can also be used to better classify, and thus diagnose and treat, different forms and disease states of cancer. Two classifications widely used in oncology that can benefit from identification of the expression levels of the genes corresponding to the polynucleotides described herein are staging of the cancerous disorder, and grading the nature of the cancerous tissue.

[0329]The polynucleotides that correspond to differentially expressed genes, as well as their encoded gene products, can be useful to monitor patients having or susceptible to cancer to detect potentially malignant events at a molecular level before they are detectable at a gross morphological level. In addition, the polynucleotides described herein, as well as the genes corresponding to such polynucleotides, can be useful as therametrics, e.g. to assess the effectiveness of therapy by using the polynucleotides or their encoded gene products, to assess, for example, tumor burden in the patient before, during, and after therapy.

[0330]Furthermore, a polynucleotide identified as corresponding to a gene that is differentially expressed in, and thus is important for, one type of cancer can also have implications for development or risk of development of other types of cancer, e.g. where a polynucleotide represents a gene differentially expressed across various cancer types.

[0331]In another embodiment, the diagnostic and/or prognostic methods of the invention involve detection of expression of a selected set of genes in a test sample to produce a test expression pattern (TEP). The TEP is compared to a reference expression pattern (REP), which is generated by detection of expression of the selected set of genes in a reference sample (e.g. a positive or negative control sample). The selected set of genes includes at least one of the genes of the invention, which genes correspond to the polynucleotide sequences described herein. Of particular interest is a selected set of genes that includes gene differentially expressed in the disease for which the test sample is to be screened.

[0332]"Reference sequences" or "reference polynucleotides" as used herein in the context of differential gene expression analysis and diagnosis/prognosis refers to a selected set of polynucleotides, which selected set includes at least one or more of the differentially expressed polynucleotides described herein. A plurality of reference sequences, preferably comprising positive and negative control sequences, can be included as reference sequences. Additional suitable reference sequences are found in GenBank, Unigene, and other nucleotide sequence databases (including, e.g. expressed sequence tag (EST), partial, and full-length sequences).

[0333]"Reference array" means an array having reference sequences for use in hybridization with a sample, where the reference sequences include all, at least one of, or any subset of the differentially expressed polynucleotides described herein. Usually such an array will include at least 2 different reference sequences, and can include any one or all of the provided differentially expressed sequences. Arrays of interest can further comprise sequences, including polymorphisms, of other genetic sequences, particularly other sequences of interest for screening for a disease or disorder (e.g. cancer, dysplasia, or other related or unrelated diseases, disorders, or conditions). The oligonucleotide sequence on the array will usually be at least about 12 nt in length, and can be of about the length of the provided sequences, or can extend into the flanking regions to generate fragments of 100 nt to 200 nt in length or more. Reference arrays can be produced according to any suitable methods known in the art. For example, methods of producing large arrays of oligonucleotides are described in references 180 & 181 using light-directed synthesis techniques. Using a computer controlled system, a heterogeneous array of monomers is converted, through simultaneous coupling at a number of reaction sites, into a heterogeneous array of polymers. Alternatively, microarrays are generated by deposition of pre-synthesized oligonucleotides onto a solid substrate, for example as described in reference 182.

[0334]A "reference expression pattern" or "REP" as used herein refers to the relative levels of expression of a selected set of genes, particularly of differentially expressed genes, that is associated with a selected cell type, e.g. a normal cell, a cancerous cell, a cell exposed to an environmental stimulus, and the like. A "test expression pattern" or "TEP" refers to relative levels of expression of a selected set of genes, particularly of differentially expressed genes, in a test sample (e.g. a cell of unknown or suspected disease state, from which mRNA is isolated).

[0335]REPs can be generated in a variety of ways according to methods well known in the art. For example, REPs can be generated by hybridizing a control sample to an array having a selected set of polynucleotides (particularly a selected set of differentially expressed polynucleotides), acquiring the hybridization data from the array, and storing the data in a format that allows for ready comparison of the REP with a TEP. Alternatively, all expressed sequences in a control sample can be isolated and sequenced, e.g. by isolating mRNA from a control sample, converting the mRNA into cDNA, and sequencing the cDNA. The resulting sequence information roughly or precisely reflects the identity and relative number of expressed sequences in the sample. The sequence information can then be stored in a format (e.g. a computer-readable format) that allows for ready comparison of the REP with a TEP. The REP can be normalized prior to or after data storage, and/or can be processed to selectively remove sequences of expressed genes that are of less interest or that might complicate analysis (e.g. some or all of the sequences associated with housekeeping genes can be eliminated from REP data).

[0336]TEPs can be generated in a manner similar to REPs, e.g. by hybridizing a test sample to an array having a selected set of polynucleotides, particularly a selected set of differentially expressed polynucleotides, acquiring the hybridization data from the array, and storing the data in a format that allows for ready comparison of the TEP with a REP. The REP and TEP to be used in a comparison can be generated simultaneously, or the TEP can be compared to previously generated and stored REPs.

[0337]In one embodiment of the invention, comparison of a TEP with a REP involves hybridizing a test sample with an array, where the reference array has one or more reference sequences for use in hybridization with a sample. The reference sequences include all, at least one of, or any subset of the differentially expressed polynucleotides described herein. Hybridization data for the test sample is acquired, the data normalized, and the produced TEP compared with a REP generated using an array having the same or similar selected set of differentially expressed polynucleotides. Probes that correspond to sequences differentially expressed between the two samples will show decreased or increased hybridization efficiency for one of the samples relative to the other.

[0338]Methods for collection of data from hybridization of samples with a reference arrays are well known in the art. For example, the polynucleotides of the reference and test samples can be generated using a detectable fluorescent label, and hybridization of the polynucleotides in the samples detected by scanning the microarrays for the presence of the detectable label using, for example, a microscope and light source for directing light at a substrate. A photon counter detects fluorescence from the substrate, while an x-y translation stage varies the location of the substrate. A confocal detection device that can be used in the subject methods is described in reference 183. A scanning laser microscope is described in reference 163. A scan, using the appropriate excitation line, is performed for each fluorophore used. The digital images generated from the scan are then combined for subsequent analysis. For any particular array element, the ratio of the fluorescent signal from one sample (e.g. a test sample) is compared to the fluorescent signal from another sample (e.g. a reference sample), and the relative signal intensity determined.

[0339]Methods for analyzing the data collected from hybridization to arrays are well known in the art. For example, where detection of hybridization involves a fluorescent label, data analysis can include the steps of determining fluorescent intensity as a function of substrate position from the data collected, removing outliers, i.e. data deviating from a predetermined statistical distribution, and calculating the relative binding affinity of the targets from the remaining data. The resulting data can be displayed as an image with the intensity in each region varying according to the binding affinity between targets and probes.

[0340]In general, the test sample is classified as having a gene expression profile corresponding to that associated with a disease or non-disease state by comparing the TEP generated from the test sample to one or more REPs generated from reference samples (e.g. from samples associated with cancer or specific stages of cancer, dysplasia, samples affected by a disease other than cancer, normal samples, etc.). The criteria for a match or a substantial match between a TEP and a REP include expression of the same or substantially the same set of reference genes, as well as expression of these reference genes at substantially the same levels (e.g. no significant difference between the samples for a signal associated with a selected reference sequence after normalization of the samples, or at least no greater than about 25% to about 40% difference in signal strength for a given reference sequence. In general, a pattern match between a TEP and a REP includes a match in expression, preferably a match in qualitative or quantitative expression level, of at least one of, all or any subset of the differentially expressed genes of the invention.

[0341]Pattern matching can be performed manually, or can be performed using a computer program. Methods for preparation of substrate matrices (e.g. arrays), design of oligonucleotides for use with such matrices, labeling of probes, hybridization conditions, scanning of hybridized matrices, and analysis of patterns generated, including comparison analysis, are described e.g. in reference 184.

[0342]H.6--HERV-K(CH)-Based Diagnostic Methods

[0343]The invention provides methods for diagnosing the presence of cancer in a test sample associated with expression of a polynucleotide in a test cell sample, comprising the steps of: i) detecting a level of expression of at least one polynucleotide of the invention, or a fragment thereof, or at least one polynucleotide found in an isolate selected from the group consisting of ATCC accession numbers given in Table 7, or a fragment thereof; and ii) comparing said level of expression of the polynucleotide in the test sample with a level of expression of polynucleotide in the control cell sample, wherein differential expression of the polynucleotide in the test cell sample relative to the level of polynucleotide expression in the control cell sample is indicative of the presence of cancer in the test cell sample.

[0344]In some embodiments of the present invention, the cancer is prostate cancer. In other embodiments of the present invention, the cancer is testicular cancer.

[0345]In yet other embodiments of the present invention, the detecting is measuring the level of an RNA transcript; measuring the level of a polynucleotide; or measuring by a method including PCR, TMA, bDNA, NAT or Nasba. In further embodiments, the polynucleotide is attached to a solid support.

[0346]The present invention also provides compositions comprising a test cell sample and an isolated polynucleotide of the present invention. The present invention further provides methods for detecting cancer associated with expression of a polypeptide in a test cell sample, comprising the steps of: i) detecting a level of expression of at least one polypeptide of the invention, or a fragment thereof and ii) comparing said level of expression of the polypeptide in the test sample with a level of expression of polypeptide in the control cell sample, wherein an altered level of expression of the polypeptide in the test cell sample relative to the level of expression of the polypeptide in the control cell sample is indicative of the presence of cancer in the test cell sample. The present invention also provides methods for detecting cancer associated with the presence of an antibody in a test cell sample, comprising the steps of i) detecting a level of an antibody of the present invention, and ii) comparing said level of said antibody in the test sample with a level of said antibody in the control cell sample, wherein an altered level of antibody in said test cell sample relative to the level of antibody in the control cell sample is indicative of the presence of cancer in the test cell sample. In some embodiments, the cancer is prostate cancer and in other embodiments, the cancer is testicular cancer.

[0347]This invention also provides methods for detecting cancer associated with elevated levels of HERV-K(CH) polynucleotides, in particular in prostate cancer, by means of (i) detecting polynucleotides having at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or at least 100% identity to the polynucleotide shown in SEQ ID NOS:7-10 or to polynucleotides in isolates deposited with the ATCC and having ATCC deposit accession numbers PTA-2561, PTA-2572, PTA-2566, PTA-2571, PTA-2562, PTA-2573, PTA-2560, PTA-2565, PTA-2568, PTA-2564, PTA-2569, PTA-2567, PTA-2559, PTA-2563, PTA-2570, as measured by the alignment program GCG Gap (Suite Version 10.1) using the default parameters: open gap=3 and extend gap=1 or polynucleotides hybridizing under high stringency conditions to the polynucleotide shown in SEQ ID NOS:7-10; (ii) detecting polypeptides, or fragments thereof encoded by the sequences of (i); and (iii) detecting antibodies specific for one or more of the polypeptides. Furthermore, (iv) detecting particles associated with overexpression of HERV-K(CH) polynucleotides may also be used in the diagnosis of cancer, in particular, prostate cancer, and monitoring its progression.

[0348]The treatment regimen of a prostate or other cancer associated with elevated levels of HERV-K(CH) polynucleotides may also monitored by detecting levels of the polynucleotides and polypeptides in order to assess the staging of the cancer and/or efficacy of particular cancer therapies.

[0349]The present invention provides methods of using the polynucleotides described herein for detecting cancer cells, in particular prostate cancer cells, facilitating diagnosis of cancer and the severity of a cancer (e.g. tumor grade, tumor burden, and the like) in a subject, facilitating a determination of the prognosis of a subject, and assessing the responsiveness of the subject to therapy (e.g. by providing a measure of therapeutic effect through, for example, assessing tumor burden during or following a chemotherapeutic regimen). Detection can be based on detection of a polynucleotide that is differentially expressed in a cancer cell, and/or detection of a polypeptide encoded by a polynucleotide that is differentially expressed in a cancer cell. The detection methods of the invention can be conducted in vitro or in vivo, on isolated cells, or in whole tissues or a bodily fluid e.g. blood, plasma, serum, urine, and the like).

[0350]The detection methods can be provided as part of a kit. Thus, the invention further provides kits for detecting the presence and/or a level of a polynucleotide that is differentially expressed in a cancer cell (e.g. by detection of an mRNA encoded by the differentially expressed gene of interest), and/or a polypeptide encoded thereby, in a biological sample. Procedures using these kits can be performed by clinical laboratories, experimental laboratories, medical practitioners, or private individuals. The kits of the invention for detecting a polypeptide encoded by a polynucleotide that is differentially expressed in a cancer cell may comprise a moiety that specifically binds the polypeptide, which may be an antibody that binds the polypeptide or fragment thereof. The kits of the invention used for detecting a polynucleotide that is differentially expressed in a prostate cancer cell may comprise a moiety that specifically hybridizes to such a polynucleotide. The kit may optionally provide additional components that are useful in the procedure, including, but not limited to, buffers, developing reagents, labels, reacting surfaces, means for detection, control samples, standards, instructions, and interpretive information.

[0351]Accordingly, the present invention provides kits for detecting prostate cancer comprising at least one of polynucleotides having the sequence as shown in SEQ ID NOS:7-10, SEQ ID NOS:14-39, or fragments thereof, or having the sequence found in an isolate deposited with the ATCC and having ATCC accession numbers PTA-2561, PTA-2572, PTA-2566, PTA-2571, PTA-2562, PTA-2573, PTA-2560, PTA-2565, PTA-2568, PTA-2564, PTA-2569, PTA-2567, PTA-2559, PTA-2563, PTA-2570 or fragments thereof.

[0352]In some embodiments, methods are provided for detecting a polypeptide encoded by a gene differentially expressed in a prostate cancer cell. Any of a variety of known methods can be used for detection, including, but not limited to, immunoassay, using antibody that binds the polypeptide, e.g. by enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and the like; and functional assays for the encoded polypeptide, e.g. binding activity or enzymatic activity.

[0353]As will be readily apparent to the ordinarily skilled artisan upon reading the present specification, the detection methods and other methods described herein can be readily varied. Such variations are within the intended scope of the invention. For example, in the above detection scheme, the probe for use in detection can be immobilized on a solid support, and the test sample contacted with the immobilized probe. Binding of the test sample to the probe can then be detected in a variety of ways, e.g. by detecting a detectable label bound to the test sample to facilitate detected of test sample-immobilized probe complexes.

[0354]The present invention further provides methods for detecting the presence of and/or measuring a level of a polypeptide in a biological sample, which polypeptide is encoded by a polynucleotide that is differentially expressed in a prostate cancer cell, using an antibody specific for the encoded polypeptide. The methods generally comprise: a) contacting the sample with an antibody specific for a polypeptide encoded by a polynucleotide that is differentially expressed in a prostate cancer cell; and b) detecting binding between the antibody and molecules of the sample.

[0355]Detection of specific binding of the antibody specific for the encoded prostate cancer-associated polypeptide, when compared to a suitable control is an indication that encoded polypeptide is present in the sample. Suitable controls include a sample known not to contain the encoded polypeptide or known not to contain elevated levels of the polypeptide; such as normal prostate tissue, and a sample contacted with an antibody not specific for the encoded polypeptide, e.g. an anti-idiotype antibody. A variety of methods to detect specific antibody-antigen interactions are known in the art and can be used in the method, including, but not limited to, standard immunohistological methods, immunoprecipitation, an enzyme immunoassay, and a radioimmunoassay. In general, the specific antibody will be detectably labeled, either directly or indirectly. Direct labels include radioisotopes; enzymes whose products are detectable (e.g. luciferase, β-galactosidase, and the like); fluorescent labels (e.g. fluorescein isothiocyanate, rhodamine, phycoerythrin, and the like); fluorescence emitting metals, e.g. ¹⁵²Eu, or others of the lanthanide series, attached to the antibody through metal chelating groups such as EDTA; chemiluminescent compounds, e.g. luminol, isoluminol, acridinium salts, and the like; bioluminescent compounds, e.g. luciferin, aequorin (green fluorescent protein), and the like. The antibody may be attached (coupled) to an insoluble support, such as a polystyrene plate or a bead. Indirect labels include second antibodies specific for antibodies specific for the encoded polypeptide ("first specific antibody"), wherein the second antibody is labeled as described above; and members of specific binding pairs, e.g. biotin-avidin, and the like. The biological sample may be brought into contact with and immobilized on a solid support or carrier, such as nitrocellulose, that is capable of immobilizing cells, cell particles, or soluble proteins. The support may then be washed with suitable buffers, followed by contacting with a detectably-labeled first specific antibody. Detection methods are known in the art and will be chosen as appropriate to the signal emitted by the detectable label. Detection is generally accomplished in comparison to suitable controls, and to appropriate standards.

[0356]In some embodiments, the methods are adapted for use in vivo, e.g. to locate or identify sites where cancer cells, such as prostate cancer cells, are present.

[0357]In some embodiments, methods are provided for detecting a cancer cell by detecting expression in the cell of a transcript that is differentially expressed in a cancer cell. Any of a variety of known methods can be used for detection, including, but not limited to, detection of a transcript by hybridization with a polynucleotide that hybridizes to a polynucleotide that is differentially expressed in a prostate cancer cell; detection of a transcript by a polymerase chain reaction using specific oligonucleotide primers; in situ hybridization of a cell using as a probe a polynucleotide that hybridizes to a gene that is differentially expressed in a prostate cancer cell. The methods can be used to detect and/or measure mRNA levels of a gene that is differentially expressed in a prostate cancer cell. In some embodiments, the methods comprise: a) contacting a sample with a polynucleotide that corresponds to a differentially expressed gene described herein under conditions that allow hybridization; and b) detecting hybridization, if any.

[0358]Detection of differential hybridization, when compared to a suitable control, is an indication of the presence in the sample of a polynucleotide that is differentially expressed in a cancer cell. Appropriate controls include, for example, a sample which is known not to contain a polynucleotide that is differentially expressed in a cancer cell, and use of a labeled polynucleotide of the same "sense" as the polynucleotide that is differentially expressed in the cancer cell. In a preferred embodiment, the cancer cell is a prostate cancer cell. Conditions that allow hybridization are known in the art, and have been described in more detail above. Detection can also be accomplished by any known method, including, but not limited to, in situ hybridization, PCR (polymerase chain reaction), RT-PCR (reverse transcription-PCR), TMA, bDNA, and Nasba and "Northern" or RNA blotting, or combinations of such techniques, using a suitably labeled polynucleotide. A variety of labels and labeling methods for polynucleotides are known in the art and can be used in the assay methods of the invention. Specific hybridization can be determined by comparison to appropriate controls.

[0359]Polynucleotide generally comprising at least 10 nt, at least 12 nt or at least 15 contiguous nucleotides of a polynucleotide provided herein, such as, for example, those having the sequence as depicted in SEQ ID NOS:7-10, and 3-28, are used for a variety of purposes, such as probes for detection of and/or measurement of, transcription levels of a polynucleotide that is differentially expressed in a prostate cancer cell. A probe that hybridizes specifically to a polynucleotide disclosed herein should provide a detection signal at least 5-, 10-, or 20-fold higher than the background hybridization provided with other unrelated sequences. It should be noted that "probe" as used herein is meant to refer to a polynucleotide sequence used to detect a differentially expressed gene product in a test sample. As will be readily appreciated by the ordinarily skilled artisan, the probe can be detectably labeled and contacted with, for example, an array comprising immobilized polynucleotides obtained from a test sample (e.g. mRNA). Alternatively, the probe can be immobilized on an array and the test sample detectably labeled. These and other variations of the methods of the invention are well within the skill in the art and are within the scope of the invention.

[0360]Nucleotide probes are used to detect expression of a gene corresponding to the provided polynucleotide. In Northern blots, mRNA is separated electrophoretically and contacted with a probe. A probe is detected as hybridizing to an mRNA species of a particular size. The amount of hybridization can be quantitated to determine relative amounts of expression, for example under a particular condition. Probes are used for in situ hybridization to cells to detect expression. Probes can also be used in vivo for diagnostic detection of hybridizing sequences. Probes are typically labeled with a radioactive isotope. Other types of detectable labels can be used such as chromophores, fluorophores, and enzymes. Other examples of nucleotide hybridization assays are described in refs. 185 and 186.

[0361]PCR is another means for detecting small amounts of target nucleic acids (see, e.g. refs. 187, 188 & 189). Two primer polynucleotides nucleotides that hybridize with the target nucleic acids are used to prime the reaction. The primers can be composed of sequence within or 3' and 5' to the HERV-K(CH) polynucleotides disclosed herein. Alternatively, if the primers are 3' and 5' to these polynucleotides, they need not hybridize to them or the complements. After amplification of the target with a thermostable polymerase, the amplified target nucleic acids can be detected by methods known in the art (e.g. Southern blot). mRNA or cDNA can also be detected by traditional blotting techniques (e.g. Southern blot, Northern blot, etc.) described in ref. 8 (e.g. without PCR amplification). In general, mRNA or cDNA generated from mRNA using a polymerase enzyme can be purified and separated using gel electrophoresis, and transferred to a solid support, such as nitrocellulose. The solid support is exposed to a labeled probe, washed to remove any unhybridized probe, and duplexes containing the labeled probe are detected.

[0362]Methods using PCR amplification can be performed on the DNA from a single cell, although it is convenient to use at least about 10⁵ cells. The use of the polymerase chain reaction is described in ref. 190, and a review of techniques may be found in pages 14.2 to 14.33 of reference 8. A detectable label may be included in the amplification reaction. Suitable detectable labels include fluorochromes, (e.g. fluorescein isothiocyanate (FITC), rhodamine, Texas Red, phycoerythrin, allophycocyanin, 6-carboxyfluorescein (6-FAM), 6-carboxy-X-rhodamine (ROX), 2',7'-dimethoxy-4',5'-dichloro-6-carboxyfluorescein, 5-carboxyfluorescein (5-FAM), N,N,N',N'-tetramethyl-6-carboxyrhodamine (TAMRA), or 6-carboxy-2',4',7',4,7-hexachlorofluorescein (HEX)), radioactive labels, (e.g. ³²P, ³5S, ³H, etc.), and the like. The label may be a two stage system, where the polynucleotides is conjugated to biotin, haptens, etc. having a high affinity binding partner, e.g. avidin, specific antibodies, etc., where the binding partner is conjugated to a detectable label. The label may be conjugated to one or both of the primers. Alternatively, the pool of nucleotides used in the amplification is labeled, so as to incorporate the label into the amplification product.

[0363]The present invention further relates to methods of detecting/diagnosing a neoplastic or preneoplastic condition in a mammal (for example, a human).

[0364]Examples of conditions that can be detected/diagnosed in accordance with these methods include, but are not limited to prostate cancers. Polynucleotides corresponding to genes that exhibit the appropriate expression pattern can be used to detect prostate cancer in a subject. Reference 191 reviews markers of cancer.

[0365]One detection/diagnostic method comprises: (a) obtaining from a mammal (eg a human) a biological sample, (b) detecting the presence in the sample of a HERV-K(CH) polypeptide and (c) comparing the amount of product present with that in a control sample. In accordance with this method, the presence in the sample of elevated levels of a HERV-K(CH) gene product indicates that the subject has a neoplastic or preneoplastic condition.

[0366]The compound is preferably a binding protein, e.g. an antibody, polyclonal or monoclonal, or antigen binding fragment thereof, which can be labeled with a detectable marker (eg fluorophore, chromophore or isotope, etc). Where appropriate, the compound can be attached to a solid support. Determination of formation of the complex can be effected by contacting the complex with a further compound (eg an antibody) that specifically binds to the first compound (or complex). Like the first compound, the further compound can be attached to a solid support and/or can be labeled with a detectable marker.

[0367]The identification of elevated levels of HERV-K(CH) polypeptide in accordance with the present invention makes possible the identification of subjects (patients) that are likely to benefit from adjuvant therapy. For example, a biological sample from a post-primary therapy subject (e.g. subject having undergone surgery) can be screened for the presence of circulating HERV-K(CH) polypeptide, the presence of elevated levels of the polypeptide, determined by studies of normal populations, being indicative of residual tumor tissue. Similarly, tissue from the cut site of a surgically removed tumor can be examined (e.g. by immunofluorescence), the presence of elevated levels of product (relative to the surrounding tissue) being indicative of incomplete removal of the tumor. The ability to identify such subjects makes it possible to tailor therapy to the needs of the particular subject. Subjects undergoing non-surgical therapy (e.g. chemotherapy or radiation therapy) can also be monitored, the presence in samples from such subjects of elevated levels of HERV-K(CH) polypeptide being indicative of the need for continued treatment. Staging of the disease (for example, for purposes of optimizing treatment regimens) can also be effected, for example, by prostate biopsy e.g. with antibody specific for a HERV-K(CH) polypeptide.

[0368]The present invention also relates to a kit that can be used in the detection of a HERV-K(CH) polypeptide. The kit can comprise a compound that specifically binds a HERV-K(CH) polypeptide, such as, for example, binding proteins including antibodies or binding fragments thereof (e.g. F(ab')₂ fragments) disposed within a container means. The kit can further comprise ancillary reagents, for processing the binding assay.

DEFINITIONS

[0369]The term "comprising" means "including" as well as "consisting" e.g. a composition "comprising" X may consist exclusively of X or may include something additional e.g. X+Y.

[0370]The term "about" in relation to a numerical value x means, for example, x±10%.

[0371]The terms "neoplastic cells", "neoplasia", "tumor", "tumor cells", "cancer" and "cancer cells", (used interchangeably) refer to cells which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation (i.e. de-regulated cell division). Neoplastic cells can be malignant or benign and include prostate cancer derived tissue.

BRIEF DESCRIPTION OF DRAWINGS

[0372]FIG. 1 is a schematic representation of a human endogenous retrovirus with a depiction of the HERV-K(CH) polynucleotides and their position relative to the retrovirus.

[0373]FIG. 2 is a schematic representation of open reading frames within the HERV-K(HML-2.HOM) (also known as `ERVK6`) genome [1].

[0374]FIG. 3 shows splicing events described in the prior art [16] for HERV-K mRNAs.

[0375]FIG. 4 shows splice sites identified near the 5' and 3' ends of the env ORF. The three reading frames are shaded differently.

[0376]FIG. 5 shows northern blot analysis of PCAV transcripts in cancer cell lines. The top arrow on the left shows the position of the genomic mRNA transcript. The next arrow shows the position of the env transcript. The bottom two arrows show the positions of other ORFs. The lanes contain RNA from the following cell lines: (1) Tera 1; (2) DU145; (3) PC3; (4) MDA Pca-2b; (5) LNCaP. Tera 1 is a teratocarcinoma cell line; the others are prostatic carcinoma cell lines.

[0377]FIG. 6 shows an alignment of env genomic DNA sequences from 27 HERV-K viruses. A consensus sequence (SEQ ID NO:157) is shown on the bottom line.

[0378]FIGS. 7-9 show alignments of inferred polypeptide sequences for gag (7), pol (8) and env (9) from various HERV-K viruses, together with consensus sequences (SEQ ID NOS:158-160).

MODES FOR CARRYING OUT THE INVENTION

[0379]Certain aspects of the present invention are described in greater detail in the non-limiting examples that follow. The examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all and only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

[0380]Source of Human Prostate Cell Samples and Isolation of Polynucleotides Expressed by them

[0381]Candidate polynucleotides that may represent genes differentially expressed in cancer were obtained from both publicly-available sources and from cDNA libraries generated from selected cell lines and patient tissues. A normalized cDNA library was prepared from one patient tumor tissue and cloned polynucleotides for spotting on microarrays were isolated from the library. Normal and tumor tissues from 13 patients were processed to generate T7 RNA polymerase transcribed polynucleotides, which were, in turn, assessed for expression in the microarrays. The tissues that served as sources for these libraries and polynucleotides are summarized in Table 4.

[0382]Normalization: The objective of normalization is to generate a cDNA library in which all transcripts expressed in a particular cell type or tissue are equally represented [refs. 192 & 193], and therefore isolation of as few as 30,000 recombinant clones in an optimally normalized library may represent the entire gene expression repertoire of a cell, estimated to number 10,000 per cell. The source materials for generating the normalized prostate libraries were cryopreserved prostate tumor tissue from a patient with Gleason grade 3+3 adenocarcinoma and normal prostate biopsies from a pool of at-risk subjects under medical surveillance. Prostate epithelia were harvested directly from frozen sections of tissue by laser capture microdissection (LCM, Arcturus Engineering Inc., Mountain View, Calif.), carried out according to methods well known in the art (e.g. ref. 194), to provide substantially homogenous cell samples.

[0383]Total RNA was extracted from LCM-harvested cells using RNeasy® Protect Kit (Qiagen, Valencia, Calif.), following manufacturer's recommended procedures. RNA was quantified using RiboGreen® RNA quantification kit (Molecular Probes, Inc. Eugene, Oreg.). One μg of total RNA was reverse transcribed and PCR amplified using SMART® PCR cDNA synthesis kit (ClonTech, Palo Alto, Calif.). The cDNA products were size-selected by agarose gel electrophoresis using standard procedures (ref. 8). The cDNA was extracted using Bio 101 Geneclean® II kit (Qbiogene, Carlsbad, Calif.). Normalization of the cDNA was carried out using kinetics of hybridization principles: 1.0 μg of cDNA was denatured by heat at 100° C. for 10 minutes, then incubated at 42° C. for 42 hours in the presence of 120 mM NaCl, 10 mM Tris.HCl (pH=8.0), 5 mM EDTA.Na.sup.+ and 50% formamide. Single-stranded cDNA ("normalized" cDNA) was purified by hydroxyapatite chromatography (#130-0520, BioRad, Hercules, Calif.) following the manufacturer's recommended procedures, amplified and converted to double-stranded cDNA by three cycles of PCR amplification, and cloned into plasmid vectors using standard procedures (ref 8). All primers/adaptors used in the normalization and cloning process are provided by the manufacturer in the SMART® PCR cDNA synthesis kit (ClonTech, Palo Alto, Calif.). Supercompetent cells (XL-2 Blue Ultracompetent Cells, Stratagene, Calif.) were transfected with the normalized cDNA libraries, plated on plated on solid media and grown overnight at 36° C.

[0384]Characterization of normalized libraries: The sequences of 10,000 recombinants per library were analyzed by capillary sequencing using the ABI PRISM 3700 DNA Analyzer (Applied Biosystems, California). To determine the representation of transcripts in a library, BLAST analysis was performed on the clone sequences to assign transcript identity to each isolated clone, i.e. the sequences of the isolated polynucleotides were first masked to eliminate low complexity sequences using the XBLAST masking program (refs. 195, 196 and 197). Generally, masking does not influence the final search results, except to eliminate sequences of relative little interest due to their low complexity, and to eliminate multiple "hits" based on similarity to repetitive regions common to multiple sequences e.g. Alu repeats. The remaining sequences were then used in a BLASTN vs. GenBank search. The sequences were also used as query sequence in a BLASTX vs. NRP (non-redundant proteins) database search.

[0385]Automated sequencing reactions were performed using a Perkin-Elmer PRISM Dye Terminator Cycle Sequencing Ready Reaction Kit containing AmpliTaq DNA Polymerase, FS, according to the manufacturer's directions. The reactions were cycled on a GeneAmp PCR System 9600 as per manufacturer's instructions, except that they were annealed at 20° C. or 30° C. for one minute. Sequencing reactions were ethanol precipitated, pellets were resuspended in 8 microliters of loading buffer, 1.5 microliters was loaded on a sequencing gel, and the data was collected by an ABI PRISM 3700 DNA Sequencer. (Applied Biosystems, Foster City, Calif.).

[0386]The number of times a sequence is represented in a library is determined by performing sequence identity analysis on cloned cDNA sequences and assigning transcript identity to each isolated clone. First, each sequence was checked to see if it was a mitochondrial, bacterial or ribosomal contaminant. Such sequences were excluded from the subsequent analysis. Second, sequence artifacts (e.g. vector and repetitive elements) were masked and/or removed from each sequence.

[0387]The remaining sequences were compared via BLAST [198] to GenBank and EST databases for gene identification and were compared with each other via FastA [199] to calculate the frequency of cDNA appearance in the normalized cDNA library. The sequences were also searched against the GenBank and GeneSeq nucleotide databases using the BLASTN program (BLASTN 1.3 MP [198]). Fourth, the sequences were analyzed against a non-redundant protein (NRP) database with the BLASTX program (BLASTX 1.3 MP [198]). This protein database is a combination of the Swiss-Prot, PIR, and NCBI GenPept protein databases. The BLASTX program was run using the default BLOSUM-62 substitution matrix with the filter parameter: "xnu+seg". The score cutoff utilized was 75.

[0388]Assembly of overlapping clones into contigs was done using the program Sequencher (Gene Codes Corp.; Ann Arbor, Mich.). The assembled contigs were analyzed using the programs in the GCG package (Genetic Computer Group, University Research Park, 575 Science Drive, Madison, Wis. 53711) Suite Version 10.1.

[0389]Summary of polynucleotides described herein: Table 6 provides a summary of polynucleotides isolated as described above and identified as corresponding to a differentially expressed gene (see below). Specifically, Table 6 provides: 1) the HERVK ORF for each clone ID; 2) the clone ID assigned to each sequence; 3) the % patients having the expression ratio of >/=2X; >/=2-5X; >/=5X; and less than 1/2 X; and the Tumor/Normal mRNA Expression Ratio per patient "Pat", eg, patient 93, patient 95, patient 96, etc.

[0390]Detection of Elevated Levels of cDNA Associated with Prostate Cancer Using Arrays

[0391]cDNA sequences representing a variety of candidate genes to be screened for differential expression in prostate cancer were assayed by hybridization on-polynucleotide arrays. The cDNA sequences included cDNA clones isolated from cell lines or tissues as described above. The cDNA sequences analyzed also included polynucleotides comprising sequence overlap with sequences in the Unigene database, and which encode a variety gene products of various origins, functionality, and levels of characterization. cDNAs were spotted onto reflective slides (Amersham) according to methods well known in the art at a density of 9,216 spots per slide representing 4608 sequences (including controls) spotted in duplicate, with approximately 0.8 μl of an approximately 200 ng/μl solution of cDNA.

[0392]PCR products of selected cDNA clones corresponding to the gene products of interest were prepared in a 50% DMSO solution. These PCR products were spotted onto Amersham aluminum microarray slides at a density of 9216 clones per array using a Molecular Dynamics Generation III spotting robot. Clones were spotted in duplicate, for a total of 4608 different sequences per chip.

[0393]cDNA probes were prepared from total RNA obtained by laser capture microdissection (LCM, Arcturus Enginering Inc., Mountain View, Calif.) of tumor tissue samples and normal tissue samples isolated from the patients described above.

[0394]Total RNA was first reverse transcribed into cDNA using a primer containing a T7 RNA polymerase promoter, followed by second strand DNA synthesis. cDNA was then transcribed in vitro to produce antisense RNA using the T7 promoter-mediated expression (e.g. ref. 200), and the antisense RNA was then converted into cDNA. The second set of cDNAs were again transcribed in vitro, using the T7 promoter, to provide antisense RNA. This antisense RNA was then fluorescently labeled, or the RNA was again converted into cDNA, allowing for third round of T7-mediated amplification to produce more antisense RNA. Thus the procedure provided for two or three rounds of in vitro transcription to produce the final RNA used for fluorescent labeling. Probes were labeled by making fluorescently labeled cDNA from the RNA starting material. Fluorescently-labeled cDNAs prepared from the tumor RNA sample were compared to fluorescently labeled cDNAs prepared from normal cell RNA sample. For example, the cDNA probes from the normal cells were labeled with Cy3 fluorescent dye (green) and cDNA probes prepared from the tumor cells were labeled with Cy5 fluorescent dye (red).

[0395]The differential expression assay was performed by mixing equal amounts of probes from tumor cells and normal cells of the same patient. The arrays were pre-hybridized by incubation for about 2 hrs at 60° C. in 5×SSC/0.2% SDS/1 mM EDTA, and then washed three times in water and twice in isopropanol. Following pre-hybridization of the array, the probe mixture was then hybridized to the array under conditions of high stringency (overnight at 42° C. in 50% formamide, 5×SSC, and 0.2% SDS. After hybridization, the array was washed at 55° C. three times as follows: 1) first wash in 1×SSC/0.2% SDS; 2) second wash in 0.1×SSC/0.2% SDS; and 3) third wash in 0.1×SSC.

[0396]The arrays were then scanned for green and red fluorescence using a Molecular Dynamics Generation III dual color laser-scanner/detector. The images were processed using BioDiscovery Autogene software, and the data from each scan set normalized. The experiment was repeated, this time labeling the two probes with the opposite color in order to perform the assay in both "color directions." Each experiment was sometimes repeated with two more slides (one in each color direction). The data from each scan was normalized, and the level fluorescence for each sequence on the array expressed as a ratio of the geometric mean of 8 replicate spots/genes from the four arrays or 4 replicate spots/gene from 2 arrays or some other permutation.

[0397]Table 6 summarizes the results for gene products differentially expressed in the prostate tumor samples relative to normal cells. The ratio of differential expression is expressed as the normalized hybridization signal associated with the tumor probe divided by the normalized hybridization signal with the normal probe; thus, a ratio greater than 1 indicates that the gene product is increased in expression in cancerous cells relative to normal cells, while a ratio of less than 1 indicates the opposite. The results from each patient are identified by "Pat" with the corresponding patient identification number. "Concordance" indicates the % of patients in which differential expression of the selected gene product in tumor cells was at least a two-fold different from normal cells.

[0398]In at least 79% of prostate patients assayed, 8 out of 10 genes, whose expression was elevated by at least 500%, were represented in HERV-K(CH) sequences.

[0399]Table 6 provides those gene products that were differentially expressed and were classified as gag, 5'-pol (reverse transcriptase) and 3'-pol (integrase) related sequences. It may be possible to examine the function of these gene products in development of cancer and metastasis through use of small molecule inhibitors known to affect the activity of such enzymes.

[0400]Analysis of the Prostate Cancer Associated Sequences

[0401]In order to determine whether there was homology to any known sequences, the PCR products of 16 different clones from one prostate tumor patient were sequenced. PCR products from these and other clones from the same library were spotted on DNA microarrays. RNA from 13 prostate tumor patients were assayed on the microarrays and then the full inserts of some of the 16 clones were sequenced (Table 6).

[0402]The 16 isolates were initially determined in a first pass sequencing reaction to have the sequences as shown in SEQ ID NOS:27-39, inclusive. The isolate from the normal prostate tissue was initially determined in a first pass sequencing reaction to have the sequence as shown in SEQ ID NO:41. A first pass sequencing reaction refers to a high-throughput process, where PCR reactions generate the sequencing template then sequencing is performed with one of the PCR primers, in a single direction. A search of public databases revealed that these 16 isolates have some degree of identity to regions of the human endogenous retrovirus HERV-K(II) sequence disclosed in Genbank accession number AB047240 and shown in SEQ ID NO:44, and also to HERV-K(10), but are nonetheless unique.

[0403]The isolates were subjected to a second round of nucleic acid sequencing and were found to have the sequences as shown in SEQ ID NOS:14-26, inclusive. The isolate from the normal prostate tissue was subjected to a second round of nucleic acid sequencing and found to have the sequence as shown in SEQ ID NO:40. This second round of sequencing is a customized process, where sequencing is performed on purified dsDNA template in a DNA vector. Sequencing is done from both ends of the template, forward and reverse, with primers designed from the flanking regions of the vector, and new primers are synthesized for every additional reaction needed to span the entire insert.

[0404]The Genbank disclosure of HERV-K(II) provides only an incomplete characterization of its genetic features and no association with any disease. The Genbank disclosure characterizes HERV-KII as having a gag gene located at nucleotide 2113-4116 and an env gene located at nucleotide 7437-8174. Detailed analysis of the reported HERV-K(II) sequence indicates that the HERV-K(II) genome includes regions related to gag, protease, 5'-end of pol (reverse transcriptase) and 3'-end of pol (integrase) domains of a retrovirus. Specifically, the location of the protease gene is from about nucleotide 3917 to about 4920 and the location of the polymerase domain is from about nucleotide 4797 to about 7468.

[0405]Composite HERV-K(CH) polynucleotide sequences are shown in SEQ ID NOS:7, 8, 9 and 10 and FIG. 1 provides a schematic illustration of a human endogenous retrovirus and the HERV-K(CH) species within the schematic illustration. SEQ ID NO:7 is a composite sequence of the polynucleotides SEQ ID NOS:14-16, inclusive, and has a consensus sequence as shown in SEQ ID NO:11. This region corresponds to the gag region of a human endogenous retrovirus. SEQ ID NOS:8 and 9 are composites sequence of the polynucleotides having a sequence as shown in SEQ ID NOS:17-20, inclusive, and has a consensus sequence as shown in SEQ ID NO:12. This region corresponds to the 5' pol region of a human endogenous retrovirus. SEQ ID NO:10 is a composite sequence of the polynucleotides having a sequence as shown in SEQ ID NOS:21-26, inclusive, and has a consensus sequence as shown in SEQ ID NO:13. This region corresponds to the 3' pol region of a human endogenous retrovirus

[0406]Homology to HERV-K(II) gag region varied from 87% to 99%. Homology to HERV-K(II) 5'-pol (reverse transcriptase) region varied from 87% to 97%. Homology to HERV-K(11) 3'-pol (integrase) region was approximately 89%. When compared to the human endogenous provirus HERV-K10, the homology of the gag region clones was approximately 79%, the 5'-pol region between 81% and 89% and the 3'-pol region was approximately 89%. Table 5 illustrates the homology of the sequences of the individual clones with the corresponding HERV-K(II) and HERV-K(10) regions. Because the presence of polyA stretches in the HERV-K(CH) sequences (and deposited isolates) may be an artifact of cloning, the % identity shown in Table 5 was determined with alignments performed with polynucleotides excluding the terminal polyA stretch.

[0407]Consensus polynucleotide sequences SEQ ID NOS:11-13 were generated with Multiple Sequence Alignment (MSA), a web implementation of the GCG Pileup and Pretty programs. The program uses a clustering algorithm similar to the Clustal program described in reference. The default values for the alignments and consensus extraction were 8 for gap open and 2 for gap extension. The poling plurality or minimum number of like sequences specified to assign a residue to the consensus sequence was 2.

[0408]The polynucleotide sequences shown in SEQ ID NOS:14-16, inclusive, were used for the consensus polynucleotide sequence shown in SEQ ID NO:11. The polynucleotide sequences shown in SEQ ID NOS:17-20, inclusive, were used for the consensus polynucleotide sequence shown in SEQ ID NO:12. The polynucleotide sequences shown in SEQ ID NOS:21-26, inclusive, were used for the consensus polynucleotide shown in SEQ ID NO:13. The "N" represents where there is no qualifying minimum representative base. i.e. at least two sequences with the same base at that site.

[0409]Northern blotting of prostate cancer cell lines using nucleotides 243-end of SEQ ID NO:150 labeled as a probe indicates that they express PCAV transcripts of several sizes, corresponding to both full-length viral genomic sequences and to sub-genomic spliced transcripts (FIG. 5). Expression of such transcripts have also been observed in teratocarcinoma cell lines [15], as shown in lane 1 of FIG. 14.

[0410]Investigation of Other Human Endogenous Retroviruses

[0411]HERV-K(CH) is a member of the HML-2 subgroup of the HERV-K family. HERV-K(II) and HERV-K(10) are also members of this sub-group.

[0412]The same microarray techniques as described above were used to study the expression of members of the HERV-K family in the HML-2 and HML-6 subgroups in prostate tumor tissue. The expression of HERV-H viruses was also studied.

[0413]The results in table 9 show that HERV-His not up-regulated in prostate tumors. The HML-6 subgroup of HERV-K is also not up-regulated. The only endogenous retroviruses that are up-regulated in prostate tumors are in the HML-2 subgroup.

[0414]Investigation of Tumors Other than Prostate Tumors

[0415]HML-2 endogenous retroviruses are up-regulated in prostate tumors. Tumor samples taken from patients with breast and colon cancer were investigated for up-regulation of HML-2 and HML-6 HERV-K viruses using the microarray techniques described above.

[0416]The results in table 10 show that the HML-2 viruses are up-regulated in tissue from prostate tumors, but not from colon or breast tumors. HML-6 expression is not up-regulated in any of the tumors.

[0417]Detection of HERV-K(CH) Sequences in Human Prostate Cancer Cells and Tissues.

[0418]DNA from prostate cancer tissue and other human cancer tissues, human colon, normal human tissues including non-cancerous prostate, and from other human cell lines are extracted following the procedure of ref. 202. The DNA is re-suspended in a solution containing 0.05 M Tris HCl buffer, pH 7.8, and 0.1 mM EDTA, and the amount of DNA recovered is determined by microfluorometry using Hoechst 33258 dye [ref. 203].

[0419]Polymerase chain reaction (PCR) is performed using Taq polymerase following the conditions recommended by the manufacturer (Perkin Elmer Cetus) with regard to buffer, Mg²+, and nucleotide concentrations. Thermocycling is performed in a DNA cycler by denaturation at 94° C. for 3 min. followed by either 35 or 50 cycles of 94° C. for 1.5 min., 50° C. for 2 min. and 72° C. for 3 min. The ability of the PCR to amplify the selected regions of the HERV-K(CH) gene is tested by using a cloned HERV-K(CH) polynucleotide(s) as a positive template(s). Optimal Mg²+, primer concentrations and requirements for the different cycling temperatures are determined with these templates. The master mix recommended by the manufacturer is used. To detect possible contamination of the master mix components, reactions without template are routinely tested.

[0420]Southern blotting and hybridization are performed as described in reference 204, using the cloned sequences labeled by the random primer procedure [205]. Prehybridization and hybridization are performed in a solution containing 6×SSPE, 5% Denhardt's, 0.5% SDS, 50% formamide, 100 μg/ml denaturated salmon testis DNA, incubated for 18 hrs at 42° C., followed by washings with 2×SSC and 0.5% SDS at room temperature and at 37° C. and finally in 0.1×SSC with 0.5% SDS at 68° C. for 30 min (ref. 8). For paraffin-embedded tissue sections the conditions described in ref. 206 are followed using primers designed to detect a 250 by sequence.

[0421]Expression of Cloned Polynucleotides in Host Cells.

[0422]To study the polypeptide products of HERV-K(CH) cDNA, restriction fragments from the HERV-K(CH) cDNA are cloned into the expression vector pMT2 (pages 16.17-16.22 of ref. 8) and transfected into COS cells grown in DMEM supplemented with 10% FCS. Transfections are performed employing calcium phosphate techniques (pages 16.32-16.40 of ref. 8) and cell lysates are prepared forty-eight hours after transfection from both transfected and untransfected COS cells. Lysates are subjected to analysis by immunoblotting using anti-peptide antibody.

[0423]In immunoblotting experiments, preparation of cell lysates and electrophoresis are performed according to standard procedures. Protein concentration is determined using BioRad protein assay solutions. After semi-dry electrophoretic transfer to nitro-cellulose, the membranes are blocked in 500 mM NaCl, 20 mM Tris, pH 7.5, 0.05% Tween-20 (TTBS) with 5% dry milk. After washing in TTBS and incubation with secondary antibodies (Amersham), enhanced chemiluminescence (ECL) protocols (Amersham) are performed as described by the manufacturer to facilitate detection.

[0424]Generation of Antibodies Against Polypeptides.

[0425]Polypeptides, unique to HERV-K(CH) are synthesized or isolated from bacterial or other (e.g. yeast, baculovirus) expression systems and conjugated to rabbit serum albumin (RSA) with m-maleimido benzoic acid N-hydroxysuccinimide ester (MBS) (Pierce, Rockford, Ill.). Immunization protocols with these peptides are performed according to standard methods. Initially, a pre-bleed of the rabbits is performed prior to immunization. The first immunization includes Freund's complete adjuvant and 500 μg conjugated peptide or 100 μg purified peptide. All subsequent immunizations, performed four weeks after the previous injection, include Freund's incomplete adjuvant with the same amount of protein. Bleeds are conducted seven to ten days after the immunizations.

[0426]For affinity purification of the antibodies, the corresponding HERV-K(CH) polypeptide is conjugated to RSA with MBS, and coupled to CNBr-activated Sepharose (Pharmacia, Sweden). Antiserum is diluted 10-fold in 10 mM Tris-HCl, pH 7.5, and incubated overnight with the affinity matrix. After washing, bound antibodies are eluted from the resin with 100 mM glycine, pH 2.5.

[0427]ELISA Assay for Detecting HERV-K(CH) Gag and/or Pol Related Sequences.

[0428]To test blood samples for antibodies that bind specifically to recombinantly produced HERV-K(CH) antigens, the following procedure is employed. After the recombinant HERV-K(CH) pol or gag or env related polypeptides are purified, the recombinant polypeptide is diluted in PBS to a concentration of 5 μg/ml (500 ng/100 μl). 100 microliters of the diluted antigen solution is added to each well of a 96-well Immulon 1 plate (Dynatech Laboratories, Chantilly, Va.), and the plate is then incubated for 1 hour at room temperature, or overnight at 4° C., and washed 3 times with 0.05% Tween 20 in PBS. Blocking to reduce nonspecific binding of antibodies is accomplished by adding to each well 200 μl of a 1% solution of bovine serum albumin in PBS/Tween 20 and incubation for 1 hour. After aspiration of the blocking solution, 100 μl of the primary antibody solution (anticoagulated whole blood, plasma, or serum), diluted in the range of 1/16 to 1/2048 in blocking solution, is added and incubated for 1 hour at room temperature or overnight at 4° C. The wells are then washed 3 times, and 100 μl goat anti-human IgG antibody conjugated to horseradish peroxidase (organon Teknika, Durham, N.C.), diluted 1/500 or 1/1000 in PBS/Tween 20, 100 μl of o-phenylenediamine dihydrochloride (OPD, Sigma) solution is added to each well and incubated for 5-15 minutes. The OPD solution is prepared by dissolving a 5 mg OPD tablet in 50 ml 1% methanol in H₂O and adding 50 μl 30% H₂O₂ immediately before use. The reaction is stopped by adding 25 l of 4M H₂SO₄ Absorbance are read at 490 nm in a microplate reader (Bio-Rad).

[0429]Preparation of Vaccines.

[0430]The present invention also relates to a method of stimulating an immune response against cells that express HERV-K(CH) polypeptides in a patient using HERV-K(CH) gag, and/or pol polypeptides of the invention that acts as an antigen produced by or associated with a malignant cell. This aspect of the invention provides a method of stimulating an immune response in a human against prostate cells or cells that express a HERV-K(CH) pol or gag polynucleotides and polypeptides. The method comprises the step of administering to a human an immunogenic amount of a polypeptide comprising: (a) the amino acid sequence of a human endogenous retrovirus HERV-K(CH) polypeptide or (b) a mutein or variant of a polypeptide comprising the amino acid sequence of a human endogenous retrovirus HERV-K(CH) polypeptide.

[0431]Generation of Transgenic Animals Expressing Polypeptides as a Means for Testing Therapeutics.

[0432]HERV-K(CH) nucleic acids are used to generate genetically modified non-human animals, or site specific gene modifications thereof, in cell lines, for the study of function or regulation of prostate tumor-related genes, or to create animal models of diseases, including prostate cancer. The term "transgenic" is intended to encompass genetically modified animals having an exogenous HERV-K(CH) gene(s) that is stably transmitted in the host cells where the gene(s) may be altered in sequence to produce a modified polypeptide, or having an exogenous HERV-K(CH) LTR promoter operably linked to a reporter gene. Transgenic animals may be made through a nucleic acid construct randomly integrated into the genome. Vectors for stable integration include plasmids, retroviruses and other animal viruses, YACs, and the like. Of interest are transgenic mammals, e.g. cows, pigs, goats, horses, etc., and particularly rodents, e.g. rats, mice, etc.

[0433]The modified cells or animals are useful in the study of HERV-K(CH) gene function and regulation. For example, a series of small deletions and/or substitutions may be made in the HERV-K(CH) gene to determine the role of different domains in prostate tumorigenesis. Specific constructs of interest include, but are not limited to, anti-sense constructs to block HERV-K(CH) gene expression, expression of dominant negative HERV-K(CH) gene mutations, and over-expression of a HERV-K(CH) gene. Expression of a HERV-K(CH) gene or variants thereof in cells or tissues where it is not normally expressed or at abnormal times of development is provided. In addition, by providing expression of polypeptides derived from HERV-K(CH) in cells in which it is otherwise not normally produced, changes in cellular behavior can be induced.

[0434]DNA constructs for random integration need not include regions of homology to mediate recombination. Conveniently, markers for positive and negative selection are included. For various techniques for transfecting mammalian cells, see ref. 207.

[0435]For embryonic stem (ES) cells, an ES cell line is employed, or embryonic cells is obtained freshly from a host, e.g. mouse, rat, guinea pig, etc. Such cells are grown on an appropriate fibroblast-feeder layer or grown in the presence of appropriate growth factors, such as leukemia inhibiting factor (LIF). When ES cells are transformed, they may be used to produce transgenic animals. After transformation, the cells are plated onto a feeder layer in an appropriate medium. Cells containing the construct may be detected by employing a selective medium. After sufficient time for colonies to grow, they are picked and analyzed for the occurrence of integration of the construct. Those colonies that are positive may then be used for embryo manipulation and blastocyst injection. Blastocysts are obtained from 4 to 6 week old superovulated females. The ES cells are trypsinized, and the modified cells are injected into the blastocoel of the blastocyst. After injection, the blastocysts are returned to each uterine horn of pseudopregnant females. Females are then allowed to go to term and the resulting chimeric animals screened for cells bearing the construct. By providing for a different phenotype of the blastocyst and the ES cells, chimeric progeny can be readily detected.

[0436]The chimeric animals are screened for the presence of the modified gene and males and females having the modification are mated to produce homozygous progeny. If the gene alterations cause lethality at some point in development, tissues or organs are maintained as allogeneic or congenic grafts or transplants, or in in vitro culture. The transgenic animals may be any non-human mammal, such as laboratory animals, domestic animals, etc. The transgenic animals are used in functional studies, drug screening, etc., e.g. to determine the effect of a candidate drug on prostate cancer, to test potential therapeutics or treatment regimens, etc.

[0437]Diagnostic Imaging Using HERV-K(CH) Specific Antibodies

[0438]The present invention encompasses the use of antibodies to HERV-K(CH) polypeptides to accurately stage prostate cancer patients at initial presentation and for early detection of metastatic spread of prostate cancer. Radioimmunoscintigraphy using monoclonal antibodies specific for HERV-K(CH) gag or HERV-K(CH) pol or portions thereof or other HERV-K(CH) polypeptides can provide an additional tumor-specific diagnostic test. The monoclonal antibodies of the instant invention are used for histopathological diagnosis of prostate carcinomas.

[0439]Subcutaneous human xenografts of prostate cancer cells in nude mice is used to test whether a technetium-99m (⁹⁹mTc)-labeled monoclonal antibody of the invention can successfully image the xenografted prostate cancer by external gamma scintography as described for seminoma cells in ref. 208. Each monoclonal antibody specific for a HERV-K(CH) polypeptide is purified from ascitic fluid of BALB/c mice bearing hybridoma tumors by affinity chromatography on polypeptide A-Sepharose. Purified antibodies, including control monoclonal antibodies such as an avidin-specific monoclonal antibody [209] are labeled with ⁹⁹mTc following reduction, using the methods of refs. 210 and 211. Nude mice bearing human prostate cancer cells are injected intraperitoneally with 200-500 μCi of ⁹⁹mTc-labeled antibody. Twenty-four hours after injection, images of the mice are obtained using a Siemens ZLC3700 gamma camera equipped with a 6 mm pinhole collimator set approximately 8 cm from the animal. To determine monoclonal antibody biodistribution following imaging, the normal organs and tumors are removed, weighed, and the radioactivity of the tissues and a sample of the injectate are measured. Additionally, HERV-K(CH)-specific antibodies conjugated to antitumor compounds are used as prostate cancer-specific chemotherapy.

Deposits

[0440]The materials listed in Table 7 were deposited with the American Type Culture Collection.

[0441]All publications and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

[0442]The foregoing description of preferred embodiments of the invention has been presented by way of illustration and example for purposes of clarity and understanding. It is not intended to be exhaustive or to limit the invention to the precise forms disclosed. It will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that many changes and modifications may be made thereto without departing from the spirit of the invention. It is intended that the scope of the invention be defined by the appended claims and their equivalents.

TABLE-US-00001 TABLE 1 GAG protease (5') probes, isolate specific Isolate Nucleotides SEQ ID K(CH) 1224-1238 161 KII 2098-2114 162 K10 874-890 163 894-908 164 910-927 165 927-944 166 989-1004 167 1019-1036 168 1046-1063 169 1063-1078 170 1084-1103 171 1131-1145 172 1148-1163 173 1164-1185 174 1206-1223 175 1216-1235 176 1243-1260 177 1258-2375 178 1277-1295 179 1300-1329 180 1347-1361 181 1367-1382 182 1392-1410 183 1412-1428 184 1426-1442 185 1445-1461 186 1463-1477 187 K10 1490-1510 188 1502-1520 189 1522-1538 190 1561-1576 191 1586-1605 192 1620-1635 193 1653-1669 194 1698-1723 195 1722-1743 196 1748-1762 197 1773-1788 198 1820-1834 199 1872-1887 200 1917-1935 201 1940-1955 202 1955-1969 203 1973-1995 204 2008-2042 205 2049-2064 206 2076-2093 207 2097-2113 208 2122-2139 209 2148-2118 210 2176-2196 211 2198-2212 212 2219-2235 213 2246-2261 214

TABLE-US-00002 TABLE 2 Protease (3'seq) Polymerase (5'seq) Probes Isolate Nucleotides SEQ ID K(CH) 170-188 215 consensus 205-221 216 253-268 217 316-336 218 401-417 219 490-504 220 538-552 221 872-886 222 K(CH) 109-125 223 1374-1388 224 1402-1416 225 KII 140-159 110 410-426 111 1127-1141 112 K10 11-38 113 37-54 114 70-90 115 226-243 116 249-264 117 308-324 118 327-342 119 381-397 120 440-454 121 541-557 122 678-698 123 722-741 124 753-767 125 771-785 126 854-869 127 872-890 128 1195-1209 129 1308-1323 130 1335-1349 131 1349-1365 132

TABLE-US-00003 TABLE 3 3' POL probes only Isolate Nucleotides SEQ ID K(CH) consensus 3-17 133 25-39 134 82-104 135 136-151 136 154-169 137 189-203 138 322-337 139 461-475 140 630-645 141 712-727 142 757-771 143 818-833 144 KII 1636-1651 145

TABLE-US-00004 TABLE 4 ORFS and sources of initial isolates/clones from prostate cDNA libraries HERVK ORF Chiron Clone ID Source of Clone gag 035JN002.E02 Prostate Cancer Tissue, Patient 101, Gleason Grade 3 + 3 gag 035JN013.H09 Prostate Cancer Tissue, Patient 101, Gleason Grade 3 + 3 gag 035JN023.F12 Prostate Cancer Tissue, Patient 101, Gleason Grade 3 + 3 gag 037XN001.D10 Normal Prostate Tissue, Pooled from 10 individuals pol5' 035JN001.F06 Prostate Cancer Tissue, Patient 101, Gleason Grade 3 + 3 pol5' 035JN003.E06 Prostate Cancer Tissue, Patient 101, Gleason Grade 3 + 3 pol5' 035JN013.C11 Prostate Cancer Tissue, Patient 101, Gleason Grade 3 + 3 pol5' 035JN013.F03 Prostate Cancer Tissue, Patient 101, Gleason Grade 3 + 3 pol3' 035JN003.G09 Prostate Cancer Tissue, Patient 101, Gleason Grade 3 + 3 pol3' 035JN010.A09 Prostate Cancer Tissue, Patient 101, Gleason Grade 3 + 3 pol3' 035JN015.F06 Prostate Cancer Tissue, Patient 101, Gleason Grade 3 + 3 pol3' 035JN020.B12 Prostate Cancer Tissue, Patient 101, Gleason Grade 3 + 3 pol3' 035JN020.D07 Prostate Cancer Tissue, Patient 101, Gleason Grade 3 + 3 pol3' 035JN022.G09 Prostate Cancer Tissue, Patient 101, Gleason Grade 3 + 3 pol3' 035JN015.H02 Prostate Cancer Tissue, Patient 101, Gleason Grade 3 + 3 pol3' 035JN016.H02 Prostate Cancer Tissue, Patient 101, Gleason Grade 3 + 3

TABLE-US-00005 TABLE 5 Identity of HERV-K(CH) polynucleotides with HERV-K(II) and HERV-K(10) % Identity % Identity Clone ID Region HERV-K(II) HERV-K(10) 035JN003.G09 3'-pol 89.423 89.423 035JN010.A09 3'-pol 89.663 89.663 035JN015.F06 3'-pol 89.423 89.423 035JN020.B12 3'-pol 89.303 89.303 035JN020.D07 3'-pol 89.614 89.614 035JN022.G09 3'-pol 89.354 89.354 035JN002.E02 gag 99.524 79.881 035JN013.H09 gag 99.017 79.975 035JN023.F12 gag 98.849 79.335 035XN001.D10 gag 87.383 79.947 035JN001.F06 5'-pol 97.211 88.844 035JN003.E06 5'-pol 97.450 86.723 035JN013.C11 5'-pol 97.156 85.444 035JN013.F03 5'-pol 87.962 81.521

TABLE-US-00006 TABLE 6 DNA microarray results: 13 patients tumor vs. normal prostate, expression of HERV-K RNA Turmor/Normal mRNA Percent Patient with Expression Ratio Expression Ratio HERVK ORF Chiron Clone ID >= 2x >= 2-5x >= 5x <= halfx Pat 93 Pat 95 gag 035JN002.E02 57.1 42.9 7.1 0.0 4.8 3.0 gag 035JN013.H09 78.6 78.6 50.0 0.0 9.3 4.5 gag 035JN023.F12 78.6 78.6 57.1 0.0 9.1 4.1 gag 037XN001.D10 64.3 64.3 14.3 0.0 5.4 3.4 pol5prime 035JN001.F06 42.9 21.4 7.1 0.0 2.0 2.6 pol5prime 035JN003.E06 42.9 21.4 7.1 0.0 2.1 2.6 pol5prime 035JN013.C11 85.7 78.6 57.1 0.0 6.9 5.6 pol5prime 035JN013.F03 85.7 71.4 21.4 0.0 4.6 3.4 pol3prime 035JN003.G09 71.4 57.1 7.1 0.0 4.1 3.3 pol3prime 035JN010.A09 85.7 78.6 71.4 0.0 8.0 4.4 pol3prime 035JN015.F06 85.7 78.6 71.4 0.0 7.6 4.0 pol3prime 035JN020.B12 85.7 78.6 64.3 0.0 7.0 4.0 pol3prime 035JN020.D07 85.7 78.6 57.1 0.0 6.0 3.2 pol3prime 035JN022.G09 78.6 78.6 57.1 0.0 6.6 4.2 pol3prime 035JN015.H02 85.7 78.6 57.1 0.0 7.9 4.2 pol3prime 035JN016.H02 71.4 71.4 14.3 0.0 3.8 3.0 Turmor/Normal mRNA Expression Ratio HERVK ORF Chiron Clone ID Pat 96 Pat 97 Pat 151 Pat 155 Pat 231 Pat 232 gag 035JN002.E02 2.1 1.0 2.3 2.5 1.9 1.7 gag 035JN013.H09 5.2 1.4 5.5 13.8 4.2 3.5 gag 035JN023.F12 5.1 1.6 5.5 17.0 4.5 3.2 gag 037XN001.D10 2.5 1.5 3.6 4.6 2.9 1.8 pol5prime 035JN001.F06 1.8 1.5 2.7 1.8 2.0 1.8 pol5prime 035JN003.E06 1.8 1.4 2.6 1.9 2.0 1.7 pol5prime 035JN013.C11 6.9 2.0 7.4 24.0 4.8 4.3 pol5prime 035JN013.F03 3.7 2.2 4.6 8.4 4.1 3.4 pol3prime 035JN003.G09 3.3 1.6 4.9 3.3 2.2 3.5 pol3prime 035JN010.A09 12.6 2.1 12.4 55.9 5.1 9.5 pol3prime 035JN015.F06 12.8 2.2 11.9 53.4 5.1 8.0 pol3prime 035JN020.B12 10.5 2.2 11.9 34.9 5.0 6.8 pol3prime 035JN020.D07 8.7 2.0 13.7 22.9 4.6 8.6 pol3prime 035JN022.G09 6.6 2.0 8.8 12.7 4.5 5.3 pol3prime 035JN015.H02 9.0 2.1 10.7 35.3 4.7 7.5 pol3prime 035JN016.H02 3.4 1.9 4.3 5.0 3.0 3.1 Turmor/Normal mRNA Expression Ratio HERVK ORF Chiron Clone ID Pat 251 Pat 282 Pat 286 Pat 294 Pat 351 gag 035JN002.E02 6.9 1.5 0.6 2.6 2.9 gag 035JN013.H09 31.2 4.5 1.0 12.1 8.6 gag 035JN023.F12 28.2 5.2 1.0 12.7 7.3 gag 037XN001.D10 10.0 1.7 1.0 3.5 4.3 pol5prime 035JN001.F06 7.8 1.2 1.0 1.9 2.3 pol5prime 035JN003.E06 7.7 1.2 1.0 1.8 2.1 pol5prime 035JN013.C11 37.4 4.4 1.0 13.1 8.8 pol5prime 035JN013.F03 21.8 2.3 1.0 5.0 5.8 pol3prime 035JN003.G09 14.9 1.5 1.0 2.5 3.9 pol3prime 035JN010.A09 70.0 5.8 1.0 26.3 9.7 pol3prime 035JN015.F06 69.7 5.9 1.0 25.3 9.1 pol3prime 035JN020.B12 44.5 5.2 1.0 15.2 8.1 pol3prime 035JN020.D07 58.2 3.8 1.0 15.8 7.6 pol3prime 035JN022.G09 28.0 2.6 1.0 5.9 7.8 pol3prime 035JN015.H02 49.5 4.8 1.0 18.2 8.7 pol3prime 035JN016.H02 14.1 1.7 1.0 2.6 5.0

TABLE-US-00007 TABLE 7 DEPOSITS Cell Line CMCC Accession No. ATCC Accession No. 035JN003G09 5400 PTA 2561 035JN010A09 5401 PTA 2572 035JN015F06 5402 PTA 2566 035JN015H02 5403 PTA 2571 035JN020B12 5405 PTA 2562 035JN020D07 5406 PTA 2573 035JN022G09 5413 PTA 2560 035JN002E02 5404 PTA 2565 035JN013H09 5408 PTA 2568 035JN023F12 5409 PTA 2564 035XN001D10 5410 PTA 2569 035JN001F06 5411 PTA 2567 035JN003E06 5412 PTA 2559 035JN013C11 5407 PTA 2563 035JN013F03 5415 PTA 2570 ATCC = American Type Culture Collection CMCC = Chiron Master Culture Collection All deposits made 10th Apr. 2000

TABLE-US-00008 TABLE 8 Sequence listing SEQ ID DESCRIPTION 1 U5 region of herv-k(hml-2.hom) [GenBank AF074086] 2 U3 region of herv-k(hml-2.hom) 3 R region of herv-k(hml-2.hom) 4 RU5 region of herv-k(hml-2.hom) 5 U3R region of herv-k(hml-2.hom) 6 Non-coding region between U5 and first 5' splice site of herv-k(hml-2.hom) 7 Composite of three HERV-K(CH) polynucleotides [SEQ IDs 14-16] positioned in the gag region. 8 & 9 Composite of four HERV-K(CH) polynucleotides [SEQ IDs 17-20] positioned in the 5' pol region 10 Composite of six HERV-K(CH) polynucleotides [SEQ IDs 21-26] positioned in the 3' pol region 11 Consensus sequence of HERV-K(CH) gag region 12 Consensus sequence of HERV-K(CH) 5' pol region 13 Consensus sequence of HERV-K(CH) 3' pol region 14 Sequence for clone 035JN002.E02. 15 Sequence for clone 035JN023.F12. 16 Sequence for clone 035JN013.H09. 17 Sequence for clone 035JN013.C11 18 Sequence for clone 035JN003.E06. 19 Sequence for clone 35JN001.F06. 20 Sequence for clone 035JN013.F03. 21 Sequence for clone 035JN020.D07. 22 Sequence for clone 035JN015.F06. 23 Sequence for clone 035JN003.G09. 24 Sequence for clone 035JN020.B12. 25 Sequence for clone 035JN022.G09. 26 Sequence for clone 035JN010.A09. 27 Sequence for clone 035JN002.E02. 28 Sequence for clone 035JN023.F12. 29 Sequence for clone 035JN013.H09. 30 Sequence for clone 035JN013.C11. 31 Sequence for clone 035JN003.E06. 32 Sequence for clone 035JN001.F06. 33 Sequence for clone 035JN013.F03. 34 Sequence for clone 035JN020.D07. 35 Sequence for clone 035JN015.F06. 36 Sequence for clone 035JN003.G09. 37 Sequence for clone 035JN020.B12. 38 Sequence for clone 035JN022.G09. 39 Sequence for clone 035JN010.A09. 40 Sequence for clone 037XN001.D10 and isolated from normal prostate tissue. 41 Sequence for clone 037XN001.D10 and isolated from normal prostate tissue. 42 EST polynucleotide sequence shown in GenBank accession number Q60732. 43 EST polynucleotide sequence SEQ ID 407 of WO 00/04149 44 Polynucleotide sequence for HERV-KII 45 Polynucleotide sequence for HERV-K10 46-49 Amino acid translations of SEQ IDs 11, 14, 15, 16 50-55 Amino acid translations of SEQ IDs 21-26 (note PSFGK motifs) 56-57 Amino acid translations of SEQ IDs 27 & 28 58 Consensus polypeptide sequence inferred from SEQ IDs 21-26 59-82 Polynucleotide probes not in SEQ IDs 42-45 83 & 84 Polynucleotide probes shared with SEQ IDs 42-45 85 HERV-K108 gag CDS 86 HERV-K108 prt CDS 87 HERV-K108 pol CDS 88 HERV-K108 env CDS 89 HERV-K108 cORF 5' CDS 90 HERV-K108 cORF 3' CDS 91 HERV-K(C7) gag CDS 92 HERV-K(C7) gag amino acid sequence 93 HERV-K(C7) pol CDS 94 HERV-K(C7) pol amino acid sequence 95 HERV-K(C7) env CDS 96 HERV-K(C7) env amino acid sequence 97 HERV-K(II) gag CDS 98 HERV-K(II) gag amino acid sequence 99 HERV-K(II) prt CDS 100 HERV-K(II) pol CDS 101 HERV-K(II) env CDS 102 HERV-K10 gag CDS 103 HERV-K10 gag(i) 104 HERV-K10 gag(ii) 105 HERV-K10 prt CDS 106 HERV-K10 prt amino acid sequence 107 HERV-K10 pol/env CDS 108 HERV-K10 pol/env amino acid sequence 109 cORF amino acid sequence 110-132 Table 2 probes (cont^d at SEQ IDs 215-225) 133-145 Table 3 probes 146 HML-2.HOM (`ERVK6`) gag amino acid sequence 147 HML-2.HOM (`ERVK6`) prt amino acid sequence 148 HML-2.HOM (`ERVK6`) pol amino acid sequence 149 HML-2.HOM (`ERVK6`) env amino acid sequence 150 LTR of herv-k(hml-2.hom) 151-154 HML-2 LTR sequences 155 & 156 herv-k(hml-2.hom) RU5 region (5' and 3' regions, respectively) 157 Env consensus nucleic acid sequence (FIG. 6) 158 Gag consensus sequence (FIG. 7) 159 Pol consensus sequence (FIG. 8) 160 Env consensus sequence (FIG. 9) 161-214 Table 1 probes 215-225 Table 2 probes (cont^d from SEQ IDs 110-132)

TABLE-US-00009 TABLE 9 Expression of HERV-H and HERV-K in prostate tumors GenBank ID HERV HML Subgroup Result AB047240 K HML-2 65 AP164611 K HML-2 63 AF164612 K HML-2 63 AF079797 K HML-6 3 BC005351 H -- 0 XM_054932 H -- 0 The "Result" column gives the % of patient samples which showed up-regulation of the GenBank sequence given in the first column in tumor tissue relative to non-tumor tissue.

TABLE-US-00010 TABLE 10 Expression of HERV-K viruses in colon and breast tumors Result GenBank ID HERV HML Subgroup Prostate Breast Colon AB047240 K HML-2 65 0 2 AF079797 K HML-6 3 6 0 AF164611 K HML-2 63 0 2 AF164612 K HML-2 63 6 2 The "Result" columns give the % of patient samples which showed up-regulation of the GenBank sequence given in the first column in tumor tissue relative to non-tumor tissue.

TABLE-US-00011 TABLE 11 HML-2 subgroup of HERV-K Family Query Target Percent Percent Query Length Target Locus Target Description Length Score Pscore Matches Similarities Alignment Query N4 7428 NT_022283S1.2 /contig_orient = 102399 72570 3.9E-47 7334 7334 98 98 none/start = 1/ end = 160119/ chrom = 2 Homo N4 7428 NT_007386S1.3 /contig_orient = 102399 72570 3.9E-47 7334 7334 98 98 complement/start = 1/end = 250001/ chrom = 6 N4 7428 NT_009509S2.3 /contig_orient = 102399 72379 5.3E-47 7329 7329 98 98 forward/start = 250002/end = 500002/ chrom = 12 N4 7428 NT_009151S32.3 /contig_orient = 102399 72707 3.1E-47 7345 7345 98 98 complement/start = 7623180/end = 7873180 N4 7428 NT_023901S1.2 /contig_orient = 102399 70366 1.3E-45 7222 7222 97 97 none/start = 1/ end = 166310/ chrom = 8 N4 7428 NT_025820S3.2 /contig_orient = 102399 67986 5.9E-44 7112 7112 95 95 complement/statt = 4556361/end = 661270 N4 7428 NT_024249S1.2 /contig_orient = 102399 67986 5.9E-44 7112 7112 95 95 none/start = 1/ end = 167403/ chrom = 11 Homo N4 7428 NT_011519S9.5 /contig_orient = 102399 68342 3.4E-44 7058 7058 95 95 forward/start = 2016320/end = 2266320 N4 7428 NT_006788S1.3 /contig_orient = 102399 68610 2.6E-44 7066 7066 95 95 complement/start = 1/end = 250000/ chrom = 5 N4 7428 NT_004858S5.3 /contig_orient = 102399 68624 2.1E-44 7072 7072 95 95 complement/start = 999278/end = 1248551 N4 7428 NT_005795S3.3 /contig_orient = 102399 67968 6.1E-44 7040 7040 94 94 forward/start = 405779/end = 655779/ chrom = 3 N4 7428 NT_025140S3.3 /contig_orient = 97618 68168 4.4E-44 7049 7049 94 94 none/start = 449919/ end = 649836/chrom = 19 N4 7428 NT_009334S8.3 /contig_orient = 102399 65447 3.4E-42 6913 6913 93 93 complement/start = 1574760/end = 1824759 N4 7428 NT_004406S4.3 /contig_orient = 85887 65099 .sup. 6E-42 6910 6910 92 93 forward/start = 797371/end = 985557/ chrom = 1 N4 7428 NT_011192S4.3 /contig_orient = 102399 62351 4.9E-40 6844 6844 90 92 forward/start = 750004/end = 949429/ chrom = 19 N4 7428 NT_007592S14.3 /contig_orient = 102399 56493 5.7E-36 6795 6795 79 91 forward/start = 3276099/end = 3526099/ chrom = 6 N4 7428 NT_011512S23.3 /contig_orient = 102399 64096 .sup. 3E-41 6818 6818 92 91 forward/start = 5505084/end = 5755084 N4 7428 NT_019638S1.3 /contig_orient = 102399 57114 2.1E-36 6273 6273 82 90 none/start = 1/ end = 250001/ chrom = 19 N4 7428 NT_022411S1.3 /contig_orient = 61348 65630 2.6E-42 6734 6734 95 90 none/start = 1/ end = 163648/ chrom = 3 N4 7428 NT_005632S1.3 /contig_orient = 102399 62739 2.6E-40 6630 6630 91 89 complement/start = 1/end = 214350/ chrom = 3 N4 7428 NT_022504S1.3 /contig_orient = 102399 56001 1.3E-35 6420 6420 86 86 forward/start = 1/end = 271641/ chrom = 3 N4 7428 NT_023397S2.3 /contig_orient = 102399 49492 4.1E-3 6275 6275 79 84 complement/start = 250002/end = 455242 N4 7428 NT_011520S13.5 /contig_orient = 102399 47530 9.6E-30 6166 6166 77 83 forward/start = 3068083/end = 3318083 N4 742 NT_019483S4.3 /contig_orient = 102399 50179 1.4E-3 6184 6184 82 83 forward/start = 750003/end = 1000003/ chrom = 8 N4 742 NT_019483S2.3 /contig_orient = 102399 50122 1.5E-31 6177 6177 82 83 forward/start = 250001/end = 500001/ chrom = 8 N4 742 NT_024033S5.3 /contig_orient = 102399 57370 1.4E-36 5859 5859 97 78 forward/start = 1000005/end = 1250005 N4 742 NT_023628S1.3 /contig_orient = 102399 56440 6.2E-36 5651 565 99 76 complement/start1/end = 151365/chrom = 7 N4 742 NT_023323S1.2 /contig_orient = 102399 45124 4.5E-28 5600 5600 82 75 none/start = 1/ end = 103061/ chrom = 5 Homo Query Query Query Target Target Open Gap Extension Query Length Target Locus Target Description Start End Start End Penalty Penalty N4 7428 NT_022283S1.2 /contig_orient = 7428 1 13506 20899 -20 -5 none/start = 1/ end = 160119/ chrom = 2 Homo N4 7428 NT_007386S1.3 /contig_orient = 1 7428 29800 37193 -20 -5 complement/start = 1/end = 250001/ chrom = 6 N4 7428 NT_009509S2.3 /contig_orient = 7428 1 136539 143951 -20 -5 forward/start = 250002/end = 500002/ chrom = 12 N4 7428 NT_009151S32.3 /contig_orient = 1 7428 114716 122137 -20 -5 complement/start = 7623180/end = 7873180 N4 7428 NT_023901S1.2 /contig_orient = 7428 1 94194 101616 -20 -5 none/start = 1/ end = 166310/ chrom = 8 N4 7428 NT_025820S3.2 /contig_orient = 1 7428 164603 172033 -20 -5 complement/statt = 4556361/end = 661270 N4 7428 NT_024249S1.2 /contig_orient = 1 7428 18873 26303 -20 -5 none/start = 1/ end = 167403/ chrom = 11 Homo N4 7428 NT_011519S9.5 /contig_orient = 1 7428 62776 69910 -20 -5 forward/start = 2016320/end = 2266320 N4 7428 NT_006788S1.3 /contig_orient = 1 7428 144115 151250 -20 -5 complement/start = 1/end = 250000/ chrom = 5 N4 7428 NT_004858S5.3 /contig_orient = 7428 1 23642 30777 -20 -5 complement/start = 999278/end = 1248551 N4 7428 NT_005795S3.3 /contig_orient = I 7428 122036 129165 -20 -5 forward/start = 405779/end = 655779/ chrom = 3 N4 7428 NT_025140S3.3 /contig_orient = 7428 1 174979 182103 -20 -5 none/start = 49919/ end = 649836/ chrom = 19 N4 7428 NT_009334S8.3 /contig_orient = 7428 1 116705 123823 -20 -5 complement/start = 1574760/end = 1824759 N4 7428 NT_004406S4.3 /contig_orient = 1 7428 103675 110860 -20 -5 forward/start = 797371/end = 985557/ chrom = 1 N4 7428 NT_011192S4.3 /contig_orient = 7428 1 17828 25313 -20 -5 forward/start = 750004/end = 949429/ chrom = 19 N4 7428 NT_007592S14.3 /contig_orient = 1 7428 141741 150230 -20 -5 forward/start = 3276099/end = 3526099/ chrom = 6 N4 7428 NT_011512S23.3 /contig_orient = 7428 38 93282 100383 -20 -5 forward/start = 5505084/end = 5755084 N4 7428 NT_019638S1.3 /contig_orient = 7427 1 179318 187384 -20 -5 none/start = 1/ end = 250001/ chrom = 19 N4 7428 NT_022411S1.3 /contig_orient = 7024 1 140614 147637 -20 -5 none/start = 1/ end = 163648/ chrom = 3 N4 7428 NT_005632S1.3 /contig_orient = 7428 7428 48116 55040 -20 -5 complement/start = 1/end = 214350/ chrom = 3 N4 7428 NT_022504S1.3 /contig_orient = 7428 1 176629 183705 -20 -5 forward/start = 1/end = 271641/ chrom = 3 N4 7428 NT_023397S2.3 /contig_orient = 1 7428 25289 33146 -20 -5 complement/start = 250002/end = 455242 N4 7428 NT_011520S13.5 /contig_orient = 1 7425 146733 154470 -20 -5 forward/start = 3068083/end = 3318083 N4 742 NT_019483S4.3 /contig_orient = 7428 1 13951 21321 -20 -5 forward/start = 750003/end = 1000003/ chrom = 8 N4 742 NT_019483S2.3 /contig_orient = 7428 1 131375 138737 -20 -5 forward/start = 250001/end = 500001/ chrom = 8 N4 742 NT_024033S5.3 /contig_orient = 1 5981 41571 47546 -20 -5 forward/start = 1000005/end = 1250005 N4 742 NT_023628S1.3 /contig_orient = 1772 7428 1 5656 -20 -5 complement/start1/end = 151365/chrom = 7 N4 742 NT_023323S1.2 /contig_orient = 6704 1 1 6758 -20 -5 none/start = 1/ end = 103061/ chrom = 5 Homo

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Sequence CWU 1

225189DNAHomo sapiens 1ctttgtctct gtgtcttttt cttttccaaa tctctcgtcc caccttacga gaaacaccca 60caggtgtgta ggggcaaccc acccctaca 892560DNAHomo sapiens 2tgtggggaaa agcaagagag atcagattgt tactgtgtct gtgtagaaag aagtagacat 60aggagactcc attttgttat gtactaagaa aaattcttct gccttgagat tctgttaatc 120tatgacctta cccccaaccc cgtgctctct gaaacatgtg ctgtgtccac tcagggttaa 180atggattaag ggcggtgcag gatgtgcttt gttaaacaga tgcttgaagg cagcatgctc 240cttaagagtc atcaccactc cctaatctca agtacccagg gacacaaaaa ctgcggaagg 300ccgcagggac ctctgcctag gaaagccagg tattgtccaa cgtttctccc catgtgatag 360cctgaaatat ggcctcgtgg gaagggaaag acctgaccgt cccccagccc gacacccgta 420aagggtctgt gctgaggagg attagtaaaa gaggaaggaa tgcctcttgc agttgagaca 480agaggaaggc atctgtctcc tgcctgtccc tgggcaatgg aatgtctcgg tataaaaccc 540gattgtatgc tccatctact 5603319DNAHomo sapiens 3gagataggga aaaaccgcct tagggctgga ggtgggacct gcgggcagca atactgcttt 60gtaaagcact gagatgttta tgtgtatgca tatctaaaag cacagcactt aatcctttac 120attgtctatg atgcaaagac ctttgttcac atgtttgtct gctgaccctc tccccacaat 180tgtcttgtga ccctgacaca tccccctctt cgagaaacac ccacagatga tcagtaaata 240ctaagggaac tcagaggctg gcgggatcct ccatatgctg aacgctggtt ccccgggtcc 300ccttctttct ttctctata 3194408DNAHomo sapiens 4gagataggga aaaaccgcct tagggctgga ggtgggacct gcgggcagca atactgcttt 60gtaaagcact gagatgttta tgtgtatgca tatctaaaag cacagcactt aatcctttac 120attgtctatg atgcaaagac ctttgttcac atgtttgtct gctgaccctc tccccacaat 180tgtcttgtga ccctgacaca tccccctctt cgagaaacac ccacagatga tcagtaaata 240ctaagggaac tcagaggctg gcgggatcct ccatatgctg aacgctggtt ccccgggtcc 300ccttctttct ttctctatac tttgtctctg tgtctttttc ttttccaaat ctctcgtccc 360accttacgag aaacacccac aggtgtgtag gggcaaccca cccctaca 4085879DNAHomo sapiens 5tgtggggaaa agcaagagag atcagattgt tactgtgtct gtgtagaaag aagtagacat 60aggagactcc attttgttat gtactaagaa aaattcttct gccttgagat tctgttaatc 120tatgacctta cccccaaccc cgtgctctct gaaacatgtg ctgtgtccac tcagggttaa 180atggattaag ggcggtgcag gatgtgcttt gttaaacaga tgcttgaagg cagcatgctc 240cttaagagtc atcaccactc cctaatctca agtacccagg gacacaaaaa ctgcggaagg 300ccgcagggac ctctgcctag gaaagccagg tattgtccaa cgtttctccc catgtgatag 360cctgaaatat ggcctcgtgg gaagggaaag acctgaccgt cccccagccc gacacccgta 420aagggtctgt gctgaggagg attagtaaaa gaggaaggaa tgcctcttgc agttgagaca 480agaggaaggc atctgtctcc tgcctgtccc tgggcaatgg aatgtctcgg tataaaaccc 540gattgtatgc tccatctact gagataggga aaaaccgcct tagggctgga ggtgggacct 600gcgggcagca atactgcttt gtaaagcact gagatgttta tgtgtatgca tatctaaaag 660cacagcactt aatcctttac attgtctatg atgcaaagac ctttgttcac atgtttgtct 720gctgaccctc tccccacaat tgtcttgtga ccctgacaca tccccctctt cgagaaacac 780ccacagatga tcagtaaata ctaagggaac tcagaggctg gcgggatcct ccatatgctg 840aacgctggtt ccccgggtcc ccttctttct ttctctata 8796108DNAHomo sapiens 6tctggtgccc aacgtggagg cttttctcta gggtgaaggt acgctcgagc gtggtcattg 60aggacaagtc gacgagagat cccgagtaca tctacagtca gccttacg 10871390DNAHomo sapiens 7gggaagagac tcaagtagga gcgcctgccc gagctgagac tagatgtgaa cctttcacca 60tgaaaatgtt aaaagatata aaggaaggag ttaaacaata tggrtccaac tccccttata 120taagaacakt attagattcc attgcycatg gaaatagact tactccttat gactgggaaa 180ttttggccaa atcttccctt tcatcctctc agtatctaca gtttaaaacc tggtggattg 240atggrgtaca rgaacaggta cgaaaaaatc aggctactaa gcccactgtt aatatagacg 300cagaccaatt gttaggaaca ggtccaaatt ggagcaccat taaccaacaa tcagtgatgc 360agaatgaggc tattgaacaa gtaagggcta tttgcctcag ggcctgggga aaaattcagg 420acccaggaac agctttccct attaattcaa ttagacaagg ctctaaagag ccatatcctg 480actttgtggc aagattacaa gatgctgctc aaaagtctat tacagatgac aatgcccgaa 540aagttattgt agaattaatg gcctatgaaa atgcaaatcc agaatgtcag tcggccataa 600agccattaaa aggaaaagtt ccagcaggag ttgatgtaat tacmgaatat gtgaaggctt 660gtgatgggat tggaggagct atgcataagg caatgctaat ggctcaagca atgagggggc 720tcactctagg aggacaagtt agaacatttg ggaaaaaatg ttataattgt ggtcaaatcg 780gtcatckgaa aaggagttgc ccaggcttaa ayaarcagaa tataataaat caagctatta 840cagcaaaaaa taaaaagcca tctggcctgt gtccaaaatg tggaaaagca aaacattggg 900ccaatcaatg tcattctaaa tttgataaag atgggcaacc attgtctgga aacaggaaga 960ggggccagcc tcaggccccc caacaaactg gggcattccc agttaaactg tttgttcctc 1020agggttttca aggacaacaa cccctacaga aaataccacc acttcaggga gtcagccaat 1080tacaacaatc caacagctgt cccgcgccac agcaggcagc accgcagtag atttatgttc 1140cacccaaatg gtctttttac tccctggaaa gcccccacaa aagattccta gaggggtata 1200tggcccgctg ccagaaggga gggtaggcct ttgagggaga tcaagtctaa atttgaaggg 1260agtccaaatt catactgggg taatttactc agattataaa gggggaattc agttagtgat 1320cagctccact gttccccgga gtgccaatcc aggtgataga attgctcaat tactgctttt 1380gccttatgca 139081416DNAHomo sapiens 8acaacaatgg catgcagaga ttactatccc agcctcccta tacagcccca ggaatcaaaa 60aatcatgact aaaatgggat agctccctaa aaagggacta ggaaagaaag aagtcccaat 120tgaggctgaa aaaaatyaaa aaagaaaagg aatagggcat cctttttagg agcggtcact 180gtagagcctc caaaacccat tccattaact tgggaaaaaa amaactgtat ggtaaatcag 240cagccgcttc caaaacaaaa rctggaggcy ttacayttat tagcaaagaa acmattagaa 300aaaggacatt gagccttcat tttcgccttg gaattctgtt tgtrattcag aaaaaatccg 360gcagatggcg tatgctaact gagccattaa tgccgtaatt caacccatgg gggctctccc 420accccggttg ccctctccag ccatggtccc ctttaattat aattgatctg aaggattgct 480tttttaccat tcctctggca aaacaggatt ttgaraaatt tgctttyacc acaccagcct 540aaataataaa gaaccagcca ccaggtttca gtggaaagta ttgcctcagg gaatgcttaa 600tagttcaact atttgtcagc tcaagctctg caaccagtta gagacaagtt ttcagactgt 660tacatcgttc actatgttga tattttgtgt gctgcagaaa cgagagacaa attaattgac 720cgttacacat ttctgcagac agaggttgcc aacgcgggrc tgacaataac atctgataag 780attcaarcct ctactccttt ccgttacttg ggaatgcagg tagaggaaag gaaaattaaa 840ccmcaaaaaa atagaaataa gaaaagacac attaaaagca ttaaatgagt ttcaaaagtt 900gctaggagat actaattgga tttggagata ttaattggat ttggccaact ctaggcattc 960ctacttatgc catgtcaaat ttgtwctctt tcttaagagg ggactcggaa ttaaatagtg 1020aaagaacgtt aactccagag gcaactaaag aaattaaatt aattgaagaa aaaattcggt 1080cagcacaagt aaatagaata gatcacttgg ccccactcca aattttgatt tttactactg 1140cacattccct aacaggcatc attgttcaaa acacagatct tgtggagtgg tccttccttc 1200ctcacagtac aattaagact tttacattgt acttggatca aatggctaca ttaattggtc 1260agggaagatt atgaataata acattgtgtg gaaatgaccc agataaaatc actgttcctt 1320tcaacaagca acaggttaga caagccttta tcaattctgg tgcatggcag attggtcttg 1380ccgattttgt gggaattatt gacaatcgtt accaca 141691420DNAHomo sapiens 9acaacaatgg catgcagaga ttactatccc agcctcccta tacagcccca ggaatcaaaa 60aatcatgact aaaatgggat agctccctaa aaagggacta ggaaagaaag aagtcccaat 120tgaggctgaa aaaaatyaaa aaagaaaagg aatagggcat cctttttagg agcggtcact 180gtagagcctc caaaacccat tccattaact tgggggaaaa aaaaamaact gtatggtaaa 240tcagcagccg cttccaaaac aaaarctgga ggcyttacay ttattagcaa agaaacmatt 300agaaaaagga cattgagcct tcattttcgc cttggaattc tgtttgtrat tcagaaaaaa 360tccggcagat ggcgtatgct aactgagcca ttaatgccgt aattcaaccc atgggggctc 420tcccaccccg gttgccctct ccagccatgg tcccctttaa ttataattga tctgaaggat 480tgctttttta ccattcctct ggcaaaacag gattttgara aatttgcttt yaccacacca 540gcctaaataa taaagaacca gccaccaggt ttcagtggaa agtattgcct cagggaatgc 600ttaatagttc aactatttgt cagctcaagc tctgcaacca gttagagaca agttttcaga 660ctgttacatc gttcactatg ttgatatttt gtgtgctgca gaaacgagag acaaattaat 720tgaccgttac acatttctgc agacagaggt tgccaacgcg ggrctgacaa taacatctga 780taagattcaa rcctctactc ctttccgtta cttgggaatg caggtagagg aaaggaaaat 840taaaccmcaa aaaaatagaa ataagaaaag acacattaaa agcattaaat gagtttcaaa 900agttgctagg agatactaat tggatttgga gatattaatt ggatttggcc aactctaggc 960attcctactt atgccatgtc aaatttgtwc tctttcttaa gaggggactc ggaattaaat 1020agtgaaagaa cgttaactcc agaggcaact aaagaaatta aattaattga agaaaaaatt 1080cggtcagcac aagtaaatag aatagatcac ttggccccac tccaaatttt gatttttact 1140actgcacatt ccctaacagg catcattgtt caaaacacag atcttgtgga gtggtccttc 1200cttcctcaca gtacaattaa gacttttaca ttgtacttgg atcaaatggc tacattaatt 1260ggtcagggaa gattatgaat aataacattg tgtggaaatg acccagataa aatcactgtt 1320cctttcaaca agcaacaggt tagacaagcc tttatcaatt ctggtgcatg gcagattggt 1380cttgccgatt ttgtgggaat tattgacaat cgttaccaca 142010837DNAHomo sapiens 10ccaaaagaat gagtcatcaa aactcagtat cactygactc aaagagcaga gttggttgcc 60gtcattacag tgttaacaag attttaatca gtctattaac attgtatcag attctgcata 120tgtagtacag gctacaaagg atattgagag agccctaatc aaatacatta tggatgatca 180gttaaacccg ctgtttaatt tgttacaaca aaatgtaaga aaawgaaatt tcccatttta 240tattactcat attcgagcac acactaattt accagggcct ttaactaaag caaatgaaca 300agctgacttg ctagtatcat ctgcattcat kgargcacaa gaacttcatg ccttgactca 360tgtaaatgca ataggattaa aaaataratt tgatatcaca tggaaacaga caaaaaatat 420tgtacaacat tgcrcccagt gtcagattct acacctggcc actcaggagg yaagagttaa 480tcccagaggt ctatgtccta atgtgttatg gcaaatggat gtcatgcacg taccytcatt 540tggaaaattg tcatttgtcc aygtgacagt tgatacttat tcacatttca tatgggcaac 600ctgccagaca ggagaaagta cttcccatgt yaagagacat ttattatytt gttttcctgt 660catgggagtt ccagaaaaag ttaaracaga caatgggcca ggttactgta gtaaagcagt 720tcaaraattc ttaaatcagt ggaaaattac acatacaata ggaattctct ataattccca 780aggacaggcc ataattgaaa gaactaatag aacactcaaa gctcaattgg ttaaaca 83711841DNAHomo sapiensmisc_feature(1)..(841)N=A,G,C,T 11gggaagagac tcaagtagga gcgcctgccc gagctgagac tagatgtgaa cctttcacca 60tgaaaatgtt aaaagatata aaggaaggag ttaaacaata tggatccaac tccccttata 120taagaacagt attagattcc attgctcatg gaaatagact tactccttat gactgggaaa 180ttttggccaa atcttccctt tcatcctctc agtatctaca gtttaaaacc tggtggattg 240atggagtaca agaacaggta cgnaaaaaat caggctacta agcccactgt taatatagac 300gcagaccaat tgttaggaac aggtccaaat tggagcacca ttaaccaaca atcagtgatg 360cagaatgagg ctattgaaca agtaagggct atttgcctca gggcctgggg aaaaattcag 420gacccaggaa cagctttccc tattaattca attagacaag gctctaaaga gccatatcct 480gactttgtgg caagattaca agatgctgct caaaagtcta ttacagatga caatgcccga 540aaagttattg tagaattaat ggcctatgaa aatgcaaatc cagaatgtca gtcggccata 600aagccattaa aaggaaaagt tccagcagga gttgatgtaa ttacagaata tgtgaaggct 660tgtgatggga ttggaggagc tatgcataag gcaatgctaa tggctcaagc aatgaggggg 720ctcactctag gaggacaagt tagaacattt gggaaaaaat gttataattg tggtcaaatc 780ggtcatctga aaaggagttg cccaggctta aataaacaga atataataaa tcaagctatt 840a 84112924DNAHomo sapiensmisc_feature(1)..(924)N=A,G,C,T 12nctgaaaaaa atnaaaaaag aaaaggaata gggcatcctt tttaggagcg gtcactgtag 60agcctccaaa acccattcca ttaacttggg naaaaaaana actgtatggt aaatcagcag 120ncgcttccaa aacaaaanct ggaggcntta canttattag caaagaaacc attagaaaaa 180ggacattgag ccttcatttt cgccttggaa ttctgtttgt aattcagaaa aaatccggca 240gatggcgtat gctaactgag ccattaatgc cgtaattcaa cccatggggg ctctcccacc 300ccggttgccc tctccagcca tggtcccctt taattataat tgatctgaag gattgctttt 360ttaccattcc tctggcaaaa caggattttg aaaaatttgc ttttaccaca ccagcctaaa 420taataaagaa ccagccacca ggtttcagtg gaaagtattg cctcagggaa tgcttaatag 480ttcaactatt tgtcagctca agctctgcaa ccagttagag acaagttttc agactgttac 540atcgttcact atgttgatat tttgtgtgct gcagaaacga gagacaaatt aattgaccgt 600tacacatttc tgcagacaga ggttgccaac gcgggactga caataacatc tgataagatt 660caaacctcta ctcctttccg ttacttggga atgcaggtag aggaaaggaa aattaaacca 720caaaaaaata gaaataagaa aagacacatt aaaagcatta aatgagtttc aaaagttgct 780aggagatact aattggattt ggagatatta attggatttg gccaactcta ggcattccta 840cttatgccat gtcaaatttg tnctctttct taagagggga ctcggaatta aatagtgaaa 900gaacgttaac tccagaggca acta 92413833DNAHomo sapiensmisc_feature(1)..(833)N=A,G,C,T 13ccaaaagaat gagtcatcaa aactcagtat cacttgactc aaagagcaga gttggttgcc 60gtcattacag tgttaacaag attttaatca gtctattaac attgtatcag attctgcata 120tgtagtacag gctacaaagg atattgagag agccctaatc aaatacatta tggatgatca 180gttaaacccg ctgtttaatt tgttacaaca aaatgtaaga aaaagaaatt tcccatttta 240tattactcat attcgagcac acactaattt accagggcct ttaactaaag caaatgaaca 300agctgacttg ctagtatcat ctgcattcat ggaagcacaa gaacttcatg ccttgactca 360tgtaaatgca ataggattaa aaaataaatt tgatatcaca tggaaacaga caaaaaatat 420tgtacaacat tgcacccagt gtcagattct acacctggcc actcaggagg caagagttaa 480tcccagaggt ctatgtccta atgtgttatg gcaaatggat gtcatgcacg taccttcatt 540tggaaaattg tcatttgtcc atgtgacagt tgatacttat tcacatttca tatgggcaac 600ctgccagaca ggagaaagta cttcccatgt taagagacat ttattatctt gttttcctgt 660catgggagtt ccagaaaaag ttaaaacaga caatgggcca ggttactgta gtaaagcagt 720tcaaaaattc ttaaatcagt ggaaaattac acatacaata ggaattctct ataattccca 780aggacaggcc ataattgaaa gaactaatag aacactcaaa gctcaattgg tta 83314868DNAHomo sapiens 14gggaagagac tcaagtagga gcgcctgccc gagctgagac tagatgtgaa cctttcacca 60tgaaaatgtt aaaagatata aaggaaggag ttaaacaata tggatccaac tccccttata 120taagaacagt attagattcc attgctcatg gaaatagact tactccttat gactgggaaa 180ttttggccaa atcttccctt tcatcctctc agtatctaca gtttaaaacc tggtggattg 240atggagtaca ggaacaggta cgaaaaaatc aggctactaa gcccactgtt aatatagacg 300cagaccaatt gttaggaaca ggtccaaatt ggagcaccat taaccaacaa tcagtgatgc 360agaatgaggc tattgaacaa gtaagggcta tttgcctcag ggcctgggga aaaattcagg 420acccaggaac agctttccct attaattcaa ttagacaagg ctctaaagag ccatatcctg 480actttgtggc aagattacaa gatgctgctc aaaagtctat tacagatgac aatgcccgaa 540aagttattgt agaattaatg gcctatgaaa atgcaaatcc agaatgtcag tcggccataa 600agccattaaa aggaaaagtt ccagcaggag ttgatgtaat tacagaatat gtgaaggctt 660gtgatgggat tggaggagct atgcataagg caatgctaat ggctcaagca atgagggggc 720tcactctagg aggacaagtt agaacatttg ggaaaaaatg ttataattgt ggtcaaatcg 780gtcatctgaa aaggagttgc ccaggcttaa ataaacagaa tataataaat caagctatta 840cagaaaaaaa aaaaaaaaaa aaaaaaaa 868151417DNAHomo sapiens 15gggaagagac tcaagtagga gcgcctgccc gagctgagac tagatgtgaa cctttcacca 60tgaaaatgtt aaaagatata aaggaaggag ttaaacaata tgggtccaac tccccttata 120taagaacatt attagattcc attgctcatg gaaatagact tactccttat gactgggaaa 180ttttggccaa atcttccctt tcatcctctc agtatctaca gtttaaaacc tggtggattg 240atggagtaca agaacaggta cgaaaaaatc aggctactaa gcccactgtt aatatagacg 300cagaccaatt gttaggaaca ggtccaaatt ggagcaccat taaccaacaa tcagtgatgc 360agaatgaggc tattgaacaa gtaagggcta tttgcctcag ggcctgggga aaaattcagg 420acccaggaac agctttccct attaattcaa ttagacaagg ctctaaagag ccatatcctg 480actttgtggc aagattacaa gatgctgctc aaaagtctat tacagatgac aatgcccgaa 540aagttattgt agaattaatg gcctatgaaa atgcaaatcc agaatgtcag tcggccataa 600agccattaaa aggaaaagtt ccagcaggag ttgatgtaat tacagaatat gtgaaggctt 660gtgatgggat tggaggagct atgcataagg caatgctaat ggctcaagca atgagggggc 720tcactctagg aggacaagtt agaacatttg ggaaaaaatg ttataattgt ggtcaaatcg 780gtcatcggaa aaggagttgc ccaggcttaa ataaacagaa tataataaat caagctatta 840cagcaaaaaa taaaaagcca tctggcctgt gtccaaaatg tggaaaagca aaacattggg 900ccaatcaatg tcattctaaa tttgataaag atgggcaacc attgtctgga aacaggaaga 960ggggccagcc tcaggccccc caacaaactg gggcattccc agttaaactg tttgttcctc 1020agggttttca aggacaacaa cccctacaga aaataccacc acttcaggga gtcagccaat 1080tacaacaatc caacagctgt cccgcgccac agcaggcagc accgcagtag atttatgttc 1140cacccaaatg gtctttttac tccctggaaa gcccccacaa aagattccta gaggggtata 1200tggcccgctg ccagaaggga gggtaggcct ttgagggaga tcaagtctaa atttgaaggg 1260agtccaaatt catactgggg taatttactc agattataaa gggggaattc agttagtgat 1320cagctccact gttccccgga gtgccaatcc aggtgataga attgctcaat tactgctttt 1380gccttatgca aaaaaaaaaa aaaaaaaaaa aaaaaaa 141716841DNAHomo sapiens 16aagagactca agtaggagcg cctgcccgag ctgagactag atgtgaacct ttcaccatga 60aaatgttaaa agatataaag gaaggagtta aacaatatgg atccaactcc ccttatataa 120gaacagtatt agattccatt gcccatggaa atagacttac tccttatgac tgggaaattt 180tggccaaatc ttccctttca tcctctcagt atctacagtt taaaacctgg tggattgatg 240gggtacaaga acaggtacga aaaaaatcag gctactaagc ccactgttaa tatagacgca 300gaccaattgt taggaacagg tccaaattgg agcaccatta accaacaatc agtgatgcag 360aatgaggcta ttgaacaagt aagggctatt tgcctcaggg cctggggaaa aattcaggac 420ccaggaacag ctttccctat taattcaatt agacaaggct ctaaagagcc atatcctgac 480tttgtggcaa gattacaaga tgctgctcaa aagtctatta cagatgacaa tgcccgaaaa 540gttattgtag aattaatggc ctatgaaaat gcaaatccag aatgtcagtc ggccataaag 600ccattaaaag gaaaagttcc agcaggagtt gatgtaatta ccgaatatgt gaaggcttgt 660gatgggattg gaggagctat gcataaggca atgctaatgg ctcaagcaat gagggggctc 720actctaggag gacaagttag aacatttggg aaaaaatgtt ataattgtgg tcaaatcggt 780catctgaaaa ggagttgccc aggcttaaac aagcaaaaaa aaaaaaaaaa aaaaaaaaaa 840a 84117873DNAHomo sapiens 17acaacaatgg catgcagaga ttactatccc agcctcccta tacagcccca ggaatcaaaa 60aatcatgact aaaatgggat agctccctaa aaagggacta ggaaagaaag aagtcccaat 120tgaggctgaa aaaaattaaa aaagaaaagg aatagggcat cctttttagg agcggtcact 180gtagagcctc caaaacccat tccattaact tgggaaaaaa aaaactgtat ggtaaatcag 240cagccgcttc caaaacaaaa gctggaggcc ttacacttat tagcaaagaa accattagaa 300aaaggacatt gagccttcat tttcgccttg gaattctgtt tgtgattcag aaaaaatccg 360gcagatggcg tatgctaact gagccattaa tgccgtaatt caacccatgg gggctctccc 420accccggttg ccctctccag ccatggtccc ctttaattat aattgatctg aaggattgct 480tttttaccat tcctctggca aaacaggatt ttgaaaaatt tgcttttacc acaccagcct 540aaataataaa gaaccagcca ccaggtttca gtggaaagta ttgcctcagg gaatgcttaa 600tagttcaact atttgtcagc tcaagctctg caaccagtta gagacaagtt ttcagactgt 660tacatcgttc actatgttga tattttgtgt gctgcagaaa cgagagacaa attaattgac 720cgttacacat ttctgcagac agaggttgcc aacgcggggc tgacaataac atctgataag 780attcaaacct ctactccttt ccgttacttg ggaatgcagg tagaggaaag gaaaattaaa 840ccccaaaaaa aaaaaaaaaa aaaaaaaaaa aaa 87318733DNAHomo sapiens 18ctgaaaaaaa tcaaaaaaga aaaggaatag ggcatccttt

ttaggagcgg tcactgtaga 60gcctccaaaa cccattccat taacttgggg gaaaaaaaaa caactgtatg gtaaatcagc 120agcgcttcca aaacaaaaac tggaggcttt acatttatta gcaaagaaac aattagaaaa 180aggacattga gccttcattt tcgccttgga attctgtttg taattcagaa aaaatccggc 240agatggcgta taatgccgta attcaaccca tgggggctct cccaccccgg ttgccctctc 300cagccatggt cccctttaat tataattgat ctgaaggatt gcttttttac cattcctctg 360gcaaaacagg attttgagaa atttgctttt accacaccag cctaaataat aaagaaccag 420ccaccaggtt tcagtggaaa gtattgcctc agggaatgct taatagttca actatttgtc 480agctcaagct ctgcaaccag ttagagacaa gttttcagac tgttacatcg ttcactatgt 540tgatattttg tgtgctgcag aaacgagaga caaattaatt gaccgttaca catttctgca 600gacagaggtt gccaacgcgg gactgacaat aacatctgat aagattcaaa cctctactcc 660tttccgttac ttgggaatgc aggtagagga aaggaaaatt aaaccacaaa aaaaaaaaaa 720aaaaaaaaaa aaa 73319785DNAHomo sapiens 19cattagaaaa aggacattga gccttcattt tcgccttgga attctgtttg taattcagaa 60aaaatccggc agatggcgta tgctaactga gccattaatg ccgtaattca acccatgggg 120gctctcccac cccggttgcc ctctccagcc atggtcccct ttaattataa ttgatctgaa 180ggattgcttt tttaccattc ctctggcaaa acaggatttt gaaaaatttg cttttaccac 240accagcctaa ataataaaga accagccacc aggtttcagt ggaaagtatt gcctcaggga 300atgcttaata gttcaactat ttgtcagctc aagctctgca accagttaga gacaagtttt 360cagactgtta catcgttcac tatgttgata ttttgtgtgc tgcagaaacg agagacaaat 420taattgaccg ttacacattt ctgcagacag aggttgccaa cgcgggactg acaataacat 480ctgataagat tcaaacctct actcctttcc gttacttggg aatgcaggta gaggaaagga 540aaattaaacc acaaaaaata gaaataagaa aagacacatt aaaagcatta aatgagtttc 600aaaagttgct aggagatact aattggattt ggagatatta attggatttg gccaactcta 660ggcattccta cttatgccat gtcaaatttg tactctttct taagagggga ctcggaatta 720aatagtgaaa gaacgttaac tccagaggca actaaagaaa aaaaaaaaaa aaaaaaaaaa 780aaaaa 785201090DNAHomo sapiens 20atctttaccc tgtataaaca tctttctctt cccagtattt ctaagcatgt gacaatgaat 60atgcaaagga agcgcagcag tccaccaggt gtgggatatg tgtggcacaa ttcaagacaa 120tgattaaacc tccacttgat gttgcaaaag agattttgaa aaatttgctt tcaccacacc 180agcctaaata ataaagaacc agccaccagg tttcagtgga aagtattgcc tcagggaatg 240cttaatagtt caactatttg tcagctcaag ctctgcaacc agttagagac aagttttcag 300actgttacat cgttcactat gttgatattt tgtgtgctgc agaaacgaga gacaaattaa 360ttgaccgtta cacatttctg cagacagagg ttgccaacgc gggactgaca ataacatctg 420ataagattca agcctctact cctttccgtt acttgggaat gcaggtagag gaaaggaaaa 480ttaaaccaca aaaaaataga aataagaaaa gacacattaa aagcattaaa tgagtttcaa 540aagttgctag gagatactaa ttggatttgg agatattaat tggatttggc caactctagg 600cattcctact tatgccatgt caaatttgtt ctctttctta agaggggact cggaattaaa 660tagtgaaaga acgttaactc cagaggcaac taaagaaatt aaattaattg aagaaaaaat 720tcggtcagca caagtaaata gaatagatca cttggcccca ctccaaattt tgatttttac 780tactgcacat tccctaacag gcatcattgt tcaaaacaca gatcttgtgg agtggtcctt 840ccttcctcac agtacaatta agacttttac attgtacttg gatcaaatgg ctacattaat 900tggtcaggga agattatgaa taataacatt gtgtggaaat gacccagata aaatcactgt 960tcctttcaac aagcaacagg ttagacaagc ctttatcaat tctggtgcat ggcagattgg 1020tcttgccgat tttgtgggaa ttattgacaa tcgttaccac aaaaaaaaaa aaaaaaaaaa 1080aaaaaaaaaa 109021705DNAHomo sapiens 21ccaaaagaat gagtcatcaa aactcagtat cacttgactc aaagagcaga gttggttgcc 60gtcattacag tgttaacaag attttaatca gtctattaac attgtatcag attctgcata 120tgtagtacag gctacaaagg atattgagag agccctaatc aaatacatta tggatgatca 180gttaaacccg ctgtttaatt tgttacaaca aaatgtaaga aaaagaaatt tcccatttta 240tattactcat attcgagcac acactaattt accagggcct ttaactaaag caaatgaaca 300agctgacttg ctagtatcat ctgcattcat ggaagcacaa gaacttcatg ccttgactca 360tgtaaatgca ataggattaa aaaataaatt tgatatcaca tggaaacaga caaaaaatat 420tgtacaacat tgcacccagt gtcagattct acacctggcc actcaggagg caagagttaa 480tcccagaggt ctatgtccta atgtgttatg gcaaatggat gtcatgcacg taccttcatt 540tggaaaattg tcatttgtcc atgtgacagt tgatacttat tcacatttca tatgggcaac 600ctgccagaca ggagaaagta cttcccatgt caagagacat ttattatctt gttttcctgt 660catgggagtt ccagaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaa 70522862DNAHomo sapiens 22ccaaaagaat gagtcatcaa aactcagtat cactcgactc aaagagcaga gttggttgcc 60gtcattacag tgttaacaag attttaatca gtctattaac attgtatcag attctgcata 120tgtagtacag gctacaaagg atattgagag agccctaatc aaatacatta tggatgatca 180gttaaacccg ctgtttaatt tgttacaaca aaatgtaaga aaaagaaatt tcccatttta 240tattactcat attcgagcac acactaattt accagggcct ttaactaaag caaatgaaca 300agctgacttg ctagtatcat ctgcattcat ggaagcacaa gaacttcatg ccttgactca 360tgtaaatgca ataggattaa aaaataaatt tgatatcaca tggaaacaga caaaaaatat 420tgtacaacat tgcgcccagt gtcagattct acacctggcc actcaggagg taagagttaa 480tcccagaggt ctatgtccta atgtgttatg gcaaatggat gtcatgcacg taccctcatt 540tggaaaattg tcatttgtcc atgtgacagt tgatacttat tcacatttca tatgggcaac 600ctgccagaca ggagaaagta cttcccatgt taagagacat ttattatctt gttttcctgt 660catgggagtt ccagaaaaag ttaaaacaga caatgggcca ggttactgta gtaaagcagt 720tcaaaaattc ttaaatcagt ggaaaattac acatacaata ggaattctct ataattccca 780aggacaggcc ataattgaaa gaactaatag aacactcaaa gctcaattgg ttaaacaaaa 840aaaaaaaaaa aaaaaaaaaa aa 86223865DNAHomo sapiens 23ccaaaagaat gagtcatcaa aactcagtat cacttgactc aaagagcaga gttggttgcc 60gtcattacag tgttaacaag attttaatca gtctattaac attgtatcag attctgcata 120tgtagtacag gctacaaagg atattgagag agccctaatc aaatacatta tggatgatca 180gttaaacccg ctgtttaatt tgttacaaca aaatgtaaga aaaagaaatt tcccatttta 240tattactcat attcgagcac acactaattt accagggcct ttaactaaag caaatgaaca 300agctgacttg ctagtatcat ctgcattcat ggaggcacaa gaacttcatg ccttgactca 360tgtaaatgca ataggattaa aaaatagatt tgatatcaca tggaaacaga caaaaaatat 420tgtacaacat tgcacccagt gtcagattct acacctggcc actcaggagg caagagttaa 480tcccagaggt ctatgtccta atgtgttatg gcaaatggat gtcatgcacg taccttcatt 540tggaaaattg tcatttgtcc atgtgacagt tgatacttat tcacatttca tatgggcaac 600ctgccagaca ggagaaagta cttcccatgt taagagacat ttattatctt gttttcctgt 660catgggagtt ccagaaaaag ttaaaacaga caatgggcca ggttactgta gtaaagcagt 720tcaaaaattc ttaaatcagt ggaaaattac acatacaata ggaattctct ataattccca 780aggacaggcc ataattgaaa gaactaatag aacactcaaa gctcaattgg ttaaacaaaa 840aaaaaaaaaa aaaaaaaaaa aaaaa 86524866DNAHomo sapiens 24ccaaaagaat gagtcatcaa aactcagtat cacttgactc aaagagcaga gttggttgcc 60gtcattacag tgttaacaag attttaatca gtctattaac attgtatcag attctgcata 120tgtagtacag gctacaaagg atattgagag agccctaatc aaatacatta tggatgatca 180gttaaacccg ctgtttaatt tgttacaaca aaatgtaaga aaatgaaatt tcccatttta 240tattactcat attcgagcac acactaattt accagggcct ttaactaaag caaatgaaca 300agctgacttg ctagtatcat ctgcattcat ggaagcacaa gaacttcatg ccttgactca 360tgtaaatgca ataggattaa aaaataaatt tgatatcaca tggaaacaga caaaaaatat 420tgtacaacat tgcacccagt gtcagattct acacctggcc actcaggagg caagagttaa 480tcccagaggt ctatgtccta atgtgttatg gcaaatggat gtcatgcacg taccttcatt 540tggaaaattg tcatttgtcc atgtgacagt tgatacttat tcacatttca tatgggcaac 600ctgccagaca ggagaaagta cttcccatgt taagagacat ttattatttt gttttcctgt 660catgggagtt ccagaaaaag ttaaaacaga caatgggcca ggttactgta gtaaagcagt 720tcaagaattc ttaaatcagt ggaaaattac acatacaata ggaattctct ataattccca 780aggacaggcc ataattgaaa gaactaatag aacactcaaa gctcaattgg ttaaacaaaa 840aaaaaaaaaa aaaaaaaaaa aaaaaa 86625882DNAHomo sapiens 25ccaaaagaat gagtcatcaa aactcagtat cacttgactc aaagagcaga gttggttgcc 60gtcattacag tgttaacaag attttaatca gtctattaac attgtatcag attctgcata 120tgtagtacag gctacaaagg atattgagag agccctaatc aaatacatta tggatgatca 180gttaaacccg ctgtttaatt tgttacaaca aaatgtaaga aaaagaaatt tcccatttta 240tattactcat attcgagcac acactaattt accagggcct ttaactaaag caaatgaaca 300agctgacttg ctagtatcat ctgcattcat tgaagcacaa gaacttcatg ccttgactca 360tgtaaatgca ataggattaa aaaataaatt tgatatcaca tggaaacaga caaaaaatat 420tgtacaacat tgcacccagt gtcagattct acacctggcc actcaggagg caagagttaa 480tcccagaggt ctatgtccta atgtgttatg gcaaatggat gtcatgcacg taccttcatt 540tggaaaattg tcatttgtcc acgtgacagt tgatacttat tcacatttca tatgggcaac 600ctgccagaca ggagaaagta cttcccatgt taagagacat ttattatctt gttttcctgt 660catgggagtt ccagaaaaag ttaagacaga caatgggcca ggttactgta gtaaagcagt 720tcaaaaattc ttaaatcagt ggaaaattac acatacaata ggaattctct ataattccca 780aggacaggcc ataattgaaa gaactaatag aacactcaaa gctcaattgg ttaagcaaaa 840aaaaaaaaaa aaaaaaaaaa aaacatgtcg gccgcctcgg cc 88226860DNAHomo sapiens 26ccaaaagaat gagtcatcaa aactcagtat cacttgactc aaagagcaga gttggttgcc 60gtcattacag tgttaacaag attttaatca gtctattaac attgtatcag attctgcata 120tgtagtacag gctacaaagg atattgagag agccctaatc aaatacatta tggatgatca 180gttaaacccg ctgtttaatt tgttacaaca aaatgtaaga aaaagaaatt tcccatttta 240tattactcat attcgagcac acactaattt accagggcct ttaactaaag caaatgaaca 300agctgacttg ctagtatcat ctgcattcat ggaagcacaa gaacttcatg ccttgactca 360tgtaaatgca ataggattaa aaaataaatt tgatatcaca tggaaacaga caaaaaatat 420tgtacaacat tgcacccagt gtcagattct acacctggcc actcaggagg caagagttaa 480tcccagaggt ctatgtccta atgtgttatg gcaaatggat gtcatgcacg taccttcatt 540tggaaaattg tcatttgtcc atgtgacagt tgatacttat tcacatttca tatgggcaac 600ctgccagaca ggagaaagta cttcccatgt taagagacat ttattatctt gttttcctgt 660catgggagtt ccagaaaaag ttaaaacaga caatgggcca ggttactgta gtaaagcagt 720tcaaaaattc ttaaatcagt ggaaaattac acatacaata ggaattctct ataattccca 780aggacaggcc ataattgaaa gaactaatag aacactcaaa gctcaattgg ttaaacaaaa 840agaaaaaaaa aaaaaaaaaa 86027778DNAHomo sapiensmisc_feature(1)..(778)N=A,G,C,T 27accggcctta cggccgggga agagntcaag taggagcgcc tgcccgagct gagactagat 60gtgaaccttt caccatgaaa atgttaaaag atataaagga aggagttaaa caatatggat 120ccaactcccc ttatataaga acagtattag attccattgc tcatggaaat agacttactc 180cttatgactg ggaaattttg gccaaatctt ccctttcatc ctctcagtat ctacagttta 240aaacctggtg gattgatgga gtacaggaac aggtacgaaa aaatcaggct actaagccca 300ctgttaatat agacgcagac caattgttag gaacaggtcc aaattggagc accattaacc 360aacaatcagt gatgcagaat gaggctattg aacaagtaag ggctatttgc ctcagggcct 420ggggaaaaat tcaggaccca ggaacagctt tccctattaa ttcaattaga caaggctcta 480aagagccata tcctgacttt gtggcaagat tacaagatgc tgctcaaaag tctattacag 540atgacaatgc ccgaaaagtt attgtagaat taatggccta tgaaaatgca aatccagaat 600gtcagtcggc cataaagcca ttaaaaggaa aagttccagc aggagttgat gtaattacag 660aatatgtgaa ggcttgtgat gggattggag gagctatgcn taaggcaatg ctaatggctc 720aagcaatgag ggggctcact ctaggaggac aagttagaac atttgggaaa aaatgttt 77828668DNAHomo sapiensmisc_feature(1)..(668)N=A,G,C,T 28ttacggcctt acggccgggg aagnntntca agtaggagcg cctgcccgag ctgagactag 60atgtgaacct ttcaccatga aaatgttaaa agatataaag gaaggagtta aacaatatgg 120gtccaactcc ccttatataa gaacattatt agattccatt gctcatggaa atagacttac 180tccttatgac tgggaaattt tggccaaatc ttccctttca tcctctcagt atctacagtt 240taaaacctgg tggattgatg gagtacaaga acaggtacga aaaaatcagg ctactaagcc 300cactgttaat atagacgcag accaattgtt aggaacaggt ccaaattgga gcaccattaa 360ccaacaatca gtgatgcaga atgaggctat tgaacaagta agggctattt gcctcagggc 420ctggggaaaa attcaggacc caggaacagc tttccctatt aattcaatta gacaaggctc 480taaagagcca tatcctgact ttgtggcaag attacaagat gctgctcaaa agtctattac 540agatgacaat gcccgaaaag ttattgtaga attaatggcc tatgaaaatg caaatccaga 600atgtcagtcg gccataaagc cattaaaagg aaaagttcca gcaggagttg atgtaattac 660agaatatn 66829659DNAHomo sapiensmisc_feature(1)..(659)N=A,G,C,T 29cggccttacg gcccggggag anntcaagta ggagcgcctg cccgagctga gactagatgt 60gaacctttca ccatgaaaat gttaaaagat ataaaggaag gagttaaaca atatggatcc 120aactcccctt atataagaac agtattagat tccattgccc atggaaatag acttactcct 180tatgactggg aaattttggc caaatcttcc ctttcatcct ctcagtatct acagtttaaa 240acctggtgga ttgatggggt acaagaacag gtacgaaaaa aatcaggcta ctaagcccac 300tgttaatata gacgcagacc aattgttagg aacaggtcca aattggagca ccattaacca 360acaatcagtg atgcagaatg aggctattga acaagtaagg gctatttgcc tcagggcctg 420gggaaaaatt caggacccag gaacagcttt ccctattaat tcaattagac aaggctctaa 480agagccatat cctgactttg tggcaagatt acaagatgct gctcaaaagt ctattacaga 540tgacaatgcc cgaaaagtta ttgtagaatt aatggcctat gaaaatgcaa atccagaatg 600tcagtcggcc ataaagccat taaaaggaaa agttccagca ggagttgatg taattaccg 65930664DNAHomo sapiensmisc_feature(1)..(664)N=A,G,C,T 30nccggcctta cggccgggnc aacaatggca tgcagagntt actatcccag cctccctata 60cagccccagg aatcaaaaaa tcatgactaa aatgggatag ctccctaaaa agggactagg 120aaagaaagaa gtcccaattg aggctgaaaa aaattaaaaa agaaaaggaa tagggcatcc 180tttttaggag cggtcactgt agagcctcca aaacccattc cattaacttg ggaaaaaaaa 240aactgtntgg taaatcagca gccgnttcca aaacaaaagc tggaggcctt acacttatta 300ncaaagaanc cattanaaaa aggacattga gccttcattt tcgccttgga attctgtttg 360tgattcaaaa aaaatccggc anatggcgta tgctaactga nccattaatg ccgtaattca 420acccatgggg gctctcccac cccggttgcc ctntccagcc atggtcccct ttaattataa 480ttgatctgaa ggattgcttt tttaccattc ctctggcaaa acaggatttt gaaaaatttg 540cttttaccac accagcctaa ataataaana accanccacc aggtttcagt ggaaagtatt 600gcctcaggga atgcttaata gttcaactat tngtcagctc aagctctgca accagttaga 660gacn 66431743DNAHomo sapiensmisc_feature(1)..(743)N=A,G,C,T 31ncctggcctt acggccgggg ctgaaaaaaa tcaaaaaaga aaaggaatag ggcatccttt 60ttaggagcgg tcactgtaga gcctccaaaa cccattccat taacttgggg gaaaaaaaaa 120caactgtatg gtaaatcagc agcgcttcca aaacaaaaac tggaggcttt acatttatta 180gcaaagaaac aattagaaaa aggacattga gccttcattt tcgccttgga attctgtttg 240taattcagaa aaaatccggc agatggcgta taatgccgta attcaaccca tgggggctct 300cccaccccgg ttgccctctc cagccatggt cccctttaat tataattgat ctgaaggatt 360gcttttttac cattcctctg gcaaaacagg attttgagaa atttgctttt accacaccag 420cctaaataat aaagaaccag ccaccaggtt tcagtggaaa gtattgcctc agggaatgct 480taatagttca actatttgtc agctcaagct ctgcaaccag ttagagacaa gttttcagac 540tgttacatcg ttcactatgt tgatattttg tgtgctgcag aaacgagaga caaattaatt 600gaccgttaca catttctgca gacagaggtt gccaacgcgg gactgacaat aacatctgat 660aagattcaaa cctctactcc tttccgttac ttgggaatgc aggtagagga aaggaaaatt 720aaaccacaaa aaaaaaaaaa aan 74332679DNAHomo sapiensmisc_feature(1)..(679)N=A,G,C,T 32nnnnncncgg gcattagaaa aaggacattg agccttcatt ttcgccttgg aattctgttt 60gtaattcaga aaaaatccgg cagatggcgt atgctaactg agccattaat gccgtaattc 120aacccatggg ggctctccca ccccggttgc cctctccagc catggtcccc tttaattata 180attgatctga aggattgctt ttttaccatt cctctggcaa aacaggattt tgaaaaattt 240gcttttacca caccagccta aataataaag aaccagccac caggtttcag tggaaagtat 300tgcctcangg aatgcttaat agttcaacta tttgtcagct caaagctctg cacccagnta 360gagacaagtt tcagactggt tcatcgtcct atgtgatatt ttgtgtgctg cagaacgaga 420gacaaattat tggccgttca catttttgca gacagaggtt gccaacgcgg gactgacaat 480aacatctgat aagattaaac ctctactcct tccgtacttg ggaatgcagg tggaggaaag 540gaaaattaac ccccnnaaaa ttgaattang aaaagacccn ttaaagcctt aaatgagttc 600aaaaagttgc taggagaaac taattggatt tggaganatt aattggattt ggcaactnta 660ggcattccta cttatgccn 67933656DNAHomo sapiensmisc_feature(1)..(656)N=A,G,C,T 33tccggcctta cggccgggnt ctttaccctg tataaacatc tttctcttcc cagtatttct 60aagcatgtga caatgaatat gcaaaggaag cgcagcagtc caccaggtgt gggatatgtg 120tggcacaatt caagacaatg attaaacctc cacttgatgt tgcaaaagag attttgaaaa 180atttgctttc accacaccag cctaaataat aaagaaccag ccaccaggtt tcagtggaaa 240gtattgcctc agggaatgct taatagttca actatttgtc agctcaagct ctgcaaccag 300ttagagacaa gttttcagac tgttacatcg ttcactatgt tgatattttg tgtgctgcag 360aaacgagaga caaattaatt gaccgttaca catttctgca gacagaggtt gccaacgcgg 420gactgacaat aacatctgat aagattcaag cctctactcc tttccgttac ttgggaatgc 480aggtagagga aaggaaaatt aaaccacaaa aaaatagaaa taagaaaaga cacattaaaa 540gcattaaatg agtttcaaaa gttgctagga gatactaatt ggatttggag atattaattg 600gatttggcca actctaggca ttcctactta tgccatgtca aatttgttct ctttct 65634723DNAHomo sapiensmisc_feature(1)..(723)N=A,G,C,T 34ttncggcctt acggccgggc caagatgagt catcaaaact cagtatcact tgactcaaag 60agcagagttg gttgccgtca ttacagtgtt aacaagattt taatcagtct attaacattg 120tatcagattc tgcatatgta gtacaggcta caaaggatat tgagagagcc ctaatcaaat 180acattatgga tgatcagtta aacccgctgt ttaatttgtt acaacaaaat gtaagaaaaa 240gaaatttccc attttatatt actcatattc gagcacacac taatttacca gggcctttaa 300ctaaagcaaa tgaacaagct gacttgctag tatcatctgc attcatggaa gcacaagaac 360ttcatgcctt gactcatgta aatgcaatag gattaaaaaa taaatttgat atcacatgga 420aacagacaaa aaatattgta caacattgca cccagtgtca gattctacac ctggccactc 480aggaggcaag agttaatccc agaggtctat gtcctaatgt gttatggcaa atggatgtca 540ttgcacgtac cttcatttgg aaaattgtca tttgtccatg tgacagntga tacttattca 600catttcatat gggcaacctg ccagacagga gaaagtactt nccatgtcaa gagacattta 660ttatcttggt ttcctggntg gggagntccc nnnnnnnann nnnnnnnaaa aaaaanannc 720nnn 72335656DNAHomo sapiens 35ttacggcctt acggccgggc caaagatgag tcatcaaaac tcagtatcac tcgactcaaa 60gagcagagtt ggttgccgtc attacagtgt taacaagatt ttaatcagtc tattaacatt 120gtatcagatt ctgcatatgt agtacaggct acaaaggata ttgagagagc cctaatcaaa 180tacattatgg atgatcagtt aaacccgctg tttaatttgt tacaacaaaa tgtaagaaaa 240agaaatttcc cattttatat tactcatatt cgagcacaca ctaatttacc agggccttta 300actaaagcaa atgaacaagc tgacttgcta gtatcatctg cattcatgga agcacaagaa 360cttcatgcct tgactcatgt aaatgcaata ggattaaaaa ataaatttga tatcacatgg 420aaacagacaa aaaatattgt acaacattgc gcccagtgtc agattctaca cctggccact 480caggaggtaa gagttaatcc cagaggtcta tgtcctaatg tgttatggca aatggatgtc 540atgcacgtac cctcatttgg aaaattgtca tttgtccatg tgacagttga tacttattca 600catttcatat gggcaacctg ccagacagga gaaagtactt cccatgttaa gagaca 65636773DNAHomo

sapiensmisc_feature(1)..(773)N=A,G,C,T 36atttgcctta cggccgggcc aaaagtatga gtcatcaaaa ctcagtatca cttgactcaa 60agagcagagt tggttgccgt cattacagtg ttaacaagat tttaatcagt ctattaacat 120tgtatcagat tctgcatatg tagtacaggc tacaaaggat attgagagag ccctaatcaa 180atacattatg gatgatcagt taaacccgct gtttaatttg ttacaacaaa atgtaagaaa 240aagaaatttc ccattttata ttactcatat tcgagcacac actaatttac cagggccttt 300aactaaagca aatgaacaag ctgacttgct agtatcatct gcattcatgg aggcacaaga 360acttcatgcc ttgactcatg taaatgcaat aggattaaaa aatagatttg atatcacatg 420gaaacagaca aaaaatattg tacaacattg cacccagtgt cagattctac acctggccac 480tcaggaggca agagttaatc ccagaggtct atgtcctaat gtgttatggc aaatggatgt 540catgcacgta ccttcatttg gaaaattgtc atttgtccat gtgacagttg atacttattc 600acatttcata tgggcaacct gccagacagg agaaagtact tcccatgtta agagacattt 660attatcttgt tttcctgtca tgggagttcc agaaaaagtt aaaacagaca atgggccang 720ttactgtagt aaagcagttc aaaaattctt aaatcagtgg aaaattacac atn 77337721DNAHomo sapiensmisc_feature(1)..(721)N=A,G,C,T 37cggccttacg gccgggccaa anatgaaggg nnnaangncg gttcccaggg acnnaggcgc 60nttncatggt tgcngtngtt acacctgtta acaagattnt aatcagtcta ttaacattgt 120atcaaattct gcatatgtag nacaggctac aaaggatatt gagagagccc taatcaaata 180cattatggat gatcagttaa acccgctgtt taatttgtta caacaaaatg taagaaaatg 240aaatttccca ttttatatta ctcatattcg agcacacact aatttaccag ggcctttnac 300taaagcaaat gaacaagctg acttgctngt atcatctgca ttcatggaag cacaagaact 360tcatgccttg actcatgtaa atgcaatagg attaaaaaat aaatttgata tcacatggaa 420acagacaaaa aatattgtac aacattgcac ccagtgtcag attctacacc tggccactca 480ggaggcaaga gttaatccca gaggtctatg tcctaatgtg ttatggcaaa tggatgtcat 540gcacgtacct tcatttggaa aattgtcatt tgtccatgtg acagntgata cttattcaca 600tttcatatgg gcaacctgcc agacangaga aagtncttcc catgttaaga gacatttatt 660attttgntnt cctgncattg ggagttccan aaaaagtaaa acagacantg ggccaggtta 720c 72138672DNAHomo sapiensmisc_feature(1)..(672)N=A,G,C,T 38tacggcctta cggccgggcc aagatgagtc atcaaaactc agtatcactt gactcaaaga 60gcagagttgg ttgccgtcnt tacagtgtta acaagatttt aatcagtcta ttaacattgt 120atcagattct gcatatgtag tacaggctac aaaggatatt gagagagccc taatcaaata 180cattatggat gatcagttaa acccgctgtt taatttgtta caacaaaatg taagaaaaag 240aaatttccca ttttatatta ctcatattcg agcacacact aatttaccag ggcctttaac 300taaagcaaat gaacaagctg acttgctagt atcatctgca ttcattgaag cacaagaact 360tcatgccttg actcatgtaa atgcnatagg attaaaaaat aaatttgata tcacctggaa 420acagacaaaa aatattgtac aacattgcac ccnnngtcag attctacacc tggccnctcn 480ngaggcaaga gttaatcccn canggctatg tcctnatgtg ttatggcaaa nggatgtnat 540gcnccnncct tcctttngaa aannnnnntt tgtnccccnn acannngata cttattcacn 600nttnntatng gnnacccccc ccacnngana aanaacctnc ccnntnnana naaantnntt 660atttttnttt tn 67239757DNAHomo sapiensmisc_feature(1)..(757)N=A,G,C,T 39nccggcctta cggccgggcc aagatgagtc atcaaaactc agtatcactt gactcaaaga 60gcagagttgg ttgccgtcat tacagtgtta acaagatttt aatcagtcta ttaacattgt 120atcagattct gcatatgtag tacaggctac aaaggatatt gagagagccc taatcaaata 180cattatggat gatcagttaa acccgctgtt taatttgtta caacaaaatg taagaaaaag 240aaatttccca ttttatatta ctcatattcg agcacacact aatttaccag ggcctttaac 300taaagcaaat gaacaagctg acttgctagt atcatctgca ttcatggaag cacaagaact 360tcatgccttg actcatgtaa atgcaatagg attaaaaaat aaatttgata tcacatggaa 420acagacaaaa aatattgtac aacattgcac ccagtgtcag attctacacc tggccactca 480ggaggcaaga gttaatccca gaggtctatg tcctaatgtg ttatggcaaa tggatgtcat 540gcacgtacct tcatttggaa aattgtcatt tgtccatgtg acagttgata cttattcaca 600tttcatatgg gcaacctgcc agacaggaga aagtacttcc catgttaaga gacatttatt 660atcttgtttt cctgtcatgg gagttccaga aaaagttaaa acagacaatg ggccaggtta 720ctggagtaaa gcagttcaaa aattcttaaa tcagtgg 75740777DNAHomo sapiens 40aaggcagtca agcaggagtt aaacaatatg gacctaactc tccttatatt agaatattat 60taaattccat tgctcatgga aatagactta tttcttatga ttgggaaatt ctggctatat 120cttccctttc accctctcag tatctccagt ttaaaacctg gtggattgat ggggtacaag 180aacaggtacg aaaaaatcag gctactaatc ctgttgctta tatagatgaa gaccaattgc 240taggaagagg tccaaactgg gacactatta accaacaatc agtaatgaaa atgaggctat 300tgaacaacta taagggctat ttgcctcagg gcctgggaaa acattcagga cccaggaacc 360tcatgccctt cttttagttc aatcagacaa ggctctaaag agccatatcc agactttgtg 420gcaaggttgc aagatgcagc tcaaaaatcc attgcaggta acgcccgaaa agttattgta 480gaaataatgg cttatcaaaa cgcaaattca gagtgtcaat cagccataaa gccattaaga 540ggaaatgttt cagcaggagt tgatgtaatt acagaatatg tgaaggcttg tgatgggatt 600ggaggagcta tgcataaggc aatgccattg gctcaagcaa ttacaggggt tgctatagga 660ggacaagtta aaacatttgg gggaaaatgt tataattgtg gtcaaatcgg tcatctaaaa 720aagaattgcc cgagcttaaa ttacccccca aaaaaaaaaa aaaaaaaaaa aaaaaaa 77741670DNAHomo sapiensmisc_feature(1)..(670)N=A,G,C,T 41nccggcctta cggccgggaa aggcagtcaa gcaggagtta aacaatatgg acctaactct 60ccttatatta gaatattatt aaattccatt gctcatggaa atagacttat ttcttatgat 120tgggaaattc tggctatatc ttccctttca ccctctcagt atctccagtt taaaacctgg 180tggattgatg gggtacaaga acaggtaccg aaaaaatcag gctactaatc ctgttgctta 240tatagatgaa gaccaattgc taggaagagg tccaaactgg gacactatta accaacaatc 300agtaatgaaa atgaggctat tgaacaacta taagggctat ttgcctcagg gcctgggaaa 360acattcagga cccaggaacc tcatgccctt cttttagttc aatcagacaa ggctctaaag 420agccatatcc agactttgtg gcaaggttgc aagatgcagc tcaaaaatcc attgcaggta 480acgcccgaaa agttattgta gaaataatgg cttatcaaaa cgcaaattca gagtgtcaat 540cagccataaa gccattaaga ggaaatgttt cagcaggagt tgatgtaatt acagaatatg 600tgaaggcttg tgatgggatt ggaggagcta tgcataaggc aatgccattg gctcaagcaa 660ttacaggggt 67042397DNAHomo sapiens 42aaaggcagtc aagcaggagt taaacaatat ggacctaact ctccttatat gagaacatta 60ttaaattcca ttgctcatgg aaatagactt atttcttatg attgggaaat tctggctaaa 120tcttcccttt caccctctca gtatctccag tttaaaacct ggtggattga tggggtacaa 180gaacaggtac gaaaaaatca ggctactaat cctgttgctt atatagatga agaccaattg 240ctaggaagag gtccaaactg ggacactatt aaccaacaat cagtaatgaa aatgaggcta 300ttgaacaact ataagggcta tttgcctcag gggcctggga aaacattcag gacccaggga 360acctcatgcc cttcttttag gttcaatcag acaaggt 39743413DNAHomo sapiens 43gctgacttgc tagtatcatc tgcattcatt gaagcacaag aacttcatgc cttgactcat 60gtaaatgcaa taggattaaa aaataaattt gatatcacat ggaaacagac aaaaaatatt 120gtacaacatt gcacccagtg tcagattcta cacctggcca ctcaggaagc aagagttaat 180cccagaggtc tatgtcctaa tgtgttatgg caaatggatg tcatgcacgt accttcattt 240ggaaaattgt catttgtcca tgtgacagtt gatacttatt cacatttcat atgggcaacc 300tgccagacag gagaaagtct tcccatgtta aaagacattt attatcttgt tttcctgtca 360tgggagttcc agaaaaagtt aaaacagaca atgggccagg ttctgtagta aag 4134411122DNAHomo sapiens 44gccaaggtgg gaggattgct tgagcacagg agtttgaggc tgaagtgagc tatgatcgca 60ccactgcaat caatcaatca ataaacttca gtcaaccctg ccaggagcta tggaacaatt 120attgtttgtt ggagtgttct gtgttgggct aaatgtgaag cctctttata cttctacctt 180actcagtcac catatggggg ctgccccaga gaggtcatga cctcaagtga ggaagtactc 240agcagctgag ccaggcccta ctgatagctg gaggatgctg ctgcccatgc tgcccactgt 300gaggcagcaa gcccttgctt gaagggggat ctggatagta tgtttctgtg tctaccaccc 360ctagaaatgg tgcctagagt gagtcatcac aaaaagaatc aggatagctt ggtgtagtgg 420caggtgccta taatcccagc tactcaggag actgtggcag gagaatgact taaaccaggg 480agttggaggt tgcagtgagg tgaggtcaca caactgcact ccagactggg tgacagagtg 540agactccatc tcaaaaaaaa aaaaaaaaag aaaagaaaag aaaaaagaaa aagaatcagg 600aaatactaat atttaaagga taggtgaatg gaggaaaata atcaattgaa ggaggctgag 660cagatgaggt caaagaagat agagatccat aacagtaacc tcatagaagc ttatggaagc 720attttgacag tgctaaaagc cacataaagt tcaagtaaga cagtttcaga aatgtataaa 780catgaatgcc tttgcagtga cttaagtgtg attctggtgt ttccttctaa aaatactgcc 840ttctcaggtg tgggaaggat tctatctttt taggctttac caccatagtt ctctgcaggc 900ttgcaatcct gaatcaggct tgacttcaga aagtgcttta aaagggaggc tgggcgcggt 960ggctcatgcc tgtaatccca gcactctgag aggctgaggt tgtggggaaa agcaagagag 1020atcagattgt tactgtgtct gtgtagaaag aagtagacat aggagactcc attttgttct 1080gtactaagaa aaattcttct gccttgagat tctgttaatc tatgacctta cccccaaccc 1140cgtgctctct gaaacaggtg ctgtgtcaaa ctcagggtta aatggattaa gggttgtgca 1200agatgtgctt tgttaaacaa atgcttgaag gcagcatggt ccttaagagt catcaccact 1260ccctaatctc aagtacccag ggacacaaac actgcggaag gccgcagaga cctctgccta 1320ggaaagcaag gtattgtcca aggtttctcc ccatgtgata gtctgaaata tggcctcgtg 1380ggaagggaaa gacctgaccg tcccccagcc tgacacccgt aaagggtctg tgctgaggag 1440gattagtgta agaggaaggc atgcctcttg cagttgagac aagaggaagg catctgtctc 1500ctgcccgtcc ctgggcaatg gaatgtctcg gtataaaacc cgattgattg tacgttccat 1560ctactgagat aggaagaaaa cgccttaggg ctggaggtgt gggacaagcc ggcagcaata 1620ctgctttgta aagcattgag atgtttatgt gtatgcatat ctaaaagcac agcacttgat 1680tctttacctt gtctgtgatg caaagacctt tgttcacgtg tttgtctgct gaccctctcc 1740ccactattgt cttgtgacca tgacacatcc ccctctcaga gaaacaccca cgaatgatca 1800ataaatacta agggaactca gagacggcgc ggatcctcca tatgctgaac gctggttccc 1860tgggtcccct tatttctttc tctatacttt gtgtcttttt cttttccaag tctctcgttc 1920caccttacga gaaacaccca caggtgtgga ggggcaaccc accccttcat ctggtgccca 1980acgtggaggc ttttctctag ggtgaaggta cgctcgagcg tggtcattga ggacaagttg 2040acgagagatc ccgagtacat ctacagtcag ccttgcggta agtttgtgcg ctcggaagaa 2100gctagggtga taatggggca aactaaaagt aaaactaaaa gtaaatatgc ctcttatctc 2160agctttatta aaattctttt aaaaagaggg ggagttagag tatctacaaa aaatctaatc 2220aagctatttc aaataataga acaattttgc ccatggtttc cagaacaagg aactttagat 2280ctaaaagatt ggaaaagaat tggcgaggaa ctaaaacaag caggtagaaa gggtaatatc 2340attccactta cagtatggaa tgattgggcc attattaaag cagctttaga accatttcaa 2400acaaaagaag atagcgtttc agtttctgat gcccctggaa gctgtgtaat agattgtaat 2460gaaaagacag ggagaaaatc ccagaaagaa acagaaagtt tacattgcga atatgtaaca 2520gagccagtaa tggctcagtc aacgcaaaat gttgactata atcaattaca gggggtgata 2580tatcctgaaa cgttaaaatt agaaggaaaa ggtccagaat tagtggggcc atcagagtct 2640aaaccacgag ggccaagtcc tcttccagca ggtcaggtgc ccgtaacatt acaacctcaa 2700acgcaggtta aagaaaataa gacccaaccg ccagtagctt atcaatactg gccgccggct 2760gaacttcagt atctgccacc cccagaaagt cagtatggat atccaggaat gcccccagca 2820ctacagggca gggcgccata tcctcagccg cccactgtga gacttaatcc tacagcatca 2880cgtagtggac aaggtggtac actgcacgca gtcattgatg aagccagaaa acagggagat 2940cttgaggcat ggcggttcct ggtaatttta caactggtac aggccgggga agagactcaa 3000gtaggagcgc ctgcccgagc tgagactaga tgtgaacctt tcaccatgaa aatgttaaaa 3060gatataaagg aaggagttaa acaatatgga tccaactccc cttatataag aacattatta 3120gattccattg ctcatggaaa tagacttact ccttatgact gggaaagttt ggccaaatct 3180tccctttcat cctctcagta tctacagttt aaaacctggt ggattgatgg agtacaagaa 3240caggtacgaa aaaatcaggc tactaagccc actgttaata tagacgcaga ccaattgtta 3300ggaacaggtc caaattggag caccattaac caacaatcag tgatgcagaa tgaggctatt 3360gaacaagtaa gggctatttg cctcagggcc tggggaaaaa ttcaggaccc aggaacagct 3420ttccctatta attcaattag acaaggctct aaagagccat atcctgactt tgtggcaaga 3480ttacaagatg ctgctcaaaa gtctattaca gatgacaatg cccgaaaagt tattgtagaa 3540ttaatggcct atgaaaatgc aaatccagaa tgtcagtcgg ccataaagcc attaaaagga 3600aaagttccag caggagttga tgtaattaca gaatatgtga aggcttgtga tgggattgga 3660ggagctatgc ataaggcaat gctaatggct caagcaatga gggggctcac tctaggagga 3720caagttagaa catttgggaa aaaatgttat aattgtggtc aaatcggtca tctgaaaagg 3780agttgcccag tcttaaataa acagaatata ataaatcaag ctattacagc aaaaaataaa 3840aagccatctg gcctgtgtcc aaaatgtgga aaaggaaaac attgggccaa tcaatgtcat 3900tctaaatttg ataaagatgg gcaaccattg tcgggaaaca ggaagagggg ccagcctcag 3960gccccccaac aaactggggc attcccagtt caactgtttg ttcctcaggg ttttcaagga 4020caacaacccc tacagaaaat accaccactt cagggagtca gccaattaca acaatccaac 4080agctgtcccg cgccacagca ggcagcgcca cagtagattt atgttccacc caaatggtct 4140ctttactccc tggagagccc ccacaaaaga ttcctagagg ggtatatggc ccgctgccag 4200aagggagggt aggccttatt ttagggagat caagtctaaa tttgaaggga gtccaaattc 4260atactggggt aatttattca gattataaag ggggaattca gttagtgatc agctccactg 4320ttccctggag tgccaatcca ggtgatagaa ttgctcaatt actgcttttg ccttatgtta 4380aaattgggga aaacaaaacg gaaagaacag gagggtttgg aagtaccaac cctgcaggaa 4440aagccactta ttgggctaat caggtctcag aggatagacc cgtgtgtaca gtcactattc 4500agggaaagag tttgaaggat tagtggatac ccaggctgat gtttctatca tcggcatagg 4560caccgcctca gaagtgtatc aaagtgccat gattttacat tgtctaggat ctgataatca 4620agaaagtacg gttcagccta tgatcacttc tattccaatc aatttatggg gccgagactt 4680gttacaacaa tggcatgcag agattactat cccagcctcc ctatacagcc ccaggaatca 4740aaaaatcatg actaaaatgg gatagctccc taaaaaggga ctaggaaaga atgaagatgg 4800cattaaagtc ccaactgagg ctgaaaaaaa tcaaaaaaag aaaaggaata gggcatcctt 4860tttagaagcg gtcactgtag agcctccaaa acccattcca ttaatttggg gggaaaaaaa 4920aaactgtatg gtaaatcagt agccgcttcc aaaacaaaaa ctggaggctt tacacttatt 4980agcaaagaaa cagttagaaa aaggacatat tgagccttca ttttcgcctt ggaattctcc 5040tgtttgtaat tcagaaaaaa tccggcagat ggcgtatgct aactgactta agagccatta 5100atgccataat tcaacccatg ggggctctcc catcccggtt gccctctcca gccatggtcc 5160cctttaatta taattgatct gaaggattgc ttttttacca ttcctctggc aaaagaggat 5220tttgaaaaat ttgcttttac tataccagcc taaataataa agaaccagcc accaggtttc 5280agtggaaagt attgcctcag ggaatgctta ataattcaac tatttgtcag actttcatag 5340ctcaagctct gcaaccagtt agagacaagt tttcagactg ttatatcgtt cattatgttg 5400atattttgtg tgctgcagaa acgagagaca aattaattga ccgttacaca tttctcagac 5460agaggttgcc aacgcgggac tgacaatagc atctgataag attcaaacct ctcctccttt 5520ccattacttg ggaatgcagg tagaggaaag gaaaattaaa ccacaaaaaa tagaaataag 5580aaaagacaca ttaaaaacat taaatgagtt tcaaaagttg gtaggagata ctaattggat 5640tcggagatat taattggatt tggccaactc taggcattcc tacttatgcc atgtcaattt 5700tgttctcttt cttaagaggg gacttggaat taaatagtga aagaatgtta cctccagagg 5760caactaaaga aattaaatta attgaagaaa aaaattcggt cagcacaagt aaataggatc 5820acttggcccc actccaaatt ttgatttttg gtactgcaca ttctctaaca gccatcattg 5880ttcaaaacac agatcttgtg gattggtcct tccttcctca tagtacaatt aagactttta 5940cattgtactt ggatcaaatg gctacattaa ttggtcaggg aagattacga ataataacat 6000tgtgtggaaa tgacccagat aaaatcactg ttcctttcaa caagcaacaa gttagacaag 6060cctttatcag ttctggtgca tggcagattg gtcttgctaa ttttctggga attattgata 6120atcattaccc aaaaacaaaa atcttccagt tcttaaaatt gactacttgg attctaccta 6180aaattaccag acgtgaacct ttagaaaatg ctctaacagt atttactgat ggttccagca 6240atggaaaagc ggcttacaca gggccgaaag aacgagtaat caaaactccg tatcaatcag 6300ctcaaagagc agagttggtt gcagtcatta cagtgttaca agattttgac caacctatca 6360atattatatc agattctgca tatgtagtac aggctacaag ggatgttgag acagctctaa 6420ttaaatatag cacggacgat catttaaacc agctattcaa tttattacaa caaactgtaa 6480gaaaaagaaa tttcccattt tatattactc atattcgagc acacactaat ttaccagggc 6540ctttgactaa agcaaatgaa caagctgact tactggtatc atctgcattc ataaaagcac 6600aagaacttct tgctttgact catgtaaatg cagcaggatt aaaaaacaaa tttgatgtca 6660catggaaaca ggcaaaagat attgtacaac attgcaccca gtgtcaagtc ttacacctgt 6720ccactcaaga ggcaggagtt aatcccagag gtctgtgtcc taatgcgtta tggcaaatgg 6780atggcacgca tgttccttca tttggaagat tatcatatgt tcatgtaaca gttgatactt 6840attcacattt catatgggca acttgccaaa caggagaaag tacttcccat gttaaaaaac 6900atttattatc ttgttttgct gtaatgggag ttccagaaaa aatcaaaact gacaatggac 6960caggatattg tagtaaagct ttccaaaaat tcttaagtca gtggaaaatt tcacatacaa 7020caggaattcc ttataattcc caaggacagg ccatagttga aagaactaat agaacactca 7080aaactcaatt agttaaacaa aaagaagggg gagacagtaa ggagtgtacc actcctcaga 7140tgcaacttaa tctagcactc tatactttaa attttttaaa catttataga aatcagacta 7200ctacttctgc aaaacaacat cttactggta aaaagcacag cccacatgaa ggaaaactaa 7260tttggtggaa agataataaa aataagacat gggaaatagg gaaggtgata acgtggggga 7320gaggttttgc ttgtgtttca ccaggagaaa atcagcttcc tgtttggata cccactagac 7380atttgaagtt ctacaatgaa cccatcggag atgcaaagaa aagggcctcc acagagatgg 7440taaccccagt cacatggatg gataatccta tagaagtata tgttaatgat agtgtatggg 7500tacctggccc cacagatgat cgctgccctg ccaaacctga ggaagaaggg atgatgataa 7560atatttccat tgtgtatcgt tatcctccta tttgcctagg gagagcacca ggatgtttaa 7620tgcctgcagt ccaaaattgg ttggtagaag tacctactgt cagtcctaac agtagattca 7680cttatcacat ggtaagcggg atgtcactca ggccacgggt aaattattta caagactttt 7740cttatcaaag atcattaaaa tttagaccta aagggaaacc ttgccccaag gaaattccca 7800aagaatcaaa aaatacagaa gttttagttt gggaagaatg tgtggccaat agtgcggtga 7860tattacaaaa caatgaattc ggaactatta tagattgggc acctcgaggt caattctacc 7920acaattgctc aggacaaact cagtcgtgtc caagtgcaca agtgagtcca gctgttgata 7980gcgacttaac agaaagtcta gacaaacata agcataaaaa attacagtct ttctaccctt 8040gggaatgggg agaaaaagga atctctaccc caagaccaga aataataagt cctgtttctg 8100gtcctgaaca tccagaatta tggaggcttt ggcctgacac cacattagaa tttggtctgg 8160aaatcaaact ttagaaacaa gagatcgtaa gccattttat actatcgacc taaattccag 8220tctaacggtt cctttacaaa gttgcgtaaa gccctcttat atgctagttg taggaaatat 8280agttattaaa ccagactccc aaactataac ctgtgaaaat tgtagattgt ttacttgcat 8340tgattcaact tttaattggc ggcaccgtat tctgctggtg agagcaagag agggcgtgtg 8400gatctctgtg tccgtggact gaccgtggga ggcctcgcca tccatccata ttttgactga 8460agtattaaaa gacattttaa atagatccaa aagattcatt tttaccttaa ttgcagtgat 8520tatgggatta attgcagtca cagctacggc tgctgtggca ggagttgcat tgcactcttc 8580tgttcagtcg gtaaactttg ttaatgattg gcaaaagaat tctacaagat tgtggaattc 8640acaatctagt attgatcaaa aattggcaaa tcaaattaat gatcttagac aaactgtcat 8700ttggatggga gacagactca tgagcttaga acattgtttc cagttacagt gtgactggaa 8760tacgtcagat ttttgtatta caccccaaat ttataatgag tctgagcatc actgggacat 8820ggttagacgc catctacagg gaagagaaga taatctcact ttagacattt ccaaattaaa 8880ataacaaatt ttcgaagcat caaaagccca tttaaatttg atgccaggaa ctgaggcaat 8940tgcaggagtt gctgatggcc tcgcaaatct taaccctgtc acttgggtta agaccatcgg 9000aagtactatg attataaatc tcatattaat ccttgtgtgc ctgttttgtc tgttgttagt 9060ctgcaggtgt acccaacagc tccgaagaga cagcgaccat cgagaacggg ccatgatgac 9120gatggcggtt ttgtcgaaaa gaaaaggggg aaatgtgggg aaaagcaaga gagatcagat 9180tgttactgtg tctgtgtaga aagaagtaga cataggagac tccattttgt tctgtactaa 9240gaaaaattct tctgccttga gattctgtta atctatgacc ttacccccaa ccccgtgctc 9300tctgaaacag gtgctgtgtc

aaactcaggg ttaaatggat taagggttgt gcaagatgtg 9360ctttgttaaa caaatgcttg aaggcagcat gctccttaag agtcatcacc actccctaat 9420ctcaagtacc cagggacaca aaaactgcgg aaggccgcag ggacctctgc ctaggaaagc 9480caggtattgt ccaaggtttc tccccatgtg atagtctgaa atatggcctc atgggaaggg 9540aaagacctga ccgtccccca gcccgacacc cgtaaagggt ctgtgctgag gaggattagt 9600ataagaggaa ggcattcctc ttgcagttga gacaagagga aggcatctgt ctcctgcccg 9660tccctgggca atggaatgtc tcggtataaa acccgattgt acgttccatc tactgagata 9720ggaagaaaac gccttagggc tggaggtggg acatgcaggc agcaatactg ctttgtaaag 9780cattgagatg tttatgtgta tgcatatcta aaagcacagc acttgattct ttaccttgtc 9840tatgatgcaa agacctttgt tcacctgttt gtctgctgac cctctcccca ctattgtctt 9900gtgaccatga cacatccccc tctcagagaa acacccacga atgatcaata aatactaagg 9960gaactcagag acggcgcgga tcctccatat gctgaacgct ggttccctgg gtccccttat 10020ttctttctct atactttgtc tctgtgtctt tttcttttcc aagtctctca ttccacctta 10080agagaaacac tcacaggtgt ggaggggcaa cccatccctt cagaggtggg tggatcacct 10140gaggtcagga gttcaagaca agcctggcca acatggtgaa accccatctc tactaaaaat 10200acaaaattag ccaggtgtgg tggcaggtgt ctgtagtccc agctacttgg gaggctgacg 10260agaatcgctt gaacctggga gggggaggtt tcagtgagcc gagattgcac cactgcactc 10320cagcctgggg gacagagtga aactctgtct caaaaaaaca acaaaaaacc ccacctatag 10380acaggactag ctacataaat aacttgcagg gctcagtgta aaatgaaagt gtgaggtccc 10440tttttcaaag acgtagaagg ccgggtgcgg tggctcatgc ctgtaatccc agcactttgg 10500gaggctgagg caggcaggtt atgaggtcag gagttcgaga cagcctgacc aatatggtga 10560aaccccatct ctactaaaaa tacaaaaatt agctgggtgt ggtagcgggc gcctgtagtc 10620ccagctactc aggaggctga ggcagaagaa ttacttgaac ccaggagacg gaggttgcag 10680tgagctgaga tcgtgccact gcactctcca gcctcctcgg tgacagagcg agactctgtc 10740tcaaaaaaaa aaaaaaaaac agaaaaaggt gctattaaag ataccaaaat ataaggcact 10800ttcctttatt ctgcaatctg tctctccact tttcatagta ttttttcatt tgttatttaa 10860catcatgttt tgtcaggtga ggacatttac tcagccagtg cagcactcac tggtatccag 10920gggccatagg tgatttgacg cacccacatg gcccaccagc tgttgagttc cacctccagc 10980cagccactgg accaacatgc agtgccctgg ctgggggcag gaaagtctaa caaaccattt 11040cattccactg tcctcctggc caaacccaca gaggacaggt aaaccccctt gtatgtgttt 11100tgtacttgga tctggggtgg gc 11122459179DNAHomo sapiens 45tgtggggaaa agcaagagag atcaaattgt tactgtgtct gtgtagaaag aagtagacat 60aggagactcc attttgttat gtgctaagaa aaattcttct gccttgagat tctgttaatc 120tatgacctta cccccaaccc cgtgctctct gaaacgtgtg ctgtgtcaac tcagggttga 180atggattaag ggcggtgcag gatgtgcttt gttaaacaga tgcttgaagg cagcatgctc 240cttaagagtc atcaccactc cctaatctca agtacccagg gacacaaaaa ctgcggaagg 300ccgcagggac ctctgcctag gaaagccagg tattgtccaa ggtttctccc catgtgatag 360tctgaaatat ggcctcgtgg gaagggaaag acctgaccgt cccccagccc gacacctgta 420aagggtctgt gctgaggagg attagtaaaa gaggaaggaa tgcctcttgc agttgagaca 480agaggaaggc atctgtctcc tgcctgtccc tgggcaatgg aatgtctcgg tataaaaccc 540gattgtatgc tccatctact gagataggga aaaaccgcct tagggctgga ggtgggacct 600gcgggcagca atactgcttt gtaaagcatt gagatgttta tgtgtatgca tatccaaaag 660cacagcactt aatcctttac attgtctatg atgccaagac ctttgttcac gtgtttgtct 720gctgaccctc tccccacaat tgtcttgtga ccctgacaca tccccctctt tgagaaacac 780ccacagatga tcaataaata ctaagggaac tcagaggctg gcgggatcct ccatatgctg 840aacgctggtt ccccgggtcc ccttatttct ttctctatac tttgtctctg tgtctttttc 900ttttccaaat ctctcgtccc accttacgag aaacacccac aggtgtgtag gggcaaccca 960cccctacatc tggtgcccaa cgtggaggct tttctctagg gtgaaggtac gctcgagcgt 1020aatcattgag gacaagtcga cgagagatcc cgagtacatc tacagtcagc cttacggtaa 1080gcttgcgcgc tcggaagaag ctagggtgat aatggggcaa actaaaagta aaattaaaag 1140taaatatgcc tcttatctca gctttattaa aattctttta aaaagagggg gagttaaagt 1200atctacaaaa aatctaatca agctatttca aataatagaa caattttgcc catggtttcc 1260agaacaagga acttcagatc taaaagattg gaaaagaatt ggtaaggaac taaaacaagc 1320aggtaggaag ggtaatatca ttccacttac agtatggaat gattgggcca ttattaaagc 1380agctttagaa ccatttcaaa cagaagaaga tagcatttca gtttctgatg cccctggaag 1440ctgtttaata gattgtaatg aaaacacaag gaaaaaatcc cagaaagaaa ccgaaagttt 1500acattgcgaa tatgtagcag agccggtaat ggctcagtca acgcaaaatg ttgactataa 1560tcaattacag gaggtgatat atcctgaaac gttaaaatta gaaggaaaag gtccagaatt 1620aatggggcca tcagagtcta aaccacgagg cacaagtcct cttccagcag gtcaggtgct 1680cgtaagatta caacctcaaa agcaggttaa agaaaataag acccaaccgc aagtagccta 1740tcaatactgc cgctggctga acttcagtat cggccacccc cagaaagtca gtatggatat 1800ccaggaatgc ccccagcacc acagggcagg gcgccatacc atcagccgcc cactaggaga 1860cttaatccta tggcaccacc tagtagacag ggtagtgaat tacatgaaat tattgataaa 1920tcaagaaagg aaggagatac tgaggcatgg caattcccag taacgttaga accgatgcca 1980cctggagaag gagcccaaga gggagagcct cccacagttg aggccagata caagtctttt 2040tcgataaaaa tgctaaaaga tatgaaagag ggagtaaaac agtatggacc caactcccct 2100tatatgagga cattattaga ttccattgct tatggacata gactcattcc ttatgattgg 2160gagattctgg caaaatcgtc tctctcaccc tctcaatttt tacaatttaa gacttggtgg 2220attgatgggg tacaagaaca ggtccgaaga aatagggctg ccaatcctcc agttaacata 2280gatgcagatc aactattagg aataggtcaa aattggagta ctattagtca acaagcatta 2340atgcaaaatg aggccattga gcaagttaga gctatctgcc ttagagcttg ggaaaaaatc 2400caagacccag gaagtacctg cccctcattt aatacagtaa gacaaggttc aaaagagccc 2460taccctgatt ttgtggcaag gctccaagat gttgctcaaa agtcaattgc cgatgaaaaa 2520gccggtaagg tcatagtgga gttgatggca tatgaaaacg ccaatcctga gtgtcaatca 2580gccattaagc cattaaaagg aaaggttcct gcaggatcag atgtaatctc agaatatgta 2640aaagcctgtg atggaatcgg aggagctatg cataaagcta tgcttatggc tcaagcaata 2700acaggagttg ttttaggagg acaagttaga acatttggag gaaaatgtta taattgtggt 2760caaattggtc acttaaaaaa gaattgccca gtcttaaaca aacagaatat aactattcaa 2820gcaactacaa caggtagaga gccacctgac ttatgtccaa gatgtaaaaa aggaaaacat 2880tgggctagtc aatgtcgttc taaatttgat aaaaatgggc aaccattgtc gggaaacgag 2940caaaggggcc agcctcaggc cccacaacaa actggggcat tcccaattca gccatttgtt 3000cctcagggtt ttcagggaca acaaccccca ctgtcccaag tgtttcaggg aataagccag 3060ttaccacaat acaacaattg tccctcacca caagcggcag tgcagcagta gatttatgta 3120ctatacaagc agtctctctg cttccagggg agcccccaca aaaaatccct acaggggtat 3180atggcccact gcctgagggg actgtaggac taatcttggg aagatcaagt ctaaatctaa 3240aaggagttca aattcatact agtgtggttg attcagacta taaaggcgaa attcaattgg 3300ttattagctc ttcaattcct tggagtgcca gtccaagaga caggattgct caattattac 3360tcctgccata tattaagggt ggaaatagtg aaataaaaag aataggaggg cttgtaagca 3420ctgatccaac aggaaaggct gcatattggg caagtcaggt ctcagagaac agacctgtgt 3480gtaaggccat tattcaagga aaacagtttg aagggttggt agacactgga gcagatgtct 3540ctattattgc tttaaatcag tggccaaaaa actggcctaa acaaaaggct gttacaggac 3600ttgtcggcat aggcacagcc tcagaagtgt atcaaagtat ggagatttta cattgcttag 3660ggccagataa tcaagaaagt actgttcagc caatgattac ttcaattcct cttaatctgt 3720ggggtcgaga tttattacaa caatggggtg cggaaatcac catgcccgct ccattatata 3780gccccacgag tcaaaaaatc atgaccaaga tgggatatat accaggaaag ggactaggga 3840aaaatgaaga tggcattaaa gttccagttg aggctaaaat aaatcaagaa agagaaggaa 3900tagggtatcc tttttagggg cggtcactgt agagcctcct aaacccatac cactaacttg 3960gaaaacagaa aaaccggtgt gggtaaatca gtggccgcta ccaaaacaaa aactggaggc 4020tttacattta ttagcaaatg aacagttaga aaagggtcac attgagcctt cgttctcacc 4080ttggaattct cctgtgtttg taattcagaa gaaatcaggc aaatggcata cgttaactga 4140cttaagggct gtaaacgccg taattcaacc catggggcct ctccaacccg ggttgccctc 4200tccggccatg atcccaaaag attggccttt aattataatt gatctaaagg attgcttttt 4260taccatccct ctggcagagc aggattgtga aaaatttgcc tttactatac cagccataaa 4320taataaagaa ccagccacca ggtttcagtg gaaagtgtta cctcagggaa tgcttaatag 4380tccaactatt tgtcagactt ttgtaggtcg agctcttcaa ccagtgagag aaaagttttc 4440agactgttat attattcatt atattgatga tattttatgt gctgcagaaa cgaaagataa 4500attaattgac tgttatacat ttctgcaagc agaggttgcc aatgctggac tggcaatagc 4560atccgataag atccaaacct ctactccttt tcattattta gggatgcaga tagaaaatag 4620aaaaattaag ccacaaaaaa tagaaataag aaaagacaca ttaaaaacac taaatgattt 4680tcaaaaatta ctaggagata ttaattggat tcggccaact ctaggcattc ctacttatgc 4740catgtcaaat ttgttctcta tcttaagagg agactcagac ttaaatagtc aaagaatatt 4800aaccccagag gcaacaaaag aaattaaatt agtggaagaa aaaattcagt cagcgcaaat 4860aaatagaata gatcccttag ccccactcca acttttgatt tttgccactg cacattctcc 4920aacaggcatc attattcaaa atactgatct tgtggagtgg tcattccttc ctcacagtac 4980agttaagact tttacattgt acttggatca aatagctaca ttaatcggtc agacaagatt 5040acgaataaca aaattatgtg gaaatgaccc agacaaaata gttgtccctt taaccaagga 5100acaagttaga caagccttta tcaattctgg tgcatggcag attggtcttg ctaattttgt 5160gggacttatt gataatcatt acccaaaaac aaagatcttc cagttcttaa aattgactac 5220ttggattcta cctaaaatta ccagacgtga acctttagaa aatgctctaa cagtatttac 5280tgatggttcc agcaatggaa aagcagctta cacagggccg aaagaacgag taatcaaaac 5340tccatatcaa tcggctcaaa gagacgagtt ggttgcagtc attacagtgt tacaagattt 5400tgaccaacct atcaatatta tatcagattc tgcatatgta gtacaggcta caagggatgt 5460tgagacagct ctaattaaat atagcatgga tgatcagtta aaccagctat tcaatttatt 5520acaacaaact gtaagaaaaa gaaatttccc attttatatt acttatattc gagcacacac 5580taatttacca gggcctttga ctaaagcaaa tgaacaagct gacttactgg tatcatctgc 5640actcataaaa gcacaagaac ttcatgcttt gactcatgta aatgcagcag gattaaaaaa 5700caaatttgat gtcacatgga aacaggcaaa agatattgta caacattgca cccagtgtca 5760agtcttacac ctgcccactc aagaggcagg agttaatccc agaggtctgt gtcctaatgc 5820attatggcaa atggatgtca cgcatgtacc ttcatttgga agattatcat atgttcatgt 5880aacagttgat acttattcac atttcatatg ggcaacttgc caaacaggag aaagtacttc 5940ccatgttaaa aaacatttat tgtcttgttt tgctgtaatg ggagttccag aaaaaatcaa 6000aactgacaat ggaccaggat attgtagtaa agctttccaa aaattcttaa gtcagtggaa 6060aatttcacat acaacaggaa ttccttataa ttcccaagga caggccatag ttgaaagaac 6120taatagaaca ctcaaaactc aattagttaa acaaaaagaa gggggagaca gtaaggagtg 6180taccactcct cagatgcaac ttaatctagc actctatact ttaaattttt taaacattta 6240tagaaatcag actactactt ctgcagaaca acatcttact ggtaaaaaga acagcccaca 6300tgaaggaaaa ctaatttggt ggaaagataa taaaaataag acatgggaaa tagggaaggt 6360gataacgtgg gggagaggtt ttgcttgtgt ttcaccagga gaaaatcagc ttcctgtttg 6420gttacccact agacatttga agttctacaa tgaacccatc ggagatgcaa agaaaagggc 6480ctccacggag atggtaacac cagtcacatg gatggataat cctatagaag tatatgttaa 6540tgatagtata tgggtacctg gccccataga tgatcgctgc cctgccaaac ctgaggaaga 6600agggatgatg ataaatattt ccattgggta tcgttatcct cctatttgcc tagggagagc 6660accaggatgt ttaatgcctg cagtccaaaa ttggttggta gaagtaccta ctgtcagtcc 6720catcagtaga ttcacttatc acatggtaag cgggatgtca ctcaggccac gggtaaatta 6780tttacaagac ttttcttatc aaagatcatt aaaatttaga cctaaaggga aaccttgccc 6840caaggaaatt cccaaagaat caaaaaatac agaagtttta gtttgggaag aatgtgtggc 6900caatagtgcg gtgatattat aaaacaatga atttggaact attatagatt gggcacctcg 6960aggtcaattc taccacaatt gctcaggaca aactcagtcg tgtccaagtg cacaagtgag 7020tccagctgtt gatagcgact taacagaaag tttagacaaa cataagcata aaaaattgca 7080gtctttctac ccttgggaat ggggagaaaa aggaatctct accccaagac caaaaatagt 7140aagtcctgtt tctggtcctg aacatccaga attatggagg cttactgtgg cctcacacca 7200cattagaatt tggtctggaa atcaaacttt agaaacaaga gattgtaagc cattttatac 7260tgtcgaccta aattccagtc taacagttcc tttacaaagt tgcgtaaagc ccccttatat 7320gctagttgta ggaaatatag ttattaaacc agactcccag actataacct gtgaaaattg 7380tagattgctt acttgcattg attcaacttt taattggcaa caccgtattc tgctggtgag 7440agcaagagag ggcgtgtgga tccctgtgtc catggaccga ccgtgggagg cctcaccatc 7500cgtccatatt ttgactgaag tattaaaagg tgttttaaat agatccaaaa gattcatttt 7560tactttaatt gcagtgatta tgggattaat tgcagtcaca gctacggctg ctgtagcagg 7620agttgcattg cactcttctg ttcagtcagt aaactttgtt aatgattggc aaaagaattc 7680tacaagattg tggaattcac aatctagtat tgatcaaaaa ttggcaaatc aaattaatga 7740tcttagacaa actgtcattt ggatgggaga cagactcatg agcttagaac atcgtttcca 7800gttacaatgt gactggaata cgtcagattt ttgtattaca ccccaaattt ataatgagtc 7860tgagcatcac tgggacatgg ttagacgcca tctacaggga agagaagata atctcacttt 7920agacatttcc aaattaaaag aacaaatttt cgaagcatca aaagcccatt taaatttggt 7980gccaggaact gaggcaattg caggagttgc tgatggcctc gcaaatctta accctgtcac 8040ttgggttaag accattggaa gtacatcgat tataaatctc atattaatcc ttgtgtgcct 8100gttttgtctg ttgttagtct gcaggtgtac ccaacagctc cgaagagaca gcgaccatcg 8160agaacgggcc atgatgacga tggcggtttt gtcgaaaaga aaagggggaa atgtggggaa 8220aagcaagaga gatcaaattg ttactgtgtc tgtgtagaaa gaagtagaca taggagactc 8280cattttgtta tgtgctaaga aaaattcttc tgccttgaga ttctgttaat ctatgacctt 8340acccccaacc ccgtgctctc tgaaacatgt gctgtgtcaa ctcagggttg aatggattaa 8400gggcggtgca ggatgtgctt tgttaaacag atgcttgaag gcagcatgct ccttaagagt 8460catcaccact ccctaatctc aagtacccag ggacacaaaa actgcagaag gccgcaggga 8520cctctgccta ggaaagccag gtattgtcca aggtttctcc ccatgtgata gtctgaaata 8580tggcctcgtg ggaagggaaa gacctgaccg tcccccagcc cgacacctgt aaagggtctg 8640tgctgaggag gattagtaaa agaggaagga atgcctcttg cagttgagac aagaggaagg 8700catctgtctc ctgcctgtcc ctgggcaatg gaatgtctcg gtataaaacc cgattgtatg 8760ctccatctac tgagataggg aaaaaccgcc ttagggctgg aggtgggacc tgcgggcagc 8820aatactgctt tgtaaagcat tgagatgttt atgtgtatgc atatccaaaa gcacagcact 8880taatccttta cattgtctat gatgccaaga cctttgttca cgtgtttgtc tgctgaccct 8940ctccccacaa ttgtcttgtg accctgacac atccccctct ttgagaaaca cccacagatg 9000atcaataaat actaagggaa ctcagaggct ggcgggatcc tccatatgct gaacgctggt 9060tccccgggtc cccttatttc tttctctata ctttgtctct gtgtcttttt cttttccaaa 9120tctctcgtcc caccttacga gaaacaccca caggtgtgta ggggcaaccc acccctaca 917946279PRTHomo sapiensMISC_FEATURE(1)..(279)Xaa=Any amino acid 46Glu Thr Gln Val Gly Ala Pro Ala Arg Ala Glu Thr Arg Cys Glu Pro1 5 10 15Phe Thr Met Lys Met Leu Lys Asp Ile Lys Glu Gly Val Lys Gln Tyr 20 25 30Gly Ser Asn Ser Pro Tyr Ile Arg Thr Val Leu Asp Ser Ile Ala His 35 40 45Gly Asn Arg Leu Thr Pro Tyr Asp Trp Glu Ile Leu Ala Lys Ser Ser 50 55 60Leu Ser Ser Ser Gln Tyr Leu Gln Phe Lys Thr Trp Trp Ile Asp Gly65 70 75 80Val Gln Glu Gln Val Arg Lys Lys Ser Gly Tyr Xaa Ala His Cys Xaa 85 90 95Tyr Arg Arg Arg Pro Ile Val Arg Asn Arg Ser Lys Leu Glu His His 100 105 110Xaa Pro Thr Ile Ser Asp Ala Glu Xaa Gly Tyr Xaa Thr Ser Lys Gly 115 120 125Tyr Leu Pro Gln Gly Leu Gly Lys Asn Ser Gly Pro Arg Asn Ser Phe 130 135 140Pro Tyr Xaa Phe Asn Xaa Thr Arg Leu Xaa Arg Ala Ile Ser Xaa Leu145 150 155 160Cys Gly Lys Ile Thr Arg Cys Cys Ser Lys Val Tyr Tyr Arg Xaa Gln 165 170 175Cys Pro Lys Ser Tyr Cys Arg Ile Asn Gly Leu Xaa Lys Cys Lys Ser 180 185 190Arg Met Ser Val Gly His Lys Ala Ile Lys Arg Lys Ser Ser Ser Arg 195 200 205Ser Xaa Cys Asn Tyr Arg Ile Cys Glu Gly Leu Xaa Trp Asp Trp Arg 210 215 220Ser Tyr Ala Xaa Gly Asn Ala Asn Gly Ser Ser Asn Glu Gly Ala His225 230 235 240Ser Arg Arg Thr Ser Xaa Asn Ile Trp Glu Lys Met Leu Xaa Leu Trp 245 250 255Ser Asn Arg Ser Ser Glu Lys Glu Leu Pro Arg Leu Lys Gln Ala Lys 260 265 270Lys Lys Lys Lys Lys Lys Lys 27547288PRTHomo sapiens 47Glu Glu Thr Gln Val Gly Ala Pro Ala Arg Ala Glu Thr Arg Cys Glu1 5 10 15Pro Phe Thr Met Lys Met Leu Lys Asp Ile Lys Glu Gly Val Lys Gln 20 25 30Tyr Gly Ser Asn Ser Pro Tyr Ile Arg Thr Val Leu Asp Ser Ile Ala 35 40 45His Gly Asn Arg Leu Thr Pro Tyr Asp Trp Glu Ile Leu Ala Lys Ser 50 55 60Ser Leu Ser Ser Ser Gln Tyr Leu Gln Phe Lys Thr Trp Trp Ile Asp65 70 75 80Gly Val Gln Glu Gln Val Arg Lys Asn Gln Ala Thr Lys Pro Thr Val 85 90 95Asn Ile Asp Ala Asp Gln Leu Leu Gly Thr Gly Pro Asn Trp Ser Thr 100 105 110Ile Asn Gln Gln Ser Val Met Gln Asn Glu Ala Ile Glu Gln Val Arg 115 120 125Ala Ile Cys Leu Arg Ala Trp Gly Lys Ile Gln Asp Pro Gly Thr Ala 130 135 140Phe Pro Ile Asn Ser Ile Arg Gln Gly Ser Lys Glu Pro Tyr Pro Asp145 150 155 160Phe Val Ala Arg Leu Gln Asp Ala Ala Gln Lys Ser Ile Thr Asp Asp 165 170 175Asn Ala Arg Lys Val Ile Val Glu Leu Met Ala Tyr Glu Asn Ala Asn 180 185 190Pro Glu Cys Gln Ser Ala Ile Lys Pro Leu Lys Gly Lys Val Pro Ala 195 200 205Gly Val Asp Val Ile Thr Glu Tyr Val Lys Ala Cys Asp Gly Ile Gly 210 215 220Gly Ala Met His Lys Ala Met Leu Met Ala Gln Ala Met Arg Gly Leu225 230 235 240Thr Leu Gly Gly Gln Val Arg Thr Phe Gly Lys Lys Cys Tyr Asn Cys 245 250 255Gly Gln Ile Gly His Leu Lys Arg Ser Cys Pro Gly Leu Asn Lys Gln 260 265 270Asn Ile Ile Asn Gln Ala Ile Thr Glu Lys Lys Lys Lys Lys Lys Lys 275 280 28548471PRTHomo sapiensMISC_FEATURE(1)..(471)Xaa=Any amino acid 48Glu Glu Thr Gln Val Gly Ala Pro Ala Arg Ala Glu Thr Arg Cys Glu1 5 10 15Pro Phe Thr Met Lys Met Leu Lys Asp Ile Lys Glu Gly Val Lys Gln 20 25 30Tyr Gly Ser Asn Ser Pro Tyr Ile Arg Thr Leu Leu Asp Ser Ile Ala 35 40 45His Gly Asn Arg Leu Thr Pro Tyr Asp Trp Glu Ile Leu Ala Lys Ser 50 55 60Ser Leu Ser Ser Ser Gln Tyr Leu Gln Phe Lys Thr Trp Trp Ile Asp65

70 75 80Gly Val Gln Glu Gln Val Arg Lys Asn Gln Ala Thr Lys Pro Thr Val 85 90 95Asn Ile Asp Ala Asp Gln Leu Leu Gly Thr Gly Pro Asn Trp Ser Thr 100 105 110Ile Asn Gln Gln Ser Val Met Gln Asn Glu Ala Ile Glu Gln Val Arg 115 120 125Ala Ile Cys Leu Arg Ala Trp Gly Lys Ile Gln Asp Pro Gly Thr Ala 130 135 140Phe Pro Ile Asn Ser Ile Arg Gln Gly Ser Lys Glu Pro Tyr Pro Asp145 150 155 160Phe Val Ala Arg Leu Gln Asp Ala Ala Gln Lys Ser Ile Thr Asp Asp 165 170 175Asn Ala Arg Lys Val Ile Val Glu Leu Met Ala Tyr Glu Asn Ala Asn 180 185 190Pro Glu Cys Gln Ser Ala Ile Lys Pro Leu Lys Gly Lys Val Pro Ala 195 200 205Gly Val Asp Val Ile Thr Glu Tyr Val Lys Ala Cys Asp Gly Ile Gly 210 215 220Gly Ala Met His Lys Ala Met Leu Met Ala Gln Ala Met Arg Gly Leu225 230 235 240Thr Leu Gly Gly Gln Val Arg Thr Phe Gly Lys Lys Cys Tyr Asn Cys 245 250 255Gly Gln Ile Gly His Arg Lys Arg Ser Cys Pro Gly Leu Asn Lys Gln 260 265 270Asn Ile Ile Asn Gln Ala Ile Thr Ala Lys Asn Lys Lys Pro Ser Gly 275 280 285Leu Cys Pro Lys Cys Gly Lys Ala Lys His Trp Ala Asn Gln Cys His 290 295 300Ser Lys Phe Asp Lys Asp Gly Gln Pro Leu Ser Gly Asn Arg Lys Arg305 310 315 320Gly Gln Pro Gln Ala Pro Gln Gln Thr Gly Ala Phe Pro Val Lys Leu 325 330 335Phe Val Pro Gln Gly Phe Gln Gly Gln Gln Pro Leu Gln Lys Ile Pro 340 345 350Pro Leu Gln Gly Val Ser Gln Leu Gln Gln Ser Asn Ser Cys Pro Ala 355 360 365Pro Gln Gln Ala Ala Pro Gln Xaa Ile Tyr Val Pro Pro Lys Trp Ser 370 375 380Phe Tyr Ser Leu Glu Ser Pro His Lys Arg Phe Leu Glu Gly Tyr Met385 390 395 400Ala Arg Cys Gln Lys Gly Gly Xaa Ala Phe Glu Gly Asp Gln Val Xaa 405 410 415Ile Xaa Arg Glu Ser Lys Phe Ile Leu Gly Xaa Phe Thr Gln Ile Ile 420 425 430Lys Gly Glu Phe Ser Xaa Xaa Ser Ala Pro Leu Phe Pro Gly Val Pro 435 440 445Ile Gln Val Ile Glu Leu Leu Asn Tyr Cys Phe Cys Leu Met Gln Lys 450 455 460Lys Lys Lys Lys Lys Lys Lys465 47049258PRTHomo sapiensMISC_FEATURE(1)..(258)Xaa=Any amino acid 49Gly Ser Gln Ala Gly Val Lys Gln Tyr Gly Pro Asn Ser Pro Tyr Ile1 5 10 15Arg Ile Leu Leu Asn Ser Ile Ala His Gly Asn Arg Leu Ile Ser Tyr 20 25 30Asp Trp Glu Ile Leu Ala Ile Ser Ser Leu Ser Pro Ser Gln Tyr Leu 35 40 45Gln Phe Lys Thr Trp Trp Ile Asp Gly Val Gln Glu Gln Val Arg Lys 50 55 60Asn Gln Ala Thr Asn Pro Val Ala Tyr Ile Asp Glu Asp Gln Leu Leu65 70 75 80Gly Arg Gly Pro Asn Trp Asp Thr Ile Asn Gln Gln Ser Val Met Lys 85 90 95Met Arg Leu Leu Asn Asn Tyr Lys Gly Tyr Leu Pro Gln Gly Leu Gly 100 105 110Lys His Ser Gly Pro Arg Asn Leu Met Pro Phe Phe Xaa Phe Asn Gln 115 120 125Thr Arg Leu Xaa Arg Ala Ile Ser Arg Leu Cys Gly Lys Val Ala Arg 130 135 140Cys Ser Ser Lys Ile His Cys Arg Xaa Arg Pro Lys Ser Tyr Cys Arg145 150 155 160Asn Asn Gly Leu Ser Lys Arg Lys Phe Arg Val Ser Ile Ser His Lys 165 170 175Ala Ile Lys Arg Lys Cys Phe Ser Arg Ser Xaa Cys Asn Tyr Arg Ile 180 185 190Cys Glu Gly Leu Xaa Trp Asp Trp Arg Ser Tyr Ala Xaa Gly Asn Ala 195 200 205Ile Gly Ser Ser Asn Tyr Arg Gly Cys Tyr Arg Arg Thr Ser Xaa Asn 210 215 220Ile Trp Gly Lys Met Leu Xaa Leu Trp Ser Asn Arg Ser Ser Lys Lys225 230 235 240Glu Leu Pro Glu Leu Lys Leu Pro Pro Lys Lys Lys Lys Lys Lys Lys 245 250 255Lys Lys50288PRTHomo sapiensMISC_FEATURE(1)..(288)Xaa=Any amino acid 50Gln Lys Asn Glu Ser Ser Lys Leu Ser Ile Thr Xaa Leu Lys Glu Gln1 5 10 15Ser Trp Leu Pro Ser Leu Gln Cys Xaa Gln Asp Phe Asn Gln Ser Ile 20 25 30Asn Ile Val Ser Asp Ser Ala Tyr Val Val Gln Ala Thr Lys Asp Ile 35 40 45Glu Arg Ala Leu Ile Lys Tyr Ile Met Asp Asp Gln Leu Asn Pro Leu 50 55 60Phe Asn Leu Leu Gln Gln Asn Val Arg Lys Arg Asn Phe Pro Phe Tyr65 70 75 80Ile Thr His Ile Arg Ala His Thr Asn Leu Pro Gly Pro Leu Thr Lys 85 90 95Ala Asn Glu Gln Ala Asp Leu Leu Val Ser Ser Ala Phe Met Glu Ala 100 105 110Gln Glu Leu His Ala Leu Thr His Val Asn Ala Ile Gly Leu Lys Asn 115 120 125Arg Phe Asp Ile Thr Trp Lys Gln Thr Lys Asn Ile Val Gln His Cys 130 135 140Thr Gln Cys Gln Ile Leu His Leu Ala Thr Gln Glu Ala Arg Val Asn145 150 155 160Pro Arg Gly Leu Cys Pro Asn Val Leu Trp Gln Met Asp Val Met His 165 170 175Val Pro Ser Phe Gly Lys Leu Ser Phe Val His Val Thr Val Asp Thr 180 185 190Tyr Ser His Phe Ile Trp Ala Thr Cys Gln Thr Gly Glu Ser Thr Ser 195 200 205His Val Lys Arg His Leu Leu Ser Cys Phe Pro Val Met Gly Val Pro 210 215 220Glu Lys Val Lys Thr Asp Asn Gly Pro Gly Tyr Cys Ser Lys Ala Val225 230 235 240Gln Lys Phe Leu Asn Gln Trp Lys Ile Thr His Thr Ile Gly Ile Leu 245 250 255Tyr Asn Ser Gln Gly Gln Ala Ile Ile Glu Arg Thr Asn Arg Thr Leu 260 265 270Lys Ala Gln Leu Val Lys Gln Lys Lys Lys Lys Lys Lys Lys Lys Lys 275 280 28551286PRTHomo sapiensMISC_FEATURE(1)..(286)Xaa=Any amino acid 51Gln Lys Asn Glu Ser Ser Lys Leu Ser Ile Thr Xaa Leu Lys Glu Gln1 5 10 15Ser Trp Leu Pro Ser Leu Gln Cys Xaa Gln Asp Phe Asn Gln Ser Ile 20 25 30Asn Ile Val Ser Asp Ser Ala Tyr Val Val Gln Ala Thr Lys Asp Ile 35 40 45Glu Arg Ala Leu Ile Lys Tyr Ile Met Asp Asp Gln Leu Asn Pro Leu 50 55 60Phe Asn Leu Leu Gln Gln Asn Val Arg Lys Arg Asn Phe Pro Phe Tyr65 70 75 80Ile Thr His Ile Arg Ala His Thr Asn Leu Pro Gly Pro Leu Thr Lys 85 90 95Ala Asn Glu Gln Ala Asp Leu Leu Val Ser Ser Ala Phe Met Glu Ala 100 105 110Gln Glu Leu His Ala Leu Thr His Val Asn Ala Ile Gly Leu Lys Asn 115 120 125Lys Phe Asp Ile Thr Trp Lys Gln Thr Lys Asn Ile Val Gln His Cys 130 135 140Thr Gln Cys Gln Ile Leu His Leu Ala Thr Gln Glu Ala Arg Val Asn145 150 155 160Pro Arg Gly Leu Cys Pro Asn Val Leu Trp Gln Met Asp Val Met His 165 170 175Val Pro Ser Phe Gly Lys Leu Ser Phe Val His Val Thr Val Asp Thr 180 185 190Tyr Ser His Phe Ile Trp Ala Thr Cys Gln Thr Gly Glu Ser Thr Ser 195 200 205His Val Lys Arg His Leu Leu Ser Cys Phe Pro Val Met Gly Val Pro 210 215 220Glu Lys Val Lys Thr Asp Asn Gly Pro Gly Tyr Cys Ser Lys Ala Val225 230 235 240Gln Lys Phe Leu Asn Gln Trp Lys Ile Thr His Thr Ile Gly Ile Leu 245 250 255Tyr Asn Ser Gln Gly Gln Ala Ile Ile Glu Arg Thr Asn Arg Thr Leu 260 265 270Lys Ala Gln Leu Val Lys Gln Lys Glu Lys Lys Lys Lys Lys 275 280 28552287PRTHomo sapiensMISC_FEATURE(1)..(287)Xaa=Any amino acid 52Gln Lys Asn Glu Ser Ser Lys Leu Ser Ile Thr Arg Leu Lys Glu Gln1 5 10 15Ser Trp Leu Pro Ser Leu Gln Cys Xaa Gln Asp Phe Asn Gln Ser Ile 20 25 30Asn Ile Val Ser Asp Ser Ala Tyr Val Val Gln Ala Thr Lys Asp Ile 35 40 45Glu Arg Ala Leu Ile Lys Tyr Ile Met Asp Asp Gln Leu Asn Pro Leu 50 55 60Phe Asn Leu Leu Gln Gln Asn Val Arg Lys Arg Asn Phe Pro Phe Tyr65 70 75 80Ile Thr His Ile Arg Ala His Thr Asn Leu Pro Gly Pro Leu Thr Lys 85 90 95Ala Asn Glu Gln Ala Asp Leu Leu Val Ser Ser Ala Phe Met Glu Ala 100 105 110Gln Glu Leu His Ala Leu Thr His Val Asn Ala Ile Gly Leu Lys Asn 115 120 125Lys Phe Asp Ile Thr Trp Lys Gln Thr Lys Asn Ile Val Gln His Cys 130 135 140Ala Gln Cys Gln Ile Leu His Leu Ala Thr Gln Glu Val Arg Val Asn145 150 155 160Pro Arg Gly Leu Cys Pro Asn Val Leu Trp Gln Met Asp Val Met His 165 170 175Val Pro Ser Phe Gly Lys Leu Ser Phe Val His Val Thr Val Asp Thr 180 185 190Tyr Ser His Phe Ile Trp Ala Thr Cys Gln Thr Gly Glu Ser Thr Ser 195 200 205His Val Lys Arg His Leu Leu Ser Cys Phe Pro Val Met Gly Val Pro 210 215 220Glu Lys Val Lys Thr Asp Asn Gly Pro Gly Tyr Cys Ser Lys Ala Val225 230 235 240Gln Lys Phe Leu Asn Gln Trp Lys Ile Thr His Thr Ile Gly Ile Leu 245 250 255Tyr Asn Ser Gln Gly Gln Ala Ile Ile Glu Arg Thr Asn Arg Thr Leu 260 265 270Lys Ala Gln Leu Val Lys Gln Lys Lys Lys Lys Lys Lys Lys Lys 275 280 28553288PRTHomo sapiensMISC_FEATURE(1)..(288)Xaa=Any amino acid 53Gln Lys Asn Glu Ser Ser Lys Leu Ser Ile Thr Xaa Leu Lys Glu Gln1 5 10 15Ser Trp Leu Pro Ser Leu Gln Cys Xaa Gln Asp Phe Asn Gln Ser Ile 20 25 30Asn Ile Val Ser Asp Ser Ala Tyr Val Val Gln Ala Thr Lys Asp Ile 35 40 45Glu Arg Ala Leu Ile Lys Tyr Ile Met Asp Asp Gln Leu Asn Pro Leu 50 55 60Phe Asn Leu Leu Gln Gln Asn Val Arg Lys Xaa Asn Phe Pro Phe Tyr65 70 75 80Ile Thr His Ile Arg Ala His Thr Asn Leu Pro Gly Pro Leu Thr Lys 85 90 95Ala Asn Glu Gln Ala Asp Leu Leu Val Ser Ser Ala Phe Met Glu Ala 100 105 110Gln Glu Leu His Ala Leu Thr His Val Asn Ala Ile Gly Leu Lys Asn 115 120 125Lys Phe Asp Ile Thr Trp Lys Gln Thr Lys Asn Ile Val Gln His Cys 130 135 140Thr Gln Cys Gln Ile Leu His Leu Ala Thr Gln Glu Ala Arg Val Asn145 150 155 160Pro Arg Gly Leu Cys Pro Asn Val Leu Trp Gln Met Asp Val Met His 165 170 175Val Pro Ser Phe Gly Lys Leu Ser Phe Val His Val Thr Val Asp Thr 180 185 190Tyr Ser His Phe Ile Trp Ala Thr Cys Gln Thr Gly Glu Ser Thr Ser 195 200 205His Val Lys Arg His Leu Leu Phe Cys Phe Pro Val Met Gly Val Pro 210 215 220Glu Lys Val Lys Thr Asp Asn Gly Pro Gly Tyr Cys Ser Lys Ala Val225 230 235 240Gln Glu Phe Leu Asn Gln Trp Lys Ile Thr His Thr Ile Gly Ile Leu 245 250 255Tyr Asn Ser Gln Gly Gln Ala Ile Ile Glu Arg Thr Asn Arg Thr Leu 260 265 270Lys Ala Gln Leu Val Lys Gln Lys Lys Lys Lys Lys Lys Lys Lys Lys 275 280 28554234PRTHomo sapiensMISC_FEATURE(1)..(234)Xaa=Any amino acid 54Gln Lys Asn Glu Ser Ser Lys Leu Ser Ile Thr Xaa Leu Lys Glu Gln1 5 10 15Ser Trp Leu Pro Ser Leu Gln Cys Xaa Gln Asp Phe Asn Gln Ser Ile 20 25 30Asn Ile Val Ser Asp Ser Ala Tyr Val Val Gln Ala Thr Lys Asp Ile 35 40 45Glu Arg Ala Leu Ile Lys Tyr Ile Met Asp Asp Gln Leu Asn Pro Leu 50 55 60Phe Asn Leu Leu Gln Gln Asn Val Arg Lys Arg Asn Phe Pro Phe Tyr65 70 75 80Ile Thr His Ile Arg Ala His Thr Asn Leu Pro Gly Pro Leu Thr Lys 85 90 95Ala Asn Glu Gln Ala Asp Leu Leu Val Ser Ser Ala Phe Met Glu Ala 100 105 110Gln Glu Leu His Ala Leu Thr His Val Asn Ala Ile Gly Leu Lys Asn 115 120 125Lys Phe Asp Ile Thr Trp Lys Gln Thr Lys Asn Ile Val Gln His Cys 130 135 140Thr Gln Cys Gln Ile Leu His Leu Ala Thr Gln Glu Ala Arg Val Asn145 150 155 160Pro Arg Gly Leu Cys Pro Asn Val Leu Trp Gln Met Asp Val Met His 165 170 175Val Pro Ser Phe Gly Lys Leu Ser Phe Val His Val Thr Val Asp Thr 180 185 190Tyr Ser His Phe Ile Trp Ala Thr Cys Gln Thr Gly Glu Ser Thr Ser 195 200 205His Val Lys Arg His Leu Leu Ser Cys Phe Pro Val Met Gly Val Pro 210 215 220Glu Lys Lys Lys Lys Lys Lys Lys Lys Lys225 23055293PRTHomo sapiensMISC_FEATURE(1)..(293)Xaa=Any amino acid 55Gln Lys Asn Glu Ser Ser Lys Leu Ser Ile Thr Xaa Leu Lys Glu Gln1 5 10 15Ser Trp Leu Pro Ser Leu Gln Cys Xaa Gln Asp Phe Asn Gln Ser Ile 20 25 30Asn Ile Val Ser Asp Ser Ala Tyr Val Val Gln Ala Thr Lys Asp Ile 35 40 45Glu Arg Ala Leu Ile Lys Tyr Ile Met Asp Asp Gln Leu Asn Pro Leu 50 55 60Phe Asn Leu Leu Gln Gln Asn Val Arg Lys Arg Asn Phe Pro Phe Tyr65 70 75 80Ile Thr His Ile Arg Ala His Thr Asn Leu Pro Gly Pro Leu Thr Lys 85 90 95Ala Asn Glu Gln Ala Asp Leu Leu Val Ser Ser Ala Phe Ile Glu Ala 100 105 110Gln Glu Leu His Ala Leu Thr His Val Asn Ala Ile Gly Leu Lys Asn 115 120 125Lys Phe Asp Ile Thr Trp Lys Gln Thr Lys Asn Ile Val Gln His Cys 130 135 140Thr Gln Cys Gln Ile Leu His Leu Ala Thr Gln Glu Ala Arg Val Asn145 150 155 160Pro Arg Gly Leu Cys Pro Asn Val Leu Trp Gln Met Asp Val Met His 165 170 175Val Pro Ser Phe Gly Lys Leu Ser Phe Val His Val Thr Val Asp Thr 180 185 190Tyr Ser His Phe Ile Trp Ala Thr Cys Gln Thr Gly Glu Ser Thr Ser 195 200 205His Val Lys Arg His Leu Leu Ser Cys Phe Pro Val Met Gly Val Pro 210 215 220Glu Lys Val Lys Thr Asp Asn Gly Pro Gly Tyr Cys Ser Lys Ala Val225 230 235 240Gln Lys Phe Leu Asn Gln Trp Lys Ile Thr His Thr Ile Gly Ile Leu 245 250 255Tyr Asn Ser Gln Gly Gln Ala Ile Ile Glu Arg Thr Asn Arg Thr Leu 260 265 270Lys Ala Gln Leu Val Lys Gln Lys Lys Lys Lys Lys Lys Lys Lys Thr 275 280 285Cys Arg Pro Pro Arg 29056375PRTHomo sapiens 56Glu Glu Thr Gln Val Gly Ala Pro Ala Arg Ala Glu Thr Arg Cys Glu1 5 10 15Pro Phe Thr Met Lys Met Leu Lys Asp Ile Lys Glu Gly Val Lys Gln 20 25 30Tyr Gly Ser Asn Ser Pro Tyr Ile Arg Thr Leu Leu Asp Ser Ile Ala 35 40 45His Gly Asn Arg Leu Thr Pro Tyr Asp Trp Glu Ile Leu Ala Lys Ser 50 55 60Ser Leu Ser Ser Ser Gln Tyr Leu Gln Phe Lys Thr Trp Trp Ile Asp65 70 75 80Gly Val Gln Glu Gln Val Arg Lys Asn Gln Ala Thr Lys Pro Thr Val 85

90 95Asn Ile Asp Ala Asp Gln Leu Leu Gly Thr Gly Pro Asn Trp Ser Thr 100 105 110Ile Asn Gln Gln Ser Val Met Gln Asn Glu Ala Ile Glu Gln Val Arg 115 120 125Ala Ile Cys Leu Arg Ala Trp Gly Lys Ile Gln Asp Pro Gly Thr Ala 130 135 140Phe Pro Ile Asn Ser Ile Arg Gln Gly Ser Lys Glu Pro Tyr Pro Asp145 150 155 160Phe Val Ala Arg Leu Gln Asp Ala Ala Gln Lys Ser Ile Thr Asp Asp 165 170 175Asn Ala Arg Lys Val Ile Val Glu Leu Met Ala Tyr Glu Asn Ala Asn 180 185 190Pro Glu Cys Gln Ser Ala Ile Lys Pro Leu Lys Gly Lys Val Pro Ala 195 200 205Gly Val Asp Val Ile Thr Glu Tyr Val Lys Ala Cys Asp Gly Ile Gly 210 215 220Gly Ala Met His Lys Ala Met Leu Met Ala Gln Ala Met Arg Gly Leu225 230 235 240Thr Leu Gly Gly Gln Val Arg Thr Phe Gly Lys Lys Cys Tyr Asn Cys 245 250 255Gly Gln Ile Gly His Arg Lys Arg Ser Cys Pro Gly Leu Asn Lys Gln 260 265 270Asn Ile Ile Asn Gln Ala Ile Thr Ala Lys Asn Lys Lys Pro Ser Gly 275 280 285Leu Cys Pro Lys Cys Gly Lys Ala Lys His Trp Ala Asn Gln Cys His 290 295 300Ser Lys Phe Asp Lys Asp Gly Gln Pro Leu Ser Gly Asn Arg Lys Arg305 310 315 320Gly Gln Pro Gln Ala Pro Gln Gln Thr Gly Ala Phe Pro Val Lys Leu 325 330 335Phe Val Pro Gln Gly Phe Gln Gly Gln Gln Pro Leu Gln Lys Ile Pro 340 345 350Pro Leu Gln Gly Val Ser Gln Leu Gln Gln Ser Asn Ser Cys Pro Ala 355 360 365Pro Gln Gln Ala Ala Pro Gln 370 37557288PRTHomo sapiens 57Glu Glu Thr Gln Val Gly Ala Pro Ala Arg Ala Glu Thr Arg Cys Glu1 5 10 15Pro Phe Thr Met Lys Met Leu Lys Asp Ile Lys Glu Gly Val Lys Gln 20 25 30Tyr Gly Ser Asn Ser Pro Tyr Ile Arg Thr Val Leu Asp Ser Ile Ala 35 40 45His Gly Asn Arg Leu Thr Pro Tyr Asp Trp Glu Ile Leu Ala Lys Ser 50 55 60Ser Leu Ser Ser Ser Gln Tyr Leu Gln Phe Lys Thr Trp Trp Ile Asp65 70 75 80Gly Val Gln Glu Gln Val Arg Lys Asn Gln Ala Thr Lys Pro Thr Val 85 90 95Asn Ile Asp Ala Asp Gln Leu Leu Gly Thr Gly Pro Asn Trp Ser Thr 100 105 110Ile Asn Gln Gln Ser Val Met Gln Asn Glu Ala Ile Glu Gln Val Arg 115 120 125Ala Ile Cys Leu Arg Ala Trp Gly Lys Ile Gln Asp Pro Gly Thr Ala 130 135 140Phe Pro Ile Asn Ser Ile Arg Gln Gly Ser Lys Glu Pro Tyr Pro Asp145 150 155 160Phe Val Ala Arg Leu Gln Asp Ala Ala Gln Lys Ser Ile Thr Asp Asp 165 170 175Asn Ala Arg Lys Val Ile Val Glu Leu Met Ala Tyr Glu Asn Ala Asn 180 185 190Pro Glu Cys Gln Ser Ala Ile Lys Pro Leu Lys Gly Lys Val Pro Ala 195 200 205Gly Val Asp Val Ile Thr Glu Tyr Val Lys Ala Cys Asp Gly Ile Gly 210 215 220Gly Ala Met His Lys Ala Met Leu Met Ala Gln Ala Met Arg Gly Leu225 230 235 240Thr Leu Gly Gly Gln Val Arg Thr Phe Gly Lys Lys Cys Tyr Asn Cys 245 250 255Gly Gln Ile Gly His Leu Lys Arg Ser Cys Pro Gly Leu Asn Lys Gln 260 265 270Asn Ile Ile Asn Gln Ala Ile Thr Glu Lys Lys Lys Lys Lys Lys Lys 275 280 28558268PRTHomo sapiens 58Gln Asp Phe Asn Gln Ser Ile Asn Ile Val Ser Asp Ser Ala Tyr Val1 5 10 15Val Gln Ala Thr Lys Asp Ile Glu Arg Ala Leu Ile Lys Tyr Ile Met 20 25 30Asp Asp Gln Leu Asn Pro Leu Phe Asn Leu Leu Gln Gln Asn Val Arg 35 40 45Lys Arg Asn Phe Pro Phe Tyr Ile Thr His Ile Arg Ala His Thr Asn 50 55 60Leu Pro Gly Pro Leu Thr Lys Ala Asn Glu Gln Ala Asp Leu Leu Val65 70 75 80Ser Ser Ala Phe Met Glu Ala Gln Glu Leu His Ala Leu Thr His Val 85 90 95Asn Ala Ile Gly Leu Lys Asn Lys Phe Asp Ile Thr Trp Lys Gln Thr 100 105 110Lys Asn Ile Val Gln His Cys Thr Gln Cys Gln Ile Leu His Leu Ala 115 120 125Thr Gln Glu Ala Arg Val Asn Pro Arg Gly Leu Cys Pro Asn Val Leu 130 135 140Trp Gln Met Asp Val Met His Val Pro Ser Phe Gly Lys Leu Ser Phe145 150 155 160Val His Val Thr Val Asp Thr Tyr Ser His Phe Ile Trp Ala Thr Cys 165 170 175Gln Thr Gly Glu Ser Thr Ser His Val Lys Arg His Leu Leu Ser Cys 180 185 190Phe Pro Val Met Gly Val Pro Glu Lys Val Lys Thr Asp Asn Gly Pro 195 200 205Gly Tyr Cys Ser Lys Ala Val Gln Lys Phe Leu Asn Gln Trp Lys Ile 210 215 220Thr His Thr Ile Gly Ile Leu Tyr Asn Ser Gln Gly Gln Ala Ile Ile225 230 235 240Glu Arg Thr Asn Arg Thr Leu Lys Ala Gln Leu Val Lys Gln Lys Lys 245 250 255Lys Lys Lys Lys Lys Lys Thr Cys Arg Pro Pro Arg 260 2655915DNAHomo sapiens 59taggcctttg aggga 156019DNAHomo sapiens 60cattagaaaa aggacattg 196117DNAHomo sapiens 61ttggaattct gtttgta 176216DNAHomo sapiens 62taactgagcc attaat 166321DNAHomo sapiens 63agccatggtc ccctttaatt a 216417DNAHomo sapiens 64ttttaccaca ccagcct 176515DNAHomo sapiens 65ttgtcagctc aagct 156615DNAHomo sapiens 66tacatcgttc actat 156715DNAHomo sapiens 67ttaaaagcat taaat 156817DNAHomo sapiens 68agaagtccca attgagg 176915DNAHomo sapiens 69ggtcttgccg atttt 157015DNAHomo sapiens 70acaatcgtta ccaca 157115DNAHomo sapiens 71aaaagaatga gtcat 157215DNAHomo sapiens 72cagtatcact tgact 157323DNAHomo sapiens 73ttttaatcag tctattaaca ttg 237416DNAHomo sapiens 74aaaggatatt gagaga 167516DNAHomo sapiens 75cctaatcaaa tacatt 167615DNAHomo sapiens 76cgctgtttaa tttgt 157716DNAHomo sapiens 77tgcattcatg gaagca 167815DNAHomo sapiens 78actcaggagg caaga 157916DNAHomo sapiens 79ttaagagaca tttatt 168016DNAHomo sapiens 80taaagcagtt caaaaa 168115DNAHomo sapiens 81aataggaatt ctcta 158216DNAHomo sapiens 82aaagctcaat tggtta 168325DNAHomo sapiens 83taggaggaca agttagaaca tttgg 258424DNAHomo sapiens 84aaaatgttat aattgtggtc aaat 24851998DNAHomo sapiens 85atggggcaaa ctaaaagtaa aattaaaagt aaatatgcct cttatctcag ctttattaaa 60attcttttaa aaagaggggg agttaaagta tctacaaaaa atctaatcaa gctatttcaa 120ataatagaac aattttgccc atggtttcca gaacaaggaa ctttagatct aaaagattgg 180aaaagaattg gtaaggaact aaaacaagca ggtaggaagg gtaatatcat tccacttaca 240gtatggaatg attgggccat tattaaagca gctttagaac catttcaaac agaagaagat 300agcgtttcag tttctgatgc ccctggaagc tgtataatag attgtaatga aaacacaagg 360aaaaaatccc agaaagaaac ggaaggttta cattgcgaat atgtagcaga gccggtaatg 420gctcagtcaa cgcaaaatgt tgactataat caattacagg aggtgatata tcctgaaacg 480ttaaaattag aaggaaaagg tccagaatta gtggggccat cagagtctaa accacgaggc 540acaagtcctc ttccagcagg tcaggtgcct gtaacattac aacctcaaaa gcaggttaaa 600gaaaataaga cccaaccgcc agtagcctat caatactggc ctccggctga acttcagtat 660cggccacccc cagaaagtca gtatggatat ccaggaatgc ccccagcacc acagggcagg 720gcgccatacc ctcagccgcc cactaggaga cttaatccta cggcaccacc tagtagacag 780ggtagtaaat tacatgaaat tattgataaa tcaagaaagg aaggagatac tgaggcatgg 840caattcccag taacgttaga accgatgcca cctggagaag gagcccaaga gggagagcct 900cccacagttg aggccagata caagtctttt tcgataaaaa agctaaaaga tatgaaagag 960ggagtaaaac agtatggacc caactcccct tatatgagga cattattaga ttccattgct 1020catggacata gactcattcc ttatgattgg gagattctgg caaaatcgtc tctctcaccc 1080tctcaatttt tacaatttaa gacttggtgg attgatgggg tacaagaaca ggtccgaaga 1140aatagggctg ccaatcctcc agttaacata gatgcagatc aactattagg aataggtcaa 1200aattggagta ctattagtca acaagcatta atgcaaaatg aggccattga gcaagttaga 1260gctatctgcc ttagagcctg ggaaaaaatc caagacccag gaagtacctg cccctcattt 1320aatacagtaa gacaaggttc aaaagagccc tatcctgatt ttgtggcaag gctccaagat 1380gttgctcaaa agtcaattgc tgatgaaaaa gcccgtaagg tcatagtgga gttgatggca 1440tatgaaaacg ccaatcctga gtgtcaatca gccattaagc cattaaaagg aaaggttcct 1500gcaggatcag atgtaatctc agaatatgta aaagcctgtg atggaatcgg aggagctatg 1560cataaagcta tgcttatggc tcaagcaata acaggagttg ttttaggagg acaagttaga 1620acatttggaa gaaaatgtta taattgtggt caaattggtc acttaaaaaa gaattgccca 1680gtcttaaata aacagaatat aactattcaa gcaactacaa caggtagaga gccacctgac 1740ttatgtccaa gatgtaaaaa aggaaaacat tgggctagtc aatgtcgttc taaatttgat 1800aaaaatgggc aaccattgtc gggaaacgag caaaggggcc agcctcaggc cccacaacaa 1860actggggcat tcccaattca gccatttgtt cctcagggtt ttcagggaca acaaccccca 1920ctgtcccaag tgtttcaggg aataagccag ttaccacaat acaacaattg tcccccgcca 1980caagcggcag tgcagcag 1998861000DNAHomo sapiens 86atgggcaacc attgtcggga aacgagcaaa ggggccagcc tcaggcccca caacaaactg 60gggcattccc aattcagcca tttgttcctc agggttttca gggacaacaa cccccactgt 120cccaagtgtt tcagggaata agccagttac cacaatacaa caattgtccc ccgccacaag 180cggcagtgca gcagtagatt tatgtactat acaagcagtc tctctgcttc caggggagcc 240cccacaaaaa acccccacag gggtatatgg acccctgcct aaggggactg taggactaat 300cttgggacga tcaagtctaa atctaaaagg agttcaaatt catactagtg tggttgattc 360agactataaa ggcgaaattc aattggttat tagctcttca attccttgga gtgccagtcc 420aagagacagg attgctcaat tattactcct gccatacatt aagggtggaa atagtgaaat 480aaaaagaata ggagggcttg gaagcactga tccaacagga aaggctgcat attgggcaag 540tcaggtctca gagaacagac ctgtgtgtaa ggccattatt caaggaaaac agtttgaagg 600gttggtagac actggagcag atgtctctat cattgcttta aatcagtggc caaaaaattg 660gcctaaacaa aaggctgtta caggacttgt cggcataggc acagcctcag aagtgtatca 720aagtacggag attttacatt gcttagggcc agataatcaa gaaagtactg ttcagccaat 780gattacttca attcctctta atctgtgggg tcgagattta ttacaacaat ggggtgcgga 840aatcaccatg cccgctccat catatagccc cacgagtcaa aaaatcatga ccaagatggg 900atatatacca ggaaagggac tagggaaaaa tgaagatggc attaaaattc cagttgaggc 960taaaataaat caagaaagag aaggaatagg gaatccttgc 1000872896DNAHomo sapiens 87atggcattaa aattccagtt gaggctaaaa taaatcaaga aagagaagga atagggaatc 60cttgctaggg gcggccactg tagagcctcc taaacccata ccattaactt ggaaaacaga 120aaaaccagtg tgggtaaatc agtggccgct accaaaacaa aaactggagg ctttacattt 180attagcaaat gaacagttag aaaagggtca tattgagcct tcgttctcac cttggaattc 240tcctgtgttt gtaattcaga agaaatcagg caaatggcgt atgttaactg acttaagggc 300tgtaaacgcc gtaattcaac ccatggggcc tctccaaccc gggttgccct ctccggccat 360gatcccaaaa gattggcctt taattataat tgatctaaag gattgctttt ttaccatccc 420tctggcagag caggattgcg aaaaatttgc ctttactata ccagccataa ataataaaga 480accagccacc aggtttcagt ggaaagtgtt acctcaggga atgcttaata gtccaactat 540ttgtcagact tttgtaggtc gagctcttca accagttaga gaaaagtttt cagactgtta 600tattattcat tgtattgatg atattttatg tgctgcagaa acgaaagata aattaattga 660ctgttataca tttctgcaag cagaggttgc caatgctgga ctggcaatag catctgataa 720gatccaaacc tctactcctt ttcattattt agggatgcag atagaaaata gaaaaattaa 780gccacaaaaa atagaaataa gaaaagacac attaaaaaca ctaaatgatt ttcaaaaatt 840actaggagat attaattgga ttcggccaac tctaggcatt cctacttatg ccatgtcaaa 900tttgttctct atcttaagag gagactcaga cttaaatagt aaaagaatgt taaccccaga 960ggcaacaaaa gaaattaaat tagtggaaga aaaaattcag tcagcgcaaa taaatagaat 1020agatccctta gccccactcc aacttttgat ttttgccact gcacattctc caacaggcat 1080cattattcaa aatactgatc ttgtggagtg gtcattcctt cctcacagta cagttaagac 1140ttttacattg tacttggatc aaatagctac attaatcggt cagacaagat tacgaataat 1200aaaattatgt gggaatgacc cagacaaaat agttgtccct ttaaccaagg aacaagttag 1260acaagccttt atcaattctg gtgcatggaa gattggtctt gctaattttg tgggaattat 1320tgataatcat tacccaaaaa caaagatctt ccagttctta aaattgacta cttggattct 1380acctaaaatt accagacgtg aacctttaga aaatgctcta acagtattta ctgatggttc 1440cagcaatgga aaagcagctt acacaggacc gaaagaacga gtaatcaaaa ctccatatca 1500atcggctcaa agagcagagt tggttgcagt cattacagtg ttacaagatt ttgaccaacc 1560tatcaatatt atatcagatt ctgcatatgt agtacaggct acaagggatg ttgagacagc 1620tctaattaaa tatagcatgg atgatcagtt aaaccagcta ttcaatttat tacaacaaac 1680tgtaagaaaa agaaatttcc cattttatat tacacatatt cgagcacaca ctaatttacc 1740agggcctttg actaaagcaa atgaacaagc tgacttactg gtatcatctg cactcataaa 1800agcacaagaa cttcatgctt tgactcatgt aaatgcagca ggattaaaaa acaaatttga 1860tgtcacatgg aaacaggcaa aagatattgt acaacattgc acccagtgtc aagtcttaca 1920cctgcccact caagaggcag gagttaatcc cagaggtctg tgtcctaatg cattatggca 1980aatggatgtc acgcatgtac cttcatttgg aagattatca tatgttcacg taacagttga 2040tacttattca catttcatat gggcaacttg ccaaacagga gaaagtactt cccatgttaa 2100aaaacattta ttgtcttgtt ttgctgtaat gggagttcca gaaaaaatca aaactgacaa 2160tggaccagga tattgtagta aagctttcca aaaattctta agtcagtgga aaatttcaca 2220tacaacagga attccttata attcccaagg acaggccata gttgaaagaa ctaatagaac 2280actcaaaact caattagtta aacaaaaaga agggggagac agtaaggagt gtaccactcc 2340tcagatgcaa cttaatctag cactctatac tttaaatttt ttaaacattt atagaaatca 2400gactactact tctgcagaac aacatcttac tggtaaaaag aacagcccac atgaaggaaa 2460actaatttgg tggaaagata ataaaaataa gacatgggaa atagggaagg tgataacgtg 2520ggggagaggt tttgcttgtg tttcaccagg agaaaatcag cttcctgttt ggatacccac 2580tagacatttg aagttctaca atgaacccat cagagatgca aagaaaagca cctccgcgga 2640gacggagaca tcgcaatcga gcaccgttga ctcacaagat gaacaaaatg gtgacgtcag 2700aagaacagat gaagttgcca tccaccaaga aggcagagcc gccaacttgg gcacaactaa 2760agaagctgac gcagttagct acaaaatatc tagagaacac aaaggtgaca caaaccccag 2820agagtatgct gcttgcagcc ttgatgattg tatcaatggt ggtaagtctc cctatgcctg 2880caggagcagc tgcagc 2896882000DNAHomo sapiens 88atgaacccat cagagatgca aagaaaagca cctccgcgga gacggagaca tcgcaatcga 60gcaccgttga ctcacaagat gaacaaaatg gtgacgtcag aagaacagat gaagttgcca 120tccaccaaga aggcagagcc gccaacttgg gcacaactaa agaagctgac gcagttagct 180acaaaatatc tagagaacac aaaggtgaca caaaccccag agagtatgct gcttgcagcc 240ttgatgattg tatcaatggt ggtaagtctc cctatgcctg caggagcagc tgcagctaac 300tatacctact gggcctatgt gcctttcccg cccttaattc gggcagtcac atggatggat 360aatcctacag aagtatatgt taatgatagt gtatgggtac ctggccccat agatgatcgc 420tgccctgcca aacctgagga agaagggatg atgataaata tttccattgg gtatcattat 480cctcctattt gcctagggag agcaccagga tgtttaatgc ctgcagtcca aaattggttg 540gtagaagtac ctactgtcag tcccatctgt agattcactt atcacatggt aagcgggatg 600tcactcaggc cacgggtaaa ttatttacaa gacttttctt atcaaagatc attaaaattt 660agacctaaag ggaaaccttg ccccaaggaa attcccaaag aatcaaaaaa tacagaagtt 720ttagtttggg aagaatgtgt ggccaatagt gcggtgatat tacaaaacaa tgaattcgga 780actattatag attgggcacc tcgaggtcaa ttctaccaca attgctcagg acaaactcag 840tcgtgtccaa gtgcacaagt gagtccagct gttgatagcg acttaacaga aagtttagac 900aaacataagc ataaaaaatt gcagtctttc tacccttggg aatggggaga aaaaggaatc 960tctaccccaa gaccaaaaat agtaagtcct gtttctggtc ctgaacatcc agaattatgg 1020aggcttactg tggcctcaca ccacattaga atttggtctg gaaatcaaac tttagaaaca 1080agagatcgta agccatttta tactattgac ctgaattcca gtctaacagt tcctttacaa 1140agttgcgtaa agccccctta tatgctagtt gtaggaaata tagttattaa accagactcc 1200cagactataa cctgtgaaaa ttgtagattg cttacttgca ttgattcaac ttttaattgg 1260caacaccgta ttctgctggt gagagcaaga gagggcgtgt ggatccctgt gtccatggac 1320cgaccgtggg aggcctcgcc atccgtccat attttgactg aagtattaaa aggtgtttta 1380aatagatcca aaagattcat ttttacttta attgcagtga ttatgggatt aattgcagtc 1440acagctacgg ctgctgtagc aggagttgca ttgcactctt ctgttcagtc agtaaacttt 1500gttaatgatt ggcaaaaaaa ttctacaaga ttgtggaatt cacaatctag tattgatcaa 1560aaattggcaa atcaaattaa tgatcttaga caaactgtca tttggatggg agacagactc 1620atgagcttag aacatcgttt ccagttacaa tgtgactgga atacgtcaga tttttgtatt 1680acaccccaaa tttataatga gtctgagcat cactgggaca tggttagacg ccatctacag 1740ggaagagaag ataatctcac tttagacatt tccaaattaa

aagaacaaat tttcgaagca 1800tcaaaagccc atttaaattt ggtgccagga actgaggcaa ttgcaggagt tgctgatggc 1860ctcgcaaatc ttaaccctgt cacttgggtt aagaccattg gaagtactac gattataaat 1920ctcatattaa tccttgtgtg cctgttttgt ctgttgttag tctgcaggtg tacccaacag 1980ctccgaagag acagcgacca 200089294DNAHomo sapiens 89agttctacaa tgaacccatc agagatgcaa agaaaagcac ctccgcggag acggagacat 60cgcaatcgag caccgttgac tcacaagatg aacaaaatgg tgacgtcaga agaacagatg 120aagttgccat ccaccaagaa ggcagagccg ccaacttggg cacaactaaa gaagctgacg 180cagttagcta caaaatatct agagaacaca aaggtgacac aaaccccaga gagtatgctg 240cttgcagcct tgatgattgt atcaatggtg gtaagtctcc ctatgcctgc agga 2949057DNAHomo sapiens 90tctgcaggtg tacccaacag ctccgaagag acagcgacca tcgagaacgg gccatga 57912001DNAHomo sapiens 91atggggcaaa ctaaaagtaa aattaaaagt aaatatgcct cttatctcag ctttattaaa 60attcttttaa aaagaggggg agttaaagta tctacaaaaa atctaatcaa gctatttcaa 120ataatagaac aattttgccc atggtttcca gaacaaggaa ctttagatct aaaagattgg 180aaaagaattg gtaaggaact aaaacaagca ggtaggaagg gtaatatcat tccacttaca 240gtatggaatg attgggccat tattaaagca gctttagaac catttcaaac agaagaagat 300agcgtttcag tttctgatgc ccctggaagc tgtataatag attgtaatga aaacacaagg 360aaaaaatccc agaaagaaac ggaaggttta cattgcgaat atgtagcaga gccggtaatg 420gctcagtcaa cgcaaaatgt tgactataat caattacagg aggtgatata tcctgaaacg 480ttaaaattag aaggaaaagg tccagaatta gtggggccat cagagtctaa accacgaggc 540acaagtcctc ttccagcagg tcaggtgcct gtaacattac aacctcaaaa gcaggttaaa 600gaaaataaga cccaaccgcc agtagcctat caatactggc ctccggctga acttcagtat 660cggccacccc cagaaagtca gtatggatat ccaggaatgc ccccagcacc acagggcagg 720gcgccatacc ctcagccgcc cactaggaga cttaatccta cggcaccacc tagtagacag 780ggtagtaaat tacatgaaat tattgataaa tcaagaaagg aaggagatac tgaggcatgg 840caattcccag taacgttaga accgatgcca cctggagaag gagcccaaga gggagagcct 900cccacagttg aggccagata caagtctttt tcgataaaaa agctgaaaga tatgaaagag 960ggagtaaaac agtatggacc caactcccct tatatgagga cattattaga ttccattgct 1020catggacata gactcattcc ttatgattgg gagattctgg caaaatcgtc tctctcaccc 1080tctcaatttt tacaatttaa gacttggtgg attgatgggg tacaagaaca ggtccgaaga 1140aatagggctg ccaatcctcc agttaacata gatgcagatc aactattagg aataggtcaa 1200aattggagta ctattagtca acaagcatta atgcaaaatg aggccattga gcaagttaga 1260gctatctgcc ttagagcctg ggaaaaaatc caagacccag gaagtacctg cccctcattt 1320aatacagtaa gacaaggttc aaaagagccc tatcctgatt ttgtggcaag gctccaagat 1380gttgctcaaa agtcaattgc tgatgaaaaa gcccgtaagg tcatagtgga gttgatggca 1440tatgaaaacg ccaatcctga gtgtcaatca gccattaagc cattaaaagg aaaggttcct 1500gcaggatcag atgtaatctc agaatatgta aaagcctgtg atggaatcgg aggagctatg 1560tataaagcta tgcttatggc tcaagcaata acaggagttg ttttaggagg acaagttaga 1620acatttggaa gaaaatgtta taattgtggt caaattggtc acttaaaaaa gaattgccca 1680gtcttaaata aacagaatat aactattcaa gcaactacaa caggtagaga gccacctgac 1740ttatgtccaa gatgtaaaaa aggaaaacat tgggctagtc aatgtcgttc taaatttgat 1800aaaaatgggc aaccattgtc gggaaacgag caaaggggcc agcctcaggc cccacaacaa 1860actggggcat tcccaattca gccatttgtt cctcagggtt ttcagggaca acaaccccca 1920ctgtcccaag tgtttcaggg aataagccag ttaccacaat acaacaattg tcccccgcca 1980caagcggcag tgcagcagta g 200192666PRTHomo sapiens 92Met Gly Gln Thr Lys Ser Lys Ile Lys Ser Lys Tyr Ala Ser Tyr Leu1 5 10 15Ser Phe Ile Lys Ile Leu Leu Lys Arg Gly Gly Val Lys Val Ser Thr 20 25 30Lys Asn Leu Ile Lys Leu Phe Gln Ile Ile Glu Gln Phe Cys Pro Trp 35 40 45Phe Pro Glu Gln Gly Thr Leu Asp Leu Lys Asp Trp Lys Arg Ile Gly 50 55 60Lys Glu Leu Lys Gln Ala Gly Arg Lys Gly Asn Ile Ile Pro Leu Thr65 70 75 80Val Trp Asn Asp Trp Ala Ile Ile Lys Ala Ala Leu Glu Pro Phe Gln 85 90 95Thr Glu Glu Asp Ser Val Ser Val Ser Asp Ala Pro Gly Ser Cys Ile 100 105 110Ile Asp Cys Asn Glu Asn Thr Arg Lys Lys Ser Gln Lys Glu Thr Glu 115 120 125Gly Leu His Cys Glu Tyr Val Ala Glu Pro Val Met Ala Gln Ser Thr 130 135 140Gln Asn Val Asp Tyr Asn Gln Leu Gln Glu Val Ile Tyr Pro Glu Thr145 150 155 160Leu Lys Leu Glu Gly Lys Gly Pro Glu Leu Val Gly Pro Ser Glu Ser 165 170 175Lys Pro Arg Gly Thr Ser Pro Leu Pro Ala Gly Gln Val Pro Val Thr 180 185 190Leu Gln Pro Gln Lys Gln Val Lys Glu Asn Lys Thr Gln Pro Pro Val 195 200 205Ala Tyr Gln Tyr Trp Pro Pro Ala Glu Leu Gln Tyr Arg Pro Pro Pro 210 215 220Glu Ser Gln Tyr Gly Tyr Pro Gly Met Pro Pro Ala Pro Gln Gly Arg225 230 235 240Ala Pro Tyr Pro Gln Pro Pro Thr Arg Arg Leu Asn Pro Thr Ala Pro 245 250 255Pro Ser Arg Gln Gly Ser Lys Leu His Glu Ile Ile Asp Lys Ser Arg 260 265 270Lys Glu Gly Asp Thr Glu Ala Trp Gln Phe Pro Val Thr Leu Glu Pro 275 280 285Met Pro Pro Gly Glu Gly Ala Gln Glu Gly Glu Pro Pro Thr Val Glu 290 295 300Ala Arg Tyr Lys Ser Phe Ser Ile Lys Lys Leu Lys Asp Met Lys Glu305 310 315 320Gly Val Lys Gln Tyr Gly Pro Asn Ser Pro Tyr Met Arg Thr Leu Leu 325 330 335Asp Ser Ile Ala His Gly His Arg Leu Ile Pro Tyr Asp Trp Glu Ile 340 345 350Leu Ala Lys Ser Ser Leu Ser Pro Ser Gln Phe Leu Gln Phe Lys Thr 355 360 365Trp Trp Ile Asp Gly Val Gln Glu Gln Val Arg Arg Asn Arg Ala Ala 370 375 380Asn Pro Pro Val Asn Ile Asp Ala Asp Gln Leu Leu Gly Ile Gly Gln385 390 395 400Asn Trp Ser Thr Ile Ser Gln Gln Ala Leu Met Gln Asn Glu Ala Ile 405 410 415Glu Gln Val Arg Ala Ile Cys Leu Arg Ala Trp Glu Lys Ile Gln Asp 420 425 430Pro Gly Ser Thr Cys Pro Ser Phe Asn Thr Val Arg Gln Gly Ser Lys 435 440 445Glu Pro Tyr Pro Asp Phe Val Ala Arg Leu Gln Asp Val Ala Gln Lys 450 455 460Ser Ile Ala Asp Glu Lys Ala Arg Lys Val Ile Val Glu Leu Met Ala465 470 475 480Tyr Glu Asn Ala Asn Pro Glu Cys Gln Ser Ala Ile Lys Pro Leu Lys 485 490 495Gly Lys Val Pro Ala Gly Ser Asp Val Ile Ser Glu Tyr Val Lys Ala 500 505 510Cys Asp Gly Ile Gly Gly Ala Met Tyr Lys Ala Met Leu Met Ala Gln 515 520 525Ala Ile Thr Gly Val Val Leu Gly Gly Gln Val Arg Thr Phe Gly Arg 530 535 540Lys Cys Tyr Asn Cys Gly Gln Ile Gly His Leu Lys Lys Asn Cys Pro545 550 555 560Val Leu Asn Lys Gln Asn Ile Thr Ile Gln Ala Thr Thr Thr Gly Arg 565 570 575Glu Pro Pro Asp Leu Cys Pro Arg Cys Lys Lys Gly Lys His Trp Ala 580 585 590Ser Gln Cys Arg Ser Lys Phe Asp Lys Asn Gly Gln Pro Leu Ser Gly 595 600 605Asn Glu Gln Arg Gly Gln Pro Gln Ala Pro Gln Gln Thr Gly Ala Phe 610 615 620Pro Ile Gln Pro Phe Val Pro Gln Gly Phe Gln Gly Gln Gln Pro Pro625 630 635 640Leu Ser Gln Val Phe Gln Gly Ile Ser Gln Leu Pro Gln Tyr Asn Asn 645 650 655Cys Pro Pro Pro Gln Ala Ala Val Gln Gln 660 665932619DNAHomo sapiens 93atgttaactg acttaagggc tgtaaacgcc gtaattcaac ccatggggcc tctccaaccc 60gggttgccct ctccggccat gatcccaaaa gattggcctt taattataat tgatctaaag 120gattgctttt ttaccatccc tctggcagag caggattgcg aaaaatttgc ctttactata 180ccagccataa ataataaaga accagccacc aggtttcagt ggaaagtgtt acctcaggga 240atgcttaata gtccaactat ttgtcagact tttgtaggtc gagctcttca accagttaga 300gaaaagtttt cagactgtta tattattcat tgtattgatg atattttatg tgctgcagaa 360acgaaagata aattaattga ctgttataca tttctgcaag cagaggttgc caatgctgga 420ctggcaatag catctgataa gatccaaacc tctactcctt ttcattattt agggatgcag 480atagaaaata gaaaaattaa gccacaaaaa atagaaataa gaaaagacac attaaaaaca 540ctaaatgatt ttcaaaaatt actaggagat attaattgga ttcggccaac tctaggcatt 600cctacttatg ccatgtcaaa tttgttctct atcttaagag gagactcaga cttaaatagt 660aaaagaatgt taaccccaga ggcaacaaaa gaaattaaat tagtggaaga aaaaattcag 720tcagcgcaaa taaatagaat agatccctta gccccactcc aacttttgat ttttgccact 780gcacattctc caacaggcat cattattcaa aatactgatc ttgtggagtg gtcattcctt 840cctcacagta cagttaagac ttttacattg tacttggatc aaatagctac attaatcggt 900cagacaagat tacgaataat aaaattatgt gggaatgacc cagacaaaat agttgtccct 960ttaaccaagg aacaagttag acaagccttt atcaattctg gtgcatggaa gattggtctt 1020gctaattttg tgggaattat tgataatcat tacccaaaaa caaagatctt ccagttctta 1080aaattgacta cttggattct acctaaaatt accagacgtg aacctttaga aaatgctcta 1140acagtattta ctgatggttc cagcaatgga aaagcagctt acacaggacc gaaagaacga 1200gtaatcaaaa ctccatatca atcggctcaa agagcagagt tggttgcagt cattacagtg 1260ttacaagatt ttgaccaacc tatcaatatt atatcagatt ctgcatatgt agtacaggct 1320acaagggatg ttgagacagc tctaattaaa tatagcatgg atgatcagtt aaaccagcta 1380ttcaatttat tacaacaaac tgtaagaaaa agaaatttcc cattttatat tacacatatt 1440cgagcacaca ctaatttacc agggcctttg actaaagcaa atgaacaagc tgacttactg 1500gtatcatctg cactcataaa agcacaagaa cttcatgctt tgactcatgt aaatgcagca 1560ggattaaaaa acaaatttga tgtcacatgg aaacaggcaa aagatattgt acaacattgc 1620acccagtgtc aagtcttaca cctgcccact caagaggcag gagttaatcc cagaggtctg 1680tgtcctaatg cattatggca aatggatgtc acgcatgtac cttcatttgg aagattatca 1740tatgttcacg taacagttga tacttattca catttcatat gggcaacttg ccaaacagga 1800gaaagtactt cccatgttaa aaaacattta ttgtcttgtt ttgctgtaat gggagttcca 1860gaaaaaatca aaactgacaa tggaccagga tattgtagta aagctttcca aaaattctta 1920agtcagtgga aaatttcaca tacaacagga attccttata attcccaagg acaggccata 1980gttgaaagaa ctaatagaac actcaaaact caattagtta aacaaaaaga agggggagac 2040agtaaggagt gtaccactcc tcagatgcaa cttaatctag cactctatac tttaaatttt 2100ttaaacattt atagaaatca gactactact tctgcagaac aacatcttac tggtaaaaag 2160aacagcccac atgaaggaaa actaatttgg tggaaagata gtaaaaataa gacatgggaa 2220atagggaagg tgataacgtg ggggagaggt tttgcttgtg tttcaccagg agaaaatcag 2280cttcctgttt ggatacccac tagacatttg aagttctaca atgaacccat cagagatgca 2340aagaaaagca cctccgcgga gacggagaca tcgcaatcga gcaccgttga ctcacaagat 2400gaacaaaatg gtgacgtcag aagaacagat gaagttgcca tccaccaaga aggcagagcc 2460gccaacttgg gcacaactaa agaagctgac gcagttagct acaaaatatc tagagaacac 2520aaaggtgaca caaaccccag agagtatgct gcttgcagcc ttgatgattg tatcaatggt 2580ggtaagtctc cctatgcctg caggagcagc tgcagctaa 261994872PRTHomo sapiens 94Met Leu Thr Asp Leu Arg Ala Val Asn Ala Val Ile Gln Pro Met Gly1 5 10 15Pro Leu Gln Pro Gly Leu Pro Ser Pro Ala Met Ile Pro Lys Asp Trp 20 25 30Pro Leu Ile Ile Ile Asp Leu Lys Asp Cys Phe Phe Thr Ile Pro Leu 35 40 45Ala Glu Gln Asp Cys Glu Lys Phe Ala Phe Thr Ile Pro Ala Ile Asn 50 55 60Asn Lys Glu Pro Ala Thr Arg Phe Gln Trp Lys Val Leu Pro Gln Gly65 70 75 80Met Leu Asn Ser Pro Thr Ile Cys Gln Thr Phe Val Gly Arg Ala Leu 85 90 95Gln Pro Val Arg Glu Lys Phe Ser Asp Cys Tyr Ile Ile His Cys Ile 100 105 110Asp Asp Ile Leu Cys Ala Ala Glu Thr Lys Asp Lys Leu Ile Asp Cys 115 120 125Tyr Thr Phe Leu Gln Ala Glu Val Ala Asn Ala Gly Leu Ala Ile Ala 130 135 140Ser Asp Lys Ile Gln Thr Ser Thr Pro Phe His Tyr Leu Gly Met Gln145 150 155 160Ile Glu Asn Arg Lys Ile Lys Pro Gln Lys Ile Glu Ile Arg Lys Asp 165 170 175Thr Leu Lys Thr Leu Asn Asp Phe Gln Lys Leu Leu Gly Asp Ile Asn 180 185 190Trp Ile Arg Pro Thr Leu Gly Ile Pro Thr Tyr Ala Met Ser Asn Leu 195 200 205Phe Ser Ile Leu Arg Gly Asp Ser Asp Leu Asn Ser Lys Arg Met Leu 210 215 220Thr Pro Glu Ala Thr Lys Glu Ile Lys Leu Val Glu Glu Lys Ile Gln225 230 235 240Ser Ala Gln Ile Asn Arg Ile Asp Pro Leu Ala Pro Leu Gln Leu Leu 245 250 255Ile Phe Ala Thr Ala His Ser Pro Thr Gly Ile Ile Ile Gln Asn Thr 260 265 270Asp Leu Val Glu Trp Ser Phe Leu Pro His Ser Thr Val Lys Thr Phe 275 280 285Thr Leu Tyr Leu Asp Gln Ile Ala Thr Leu Ile Gly Gln Thr Arg Leu 290 295 300Arg Ile Ile Lys Leu Cys Gly Asn Asp Pro Asp Lys Ile Val Val Pro305 310 315 320Leu Thr Lys Glu Gln Val Arg Gln Ala Phe Ile Asn Ser Gly Ala Trp 325 330 335Lys Ile Gly Leu Ala Asn Phe Val Gly Ile Ile Asp Asn His Tyr Pro 340 345 350Lys Thr Lys Ile Phe Gln Phe Leu Lys Leu Thr Thr Trp Ile Leu Pro 355 360 365Lys Ile Thr Arg Arg Glu Pro Leu Glu Asn Ala Leu Thr Val Phe Thr 370 375 380Asp Gly Ser Ser Asn Gly Lys Ala Ala Tyr Thr Gly Pro Lys Glu Arg385 390 395 400Val Ile Lys Thr Pro Tyr Gln Ser Ala Gln Arg Ala Glu Leu Val Ala 405 410 415Val Ile Thr Val Leu Gln Asp Phe Asp Gln Pro Ile Asn Ile Ile Ser 420 425 430Asp Ser Ala Tyr Val Val Gln Ala Thr Arg Asp Val Glu Thr Ala Leu 435 440 445Ile Lys Tyr Ser Met Asp Asp Gln Leu Asn Gln Leu Phe Asn Leu Leu 450 455 460Gln Gln Thr Val Arg Lys Arg Asn Phe Pro Phe Tyr Ile Thr His Ile465 470 475 480Arg Ala His Thr Asn Leu Pro Gly Pro Leu Thr Lys Ala Asn Glu Gln 485 490 495Ala Asp Leu Leu Val Ser Ser Ala Leu Ile Lys Ala Gln Glu Leu His 500 505 510Ala Leu Thr His Val Asn Ala Ala Gly Leu Lys Asn Lys Phe Asp Val 515 520 525Thr Trp Lys Gln Ala Lys Asp Ile Val Gln His Cys Thr Gln Cys Gln 530 535 540Val Leu His Leu Pro Thr Gln Glu Ala Gly Val Asn Pro Arg Gly Leu545 550 555 560Cys Pro Asn Ala Leu Trp Gln Met Asp Val Thr His Val Pro Ser Phe 565 570 575Gly Arg Leu Ser Tyr Val His Val Thr Val Asp Thr Tyr Ser His Phe 580 585 590Ile Trp Ala Thr Cys Gln Thr Gly Glu Ser Thr Ser His Val Lys Lys 595 600 605His Leu Leu Ser Cys Phe Ala Val Met Gly Val Pro Glu Lys Ile Lys 610 615 620Thr Asp Asn Gly Pro Gly Tyr Cys Ser Lys Ala Phe Gln Lys Phe Leu625 630 635 640Ser Gln Trp Lys Ile Ser His Thr Thr Gly Ile Pro Tyr Asn Ser Gln 645 650 655Gly Gln Ala Ile Val Glu Arg Thr Asn Arg Thr Leu Lys Thr Gln Leu 660 665 670Val Lys Gln Lys Glu Gly Gly Asp Ser Lys Glu Cys Thr Thr Pro Gln 675 680 685Met Gln Leu Asn Leu Ala Leu Tyr Thr Leu Asn Phe Leu Asn Ile Tyr 690 695 700Arg Asn Gln Thr Thr Thr Ser Ala Glu Gln His Leu Thr Gly Lys Lys705 710 715 720Asn Ser Pro His Glu Gly Lys Leu Ile Trp Trp Lys Asp Ser Lys Asn 725 730 735Lys Thr Trp Glu Ile Gly Lys Val Ile Thr Trp Gly Arg Gly Phe Ala 740 745 750Cys Val Ser Pro Gly Glu Asn Gln Leu Pro Val Trp Ile Pro Thr Arg 755 760 765His Leu Lys Phe Tyr Asn Glu Pro Ile Arg Asp Ala Lys Lys Ser Thr 770 775 780Ser Ala Glu Thr Glu Thr Ser Gln Ser Ser Thr Val Asp Ser Gln Asp785 790 795 800Glu Gln Asn Gly Asp Val Arg Arg Thr Asp Glu Val Ala Ile His Gln 805 810 815Glu Gly Arg Ala Ala Asn Leu Gly Thr Thr Lys Glu Ala Asp Ala Val 820 825 830Ser Tyr Lys Ile Ser Arg Glu His Lys Gly Asp Thr Asn Pro Arg Glu 835 840 845Tyr Ala Ala Cys Ser Leu Asp Asp Cys Ile Asn Gly Gly Lys Ser Pro 850 855 860Tyr Ala Cys Arg Ser Ser Cys Ser865 870952085DNAHomo sapiens 95atgcaaagaa aagcacctcc gcggagacgg agacatcgca atcgagcacc gttgactcac 60aagatgaaca aaatggtgac gtcagaagaa cagatgaagt tgccatccac caagaaggca 120gagccgccaa cttgggcaca actaaagaag ctgacgcagt tagctacaaa atatctagag 180aacacaaagg tgacacaaac cccagagagt atgctgcttg cagccttgat gattgtatca 240atggtggtaa gtctccctat gcctgcagga

gcagctgcag ctaactatac ctactgggcc 300tatgtgcctt tcccgccctt aattcgggca gtcacatgga tggataatcc tacagaagta 360tatgttaatg atagtgtatg ggtacctggc cccatagatg atcgctgccc tgccaaacct 420gaggaagaag ggatgatgat aaatatttcc attgggtatc attatcctcc tatttgccta 480gggagagcac caggatgttt aatgcctgca gtccaaaatt ggttggtaga agtacctact 540gtcagtccca tctgtagatt cacttatcac atggtaagcg ggatgtcact caggccacgg 600gtaaattatt tacaagactt ttcttatcaa agatcattaa aatttagacc taaagggaaa 660ccttgcccca aggaaattcc caaagaatca aaaaatacag aagttttagt ttgggaagaa 720tgtgtggcca atagtgcggt gatattacaa aacaatgaat tcggaactat tatagattgg 780gcacctcgag gtcaattcta ccacaattgc tcaggacaaa ctcagtcgtg tcaaagtgca 840caagtgagtc cagctgttga tagcgactta acagaaagtt tagacaaaca taagcataaa 900aaattgcagt ctttctaccc ttgggaatgg ggagaaaaag gaatctctac cccaagacca 960aaaatagtaa gtcctgtttc tggtcctgaa catccagaat tatggaggct tactgtggcc 1020tcacaccaca ttagaatttg gtctggaaat caaactttag aaacaagaga tcgtaagcca 1080ttttatacta ttgacctgaa ttccagtcta acagttcctt tacaaagttg cgtaaagccc 1140ccttatatgc tagttgtagg aaatatagtt attaaaccag actcccagac tataacctgt 1200gaaaattgta gattgcttac ttgcattgat tcaactttta attggcaaca ccgtattctg 1260ctggtgagag caagagaggg cgtgtggatc cctgtgtcca tggaccgacc gtgggaggcc 1320tcgccatccg tccatatttt gactgaagta ttaaaaggtg ttttaaatag atccaaaaga 1380ttcattttta ctttaattgc agtgattatg ggattaattg cagtcacagc tacggctgct 1440gtagcaggag ttgcattgca ctcttctgtt cagtcagtaa actttgttaa tgattggcaa 1500aaaaattcta caagattgtg gaattcacaa tctagtattg atcaaaaatt ggcaaatcaa 1560attaatgatc ttagacaaac tgtcatttgg atgggagaca gactcatgag cttagaacat 1620cgtttccagt tacaatgtga ctggaatacg tcagattttt gtattacacc ccaaatttat 1680aatgagtctg agcatcactg ggacatggtt agacgccatc tacagggaag agaagataat 1740ctcactttag acatttccaa attaaaagaa caaattttcg aagcatcaaa agcccattta 1800aatttggtgc caggaactga ggcaattgca ggagttgctg atggcctcgc aaatcttaac 1860cctgtcactt gggttaagac cattggaagt actacgatta taaatctcat attaatcctt 1920gtgtgcctgt tttgtctgtt gttagtctgc aggtgtaccc aacagctccg aagagacagc 1980gaccatcgag aacgggccat gatgacgatg gcggttttgt cgaaaagaaa agggggaaat 2040gtggggaaaa gcaagagaga tcagattgtt actgtgtctg tgtag 208596694PRTHomo sapiens 96Met Gln Arg Lys Ala Pro Pro Arg Arg Arg Arg His Arg Asn Arg Ala1 5 10 15Pro Leu Thr His Lys Met Asn Lys Met Val Thr Ser Glu Glu Gln Met 20 25 30Lys Leu Pro Ser Thr Lys Lys Ala Glu Pro Pro Thr Trp Ala Gln Leu 35 40 45Lys Lys Leu Thr Gln Leu Ala Thr Lys Tyr Leu Glu Asn Thr Lys Val 50 55 60Thr Gln Thr Pro Glu Ser Met Leu Leu Ala Ala Leu Met Ile Val Ser65 70 75 80Met Val Val Ser Leu Pro Met Pro Ala Gly Ala Ala Ala Ala Asn Tyr 85 90 95Thr Tyr Trp Ala Tyr Val Pro Phe Pro Pro Leu Ile Arg Ala Val Thr 100 105 110Trp Met Asp Asn Pro Thr Glu Val Tyr Val Asn Asp Ser Val Trp Val 115 120 125Pro Gly Pro Ile Asp Asp Arg Cys Pro Ala Lys Pro Glu Glu Glu Gly 130 135 140Met Met Ile Asn Ile Ser Ile Gly Tyr His Tyr Pro Pro Ile Cys Leu145 150 155 160Gly Arg Ala Pro Gly Cys Leu Met Pro Ala Val Gln Asn Trp Leu Val 165 170 175Glu Val Pro Thr Val Ser Pro Ile Cys Arg Phe Thr Tyr His Met Val 180 185 190Ser Gly Met Ser Leu Arg Pro Arg Val Asn Tyr Leu Gln Asp Phe Ser 195 200 205Tyr Gln Arg Ser Leu Lys Phe Arg Pro Lys Gly Lys Pro Cys Pro Lys 210 215 220Glu Ile Pro Lys Glu Ser Lys Asn Thr Glu Val Leu Val Trp Glu Glu225 230 235 240Cys Val Ala Asn Ser Ala Val Ile Leu Gln Asn Asn Glu Phe Gly Thr 245 250 255Ile Ile Asp Trp Ala Pro Arg Gly Gln Phe Tyr His Asn Cys Ser Gly 260 265 270Gln Thr Gln Ser Cys Gln Ser Ala Gln Val Ser Pro Ala Val Asp Ser 275 280 285Asp Leu Thr Glu Ser Leu Asp Lys His Lys His Lys Lys Leu Gln Ser 290 295 300Phe Tyr Pro Trp Glu Trp Gly Glu Lys Gly Ile Ser Thr Pro Arg Pro305 310 315 320Lys Ile Val Ser Pro Val Ser Gly Pro Glu His Pro Glu Leu Trp Arg 325 330 335Leu Thr Val Ala Ser His His Ile Arg Ile Trp Ser Gly Asn Gln Thr 340 345 350Leu Glu Thr Arg Asp Arg Lys Pro Phe Tyr Thr Ile Asp Leu Asn Ser 355 360 365Ser Leu Thr Val Pro Leu Gln Ser Cys Val Lys Pro Pro Tyr Met Leu 370 375 380Val Val Gly Asn Ile Val Ile Lys Pro Asp Ser Gln Thr Ile Thr Cys385 390 395 400Glu Asn Cys Arg Leu Leu Thr Cys Ile Asp Ser Thr Phe Asn Trp Gln 405 410 415His Arg Ile Leu Leu Val Arg Ala Arg Glu Gly Val Trp Ile Pro Val 420 425 430Ser Met Asp Arg Pro Trp Glu Ala Ser Pro Ser Val His Ile Leu Thr 435 440 445Glu Val Leu Lys Gly Val Leu Asn Arg Ser Lys Arg Phe Ile Phe Thr 450 455 460Leu Ile Ala Val Ile Met Gly Leu Ile Ala Val Thr Ala Thr Ala Ala465 470 475 480Val Ala Gly Val Ala Leu His Ser Ser Val Gln Ser Val Asn Phe Val 485 490 495Asn Asp Trp Gln Lys Asn Ser Thr Arg Leu Trp Asn Ser Gln Ser Ser 500 505 510Ile Asp Gln Lys Leu Ala Asn Gln Ile Asn Asp Leu Arg Gln Thr Val 515 520 525Ile Trp Met Gly Asp Arg Leu Met Ser Leu Glu His Arg Phe Gln Leu 530 535 540Gln Cys Asp Trp Asn Thr Ser Asp Phe Cys Ile Thr Pro Gln Ile Tyr545 550 555 560Asn Glu Ser Glu His His Trp Asp Met Val Arg Arg His Leu Gln Gly 565 570 575Arg Glu Asp Asn Leu Thr Leu Asp Ile Ser Lys Leu Lys Glu Gln Ile 580 585 590Phe Glu Ala Ser Lys Ala His Leu Asn Leu Val Pro Gly Thr Glu Ala 595 600 605Ile Ala Gly Val Ala Asp Gly Leu Ala Asn Leu Asn Pro Val Thr Trp 610 615 620Val Lys Thr Ile Gly Ser Thr Thr Ile Ile Asn Leu Ile Leu Ile Leu625 630 635 640Val Cys Leu Phe Cys Leu Leu Leu Val Cys Arg Cys Thr Gln Gln Leu 645 650 655Arg Arg Asp Ser Asp His Arg Glu Arg Ala Met Met Thr Met Ala Val 660 665 670Leu Ser Lys Arg Lys Gly Gly Asn Val Gly Lys Ser Lys Arg Asp Gln 675 680 685Ile Val Thr Val Ser Val 690972004DNAHomo sapiens 97atggggcaaa ctaaaagtaa aactaaaagt aaatatgcct cttatctcag ctttattaaa 60attcttttaa aaagaggggg agttagagta tctacaaaaa atctaatcaa gctatttcaa 120ataatagaac aattttgccc atggtttcca gaacaaggaa ctttagatct aaaagattgg 180aaaagaattg gcgaggaact aaaacaagca ggtagaaagg gtaatatcat tccacttaca 240gtatggaatg attgggccat tattaaagca gctttagaac catttcaaac aaaagaagat 300agcgtttcag tttctgatgc ccctggaagc tgtgtaatag attgtaatga aaagacaggg 360agaaaatccc agaaagaaac agaaagttta cattgcgaat atgtaacaga gccagtaatg 420gctcagtcaa cgcaaaatgt tgactataat caattacagg gggtgatata tcctgaaacg 480ttaaaattag aaggaaaagg tccagaatta gtggggccat cagagtctaa accacgaggg 540ccaagtcctc ttccagcagg tcaggtgccc gtaacattac aacctcaaac gcaggttaaa 600gaaaataaga cccaaccgcc agtagcttat caatactggc cgccggctga acttcagtat 660ctgccacccc cagaaagtca gtatggatat ccaggaatgc ccccagcact acagggcagg 720gcgccatatc ctcagccgcc cactgtgaga cttaatccta cagcatcacg tagtggacaa 780ggtggtacac tgcacgcagt cattgatgaa gccagaaaac agggagatct tgaggcatgg 840cggttcctgg taattttaca actggtacag gccggggaag agactcaagt aggagcgcct 900gcccgagctg agactagatg tgaacctttc accatgaaaa tgttaaaaga tataaaggaa 960ggagttaaac aatatggatc caactcccct tatataagaa cattattaga ttccattgct 1020catggaaata gacttactcc ttatgactgg gaaagtttgg ccaaatcttc cctttcatcc 1080tctcagtatc tacagtttaa aacctggtgg attgatggag tacaagaaca ggtacgaaaa 1140aatcaggcta ctaagcccac tgttaatata gacgcagacc aattgttagg aacaggtcca 1200aattggagca ccattaacca acaatcagtg atgcagaatg aggctattga acaagtaagg 1260gctatttgcc tcagggcctg gggaaaaatt caggacccag gaacagcttt ccctattaat 1320tcaattagac aaggctctaa agagccatat cctgactttg tggcaagatt acaagatgct 1380gctcaaaagt ctattacaga tgacaatgcc cgaaaagtta ttgtagaatt aatggcctat 1440gaaaatgcaa atccagaatg tcagtcggcc ataaagccat taaaaggaaa agttccagca 1500ggagttgatg taattacaga atatgtgaag gcttgtgatg ggattggagg agctatgcat 1560aaggcaatgc taatggctca agcaatgagg gggctcactc taggaggaca agttagaaca 1620tttgggaaaa aatgttataa ttgtggtcaa atcggtcatc tgaaaaggag ttgcccagtc 1680ttaaataaac agaatataat aaatcaagct attacagcaa aaaataaaaa gccatctggc 1740ctgtgtccaa aatgtggaaa aggaaaacat tgggccaatc aatgtcattc taaatttgat 1800aaagatgggc aaccattgtc gggaaacagg aagaggggcc agcctcaggc cccccaacaa 1860actggggcat tcccagttca actgtttgtt cctcagggtt ttcaaggaca acaaccccta 1920cagaaaatac caccacttca gggagtcagc caattacaac aatccaacag ctgtcccgcg 1980ccacagcagg cagcgccaca gtag 200498667PRTHomo sapiens 98Met Gly Gln Thr Lys Ser Lys Thr Lys Ser Lys Tyr Ala Ser Tyr Leu1 5 10 15Ser Phe Ile Lys Ile Leu Leu Lys Arg Gly Gly Val Arg Val Ser Thr 20 25 30Lys Asn Leu Ile Lys Leu Phe Gln Ile Ile Glu Gln Phe Cys Pro Trp 35 40 45Phe Pro Glu Gln Gly Thr Leu Asp Leu Lys Asp Trp Lys Arg Ile Gly 50 55 60Glu Glu Leu Lys Gln Ala Gly Arg Lys Gly Asn Ile Ile Pro Leu Thr65 70 75 80Val Trp Asn Asp Trp Ala Ile Ile Lys Ala Ala Leu Glu Pro Phe Gln 85 90 95Thr Lys Glu Asp Ser Val Ser Val Ser Asp Ala Pro Gly Ser Cys Val 100 105 110Ile Asp Cys Asn Glu Lys Thr Gly Arg Lys Ser Gln Lys Glu Thr Glu 115 120 125Ser Leu His Cys Glu Tyr Val Thr Glu Pro Val Met Ala Gln Ser Thr 130 135 140Gln Asn Val Asp Tyr Asn Gln Leu Gln Gly Val Ile Tyr Pro Glu Thr145 150 155 160Leu Lys Leu Glu Gly Lys Gly Pro Glu Leu Val Gly Pro Ser Glu Ser 165 170 175Lys Pro Arg Gly Pro Ser Pro Leu Pro Ala Gly Gln Val Pro Val Thr 180 185 190Leu Gln Pro Gln Thr Gln Val Lys Glu Asn Lys Thr Gln Pro Pro Val 195 200 205Ala Tyr Gln Tyr Trp Pro Pro Ala Glu Leu Gln Tyr Leu Pro Pro Pro 210 215 220Glu Ser Gln Tyr Gly Tyr Pro Gly Met Pro Pro Ala Leu Gln Gly Arg225 230 235 240Ala Pro Tyr Pro Gln Pro Pro Thr Val Arg Leu Asn Pro Thr Ala Ser 245 250 255Arg Ser Gly Gln Gly Gly Thr Leu His Ala Val Ile Asp Glu Ala Arg 260 265 270Lys Gln Gly Asp Leu Glu Ala Trp Arg Phe Leu Val Ile Leu Gln Leu 275 280 285Val Gln Ala Gly Glu Glu Thr Gln Val Gly Ala Pro Ala Arg Ala Glu 290 295 300Thr Arg Cys Glu Pro Phe Thr Met Lys Met Leu Lys Asp Ile Lys Glu305 310 315 320Gly Val Lys Gln Tyr Gly Ser Asn Ser Pro Tyr Ile Arg Thr Leu Leu 325 330 335Asp Ser Ile Ala His Gly Asn Arg Leu Thr Pro Tyr Asp Trp Glu Ser 340 345 350Leu Ala Lys Ser Ser Leu Ser Ser Ser Gln Tyr Leu Gln Phe Lys Thr 355 360 365Trp Trp Ile Asp Gly Val Gln Glu Gln Val Arg Lys Asn Gln Ala Thr 370 375 380Lys Pro Thr Val Asn Ile Asp Ala Asp Gln Leu Leu Gly Thr Gly Pro385 390 395 400Asn Trp Ser Thr Ile Asn Gln Gln Ser Val Met Gln Asn Glu Ala Ile 405 410 415Glu Gln Val Arg Ala Ile Cys Leu Arg Ala Trp Gly Lys Ile Gln Asp 420 425 430Pro Gly Thr Ala Phe Pro Ile Asn Ser Ile Arg Gln Gly Ser Lys Glu 435 440 445Pro Tyr Pro Asp Phe Val Ala Arg Leu Gln Asp Ala Ala Gln Lys Ser 450 455 460Ile Thr Asp Asp Asn Ala Arg Lys Val Ile Val Glu Leu Met Ala Tyr465 470 475 480Glu Asn Ala Asn Pro Glu Cys Gln Ser Ala Ile Lys Pro Leu Lys Gly 485 490 495Lys Val Pro Ala Gly Val Asp Val Ile Thr Glu Tyr Val Lys Ala Cys 500 505 510Asp Gly Ile Gly Gly Ala Met His Lys Ala Met Leu Met Ala Gln Ala 515 520 525Met Arg Gly Leu Thr Leu Gly Gly Gln Val Arg Thr Phe Gly Lys Lys 530 535 540Cys Tyr Asn Cys Gly Gln Ile Gly His Leu Lys Arg Ser Cys Pro Val545 550 555 560Leu Asn Lys Gln Asn Ile Ile Asn Gln Ala Ile Thr Ala Lys Asn Lys 565 570 575Lys Pro Ser Gly Leu Cys Pro Lys Cys Gly Lys Gly Lys His Trp Ala 580 585 590Asn Gln Cys His Ser Lys Phe Asp Lys Asp Gly Gln Pro Leu Ser Gly 595 600 605Asn Arg Lys Arg Gly Gln Pro Gln Ala Pro Gln Gln Thr Gly Ala Phe 610 615 620Pro Val Gln Leu Phe Val Pro Gln Gly Phe Gln Gly Gln Gln Pro Leu625 630 635 640Gln Lys Ile Pro Pro Leu Gln Gly Val Ser Gln Leu Gln Gln Ser Asn 645 650 655Ser Cys Pro Ala Pro Gln Gln Ala Ala Pro Gln 660 665991004DNAHomo sapiens 99atgggcaacc attgtcggga aacaggaaga ggggccagcc tcaggccccc caacaaactg 60gggcattccc agttcaactg tttgttcctc agggttttca aggacaacaa cccctacaga 120aaataccacc acttcaggga gtcagccaat tacaacaatc caacagctgt cccgcgccac 180agcaggcagc gccacagtag atttatgttc cacccaaatg gtctctttac tccctggaga 240gcccccacaa aagattccta gaggggtata tggcccgctg ccagaaggga gggtaggcct 300tattttaggg agatcaagtc taaatttgaa gggagtccaa attcatactg gggtaattta 360ttcagattat aaagggggaa ttcagttagt gatcagctcc actgttccct ggagtgccaa 420tccaggtgat agaattgctc aattactgct tttgccttat gttaaaattg gggaaaacaa 480aacggaaaga acaggagggt ttggaagtac caaccctgca ggaaaagcca cttattgggc 540taatcaggtc tcagaggata gacccgtgtg tacagtcact attcagggaa agagtttgaa 600ggattagtgg atacccaggc tgatgtttct atcatcggca taggcaccgc ctcagaagtg 660tatcaaagtg ccatgatttt acattgtcta ggatctgata atcaagaaag tacggttcag 720cctatgatca cttctattcc aatcaattta tggggccgag acttgttaca acaatggcat 780gcagagatta ctatcccagc ctccctatac agccccagga atcaaaaaat catgactaaa 840atgggatagc tccctaaaaa gggactagga aagaatgaag atggcattaa agtcccaact 900gaggctgaaa aaaatcaaaa aaagaaaagg aatagggcat cctttttaga agcggtcact 960gtagagcctc caaaacccat tccattaatt tggggggaaa aaaa 10041002671DNAHomo sapiens 100atggcattaa agtcccaact gaggctgaaa aaaatcaaaa aaagaaaagg aatagggcat 60cctttttaga agcggtcact gtagagcctc caaaacccat tccattaatt tggggggaaa 120aaaaaaactg tatggtaaat cagtagccgc ttccaaaaca aaaactggag gctttacact 180tattagcaaa gaaacagtta gaaaaaggac atattgagcc ttcattttcg ccttggaatt 240ctcctgtttg taattcagaa aaaatccggc agatggcgta tgctaactga cttaagagcc 300attaatgcca taattcaacc catgggggct ctcccatccc ggttgccctc tccagccatg 360gtccccttta attataattg atctgaagga ttgctttttt accattcctc tggcaaaaga 420ggattttgaa aaatttgctt ttactatacc agcctaaata ataaagaacc agccaccagg 480tttcagtgga aagtattgcc tcagggaatg cttaataatt caactatttg tcagactttc 540atagctcaag ctctgcaacc agttagagac aagttttcag actgttatat cgttcattat 600gttgatattt tgtgtgctgc agaaacgaga gacaaattaa ttgaccgtta cacatttctc 660agacagaggt tgccaacgcg ggactgacaa tagcatctga taagattcaa acctctcctc 720ctttccatta cttgggaatg caggtagagg aaaggaaaat taaaccacaa aaaatagaaa 780taagaaaaga cacattaaaa acattaaatg agtttcaaaa gttggtagga gatactaatt 840ggattcggag atattaattg gatttggcca actctaggca ttcctactta tgccatgtca 900attttgttct ctttcttaag aggggacttg gaattaaata gtgaaagaat gttacctcca 960gaggcaacta aagaaattaa attaattgaa gaaaaaaatt cggtcagcac aagtaaatag 1020gatcacttgg ccccactcca aattttgatt tttggtactg cacattctct aacagccatc 1080attgttcaaa acacagatct tgtggattgg tccttccttc ctcatagtac aattaagact 1140tttacattgt acttggatca aatggctaca ttaattggtc agggaagatt acgaataata 1200acattgtgtg gaaatgaccc agataaaatc actgttcctt tcaacaagca acaagttaga 1260caagccttta tcagttctgg tgcatggcag attggtcttg ctaattttct gggaattatt 1320gataatcatt acccaaaaac aaaaatcttc cagttcttaa aattgactac ttggattcta 1380cctaaaatta ccagacgtga acctttagaa aatgctctaa cagtatttac tgatggttcc 1440agcaatggaa aagcggctta cacagggccg aaagaacgag taatcaaaac tccgtatcaa 1500tcagctcaaa gagcagagtt ggttgcagtc attacagtgt tacaagattt tgaccaacct 1560atcaatatta tatcagattc tgcatatgta gtacaggcta caagggatgt tgagacagct 1620ctaattaaat atagcacgga cgatcattta aaccagctat tcaatttatt acaacaaact 1680gtaagaaaaa gaaatttccc attttatatt actcatattc gagcacacac taatttacca 1740gggcctttga ctaaagcaaa tgaacaagct gacttactgg tatcatctgc attcataaaa

1800gcacaagaac ttcttgcttt gactcatgta aatgcagcag gattaaaaaa caaatttgat 1860gtcacatgga aacaggcaaa agatattgta caacattgca cccagtgtca agtcttacac 1920ctgtccactc aagaggcagg agttaatccc agaggtctgt gtcctaatgc gttatggcaa 1980atggatggca cgcatgttcc ttcatttgga agattatcat atgttcatgt aacagttgat 2040acttattcac atttcatatg ggcaacttgc caaacaggag aaagtacttc ccatgttaaa 2100aaacatttat tatcttgttt tgctgtaatg ggagttccag aaaaaatcaa aactgacaat 2160ggaccaggat attgtagtaa agctttccaa aaattcttaa gtcagtggaa aatttcacat 2220acaacaggaa ttccttataa ttcccaagga caggccatag ttgaaagaac taatagaaca 2280ctcaaaactc aattagttaa acaaaaagaa gggggagaca gtaaggagtg taccactcct 2340cagatgcaac ttaatctagc actctatact ttaaattttt taaacattta tagaaatcag 2400actactactt ctgcaaaaca acatcttact ggtaaaaagc acagcccaca tgaaggaaaa 2460ctaatttggt ggaaagataa taaaaataag acatgggaaa tagggaaggt gataacgtgg 2520gggagaggtt ttgcttgtgt ttcaccagga gaaaatcagc ttcctgtttg gatacccact 2580agacatttga agttctacaa tgaacccatc ggagatgcaa agaaaagggc ctccacagag 2640atggtaaccc cagtcacatg gatggataat c 26711011665DNAHomo sapiens 101gtcacatgga tggataatcc tatagaagta tatgttaatg atagtgtatg ggtacctggc 60cccacagatg atcgctgccc tgccaaacct gaggaagaag ggatgatgat aaatatttcc 120attgtgtatc gttatcctcc tatttgccta gggagagcac caggatgttt aatgcctgca 180gtccaaaatt ggttggtaga agtacctact gtcagtccta acagtagatt cacttatcac 240atggtaagcg ggatgtcact caggccacgg gtaaattatt tacaagactt ttcttatcaa 300agatcattaa aatttagacc taaagggaaa ccttgcccca aggaaattcc caaagaatca 360aaaaatacag aagttttagt ttgggaagaa tgtgtggcca atagtgcggt gatattacaa 420aacaatgaat tcggaactat tatagattgg gcacctcgag gtcaattcta ccacaattgc 480tcaggacaaa ctcagtcgtg tccaagtgca caagtgagtc cagctgttga tagcgactta 540acagaaagtc tagacaaaca taagcataaa aaattacagt ctttctaccc ttgggaatgg 600ggagaaaaag gaatctctac cccaagacca gaaataataa gtcctgtttc tggtcctgaa 660catccagaat tatggaggct ttggcctgac accacattag aatttggtct ggaaatcaaa 720ctttagaaac aagagatcgt aagccatttt atactatcga cctaaattcc agtctaacgg 780ttcctttaca aagttgcgta aagccctctt atatgctagt tgtaggaaat atagttatta 840aaccagactc ccaaactata acctgtgaaa attgtagatt gtttacttgc attgattcaa 900cttttaattg gcggcaccgt attctgctgg tgagagcaag agagggcgtg tggatctctg 960tgtccgtgga ctgaccgtgg gaggcctcgc catccatcca tattttgact gaagtattaa 1020aagacatttt aaatagatcc aaaagattca tttttacctt aattgcagtg attatgggat 1080taattgcagt cacagctacg gctgctgtgg caggagttgc attgcactct tctgttcagt 1140cggtaaactt tgttaatgat tggcaaaaga attctacaag attgtggaat tcacaatcta 1200gtattgatca aaaattggca aatcaaatta atgatcttag acaaactgtc atttggatgg 1260gagacagact catgagctta gaacattgtt tccagttaca gtgtgactgg aatacgtcag 1320atttttgtat tacaccccaa atttataatg agtctgagca tcactgggac atggttagac 1380gccatctaca gggaagagaa gataatctca ctttagacat ttccaaatta aaataacaaa 1440ttttcgaagc atcaaaagcc catttaaatt tgatgccagg aactgaggca attgcaggag 1500ttgctgatgg cctcgcaaat cttaaccctg tcacttgggt taagaccatc ggaagtacta 1560tgattataaa tctcatatta atccttgtgt gcctgttttg tctgttgtta gtctgcaggt 1620gtacccaaca gctccgaaga gacagcgacc atcgagaacg ggcca 1665102852DNAHomo sapiens 102atggggcaaa ctaaaagtaa aattaaaagt aaatatgcct cttatctcag ctttattaaa 60attcttttaa aaagaggggg agttaaagta tctacaaaaa atctaatcaa gctatttcaa 120ataatagaac aattttgccc atggtttcca gaacaaggaa cttcagatct aaaagattgg 180aaaagaattg gtaaggaact aaaacaagca ggtaggaagg gtaatatcat tccacttaca 240gtatggaatg attgggccat tattaaagca gctttagaac catttcaaac agaagaagat 300agcatttcag tttctgatgc ccctggaagc tgtttaatag attgtaatga aaacacaagg 360aaaaaatccc agaaagaaac cgaaagttta cattgcgaat atgtagcaga gccggtaatg 420gctcagtcaa cgcaaaatgt tgactataat caattacagg aggtgatata tcctgaaacg 480ttaaaattag aaggaaaagg tccagaatta atggggccat cagagtctaa accacgaggc 540acaagtcctc ttccagcagg tcaggtgctc gtaagattac aacctcaaaa gcaggttaaa 600gaaaataaga cccaaccgca agtagcctat caatactgcc gctggctgaa cttcagtatc 660ggccaccccc agaaagtcag tatggatatc caggaatgcc cccagcacca cagggcaggg 720cgccatacca tcagccgccc actaggagac ttaatcctat ggcaccacct agtagacagg 780gtagtgaatt acatgaaatt attgataaat caagaaagga aggagatact gaggcatggc 840aattcccagt aa 852103283PRTHomo sapiens 103Met Gly Gln Thr Lys Ser Lys Ile Lys Ser Lys Tyr Ala Ser Tyr Leu1 5 10 15Ser Phe Ile Lys Ile Leu Leu Lys Arg Gly Gly Val Lys Val Ser Thr 20 25 30Lys Asn Leu Ile Lys Leu Phe Gln Ile Ile Glu Gln Phe Cys Pro Trp 35 40 45Phe Pro Glu Gln Gly Thr Ser Asp Leu Lys Asp Trp Lys Arg Ile Gly 50 55 60Lys Glu Leu Lys Gln Ala Gly Arg Lys Gly Asn Ile Ile Pro Leu Thr65 70 75 80Val Trp Asn Asp Trp Ala Ile Ile Lys Ala Ala Leu Glu Pro Phe Gln 85 90 95Thr Glu Glu Asp Ser Ile Ser Val Ser Asp Ala Pro Gly Ser Cys Leu 100 105 110Ile Asp Cys Asn Glu Asn Thr Arg Lys Lys Ser Gln Lys Glu Thr Glu 115 120 125Ser Leu His Cys Glu Tyr Val Ala Glu Pro Val Met Ala Gln Ser Thr 130 135 140Gln Asn Val Asp Tyr Asn Gln Leu Gln Glu Val Ile Tyr Pro Glu Thr145 150 155 160Leu Lys Leu Glu Gly Lys Gly Pro Glu Leu Met Gly Pro Ser Glu Ser 165 170 175Lys Pro Arg Gly Thr Ser Pro Leu Pro Ala Gly Gln Val Leu Val Arg 180 185 190Leu Gln Pro Gln Lys Gln Val Lys Glu Asn Lys Thr Gln Pro Gln Val 195 200 205Ala Tyr Gln Tyr Cys Arg Trp Leu Asn Phe Ser Ile Gly His Pro Gln 210 215 220Lys Val Ser Met Asp Ile Gln Glu Cys Pro Gln His His Arg Ala Gly225 230 235 240Arg His Thr Ile Ser Arg Pro Leu Gly Asp Leu Ile Leu Trp His His 245 250 255Leu Val Asp Arg Val Val Asn Tyr Met Lys Leu Leu Ile Asn Gln Glu 260 265 270Arg Lys Glu Ile Leu Arg His Gly Asn Ser Gln 275 280104434PRTHomo sapiens 104Met Pro Pro Ala Pro Gln Gly Arg Ala Pro Tyr His Gln Pro Pro Thr1 5 10 15Arg Arg Leu Asn Pro Met Ala Pro Pro Ser Arg Gln Gly Ser Glu Leu 20 25 30His Glu Ile Ile Asp Lys Ser Arg Lys Glu Gly Asp Thr Glu Ala Trp 35 40 45Gln Phe Pro Val Thr Leu Glu Pro Met Pro Pro Gly Glu Gly Ala Gln 50 55 60Glu Gly Glu Pro Pro Thr Val Glu Ala Arg Tyr Lys Ser Phe Ser Ile65 70 75 80Lys Met Leu Lys Asp Met Lys Glu Gly Val Lys Gln Tyr Gly Pro Asn 85 90 95Ser Pro Tyr Met Arg Thr Leu Leu Asp Ser Ile Ala Tyr Gly His Arg 100 105 110Leu Ile Pro Tyr Asp Trp Glu Ile Leu Ala Lys Ser Ser Leu Ser Pro 115 120 125Ser Gln Phe Leu Gln Phe Lys Thr Trp Trp Ile Asp Gly Val Gln Glu 130 135 140Gln Val Arg Arg Asn Arg Ala Ala Asn Pro Pro Val Asn Ile Asp Ala145 150 155 160Asp Gln Leu Leu Gly Ile Gly Gln Asn Trp Ser Thr Ile Ser Gln Gln 165 170 175Ala Leu Met Gln Asn Glu Ala Ile Glu Gln Val Arg Ala Ile Cys Leu 180 185 190Arg Ala Trp Glu Lys Ile Gln Asp Pro Gly Ser Thr Cys Pro Ser Phe 195 200 205Asn Thr Val Arg Gln Gly Ser Lys Glu Pro Tyr Pro Asp Phe Val Ala 210 215 220Arg Leu Gln Asp Val Ala Gln Lys Ser Ile Ala Asp Glu Lys Ala Gly225 230 235 240Lys Val Ile Val Glu Leu Met Ala Tyr Glu Asn Ala Asn Pro Glu Cys 245 250 255Gln Ser Ala Ile Lys Pro Leu Lys Gly Lys Val Pro Ala Gly Ser Asp 260 265 270Val Ile Ser Glu Tyr Val Lys Ala Cys Asp Gly Ile Gly Gly Ala Met 275 280 285His Lys Ala Met Leu Met Ala Gln Ala Ile Thr Gly Val Val Leu Gly 290 295 300Gly Gln Val Arg Thr Phe Gly Gly Lys Cys Tyr Asn Cys Gly Gln Ile305 310 315 320Gly His Leu Lys Lys Asn Cys Pro Val Leu Asn Lys Gln Asn Ile Thr 325 330 335Ile Gln Ala Thr Thr Thr Gly Arg Glu Pro Pro Asp Leu Cys Pro Arg 340 345 350Cys Lys Lys Gly Lys His Trp Ala Ser Gln Cys Arg Ser Lys Phe Asp 355 360 365Lys Asn Gly Gln Pro Leu Ser Gly Asn Glu Gln Arg Gly Gln Pro Gln 370 375 380Ala Pro Gln Gln Thr Gly Ala Phe Pro Ile Gln Pro Phe Val Pro Gln385 390 395 400Gly Phe Gln Gly Gln Gln Pro Pro Leu Ser Gln Val Phe Gln Gly Ile 405 410 415Ser Gln Leu Pro Gln Tyr Asn Asn Cys Pro Ser Pro Gln Ala Ala Val 420 425 430Gln Gln105279DNAHomo sapiens 105atggagattt tacattgctt agggccagat aatcaagaaa gtactgttca gccaatgatt 60acttcaattc ctcttaatct gtggggtcga gatttattac aacaatgggg tgcggaaatc 120accatgcccg ctccattata tagccccacg agtcaaaaaa tcatgaccaa gatgggatat 180ataccaggaa agggactagg gaaaaatgaa gatggcatta aagttccagt tgaggctaaa 240ataaatcaag aaagagaagg aatagggtat cctttttag 27910692PRTHomo sapiens 106Met Glu Ile Leu His Cys Leu Gly Pro Asp Asn Gln Glu Ser Thr Val1 5 10 15Gln Pro Met Ile Thr Ser Ile Pro Leu Asn Leu Trp Gly Arg Asp Leu 20 25 30Leu Gln Gln Trp Gly Ala Glu Ile Thr Met Pro Ala Pro Leu Tyr Ser 35 40 45Pro Thr Ser Gln Lys Ile Met Thr Lys Met Gly Tyr Ile Pro Gly Lys 50 55 60Gly Leu Gly Lys Asn Glu Asp Gly Ile Lys Val Pro Val Glu Ala Lys65 70 75 80Ile Asn Gln Glu Arg Glu Gly Ile Gly Tyr Pro Phe 85 901074086DNAHomo sapiens 107atggggcctc tccaacccgg gttgccctct ccggccatga tcccaaaaga ttggccttta 60attataattg atctaaagga ttgctttttt accatccctc tggcagagca ggattgtgaa 120aaatttgcct ttactatacc agccataaat aataaagaac cagccaccag gtttcagtgg 180aaagtgttac ctcagggaat gcttaatagt ccaactattt gtcagacttt tgtaggtcga 240gctcttcaac cagtgagaga aaagttttca gactgttata ttattcatta tattgatgat 300attttatgtg ctgcagaaac gaaagataaa ttaattgact gttatacatt tctgcaagca 360gaggttgcca atgctggact ggcaatagca tccgataaga tccaaacctc tactcctttt 420cattatttag ggatgcagat agaaaataga aaaattaagc cacaaaaaat agaaataaga 480aaagacacat taaaaacact aaatgatttt caaaaattac taggagatat taattggatt 540cggccaactc taggcattcc tacttatgcc atgtcaaatt tgttctctat cttaagagga 600gactcagact taaatagtca aagaatatta accccagagg caacaaaaga aattaaatta 660gtggaagaaa aaattcagtc agcgcaaata aatagaatag atcccttagc cccactccaa 720cttttgattt ttgccactgc acattctcca acaggcatca ttattcaaaa tactgatctt 780gtggagtggt cattccttcc tcacagtaca gttaagactt ttacattgta cttggatcaa 840atagctacat taatcggtca gacaagatta cgaataacaa aattatgtgg aaatgaccca 900gacaaaatag ttgtcccttt aaccaaggaa caagttagac aagcctttat caattctggt 960gcatggcaga ttggtcttgc taattttgtg ggacttattg ataatcatta cccaaaaaca 1020aagatcttcc agttcttaaa attgactact tggattctac ctaaaattac cagacgtgaa 1080cctttagaaa atgctctaac agtatttact gatggttcca gcaatggaaa agcagcttac 1140acagggccga aagaacgagt aatcaaaact ccatatcaat cggctcaaag agacgagttg 1200gttgcagtca ttacagtgtt acaagatttt gaccaaccta tcaatattat atcagattct 1260gcatatgtag tacaggctac aagggatgtt gagacagctc taattaaata tagcatggat 1320gatcagttaa accagctatt caatttatta caacaaactg taagaaaaag aaatttccca 1380ttttatatta cttatattcg agcacacact aatttaccag ggcctttgac taaagcaaat 1440gaacaagctg acttactggt atcatctgca ctcataaaag cacaagaact tcatgctttg 1500actcatgtaa atgcagcagg attaaaaaac aaatttgatg tcacatggaa acaggcaaaa 1560gatattgtac aacattgcac ccagtgtcaa gtcttacacc tgcccactca agaggcagga 1620gttaatccca gaggtctgtg tcctaatgca ttatggcaaa tggatgtcac gcatgtacct 1680tcatttggaa gattatcata tgttcatgta acagttgata cttattcaca tttcatatgg 1740gcaacttgcc aaacaggaga aagtacttcc catgttaaaa aacatttatt gtcttgtttt 1800gctgtaatgg gagttccaga aaaaatcaaa actgacaatg gaccaggata ttgtagtaaa 1860gctttccaaa aattcttaag tcagtggaaa atttcacata caacaggaat tccttataat 1920tcccaaggac aggccatagt tgaaagaact aatagaacac tcaaaactca attagttaaa 1980caaaaagaag ggggagacag taaggagtgt accactcctc agatgcaact taatctagca 2040ctctatactt taaatttttt aaacatttat agaaatcaga ctactacttc tgcagaacaa 2100catcttactg gtaaaaagaa cagcccacat gaaggaaaac taatttggtg gaaagataat 2160aaaaataaga catgggaaat agggaaggtg ataacgtggg ggagaggttt tgcttgtgtt 2220tcaccaggag aaaatcagct tcctgtttgg ttacccacta gacatttgaa gttctacaat 2280gaacccatcg gagatgcaaa gaaaagggcc tccacggaga tggtaacacc agtcacatgg 2340atggataatc ctatagaagt atatgttaat gatagtatat gggtacctgg ccccatagat 2400gatcgctgcc ctgccaaacc tgaggaagaa gggatgatga taaatatttc cattgggtat 2460cgttatcctc ctatttgcct agggagagca ccaggatgtt taatgcctgc agtccaaaat 2520tggttggtag aagtacctac tgtcagtccc atcagtagat tcacttatca catggtaagc 2580gggatgtcac tcaggccacg ggtaaattat ttacaagact tttcttatca aagatcatta 2640aaatttagac ctaaagggaa accttgcccc aaggaaattc ccaaagaatc aaaaaataca 2700gaagttttag tttgggaaga atgtgtggcc aatagtgcgg tgatattata aaacaatgaa 2760tttggaacta ttatagattg ggcacctcga ggtcaattct accacaattg ctcaggacaa 2820actcagtcgt gtccaagtgc acaagtgagt ccagctgttg atagcgactt aacagaaagt 2880ttagacaaac ataagcataa aaaattgcag tctttctacc cttgggaatg gggagaaaaa 2940ggaatctcta ccccaagacc aaaaatagta agtcctgttt ctggtcctga acatccagaa 3000ttatggaggc ttactgtggc ctcacaccac attagaattt ggtctggaaa tcaaacttta 3060gaaacaagag attgtaagcc attttatact gtcgacctaa attccagtct aacagttcct 3120ttacaaagtt gcgtaaagcc cccttatatg ctagttgtag gaaatatagt tattaaacca 3180gactcccaga ctataacctg tgaaaattgt agattgctta cttgcattga ttcaactttt 3240aattggcaac accgtattct gctggtgaga gcaagagagg gcgtgtggat ccctgtgtcc 3300atggaccgac cgtgggaggc ctcaccatcc gtccatattt tgactgaagt attaaaaggt 3360gttttaaata gatccaaaag attcattttt actttaattg cagtgattat gggattaatt 3420gcagtcacag ctacggctgc tgtagcagga gttgcattgc actcttctgt tcagtcagta 3480aactttgtta atgattggca aaagaattct acaagattgt ggaattcaca atctagtatt 3540gatcaaaaat tggcaaatca aattaatgat cttagacaaa ctgtcatttg gatgggagac 3600agactcatga gcttagaaca tcgtttccag ttacaatgtg actggaatac gtcagatttt 3660tgtattacac cccaaattta taatgagtct gagcatcact gggacatggt tagacgccat 3720ctacagggaa gagaagataa tctcacttta gacatttcca aattaaaaga acaaattttc 3780gaagcatcaa aagcccattt aaatttggtg ccaggaactg aggcaattgc aggagttgct 3840gatggcctcg caaatcttaa ccctgtcact tgggttaaga ccattggaag tacatcgatt 3900ataaatctca tattaatcct tgtgtgcctg ttttgtctgt tgttagtctg caggtgtacc 3960caacagctcc gaagagacag cgaccatcga gaacgggcca tgatgacgat ggcggttttg 4020tcgaaaagaa aagggggaaa tgtggggaaa agcaagagag atcaaattgt tactgtgtct 4080gtgtag 40861081361PRTHomo sapiensMISC_FEATURE(1)..(1361)Xaa=Any amino acid 108Met Gly Pro Leu Gln Pro Gly Leu Pro Ser Pro Ala Met Ile Pro Lys1 5 10 15Asp Trp Pro Leu Ile Ile Ile Asp Leu Lys Asp Cys Phe Phe Thr Ile 20 25 30Pro Leu Ala Glu Gln Asp Cys Glu Lys Phe Ala Phe Thr Ile Pro Ala 35 40 45Ile Asn Asn Lys Glu Pro Ala Thr Arg Phe Gln Trp Lys Val Leu Pro 50 55 60Gln Gly Met Leu Asn Ser Pro Thr Ile Cys Gln Thr Phe Val Gly Arg65 70 75 80Ala Leu Gln Pro Val Arg Glu Lys Phe Ser Asp Cys Tyr Ile Ile His 85 90 95Tyr Ile Asp Asp Ile Leu Cys Ala Ala Glu Thr Lys Asp Lys Leu Ile 100 105 110Asp Cys Tyr Thr Phe Leu Gln Ala Glu Val Ala Asn Ala Gly Leu Ala 115 120 125Ile Ala Ser Asp Lys Ile Gln Thr Ser Thr Pro Phe His Tyr Leu Gly 130 135 140Met Gln Ile Glu Asn Arg Lys Ile Lys Pro Gln Lys Ile Glu Ile Arg145 150 155 160Lys Asp Thr Leu Lys Thr Leu Asn Asp Phe Gln Lys Leu Leu Gly Asp 165 170 175Ile Asn Trp Ile Arg Pro Thr Leu Gly Ile Pro Thr Tyr Ala Met Ser 180 185 190Asn Leu Phe Ser Ile Leu Arg Gly Asp Ser Asp Leu Asn Ser Gln Arg 195 200 205Ile Leu Thr Pro Glu Ala Thr Lys Glu Ile Lys Leu Val Glu Glu Lys 210 215 220Ile Gln Ser Ala Gln Ile Asn Arg Ile Asp Pro Leu Ala Pro Leu Gln225 230 235 240Leu Leu Ile Phe Ala Thr Ala His Ser Pro Thr Gly Ile Ile Ile Gln 245 250 255Asn Thr Asp Leu Val Glu Trp Ser Phe Leu Pro His Ser Thr Val Lys 260 265 270Thr Phe Thr Leu Tyr Leu Asp Gln Ile Ala Thr Leu Ile Gly Gln Thr 275 280 285Arg Leu Arg Ile Thr Lys Leu Cys Gly Asn Asp Pro Asp Lys Ile Val 290 295 300Val Pro Leu Thr Lys Glu Gln Val Arg Gln Ala Phe Ile Asn Ser Gly305 310 315 320Ala Trp Gln Ile Gly Leu Ala Asn Phe Val Gly Leu Ile Asp Asn His

325 330 335Tyr Pro Lys Thr Lys Ile Phe Gln Phe Leu Lys Leu Thr Thr Trp Ile 340 345 350Leu Pro Lys Ile Thr Arg Arg Glu Pro Leu Glu Asn Ala Leu Thr Val 355 360 365Phe Thr Asp Gly Ser Ser Asn Gly Lys Ala Ala Tyr Thr Gly Pro Lys 370 375 380Glu Arg Val Ile Lys Thr Pro Tyr Gln Ser Ala Gln Arg Asp Glu Leu385 390 395 400Val Ala Val Ile Thr Val Leu Gln Asp Phe Asp Gln Pro Ile Asn Ile 405 410 415Ile Ser Asp Ser Ala Tyr Val Val Gln Ala Thr Arg Asp Val Glu Thr 420 425 430Ala Leu Ile Lys Tyr Ser Met Asp Asp Gln Leu Asn Gln Leu Phe Asn 435 440 445Leu Leu Gln Gln Thr Val Arg Lys Arg Asn Phe Pro Phe Tyr Ile Thr 450 455 460Tyr Ile Arg Ala His Thr Asn Leu Pro Gly Pro Leu Thr Lys Ala Asn465 470 475 480Glu Gln Ala Asp Leu Leu Val Ser Ser Ala Leu Ile Lys Ala Gln Glu 485 490 495Leu His Ala Leu Thr His Val Asn Ala Ala Gly Leu Lys Asn Lys Phe 500 505 510Asp Val Thr Trp Lys Gln Ala Lys Asp Ile Val Gln His Cys Thr Gln 515 520 525Cys Gln Val Leu His Leu Pro Thr Gln Glu Ala Gly Val Asn Pro Arg 530 535 540Gly Leu Cys Pro Asn Ala Leu Trp Gln Met Asp Val Thr His Val Pro545 550 555 560Ser Phe Gly Arg Leu Ser Tyr Val His Val Thr Val Asp Thr Tyr Ser 565 570 575His Phe Ile Trp Ala Thr Cys Gln Thr Gly Glu Ser Thr Ser His Val 580 585 590Lys Lys His Leu Leu Ser Cys Phe Ala Val Met Gly Val Pro Glu Lys 595 600 605Ile Lys Thr Asp Asn Gly Pro Gly Tyr Cys Ser Lys Ala Phe Gln Lys 610 615 620Phe Leu Ser Gln Trp Lys Ile Ser His Thr Thr Gly Ile Pro Tyr Asn625 630 635 640Ser Gln Gly Gln Ala Ile Val Glu Arg Thr Asn Arg Thr Leu Lys Thr 645 650 655Gln Leu Val Lys Gln Lys Glu Gly Gly Asp Ser Lys Glu Cys Thr Thr 660 665 670Pro Gln Met Gln Leu Asn Leu Ala Leu Tyr Thr Leu Asn Phe Leu Asn 675 680 685Ile Tyr Arg Asn Gln Thr Thr Thr Ser Ala Glu Gln His Leu Thr Gly 690 695 700Lys Lys Asn Ser Pro His Glu Gly Lys Leu Ile Trp Trp Lys Asp Asn705 710 715 720Lys Asn Lys Thr Trp Glu Ile Gly Lys Val Ile Thr Trp Gly Arg Gly 725 730 735Phe Ala Cys Val Ser Pro Gly Glu Asn Gln Leu Pro Val Trp Leu Pro 740 745 750Thr Arg His Leu Lys Phe Tyr Asn Glu Pro Ile Gly Asp Ala Lys Lys 755 760 765Arg Ala Ser Thr Glu Met Val Thr Pro Val Thr Trp Met Asp Asn Pro 770 775 780Ile Glu Val Tyr Val Asn Asp Ser Ile Trp Val Pro Gly Pro Ile Asp785 790 795 800Asp Arg Cys Pro Ala Lys Pro Glu Glu Glu Gly Met Met Ile Asn Ile 805 810 815Ser Ile Gly Tyr Arg Tyr Pro Pro Ile Cys Leu Gly Arg Ala Pro Gly 820 825 830Cys Leu Met Pro Ala Val Gln Asn Trp Leu Val Glu Val Pro Thr Val 835 840 845Ser Pro Ile Ser Arg Phe Thr Tyr His Met Val Ser Gly Met Ser Leu 850 855 860Arg Pro Arg Val Asn Tyr Leu Gln Asp Phe Ser Tyr Gln Arg Ser Leu865 870 875 880Lys Phe Arg Pro Lys Gly Lys Pro Cys Pro Lys Glu Ile Pro Lys Glu 885 890 895Ser Lys Asn Thr Glu Val Leu Val Trp Glu Glu Cys Val Ala Asn Ser 900 905 910Ala Val Ile Leu Xaa Asn Asn Glu Phe Gly Thr Ile Ile Asp Trp Ala 915 920 925Pro Arg Gly Gln Phe Tyr His Asn Cys Ser Gly Gln Thr Gln Ser Cys 930 935 940Pro Ser Ala Gln Val Ser Pro Ala Val Asp Ser Asp Leu Thr Glu Ser945 950 955 960Leu Asp Lys His Lys His Lys Lys Leu Gln Ser Phe Tyr Pro Trp Glu 965 970 975Trp Gly Glu Lys Gly Ile Ser Thr Pro Arg Pro Lys Ile Val Ser Pro 980 985 990Val Ser Gly Pro Glu His Pro Glu Leu Trp Arg Leu Thr Val Ala Ser 995 1000 1005His His Ile Arg Ile Trp Ser Gly Asn Gln Thr Leu Glu Thr Arg 1010 1015 1020Asp Cys Lys Pro Phe Tyr Thr Val Asp Leu Asn Ser Ser Leu Thr 1025 1030 1035Val Pro Leu Gln Ser Cys Val Lys Pro Pro Tyr Met Leu Val Val 1040 1045 1050Gly Asn Ile Val Ile Lys Pro Asp Ser Gln Thr Ile Thr Cys Glu 1055 1060 1065Asn Cys Arg Leu Leu Thr Cys Ile Asp Ser Thr Phe Asn Trp Gln 1070 1075 1080His Arg Ile Leu Leu Val Arg Ala Arg Glu Gly Val Trp Ile Pro 1085 1090 1095Val Ser Met Asp Arg Pro Trp Glu Ala Ser Pro Ser Val His Ile 1100 1105 1110Leu Thr Glu Val Leu Lys Gly Val Leu Asn Arg Ser Lys Arg Phe 1115 1120 1125Ile Phe Thr Leu Ile Ala Val Ile Met Gly Leu Ile Ala Val Thr 1130 1135 1140Ala Thr Ala Ala Val Ala Gly Val Ala Leu His Ser Ser Val Gln 1145 1150 1155Ser Val Asn Phe Val Asn Asp Trp Gln Lys Asn Ser Thr Arg Leu 1160 1165 1170Trp Asn Ser Gln Ser Ser Ile Asp Gln Lys Leu Ala Asn Gln Ile 1175 1180 1185Asn Asp Leu Arg Gln Thr Val Ile Trp Met Gly Asp Arg Leu Met 1190 1195 1200Ser Leu Glu His Arg Phe Gln Leu Gln Cys Asp Trp Asn Thr Ser 1205 1210 1215Asp Phe Cys Ile Thr Pro Gln Ile Tyr Asn Glu Ser Glu His His 1220 1225 1230Trp Asp Met Val Arg Arg His Leu Gln Gly Arg Glu Asp Asn Leu 1235 1240 1245Thr Leu Asp Ile Ser Lys Leu Lys Glu Gln Ile Phe Glu Ala Ser 1250 1255 1260Lys Ala His Leu Asn Leu Val Pro Gly Thr Glu Ala Ile Ala Gly 1265 1270 1275Val Ala Asp Gly Leu Ala Asn Leu Asn Pro Val Thr Trp Val Lys 1280 1285 1290Thr Ile Gly Ser Thr Ser Ile Ile Asn Leu Ile Leu Ile Leu Val 1295 1300 1305Cys Leu Phe Cys Leu Leu Leu Val Cys Arg Cys Thr Gln Gln Leu 1310 1315 1320Arg Arg Asp Ser Asp His Arg Glu Arg Ala Met Met Thr Met Ala 1325 1330 1335Val Leu Ser Lys Arg Lys Gly Gly Asn Val Gly Lys Ser Lys Arg 1340 1345 1350Asp Gln Ile Val Thr Val Ser Val 1355 1360109105PRTHomo sapiens 109Met Asn Pro Ser Glu Met Gln Arg Lys Ala Pro Pro Arg Arg Arg Arg1 5 10 15His Arg Asn Arg Ala Pro Leu Thr His Lys Met Asn Lys Met Val Thr 20 25 30Ser Glu Glu Gln Met Lys Leu Pro Ser Thr Lys Lys Ala Gly Pro Pro 35 40 45Thr Trp Ala Gln Leu Lys Lys Leu Thr Gln Leu Ala Thr Lys Tyr Leu 50 55 60Glu Asn Thr Lys Val Thr Gln Thr Pro Glu Ser Met Leu Leu Ala Ala65 70 75 80Leu Met Ile Val Ser Met Val Ser Ala Gly Val Pro Asn Ser Ser Glu 85 90 95Glu Thr Ala Thr Ile Glu Asn Gly Pro 100 10511020DNAHomo sapiens 110gaaaaaaatc aaaaaaagaa 2011117DNAHomo sapiens 111agccattaat gccataa 1711215DNAHomo sapiens 112taaataggat cactt 1511328DNAHomo sapiens 113ggtgcggaaa tcaccatgcc cgctccat 2811418DNAHomo sapiens 114attatatagc cccacgag 1811521DNAHomo sapiens 115caagatggga tatataccag g 2111618DNAHomo sapiens 116aaaacagaaa aaccggtg 1811716DNAHomo sapiens 117aaatcagtgg ccgcta 1611817DNAHomo sapiens 118agttagaaaa gggtcac 1711916DNAHomo sapiens 119tgagccttcg ttctca 1612017DNAHomo sapiens 120aggcaaatgg catacgt 1712115DNAHomo sapiens 121ggcctctcca acccg 1512217DNAHomo sapiens 122gagcaggatt gtgaaaa 1712321DNAHomo sapiens 123tcttcaacca gtgagagaaa a 2112420DNAHomo sapiens 124attatattga tgatatttta 2012515DNAHomo sapiens 125aacgaaagat aaatt 1512615DNAHomo sapiens 126tgactgttat acatt 1512716DNAHomo sapiens 127ttcattattt agggat 1612819DNAHomo sapiens 128agatagaaaa tagaaaaat 1912915DNAHomo sapiens 129attattcaaa atact 1513016DNAHomo sapiens 130aataacaaaa ttatgt 1613115DNAHomo sapiens 131agacaaaata gttgt 1513217DNAHomo sapiens 132tccctttaac caaggaa 1713315DNAHomo sapiens 133aaaagaatga gtcat 1513415DNAHomo sapiens 134cagtatcact tgact 1513523DNAHomo sapiens 135ttttaatcag tctattaaca ttg 2313616DNAHomo sapiens 136aaaggatatt gagaga 1613716DNAHomo sapiens 137cctaatcaaa tacatt 1613815DNAHomo sapiens 138cgctgtttaa tttgt 1513916DNAHomo sapiens 139tgcattcatg gaagca 1614015DNAHomo sapiens 140actcaggagg caaga 1514116DNAHomo sapiens 141ttaagagaca tttatt 1614216DNAHomo sapiens 142taaagcagtt caaaaa 1614315DNAHomo sapiens 143aataggaatt ctcta 1514416DNAHomo sapiens 144aaagctcaat tggtta 1614516DNAHomo sapiens 145acggacgatc atttaa 16146666PRTHomo sapiens 146Met Gly Gln Thr Lys Ser Lys Ile Lys Ser Lys Tyr Ala Ser Tyr Leu1 5 10 15Ser Phe Ile Lys Ile Leu Leu Lys Arg Gly Gly Val Lys Val Ser Thr 20 25 30Lys Asn Leu Ile Lys Leu Phe Gln Ile Ile Glu Gln Phe Cys Pro Trp 35 40 45Phe Pro Glu Gln Gly Thr Leu Asp Leu Lys Asp Trp Lys Arg Ile Gly 50 55 60Lys Glu Leu Lys Gln Ala Gly Arg Lys Gly Asn Ile Ile Pro Leu Thr65 70 75 80Val Trp Asn Asp Trp Ala Ile Ile Lys Ala Ala Leu Glu Pro Phe Gln 85 90 95Thr Glu Glu Asp Ser Val Ser Val Ser Asp Ala Pro Gly Ser Cys Ile 100 105 110Ile Asp Cys Asn Glu Asn Thr Gly Lys Lys Ser Gln Lys Glu Thr Glu 115 120 125Gly Leu His Cys Glu Tyr Val Ala Glu Pro Val Met Ala Gln Ser Thr 130 135 140Gln Asn Val Asp Tyr Asn Gln Leu Gln Glu Val Ile Tyr Pro Glu Thr145 150 155 160Leu Lys Leu Glu Gly Lys Gly Pro Glu Leu Val Gly Pro Ser Glu Ser 165 170 175Lys Pro Arg Gly Thr Ser Pro Leu Pro Ala Gly Gln Val Pro Val Thr 180 185 190Leu Gln Pro Gln Lys Gln Val Lys Glu Asn Lys Thr Gln Pro Pro Val 195 200 205Ala Tyr Gln Tyr Trp Pro Pro Ala Glu Leu Gln Tyr Arg Pro Pro Pro 210 215 220Glu Ser Gln Tyr Gly Tyr Pro Gly Met Pro Pro Ala Pro Gln Gly Arg225 230 235 240Ala Pro Tyr Pro Gln Pro Pro Thr Arg Arg Leu Asn Pro Thr Ala Pro 245 250 255Pro Ser Arg Gln Gly Ser Lys Leu His Glu Ile Ile Asp Lys Ser Arg 260 265 270Lys Glu Gly Asp Thr Glu Ala Trp Gln Phe Pro Val Thr Leu Glu Pro 275 280 285Met Pro Pro Gly Glu Gly Ala Gln Glu Gly Glu Pro Pro Thr Val Glu 290 295 300Ala Arg Tyr Lys Ser Phe Ser Ile Lys Lys Leu Lys Asp Met Lys Glu305 310 315 320Gly Val Lys Gln Tyr Gly Pro Asn Ser Pro Tyr Met Arg Thr Leu Leu 325 330 335Asp Ser Ile Ala His Gly His Arg Leu Ile Pro Tyr Asp Trp Glu Ile 340 345 350Gln Ala Lys Ser Ser Leu Ser Pro Ser Gln Phe Leu Gln Phe Lys Thr 355 360 365Trp Trp Ile Asp Gly Val Gln Glu Gln Val Arg Arg Asn Arg Ala Ala 370 375 380Asn Pro Pro Val Asn Ile Asp Ala Asp Gln Leu Leu Gly Ile Gly Gln385 390 395 400Asn Trp Ser Thr Ile Ser Gln Gln Ala Leu Met Gln Asn Glu Ala Ile 405 410 415Glu Gln Val Arg Ala Ile Cys Leu Arg Ala Trp Glu Lys Ile Gln Asp 420 425 430Pro Gly Ser Thr Cys Pro Ser Phe Asn Thr Val Arg Gln Gly Ser Lys 435 440 445Glu Pro Tyr Pro Asp Phe Val Ala Arg Leu Gln Asp Val Ala Gln Lys 450 455 460Ser Ile Ala Asp Glu Lys Ala Arg Lys Val Ile Val Glu Leu Met Ala465 470 475 480Tyr Glu Asn Ala Asn Pro Glu Cys Gln Ser Ala Ile Lys Pro Leu Lys 485 490 495Gly Lys Val Pro Ala Gly Ser Asp Val Ile Ser Glu Tyr Val Lys Ala 500 505 510Cys Asp Gly Ile Gly Gly Ala Met His Lys Ala Met Leu Met Ala Gln 515 520 525Ala Ile Thr Gly Val Val Leu Gly Gly Gln Val Arg Thr Phe Gly Arg 530 535 540Lys Cys Tyr Asn Cys Gly Gln Ile Gly His Leu Lys Lys Asn Cys Pro545 550 555 560Val Leu Asn Lys Gln Asn Ile Thr Ile Gln Ala Thr Thr Thr Gly Arg 565 570 575Glu Pro Pro Asp Leu Cys Pro Arg Cys Lys Lys Gly Lys His Trp Ala 580 585 590Ser Gln Cys Arg Ser Lys Phe Asp Lys Asn Gly Gln Pro Leu Ser Gly 595 600 605Asn Glu Gln Arg Gly Gln Pro Gln Ala Pro Gln Gln Thr Gly Ala Phe 610 615 620Pro Ile Gln Pro Phe Val Pro Gln Gly Phe Gln Gly Gln Gln Pro Pro625 630 635 640Leu Ser Gln Val Phe Gln Gly Ile Ser Gln Leu Pro Gln Tyr Asn Asn 645 650 655Cys Pro Pro Pro Gln Ala Ala Val Gln Gln 660 665147333PRTHomo sapiens 147Trp Ala Thr Ile Val Gly Lys Arg Ala Lys Gly Pro Ala Ser Gly Pro1 5 10 15Thr Thr Asn Trp Gly Ile Pro Asn Ser Ala Ile Cys Ser Ser Gly Phe 20 25 30Ser Gly Thr Thr Thr Pro Thr Val Pro Ser Val Ser Gly Asn Lys Pro 35 40 45Val Thr Thr Ile Gln Gln Leu Ser Pro Ala Thr Ser Gly Ser Ala Ala 50 55 60Val Asp Leu Cys Thr Ile Gln Ala Val Ser Leu Leu Pro Gly Glu Pro65 70 75 80Pro Gln Lys Thr Pro Thr Gly Val Tyr Gly Pro Leu Pro Lys Gly Thr 85 90 95Val Gly Leu Ile Leu Gly Arg Ser Ser Leu Asn Leu Lys Gly Val Gln 100 105 110Ile His Thr Ser Val Val Asp Ser Asp Tyr Lys Gly Glu Ile Gln Leu 115 120 125Val Ile Ser Ser Ser Ile Pro Trp Ser Ala Ser Pro Arg Asp Arg Ile 130 135 140Ala Gln Leu Leu Leu Leu Pro Tyr Ile Lys Gly Gly Asn Ser Glu Ile145 150 155 160Lys Arg Ile Gly Gly Leu Gly Ser Thr Asp Pro Thr Gly Lys Ala Ala 165 170 175Tyr Trp Ala Ser Gln Val Ser

Glu Asn Arg Pro Val Cys Lys Ala Ile 180 185 190Ile Gln Gly Lys Gln Phe Glu Gly Leu Val Asp Thr Gly Ala Asp Val 195 200 205Ser Ile Ile Ala Leu Asn Gln Trp Pro Lys Asn Trp Pro Lys Gln Lys 210 215 220Ala Val Thr Gly Leu Val Gly Ile Gly Thr Ala Ser Glu Val Tyr Gln225 230 235 240Ser Thr Glu Ile Leu His Cys Leu Gly Pro Asp Asn Gln Glu Ser Thr 245 250 255Val Gln Pro Met Ile Thr Ser Ile Pro Leu Asn Leu Trp Gly Arg Asp 260 265 270Leu Leu Gln Gln Trp Gly Ala Glu Ile Thr Met Pro Ala Pro Ser Tyr 275 280 285Ser Pro Thr Ser Gln Lys Ile Met Thr Lys Met Gly Tyr Ile Pro Gly 290 295 300Lys Gly Leu Gly Lys Asn Glu Asp Gly Ile Lys Ile Pro Val Glu Ala305 310 315 320Lys Ile Asn Gln Glu Arg Glu Gly Ile Gly Asn Pro Cys 325 330148956PRTHomo sapiens 148Asn Lys Ser Arg Lys Arg Arg Asn Arg Glu Ser Leu Leu Gly Ala Ala1 5 10 15Thr Val Glu Pro Pro Lys Pro Ile Pro Leu Thr Trp Lys Thr Glu Lys 20 25 30Pro Val Trp Val Asn Gln Trp Pro Leu Pro Lys Gln Lys Leu Glu Ala 35 40 45Leu His Leu Leu Ala Asn Glu Gln Leu Glu Lys Gly His Ile Glu Pro 50 55 60Ser Phe Ser Pro Trp Asn Ser Pro Val Phe Val Ile Gln Lys Lys Ser65 70 75 80Gly Lys Trp Arg Met Leu Thr Asp Leu Arg Ala Val Asn Ala Val Ile 85 90 95Gln Pro Met Gly Pro Leu Gln Pro Gly Leu Pro Ser Pro Ala Met Ile 100 105 110Pro Lys Asp Trp Pro Leu Ile Ile Ile Asp Leu Lys Asp Cys Phe Phe 115 120 125Thr Ile Pro Leu Ala Glu Gln Asp Cys Glu Lys Phe Ala Phe Thr Ile 130 135 140Pro Ala Ile Asn Asn Lys Glu Pro Ala Thr Arg Phe Gln Trp Lys Val145 150 155 160Leu Pro Gln Gly Met Leu Asn Ser Pro Thr Ile Cys Gln Thr Phe Val 165 170 175Gly Arg Ala Leu Gln Pro Val Arg Glu Lys Phe Ser Asp Cys Tyr Ile 180 185 190Ile His Cys Ile Asp Asp Ile Leu Cys Ala Ala Glu Thr Lys Asp Lys 195 200 205Leu Ile Asp Cys Tyr Thr Phe Leu Gln Ala Glu Val Ala Asn Ala Gly 210 215 220Leu Ala Ile Ala Ser Asp Lys Ile Gln Thr Ser Thr Pro Phe His Tyr225 230 235 240Leu Gly Met Gln Ile Glu Asn Arg Lys Ile Lys Pro Gln Lys Ile Glu 245 250 255Ile Arg Lys Asp Thr Leu Lys Thr Leu Asn Asp Phe Gln Lys Leu Leu 260 265 270Gly Asp Ile Asn Trp Ile Arg Pro Thr Leu Gly Ile Pro Thr Tyr Ala 275 280 285Met Ser Asn Leu Phe Ser Ile Leu Arg Gly Asp Ser Asp Leu Asn Ser 290 295 300Lys Arg Met Leu Thr Pro Glu Ala Thr Lys Glu Ile Lys Leu Val Glu305 310 315 320Glu Lys Ile Gln Ser Ala Gln Ile Asn Arg Ile Asp Pro Leu Ala Pro 325 330 335Leu Gln Leu Leu Ile Phe Ala Thr Ala His Ser Pro Thr Gly Ile Ile 340 345 350Ile Gln Asn Thr Asp Leu Val Glu Trp Ser Phe Leu Pro His Ser Thr 355 360 365Val Lys Thr Phe Thr Leu Tyr Leu Asp Gln Ile Ala Thr Leu Ile Gly 370 375 380Gln Thr Arg Leu Arg Ile Ile Lys Leu Cys Gly Asn Asp Pro Asp Lys385 390 395 400Ile Val Val Pro Leu Thr Lys Glu Gln Val Arg Gln Ala Phe Ile Asn 405 410 415Ser Gly Ala Trp Lys Ile Gly Leu Ala Asn Phe Val Gly Ile Ile Asp 420 425 430Asn His Tyr Pro Lys Thr Lys Ile Phe Gln Phe Leu Lys Leu Thr Thr 435 440 445Trp Ile Leu Pro Lys Ile Thr Arg Arg Glu Pro Leu Glu Asn Ala Leu 450 455 460Thr Val Phe Thr Asp Gly Ser Ser Asn Gly Lys Ala Ala Tyr Thr Gly465 470 475 480Pro Lys Glu Arg Val Ile Lys Thr Pro Tyr Gln Ser Ala Gln Arg Ala 485 490 495Glu Leu Val Ala Val Ile Thr Val Leu Gln Asp Phe Asp Gln Pro Ile 500 505 510Asn Ile Ile Ser Asp Ser Ala Tyr Val Val Gln Ala Thr Arg Asp Val 515 520 525Glu Thr Ala Leu Ile Lys Tyr Ser Met Asp Asp Gln Leu Asn Gln Leu 530 535 540Phe Asn Leu Leu Gln Gln Thr Val Arg Lys Arg Asn Phe Pro Phe Tyr545 550 555 560Ile Thr His Ile Arg Ala His Thr Asn Leu Pro Gly Pro Leu Thr Lys 565 570 575Ala Asn Glu Gln Ala Asp Leu Leu Val Ser Ser Ala Leu Ile Lys Ala 580 585 590Gln Glu Leu His Ala Leu Thr His Val Asn Ala Ala Gly Leu Lys Asn 595 600 605Lys Phe Asp Val Thr Trp Lys Gln Ala Lys Asp Ile Val Gln His Cys 610 615 620Thr Gln Cys Gln Val Leu His Leu Pro Thr Gln Glu Ala Gly Val Asn625 630 635 640Pro Arg Gly Leu Cys Pro Asn Ala Leu Trp Gln Met Asp Val Thr His 645 650 655Val Pro Ser Phe Gly Arg Leu Ser Tyr Val His Val Thr Val Asp Thr 660 665 670Tyr Ser His Phe Ile Trp Ala Thr Cys Gln Thr Gly Glu Ser Thr Ser 675 680 685His Val Lys Lys His Leu Leu Ser Cys Phe Ala Val Met Gly Val Pro 690 695 700Glu Lys Ile Lys Thr Asp Asn Gly Pro Gly Tyr Cys Ser Lys Ala Phe705 710 715 720Gln Lys Phe Leu Ser Gln Trp Lys Ile Ser His Thr Thr Gly Ile Pro 725 730 735Tyr Asn Ser Gln Gly Gln Ala Ile Val Glu Arg Thr Asn Arg Thr Leu 740 745 750Lys Thr Gln Leu Val Lys Gln Lys Glu Gly Gly Asp Ser Lys Glu Cys 755 760 765Thr Thr Pro Gln Met Gln Leu Asn Leu Ala Leu Tyr Thr Leu Asn Phe 770 775 780Leu Asn Ile Tyr Arg Asn Gln Thr Thr Thr Ser Ala Glu Gln His Leu785 790 795 800Thr Gly Lys Lys Asn Ser Pro His Glu Gly Lys Leu Ile Trp Trp Lys 805 810 815Asp Asn Lys Asn Lys Thr Trp Glu Ile Gly Lys Val Ile Thr Trp Gly 820 825 830Arg Gly Phe Ala Cys Val Ser Pro Gly Glu Asn Gln Leu Pro Val Trp 835 840 845Ile Pro Thr Arg His Leu Lys Phe Tyr Asn Glu Pro Ile Arg Asp Ala 850 855 860Lys Lys Ser Thr Ser Ala Glu Thr Glu Thr Ser Gln Ser Ser Thr Val865 870 875 880Asp Ser Gln Asp Glu Gln Asn Gly Asp Val Arg Arg Thr Asp Glu Val 885 890 895Ala Ile His Gln Glu Gly Arg Ala Ala Asn Leu Gly Thr Thr Lys Glu 900 905 910Ala Asp Ala Val Ser Tyr Lys Ile Ser Arg Glu His Lys Gly Asp Thr 915 920 925Asn Pro Arg Glu Tyr Ala Ala Cys Ser Leu Asp Asp Cys Ile Asn Gly 930 935 940Gly Lys Ser Pro Tyr Ala Cys Arg Ser Ser Cys Ser945 950 955149699PRTHomo sapiens 149Met Asn Pro Ser Glu Met Gln Arg Lys Ala Pro Pro Arg Arg Arg Arg1 5 10 15His Arg Asn Arg Ala Pro Leu Thr His Lys Met Asn Lys Met Val Thr 20 25 30Ser Glu Glu Gln Met Lys Leu Pro Ser Thr Lys Lys Ala Glu Pro Pro 35 40 45Thr Trp Ala Gln Leu Lys Lys Leu Thr Gln Leu Ala Thr Lys Tyr Leu 50 55 60Glu Asn Thr Lys Val Thr Gln Thr Pro Glu Ser Met Leu Leu Ala Ala65 70 75 80Leu Met Ile Val Ser Met Val Val Ser Leu Pro Met Pro Ala Gly Ala 85 90 95Ala Ala Ala Asn Tyr Thr Tyr Trp Ala Tyr Val Pro Phe Pro Pro Leu 100 105 110Ile Arg Ala Val Thr Trp Met Asp Asn Pro Thr Glu Val Tyr Val Asn 115 120 125Asp Ser Val Trp Val Pro Gly Pro Ile Asp Asp Arg Cys Pro Ala Lys 130 135 140Pro Glu Glu Glu Gly Met Met Ile Asn Ile Ser Ile Gly Tyr His Tyr145 150 155 160Pro Pro Ile Cys Leu Gly Arg Ala Pro Gly Cys Leu Met Pro Ala Val 165 170 175Gln Asn Trp Leu Val Glu Val Pro Thr Val Ser Pro Ile Cys Arg Phe 180 185 190Thr Tyr His Met Val Ser Gly Met Ser Leu Arg Pro Arg Val Asn Tyr 195 200 205Leu Gln Asp Phe Ser Tyr Gln Arg Ser Leu Lys Phe Arg Pro Lys Gly 210 215 220Lys Pro Cys Pro Lys Glu Ile Pro Lys Glu Ser Lys Asn Thr Glu Val225 230 235 240Leu Val Trp Glu Glu Cys Val Ala Asn Ser Ala Val Ile Leu Gln Asn 245 250 255Asn Glu Phe Gly Thr Ile Ile Asp Trp Ala Pro Arg Gly Gln Phe Tyr 260 265 270His Asn Cys Ser Gly Gln Thr Gln Ser Cys Pro Ser Ala Gln Val Ser 275 280 285Pro Ala Val Asp Ser Asp Leu Thr Glu Ser Leu Asp Lys His Lys His 290 295 300Lys Lys Leu Gln Ser Phe Tyr Pro Trp Glu Trp Gly Glu Lys Gly Ile305 310 315 320Ser Thr Pro Arg Pro Lys Ile Val Ser Pro Val Ser Gly Pro Glu His 325 330 335Pro Glu Leu Trp Arg Leu Thr Val Ala Ser His His Ile Arg Ile Trp 340 345 350Ser Gly Asn Gln Thr Leu Glu Thr Arg Asp Arg Lys Pro Phe Tyr Thr 355 360 365Ile Asp Leu Asn Ser Ser Leu Thr Val Pro Leu Gln Ser Cys Val Lys 370 375 380Pro Pro Tyr Met Leu Val Val Gly Asn Ile Val Ile Lys Pro Asp Ser385 390 395 400Gln Thr Ile Thr Cys Glu Asn Cys Arg Leu Leu Thr Cys Ile Asp Ser 405 410 415Thr Phe Asn Trp Gln His Arg Ile Leu Leu Val Arg Ala Arg Glu Gly 420 425 430Val Trp Ile Pro Val Ser Met Asp Arg Pro Trp Glu Ala Ser Pro Ser 435 440 445Val His Ile Leu Thr Glu Val Leu Lys Gly Val Leu Asn Arg Ser Lys 450 455 460Arg Phe Ile Phe Thr Leu Ile Ala Val Ile Met Gly Leu Ile Ala Val465 470 475 480Thr Ala Thr Ala Ala Val Ala Gly Val Ala Leu His Ser Ser Val Gln 485 490 495Ser Val Asn Phe Val Asn Asp Trp Gln Lys Asn Ser Thr Arg Leu Trp 500 505 510Asn Ser Gln Ser Ser Ile Asp Gln Lys Leu Ala Asn Gln Ile Asn Asp 515 520 525Leu Arg Gln Thr Val Ile Trp Met Gly Asp Arg Leu Met Ser Leu Glu 530 535 540His Arg Phe Gln Leu Gln Cys Asp Trp Asn Thr Ser Asp Phe Cys Ile545 550 555 560Thr Pro Gln Ile Tyr Asn Glu Ser Glu His His Trp Asp Met Val Arg 565 570 575Arg His Leu Gln Gly Arg Glu Asp Asn Leu Thr Leu Asp Ile Ser Lys 580 585 590Leu Lys Glu Gln Ile Phe Glu Ala Ser Lys Ala His Leu Asn Leu Val 595 600 605Pro Gly Thr Glu Ala Ile Ala Gly Val Ala Asp Gly Leu Ala Asn Leu 610 615 620Asn Pro Val Thr Trp Val Lys Thr Ile Gly Ser Thr Thr Ile Ile Asn625 630 635 640Leu Ile Leu Ile Leu Val Cys Leu Phe Cys Leu Leu Leu Val Cys Arg 645 650 655Cys Thr Gln Gln Leu Arg Arg Asp Ser Asp His Arg Glu Arg Ala Met 660 665 670Met Thr Met Ala Val Leu Ser Lys Arg Lys Gly Gly Asn Val Gly Lys 675 680 685Ser Lys Arg Asp Gln Ile Val Thr Val Ser Val 690 695150968DNAHomo sapiens 150tgtggggaaa agcaagagag atcagattgt tactgtgtct gtgtagaaag aagtagacat 60aggagactcc attttgttat gtactaagaa aaattcttct gccttgagat tctgttaatc 120tatgacctta cccccaaccc cgtgctctct gaaacatgtg ctgtgtccac tcagggttaa 180atggattaag ggcggtgcag gatgtgcttt gttaaacaga tgcttgaagg cagcatgctc 240cttaagagtc atcaccactc cctaatctca agtacccagg gacacaaaaa ctgcggaagg 300ccgcagggac ctctgcctag gaaagccagg tattgtccaa cgtttctccc catgtgatag 360cctgaaatat ggcctcgtgg gaagggaaag acctgaccgt cccccagccc gacacccgta 420aagggtctgt gctgaggagg attagtaaaa gaggaaggaa tgcctcttgc agttgagaca 480agaggaaggc atctgtctcc tgcctgtccc tgggcaatgg aatgtctcgg tataaaaccc 540gattgtatgc tccatctact gagataggga aaaaccgcct tagggctgga ggtgggacct 600gcgggcagca atactgcttt gtaaagcact gagatgttta tgtgtatgca tatctaaaag 660cacagcactt aatcctttac attgtctatg atgcaaagac ctttgttcac atgtttgtct 720gctgaccctc tccccacaat tgtcttgtga ccctgacaca tccccctctt cgagaaacac 780ccacagatga tcagtaaata ctaagggaac tcagaggctg gcgggatcct ccatatgctg 840aacgctggtt ccccgggtcc ccttctttct ttctctatac tttgtctctg tgtctttttc 900ttttccaaat ctctcgtccc accttacgag aaacacccac aggtgtgtag gggcaaccca 960cccctaca 968151962DNAHomo sapiens 151tgtggggaaa agcaagagag atcagattgt cactgtatct gtgtagaaag aagtagacat 60gggagactcc attttgttat gtactaagaa aaattcttct gccttgagat tctgtgacct 120tacccccaac cccgtgctct ctgaaacatg tgctgtgtca aactcagggt taaatggatt 180aagggcggtg caggatgtgc tttgttaaac agatgcttga aggcagcatg ctccttaaga 240gtcatcacca ctccctaatc tcaagtaccc agggacacaa acactgcgga aggccgcagg 300gacctctgcc taggaaagcc aggtattgtc caaggtttct ccccatgtga tagtctgaaa 360tatggcctcg tgggaaggga aagacctgac cgtcccccag cccgacaccc gtaaagggtc 420tgtgctgagg aggattagta aaagaggaag gcatgcctct tgcagttgag acaagaggaa 480ggcatctgtc tcctgcccgt ccctgggcaa tggaatgtct cggtataaaa ccggattgta 540cgttccatct actgagatag ggaaaaaccg ccttagggct ggaggtggga cctgcgggca 600gcaatactgc tttttaaagc attgagatgt ttatgtgtat gcatatctaa aagcacagca 660cttaatcctt taccttgtct atgatgcaaa gatctttgtt cacgtgtttg tctgctgacc 720ctctccccac tattgtcttg tgaccctgac acatccccct ctcggagaaa cacccacgaa 780tgaccaataa atactaaagg gaactcagag gctggcggga tcctccatat gctgaacgct 840ggttccccgg gcccccttat ttctttctct acactttgtc tctgtgtctt tttctttcct 900aagtctctcg ttccacctta cgagaaacac ccacaggtgt ggaggggcaa cccaccccta 960ca 962152968DNAHomo sapiens 152tgtggggaaa agcaagagag atcagattgt tactgtgtct gtgtagaaag aagtagacat 60gggagactcc attttgttat gtgctaagaa aaattcttct gccttgagat tctgttaatc 120tatgacctta cccccaaccc cgtgctctct gaaacatgtg ctgtgtcaac tcagggttga 180atggattaag ggcggtgcag gatgtgcttt gttaaacaga tgcttgaagg cagcatgctc 240cttaagagtc atcaccactc cctaatctca agtacccagg gacacaaaaa ctgcggaagg 300ccgcagggac ctctgcctag gaaagccagg tattgtccaa ggtttctccc catgtgatag 360tctgaaatat ggcctcgtgg gaagggaaag acctgaccat cccccagccc gacacccata 420aagggtctgt gctgaggagg attagtataa gaggaaggca tgcctcttgc agttgagaca 480agaggaaggc atctgtctcc tgcctgtccc tgggcaatgg aatgtctcgg tataaaaccc 540gattgtatgc tccatctact gagataggga aaaaccgcct tagggctgga ggtgggacct 600gcgggcagca atactgcctt gtaaagcatt gagatgttta tgtgtatgca tatctaaaag 660cacagcactt aatcctttac attgtctatg atgcaaagac ctttgttcac gtgtttgtct 720gctgaccctc tccccacaat tgtcttgtga ccctgacaca tccccctctt tgagaaacac 780ccacagatga tcaataaata ctaagggaac tcagaggctg gcgggatcct ccatatgctg 840aacgctggtt ccccggttcc ccttatttct ttctctatac tttgtctctg tgtctttttc 900ttttccaaat ctctcgtccc accttacgag aaacacccac aggtgtgtag gggcaaccca 960cccctaca 968153968DNAHomo sapiens 153tgtggggaaa agcaagagag atcagattgt tacagtgtct gtgtagaaag aagtagacat 60aggagactcc attttgttct gtactaagaa aaattcttct gccttgaaat tctgttaatc 120tataacctta cccccaaccc cgtgctcttt gaaacatgtg ctgtgtcaac tcagagttaa 180atggattaag tgcggtgcaa gatgtgcttt gttaaacaga tgcttgaagg cagcatgctc 240cttgagagtc atcaccactc cctaatctca agtacccagg gacacaaaaa ctgcggaagg 300cctcagggac ctctgcctag gaaagccagg tattgtccaa ggtttctccc catgtgatag 360tctgaaatat ggcctcgtgg gaagggaaag acctgaccat cccccagccc gacacccgta 420aagggtctgt gctgaggagg attagtaaaa gaggaaggaa cgcctcttgc agttgagaca 480agaggaaggc atctgtctcc tgcctgtccc tgggcaatgg aatgtcccgg tataaaaccc 540gattgtatgc tccatctact gagataggga aaaaccgcct tagggctgga ggtgggacct 600gcgggcagca atactgcttt gtaaagcatt gagctgttta tgtgtatgca tatctaaaag 660cacagcactt aatcctttac attgtctatg atgcaaagac ctttgttcac gtgtttgtct 720gctgaccctc tccccacaat tgtcttgtga ccctgacaca tccccctctt cgagaaacac 780ccacgaatga tgaataaata ctaagggaac tcagaggctg gcgggatcct ccatatgctg 840aacgctggtt ccccgggtcc ccttacttct ttctctgtac tttgtctctg

tgtctttttc 900tttcctaagt ctctcgttcc accttacgag aaatacccac aggtgtggag gggcaaccca 960cccctaca 968154968DNAHomo sapiens 154tgtggggaaa agcaagagag atcagattgt tactgtgtct gtgtagaaag aagtagacat 60aggagactcc attttgttct gtactaagaa aaattcttct gccttgagat tctgttaatc 120tataacctta cccccaaccc cgtgctctct gaaacatgtg ctatgtcaac tcagagttga 180atggattaag ggcggtgcaa gatgtgcttt gttaaacaga tgcttgaagg cagcacgctc 240cttaagagtc atcaccactc cctaatctca agtacccagg gacacaaaaa ctgcggaagg 300ccgcagggac ctctgcctag gaaagccagg tattgtccaa ggtttctccc catgtgatag 360tctgaaatat ggcctcgtgg gaagggaaag acctgaccat cccccagccc gacacctgta 420aagggtctgt gctgaggagg attagtataa gaggaaggca tgcctcttgc agttgagaca 480agaggaaggc atctgtctcc tgcccgtccc tgggcaatgg aatgtctcgg tataaaaccc 540gattgtatgt tccatctact gagataggga aaaaccgcct tagggctgga ggtgggacct 600gcgggcagca atactgcttt gtaaagcatt gagatgttta tgtgtatgca tatctaaaag 660cacagcactt aatcctttac cttgtctatg atgcaaagac ctttgttcac gtgtttgtct 720gctgaccctc tccccacgat tgtcttgtga ccctgacaca tccccgtctt cgagaaacac 780ccacgaatga tcaataaata ctaagggaac tcagaggctg gcgggatcct ccatatgctg 840aacgctggtt ccccaggtcc ccttatttct ttctctatac tttgtctctg tgtctttttc 900ttttccaagt ctctcgttcc atcttacgag aaacacccac aggtgtggag gggcaaccca 960cccctaca 968155150DNAHomo sapiens 155gagataggga aaaaccgcct tagggctgga ggtgggacct gcgggcagca atactgcttt 60gtaaagcact gagatgttta tgtgtatgca tatctaaaag cacagcactt aatcctttac 120attgtctatg atgcaaagac ctttgttcac 150156258DNAHomo sapiens 156atgtttgtct gctgaccctc tccccacaat tgtcttgtga ccctgacaca tccccctctt 60cgagaaacac ccacagatga tcagtaaata ctaagggaac tcagaggctg gcgggatcct 120ccatatgctg aacgctggtt ccccgggtcc ccttctttct ttctctatac tttgtctctg 180tgtctttttc ttttccaaat ctctcgtccc accttacgag aaacacccac aggtgtgtag 240gggcaaccca cccctaca 2581572707DNAHomo sapiensmisc_feature(1)..(2707)N=A,G,C,T 157nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 60nnnacatttg aagttctaca atgaacccat cngagatgca aagaaannnn nnnnnnagcn 120cctccncgga gacggaaaca ccgcaatcga gcancnnnnn nnnnnnnnnt ngactcacaa 180gatgaanaaa atggtgannt cagaagaaca gatgaagttg ccatccacca agaangcnga 240gccgccgact tgggcacaan taaagaagct gacacagtta gctanaaaan nnnnnctnga 300gaacacaaag gtgacacaaa ctccagagan tatgctgctt gcagctttga tgattgtatc 360aatggtggta agtctcccna tgcctgcagg agcagctgca gctaantata cntactgggc 420ctatgtgcct ttcccgccct taattcgggc agtcacatgg atggataatc ctattgaagt 480atatgttaat aatagtgtat gggntacctg gccccacaga tgatcgttgc cctgccaaac 540ctgaggaaga aggaatgatg ataaatattt ccattgggta tcnttatcct cctatttgcc 600tagggagagc accaggatgt ttaatngcct gcantccaaa attggttggt agaagtacct 660actgtcagtn ccancagtag attcacttat cacatggtaa gnggnatgtc actcaggcca 720cnggtaaatn atttacanga cttttcttat caaagatcat taaaatttag ncctaaaggg 780aaaccttgcc ccaaggaaat tcccaaagna tcaaaanann cagaagtttt agtttgggaa 840gaatgtgtgg cnaatagtgc ngtgatatta caaaacaatg aatttggaac tattatagat 900tgggcacctc gaggtcaatt ctancacann nnnnnnnnnn nnnnnnnnnn nnattgcnca 960ggncaaactc antcntgtcc nagngcacaa gnnnnnnnnn nnnnnagtcc agctgttgat 1020agngacttaa cagaaagtnt agacnaannt nannntanaa nnttanantc nntctanccn 1080tggnaatggg gngaaaangg aatntcnncn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1140nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1200nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1260nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1320nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1380nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1440nnnnnnnnnn nccnngacca aanntantna gtcctgttnc tggtcctgaa catccagaat 1500tatggangct tactgtggcc tcannaccac attagaattt ggtctggaaa tcaanctnta 1560gaaacaagag atcntaagcc atnttatact atcnacctaa attccagtct nacanttcct 1620ttncaaagtt gngtaaagcc cccttatatn gctagttgta ggaaatannt agttattaaa 1680ccagantccc aaactatann acctgtgaaa attgtagatt gtttacttgc attgattcaa 1740cttttaattg gcagcaccgt attctgctng tgagagcaag aganggngtg tggatccctg 1800tgtccatgga ccgaccgtgg gaggcntcnc catccntcca tattttnacn gaagtattaa 1860aaggnnttnt aantagatcc aaaagattca tttttacttt aattgcagtg attatgggnn 1920tnattgcagt cacagctacn gctgcngnng cngganttgc nttncactcn tctgttcann 1980cngnanantn tgtnaatnat tggcaaaana anttcnncaa nattgtggaa ttcncananc 2040nnnnatngat caaaaattgg caaatcaaat taatgatctt agacaaactg tcatttggat 2100gggaganagn ctcatgagct tngaanatcn tttncagtta cantgtgact ggaatacgtc 2160agatttttgt attacaccnc aannntataa tgagtctgag catcactggg acatggttag 2220angccatcta canggaagag aagataatct nactttagac atttcnaaat taaaagaann 2280nnnnnnnnnn nncaaatttt nnaancatca aaagcccatt taaatttggt gccaggaact 2340gaggcaatng nnnnagntgc tgatggcctc ncaaatctta accctgtcac ttgggttaan 2400accatnngaa gtncnacnat tntaaatntc atattaatcc ttgtntgcct gttntgtctg 2460ttgttnnagt ctncaggtgt anccancagc tccgaagaga cagcgaccan cnagaacggg 2520ccatgatgac gatggnggtt ttgtcnaaaa gaaaaggggg nnanatgtng ggaaaagnna 2580gagagatcag antgttactg tngtctntgt agaaanangn agacatanga gactccattt 2640tgnnntgtac nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2700nnnnnnn 2707158673PRTHomo sapiensMISC_FEATURE(1)..(673)Xaa=Any amino acid 158Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 10 15Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 20 25 30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 40 45Xaa Xaa Cys Pro Trp Phe Pro Glu Gln Gly Xaa Leu Asp Leu Xaa Asp 50 55 60Trp Lys Arg Ile Gly Xaa Glu Leu Lys Gln Ala Gly Arg Lys Gly Asn65 70 75 80Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 85 90 95Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asp Ala 100 105 110Pro Gly Ser Cys Ile Ile Asp Cys Asn Glu Xaa Thr Xaa Lys Lys Ser 115 120 125Gln Lys Glu Thr Glu Xaa Leu His Cys Glu Tyr Val Xaa Xaa Xaa Xaa 130 135 140Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa145 150 155 160Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 165 170 175Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Ala Gly 180 185 190Gln Val Xaa Val Thr Leu Gln Pro Gln Xaa Gln Val Lys Glu Asn Lys 195 200 205Thr Gln Xaa Pro Val Ala Tyr Gln Tyr Trp Pro Pro Xaa Xaa Xaa Xaa 210 215 220Xaa Xaa Xaa Xaa Xaa Xaa Ser Gln Tyr Gly Tyr Xaa Gly Met Pro Pro225 230 235 240Ala Xaa Gln Xaa Arg Xaa Pro Tyr Pro Gln Pro Pro Thr Xaa Arg Xaa 245 250 255Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 260 265 270Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 275 280 285Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 290 295 300Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa305 310 315 320Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 325 330 335Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 340 345 350Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 355 360 365Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 370 375 380Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa385 390 395 400Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 405 410 415Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 420 425 430Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 435 440 445Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 450 455 460Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa465 470 475 480Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 485 490 495Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 500 505 510Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 515 520 525Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 530 535 540Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa545 550 555 560Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 565 570 575Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 580 585 590Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Cys Xaa Ser Lys Phe Asp Lys Xaa 595 600 605Gly Gln Pro Leu Ser Gly Asn Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 610 615 620Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa625 630 635 640Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 645 650 655Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 660 665 670Xaa1591035PRTHomo sapiensMISC_FEATURE(1)..(1035)Xaa=Any amino acid 159Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 10 15Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 20 25 30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 40 45Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 50 55 60Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa65 70 75 80Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 85 90 95Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 100 105 110Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 115 120 125Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 130 135 140Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa145 150 155 160Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 165 170 175Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 180 185 190Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 195 200 205Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 210 215 220Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa225 230 235 240Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asp Xaa Leu Ala Pro Leu 245 250 255Gln Leu Leu Ile Phe Ala Thr Ala His Ser Xaa Thr Gly Ile Ile Ile 260 265 270Gln Asn Thr Asp Leu Val Glu Trp Ser Phe Leu Pro His Ser Thr Val 275 280 285Lys Thr Phe Thr Leu Tyr Leu Asp Gln Met Ala Thr Leu Ile Gly Gln 290 295 300Xaa Arg Leu Arg Ile Ile Xaa Leu Cys Gly Asn Asp Pro Asp Lys Ile305 310 315 320Xaa Val Pro Xaa Xaa Lys Xaa Gln Val Arg Gln Ala Phe Ile Xaa Ser 325 330 335Gly Ala Trp Xaa Ile Gly Leu Ala Asn Phe Leu Gly Ile Ile Asp Asn 340 345 350His Tyr Pro Lys Thr Lys Ile Phe Gln Phe Leu Lys Leu Thr Thr Trp 355 360 365Ile Leu Pro Lys Ile Thr Arg Arg Glu Pro Leu Glu Asn Ala Leu Thr 370 375 380Val Phe Thr Asp Gly Ser Ser Asn Gly Lys Ala Ala Tyr Thr Gly Pro385 390 395 400Lys Glu Arg Val Ile Lys Thr Pro Tyr Gln Ser Ala Gln Arg Ala Glu 405 410 415Leu Val Ala Val Ile Thr Val Leu Gln Asp Phe Asp Gln Pro Ile Asn 420 425 430Ile Ile Ser Asp Ser Ala Tyr Val Val Gln Ala Thr Arg Asp Val Glu 435 440 445Thr Ala Leu Ile Lys Tyr Ser Xaa Asp Asp Xaa Leu Asn Gln Leu Phe 450 455 460Asn Leu Leu Gln Gln Thr Val Arg Lys Arg Asn Phe Pro Phe Tyr Ile465 470 475 480Thr His Ile Arg Ala His Thr Asn Leu Pro Gly Pro Leu Thr Lys Ala 485 490 495Asn Glu Gln Ala Asp Leu Leu Val Ser Ser Ala Xaa Ile Lys Ala Gln 500 505 510Glu Leu Xaa Ala Leu Thr His Val Asn Ala Ala Gly Leu Lys Asn Lys 515 520 525Phe Asp Val Thr Trp Lys Gln Ala Lys Asp Ile Val Gln His Cys Thr 530 535 540Gln Cys Gln Val Leu His Leu Xaa Thr Gln Glu Ala Gly Val Asn Pro545 550 555 560Arg Gly Leu Cys Pro Asn Ala Leu Trp Gln Met Asp Xaa Thr His Val 565 570 575Xaa Ser Phe Gly Arg Leu Ser Tyr Val His Val Thr Val Asp Thr Tyr 580 585 590Ser His Phe Ile Trp Ala Thr Cys Gln Thr Gly Glu Ser Thr Ser His 595 600 605Val Lys Lys His Leu Leu Ser Cys Phe Ala Val Met Gly Val Pro Glu 610 615 620Lys Ile Lys Thr Asp Asn Gly Pro Gly Tyr Cys Ser Lys Ala Phe Gln625 630 635 640Lys Phe Leu Ser Gln Trp Lys Ile Ser His Thr Thr Gly Ile Pro Tyr 645 650 655Asn Ser Gln Gly Gln Ala Ile Val Glu Arg Thr Asn Arg Thr Leu Lys 660 665 670Thr Gln Leu Val Lys Gln Lys Glu Gly Gly Asp Ser Lys Glu Cys Thr 675 680 685Thr Pro Gln Met Gln Leu Asn Leu Ala Leu Tyr Thr Leu Asn Phe Leu 690 695 700Asn Ile Tyr Arg Asn Gln Thr Thr Thr Ser Ala Xaa Gln His Leu Thr705 710 715 720Gly Lys Lys Xaa Ser Pro His Glu Gly Lys Leu Ile Trp Trp Lys Asp 725 730 735Xaa Lys Asn Lys Thr Trp Glu Ile Gly Lys Val Ile Thr Trp Gly Arg 740 745 750Gly Phe Ala Cys Val Ser Pro Gly Glu Asn Gln Leu Pro Val Trp Ile 755 760 765Pro Thr Arg His Leu Lys Phe Tyr Asn Glu Pro Ile Xaa Asp Ala Lys 770 775 780Lys Xaa Xaa Ser Xaa Glu Xaa Xaa Thr Xaa Xaa Xaa Xaa Xaa Xaa Xaa785 790 795 800Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 805 810 815Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 820 825 830Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 835 840 845Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 850 855 860Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa865 870 875 880Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 885 890 895Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 900 905 910Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 915 920 925Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Thr Ile Xaa Xaa Xaa 930 935 940Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa945 950 955 960Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Ala Xaa Xaa Xaa Asp Xaa Xaa Xaa 965 970 975Xaa Xaa Xaa Lys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Pro Xaa 980 985 990Glu Trp Gly Xaa Xaa Xaa Ile Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Ser 995 1000 1005Pro Xaa Ser Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1010 1015 1020Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1025 1030

10351601081PRTHomo sapiensMISC_FEATURE(1)..(1081)Xaa=Any amino acid 160Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 10 15Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 20 25 30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 40 45Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 50 55 60Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa65 70 75 80Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 85 90 95Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 100 105 110Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 115 120 125Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 130 135 140Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa145 150 155 160Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 165 170 175Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 180 185 190Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 195 200 205Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 210 215 220Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa225 230 235 240Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 245 250 255Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 260 265 270Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 275 280 285Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 290 295 300Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa305 310 315 320Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 325 330 335Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 340 345 350Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 355 360 365Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 370 375 380Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa385 390 395 400Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 405 410 415Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 420 425 430Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 435 440 445Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 450 455 460Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa465 470 475 480Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Ile Xaa 485 490 495Xaa Val Thr Trp Met Asp Asn Pro Xaa Glu Val Tyr Val Asn Asp Ser 500 505 510Val Trp Val Pro Gly Pro Xaa Asp Asp Xaa Cys Pro Ala Lys Pro Glu 515 520 525Glu Glu Gly Met Met Ile Asn Ile Ser Ile Xaa Tyr Xaa Tyr Pro Pro 530 535 540Ile Cys Leu Gly Arg Ala Pro Gly Cys Leu Met Pro Ala Val Gln Asn545 550 555 560Trp Leu Val Glu Val Pro Thr Val Ser Pro Xaa Xaa Arg Phe Thr Tyr 565 570 575His Met Val Ser Gly Met Ser Leu Arg Pro Arg Val Asn Xaa Leu Gln 580 585 590Asp Phe Ser Tyr Gln Arg Ser Leu Lys Phe Arg Pro Lys Gly Lys Pro 595 600 605Cys Pro Lys Glu Ile Pro Lys Glu Ser Lys Asn Thr Glu Val Leu Val 610 615 620Trp Glu Glu Cys Val Ala Asn Ser Xaa Val Ile Leu Gln Asn Asn Glu625 630 635 640Phe Gly Thr Ile Ile Asp Trp Ala Pro Arg Gly Gln Phe Tyr His Asn 645 650 655Cys Ser Gly Gln Thr Gln Ser Cys Xaa Ser Ala Gln Val Ser Pro Ala 660 665 670Val Asp Ser Asp Leu Thr Glu Ser Leu Asp Lys His Lys His Lys Lys 675 680 685Leu Gln Ser Phe Tyr Pro Trp Glu Trp Gly Glu Lys Gly Ile Ser Thr 690 695 700Pro Arg Pro Xaa Ile Ile Ser Pro Val Ser Gly Pro Glu His Pro Glu705 710 715 720Leu Trp Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Arg Ile Xaa Xaa Xaa 725 730 735Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 740 745 750Leu Asn Ser Xaa Leu Thr Val Pro Leu Gln Ser Cys Val Lys Pro Xaa 755 760 765Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 770 775 780Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asp Ser Thr Xaa785 790 795 800Xaa Trp Xaa Xaa Xaa Ile Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 805 810 815Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 820 825 830Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 835 840 845Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 850 855 860Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa865 870 875 880Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 885 890 895Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 900 905 910Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 915 920 925Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 930 935 940Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa945 950 955 960Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 965 970 975Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 980 985 990Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 995 1000 1005Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1010 1015 1020Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Arg 1025 1030 1035Cys Thr Gln Gln Leu Arg Arg Asp Ser Asp Xaa Xaa Xaa Xaa Xaa 1040 1045 1050Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1055 1060 1065Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1070 1075 108016115DNAHomo sapiens 161taggcctttg aggga 1516217DNAHomo sapiens 162taggccttat tttaggg 1716317DNAHomo sapiens 163gagaaggagc ccaagag 1716415DNAHomo sapiens 164gagcctccca cagtt 1516517DNAHomo sapiens 165aggccagata caagtct 1716618DNAHomo sapiens 166ttttcgataa aaatgcta 1816716DNAHomo sapiens 167ttatatgagg acatta 1616818DNAHomo sapiens 168ttatggacat agactcat 1816918DNAHomo sapiens 169ttgggagatt ctggcaaa 1817016DNAHomo sapiens 170aatcgtctct ctcacc 1617120DNAHomo sapiens 171aatttttaca atttaagact 2017215DNAHomo sapiens 172gtccgaagaa atagg 1517316DNAHomo sapiens 173tgccaatcct ccagtt 1617422DNAHomo sapiens 174aacatagatg cagatcaact at 2217518DNAHomo sapiens 175agtactatta gtcaacaa 1817620DNAHomo sapiens 176gtcaacaagc attaatgcaa 2017718DNAHomo sapiens 177ccattgagca agttagag 1817818DNAHomo sapiens 178gagctatctg ccttagag 1817920DNAHomo sapiens 179cttgggaaaa aatccaagac 2018030DNAHomo sapiens 180gaagtacctg cccctcattt aatacagtaa 3018115DNAHomo sapiens 181ccctaccctg atttt 1518216DNAHomo sapiens 182aaggctccaa gatgtt 1618319DNAHomo sapiens 183tcaattgccg atgaaaaag 1918417DNAHomo sapiens 184cggtaaggtc atagtgg 1718517DNAHomo sapiens 185tggagttgat ggcatat 1718617DNAHomo sapiens 186aaacgccaat cctgagt 1718715DNAHomo sapiens 187tcaatcagcc attaa 1518821DNAHomo sapiens 188aaaggttcct gcaggatcag a 2118919DNAHomo sapiens 189aggatcagat gtaatctca 1919017DNAHomo sapiens 190aatatgtaaa agcctgt 1719116DNAHomo sapiens 191ataaagctat gcttat 1619220DNAHomo sapiens 192aataacagga gttgttttag 2019316DNAHomo sapiens 193acatttggag gaaaat 1619417DNAHomo sapiens 194attggtcact taaaaaa 1719517DNAHomo sapiens 195attggtcact taaaaaa 1719622DNAHomo sapiens 196ggtagagagc cacctgactt at 2219715DNAHomo sapiens 197aagatgtaaa aaagg 1519816DNAHomo sapiens 198gctagtcaat gtcgtt 1619915DNAHomo sapiens 199gggaaacgag caaag 1520016DNAHomo sapiens 200ccaattcagc catttg 1620119DNAHomo sapiens 201ccactgtccc aagtgtttc 1920216DNAHomo sapiens 202aataagccag ttacca 1620315DNAHomo sapiens 203acaatacaac aattg 1520423DNAHomo sapiens 204ctcaccacaa gcggcagtgc agc 2320535DNAHomo sapiens 205tactatacaa gcagtctctc tgcttccagg ggagc 3520616DNAHomo sapiens 206aaaaaatccc tacagg 1620718DNAHomo sapiens 207cactgcctga ggggactg 1820817DNAHomo sapiens 208gactaatctt gggaaga 1720918DNAHomo sapiens 209aaatctaaaa ggagttca 1821021DNAHomo sapiens 210ctagtgtggt tgattcagac t 2121120DNAHomo sapiens 211cgaaattcaa ttggttatta 2021215DNAHomo sapiens 212tcttcaattc cttgg 1521317DNAHomo sapiens 213agtccaagag acaggat 1721419DNAHomo sapiens 214ttattactcc tgccatata 1921519DNAHomo sapiens 215cattagaaaa aggacattg 1921617DNAHomo sapiens 216ttggaattct gtttgta 1721716DNAHomo sapiens 217taactgagcc attaat 1621821DNAHomo sapiens 218agccatggtc ccctttaatt a 2121917DNAHomo sapiens 219ttttaccaca ccagcct 1722015DNAHomo sapiens 220ttgtcagctc aagct 1522115DNAHomo sapiens 221tacatcgttc actat 1522215DNAHomo sapiens 222ttaaaagcat taaat 1522317DNAHomo sapiens 223agaagtccca attgagg 1722415DNAHomo sapiens 224ggtcttgccg atttt 1522515DNAHomo sapiens 225acaatcgtta ccaca 15

Claims

1. An isolated polynucleotide comprising:(a) a nucleotide sequence of or corresponding to an RNA expression product of a human endogenous MMTV-like subgroup 2 (HML-2) retrovirus,(b) a fragment of at least 7 nucleotides of (a),(c) a nucleotide sequence having at least 75% identity to (a), or(d) the complement of (a), (b), or (c),wherein said HML-2 retrovirus is HERV-K(CH).

2. The isolated polynucleotide of claim 1, wherein said RNA expression product comprises a Gag or Pol encoding sequence of HERV-K(CH).

3. The isolated polynucleotide of claim 2, wherein said RNA expression product comprises a nucleotide sequence corresponding to a DNA sequence selected from the group consisting of SEQ ID NOS: 14-26.

4. A method for the treatment or diagnosis of prostate cancer, testicular cancer, multiple sclerosis or insulin-dependent diabetes mellitus, the method comprising administering to a patient, or contacting a biological sample of the patient with, an isolated polynucleotide of claim 1.

5. The method of claim 4, for the treatment of prostate cancer.

6. An isolated polynucleotide having formula 5'-A-B-C-3', wherein: -A- is a nucleotide sequence consisting of a nucleotides; -C- is a nucleotide sequence consisting of c nucleotides; and -B- is a nucleotide sequence consisting of either(a) a fragment of at least 7 nucleotides of or corresponding to an RNA expression product of a human endogenous MMTV-like subgroup 2 (HML-2) retrovirus, or(b) the complement of a fragment (a),wherein (i) said polynucleotide is neither (a) nor (b), (ii) a+c≧1, and (iii) said HML-2 retrovirus is HERV-K(CH).

7. The isolated polynucleotide of claim 6, wherein said RNA expression product comprises a Gag or Pol encoding sequence of HERV-K(CH).

8. The isolated polynucleotide of claim 7, wherein said RNA expression product comprises a nucleotide sequence corresponding to a DNA sequence selected from the group consisting of SEQ ID NOS: 14-26.

9. The isolated polynucleotide of claim 1 or claim 6, comprising a detectable label.

10. A kit comprising primers for amplifying a template sequence contained within an isolated polynucleotide of claim 1, said kit comprising a first primer and a second primer, wherein said first primer is substantially complementary to said template sequence and said second primer is substantially complementary to a complement of said template sequence, wherein parts of said primers that have complementarity define the termini of said template sequence to be amplified.

11. An isolated polypeptide comprising:(a) an amino acid sequence encoded by a nucleotide sequence of an RNA expression product of a human endogenous MMTV-like subgroup 2 (HML-2) retrovirus,(b) a fragment of at least 7 amino acids of (a), or(c) an amino acid sequence having at least 75% identity to (a),wherein said HML-2 retrovirus is HERV-K(CH).

12. The isolated polypeptide of claim 11, wherein (a) is an amino acid selected from the group consisting of SEQ ID NOS: 46-57.

13. The isolated polypeptide of claim 11, wherein said RNA expression product comprises a Gag or Pol encoding sequence of HERV-K(CH).

14. The isolated polypeptide of claim 13, wherein said RNA expression product comprises a nucleotide sequence corresponding to a DNA sequence selected from the group consisting of SEQ ID NOS: 14-26.

15. An isolated polypeptide having a formula NH₂-A-B-C-COOH, wherein -A- is an amino acid sequence consisting of a amino acids; -C- is an amino acid sequence consisting of c amino acids; and -B- is a fragment of at least 5 amino acids of an amino acid sequence encoded by a nucleotide sequence of an RNA expression product of a human endogenous MMTV-like subgroup 2 (HML-2) retrovirus, wherein (i) said polypeptide is not a fragment of an amino acid sequence encoded by a nucleotide sequence of said RNA expression product, (ii) a+c≧1, and (iii) wherein said HML-2 retrovirus is HERV-K(CH).

16. The isolated polypeptide of claim 15, wherein -B- is a fragment of at least 5 amino acids of an amino acid sequence selected from the group consisting of SEQ ID NOS: 46-57.

17. The isolated polypeptide of claim 15, wherein said RNA expression product comprises a Gag or Pol encoding sequence of HERV-K(CH).

18. The isolated polypeptide of claim 17, wherein said RNA expression product comprises a nucleotide sequence corresponding to a DNA sequence selected from the group consisting of SEQ ID NOS: 14-26.

19. A polypeptide of claim 11 or claim 15, wherein said polypeptide is attached to a solid support.

20. A polypeptide of claim 11 or claim 15, wherein said polypeptide comprises a detectable label.

21. An antibody for use in the diagnosis of prostate cancer, said antibody having binding affinity for the polypeptide of claim 11 or claim 15.

22. The antibody of claim 21, wherein said antibody is a monoclonal antibody.

23. The antibody of claim 21, wherein said antibody is attached to a solid support.

24. A pharmaceutical composition comprising:(a) a polynucleotide of claim 1 or claim 6, a polypeptide of claim 11 or claim 17, or an antibody of claim 23, and(b) a pharmaceutically acceptable carrier.

25. An immunogenic composition comprising:(a) a polynucleotide of claim 1 or claim 6 or a polypeptide of claim 11 or claim 17, and(b) a pharmaceutically acceptable carrier.

26. The immunogenic composition of claim 25, further comprising an adjuvant.

27. The immunogenic composition of claim 25, wherein said adjuvant comprises an oil-in-water emulsion or an aluminum salt.

28. A method of raising an immune response in a patient, the method comprising administering an immunogenic dose of the immunogenic composition of claim 25 to said patient.

29. A composition comprising:(a) a prostate cell, and(b) a polynucleotide of claim 1 or claim 6, a polypeptide of claim 11 or claim 15, or an antibody of claim 21, and(c) a pharmaceutically acceptable carrier.

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