EP1735468A2

EP1735468A2 - Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of prostate cancer

Info

Publication number: EP1735468A2
Application number: EP05805032A
Authority: EP
Inventors: Dvir Dahary; Sarah Pollock; Zurit Levine; Rotem Sorek; Michal Ayalon-Soffer; Pinchas Akiva; Amir Toporik; Osnat Sella-Tavor; Shirley Sameah-Greenwald
Original assignee: Compugen USA Inc
Current assignee: Compugen USA Inc
Priority date: 2004-01-27
Filing date: 2005-01-27
Publication date: 2006-12-27
Also published as: CA2554707A1

Abstract

Novel markers for prostate cancer that are both sensitive and accurate. Furthermore, these markers are able to distinguish between prostate cancer and benign prostate hyperplasia ('BPH'). These markers are overexpressed in prostate cancer specifically, as opposed to normal prostate tissue and/or BPH. The measurement of these markers, alone or in combination, in patient samples provides information that the diagnostician can correlate with a probable diagnosis of prostate cancer. The markers of the present invention, alone or in combination, show a high degree of differential detection between prostate cancer and non-cancerous states.

Description

Novel Nucleotide and Amino Acid Sequences, and Assays and Methods of use thereof for Diagnosis of Prostate Cancer

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

BACKGROUND OF THE INVENTION

Prostate cancer is the most commonly diagnosed malignancy and the second most frequent cause of cancer-related deaths in the western male population. Prostate cancer therapies are most effective in the earlier stages of the disease, before metastasis has occurred. Treatment is expected to be even more effective before significant local growth of the cancerous tissue has taken place. Therefore, efforts to control the disease (i.e., to decrease prostate cancer mortality) have focused on increasing detection of the cancer while it is still locally confined and potentially curable, through diagnostic assays that are suitable for early detection of prostate cancer. Unfortunately, such detection also has significant drawbacks, because diagnostic assays that use currently available prostate cancer markers lead to high numbers of false positive diagnoses, and/or are not sufficiently sensitive (potentially leading to high numbers of false negative diagnoses). Measurements of serum concentrations of prostatic marker enzymes have recognized value in the clinical detection, diagnosis and management of prostate cancer. The two most widely used prostatic marker enzymes are prostatic acid phosphatase (PAP) and prostate- specific antigen (PSA). Normally, both enzymes are secreted from the prostatic epithelial cells into the seminal fluid, but in patients with prostatic disease they leak into the circulation, where they can be detected by means of immunological assays (Armbruster, Clin. Che. 39:181-95 (1993)).

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

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

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

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

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

The background art does not teach or suggest markers for prostate cancer that are sufficiently sensitive and/or accurate, alone or in combination. The present invention overcomes these deficiencies of the background art by providing novel markers for prostate cancer that are both sensitive and accurate. Furthermore, at least some of these markers are able to distinguish between prostate cancer and benign prostate hyperplasia ("BPH"). These markers are differentially expressed, and preferably overexpressed in prostate cancer specifically, as opposed to normal prostate tissue and/or BPH. The measurement of these markers, alone or in combination, in patient samples (biological samples) provides information that the diagnostician can correlate with a probable diagnosis of prostate cancer. The markers of the present invention, alone or in combination, show a high degree of differential detection between prostate cancer and non-cancerous states.

According to preferred embodiments of the present invention, examples of suitable biological samples include but are not limited to blood, serum, plasma, blood cells, urine, sputum, saliva, stool, spinal fluid or CSF, lymph fluid, the external secretions of the skin, respiratory, intestinal, and genitourinary tracts, tears, milk, neuronal tissue, prostate tissue or mucous and any human organ or tissue, or any sample obtained by lavage (for example of the bronchial system), and also samples of in vivo cell culture constituents. In a preferred embodiment, the biological sample comprises prostate tissue and/or other tissues of the male genitalia, or reproductive or urinary tracts, and/or a serum (and/or any blood) sample and/or a urine sample and/or a semen sample and/or any other tissue or liquid sample. The sample can optionally be diluted with a suitable eluant before contacting the sample to an antibody and/or performing any other diagnostic assay. Information given in the text with regard to cellular localization was determined according to four different software programs: (i) tmhmm (from Center for Biological Sequence Analysis, Technical University of Denmark DTU, http://www.cbs.dm.dl^services/TMHMM/TMHMM2.0b.guide.php) or (ii) tmpred (from EMBnet, maintained by the ISREC Bionformatics group and the LICR Information Technology Office, Ludwig Institute for Cancer Research, Swiss Institute of Bioinformatics, http://www.ch.embnet.org/software/TMPRED_form.htinl) for transmembrane region prediction; (iii) signalpjhmm or (iv) signalp_nn (both from Center for Biological Sequence Analysis, Technical University of Denmark DTU, http://www.cbs.dtu.dk/services/SignalP/backgrounoVprediction.php) for signal peptide prediction. The terms "signalp_hmm" and "signalp_nn" refer to two modes of operation for the program SignalP: hmm refers to Hidden Markov Model, while nn refers to neural networks. Localization was also determined through manual inspection of known protein localization and/or gene structure, and the use of heuristics by the individual inventor. In some cases for the manual inspection of cellular localization prediction inventors used the ProLoc computational platform [Einat Hazkani-Covo, Erez Levanon, Galit Rotman, Dan Graur and Amit Novik; (2004) "Evolution of multicellularity in metazoa: comparative analysis of the subcellular localization of proteins in Saccharomyces, Drosophila and Caenorhabditis." Cell Biology International 2004;28(3):171-8.], which predicts protein localization based on various parameters including, protein domains (e.g., prediction of trans-membranous regions and localization thereof within the protein), pi, protein length, amino acid composition, homology to pre-annotated proteins, recognition of sequence patterns which direct the protein to a certain organelle (such as, nuclear localization signal, NLS, mitochondria localization signal), signal peptide and anchor modeling and using unique domains from Pfam that are specific to a single compartment.

Information is given in the text with regard to SNPs (single nucleotide polymorphisms). A description of the abbreviations is as follows. "T - > C", for example, means that the SNP results in a change at the position given in the table from T to C. Similarly, "M - > Q", for example, means that the SNP has caused a change in the corresponding amino acid sequence, from methionine (M) to glutamine (Q). If, in place of a letter at the right hand side for the nucleotide sequence SNP, there is a space, it indicates that a frameshift has occurred. A frameshift may also be indicated with a hyphen (-). A stop codon is indicated with an asterisk at the right hand side (*). As part of the description of an SNP, a comment may be found in parentheses after the above description of the SNP itself. This comment may include an FTId, which is an identifier to a SwissProt entry that was created with the indicated SNP. An FTId is a unique and stable feature identifier, which allows construction of links directly from position- specific annotation in the feature table to specialized protein-related databases. The FTId is always the last component of a feature in the description field, as follows: FTId=XXX_number, in which XXX is the 3- letter code for the specific feature key, separated by an underscore from a 6-digit number. In the table of the amino acid mutations of the wild type proteins of the selected splice variants of the invention, the header of the first column is "SNP position(s) on amino acid sequence", representing a position of a known mutation on amino acid sequence. SNPs may optionally be used as diagnostic markers according to the present invention, alone or in combination with one or more other SNPs and/or any other diagnostic marker. Preferred embodiments of the present invention comprise such SNPs, including but not limited to novel SNPs on the known (WT or wild type) protein sequences given below, as well as novel nucleic acid and/or amino acid sequences formed through such SNPs, and/or any SNP on a variant amino acid and/or nucleic acid sequence described herein.

Information given in the text with regard to the Homology to the known proteins was determined by Smith- Waterman version 5.1.2 using special (non default) parameters as follows: -model=sw .model -GAPEXT=O -GAPOP=IOO-O

-MATRIX=blosuml 00

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

- library-based statistics: P- value without including the level of expression in cell- lines (Pl)

- library based statistics: P- value including the level of expression in cell- lines (P2)

- EST clone statistics: P- value without including the level of expression in cell- lines (SPl)

- EST clone statistics: predicted overexpression ratio without including the level of expression in cell- lines (R3)

- EST clone statistics: P- value including the level of expression in cell- lines (SP2)

- EST clone statistics: predicted overexpression ratio including the level of expression in cell- lines (R4) Library-based statistics refer to statistics over an entire library, while EST clone statistics refer to expression only for ESTs from a particular tissue or cancer.

Information is given with regard to overexpression of a cluster in cancer based on microarrays. As a microarray reference, in the specific segment paragraphs, the unabbreviated tissue name was used as the reference to the type of chip for which expression was measured. There are two types of microarray results: those from microarrays prepared according to a design by the present inventors, for which the microarray fabrication procedure is described in detail in Materials and Experimental Procedures section herein; and those results from microarrays using Affymetrix technology. As a microarray reference, in the specific segment paragraphs, the unabbreviated tissue name was used as the reference to the type of chip for which expression was measured. For microarrays prepared according to a design by the present inventors, the probe name begins with the name of the cluster (gene), followed by an identifying number. Oligonucleotide microarray results taken from Affymetrix data were from chips available from Affymetrix Inc, Santa Clara, CA, USA (see for example data regarding the Human Genome U133 (HG-U133) Set at www.affymetrix.com/products/arrays/specific/hgul33.affx; GeneChip Human Genome U133A 2.0 Array at www.affymetrix.com/products/arrays/specific/hgul33av2.affx; and Human Genome U133 Plus 2.0 Array at www.affymetrix.com/products/arrays/specific/hgul33plus.affx). The probe names follow the Affymetrix naming convention. The data is available from NCBI Gene Expression Omnibus (see www.ncbi.nlm.nih.gov/projects/geo/ and Edgar et al, Nucleic Acids Research, 2002, Vol. 30, No. 1 207-210). The dataset (including results) is available from www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE1133 for the Series GSEl 133 database (published on March 2004); a reference to these results is as follows: Su et al (Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6062-7. Epub 2004 Apr 09). A list of probes designed according to the present inventors is given below. >H53626_0_16_0 ATGCGGGCATGTACATCTGCCTTGGCGCCAACACCATGGGCTACAGCTTC >H53626_0_0_8391

GGGTCTGGGGTGCTCTCCTGGTCTTTGTGTCGGCGTTCCCCTCCCTACCT >HSMUC1A_O_37_O

AAAAGGAGACTTCGGCTACCCAGAGAAGTTCAGTGCCCAGCTCTACTGAG >HSMUC1 A_0_0_l 1364

AAAGGCTGGCATAGGGGGAGGTTTCCCAGGTAGAAGAAGAAGTGTCAGCA >HSMUC1A_O_O_11365

AATTAACCCTTTGAGAGCTGGCCAGGACTCTGGACTGATTACCCCAGCCT >HSSTROL3_0_0_12518

ATGAGAGTAACCTCACCCGTGCACTAGTTTACAGAGCATTCACTGCCCCA >HSSTROL3_0_0_12517 CAGAGATGAGAGCCTGGAGCATTGCAGATGCCAGGGACTTCACAAATGAA >HSCOC4_0_0_9892

AAGGACCAGAGTCCATGCCAAGACCACCCTTCAGCTTCCAAGGCCCTCCA >HSCOC4_0_39_0

ATCCTCCAGCCATGAGGCTGCTCTGGGGGCTGATCTGGGCATCCAGCTTC >HSCOC4_0_0_9883

CCTGTTTGCTCTGACACCAACTTCCTACCCTCTCAGCCTCAAAGTAACTC

>HSCOC4_0_0_9885

GCTGAGGTGTGGCCGAGGACCTGACCATCTGGAAGTGTGAAAATCCCCTT

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

"COL" for "colon"; "EPI" for "epithelial";

"GEN" for "general"; "LIVER" for "liver"; "LUN" for "lung"; "LYMPH" for "lymph nodes"; "MARROW" for "bone marrow";

"OVA" for "ovary"; "PANCREAS" for "pancreas"; "PRO" for "prostate"; "STOMACH" for "stomach"; "TCELL" for "T cells"; "THYROID" for "Thyroid";

"MAM" for "breast"; "BRAIN" for "brain"; "UTERUS" for "uterus"; "SKIN" for "skin"; "KIDNEY" for "kidney";

"MUSCLE" for "muscle";

"ADREN" for "adrenal"; "HEAD" for "head and neck"; "BLADDER" for "bladder";

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

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

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

As used herein the phrase "diagnostic" means identifying the presence or nature of a pathologic condition. Diagnostic methods differ in their sensitivity and specificity. The "sensitivity" of a diagnostic assay is the percentage of diseased individuals who test positive (percent of "true positives"). Diseased individuals not detected by the assay are "false negatives." Subjects who are not diseased and who test negative in the assay are termed "true negatives." The "specificity" of a diagnostic assay is 1 minus the false positive rate, where the "false positive" rate is defined as the proportion of those without the disease who test positive. While a particular diagnostic method may not provide a definitive diagnosis of a condition, it suffices if the method provides a positive indication that aids in diagnosis. As used herein the phrase "diagnosing" refers to classifying a disease or a symptom, determining a severity of the disease, monitoring disease progression, forecasting an outcome of a disease and/or prospects of recovery. The term "detecting" may also optionally encompass any of the above.

Diagnosis of a disease according to the present invention can be affected by deteπiiiriing a level of a polynucleotide or a polypeptide of the present invention in a biological sample obtained from the subject, wherein the level determined can be correlated with predisposition to, or presence or absence of the disease. It should be noted that a "biological sample obtained from the subject" may also optionally comprise a sample that has not been physically removed from the subject, as described in greater detail below. As used herein, the term "level" refers to expression levels of RNA and/or protein or to

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

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

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

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

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

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

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

A "label" includes any moiety or item detectable by spectroscopic, photo chemical, biochemical, immunochemical, or chemical means. For example, useful labels include ³²P, ³⁵S, fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin-streptavadin, dioxigenin, haptens and proteins for which antisera or monoclonal antibodies are available, or nucleic acid molecules with a sequence complementary to a target.

The label often generates a measurable signal, such as a radioactive, chromogenic, or fluorescent signal, that can be used to quantify the amount of bound label in a sample. The label can be incorporated in or attached to a primer or probe either covalently, or through ionic, van der Waals or hydrogen bonds, e.g., incorporation of radioactive nucleotides, or biotinylated nucleotides that are recognized by streptavadin. The label may be directly or indirectly detectable. Indirect detection can involve the binding of a second label to the first label, directly or indirectly. For example, the label can be the ligand of a binding partner, such as biotin, which is a binding partner for streptavadin, or a nucleotide sequence, which is the binding partner for a complementary sequence, to which it can specifically hybridize. The binding partner may itself be directly detectable, for example, an antibody may be itself labeled with a fluorescent molecule. The binding partner also may be indirectly detectable, for example, a nucleic acid having a complementary nucleotide sequence can be a part of a branched DNA molecule that is in turn detectable through hybridization with other labeled nucleic acid molecules (see, e.g., P. D. Fahrlander and A. Klausner, Bio/Technology 6:1165 (1988)). Quantitation of the signal is achieved by, e.g., scintillation counting, densitometry, or flow cytometry.

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

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

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

According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 1,2, 3 and 4. According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88 and 89.

According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 327, 328, 329, 330. According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: SEQ ID NOs. 5, 6, 7, 8, 9 and 10.

According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114 and 115. According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 331, 332, 333, 334 and 335.

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

According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128 and 129. According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 336.

According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 12. According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 130, 131, 132, 133, 134 and 135.

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

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

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

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

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

According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220 and 221. According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357 and 358.

According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 13 and 14. According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 136. 137, 138, 139, 140, 141 and 142. According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 338 and 339.

According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 40, 41 and 42. According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 238, 239, 240. 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269 and 270.

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

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

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

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

According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 44 and 45. According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303 and 304.

According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 368 and 369. According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58 and 59.

According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a segment SEQ ID NOs: 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325 and 326. According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs: 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382 and 383.

According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 383, comprising a first amino acid sequence being at least 90 % homologous to corresponding to amino acids 1 - 45 of SEQ ID

NO. 398 , which also corresponds to amino acids 1 - 45 of SEQ ID NO. 383, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 46 - 85 of SEQ ID NO. 383, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

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

ID NO. 383.

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

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

ID NO. 359 .

According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NOs.360 , comprising a first amino acid sequence being at least 90 % homologous to corresponding to amino acids 1 - 163 of SEQ ID NOs. 391 , which also corresponds to amino acids 1 - 163 of SEQ ID NO.360 , a bridging amino acid H corresponding to amino acid 164 of SEQ ID NO. 360 , a second amino acid sequence being at least 90 % homologous to corresponding to amino acids 165 - 358 of SEQ ID NOs. 391 , which also corresponds to amino acids 165 - 358 of SEQ ID NO. 360 , and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 359 - 382 of SEQ ID NO. 360 , wherein said first amino acid sequence, bridging amino acid, second amino acid sequence and third amino acid sequence are contiguous and in a sequential order. According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 360 , comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 359 - 382in SEQ ID NO. 360 . According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 361 , comprising a first amino acid sequence being at least 90 % homologous to corresponding to amino acids 1 - 163 of SEQ ID NOs. 391 , which also corresponds to amino acids 1 - 163 of SEQ ID NO. 361 , a bridging amino acid H corresponding to amino acid 164 of SEQ ID NO. 361 , a second amino acid sequence being at least 90 % homologous to corresponding to amino acids 165 - 359 of SEQ ID NOs. 391 , which also corresponds to amino acids 165 - 359 of SEQ ID NO. 361 , and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 360 - 370 of SEQ ID NO. 361 , wherein said first amino acid sequence, bridging amino acid, second amino acid sequence and third amino acid sequence are contiguous and in a sequential order. According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 361 , comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 360 - 370 in SEQ ID NO. 361 .

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

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

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

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

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

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

According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID 'NO. 340 , comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 866 - 887 in SEQ ID NO. 340 . According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 341 , comprising a first amino acid sequence being at least 90 % homologous to corresponding to amino acids 1 - 818 of CO4_HUMAN, which also corresponds to amino acids 1 - 818 of SEQ ID NO. 341 ,and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 819 - 843 of SEQ ID NO. 341 , wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

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

SEQ ID NO. 341 .

According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ SEQ ID NO. 342 , comprising a first amino acid sequence being at least 90 % homologous to corresponding to amino acids 1 - 1052 of

CO4_HUMAN, which also corresponds to amino acids 1 - 1052 of SEQ ID NO. 342 , and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1053 - 1084 of SEQ ID NO. 342 , wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

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

342.

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

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

ID NO. 343 .

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

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

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

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

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

According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 347 , comprising a first amino acid sequence being at least 90 % homologous to corresponding to amino acids 1 - 1529 of SEQ ID NO. 389 , which also corresponds to amino acids 1 - 1529 of SEQ ID NO. 347 , and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1530 - 1533 of SEQ ID NO. 347 , wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order. According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 347 , comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1530 - 1533 in SEQ ID NO. 347 . According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 348 , comprising a first amino acid sequence being at least 90 % homologous to corresponding to amino acids 1 - 1653 of SEQ ID NO. 389 , which also corresponds to amino acids 1 - 1653 of SEQ ID NO. 348 , and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1654 - 1670 of SEQ ID NO. 348 , wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

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

According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 349 , comprising a first amino acid sequence being at least 90 % homologous to corresponding to amino acids 1 - 1626 of SEQ ID NO. 389 , which also corresponds to amino acids 1 - 1626 of SEQ ID NO. 349 , and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1627 - 1685 of SEQ ID NO. 349 , wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order. According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 349 , comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1627 - 1685 in SEQ ID NO. 349 . According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 350 , comprising a first amino acid sequence being at least 90 % homologous to corresponding to amino acids 1 - 1528 of SEQ ID NO. 389 , which also corresponds to amino acids 1 - 1528 of SEQ ID NO. 350 , and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1529 - 1579 of SEQ ID NO. 350 , wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

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

SEQ ID NO. 350 .

According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 351 , comprising a first amino acid sequence being at least 90 % homologous to corresponding to amino acids 1 - 1593 of SEQ ID

NO. 389 , which also corresponds to amino acids 1 - 1593 of SEQ ID NO. 351 , and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1594 - 1657 of SEQ ID NO. 351 , wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

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

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

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

According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 353 , comprising a first amino acid sequence being at least 90 % homologous to corresponding to amino acids 1 - 1232 of SEQ ID

NO. 390, which also corresponds to amino acids 1 - 1232 of SEQ ID NO. 353 , and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1233 - 1253 of SEQ ID NO. 353 , wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

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

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

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

SEQ ID NO. 354 .

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

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

According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 356 , comprising a first amino acid sequence being at least 90 % homologous to corresponding to amino acids 1 - 236 of CO4_HUMAN, which also corresponds to amino acids 1 - 236 of SEQ ID NO. 356 , and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 237 - 263 of SEQ ID NO. 356 , wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order. According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 356 , comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 237 - 263 in SEQ ID NO. 356. According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 357 , comprising a first amino acid sequence being at least 90 % homologous to corresponding to amino acids 1 - 1529 of SEQ ID NO. 389 , which also corresponds to amino acids 1 - 1529 of SEQ ID NO. 357 , and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1530 - 1533 of SEQ ID NO. 357 , wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

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

ID NO. 357 .

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

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

According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 358 , comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1542 - 1555 in SEQ ID NO. 358 . According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 339 , comprising a first amino acid sequence being at least 90 % homologous to corresponding to amino acids 1 - 27 of SEQ ID NO. 387 , which also corresponds to amino acids 1 - 27 of SEQ ID NO. 339 , and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 28 - 41 of SEQ ID NO. 339 , wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

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

ID NO. 339 .

According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 364 , comprising a first amino acid sequence being at least 90 % homologous to corresponding to amino acids 1 - 1617 of SEQ ID

NO. 393 , which also corresponds to amino acids 1 - 1617 of SEQ ID NO. 364 , and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 1618 - 1645 of SEQ ID NO. 364 , wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

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

SEQ ID NO. 364 .

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

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

SEQ ID NO. 365 .

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

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

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

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

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

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

According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 367 , comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 258 - 310 in SEQ ID NO. 367 . According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 368 , comprising a first amino acid sequence being at least 90 % homologous to corresponding to amino acids 1 - 357 of Q8N441, which also corresponds to amino acids 1 - 357 of SEQ DD NO. 368 , second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 358 - 437 of SEQ ID NO. 368 , and a third amino acid sequence being at least 90 % homologous to corresponding to amino acids 358 - 504 of Q8N441, which also corresponds to amino acids 438 - 584 of SEQ ID NO. 368 , wherein said first, second and third amino acid sequences are contiguous and in a sequential order.

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

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

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

SEQ ID NO. 369 .

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

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

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

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

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

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

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

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

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

According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 329 , comprising a first amino acid sequence being at least 90 % homologous to corresponding to amino acids 1 - 336 of SEQ ID

NO. 384 , which also corresponds to amino acids 1 - 336 of SEQ ID NO. 329 , and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence corresponding to amino acids 337 - 373 of SEQ ID NO. 329 , wherein said first and second amino acid sequences are contiguous and in a sequential order.

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

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

According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 330 , comprising a first amino acid sequence being at least 90 % homologous to corresponding to amino acids 1 - 229 of SEQ ID

NO. 384 , which also corresponds to amino acids 1 - 229 of SEQ ID NO. 330 , and a second amino acid sequence VSIS corresponding to amino acids 230 - 233 of SEQ ID NO. 330 , wherein said first and second amino acid sequences are contiguous and in a sequential order.

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

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

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

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

ID NO. 332 .

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

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

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

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

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

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

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

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

ID NO. 333 .

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

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

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

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

According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 335 , comprising a first amino acid sequence being at least 90 % homologous to amino acids 1 - 63 of Q8N2G4, which also corresponds to amino acids 1 - 63 of SEQ ID NO. 335 , and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 64 - 90 of SEQ ID NO. 335 , wherein said first and second amino acid sequences are contiguous and in a sequential order. According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 335 , comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 64 - 90 in SEQ ID NO. 335 . According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 335 , comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 1 - 5 of SEQ ID NO. 335 , second amino acid sequence being at least 90 % homologous to amino acids 22 - 79 of BAC85273, which also corresponds to amino acids 6 - 63 of SEQ ID NO. 335 , and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 64 - 90 of SEQ ID NO. 335 , wherein said first, second and third amino acid sequences are contiguous and in a sequential order. According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a head of SEQ ID NO. 335 , comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to amino acids 1 - 5 of SEQ ID NO. 335 . According to preferred embodiments of the present invention, there is provided an isolated polypeptide encoding for a tail of SEQ ID NO. 335 , comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologaus to the amino acids 64 - 90in SEQ ID NO. 335 . According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 335 , comprising a first amino acid sequence being at least 90 % homobgous to amino acids 24 - 86 of BAC85518, which also corresponds to amino acids 1 - 63 of SEQ ID NO. 335 , and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 64 - 90 of SEQ ID NO. 335 , wherein said first and second amino acid sequences are contiguous and in a sequential order.

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

According to preferred embodiments of the present invention, there is provided an isolated chimeric polypeptide encoding for SEQ ID NO. 336 , comprising a first amino acid sequence being at least 90 % homologous to amino acids 1 - 247 of SEQ ID NO. 385 , which also corresponds to amino acids 1 - 247 of SEQ ID NO. 336 , and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least

90% and most preferably at least 95% homologous to a polypeptide sequence corresponding to amino acids 248 - 255 of SEQ ID NO. 336 , wherein said first and second amino acid sequences are contiguous and in a sequential order.

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

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

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

ID NO. 337 .

According to preferred embodiments of the present invention, there is provided an antibody from cluster HSECADH, Rl 1723, S78694, HUMTREFAC, HSCOC4, HSSTROL3, HUMF5A, Z40511, H53626 and HSMUClA, capable of specifically binding to an epitope of an amino acid sequence.

Optionally the amino acid sequence corresponds to a bridge, edge portion, tail, head or insertion. Optionally the antibody is capable of differentiating between a splice variant having said epitope and a corresponding known protein.

According to preferred embodiments of the present invention, there is provided a kit for detecting prostate cancer, comprising a kit from cluster HSECADH, Rl 1723, S78694, HUMTREFAC, HSCOC4, HSSTROL3, HUMF5A, Z40511, H53626 and HSMUClA for detecting overexpression of a splice variant.

Optionally the kit comprises a NAT-based technology.

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

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

Optionally the kit comprises an antibody.

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

According to preferred embodiments of the present invention, there is provided a method for detecting prostate cancer, comprising detecting overexpression of a splice variant from cluster HSECADH₃ Rl 1723, S78694, HUMTREFAC, HSCOC4, HSSTROL3, HUMF5A, Z40511, H53626 and HSMUClA.

Optionally detecting overexpression is performed with a NAT-based technology. Optionally detecting overexpression is performed with an immunoassay. Optionally the immunoassay comprises an antibody.

According to preferred embodiments of the present invention, there is provided a biomarker capable of detecting prostate cancer, comprising nucleic acid sequences or a fragment thereof, or amino acid sequences or a fragment thereof from cluster HSECADH, Rl 1723, S78694, HUMTREFAC, HSCOC4, HSSTROL3, HUMF5A, Z40511, H53626 and HSMUClA,. According to preferred embodiments of the present invention, there is provided a method for screening for prostate cancer, comprising detecting prostate cancer cells with a biomarker or an antibody or a method or assay from cluster HSECADH, Rl 1723, S78694, HUMTREFAC, HSCOC4, HSSTROL3, HUMF5A, Z40511, H53626 and HSMUClA .

According to preferred embodiments of the present invention, there is provided a method for diagnosing prostate cancer, comprising detecting prostate cancer cells with a biomarker or an antibody or a method or assay from cluster HSECADH, Rl 1723, S78694, HUMTREFAC, HSCOC4, HSSTROL3, HUMF5A, Z40511, H53626 and HSMUClA .

According to preferred embodiments of the present invention, there is provided a method for monitoring disease progression, treatment efficacy, relapse of prostate cancer, comprising detecting prostate cancer cells with a biomarker or an antibody or a method or assay from cluster HSECADH, Rl 1723, S78694, HUMTREFAC, HSCOC4, HSSTROL3, HUMF5A,

Z40511, H53626 and HSMUClA.

According to preferred embodiments of the present invention, there is provided a method of selecting a therapy for prostate cancer, comprising detecting prostate cancer cells with a biomarker or an antibody or a method or assay from cluster HSECADH, Rl 1723, S78694, HUMTREFAC, HSCOC4, HSSTROL3, HUMF5A, Z40511, H53626 and HSMUClA .

According to preferred embodiments of the present invention, preferably any of the above nucleic acid and/or amino acid sequences further comprises any sequence having at least about 70%, preferably at least about 80%, more preferably at least about 90%, most preferably at least about 95% homology thereto. All nucleic acid sequences and/or amino acid sequences shown herein as embodiments of the present invention relate to their isolated form, as isolated polynucleotides (including for all transcripts), oligonucleotides (including for all segments, amplicons and primers), peptides (including for all tails, bridges, insertions or heads, optionally including other antibody epitopes as described herein) and/or polypeptides (including for all proteins). It should be noted that oligonucleotide and polynucleotide, or peptide and polypeptide, may optionally be used interchangeably.

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

BRIEF DESCRIPTION OF DRAWINGS

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

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

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

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

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

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

Figure 7 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster Rl 1723, demonstrating overexpression in epithelial malignant tumors, a mixture of malignant tumors from different tissues and kidney malignant tumors. Figure 8 is a histogram showing over expression of the Rl 1723 transcripts which are detectable by amplicon as depicted in sequence name Rl 1723 segl3 in cancerous prostate samples relative to the normal samples.

Figure 9 is a histogram showing expression of Rl 1723 transcripts, which are detectable by amplicon as depicted in sequence name R11723segl3, in different normal tissues.

Figures 1OA are histograms showing over expression of the Rl 1723 transcripts, which are detectable by amplicon as depicted in sequence name Rl 1723 juncll-18 in cancerous prostate samples relative to the normal samples (Figure 10A) or expression in normal tissues (Figure 10B).

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

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

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

Figure 14 is a histogram showing the over expression of the Stromelysin-3 precursor transcripts, which are detectable by amplicon as depicted in sequence name HSSTROL3 seg24, in cancerous Prostate samples relative to the normal samples. Figure 15 is a histogram demonstrating the expression of Stromelysin-3 transcripts which are detectable by amplicon as depicted in sequence name HSSTROL3 seg24 in different normal tissues.

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

Figure 17 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster HSMUClA, demonstrating overexpression in a mixture of malignant tumors from different tissues, breast malignant tumors, pancreas carcinoma and prostate cancer. FIG. 18A-B is a histogram showing the relative expression of AA315457 variants in normal, benign and tumor derived prostate samples as determined by real time PCR using primers for SEQ ID NO: 413. Figure 18B is a duplicate experiment.

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

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

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

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

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

DESCRIPTION OF PREFERRED EMBODIMENTS The present invention is of novel markers for prostate cancer that are both sensitive and accurate. Biomolecular sequences (amino acid and/or nucleic acid sequences) uncovered using the methodology of the present invention and described herein can be efficiently utilized as tissue or pathological markers and/or as drugs or drug targets for treating or preventing a disease. These markers are specifically released to the bloodstream under conditions of prostate cancer and/or other prostate pathology, and/or are otherwise expressed at a much higher level and/or specifically expressed in prostate cancer tissue or cells. The measurement of these markers, alone or in combination, in patient samples provides information that the diagnostician can correlate with a probable diagnosis of prostate cancer and/or pathology. The present invention therefore also relates to diagnostic assays for prostate cancer and/or prostate pathology, and methods of use of such markers for detection of prostate cancer and/or prostate pathology, optionally and preferably in a sample taken from a subject (patient), which is more preferably some type of blood sample.

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

Biomolecular sequences (amino acid and/or nucleic acid sequences) uncovered using the methodology of the present invention and described herein can be efficiently utilized as tissue or pathological markers and/or as drugs or drug targets for treating or preventing a disease. These markers are specifically released to the bloodstream under conditions of prostate cancer (or one of the above indicative conditions), and/or are otherwise expressed at a much higher level and/or specifically expressed in prostate cancer tissue or cells, and/or tissue or cells under one of the above indicative conditions. The measurement of these markers, alone or in combination, in patient samples provides information that the diagnostician can correlate with a probable diagnosis of prostate cancer and/or a condition that it is indicative of a higher risk for prostate cancer.

The present invention therefore also relates to diagnostic assays for prostate cancer and/or an indicative condition, and methods of use of such markers for detection of prostate cancer and/or an indicative condition, optionally and preferably in a sample taken from a subject (patient), which is more preferably some type of blood sample. According to a preferred embodiment of the present invention, use of the marker optionally and preferably permits a non-cancerous prostate disease state to be distinguished from prostate cancer and/or an indicative condition. A non limiting example of a non-cancerous prostate disease state includes BPH. According to another preferred embodiment of the present invention, use of the marker optionally and preferably permits an indicative condition to be distinguished from prostate cancer.

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

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

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

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

Optionally and preferably, a bridge between a tail or a head or a unique insertion, and a "known protein" portion of a variant, comprises at least about 10 amino acids, more preferably at least about 20 amino acids, most preferably at least about 30 amino acids, and even more preferably at least about 40 amino acids, in which at least one amino acid is from the tail/head/insertion and at least one amino acid is from the "known protein" portion of a variant. Also optionally, the bridge may comprise any number of amino acids from about 10 to about 40 amino acids (for example, 10, 11, 12, 13...37, 38, 39, 40 amino acids in length, or any number in between). It should be noted that a bridge cannot be extended beyond the length of the sequence in either direction, and it should be assumed that every bridge description is to be read in such manner that the bridge length does not extend beyond the sequence itself.

Furthermore, bridges are described with regard to a sliding window in certain contexts below. For example, certain descriptions of the bridges feature the following format: a bridge between two edges (in which a portion of the known protein is not present in the variant) may optionally be described as follows: a bridge portion of CONTIG-N AME_P1 (representing the name of the protein), comprising a polypeptide having a length "n", wherein n is at least about 10 amino acids in length, optionally at least about 20 amino acids in length, preferably at least about 30 amino acids in length, more preferably at least about 40 amino acids in length and most preferably at least about 50 amino acids in length, wherein at least two amino acids comprise XX (2 amino acids in the center of the bridge, one from each end of the edge), having a structure as follows (numbering according to the sequence of CONTIG-N AME_P1): a sequence starting from any of amino acid numbers 49- x to 49 (for example); and ending at any of amino acid numbers 50 + ((n-2) - x) (for example), in which x varies from 0 to n-2. In this example, it should also be read as including bridges in which n is any number of amino acids between 10-50 amino acids in length. Furthermore, the bridge polypeptide cannot extend beyond the sequence, so it should be read such that 49-x (for example) is not less than 1, nor 50 + ((n-2) - x) (for example) greater than the total sequence length.

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

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

In another embodiment, this invention provides a method for detecting a splice variant according to the present invention in a biological sample, comprising: contacting a biological sample with an antibody specifically recognizing a splice variant according to the present invention under conditions whereby the antibody specifically interacts with the splice variant in the biological sample but do not recognize known corresponding proteins (wherein the known protein is discussed with regard to its splice variant(s) in the Examples below), and detecting said interaction; wherein the presence of an interaction correlates with the presence of a splice variant in the biological sample. In another embodiment, this invention provides a method for detecting a splice variant nucleic acid sequences in a biological sample, comprising: hybridizing the isolated nucleic acid molecules or oligonucleotide fragments of at least about a minimum length to a nucleic acid material of a biological sample and detecting a hybridization complex; wherein the presence of a hybridization complex correlates with the presence of a splice variant nucleic acid sequence in the biological sample. According to the present invention, the splice variants described herein are non-limiting examples of markers for diagnosing prostate cancer and/or prostate pathology. Each splice variant marker of the present invention can be used alone or in combination, for various uses, including but not limited to, prognosis, prediction, screening, early diagnosis, determination of progression, therapy selection and treatment monitoring of prostate cancer and/or prostate pathology.

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

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

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

Non- limiting examples of methods or assays are described below. The present invention also relates to kits based upon such diagnostic methods or assays.

Nucleic acid sequences and Oligonucleotides

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

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

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

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

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

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

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

Alternatively, an oligonucleotide probe of the present invention can be designed to hybridize with a nucleic acid sequence encompassed by any of the above nucleic acid sequences, particularly the portions specified above, including but not limited to a nucleotide sequence coding for an amino sequence of a bridge, tail, head and/or insertion according to the present invention, and/or the equivalent portions of any nucleotide sequence given herein (including but not limited to a nucleotide sequence of a node, segment or amplicon described herein). Oligonucleotides designed according to the teachings of the present invention can be generated according to any oligonucleotide synthesis method known in the art such as enzymatic synthesis or solid phase synthesis. Equipment and reagents for executing solid-phase synthesis are commercially available from, for example, Applied Biosystems. Any other means for such synthesis may also be employed; the actual synthesis of the oligonucleotides is well within the capabilities of one skilled in the art and can be accomplished via established methodologies as detailed in, for example, "Molecular Cloning: A laboratory Manual" Sambrook et al., (1989); "Current Protocols in Molecular Biology" Volumes I-III Ausubel, R. M., ed. (1994); Ausubel et al., "Current Protocols in Molecular Biology", John Wiley and Sons, Baltimore, Maryland (1989); Perbal, "A Practical Guide to Molecular Cloning", John Wiley & Sons, New York (1988) and "Oligonucleotide Synthesis" Gait, M. J., ed. (1984) utilizing solid phase chemistry, e.g. cyanoethyl phosphoramidite followed by deprotection, desalting and purification by for example, an automated trityl-on method or HPLC.

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

The oligonucleotides of the present invention may comprise heterocylic nucleosides consisting of purines and the pyrimidines bases, bonded in a 3' to 5' phosphodiester linkage. Preferably used oligonucleotides are those modified at one or more of the backbone, internucleoside linkages or bases, as is broadly described hereinunder.

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

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

Alternatively, modified oligonucleotide backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH₂ component parts, as disclosed in U.S. Pat. Nos. 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,264,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,610,289; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623, 070; 5,663,312; 5,633,360; 5,677,437; and 5,677,439. Other oligonucleotides which can be used according to the present invention, are those modified in both sugar and the internucleoside linkage, Le., the backbone, of the nucleotide units are replaced with novel groups. The base units are maintained for complementation with the appropriate polynucleotide target. An example for such an oligonucleotide mimetic, includes peptide nucleic acid (PNA). United States patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos. 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Other backbone modifications, which can be used in the present invention are disclosed in U.S. Pat. No: 6,303,374.

Oligonucleotides of the present invention may also include base modifications or substitutions. As used herein, "unmodified" or "natural" bases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). Modified bases include but are not limited to other synthetic and natural bases such as 5- methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8- substituted adenines and guanines, 5- halo particularly 5-bromo, 5-trifluoromethyl and other 5- substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8- azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine. Further bases particularly useful for increasing the binding affinity of the oligomeric compounds of the invention include 5-substituted pyrirnidines, 6-azapyrimidines and N-2, N-6 and O-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6- 1.2 ⁰C and are presently preferred base substitutions, even more particularly when combined with 2'-O-methoxyethyl sugar modifications. Another modification of the oligonucleotides of the invention involves chemically linking to the oligonucleotide one or more moieties or conjugates, which enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. Such moieties include but are not limited to lipid moieties such as a cholesterol moiety, cholic acid, a thioether, e.g., hexyl-S- tritylthiol, a thiocholesterol, an aliphatic chain, e.g., dodecandiol or undecyl residues, a phospholipid, e.g., di-hexadecyl-rac- glycerol or triethylammonium 1,2-di-O-hexadecyl-rac- glycero-3-H-phosphonate, a polyamine or a polyethylene glycol chain, or adamantane acetic acid, a palmityl moiety, or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety, as disclosed in U.S. Pat. No: 6,303,374.

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

It will be appreciated that oligonucleotides of the present invention may include further modifications for more efficient use as diagnostic agents and/or to increase bioavailability, therapeutic efficacy and reduce cytotoxicity. To enable cellular expression of the polynucleotides of the present invention, a nucleic acid construct according to the present invention may be used, which includes at least a coding region of one of the above nucleic acid sequences, and further includes at least one cis acting regulatory element. As used herein, the phrase "cis acting regulatory element" refers to a polynucleotide sequence, preferably a promoter, which binds a trans acting regulator and regulates the transcription of a coding sequence located downstream thereto. Any suitable promoter sequence can be used by the nucleic acid construct of the present invention.

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

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

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

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

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

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

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

Thus, the isolated polynucleotides (oligonucleotides) of the present invention are preferably hybridizable with any of the herein described nucleic acid sequences under moderate to stringent hybridization conditions. Moderate to stringent hybridization conditions are characterized by a hybridization solution such as containing 10 % dextrane sulfate, 1 M NaCl, 1 % SDS and 5 x 10^ cpm ³²P labeled probe, at 65 ⁰C, with a final wash solution of 0.2 x SSC and 0.1 % SDS and final wash at 65⁰C and whereas moderate hybridization is effected using a hybridization solution containing 10 % dextrane sulfate, 1 M NaCl, 1 % SDS and 5 x 10⁶ cpm ³²P labeled probe, at 65 ⁰C, with a final wash solution of 1 x SSC and 0.1 % SDS and final wash at 50 ⁰C.

More generally, hybridization of short nucleic acids (below 200 bp in length, e.g. 17-40 bp in length) can be effected using the following exemplary hybridization protocols which can be modified according to the desired stringency; (i) hybridization solution of 6 x SSC and 1 % SDS or 3 M TMACI, 0.01 M sodium phosphate (pH 6.8), 1 mM EDTA (pH 7.6), 0.5 % SDS, 100 μg/ml denatured salmon sperm DNA and 0.1 % nonfat dried milk, hybridization temperature of 1 - 1.5 ⁰C below the T_1n, final wash solution of 3 M TMACI, 0.01 M sodium phosphate (pH 6.8), 1 mM EDTA (pH 7.6), 0.5 % SDS at 1 - 1.5 ⁰C below the T_m; (H) hybridization solution of 6 x SSC and 0.1 % SDS or 3 M TMACI, 0.01 M sodium phosphate (pH 6.8), 1 mM EDTA (pH 7.6), 0.5 % SDS, 100 μg/ml denatured salmon sperm DNA and 0.1 % nonfat dried milk, hybridization temperature of 2 - 2.5 ⁰C below the T_m, final wash solution of 3 M TMACI, 0.01 M sodium phosphate (pH 6.8), 1 mM EDTA (pH 7.6), 0.5 % SDS at 1 - 1.5 ⁰C below the T_m, final wash solution of 6 x SSC, and final wash at 22 ⁰C; (Hi) hybridization solution of 6 x SSC and 1 % SDS or 3 M TMACI, 0.01 M sodium phosphate (pH 6.8), 1 mM EDTA (pH 7.6), 0.5 % SDS, 100 μg/ml denatured salmon sperm DNA and 0.1 % nonfat dried milk, hybridization temperature. The detection of hybrid duplexes can be carried out by a number of methods. Typically, hybridization duplexes are separated from unhybridized nucleic acids and the labels bound to the duplexes are then detected. Such labels refer to radioactive, fluorescent, biological or enzymatic tags or labels of standard use in the art. A label can be conjugated to either the oligonucleotide probes or the nucleic acids derived from the biological sample.

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

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

Those skilled in the art will appreciate that wash steps may be employed to wash away excess target DNA or probe as well as unbound conjugate. Further, standard heterogeneous assay formats are suitable for detecting the hybrids using the labels present on the oligonucleotide primers and probes. It will be appreciated that a variety of controls may be usefully employed to improve accuracy of hybridization assays. For instance, samples may be hybridized to an irrelevant probe and treated with RNAse A prior to hybridization, to assess false hybridization.

Although the present invention is not specifically dependent on the use of a label for the detection of a particular nucleic acid sequence, such a label might be beneficial, by increasing the sensitivity of the detection. Furthermore, it enables automation. Probes can be labeled according to numerous well known methods. As commonly known, radioactive nucleotides can be incorporated into probes of the invention by several methods. Non- limiting examples of radioactive labels include ³H, ¹⁴C, ³²P, and ³⁵S.

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

It will be appreciated that a variety of controls may be usefully employed to improve accuracy of hybridization assays. Probes of the invention can be utilized with naturally occurring sugar-phosphate backbones as well as modified backbones including phosphorothioates, dithionates, alkyl phosphonates and a-nucleotides and the like. Probes of the invention can be constructed of either ribonucleic acid (RNA) or deoxyribonucleic acid (DNA), and preferably of DNA.

NAT Assays

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

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

Amplification of a selected, or target, nucleic acid sequence may be carried out by a number of suitable methods. See generally Kwoh et al., 1990, Am. Biotechnol. Lab. 8:14 Numerous amplification techniques have been described and can be readily adapted to suit particular needs of a person of ordinary skill. Non- limiting examples of amplification techniques include polymerase chain reaction (PCR), ligase chain reaction (LCR), strand displacement amplification (SDA), transcription-based amplification, the q3 replicase system and NASBA (Kwoh et al., 1989, Proc. Natl. Acad. Sci. USA 86, 1173-1177; Lizardi et al., 1988, BioTechnology 6:1197-1202; Malek et al., 1994, Methods MoI. Biol., 28:253-260; and Sambrook et al., 1989, supra). The terminology "amplification pair" (or "primer pair") refers herein to a pair of oligonucleotides (oligos) of the present invention, which are selected to be used together in amplifying a selected nucleic acid sequence by one of a number of types of amplification processes, preferably a polymerase chain reaction. Other types of amplification processes include ligase chain reaction, strand displacement amplification, or nucleic acid sequence-based amplification, as explained in greater detail below. As commonly known in the art, the oligos are designed to bind to a complementary sequence under selected conditions.

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

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

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

John Wiley & Sons Inc., N.Y.).

It will be appreciated that antisense oligonucleotides may be employed to quantify expression of a splice isoform of interest. Such detection is effected at the pre-mRNA level.

Essentially the ability to quantitate transcription from a splice site of interest can be effected based on splice site accessibility. Oligonucleotides may compete with splicing factors for the splice site sequences. Thus, low activity of the antisense oligonucleotide is indicative of splicing activity.

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

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

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

Ligase Chain Reaction (LCR or LAR): The ligase chain reaction [LCR; sometimes referred to as "Ligase Amplification Reaction" (LAR)] has developed into a well-recognized alternative method of amplifying nucleic acids. In LCR, four oligonucleotides, two adjacent oligonucleotides which uniquely hybridize to one strand of target DNA, and a complementary set of adjacent oligonucleotides, which hybridize to the opposite strand are mixed and DNA ligase is added to the mixture. Provided that there is complete complementarity at the junction, ligase will covalently link each set of hybridized molecules. Importantly, in LCR₅ two probes are ligated together only when they base-pair with sequences in the target sample, without gaps or mismatches. Repeated cycles of denaturation, and ligation amplify a short segment of DNA. LCR has also been used in combination with PCR to achieve enhanced detection of single-base changes: see for example Segev, PCT Publication No. W09001069 Al (1990). However, because the four oligonucleotides used in this assay can pair to form two short ligatable fragments, there is the potential for the generation of target- independent background signal. The use of LCR for mutant screening is limited to the examination of specific nucleic acid positions. Self-Sustained Synthetic Reaction (3SR/NASBA): The self- sustained sequence replication reaction (3SR) is a transcription-based in vitro amplification system that can exponentially amplify RNA sequences at a uniform temperature. The amplified RNA can then be utilized for mutation detection. In this method, an oligonucleotide primer is used to add a phage RNA polymerase promoter to the 5¹ end of the sequence of interest. In a cocktail of enzymes and substrates that includes a second primer, reverse transcriptase, RNase H, RNA polymerase and ribo-and deoxyribonucleoside triphosphates, the target sequence undergoes repeated rounds of transcription, cDNA synthesis and second- strand synthesis to amplify the area of interest. The use of 3SR to detect mutations is kinetically limited to screening small segments of DNA (e.g., 200-300 base pairs).

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

A successful diagnostic method must be very specific. A straight-forward method of controlling the specificity of nucleic acid hybridization is by controlling the temperature of the reaction. While the 3SR/NASBA, and Qβ systems are all able to generate a large quantity of signal, one or more of the enzymes involved in each cannot be used at high temperature (i.e., > 55 degrees C). Therefore the reaction temperatures cannot be raised to prevent non-specific hybridization of the probes. If probes are shortened in order to make them melt more easily at low temperatures, the likelihood of having more than one perfect match in a complex genome increases. For these reasons, PCR and LCR currently dominate the research field in detection technologies. The basis of the amplification procedure in the PCR and LCR is the fact that the products of one cycle become usable templates in all subsequent cycles, consequently doubling the population with each cycle. The final yield of any such doubling system can be expressed as: (1+X)ⁿ =y, where "X" is the mean efficiency (percent copied in each cycle), "n" is the number of cycles, and "y" is the overall efficiency, or yield of the reaction. If every copy of a target DNA is utilized as a template in every cycle of a polymerase chain reaction, then the mean efficiency is

100 %. If 20 cycles of PCR are performed, then the yield will be 2²⁰, or 1,048,576 copies of the starting material. If the reaction conditions reduce the mean efficiency to 85 %, then the yield in those 20 cycles will be only 1.85^0, or 220,513 copies of the starting material. In other words, a PCR running at 85 % efficiency will yield only 21 % as much final product, compared to a reaction running at 100 % efficiency. A reaction that is reduced to 50 % mean efficiency will yield less than 1 % of the possible product.

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

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

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

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

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

When a sufficient amount of a nucleic acid to be detected is available, there are advantages to detecting that sequence directly, instead of making more copies of that target, (e.g., as in PCR and LCR). Most notably, a method that does not amplify the signal exponentially is more amenable to quantitative analysis. Even if the signal is enhanced by attaching multiple dyes to a single oligonucleotide, the correlation between the final signal intensity and amount of target is direct. Such a system has an additional advantage that the products of the reaction will not themselves promote further reaction, so contamination of lab surfaces by the products is not as much of a concern. Recently devised techniques have sought to eliminate the use of radioactivity and/or improve the sensitivity in automatable formats. Two examples are the "Cycling Probe Reaction" (CPR), and "Branched DNA" (bDNA). Cycling probe reaction (CPR): The cycling probe reaction (CPR), uses a long chimeric oligonucleotide in which a central portion is made of RNA while the two termini are made of DNA. Hybridization of the probe to a target DNA and exposure to a thermostable RNase H causes the RNA portion to be digested. This destabilizes the remaining DNA portions of the duplex, releasing the remainder of the probe from the target DNA and allowing another probe molecule to repeat the process. The signal, in the form of cleaved probe molecules, accumulates at a linear rate. While the repeating process increases the signal, the RNA portion of the oligonucleotide is vulnerable to RNases that may carried through sample preparation.

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

The detection of at least one sequence change according to various preferred embodiments of the present invention may be accomplished by, for example restriction fragment length polymorphism (RFLP analysis), allele specific oligonucleotide (ASO) analysis,

Denaturing/Temperature Gradient Gel Electrophoresis (DGGE/TGGE), Single-Strand

Conformation Polymorphism (SSCP) analysis or Dideoxy fingerprinting (ddF).

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

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

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

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

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

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

A handful of rare- cutting restriction enzymes with 8 base-pair specificities have been isolated and these are widely used in genetic mapping, but these enzymes are few in number, are limited to the recognition of G+C-rich sequences, and cleave at sites that tend to be highly clustered. Recently, endonucleases encoded by group I introns have been discovered that might have greater than 12 base-pair specificity, but again, these are few in number. Allele specific oligonucleotide (ASO): If the change is not in a recognition sequence, then allele-specific oligonucleotides (ASOs), can be designed to hybridize in proximity to the mutated nucleotide, such that a primer extension or ligation event can bused as the indicator of a match or a mis- match. Hybridization with radioactively labeled allelic specific oligonucleotides (ASO) also has been applied to the detection of specific point mutations. The method is based on the differences in the melting temperature of short DNA fragments differing by a single nucleotide. Stringent hybridization and washing conditions can differentiate between mutant and wild-type alleles. The ASO approach applied to PCR products also has been extensively utilized by various researchers to detect and characterize point mutations in ras genes and gsp/gip oncogenes. Because of the presence of various nucleotide changes in multiple positions, the ASO method requires the use of many oligonucleotides to cover all possible oncogenic mutations.

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

Denaturing/Temperature Gradient Gel Electrophoresis (DGGE/TGGE): Two other methods rely on detecting changes in electrophoretic mobility in response to minor sequence changes. One of these methods, termed "Denaturing Gradient Gel Electrophoresis" (DGGE) is based on the observation that slightly different sequences will display different patterns of local melting when electrophoretically resolved on a gradient gel. In this manner, variants can be distinguished, as differences in melting properties of homoduplexes versus heteroduplexes differing in a single nucleotide can detect the presence of mutations in the target sequences because of the corresponding changes in their electrophoretic mobilities. The fragments to be analyzed, usually PCR products, are "clamped" at one end by a long stretch of GC base pairs (30-80) to allow complete denaturation of the sequence of interest without complete dissociation of the strands. The attachment of a GC "clamp" to the DNA fragments increases the fraction of mutations that can be recognized by DGGE. Attaching a GC clamp to one primer B critical to ensure that the amplified sequence has a low dissociation temperature. Modifications of the technique have been developed, using temperature gradients, and the method can be also applied to RNA-.RNA duplexes. Limitations on the utility of DGGE include the requirement that the denaturing conditions must be optimized for each type of DNA to be tested. Furthermore, the method requires specialized equipment to prepare the gels and maintain the needed high temperatures during electrophoresis. The expense associated with the synthesis of the clamping tail on one oligonucleotide for each sequence to be tested is also a major consideration. In addition, long running times are required for DGGE. The long running time of DGGE was shortened in a modification of DGGE called constant denaturant gel electrophoresis (CDGE). CDGE requires that gels be performed under different denaturant conditions in order to reach high efficiency for the detection of mutations. A technique analogous to DGGE, termed temperature gradient gel electrophoresis

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

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

The SSCP process involves denaturing a DNA segment (e.g., a PCR product) that is labeled on both strands, followed by slow electrophoretic separation on a non-denaturing polyacrylamide gel, so that intra- molecular interactions can form and not be disturbed during the run. This technique is extremely sensitive to variations in gel composition and temperature. A serious limitation of this method is the relative difficulty encountered in comparing data generated in different laboratories, under apparently similar conditions. Dideoxy fingerprinting (ddF): The dideoxy fmgeφrinting (ddF) is another technique developed to scan genes for the presence of mutations. The ddF technique combines components of Sanger dideoxy sequencing with SSCP. A dideoxy sequencing reaction is performed using one dideoxy terminator and then the reaction products are electrophoresed on nondenaturing polyacrylamide gels to detect alterations in mobility of the termination segments as in SSCP analysis. While ddF is an improvement over SSCP in terms of increased sensitivity, ddF requires the use of expensive dideoxynucleotides and this technique is still limited to the analysis of fragments of the size suitable for SSCP (i.e., fragments of 200-300 bases for optimal detection of mutations).

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

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

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

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

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

Amino acid sequences and peptides

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

Polypeptide products can be biochemically synthesized such as by employing standard solid phase techniques. Such methods include but are not limited to exclusive solid phase synthesis, partial solid phase synthesis methods, fragment condensation, classical solution synthesis. These methods are preferably used when the peptide is relatively short (i.e., 10 kDa) and/or when it cannot be produced by recombinant techniques (i.e., not encoded by a nucleic acid sequence) and therefore involves different chemistry. Solid phase polypeptide synthesis procedures are well known in the art and further described by John Morrow Stewart and Janis Dillaha Young, Solid Phase Peptide Syntheses (2nd Ed., Pierce Chemical Company, 1984).

Synthetic polypeptides can optionally be purified by preparative high performance liquid chromatography [Creighton T. (1983) Proteins, structures and molecular principles. WH Freeman and Co. N.Y.], after which their composition can be confirmed via amino acid sequencing. In cases where large amounts of a polypeptide are desired, it can be generated using recombinant techniques such as described by Bitter et al., (1987) Methods in En2ymol. 153:516- 544, Studier et al. (1990) Methods in Enzymol. 185:60-89, Brisson et al. (1984) Nature 310:511- 514, Takamatsu et al. (1987) EMBO J. 6:307-311, Coruzzi et al. (1984) EMBO J. 3:1671-1680 and Brogli et al., (1984) Science 224:838-843, Gurley et al. (1986) MoI. Cell. Biol. 6:559-565 and Weissbach & Weissbach, 1988, Methods for Plant Molecular Biology, Academic Press, NY, Section VDI, pp 421-463.

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

It will be appreciated that peptides identified according the present invention may be degradation products, synthetic peptides or recombinant peptides as well as peptidomimetics, typically, synthetic peptides and peptoids and semipeptoids which are peptide analogs, which may have, for example, modifications rendering the peptides more stable while in a body or more capable of penetrating into cells. Such modifications include, bat are not limited to N terminus modification, C terminus modification, peptide bond modification, including, but not limited to, CH2-NH, CH2-S, CH2-S=O, O=C-NH, CH2-O, CH2-CH2, S=C-NH, CH=CH or CF=CH, backbone modifications, and residue modification. Methods for preparing peptidomimetic compounds are well known in the art and are specified. Further details in this respect are provided hereinunder. Peptide bonds (CO-NH-) within the peptide may be substituted, for example, by N- methylated bonds (-N(CH3)-CO-), ester bonds (-C(R)H-C-O-O-C(R)-N-), ketomethylen bonds (-CO-CH2-), α-aza bonds (-NH-N(R)-CO-), wherein R is any alkyl, e.g., methyl, carba bonds (- CH2-NH-), hydroxyethylene bonds (-CH(0H)-CH2-), thioamide bonds (-CS-NH-), olefinic double bonds (-CH=CH-), retro amide bonds (-NH-C0-), peptide derivatives (-N(R)-CH2-C0-), wherein R is the "normal" side chain, naturally presented on the carbon atom.

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

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

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

As used herein in the specification and in the claims section below the term "amino acid" or "amino acids" is understood to include the 20 naturally occurring amino acids; those amino acids often modified post-translationally in vivo, including, for example, hydroxyproline, phosphoserine and phosphothreonine; and other unusual amino acids including, but not limited to, 2-aminoadipic acid, hydroxylysine, isodesmosine, nor-valine, nor-leucine and ornithine. Furthermore, the term "amino acid" includes both D- and L-amino acids. Table 1 non-conventional or modified amino acids which can be used with the present invention. Table 1

Table 1 Cont.

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

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

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

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

In cases where large amounts of the peptides of the present invention are desired, the peptides of the present invention can be generated using recombinant techniques such as described by Bitter et al., (1987) Methods in Enzymol. 153:516-544, Studier et al. (1990)

Methods in Enzymol. 185:60-89, Brisson et al. (1984) Nature 310:511-514, Takamatsu et al.

(1987) EMBO J. 6:307-311, Coruzzi et al. (1984) EMBO J. 3:1671-1680 and Brogli et al.,

(1984) Science 224:838-843, Gurley et al. (1986) MoI. Cell. Biol. 6:559-565 and Weissbach & Weissbach, 1988, Methods for Plant Molecular Biology, Academic Press, NY, Section VIII, pp

421-463 and also as described above.

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

The functional fragments of antibodies, such as Fab, F(ab')2, and Fv that are capable of binding to macrophages, are described as follows: (1) Fab, the fragment which contains a monovalent antigen-binding fragment of an antibody molecule, can be produced by digestion of whole antibody with the enzyme papain to yield an intact light chain and a portion of one heavy chain; (2) Fab', the fragment of an antibody molecule that can be obtained by treating whole antibody with pepsin, followed by reduction, to yield an intact light chain and a portion of the heavy chain; two Fab¹ fragments are obtained per antibody molecule; (3) (Fab')2, the fragment of the antibody that can be obtained by treating whole antibody with the enzyme pepsin without subsequent reduction; F(ab')2 is a dimer of two Fab' fragments held together by two disulfide bonds; (4) Fv, defined as a genetically engineered fragment containing the variable region of the light chain and the variable region of the heavy chain expressed as two chains; and (5) Single chain antibody ("SCA"), a genetically engineered molecule containing the variable region of the light chain and the variable region of the heavy chain, linked by a suitable polypeptide linker as a genetically fused single chain molecule.

Methods of producing polyclonal and monoclonal antibodies as well as fragments thereof are well known in the art (See for example, Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York, 1988, incorporated herein by reference). Antibody fragments according to the present invention can be prepared by proteolytic hydrolysis of the antibody or by expression in E. coli or mammalian cells (e.g. Chinese hamster ovary cell culture or other protein expression systems) of DNA encoding the fragment. Antibody fragments can be obtained by pepsin or papain digestion of whole antibodies by conventional methods. For example, antibody fragments can be produced by enzymatic cleavage of antibodies with pepsin to provide a 5S fragment denoted F(ab')2. This fragment can be further cleaved using a thiol reducing agent, and optionally a blocking group for the sulfhydryl groups resulting from cleavage of disulfide linkages, to produce 3.5S Fab' monovalent fragments. Alternatively, an enzymatic cleavage using pepsin produces two monovalent Fab' fragments and an Fc fragment directly. These methods are described, for example, by Goldenberg, U.S. Pat. Nos. 4,036,945 and 4,331,647, and references contained therein, which patents are hereby incorporated by reference in their entirety. See also Porter, R. R. [Biochem. J. 73: 119-126 (1959)]. Other methods of cleaving antibodies, such as separation of heavy chains to form monovalent light-heavy chain fragments, further cleavage of fragments, or other enzymatic, chemical, or genetic techniques may also be used, so long as the fragments bind to the antigen that is recognized by the intact antibody. Fv fragments comprise an association of VH and VL chains. This association may be noncovalent, as described in Inbar et al. [Proc. Nat'l Acad. Sci. USA 69:2659-62 (1972O]. Alternatively, the variable chains can be linked by an intermolecular disulfide bond or cross- linked by chemicals such as glutaraldehyde. Preferably, the Fv fragments comprise VH and VL chains connected by a peptide linker. These single- chain antigen binding proteins (sFv) are prepared by constructing a structural gene comprising DNA sequences encoding the VH and VL domains connected by an oligonucleotide. The structural gene is inserted into an expression vector, which is subsequently introduced into a host cell such as E. coli. The recombinant host cells synthesize a single polypeptide chain with a linker peptide bridging the two V domains. Methods for producing sFvs are described, for example, by [Whitlow and Filpula, Methods 2: 97-105 (1991); Bird et al., Science 242:423-426 (1988); Pack et al., Bio/Technology 11:1271-77 (1993); and U.S. Pat. No. 4,946,778, which is hereby incorporated by reference in its entirety.

Another form of an antibody fragment is a peptide coding for a single complementarity- determining region (CDR). CDR peptides ('minimal recognition units") can be obtained by constructing genes encoding the CDR of an antibody of interest. Such genes are prepared, for example, by using the polymerase chain reaction to synthesize the variable region from RNA of antibody-producing cells. See, for example, Larrick and Fry [Methods, 2: 106-10 (1991)]. Humanized forms of non-human (e.g., murine) antibodies are chimeric molecules of immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab') or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin [Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323- 329 (1988); andPresta, Curr. Op. Struct. Biol., 2:593-596 (1992)].

Methods for humanizing non-human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non- human. These non-human amino acid residues are often referred to as import residues, which are typically taken from an import variable domain. Humanization can be essentially performed following the method of Whiter and co-workers [Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Verhoeyen et al., Science, 239:1534- 1536 (1988)], by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such humanized antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies. Human antibodies can also be produced using various techniques known in the art, including phage display libraries [Hoogenboom and Winter, J. MoL Biol, 227:381 (1991); Marks et al., J. MoI. Biol., 222:581 (1991)]. The techniques of Cole et al. and Boemer et al. are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boerner et al., J. Immunol., 147(l):86-95 (1991)]. Similarly, human antibodies can be made by introduction of human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in the following scientific publications: Marks et al., Bio/Technology 10,: 779- 783 (1992); Lonberg et al., Nature 368: 856-859 (1994); Morrison, Nature 368 812-13 (1994); Fishwild et al., Nature Biotechnology 14, 845-51 (1996); Neuberger, Nature Biotechnology 14: 826 (1996); and Lonberg and Huszar, Intern. Rev. Immunol. 13, 65-93 (1995).

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

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

Optionally, a unique epitope may be created in a variant due to a change in one or more post-translational modifications, including but not limited to glycosylation and/or phosphorylation, as described below. Such a change may also cause a new epitope to be created, for example through removal of glycosylation at a particular site. An epitope according to the present invention may also optionally comprise part or all of a unique sequence portion of a variant according to the present invention in combination with at least one other portion of the variant which is not contiguous to the unique sequence portion in the linear polypeptide itself, yet which are able to form an epitope in combination. One or more unique sequence portions may optionally combine with one or more other non-contiguous portions of the variant (including a portion which may have high homology to a portion of the known protein) to form an epitope. Immunoassays

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

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

Optionally, the antibody can be fixed to a solid support to facilitate washing and subsequent isolation of the complex, prior to contacting the antibody with a sample. Examples of solid supports include but are not limited to glass or plastic in the form of, e.g., a microliter plate, a stick, a bead, or a microbead. Antibodies can also be attached to a solid support. After incubating the sample with antibodies, the mixture is washed and the antibody- marker complex formed can be detected. This can be accomplished by incubating the washed mixture with a detection reagent. Alternatively, the marker in the sample can be detected using an indirect assay, wherein, for example, a second, labeled antibody is used to detect bound marker-specific antibody, and/or in a competition or inhibition assay wherein, for example, a monoclonal antibody which binds to a distinct epitope of the marker are incubated simultaneously with the mixture.

Throughout the assays, incubation and/or washing steps may be required after each combination of reagents. Incubation steps can vary from about 5 seconds to several hours, preferably from about 5 minutes to about 24 hours. However, the incubation time will depend upon the assay format, marker, volume of solution, concentrations and the like. Usually the assays will be carried out at ambient temperature, although they can be conducted over a range of temperatures, such as 10 ⁰C to 40 ⁰C.

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

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

Radioimmunoassay (RIA): In one version, this method involves precipitation of the desired substrate and in the methods detailed hereinbelow, with a specific antibody and

J25 radiolabeled antibody binding protein (e.g., protein A labeled with 1 ) immobilized on a precipitable carrier such as agarose beads. The number of counts in the precipitated pellet is proportional to the amount of substrate.

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

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

Western blot: This method involves separation of a substrate from other protein by means of an acrylamide gel followed by transfer of the substrate to a membrane (e.g., nylon or PVDF).

Presence of the substrate is then detected by antibodies specific to the substrate, which are in turn detected by antibody binding reagents. Antibody binding reagents may be, for example, protein

A, or other antibodies. Antibody binding reagents may be radiolabeled or enzyme linked as described hereinabove. Detection may be by autoradiography, colorimetric reaction or chemiluminescence. This method allows both quantitation of an amount of substrate and determination of its identity by a relative position on the membrane which is indicative of a migration distance in the acrylamide gel during electrophoresis.

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

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

Radio-imaging Methods

These methods include but are not limited to, positron emission tomography (PET) single photon emission computed tomography (SPECT). Both of these techniques are non¬ invasive, and can be used to detect and/or measure a wide variety of tissue events and/or functions, such as detecting cancerous cells for example. Unlike PET, SPECT can optionally be used with two labels simultaneously. SPECT has some other advantages as well, for example with regard to cost and the types of labels that can be used. For example, US Patent No. etaletal

6,696,686 describes the use of SPECT for detection of breast cancer, and is hereby incorporated by reference as if fully set forth herein.

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

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

The following sections relate to Candidate Marker Examples.

CANDIDATE MARKER EXAMPLES SECTION

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

Description of the methodology undertaken to uncover the biomolecular sequences of the present invention Human ESTs and cDNAs were obtained from GenBank versions 136 (June 15, 2003 ftp.ncbi.nih.gov/genbank/release.notes/gbl36.release.notes); NCBI genome assembly of April 2003; RefSeq sequences from June 2003; Genbank version 139 (December 2003); Human Genome from NCBI (Build 34) (from Oct 2003); and RefSeq sequences from December 2003; and the LifeSeq library from Incyte Corporation (Wilmington, DE, USA; ESTs only). With regard to GenBank sequences, the human EST sequences from the EST (GBEST) section and the human mRNA sequences from the primate (GBPRI) section were used; also the human nucleotide RefSeq mRNA sequences were used (see for example www.ncbi.nlm.nih.gov/Genbank/GenbankOverview.html and for a reference to the EST section, see www.ncbi.nhn.nih.gov/dbEST/; a general reference to dbEST, the EST database in

GenBank, may be found in Boguski et al, Nat Genet. 1993 Aug;4(4):332-3; all of which are hereby incorporated by reference as if fully set forth herein).

Novel splice variants were predicted using the LEADS clustering and assembly system as described in Sorek, R., Ast, G. & Graur, D. Alu-containing exons are alternatively spliced. Genome Res 12, 1060-7 (2002); US patent No: 6,625,545; and U.S. Pat. Appl. No. 10/426,002, published as US20040101876 on May 27 2004; all of which are hereby incorporated by reference as if fully set forth herein. Briefly, the software cleans the expressed sequences from repeats, vectors and immunoglobulins. It then aligns the expressed sequences to the genome taking alternatively splicing into account and clusters overlapping expressed sequences into "clusters" that represent genes or partial genes.

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

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

Identification of differentially expressed gene products — Algorithm

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

Library annotation - EST libraries are manually classified according to: (i) Tissue origin

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

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

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

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

EXAMPLE 2

Identification of genes over expressed in cancer. Two different scoring algorithms were developed.

Libraries score -candidate sequences which are supported by a number of cancer libraries, are more likely to serve as specific and effective diagnostic markers. The basic algorithm - for each cluster the number of cancer and normal libraries contributing sequences to the cluster was counted. Fisher exact test was used to check if cancer libraries are significantly over-represented in the cluster as compared to the total number of cancer and normal libraries.

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

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

The algorithm - Clone counting: For counting EST clones each library protocol class was given a weight based on our belief of how much the protocol reflects actual expression levels: (i) non-normalized : 1 (ii) normalized : 0.2 (iii) all other classes : 0.1 Clones number score - The total weighted number of EST clones from cancer libraries was compared to the EST clones from normal libraries. To avoid cases where one library contributes to the majority of the score, the contribution of the library that gives most clones for a given cluster was limited to 2 clones. The score was computed as

where: c - weighted number of "cancer" clones in the cluster. C- weighted number of clones in all "cancer" libraries. n - weighted number of "normal" clones in the cluster.

Ν- weighted number of clones in all "normal" libraries.

Clones number score significance - Fisher exact test was used to check if EST clones from cancer libraries are significantly over-represented in the cluster as compared to the total number of EST clones from cancer and normal libraries. Two search approaches were used to find either general cancer- specific candidates or tumor specific candidates.

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

EXAMPLE 3

Identification of tissue specific genes

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

The algorithm - for each tested tissue T and for each tested cluster the following were examined: 1. Each cluster includes at least 2 libraries from the tissue T. At least 3 clones (weighed - as described above) from tissue T in the cluster; and

2. Clones from the tissue T are at least 40 % from all the clones participating in the tested cluster Fisher exact test P- values were computed both for library and weighted clone counts to check that the counts are statistically significant.

EXAMPLE 4

Identification of splice variants over expressed in cancer of clusters which are not over expressed in cancer

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

Identification of unique sequence regions in splice variants

A Region is defined as a group of adjacent exons that always appear or do not appear together in each splice variant. A "segment" (sometimes referred also as "seg" or "node") is defined as the shortest contiguous transcribed region without known splicing inside.

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

(i) Unspliced; (ii) Not covered by RNA;

(iii) Not covered by spliced ESTs; and

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

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

(i) Aligned to the genome; and

(ii) Regions supported by more than 2 ESTs.

The algorithm

Each unique sequence region divides the set of transcripts into 2 groups: (i) Transcripts containing this region (group TA).

(ii) Transcripts not containing this region (group TB). The set of EST clones of every cluster is divided into 3 groups: (i) Supporting (originating from) transcripts of group TA (Sl). (ii) Supporting transcripts of group TB (S2). (iii) Supporting transcripts from both groups (S3). Library and clones number scores described above were given to Sl group.

Fisher Exact Test P- values were used to check if: Sl is significantly enriched by cancer EST clones compared to S2; and Sl is significantly enriched by cancer EST clones compared to cluster background (S1+S2+S3). Identification of unique sequence regions and division of the group of transcripts accordingly is illustrated in Figure 2. Each of these unique sequence regions corresponds to a segment, also termed herein a "node".

Region 1: common to all transcripts, thus it is not considered; Region 2: specific to Transcript 1: T_l unique regions (2+6) against T_2+3 unique regions (3+4); Region 3: specific to Transcripts 2+3: T_2+3 unique regions (3+4) against Tl unique regions (2+6); Region 4: specific to Transcript 3: T_3 unique regions (4) against Tl+2 unique regions (2+5+6); Region 5: specific to Transcript 1+2: T_l+2 unique regions (2+5+6) against T3 unique regions (4); Region 6: specific to Transcript 1: same as region 2.

EXAMPLE 5

Identification of cancer specific splice variants of genes over expressed in cancer

A search for EST supported (no mRNA) regions for genes of: (i) known cancer markers

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

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

(i) 3 spliced ESTs; or (ii) 2 spliced ESTs from 2 libraries;

(iii) 10 unspliced ESTs from 2 libraries, or (iv) 3 libraries.

Actual Marker Examples

The following examples relate to specific actual marker examples.

EXPERIMENTAL EXAMPLES SECTION

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

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

Experimental Procedures" section below.

Table 2: Tissue samples in testing panel

Materials and Experimental Procedures

RNA preparation - RNA was obtained from Clontech (Franklin Lakes, NJ USA 07417, www.clontech.com), BioChain Inst. Inc. (Hayward, CA 94545 USA www.biochain.com), ABS (Wilmington, DE 19801, USA, http://www.absbioreagents.com) or Ambion (Austin, TX 78744 USA, http://www.ambion.com). Alternatively, RNA was generated from tissue samples using TRI-Reagent (Molecular Research Center), according to Manufacturer's instructions. Tissue and RNA samples were obtained from patients or from postmortem. Total RNA samples were treated with DNaseI (Ambion) and purified using RNeasy columns (Qiagen).

RT PCR - Purified RNA (1 μg) was mixed with 150 ng Random Hexamer primers (Invitrogen) and 500 μM dNTP in a total volume of 15.6 μl. The mixture was incubated for 5 min at 65 °C and then quickly chilled on ice. Thereafter, 5 μl of 5X Superscript!! first strand buffer (Invitrogen), 2.4μl 0.1M DTT and 40 units RNasin (Promega) were added, and the mixture was incubated for 10 min at 25 ⁰C, followed by further incubation at 42 ⁰C for 2 min. Then, 1 μl (200units) of Superscript]! (Invitrogen) was added and the reaction (final volume of 25μl) was incubated for 50 min at 42 °C and then inactivated at 70 ⁰C for 15min. The resulting cDNA was diluted 1:20 in TE buffer (10 mM Tris pH=8, 1 mM EDTA pH=8).

Real-Time RT-PCR analysis- cDNA (5μl), prepared as described above, was used as a template in Real- Time PCR reactions using the SYBR Green I assay (PE Applied Biosystem) with specific primers and UNG Enzyme (Eurogentech or ABI or Roche). The amplification was effected as follows: 50 ⁰C for 2 min, 95 ⁰C for 10 min, and then 40 cycles of 95 ⁰C for 15sec, followed by 60 ⁰C for 1 min. Detection was performed by using the PE Applied Biosystem SDS 7000. The cycle in which the reactions achieved a threshold level (Ct) of fluorescence was registered and was used to calculate the relative transcript quantity in the RT reactions. The relative quantity was calculated using the equation Q=efficiency^Λ"Ct. The efficiency of the PCR reaction was calculated from a standard curve, created by using serial dilutions of several reverse transcription (RT) reactions. To minimize inherent differences in the RT reaction, the resulting relative quantities were normalized to the geometric mean of the relative quantities of several housekeeping (HSKP) genes. Schematic summary of quantitative reattime PCR analysis is presented in Figure 3. As shown, the x-axis shows the cycle number. The GT/ = Threshold Cycle point, which is the cycle that the amplification curve crosses the fluorescence threshold that was set in the experiment. This point is a calculated cycle number in which PCR product signal is above the background level (passive dye ROX) and still in the Geometric/Exponential phase (as shown, once the level of fluorescence crosses the measurement threshold, it has a geometrically increasing phase, during which measurements are most accurate, followed by a linear phase and a plateau phase; for quantitative measurements, the latter two phases do not provide accurate measurements). The y-axis shows the normalized reporter fluorescence. It should be noted that this type of analysis provides relative quantification.

The sequences of the housekeeping genes measured in all the examples below on prostate panel were as follows: SDHA (GenBank Accession No. NM_004168) SDHA Forward primer: TGGGAACAAGAGGGCATCTG SDHA Reverse primer: CCACCACTGCATCAAATTCATG SDHA-amplicon :

TGGGAACAAGAGGGCATCTGCTAAAGTTTCAGATTCCATTTCTGCTCAGTATCCAGT AGTGGATCATGAATTTGATGCAGTGGTGG

PBGD (GenBank Accession No. BC019323), PBGD Forward primer: TGAGAGTGATTCGCGTGGG

PBGD Reverse primer: CCAGGGTACGAGGCTTTCAAT

PBGD- amplicon:

TGAGAGTGATTCGCGTGGGTACCCGCAAGAGCCAGCTTGCTCGCATACAGACGGAC

AGTGTGGTGGCAACATTGAAAGCCTCGTACCCTGG

HPRTl (GenBank Accession No. NM_000194),

HPRTl Forward primer: TGACACTGGCAAAACAATGCA

HPRTl Reverse primer: GGTCCTTTTCACCAGCAAGCT

HPRTl -amplicon: TGACACTGGCAAAACAATGCAGACTTTGCTTTCCTTGGTCAGGCAGTATAATCCAA

AGATGGTCAAGGTCGCAAGCTTGCTGGTGAAAAGGACC

RPLl 9 (GenBank Accession No. NM_000981 RPL19Forward primer: TGGCAAGAAGAAGGTCTGGTTAG RPL19Reverse primer: TGATCAGCCCATCTTTGATGAG

RPL19-amplicon :

TGGCAAGAAGAAGGTCTGGTTAGACCCCAATGAGACCAATGAAATCGCCAATGCCA ACTCCCGTCAGCAGATCCGGAAGCTCATCAAAGATGGGCTGATCA

The sequences of the housekeeping genes measured in all the examples on normal tissue samples panel were as follows: RPL19 (GenBank Accession No. NM_000981),

RPL19 Forward primer: TGGCAAGAAGAAGGTCTGGTTAG

RPLl 9 Reverse primer: TGATCAGCCCATCTTTGATGAG RPLl 9 -amplicon:

TGGCAAGAAGAAGGTCTGGTTAGACCCCAATGAGACCAATGAAATCGCCAATGCCA

ACTCCCGTCAGCAGATCCGGAAGCTCATCAAAGATGGGCTGATCA TATA box (GenBank Accession No. NM_003194),

TATA box Forward primer : CGGTTTGCTGCGGTAATCAT TATA box Reverse primer: TTTCTTGCTGCCAGTCTGGAC

TATA box -amplicon:

CGGTTTGCTGCGGTAATCATGAGGATAAGAGAGCCACGAACCACGGCACTGATTTT

CAGTTCTGGGAAAATGGTGTGCACAGGAGCCAAGAGTGAAGAACAGTCCAGACTG

GCAGCAAGAAA UBC (GenBank Accession No. BC000449)

UBC Forward primer: ATTTGGGTCGCGGTTCTTG

UBC Reverse primer: TGCCTTGACATTCTCGATGGT

UBC -amplicon:

ATTTGGGTCGCGGTTCTTGTTTGTGGATCGCTGTGATCGTCACTTGACAATGCAGAT CTTCGTGAAGACTCTGACTGGTAAGACCATCACCCTCGAGG

TTGAGCCCAGTGACACCATCGAGAATGTCAAGGCA

SDHA (GenBank Accession No. NM_004168) SDHA Forward primer:

TGGGAACAAGAGGGCATCTG

SDHA Reverse primer: CCACCACTGCATCAAATTCATG SDHA-amplicon :

TGGGAACAAGAGGGCATCTGCTAAAGTTTCAGATTCCATTTCTGCTCAGTATCCAGT

AGTGGATCATGAATTTGATGCAGTGGTGG

Oligonucleotide-based micro-array experiment protocol- Microarray fabrication Microarrays (chips) w≤re printed by pin deposition using the MicroGrid II MGII 600 robot from BioRobtics Limited (Cambridge, UK). 50-mer oligonucleotides target sequences were designed by Compugen Ltd (Tel- Aviv, IL) as described by A. Shoshan et al, "Optical technologies and informatics", Proceedings of SPIE. VoI 4266, pp. 86-95 (2001). The designed oligonucleotides were synthesized and purified by desalting with the Sigma-Genosys system (The Woodlands, TX, US) and all of the oligonucleotides were joined to a C6 amino- modified linker at the 5' end, or being attached directly to CodeLmk slides (Cat #25-6700-01. Amersham Bioscience, Piscataway, NJ, US). The 50-mer oligonucleotides, forming the target sequences, were first suspended in Ultra-pure DDW (Cat # 01-866- IA Kibbutz Beit-Haemek, Israel) to a concentration of 50μM. Before printing the slides, the oligonucleotides were resuspended in 30OmM sodium phosphate (pH 8.5) to final concentration of 15OmM and printed at 35-40% relative humidity at 21⁰C.

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

Post-coupling processing of printed slides

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

Slides were treated for blocking of the residual reactive groups by incubating them in blocking solution at 5O⁰C for 15 minutes (lOml/slide of buffer containing 0.1M Tris, 5OmM ethanolamine, 0.1% SDS). The slides were then rinsed twice with Ultra-pure DDW (double distilled water). The slides were then washed with wash solution (10ml/slide. 4X SSC, 0.1% SDS)) at 50⁰C for 30 minutes on the shaker. The slides were then rinsed twice with Ultra-pure DDW, followed by drying by centrifugation for 3 minutes at 800 rpm. Next, in order to assist in automatic operation of the hybridization protocol, the slides were treated with Ventana Discovery hybridization station barcode adhesives. The printed slides were loaded on a Bio-Optica (Milan, Italy) hematology staining device and were incubated for 10 minutes in 50ml of 3-Aminopropyl Triethoxysilane (Sigma A3648 lot #122K589). Excess fluid was dried and slides were then incubated for three hours in 20 rnm/Hg in a dark vacuum desiccator (Pelco 2251, Ted Pella, Inc. Redding CA).

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

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

The slides were then scanned with GenePix 4000B dual laser scanner from Axon Instruments Inc, and analyzed by GenePix Pro 5.0 software. Schematic summary of the oligonucleotide based microarray fabrication and the experimental flow is presented in Figures4 and5.

Briefly, as shown in Figure 4, DNA oligonucleotides at 25uM were deposited (printed) onto Amersham 'CodeLink' glass slides generating a well defined 'spot'. These slides are covered with a long-chain, hydrophilic polymer chemistry that creates an active 3-D surface that covalently binds the DNA oligonucleotides 5 '-end via the

C6-amine modification. This binding ensures that the full length of the DNA oligonucleotides is available for hybridization to the cDNA and also allows lower background, high sensitivity and reproducibility.

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

DESCRIPTION FOR CLUSTER HSECADH

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

Table 4 - Transcripts of interest

2560

105

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

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

Protein Epithelial-cadherin is known or believed to have the following function(s): Cadherins are calcium dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. E-cadherin has a potent invasive suppressor role. It is also a ligand for integrin alpha- E/beta-7. The sequence for protein Epithelial-cadherin precursor is given at the end of the application, as "Epithelial-cadherin precursor amino acid sequence". Known polymorphisms for this sequence are as shown in Table 7.

Table 7 — Amino acid mutations for Known Protein

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

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

The GO assignment relies on information from one or more of the SwissProt/TremBl Protein knowledgebase, available from <http://www.expasy.ch/sprot/>; or Locuslink, available from <http://www.ncbi.nhn.nih.gov/projects/LocusLink/>.

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

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

Table 8 - Normal tissue distribution

As noted above, cluster HSECADH features 4 transcript(s), which were listed in Table 4 above. These transcript(s) encode for protein(s) which are variant(s) of protein Epithelial- cadherin precursor. A description of each variant protein according to the present invention is now provided.

Variant protein HSECADHJP9 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSECADH_T11. An alignment is given to the known protein (Epithelial-cadherin precursor) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between HSECADH_P9 and Q9UII7 (SEQ ID NO:483): 1.An isolated chimeric polypeptide encoding for HSECADH_P9, comprising a first amino acid sequence being at least 90 % homologous to

MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFΠERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEG corresponding to amino acids 1 - 274 of Q9UII7, which also corresponds to amino acids 1 - 274 of HSECADH J?9, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence TACRSRIANSCHSGDSWRNSCFANSDSAALAVSSEESGGQRALTAPRG corresponding to amino acids 275 - 322 of HSECADH_P9, wherein said first and second amino acid sequences are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSECADH P9, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TACRSRIANSCHSGDSWRNSCFANSDSAALAVSSEESGGQRALTAPRG in

HSECADH_P9.

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

5 1.An isolated chimeric polypeptide encoding for HSECADH_P9, comprising a first amino acid sequence being at least 90 % homologous to

MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI i o KSNKDKEGKVFYSITGQGADTPPVGVFΠERETGWLKVTEPLDRERIATYTLFSHAVSSN

GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEG corresponding to amino acids 1 - 274 of Q9UII8, which also corresponds to amino acids 1 - 274 of HSECADH P9, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having

15 the sequence TACRSRIANSCHSGDSWRNSCFANSDSAALAVSSEESGGQRALTAPRG corresponding to amino acids 275 - 322 of HSECADH P9, wherein said first and second amino acid sequences are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSECADH_P9, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably

20 at least about 90% and most preferably at least about 95% homologous to the sequence TACRSRIANSCHSGDSWRNSCFANSDSAALAVSSEESGGQRALTAPRG in

HSECADH_P9.

Comparison report between HSECADH_P9 and CAD1_HUMAN:

1.An isolated chimeric polypeptide encoding for HSECADH_P9, comprising a first amino

25 acid sequence being at least 90 % homologous to

MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYTSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN

30 GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEG corresponding to amino acids 1 - 274 of CAD IJHUMAN, which also corresponds to amino acids 1 - 274 of HSECADH_P9, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence

TACRSWANSCHSGDSWRNSCFANSDSAALAVSSEESGGQRALTAPRG corresponding to amino acids 275 - 322 of HSECADH P9, wherein said first and second amino acid sequences are contiguous and in a sequential order.

HSECADH P9.

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

Variant protein HSECADH_P9 also has the following non- silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 10, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSECADH_P9 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 10— Amino acid mutations

Variant protein HSECADH_P9 is encoded by the following transcript(s): HSECADH Tll, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSECADH Tl 1 is shown in bold; this coding portion starts at position 125 and ends at position 1090. The transcript also has the following SNPs as listed in Table 11 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSECADH_P9 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 11 - Nucleic acid SNPs

Variant protein HSECADH_P13 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSECADH_T18. An alignment is given to the known protein (Epithelialrcadherin precursor) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between HSECADHJP13 and Q9UII7:

1.An isolated chimeric polypeptide encoding for HSECADH_P13, comprising a first amino acid sequence being at least 90 % homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFD AESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKPJDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNT YNAAIAYTILSQDPELPDKNMFTINRNTGVISVVTTGLDRESFPTYTLWQAADLQGEGL

STTATAVITVTDTNDNPPIFNPTT corresponding to amino acids 1 - 379 of Q9UII7, which also corresponds to amino acids 1 - 379 of HSECADH P13, and a second amino acid sequence VTL corresponding to amino acids 380 - 382 of HSECADH P 13, wherein said first and second amino acid sequences are contiguous and in a sequential order.

Comparison report between HSECADH_P13 and Q9UTI8:

1.An isolated chimeric polypeptide encoding for HSECADH P13, comprising a first amino acid sequence being at least 90 % homologous to

MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNT YNAAIAYTILSQDPELPDKNMFTINRNTGVISWTTGLDRESFPTYTLWQAADLQGEGL

STTATAVITVTDTNDNPPIFNPTT corresponding to amino acids 1 - 379 of Q9UII8, which also corresponds to amino acids 1 - 379 of HSECADH_P13, and a second amino acid sequence VIL corresponding to amino acids 380 - 382 of HSECADH P 13, wherein said first and second amino acid sequences are contiguous and in a sequential order.

Comparison report between HSECADH_P13 and CAD1_HUMAN: 1.An isolated chimeric polypeptide encoding for HSECADH_P13, comprising a first amino acid sequence being at least 90 % homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRPHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNT YNAAIAYTILSQDPELPDKNMFTINRNTGVISWTTGLDRESFPTYTLWQAADLQGEGL STTATAVITVTDTM)NPPIFNPTT corresponding to amino acids 1 - 379 of CAD1_HUMAN, which also corresponds to amino acids 1 - 379 of HSECADH P13, and a second amino acid sequence VIL corresponding to amino acids 380 - 382 of HSECADH P 13, wherein said first and second amino acid sequences are contiguous and in a sequential order.

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

Variant protein HSECADH_P13 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 12, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSECADH_P13 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 12 - Amino acid mutations

Variant protein HSECADH_P13 is encoded by the following transcript(s): HSECADH-Tl 8, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSECADHJT 18 is shown in bold; this coding portion starts at position 125 and ends at position 1270. The transcript also has the following SNPs as listed in Table 13 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSECADH_P13 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 13 - Nucleic acid SNPs

Variant protein HSECADH-P 14 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSECADH_T19. An alignment is given to the known protein (Epithelialrcadherin precursor) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between HSECADH_P14 and Q9UII7:

1.An isolated chimeric polypeptide encoding for HSECADH_P14, comprising a first amino acid sequence being at least 90 % homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFD AESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNT YNAAIAYTILSQDPELPDKNMFTINRNTGVISWTTGLDRE corresponding to amino acids 1 - 336 of Q9UII7, which also corresponds to amino acids 1 - 336 of HSECADH_P14, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence VRGQEDPEGVEDKCVLAQSRGQSKILLGQLSVNTVMV corresponding to amino acids 337 - 373 of HSECADH P14, wherein said first and second amino acid sequences are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSECADH_P14, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VRGQEDPEGVEDKCVLAQSRGQSKILLGQLSVNTVMV in HSECADH_P14.

Comparison report between HSECADH_P14 and Q9UII8:

1.An isolated chimeric polypeptide encoding for HSECADHJP 14, comprising a first amino acid sequence being at least 90 % homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNT YNAAIAYTILSQDPELPDKNMFTINRNTGVISVVTTGLDRE corresponding to amino acids 1 - 336 of Q9UII8, which also corresponds to amino acids 1 - 336 of HSECADH_P14, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence VRGQEDPEGVEDKCVLAQSRGQSKILLGQLSVNTVMV corresponding to amino acids 337 - 373 of HSECADHJP14, wherein said first and second amino acid sequences are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSECADH_P14, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VRGQEDPEGVEDKCVLAQSRGQSKILLGQLSVNTVMV in HSECADH_P14. Comparison report between HSECADHJP14 and CADIJTUMAN: 1.An isolated chimeric polypeptide encoding for HSECADH P14, comprising a first amino acid sequence being at least 90 % homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTWRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNT YNAAIAYTILSQDPELPDKNMFTINRNTGVISVVTTGLDRE corresponding to amino acids 1 - 336 of CAD IJHUMAN, which also corresponds to amino acids 1 - 336 of HSECADH_P14, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence VRGQEDPEGVEDKCVLAQSRGQSKILLGQLSVNTVMV corresponding to amino acids 337 - 373 of HSECADH_P14, wherein said first and second amino acid sequences are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSECADH-P 14, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VRGQEDPEGVEDKCVLAQSRGQSKILLGQLSVNTVMV in HSECADH_P14.

Variant protein HSECADH_P14 also has the following non- silent SNPs (Single

Nucleotide Polymorphisms) as listed in Table 14, (given according to tieir position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSECADHJP 14 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 14 - Amino acid mutations

Variant protein HSECADH_P14 is encoded by the following transcript(s): HSECADH Tl 9, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSECADHJT 19 is shown in bold; this coding portion starts at position 125 and ends at position 1243. The transcript also has the following SNPs as listed in Table 15 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSECADH_P14 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 15 - Nucleic acid SNPs

Variant protein HSECADHJP 15 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSECADHJT20. An alignment s given to the known protein (Epithelial-cadherin precursor) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between HSECADH_P15 and Q9UII7: 1.An isolated chimeric polypeptide encoding for HSECADH_P15, comprising a first amino acid sequence being at least 90 % homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYT corresponding to amino acids 1 - 229 of Q9UII7, which also corresponds to amino acids 1 - 229 of HSECADH_P15, and a second amino acid sequence VSIS corresponding to amino acids 230 - 233 of HSECADH P 15, wherein said first and second amino acid sequences are contiguous and in a sequential order.

Comparison report between HSECADH_P15 and Q9UII8:

1.An isolated chimeric polypeptide encoding for HSECADH P 15, comprising a first amino acid sequence being at least 90 % homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHP GFDAESYTFTVPRRHLERGRVLGRVNFED

CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVΎAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI

KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYT corresponding to amino acids 1 - 229 of Q9UII8, which also corresponds to amino acids 1 - 229 of HSECADH_P15, and a second amino acid sequence VSIS corresponding to amino acids 230 - 233 of HSECADH P 15, wherein said first and second amino acid sequences are contiguous and in a sequential order.

Comparison report between HSECADHJP 15 and CAD1_HUMAN: 1.An isolated chimeric polypeptide encoding for HSECADH P 15, comprising a first amino acid sequence being at least 90 % homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYT corresponding to amino acids 1 - 229 of CAD1_HUMAN, which also corresponds to amino acids 1 - 229 of HSECADH_P15, and a second amino acid sequence VSIS corresponding to amino acids 230 - 233 of HSECADH_P15, wherein said first and second amino acid sequences are contiguous and in a sequential order.

Variant protein HSECADH_P15 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 16, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSECADH_P15 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 16 - Ammo acid mutations

Variant protein HSECADH P 15 is encoded by the following transcript(s): HSECADH_T20, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSECADH_T20 is shown in bold; this coding portion starts at position 125 and ends at position 823. The transcript also has the following SNPs as listed in Table 17 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSECADH_P15 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 17- Nucleic acid SNPs

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

Segment cluster HSECADH_node_0 according to the present invention is supported by 17 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADHJTll, HSECADH_T18, HSECADH_T19 and HSECADH_T20. Table 18 below describes the starting and ending position of this segment on each transcript. Table 18 - Segment location on transcripts

Segment cluster HSECADH_node_14 according to the present invention is supported by 40 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADHJT11, HSECADH_T18, HSECADHJT19 and HSECADH_T20. Table 19 below describes the starting and ending position of this segment on each transcript.

Table 19 - Segment location on transcripts

Segment cluster HSECADH_node_15 according to the present invention is supported by 1 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T20. Table 20 below describes the starting and ending position of this segment on each transcript.

Table 20 - Segment location on transcripts

Segment cluster HSECADH_node_21 according to the present invention is supported by 40 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADHJT18 and HSECADH_T19. Table 21 below describes the starting and ending position of this segment on each transcript.

Table 21 - Segment location on transcripts

Segment cluster HSECADH_node_22 according to the present invention is supported by 1 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T19. Table 22 below describes the starting and ending position of this segment on each transcript.

Table 22 - Segment location on transcripts

Segment cluster HSECADH_node_25 according to the present invention is supported by 34 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T18. Table 23 below describes the starting and ending position of this segment on each transcript. Table 23 - Segment location on transcripts

Segment cluster HSECADH_node_26 according to the present invention is supported by 1 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T18. Table 24 below describes the starting and ending position of this segment on each transcript.

Table 24 - Segment location on transcripts

Segment cluster HSECADH_node_48 according to the present invention is supported by 44 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11. Table 25 below describes the starting and ending position of this segment on each transcript.

Table 25 - Segment location on transcripts

Segment cluster HSECADH_node_52 according to the present invention is supported by 39 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11. Table 26 below describes the starting and ending position of this segment on each transcript.

Table 26 - Segment location on transcripts

Segment cluster HSECADH_node_53 according to the present invention is supported by 59 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADHJT11. Table 27 below describes the starting and ending position of this segment on each transcript.

Table 27 - Segment location on transcripts

Segment cluster HSECADH_node_54 according to the present invention is supported by 44 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADHJTll. Table 28 below describes the starting and ending position of this segment on each transcript. Table 28 - Segment location on transcripts

Segment cluster HSECADH_node_57 according to the present invention is supported by 67 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADHJTll. Table 29 below describes the starting and ending position of this segment on each transcript.

Table 29 - Segment location on transcripts

Segment cluster HSECADH_node_60 according to the present invention is supported by

260 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH-Tl 1. Table 30 below describes the starting and ending position of this segment on each transcript. Table 30 - Segment location on transcripts

Segment cluster HSECADH_node_62 according to the present invention is supported by 173 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11. Table 31 below describes the starting and ending position of this segment on each transcript.

Table 31 - Segment location on transcripts

Segment cluster HSECADH_node_63 according to the present invention is supported by 162 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11. Table 32 below describes the starting and ending position of this segment on each transcript.

Table 32 - Segment location on transcripts

Segment cluster HSECADH_node_7 according to the present invention is supported by

21 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADHjril, HSECADHJT18, HSECADHJT19 and HSECADHJT20. Table 33 below describes the starting and ending position of this segment on each transcript.

Table 33 - Segment location on transcripts

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

Segment cluster HSECADH_node_l according to the present invention can be found in the following transcript(s): HSECADH_T11, HSECADH_T18, HSECADH_T19 and HSECADH T20. Table 34 below describes the starting and ending position of this segment on each transcript.

Table 34 - Segment location on transcripts

Segment cluster HSECADH_node_l 1 according to the present invention is supported by

23 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11, HSECADH_T18, HSECADH_T19 and HSECADH_T20. Table 35 below describes the starting and ending position of this segment on each transcript. Table 35 - Segment location on transcripts

Segment cluster HSECADH_node_12 according to the present invention is supported by 26 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADHJTl l, HSECADHJT18, HSECADH_T19 and HSECADH_T20. Table 36 below describes the starting and ending position of this segment on each transcript.

Table 36 - Segment location on transcripts

Segment cluster HSECADH_node_17 according to the present invention can be found in the following transcript(s): HSECADH T11, HSECADHJT18 and HSECADH_T19. Table 37 below describes the starting and ending position of this segment on each transcript.

Table 37 - Segment location on transcripts

Segment cluster HSECADH_node_18 according to the present invention is supported by 41 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11, HSECADHJT18 and HSECADH_T19. Table 38 below describes the starting and ending position of this segment on each transcript.

Table 38 - Segment location on transcripts

Segment cluster HSECADH_node_19 according to the present invention can be found in the following transcript(s): HSECADH_T18 and HSECADH_T19. Table 39 below describes the starting and ending position of this segment on each transcript.

Table 39 - Segment location on transcripts

Segment cluster HSECADH_node_3 according to the present invention is supported by 18 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADHJTll, HSECADH_T18, HSECADH_T19 and HSECADH_T20. Table 40 below describes the starting and ending position of this segment on each transcript.

Table 40 - Segment location on transcripts

Segment cluster HSECADH_node_42 according to the present invention is supported by 43 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11. Table 41 below describes the starting and ending position of this segment on each transcript.

Table 41 - Segment location on transcripts

Segment cluster HSECADH_node_45 according to the present invention is supported by 39 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11. Table 42 below describes the starting and ending position of this segment on each transcript.

Table 42 - Segment location on transcripts

Segment cluster HSECADH_node_46 according to the present invention is supported by 40 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11. Table 43 below describes the starting and ending position of this segment on each transcript.

Table 43 - Segment location on transcripts

Segment cluster HSECADH_node_55 according to the present invention is supported by 36 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11. Table 44 below describes the starting and ending position of this segment on each transcript.

Table 44 - Segment location on transcripts

Segment cluster HSECADH_node_56 according to the present invention is supported by 42 libraries. The number of libraries was determined as previously described. This segment can be found in the fellowing transcript(s): HSECADH T11. Table 45 below describes the starting and ending position of this segment on each transcript.

Table 45 - Segment location on transcripts

Segment cluster HSECADH_node_58 according to the present invention is supported by 61 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSECADH_T11. Table 46 below describes the starting and ending position of this segment on each transcript.

Table 46 - Segment location on transcripts

Segment cluster HSECADH_node_59 according to the present invention can be found in the following transcript(s): HSECADH T11. Table 47 below describes the starting and ending position of this segment on each transcript.

Table 47 - Segment location on transcripts

Variant protein alignment to the previously known protein: Sequence name: /tmp/2x0I2XZlA3/JXvUszCm3O:Q9UIl7

Sequence documentation:

Alignment of: HSECADH_P9 x Q9UII7

Alignment segment 1/1:

Quality: 2727.00 Escore: 0

Matching length: 274 Total length: 274

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00 Total Percent Similarity: 100.00 Total Percent

Identity: 100.00

Gaps: Alignment:

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50 I I Il Il I Il I I I I I I M I I I M I I I I I I I I I Il Il I I I I I M I M I I I I I

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50

51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100

I I I I I I I Il I I Il Il I Il Il I I I I I I I I I I I Il I I I Il I I I Il I I Il Il I 51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100

101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150

II I I I I I I I Il I Il Il I Il I Il I I I I I Il Il I I I I I I I III Il I I Il I I I

101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150 . . . . .

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

I Il I I I I I Il Il Il Il I Il I Il I I Il Il I Il I I I I I I I I I I I I Il Il III

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

201 PVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILI 250

II I I Il Il Il I I Il I I Il I I I I I I I I I I I I I Il I Il Il Il Il I I I I I I Il

201 PVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILI 250

251 TVTDQNDNKPEFTQEVFKGSVMEG 274 I I I M I M M I I I M I I M I I M I

251 TVTDQNDNKPEFTQEVFKGSVMEG 274 Sequence name: /tmp/2x0I2XZlA3/JXvUszCm3O:Q9UIl8

Sequence documentation:

Alignment of: HSECADH_P9 x Q9UII8

Alignment segment 1/1:

Quality: 2727.00

Escore: 0

Matching length: 274 Total length: 274

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps: 0

Alignment:

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50

I I Il I Il I Il I I Il I I I I I I I I I I I Il I I Il I I I I Il Il Il Il I I Il I I I

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50

51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100

I Il I Il Il Il I I Il Il I I I Il I I I I I I Il I I I I I I Il I I I Il I Il I Il Il

51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100

101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150 101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

I I Il I I I I I I I I I I I I I I I I I I Il I Il I I I Il I I I I I I I I I I I I I I I I I I 151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

201 PVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILI 250

I I I I I I I Il I I Il I Il I I Il Il I I I Il I I Il Il Il Il I I Il Il I I I I I I I 201 PVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILI 250

251 TVTDQNDNKPEFTQEVFKGSVMEG 274

M I I M I M I I M I M M I I I I I I

251 TVTDQNDNKPEFTQEVFKGSVMEG 274

Sequence name: /tmp/2x0l2XZlA3/JXvϋszCm3O:CADl_HϋMAN

Sequence documentation:

Alignment of: HSECADH_P9 x CADIJHUMAN

Alignment segment 1/1:

Quality: 2727.00

Escore: 0 Matching length: 274 Total length: 274 Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent

Identity: 100.00 Gaps: 0

Alignment:

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50 I M M I I M M I M I M I I I I I M I I M I I I M M M I M M I M M I I I

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50

51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100

Il I Il I Il I I I IM I Il I M I I M M I I I M I I M Il M I Il I M I Il M 51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100

101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150

I Il I I M M I I M M Il Il Il M M I Il I M I M M Il I M Il M Il I I I

101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150 . . . . .

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

II I M I I I I M Il M I I Il M M M M I M I Il Il I Il M I I I Il I I I I I

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

201 PVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILI 250 Il M Il M I Il I M I Il I I M Il Il I Il I Il I I Il Il Il Il Il Il I I Il I

201 PVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILI 250

251 TVTDQNDNKPEFTQEVFKGSVMEG 274 Il Il I Il I I I Il I Il Il I I I M Il

251 TVTDQNDNKPEFTQEVFKGSVMEG 274

Sequence name: /tmp/e5Y8HiBmjB/iwybld8ikl:Q9UII7

Sequence documentation:

Alignment of: HSECADH_P13 x Q9UII7

Alignment segment 1/1:

Quality: 3720.00 Escore: 0

Matching length: 379 Total length: 379 Matching Percent Similarity: 100.00 Matching Percent

Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps:

Alignment:

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50 I I I I I I I M I I I I I I I I I I I I I I I I I M I I I I I M M M I I I I I I I I I I I

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50 . . . . .

51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100 I I I I I I I I I Il I I I I I I I I I I I Il I Il I I I I I I I I I I I I Il I I I I I I I I I

51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100

101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150 Il I M I I I I I M M I Il M M I Il I I M I I I I I I I I I I M I I M I M Il I

101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200 I I I I Il Il I I I Il I I Il Il I I I I Il Il I I I Il I I Il I I Il I I I Il I Il I I 151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

201 PVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILI 250

I I Il I I Il Il I I I I Il I Il Il I I Il I I Il Il I I I I I I I I I Il I I I I Il I I

201 PVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILI 250 . . . . .

251 TVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNTYNAAI 300

I I I I I I l I I I I I I I I l I l I I l I I I I I I I I l I l I l I I l I I I I l I I l I I I I l

251 TVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNTYNAAI 300

301 AYTILSQDPELPDKNMFTINRNTGVISWTTGLDRESFPTYTLWQAADL 350

II I I I I Il I I Il I Il I I Il I I I I I I I I I I I I I I I I Il I I I I I Il I I Il I I

301 AYTILSQDPELPDKNMFTINRNTGVISWTTGLDRESFPTYTLWQAADL 350

351 QGEGLSTTATAVITVTDTNDNPPIFNPTT 379 I I I I I I I I I I I I I I M I I I M I M I M I I

351 QGEGLSTTATAVITVTDTNDNPPIFNPTT 379 Sequence name: /tmp/e5Y8HiBmjB/iwybld8ikl:Q9UII8

Sequence documentation:

Alignment of: HSECADH P13 x Q9UII8

Alignment segment 1/1:

Quality: 3720.00

Escore: 0

Matching length: 379 Total length: 379

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps: 0

Alignment:

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50

51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

I I I I I I I I I I I I I I I I I I I Il Il I Il I Il I I Il I I I I I I Il I I Il I I I I I 151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

201 PVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILI 250

I Il I I Il Il I I I I I Il I I I I I I I I I Il I Il Il Il I I I Il I I Il I I I Il Il

201 PVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILI 250 . . . . .

251 TVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNTYNAAI 300

I M M M I I M MI I IMIIMI IIM MM I M I M MI M I M M M I

251 TVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNTYNAAI 300

301 AYTILSQDPELPDKNMFTINRNTGVISWTTGLDRESFPTYTLVVQAADL 350

II Il I Il Il Il I Il Il I Il Il Il Il Il Il Il Il Il Il I Il Il Il Il Il Il

301 AYTILSQDPELPDKNMFTINRNTGVISWTTGLDRESFPTYTLWQAADL 350

351 QGEGLSTTATAVITVTDTNDNPPIFNPTT 379 I I M I M M I Il M I I I M I I Il M M M

351 QGEGLSTTATAVITVTDTNDNPPIFNPTT 379

Sequence name: /tmp/e5Y8HiBmjB/iwybld8ikl:CADl_HϋMAN

Sequence documentation: Alignment of: HSECADH_P13 x CADl_HUMAN

Alignment segment 1/1:

Quality: 3720.00 Escore: 0

Matching length: 379 Total length: 379

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps: 0

Alignment:

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50

I M I M M I M M M I I I I I M M M I M I I M I I I I I I I I I I I I M I M

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50

51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100

M I M I I M I I I M M I M I M I I M M M M M M M M I I I I I I I I I I

51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100

101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150

I I I M I M I I I M I M M I I I I M I M I M I I I I I Il I I M M I M I I M

101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

I M I I M I M I M M I I I M M I M I M I I M M M M M I I I I I I I I I I

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200 201 PVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILI 250

I I I I I I Il I Il I I I I I I I I Il Il Il I I I I I I I Il I I i I I I I I I I Il Il I I

201 PVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILI 250 . . . . .

251 TVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNTYNAAI 300

II Il Il I Il Il I Il I I I I I I Il Il I I I Il I I Il I Il Il I Il I I Il Il Il I

251 TVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNTYNAAI 300

301 AYTILSQDPELPDKNMFTINRNTGVISWTTGLDRESFPTYTLVVQAADL 350

I I I I Il I I Il I I I I Il I I I I Il I I I Il I I Il I Il I I I Il I I Il I Il Il Il

301 AYTILSQDPELPDKNMFTINRNTGVISWTTGLDRESFPTYTLWQAADL 350

351 QGEGLSTTATAVITVTDTNDNPPIFNPTT 379 I M Il I I I M I I Il I M Il I I I I I Il I I I

351 QGEGLSTTATAVITVTDTNDNPPIFNPTT 379

Sequence name: /tmp/RtiX8vFyZe/iovNeRHKWU:Q9ϋII7

Sequence documentation:

Alignment of: HSECADH_P14 x Q9UII7

Alignment segment 1/1: Quality: 3313.00

Escore: 0

Matching length: 336 Total length: 336 Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent

Identity: 100.00

Gaps: 0

Alignment:

• • • • >

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50

I I I I I Il I Il I I I Il I I I I I I Il I I I I I I I I I I I I I I I I I I I I I I I I I I I 1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50

51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100

I I I Il I I I I I Il Il Il I I Il Il I I I I I Il I I Il Il Il Il Il Il I I I I I I I 51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100 . . . . .

101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150

I Il I I Il Il Il I I Il III I I I Il Il I I I I Il I I I Il I I I Il I I Il I I Il I

101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

II I I I Il I I Il Il I Il I I Il I I I I Il I Il Il Il I Il I I I I Il Il Il I I I I

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

201 PVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILT 250 M I I I I I I M I M I I I I I I I I I M I I I M M I I I I M I I M I Il M M I I

201 PVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILI 250 251 TVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNTYNAAI 300

I I I I I I I I I I I Il Il I Il I I Il I I I I I I I Il Il I I I I I I I I I I I I I I Il I

251 TVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNTYNAAI 300 . . .

301 AYTILSQDPELPDKNMFTINRNTGVISWTTGLDRE 336

II I Il I I I I I I Il Il Il Il I I I I I I I I I Il I Il I I I

301 AYTILSQDPELPDKNMFTINRNTGVISWTTGLDRE 336

Sequence name: /tmp/RtiX8vFyZe/iovNeRHKWU:Q9UII8

Sequence documentation:

Alignment of: HSECADH_P14 x Q9UII8

Alignment segment 1/1:

Quality: 3313.00

Escore: 0 Matching length: 336 Total length: 336

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps: 0 Alignment:

• > • • •

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50

S M MI M IIII MI M IIII I I M I I III IM IM M M I M III M III

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50

51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100

M I I I I I M I I I I I M I M I I M I M I M I Il I M I M I Il M I I I I I M 0 51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100

101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150

I I I I I Il I I M M M I I I I M I I Il I I I M I M I I M I M I I M M I I M

101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150 5 . . . . .

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

M I M I I I M I I I M I M M I I M M I I I M M I I M M M M M M I M

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

0 201 PVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILI 250

I M I I I M M I I I I M Il M M M I M I I Il I I M I M M I M M M I M

201 PVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILI 250

251 TVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNTYNAAI 300 5 I I M I M I I M M M I I I I M I I I I M I I I I I I M I I M Il M M I I I M

251 TVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNTYNAAI 300

301 AYTILSQDPELPDKNMFTINRNTGVISWTTGLDRE 336

I I M I I M M M M I M I I M I Il M I I I Il I M M 0 301 AYTILSQDPELPDKNMFTINRNTGVISVVTTGLDRE 336

Sequence name: /tmp/RtiX8vFyZe/iovNeRHKWU:CADl_HUMAN

Sequence documentation:

Alignment of: HSECADH_P14 x CADIJEUMAN

Alignment segment 1/1:

Quality: 3313.00 Escore: 0

Matching length: 336 Total length: 336

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00 Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps: 0

Alignment:

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50

51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100 51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100

101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150

Il I I I I Il Il I Il I I I I I I Il I I I I Il I Il I I I I I I I I I I I I Il I I I I I I 101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

I M I I M M M M I M M I M I I I M M M I M M I I I M I M I I M M I

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200 . . . . .

201 PVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILI 250

M I l M I l I MM I M IM I l I l M M M M I I l M I I I l I l I l M I I M

201 PVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILI 250

251 TVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNTYNAAI 300

M M M I I I Il Il I I M M I Il I M M M M M Il I M M M I M Il Il I

251 TVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNTYNAAI 300

301 AYTILSQDPELPDKNMFTINRNTGVISWTTGLDRE 336 I I M I I M Il I I I I M M Il M M M Il M I M I M

301 AYTILSQDPELPDKNMFTINRNTGVISWTTGLDRE 336

Sequence name: /tmp/rMRrwmuokD/lrmk2jOfgw:Q9UII7

Sequence documentation: Alignment of: HSECADH P15 x Q9UII7

Alignment segment 1/1:

Quality: 2289.00

Escore: 0

Matching length: 229 Total length: 229

Matching Percent Similarity: 100.00 ' Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps: 0

Alignment:

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50

51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100

101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200 201 PVGVFIIERETGWLKVTEPLDRERIATYT 229

201 PVGVFIIERETGWLKVTEPLDRERIATYT 229

Sequence name: /tmp/rMRrwmuokD/lrmk2jOfgw:Q9UII8

Sequence documentation:

Alignment of: HSECADH_P15 x Q9UII8

Alignment segment 1/1:

Quality: 2289.00 Escore: 0

Matching length: 229 Total length: 229

Gaps: 0

Alignment:

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50 I I I I I Il I I Il I I I I I I I I I I I I I I I I I Il I I I I I I I I Il I I I I i I I I I I

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50

_* • • • •

51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100 M I MII I IIM IM I IIM IM M I M IMIM I MIIM M MI II II

51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100

101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150

II I Il I I I M M Il Il Il Il Il I I M M I M I M M Il I I M M M Il I I 101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

Il I I I M I I I Il Il Il M I M M Il Il M I I Il I I I M I I I Il Il I Il Il

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

201 PVGVFIIERETGWLKVTEPLDRERIATYT 229

I I I Il Il M M I I I M M Il M M I Il M

201 PVGVFIIERETGWLKVTEPLDRERIATYT 229

Sequence name: /tmp/rMRrwmuokD/lrmk2jOfgw:CADl_HUMAN

Sequence documentation:

Alignment of: HSECADH_P15 x CAD1_HUMAN

Alignment segment 1/1: Quality: 2289.00 Escore: 0

Matching length: 229 Total length: 229

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00 Gaps: 0

Alignment:

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50

M M MI I I III I MMII I M I I II I I I I I I I MI MI I MI III IMI

1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGR 50

51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100

M I M M M M I Il I Il I M Il I M I M M M M Il M I Il M I I I I I M

51 VLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLV 100

101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150

M I I Il I Il Il M I I I I M I I M Il I Il M M M I Il Il I I M I M I M I

101 YAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQAELLTFPNSSPGLR 150

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

M I M M I M Il I M III I M M I M I I I M M M M M M Il MM I M

151 RQKRDWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTP 200

201 PVGVFIIERETGWLKVTEPLDRERIATYT 229 201 PVGVFIIERETGWLKVTEPLDRERIATYT 229

DESCRIPTION FOR CLUSTER Rl 1723

Cluster Rl 1723 features 6 transcript(s) and 26 segment(s) of interest, the names for which are given in Tables 48 and 49, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 50.

Table 48 - Transcripts of interest

Cluster Rl 1723 can be used as a diagnostic marker according to overexpression of transcripts of this cluster in cancer. Expression of such transcripts in normal tissues is also given according to the previously described methods. The term "number" in the right hand column of the table and the numbers on the y-axis of Figure 7 refer to weighted expression of ESTs in each category, as "parts per million" (ratio of the expression of ESTs for a particular cluster to the expression of all ESTs in that category, according to parts per million). Overall, the following results were obtained as shown with regard to the histograms in Figure 7 and Table 51. This cluster is overexpressed (at least at a minimum level) in the following pathological conditions: epithelial malignant tumors, a mixture of malignant tumors from different tissues and kidney malignant tumors.

Table 51 - Normal tissue distribution

Table 52 - P values and ratios for expression in cancerous tissue

As noted above, cluster Rl 1723 features 6 transcript(s), which were listed in Table 48 above. A description of each variant protein according to the present invention is now provided.

Variant protein R11723_PEA_1_P2 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) R11723_PEA_1_T6. The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans- membrane region prediction program predicts that this protein has a trans -membrane region..

Variant protein R11723_PEA_1_P2 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 53, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein R11723_PEA_1_P2 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 53 - Amino acid mutations

Variant protein R11723_PEA_1_P2 is encoded by~ the following transcript(s): R11723_PEA_1_T6, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript R11723_PEA_1_T6 is shown in bold; this coding portion starts at position 1716 and ends at position 2051. The transcript also has the following SNPs as listed in Table 54 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein R11723_PEA_1_P2 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 54 - Nucleic acid SNPs

Variant protein R11723_PEA_1_P6 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) R11723_PEA_1_T15. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: Comparison report between Rl 1723_PEA_1_P6 and Q8IXM0 (SEQ ID NO:485): 1.An isolated chimeric polypeptide encoding fir R11723 PEA 1JP6, comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence

MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAGIMYRKSCASSAACLIASAGSPCRGLAPGREEQRALHKAGAVGGGVR corresponding to amino acids 1 - 110 of R11723_PEA_1_P6, and a second amino acid sequence being at least 90 % homologous to MYAQALLWGVLQRQAAAQHLHEHPPKLLRGHRVQERVDDRAEVEKRLREGEEDHV RPEVGPRPVVLGFGRSHDPPNLVGHPAYGQCHNNQPWADTSRRERQRKEKHSMRTQ corresponding to amino acids 1 - 112 of Q8IXM0, which also corresponds to amino acids 111 - 222 of R11723_PEA_1_P6, wherein said first and second amino acid sequences are contiguous and in a sequential order. 2.An isolated polypeptide encoding for a head of R11723_PEA_1_P6, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAGIMYRKSCASSAACLIASAGSPCRGLAPGREEQRALHKAGAVGGGVR of

R11723_PEA_1_P6.

Comparison report between Rl 1723_PEA_1_P6 and Q96AC2 (SEQ ID NO:486): 1.An isolated chimeric polypeptide encoding for R11723_PEA_1_P6, comprising a first amino acid sequence being at least 90 % homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAGIMYRKSCASSAACLIASAG corresponding to amino acids 1 - 83 of Q96AC2, which also corresponds to amino acids 1 - 83 of R11723_PEA_1_P6, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLWGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPWLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ corresponding to amino acids 84 - 222 of R11723_PEA_1_P6, wherein said first and second amino acid sequences are contiguous and in a sequential order. 2.An isolated polypeptide encoding for a tail of R11723_PEA_1_P6, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence

SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLWGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPWLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ in Rl 1723_PEA_1_P6.

Comparison report between R11723_PEA_1_P6 and Q8N2G4 (SEQ ID NO:487): 1.An isolated chimeric polypeptide encoding for Rl 1723_PEA_1_P6, comprising a first amino acid sequence being at least 90 % homologous to

MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFΓVNCTVNVQDMCQKEV

MEQSAGIMYRKSCASSAACLIASAG corresponding to amino acids 1 - 83 of Q8N2G4, which also corresponds to amino acids 1 - 83 of R11723_PEA_1_P6, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLWGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPWLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ corresponding to amino acϋs 84 - 222 of R11723_PEA_1_P6, wherein said first and second amino acid sequences are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of R11723_PEA_1_P6, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLWGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPWLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ in R11723_PEA_1_P6.

Comparison report between Rl 1723_PEA_1_P6 and BAC85518 (SEQ ID NO:488): 1.An isolated chimeric polypeptide encoding for R11723_PEA_1_P6, comprising a first amino acid sequence being at least 90 % homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAGIMYRKSCASSAACLIASAG corresponding to amino acids 24 - 106 of BAC85518, which also corresponds to amino acids 1 - 83 of Rl 1723 PEA 1JP6, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLWGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPWLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ corresponding to amino acids 84 - 222 of R11723_PEA_1_P6, wherein said first and second amino acid sequences are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of R11723_PEA_1_P6, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence

The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans -membrane region prediction program predicts that this protein has a trans -membrane region.. Variant protein R11723_PEA_1_P6 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 55, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein R11723_PEA_1_P6 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 55 -Amino acid mutations

Variant protein R11723_PEA_1_P6 is encoded by the following transcript(s): R11723_PEA_1_T15, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript R11723_PEA_1_T15 is shown in bold; this coding portion starts at position 434 and ends at position 1099. The transcript also has the following SNPs as listed in

Table 56 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein R11723_PEA_1_P6 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 56 - Nucleic acid SNPs

Variant protein Rl 1723_PEA_1 JP7 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s)

R11723_PEA_1_T17. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between Rl 1723_PEA_1_P7 and Q96AC2:

1.An isolated chimeric polypeptide encoding for R11723_PEA_1_P7, comprising a first amnio acid sequence being at least 90 % homologous to

MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFΓVNCTVNVQDMCQKEV

MEQSAG corresponding to amino acids 1 - 64 of Q96AC2, which also corresponds to amnio acids 1 - 64 of R11723_PEA_1_P7, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT corresponding to amino acids 65 - 93 of R11723_PEA_1_P7, wherein said first and second amino acid sequences are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of R11723_PEA_1_P7, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT in R11723_PEA_1_P7. Comparison report between Rl 1723_PEA_1_P7 and Q8N2G4:

LAn isolated chimeric polypeptide encoding for R11723_PEA_1_P7, comprising a first amino acid sequence being at least 90 % homologous to

MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFΓVNCTVNVQDMCQKEV

MEQSAG corresponding to amino acids 1 - 64 of Q8N2G4, which also corresponds to amino acids 1 - 64 of R11723JPEA_1_P7, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT corresponding to amino acids 65 - 93 of R11723_PEA_1_P7, wherein said first and second amino acid sequences are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of R11723_PEA_1_P7, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT in R11723_PEA_1_P7.

Comparison report between Rl 1723_PEA_1_P7 and BAC85273 (SEQ ID NO:489):

1.An isolated chimeric polypeptide encoding for R11723_PEA_1_P7, comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MWVLG corresponding to amino acids 1 - 5 of Rl 1723_PEA_1_P7, second amino acid sequence being at least 90 % homologous to

IAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFΓVNCTVNVQDMCQKEVMEQSAG corresponding to amino acids 22 - 80 of BAC85273, which also corresponds to amino acids 6 - 64 of R11723_PEA_1_P7, and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence

SHCVTRLECSGTISAHCNLCLPGSNDHPT corresponding to amino acids 65 - 93 of R11723_PEA_1_P7, wherein said first, second and third amino acid sequences are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a head of R11723_PEA_1_P7, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence MWVLG of Rl 1723_PEA_1_P7.

3.An isolated polypeptide encoding for a tail of R11723_PEA_1_P7, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT in R11723_PEA_1_P7. Comparison report between Rl 1723_PEA_1JP7 and BAC85518:

1.An isolated chimeric polypeptide encoding for R11723JPEA_1_P7, comprising a first amino acid sequence being at least 90 % homologous to

MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAG corresponding to amino acids 24 - 87 of BAC85518, which also corresponds to amino acids 1 - 64 of R11723JPEA_1_P7, and a second amino acid sequence being at least

70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence

SHCVTRLECSGTISAHCNLCLPGSNDHPT corresponding to amino acids 65 - 93 of R11723_PEA_1_P7, wherein said first and second amino acid sequences are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of R11723_PEA_1_P7, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT in Rl 1723_PEA_1_P7.

Variant protein R11723_PEA_1_P7 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 57, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein R11723_PEA_1_P7 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 57 - Amino acid mutations SNP ρosition(s) on amino acid Alternative amino acid(s) Previously known SNP? sequence

67 C -> S Yes

Variant protein R11723_PEA_1JP7 is encoded by the following transcript(s): R11723_PEA_1_T17, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript R11723_PEA_1_T17 is shown in bold; this coding portion starts at position 434 and ends at position 712. The transcript also has the following SNPs as listed in Table 58 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein R11723_PEA_1_P7 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 58 - Nucleic acid SNPs

Variant protein R11723_PEA_1_P13 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) R11723_PEA_1_T19 and R11723_PEA_1_T5. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between Rl 1723_PEA_1_P13 and Q96AC2: 1.An isolated chimeric polypeptide encoding for R11723JPEA_1_P13, comprising a first amino acid sequence being at least 90 % homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSA corresponding to amino acids 1 - 63 of Q96AC2, which also corresponds to amino acids 1 - 63 of R11723_PEA_1_P13, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence DTKRTNTLLFEMRHFAKQLTT corresponding to amino acids 64 - 84 of Rl 1723_PEA_1_P13, wherein said first and second amino acid sequences are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of R11723 PEA 1 P13, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DTKRTNTLLFEMRHFAKQLTT in R11723JPEA_1_P13.

Variant protein R11723_PEA_1JP13 is encoded by the following transcript(s):

R11723_PEA_1_T19, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript R11723_PEA_1_T19 is shown in bold; this coding portion starts at position 434 and ends at position 685. The transcript also has the following SNPs as listed in Table 59 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein R11723_PEA_1JP13 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 59 - Nucleic acid SNPs

Variant protein R11723_PEA_l_P10 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) R11723_PEA_l_T20. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between Rl 1723_PEA_l_P10 and Q96AC2: 1.An isolated chimeric polypeptide encoding for R11723_PEA_l_P10, comprising a first amino acid sequence being at least 90 % homologous to

MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFΓVNCTVNVQDMCQKEV

MEQSA corresponding to amino acids 1 - 63 of Q96AC2, which also corresponds to amino acids 1 - 63 of R11723_PEA_l_P10, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK corresponding to amino acids 64 - 90 of R11723_PEA_l_P10, wherein said first and second amino acid sequences are contiguous and in a sequential order. 2.An isolated polypeptide encoding for a tail of R11723_PEA_l_P10, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK in Rl 1723_PEA_l_P10.

Comparison report between Rl 1723_PEA_l_P10 and Q8N2G4:

LAn isolated chimeric polypeptide encoding for R11723_PEA_l_P10, comprising a first amino acid sequence being at least 90 % homologous to IVTVmXjIAATFCGLFLLPGFALQIQCYQCEE

MEQSA corresponding to amino acids 1 - 63 of Q8N2G4, which also corresponds to amino acids 1 - 63 of R11723_PEA_l_P10, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK corresponding to amino acids 64 - 90 of Rl 1723 PE A l P 10, wherein said first and second amino acid sequences are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of R11723_PEA_l_P10, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK in R11723_PEA_l_P10.

Comparison report between Rl 1723_PEA_l_P10 and BAC85273: 1.An isolated chimeric polypeptide encoding for R11723_PEA_l_P10, comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MWVLG corresponding to amino acids 1 - 5 of R11723JPEA 1 P10, second amino acid sequence being at least 90 % homologous to IAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEVMEQSA corresponding to amino acids 22 - 79 of BAC85273, which also corresponds to amino acids 6 - 63 of R11723_PEA_l_P10, and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK corresponding to amino acids 64 - 90 of R11723_PEA_l_P10, wherein said first, second and third amino acid sequences are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a head of R11723_PEA_l_P10, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence MWVLG of Rl 1723_PEA_l_P10. 3.An isolated polypeptide encoding for a tail of R11723_PEA_l_P10, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK in R11723_PEA_l_P10.

Comparison report between Rl 1723_PEA_l_P10 and BAC85518: 1.An isolated chimeric polypeptide encoding for R11723_PEA_l_P10, comprising a first amino acid sequence being at least 90 % homologous to

MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNΠDCSSPEFIVNCTVNVQDMCQKEV MEQSA corresponding to amino acids 24 - 86 of BAC85518, which also corresponds to amino acids 1 - 63 of R11723_PEA_l_P10, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK corresponding to amino acids 64 - 90 of Rl 1723_PEA_l_P10, wherein said first and second amino acid sequences are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of R11723_PEA_l_P10, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK in Rl 1723_PEA_l_P10.

Variant protein R11723_PEA_l_P10 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 60, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein R11723_PEA_l_P10 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 60 - Amino acid mutations

Variant protein R11723_PEA_l_P10 is encoded by the following transcript(s): R11723_PEA_l_T20, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript R11723_PEA_l_T20 is shown in bold; this coding portion starts at position 434 and ends at position 703. The transcript also has the following SNPs as listed in Table 61 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein Rl 1723_PEA_l_P10 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 61 - Nucleic acid SNPs

As noted above, cluster Rl 1723 features 26 segment(s), which were listed in Table 49 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.

Segment cluster Rl 1723_PEA_l_node_13 according to the present invention is supported by 5 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_1_T19, R11723_PEA_1_T5 and R11723_PEA_1_T6. Table 62 below describes the starting and ending position of this segment on each transcript.

Table 62 - Segment location on transcripts

Segment cluster R11723_PEA_l_node_16 according to the present invention is supported by 3 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_1_T17, R11723_PEA_1_T19 and R11723_PEA_l_T20. Table 63 below describes the starting and ending position of this segment on each transcript.

Table 63 - Segment location on transcripts

Segment cluster R11723_PEA_l_node_19 according to the present invention is supported by 45 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Rl 1723_PEA_1_T5 and R11723_PEA_1_T6. Table 64 below describes the starting and ending position of this segment on each transcript.

Table 64 - Segment location on transcripts

Segment cluster R11723_PEA_l_node_2 according to the present invention is supported by 29 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_1_T15, R11723_PEA_1_T17, R11723_PEA_1_T19, R11723_PEA_l_T20, R11723_PEA_1_T5 and R11723_PEA_1_T6. Table 65 below describes the starting and ending position of this segment on each transcript.

Table 65 - Segment location on transcripts

Segment cluster R11723_PEA_l_node_22 according to the present invention is supported by 65 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Rl 1723_PEA_1_T5 and R11723_PEA_1_T6. Table 66below describes the starting and ending position of this segment on each transcript.

Table 66 - Segment location on transcripts

Segment cluster R11723_PEA_l_node_31 according to the present invention is supported by 70 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_1_T15, R11723JPEA_1_T5 and R11723_PEA_1_T6. Table 67 below describes the starting and ending position of this segment on each transcript (it should be noted that these transcripts show alternative polyadenylation).

Table 67 - Segment location on transcripts

Segment cluster Rl 1723_PEA_l_node_10 according to the present invention is supported by 38 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_1_T15, R11723_PEA_1_T17,

R11723_PEA_1_T19, R11723_PEA_l_T20, R11723_PEA_1_T5 and R11723_PEA_1_T6. Table 68 below describes the starting and ending position of this segment on each transcript.

Table 68 - Segment location on transcripts

Segment cluster R11723_PEA_l_node_ll according to the present invention is supported by 42 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_1_T15, R11723_PEA_1_T17, R11723_PEA_1_T19, R11723_PEA_l_T20, R11723_PEA_1_T5 and R11723_PEA_1_T6. Table 69 below describes the starting and ending position of this segment on each transcript.

Table 69 - Segment location on transcripts

Segment cluster R11723_PEA_l_node_15 according to the present invention can be found in the following transcript(s): Rl 1723_PEA_l_T20. Table 70 below describes the starting and ending position of this segment on each transcript.

Table 70 - Segment location on transcripts

Segment cluster Rl 1723_PEA_l_node_18 according to the present invention is supported by 40 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_1_T15, Rl 1723_PEA_1_T5 and R11723_PEA_1_T6. Table 71 below describes the starting and ending position of this segment on each transcript. Table 72 - Segment location on transcripts

Segment cluster R11723_PEA_l_node_20 according to the present invention can be found in the following transcript(s): R11723_PEA_1_T5 and R11723_PEA_1_T6. Table 73 below describes the starting and ending position of this segment on each transcript.

Table 73 - Segment location on transcripts

Segment cluster R11723_PEA_l_node_21 according to the present invention is supported by 36 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Rl 1723_PEA_1_T5 and Rl 1723_PEA_1_T6. Table 74 below describes the starting and ending position of this segment on each transcript.

Table 74 - Segment location on transcripts

Segment cluster R11723_PEA_l_node_23 according to the present invention is supported by 39 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_1_T5 and R11723_PEA_1_T6. Table 75 below describes the starting and ending position of this segment on each transcript. Table 75 - Segment location on transcripts

Segment cluster Rl 1723_PEA_l_node_24 according to the present invention is supported by 51 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_1_T15, Rl 1723_PEA_1_T5 and Rl 1723_PEA_1_T6. Table 76 below describes the starting and ending position of this segment on each transcript.

Table 76 - Segment location on transcripts

Segment cluster R11723_PEA_l_node_25 according to the present invention is supported by 54 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_1_T15, Rl 1723_PEA_1_T5 and R11723_PEA_1_T6. Table 77 below describes the starting and ending position of this segment on each transcript.

Table 77 - Segment location on transcripts

Segment cluster Rl 1723_PEA_l_node_26 according to the present invention is supported by 62 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_1_T15, R11723_PEA_1_T5 and R11723_PEA_1_T6. Table 78 below describes the starting and ending position of this segment on each transcript.

Table 78 - Segment location on transcripts

Segment cluster Rl 1723_PEA_l_node_27 according to the present invention is supported by 67 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_1_T15, Rl 1723_PEA_1_T5 and R11723_PEA_1_T6. Table 79 below describes the starting and ending position of this segment on each transcript. Table 79 - Segment location on transcripts

Segment cluster Rl 1723_PEA_l_node_28 according to the present invention can be found in the following transcript(s): R11723_PEA_1_T15, R11723_PEA_1_T5 and R11723_PEA_1_T6. Table 80 below describes the starting and ending position of this segment on each transcript. Table 80 - Segment location on transcripts

Segment cluster R11723_PEA_l_node_29 according to the present invention is supported by 69 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_ 1_T15, R11723_PEA_1_T5 and R11723_PEA_1_T6. Table 81 below describes the starting and ending position of this segment on each transcript.

Table 81 - Segment location on transcripts

Segment cluster Rl 1723_PEA_l_node_3 according to the present invention can be found in the following transcripts): R11723_PEA_1_T15, R11723_PEA_1_T17, R11723_PEA_1_T19, R11723_PEA_l_T20, Rl 1723_PEA_1_T5 and R11723_PEA_1_T6. Table 82 below describes the starting and ending position of this segment on each transcript.

Table 82 - Segment location on transcripts

Segment cluster R11723_PEA_l_node_30 according to the present invention can be found in the following transcript(s): R11723_PEA_1_T15, R11723_PEA_1_T5 and R11723_PEA_1_T6. Table 83 below describes the starting and ending position of this segment on each transcript.

Table 83 - Segment location on transcripts

Segment cluster R11723_PEA_l_node_4 according to the present invention is supported by 25 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_1_T15, R11723_PEA_1_T17, R11723_PEA_1_T19, R11723_PEA_l_T20, Rl 1723_PEA__1_T5 and R11723_PEA_1_T6. Table 84 below describes the starting and ending position of this segment on each transcript. Table 84 - Segment location on transcripts

Segment cluster R11723_PEA_l_node_5 according to the present invention is supported by 26 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_1_T15, R11723_PEA_1_T17, R11723_PEA_1_T19, R11723_PEA_l_T20, R11723_PEA_1_T5 and R11723_PEA_1_T6. Table 84 below describes the starting and ending position of this segment on each transcript.

Table 85 - Segment location on transcripts

Segment cluster R11723_PEA_l_node_6 according to the present invention is supported by 27 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_1_T15, R11723_PEA_1_T17, R11723_PEA_1_T19, R11723_PEA_l_T20, R11723_PEA_1_T5 and Rl 1723_PEA_1_T6. Table 86 below describes the starting and ending position of this segment on each transcript. Table 86 - Segment location on transcripts

Segment cluster R11723_PEA_l_node_7 according to the present invention is supported by 29 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_1_T15, R11723_PEA_1_T17, R11723_PEA_1_T19, R11723_PEA_l_T20, R11723_PEA_1_T5 and R11723_PEA_1_T6. Table 87 below describes the starting and ending position of this segment on each transcript.

Table 87 - Segment location on transcripts

Segment cluster R11723_PEA_l_node_8 according to the present invention is supported by 2 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): R11723_PEA_1_T6. Table 88 below describes the starting and ending position of this segment on each transcript. Table 88 - Segment location on transcripts

It should be noted that the variants of this cluster are variants of the hypothetical protein

PSECOl 81 (referred to herein as "PSEC"). Furthermore, use of the known protein (WT protein) for detection of ovarian cancer, alone or in combination with one or more variants of this cluster and/or of any other cluster and/or of any known marker, also comprises an embodiment of the present invention. It should be noted that the nucleotide transcript sequence of known protein (PSEC, also referred to herein as the "wild type" or WT protein) features at least one SNP that appears to affect the coding region, in addition to certain silent SNPs. This SNP does not have an effect on the R11723_PEA_1_T5 splice variant sequence): "G-> " resulting in a missing nucleotide (affects amino acids from position 91 onwards). The missing nucleotide creates a frame shift, resulting in a new protein. This SNP was not previously identified and is supported by 5 ESTs out of -70 ESTs in this exon.

Variant protein alignment to the previously known protein: Sequence name: /tmp/gp6eQTLWqk/mFtjUpUzhb:Q8IXM0

Sequence documentation:

Alignment of: R11723_PEA_1_P6 x Q8IXM0

Alignment segment 1/1:

Quality: 1128.00

Escore: 0

Matching length: 112 Total length: 112

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps: 0

Alignment: B2005/002560

184

111 MYAQALLWGVLQRQAAAQHLHEHPPKLLRGHRVQERVDDRAEVEKRLRE 160

I I I I Il I I I I I I I I I I I I Il I Il I I I I I i I I I I I Il I I Il I I I I I I I I I I

1 MYAQALLVVGVLQRQAAAQHLHEHPPKLLRGHRVQERVDDRAEVEKRLRE 50

161 GEEDHVRPEVGPRPVVLGFGRSHDPPNLVGHPAYGQCHNNQPWADTSRRE 210

I Il I I I I I I I Il I I I III I I I Il I ! M Il I I I I I I I i I Il I I I I I I I I Il

51 GEEDHVRPEVGPRPWLGFGRSHDPPNLVGHPAYGQCHNNQPWADTSRRE 100

211 RQRKEKHSMRTQ 222 I I M M I I I I I I

101 RQRKEKHSMRTQ 112

Sequence name: /tmp/gp6eQTLWqk/mFtjUpϋzhb:Q96AC2

Sequence documentation:

Alignment of: R11723_PEA_1_P6 x Q96AC2

Alignment segment 1/1:

Quality: 835.00

Escore: 0

Matching length: 83 Total length: 83 Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00 Total Percent Similarity: 100.00 Total Percent

Identity: 100.00

Gaps: 0

Alignment:

1 MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNV 50

I I I I I I I I Il I I I I I I I I I I I I Il I I Il I I I I I Il I Il I I I I I I I Il I I I 1 MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNV 50 . . .

51 QDMCQKEVMEQSAGIMYRKSCASSAACLIASAG 83

I I I I Il I Il I I Il I I I I I I I I I I I I I Il Il I Il

51 QDMCQKEVMEQSAGIMYRKSCASSAACLIASAG 83

Sequence name: /tmp/gp6eQTLWqk/mFtjUpUzhb:Q8N2G4

Sequence documentation:

Alignment of: R11723_PEA_1_P6 x Q8N2G4

Alignment segment 1/1:

Quality: 835.00

Escore: 0 Matching length: 83 Total length: 83 • Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00 Gaps: 0

Alignment:

1 MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNV 50 I I I I I M I I I I I I I I I M I I I I I I M I M M I I M I ! ] I I I I I I I I I I I I

1 MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNV 50

51 QDMCQKEVMEQSAGIMYRKSCASSAACLIASAG 83

Il I Il I I Il Il I I Il I I I I ! i I Il I I I I I I Il I 51 QDMCQKEVMEQSAGIMYRKSCASSAACLIASAG 83

Sequence name: /tmp/gp6eQTLWqk/mFtjUpUzhb:BAC85518

Sequence documentation:

Alignment of: R11723_PEA_1_P6 x BAC85518

Alignment segment 1/1:

Quality: 835.00

Escore: 0 Matching length: 83 Total length: 83

Identity: 100.00

Gaps: 0

Alignment: . . . . .

1 MWVLGIAATFCGLFLLPGFALQIQCΫQCEEFQLNNDCSSPEFIVNCTWV 50

I I I I I Il I I I Il Il I I Il Il I I I I I I I I I I Il I Il I Il I I Il I I I Il Il I

24 MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIλ/NCTVNV 73

51 QDMCQKEVMEQSAGIMYRKSCASSAACLIASAG 83

II I I I Il I I I I Il I I I Il I I I I Il I Il I I Il I I

74 QDMCQKEVMEQSAGIMYRKSCASSAACLIASAG 106

Sequence name: /tmp/VXjdFlzdBX/bexTxThOTh:Q96AC2

Sequence documentation:

Alignment of: R11723_PEA_1_P7 x Q96AC2

Alignment segment 1/1: IB2005/002560

188

Quality: 654.00

Escore:

Matching length: 64 Total length: 64

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps:

Alignment:

1 MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNV 50

1 MWLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNV 50

51 QDMCQKEVMEQSAG 64

Sequence name: /tmp/VXjdFlzdBX/bexTxThOTh:Q8N2G4

Sequence documentation:

Alignment of: R11723 PEA 1 P7 x Q8N2G4 Alignment segment 1/1:

Quality: 654.00

Escore: 0

Matching length 64 Total length: 64

Matching Percent Similarity 100.00 Matching Percent

Identity: 100.00

Total Percent Similarity: 100.00 Total Percent

Identity: 100.00

Gaps:

Alignment:

1 MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNV 50

51 QDMCQKEVMEQSAG 64

M I I I M I I I M I I

51 QDMCQKEVMEQSAG 64

Sequence name: /tmp/VXjdFlzdBX/bexTxThOTh:BAC85273

Sequence documentation: Alignment of: R11723_PEA_1_P7 x BAC85273

Alignment segment 1/1:

Quality: 600.00

Escore: 0

Matching length: 59 Total length: 59

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps: 0

Alignment:

6 IAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQ 55

22 IAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQ 71

56 KEVMEQSAG 64

I I I I I I Il I

72 KEVMEQSAG 80

Sequence name: /tmp/VXjdFlzdBX/bexTxThOTh:BAC85518 Sequence documentation:

Alignment of: R11723 PEA 1_P7 x BAC85518

Alignment segment 1/1:

Quality: 654.00 Escore: 0

Matching length: 64 Total length: 64

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps:

Alignment:

1 MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCT-VNV 50

I I I I I Il I Il I I Il I I I I I Il I I I I I I I I I I I Il I I I I I I Il I Il I I I I I

24 MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNV 73

51 QDMCQKEVMEQSAG 64

74 QDMCQKEVMEQSAG 87 IB2005/002560

192

Sequence name: /tmp/OLMSexEmIh/pc7Z7XmlYR:Q96AC2

Sequence documentation:

Alignment of: R11723 PEA 1 PlO x Q96AC2

Alignment segment 1/1:

Quality: 645.00 Escore: 0

Matching length: 63 Total length: 63

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent

Identity: 100.00

Gaps:

Alignment:

1 MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNV 50

51 QDMCQKEVMEQSA 63

51 QDMCQKEVMEQSA 63 Sequence name: /tmp/OLMSexEmIh/pc7Z7XmlYR:Q8N2G4

Sequence documentation:

Alignment of: R11723 PEA 1 PlO x Q8N2G4

Alignment segment 1/1:

Quality: 645.00

Escore: 0

Matching length: 63 Total length: 63 Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps:

Alignment:

1 MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNV 50

51 QDMCQKEVMEQSA 63

Sequence name: /tmp/OLMSexEmIh/pc7Z7XmlYR:BAC85273

Sequence documentation:

Alignment of: R11723_PEA_l_P10 x BAC85273

Alignment segment 1/1:

Quality: 591.00

Escore: 0

Matching length 58 Total length: 58

Matching Percent Similarity 100.00 Matching Percent

Identity: 100.00

Total Percent Similarity: 100.00 Total Percent

Identity: 100.00

Gaps:

Alignment:

6 IAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQ 55

22 IAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQ 71

56 KEVMEQSA 63 I Il Il I I I 72 KEVMEQSA 79

Sequence name: /tmp/OLMSexEmlh/pcTZTXmlYRiBACδSSlδ

Sequence documentation:

Alignment of: R11723_PEA_1_P1O x BAC85518

Alignment segment 1/1:

Quality: 645.00

Escore: 0

Matching length: 63 Total length: 63

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps: 0

Alignment:

1 MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNV 50

I M I I M I I I I I M I I I M I I I M I I I M I I I M I M I M I I I I M I I M

24 MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNV 73

51 QDMCQKEVMEQSA 63

74 QDMCQKEVMEQSA 86

Alignment of: R11723 PEA 1 P13 x Q96AC2

Alignment segment 1/1:

Quality: 645.00

Escore: 0

Matching length 63 Total length: 63

Matching Percent Similarity 100.00 Matching Percent

Identity: 100.00

Total Percent Similarity: 100.00 Total Percent

Identity: 100.00

Gaps:

Alignment:

1 MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNV 50

51 QDMCQKEVMEQSA 63

I I I I I I I I I I I I I

51 QDMCQKEVMEQSA 63 2560

197

Expression of Rl 1723 transcripts which are detectable by amplicon as depicted in sequence name Rl 1723 segl3 in normal and cancerous prostate tissues

Expression of transcripts detectable by or according to segl3, R11732segl3 amplicon(s) and R11732segl3F and R11732segl3R primers was measured by real time PCR. In parallel the expression of four housekeeping genes -PBGD (GenBank Accession No. BCO 19323; amplicon - PBGD-amplicon), HPRTl (GenBank Accession No. NM_000194; amplicon - HPRTl- amplicon), SDHA (GenBank Accession No. NM_004168; amplicon - SDHA-amplicon), RPL19 (GenBank Accession No. NM_000981; RPL19 amplicon) was measured similarly. For each RT sample, the expression of the above amplicon was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal post-mortem (PM) samples (Sample Nos. 42,48-53,59-63, Table 1 above, "Tissue samples in testing panel"), to obtain a value of fold up- regulation for each sample relative to median of the normal PM samples.

Figure 8 is a histogram showing over expression of the above- indicated transcripts in cancerous prostate samples relative to the normal samples. Values represent the average of duplicate experiments. Error bars indicate the minimal and maximal values obtained).

As is evident from Figure 8, the expression of transcripts detectable by the above amplicon in cancer samples was higher than in the non-cancerous samples (Sample Nos. 42,48- 53,59-63, Table 1 above, "Tissue samples in testing panel"). Notably an over- expression of at least 5 fold was found in 4 out of 19 adenocarcinoma samples

Statistical analysis was applied to verify the significance of these results, as described below.

The P value for the difference in the expression levels of transcripts detectable by the above amplicon(s) in prostate cancer samples versus the normal tissue samples was determined by T test as 7.57E-02. The above values demonstrate statistical significance of the results. Primer pairs are also optionally and preferably encompassed within the present invention; for example, for the above experiment, the following primer pair was used as a non- limiting illustrative example only of a suitable primer pair: Rl 1732segl3F forward primer; and Rl 1732segl3R reverse primer. The present invention also preferably encompasses any amplicon obtained through the use of any suitable primer pair; for example, for the above experiment, the following amplicon was obtained as a non- limiting illustrative example only of a suitable amplicon: R11732segl3

R11732segl3F (SEQ ID NO:490)- ACACTAAAAGAACAAACACCTTGCTC Rl 1732segl3R (SEQ ID NO:491> TCCTCAGAAGGCACATGAAAGA

R11732segl3 (SEQ IDNO:492) -

ACACTAAAAGAACAAACACCTTGCTCTTCGAGATGAGACATTTTGCCAAGCAGTTG ACCACTTAGTTCTCAAGAAGCAACTATCTCTTTCATGTGCCTTCTGAGGA

Expression of Rl 1723 transcripts which are detectable by amplicon as depicted in sequence name R11723segl3 in different normal tissues

Expression of Rl 1723 transcripts detectable by or according to R11723segl3 amplicon and R11723segl3F, R11723segl3R was measured by real time PCR. In parallel the expression of four housekeeping genes: RPL19 (GenBank Accession No. NM_000981; RPL19 amplicon), TATA box (GenBank Accession No. NM_003194; TATA amplicon), Ubiquitin (GenBank Accession No. BC000449; amplicon - Ubiquitin- amplicon) and SDHA (GenBank Accession No. NM_004168; amplicon - SDHA-amplicon) was measured similarly. For each RT sample, the expression of the above amplicon was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the ovary samples (Sample Nos. 18-20 Table 2 "Tissue samples in normal panel", above), to obtain a value of relative expression of each sample relative to median of the ovary samples. Primers and amplicon are as above. The results are presented in Figure 9, demonstrating the expression of Rl 1723 transcripts which are detectable by amplicon as depicted in sequence name R11723segl3 in different normal tissues.

Expression of Rl 1723 transcripts, which are detectable by amplicon as depicted in sequence name R11723 juncll-18 in normal and cancerous prostate tissues.

Expression of transcripts detectable by or according to juncl l-18 R11732juncll-18 amplicon and R11732juncll-18F and R11732juncll-18R primers was measured by real time PCR (this junction is found in the known protein sequence or "wild type" (WT) sequence, also termed herein the PSEC sequence). In parallel the expression of four housekeeping genes - PBGD (GenBank Accession No. BC019323; amplicon - PBGD-amplicon), HPRTl (GenBank Accession No. NM_000194; amplicon - HPRTl -amplicon), SDHA (GenBank Accession No. NM_004168; amplicon - SDHA-amplicon), and RPL19 (GenBank Accession No. NM_000981; RPLl 9 amplicon) was measured similarly. For each RT sample, the expression of the above amplicon was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal post-mortem (PM) samples (Sample Nos. 42,48-53,59-63 Table 1, above "Tissue samples in prostate cancer testing panel"), to obtain a value of fold up -regulation for each sample relative to median of the normal PM samples.

Figure 1OA is a histogram showing over expression of the above- indicated transcripts in cancerous prostate samples relative to the normal samples.

As is evident from Figure 1OA, the expression of transcripts detectable by the above amplicon in a few cancer samples was higher than in the non-cancerous samples (Sample Nos. 42, 48-53, 59-63, Table 1, above: "Tissue samples in prostate cancer testing panel"). Notably an over- expression of at least 5 fold was found in 2 out of 19 adenocarcinoma samples Primer pairs are also optionally and preferably encompassed within the present invention; for example, for the above experiment, the following primer pair was used as a non- limiting illustrative example only of a suitable primer pair: R11732juncll-18F forward primer; and Rl 1732 juncl 1-18R reverse primer. The present invention also preferably encompasses any amplicon obtained through the use of any suitable primer pair; for example, for the above experiment, the following amplicon was obtained as a non- limiting illustrative example only of a suitable amplicon: Rl 1732 juncl 1- 18

Rl 1723juncl 1-18F (SEQ ID NO:493) - AGTGATGGAGCAAAGTGCCG

Rl 1723 juncl 1-18R (SEQ ID NO:494>- CAGCAGCTGATGCAAACTGAG R11723 juncll-18 (SEQ ID NO:495) -

AGTGATGGAGCAAAGTGCCGGGATCATGTACCGCAAGTCCTGTGCATCATCAGCGG CCTGTCTCATCGCCTCTGCCGGGTACCAGTCCTTCTGCTCCCCAGGGAAACTGAACT CAGTTTGCATCAGCTGCTG

Expression of Rl 1723 transcripts, which were detected by amplicon as depicted in the sequence name Rl 1723 juncll-18 in different normal tissues.

Expression of Rl 1723 transcripts detectable by or according to R11723segl3 amplicon and R11723 juncl 1-18F, R11723 juncll-18R was measured by real time PCR. In parallel the expression of four housekeeping genes RPL19 (GenBank Accession No. NM_000981; RPL19 amplicon), TATA box (GenBank Accession No. NM_003194; TATA amplicon), UBC (GenBank Accession No. BC000449; amplicon - Ubiquitin-amplicon) and SDHA (GenBank Accession No. NM_004168; amplicon - SDHA- amplicon) was measured similarly. For each RT sample, the expression of the above amplicon was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the ovary samples (Sample Nos. 18-20, Table 2, "Tissue samples in normal panel", above), to obtain a value of relative expression of each sample relative to median of the ovary samples. Results are shown in Figure 1OB; primers and amplicon are as above.

The expression of variant transcripts relating to the Rl 1723 cluster (also known as PSEC) was found to be similar to that of the WT (known or wild type) protein; however in some cancers, expression of one or more variant transcripts was found to be higher (Rl 1723_T5 for example in certain tissues).

DESCRIPTION FOR CLUSTER S78694

Cluster S78694 features 1 transcript(s) and 14 segment(s) of interest, the names for which are given in Tables 89 and 90, respectively, the sequences themselves are given at the end of the applicatbn. The selected protein variants are given in table 91.

Table 89 - Transcripts of interest

These sequences are variants of the known protein Protein- lysine 6-oxidase precursor (SwissProt accession identifier LYOX-HUMAN; known also according to the synonyms EC 1.4.3.13; Lysyl oxidase), SEQ ID NO: 385, referred to herein as the previously known protein.

Protein Protein- lysine 6-oxidase precursor is known or believed to have the following function(s): Responsible for the posttranslational oxidative deamination of peptidyl lysine residues in precursors to fibrous collagen and elastin. In addition to cross- linking of extracellular matrix proteins, may have a direct role in tumor suppression. The sequence for protein Protein- lysine 6-oxidase precursor is given at the end of the application, as "Protein- lysine 6-oxidase precursor amino acid sequence". Known polymorphisms for this sequence are as shown in Table 92.

Table 92 -Amino acid mutations for Known Protein

Protein Protein- lysine 6-oxidase precursor localization is believed to be Extracellular. The following GO Annotation(s) apply to the previously known protein. The following annotation(s) were found: protein modification, which are annotation(s) related to Biological

Process; protein- lysine 6-oxidase; copper binding; oxidoreductase, which are annotation(s) related to Molecular Function; and extracellular matrix, which are annotation(s) related to Cellular Component.

As noted above, cluster S78694 features 1 transcript(s), which were listed in Table 89 above. These transcript(s) encode for protein(s) which are variant(s) of protein Protein- lysine 6- oxidase precursor. A description of each variant protein according to the present invention is now provided.

Variant protein S78694 P3 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) S78694_T7. An alignment is given to the known protein (Protein- lysine 6-oxidase precursor) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between S78694_P3 and LYOXJHUMAN:

LAn isolated chimeric polypeptide encoding for S78694_P3, comprising a first amino acid sequence being at least 90 % homologous to MRFAWTVLLLGPLQLCALVHCAPPAAGQQQPPREPPAAPGAWRQQIQWENNGQVFSL LSLGSQYQPQRRRDPGAAVPGAANASAQQPRTPILLIRDNRTAAARTRTAGSSGVTAGR PRPTARHWFQAGYSTSRAREAGASRAENQTAPGEVPALSNLRPPSRVDGMVGDDPYNP YKYSDDNPYYNYYDTYERPRPGGRYRPGYGTGYFQYGLPDLVADPYYIQASTYVQKM SMYNLRCAAEENCLAS corresponding to amino acids 1 - 247 of LYOXJHUMAN, which also corresponds to amino acids 1 - 247 of S78694_P3, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence IQGRCQRL corresponding to amino acids 248 - 255 of S78694_P3, wherein said first and second amino acid sequences are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a 1ail of S78694_P3, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence IQGRCQRL in S78694_P3.

The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans -membrane region.. Variant protein S78694_P3 also has the following non-silent SNPs (Single Nucleotide

Polymorphisms) as listed in Table 93, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein S78694 P3 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 93 - Amino acid mutations

Variant protein S78694_P3 is encoded by the following transcript(s): S78694_T7, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript S78694_T7 is shown in bold; this coding portion starts at position 381 and ends at position 1145. The transcript also has the following SNPs as listed in Table 94 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein S78694_P3 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 94 - Nucleic acid SNPs

As noted above, cluster S78694 features 14 segment(s), which were listed in Table 90 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.

Segment cluster S78694_node_0 according to the present invention is supported by 49 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694JT7. Table 94 below describes the starting and ending position of this segment on each transcript. Table 94 - Segment location on transcripts

Segment cluster S78694_node_10 according to the present invention is supported by 54 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7. Table 95 below describes the starting and ending position of this segment on each transcript.

»

Table 95 - Segment location on transcripts

Segment cluster S78694_node_12 according to the present invention is supported by 57 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7. Table 96 below describes the starting and ending position of this segment on each transcript.

Table 96 - Segment location on transcripts

Segment cluster S78694_node_19 according to the present invention is supported by 151 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694JT7. Table 97 below describes the starting and ending position of this segment on each transcript. Table 97 - Segment location on transcripts

Segment cluster S78694_node_21 according to the present invention is supported by 89 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694JT7. Table 98 below describes the starting and ending position of this segment on each transcript.

Table 98 - Segment location on transcripts

Segment cluster S78694_node_4 according to the present invention is supported by 48 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7. Table 99 below describes the starting and ending position of this segment on each transcript. Table 99 - Segment location on transcripts

Segment cluster S78694_node_l according to the present invention is supported by 39 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7. Table 100 below describes the starting and ending position of this segment on each transcript. Table 100 - Segment location on transcripts

Segment cluster S78694_node_14 according to the present invention is supported by 51 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7. Table 101 below describes the starting and ending position of this segment on each transcript.

Table 101 - Segment location on transcripts

Segment cluster S78694_node_16 according to the present invention can be found in the following transcript(s): S78694JT7. Table 102 below describes the starting and ending position of this segment on each transcript.

Table 102 - Segment location on transcripts

Segment cluster S78694_node_17 according to the present invention is supported by 45 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7. Table 103 below describes the starting and ending position of this segment on each transcript.

Table 103 - Segment location on transcripts

Segment cluster S78694_node_2 according to the present invention can be found in the following transcript(s): S78694_T7. Table 104 below describes the starting and ending position of this segment on each transcript.

Table 104 - Segment location on transcripts

Segment cluster S78694_node_20 according to the present invention can be found in the following transcript(s): S78694_T7. Table 105 below describes the starting and ending position of this segment on each transcript.

Table 105 - Segment location on transcripts

Segment cluster S78694_node_3 according to the present invention is supported by 38 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7. Table 106 below describes the starting and ending position of this segment on each transcript.

Table 106 - Segment location on transcripts

Segment cluster S78694_node_7 according to the present invention is supported by 37 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): S78694_T7. Table 107 below describes the starting and ending position of this segment on each transcript.

Table 107 - Segment location on transcripts

Variant protein alignment to the previously known protein:

Sequence name: /tmp/Z5Xtlz65PJ/KPuD7VdmQ2:LYOX_HUMAN

Sequence documentation:

Alignment of: S78694_P3 x LYOX_HUMAN

Alignment segment 1/1:

Quality: 2477.00 Escore: 0

Matching length: 247 Total length: 247

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00 Gaps: 0

Alignment: 1 MRFAWTVLLLGPLQLCALVHCAPPAAGQQQPPREPPAAPGAWRQQIQWEN 50

I I l I I I I I I I I I l I I I I I I I I I l I I I I l I I I I l I I l I I I l I I I I I I I I I I

1 MRFAWTVLLLGPLQLCALVHCAPPAAGQQQPPREPPAAPGAWRQQIQWEN 50

51 NGQVFSLLSLGSQYQPQRRRDPGAAVPGAANASAQQPRTPILLIRDNRTA 100

M M I M M I M M M I I I I M I M I M I I I M I I I I M M I I I I I M M

51 NGQVFSLLSLGSQYQPQRRRDPGAAVPGAANASAQQPRTPILLIRDNRTA 100

101 AARTRTAGSSGVTAGRPRPTARHWFQAGYSTSRAREAGASRAENQTAPGE 150 I M M M M M M I M M I I I M M M M M M M M M M M M M M I

101 AARTRTAGSSGVTAGRPRPTARHWFQAGYSTSRAREAGASRAENQTAPGE 150

151 VPALSNLRPPSRVDGMVGDDPYNPYKYSDDNPYYNYYDTYERPRPGGRYR 200

I M M I M I I M M M I M I I I I I I Il Il I M I I M I M M M M M I I I 151 VPALSNLRPPSRVDGMVGDDPYNPYKYSDDNPYYNYYDTYERPRPGGRYR 200

201 PGYGTGYFQYGLPDLVADPYYIQASTYVQKMSMYNLRCAAEENCLAS 247

I M M I I I I I M M M I M I I I l I I I l I l I I M I I l I M M I M I I I

201 PGYGTGYFQYGLPDLVADPYYIQASTYVQKMSMYNLRCAAEENCLAS 247

DESCRIPTION FOR CLUSTER W60282

Cluster W60282 features 1 transcript(s) and 6 segment(s) of interest, the names for which are given in Tables 108 and 109, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 110.

Table 108 - Transcripts of interest

60

212 Table 109 - Segments of interest

These sequences are variants of the known protein Kallikrein 11 precursor (SwissProt accession identifier KLKB_HUMAN; known also according to the synonyms EC 3.4.21.-; Hippostasin; Trypsin-like protease), SEQ ID NO: 386, referred to herein as the previously known protein.

Protein Kallikrein 11 precursor is known or believed to have the following function(s): Possible multifunctional protease. Efficiently cleaves bz-Phe-Arg-4-methylcoumaryl-7-amide, a kallikrein substrate, and weakly cleaves other substrates for kallikrein and trypsin. The sequence for protein Kallikrein 11 precursor is given at the end of the application, as "Kallikrein 11 precursor amino acid sequence". Protein Kallikrein 11 precursor localization is believed to be Secreted. The following GO Annotation(s) apply to the previously known protein. The following annotation(s) were found: proteolysis and peptidolysis, which are annotation(s) related to Biological Process; and chymotrypsin; trypsin; serine-type peptidase; hydrolase, which are annotation(s) related to Molecular Function.

The GO assignment relies on information from one or more of the SwissProt/TremBl Protein knowledgebase, available from <http://www.expasy.ch/sprot/>; or Locuslink, available from <http://www.ncbi.nbn.nih.gov/projects/LocusLink/>. As noted above, cluster W60282 features 1 transcript(s), which were listed in Table 108 above. These transcript(s) encode for protein(s) which are variant(s) of protein Kallikrein 11 precursor. A description of each variant protein according to the present invention is now provided.

Variant protein W60282_PEA_l_P14 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) W6O282_PEA_1_T11. An alignment is given to the known protein (Kallikrein 11 precursor) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: Comparison report between W60282_PEA_l_P14 and Q8IXD7 (SEQ ID NO:496): 1.An isolated chimeric polypeptide encoding for W60282_PEA_l_P14, comprising a first amino acid sequence being at least 90 % homologous to MRILQLILLALATGLVGGETRIIKGFECKPHSQPWQAALFEKTRLLCGATLIAPRWLLTA AHCLE-P corresponding to amino acids 1 - 66 of Q8IXD7, which also corresponds to amino acids 1 - 66 of W60282_PEA_l_P14, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence TPASHLAMRQHHHH corresponding to amino acids 67 - 80 of W60282_PEA_l_P14, wherein said first and second amino acid sequences are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of W60282_PEA_l_P14, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TPASHLAMRQHHHH in W60282_PEA_l_P14.

Variant protein W60282_PEA_l_P14 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 111, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein W60282_PEA_l_P14 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 111 - Amino acid mutations

Variant protein W60282_PEA_l_P14 is encoded by the following transcript(s): W6O282_PEA_1_T11, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript W6O282_PEA_1_T11 is shown in bold; this coding portion starts at position 705 and ends at position 944. The transcript also has the following SNPs as listed in Table 112 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein W60282_PEA_l_P14 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 112 - Nucleic acid SNPs

As noted above, cluster W60282 features 6 segment(s), which were listed in Table 109 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.

Segment cluster W60282_PEA_l_node_10 according to the present invention is supported by 45 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): W6O282_PEA_1_T11. Table 113 below describes the starting and ending position of this segment on each transcript.

Table 113 - Segment location on transcripts

Segment cluster W60282JPEA_l_node_18 according to the present invention is supported by 49 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): W6O282_PEA_1_T11. Table 114 below describes the starting and ending position of this segment on each transcript.

Table 114 - Segment location on transcripts

Segment cluster W60282_PEA_l_node_22 according to the present invention is supported by 67 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): W6O282_PEA_1_T11. Table 115 below describes the starting and ending position of this segment on each transcript. Table 115 - Segment location on transcripts

Segment cluster W60282_PEA_l_node_5 according to the present invention is supported by 20 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): W6O282_PEA_1_T11. Table 116 below describes the starting and ending position of this segment on each transcript.

Table 116 - Segment location on transcripts

Segment cluster W60282_PEA_l_node_21 according to the present invention is supported by 48 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): W6O282_PEA_1_T11. Table 117 below describes the starting and ending position of this segment on each transcript.

Table 117 - Segment location on transcripts

Segment cluster W60282_PEA_l_node_8 according to the present invention is supported by 39 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): W6O282_PEA_1_T11. Table 118 below describes the starting and ending position of this segment on each transcript. Table 118 - Segment location on transcripts

Variant protein alignment to the previously known protein:

Sequence name: /tmp/rL7Wdc5hYg/eLOAfKIgqD:KLKB_HUMAN

Sequence documentation:

Alignment of: W60282 PEA 1 P14 x KLKB_HUMAN

Alignment segment 1/1:

Quality: 645.00 Escore: 0

Matching length: 72 Total length: 72 Matching Percent Similarity: 94.44 Matching Percent Identity: 94.44

Total Percent Similarity: 94.44 Total Percent Identity: 94.44

Gaps:

Alignment:

1 MRILQLILLALATGLVGGETRIIKGFECKPHSQPWQAALFEKTRLLCGAT 50 1 MRILQLILLALATGLVGGETRIIKGFECKPHSQPWQAALFEKTRLLCGAT 50

51 LIAPRWLLTAAHCLKPTPASHL 72

51 LIAPRWLLTAAHCLKPRYIVHL 72

Sequence name: /tmp/rL7Wdc5hYg/eLOAfKIgqD:Q8IXD7

Sequence documentation:

Alignment of: W6O282_PEA_1_P14 x Q8IXD7

Alignment segment 1/1:

Quality: 642.00

Escore: 0

Matching length: 66 Total length: 66

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps: 0

Alignment: 1 MRILQLILLALATGLVGGETRIIKGFECKPHSQPWQAALFEKTRLLCGAT 50

1 MRILQLILLALATGLVGGETRIIKGFECKPHSQPWQAALFEKTRLLCGAT 50

51 LIAPRWLLTAAHCLKP 66

DESCRIPTION FOR CLUSTER HUMTREFAC

Cluster HUMTREFAC features 2 transcript(s) and 7 segment(s) of interest, the names for which are given in Tables 119 and 120, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 121.

Table 119 - Transcripts of interest

Table 120 - Segments of interest

Table 121 - Proteins of interest

These sequences are variants of the known protein Trefoil factor 3 precursor (SwissProt accession identifier TFF3_HUMAN; known also according to the synonyms Intestinal trefoil factor; hPl.B), SEQ ID NO: 387, referred to herein as the previously known protein.

Protein Trefoil factor 3 precursor is known or believed to have the following function(s): May have a role in promoting cell migration (motogen). The sequence for protein Trefoil factor 3 precursor is given at the end of the application, as "Trefoil factor 3 precursor amino acid sequence". Known polymorphisms for this sequence are as shown in Table 122.

Table 122 - Amino acid mutations for Known Protein

Protein Trefoil factor 3 precursor localization is believed to be Secreted.

The following GO Annotation(s) apply to the previously known protein. The following annotation(s) were found: defense response; digestion, which are annotation(s) related to Biological Process; and extracellular, which are annotation(s) related to Cellular Component.

The GO assignment relies on information from one or more of the SwissProt/TremBl Protein knowledgebase, available from <http://www.expasy.ch/sprot/>; or Locuslink, available from <http://www.ncbi.nlm.nih.gov/projects/LocusLink/>.

Cluster HUMTREFAC can be used as a diagnostic marker according to overexpression of transcripts of this cluster in cancer. Expression of such transcripts in normal tissues is also given according to the previously described methods. The term "number" in the left hand column of the table and the numbers on the y-axis of Figure 11 refer to weighted expression of ESTs in each category, as "parts per million" (ratio of the expression of ESTs for a particular cluster to the expression of all ESTs in that category, according to parts per million). Overall, the following results were obtained as shown with regard to the histograms in Figure 11 and Table 123. This cluster is overexpressed (at least at a minimum level) in the following pathological conditions: a mixture of malignant tumors from different tissues, breast malignant tumors, pancreas carcinoma and prostate cancer.

Table 123 - Normal tissue distribution

Table 124 - P values and ratios for expression in cancerous tissue

As noted above, cluster HUMTREFAC features 2 transcript(s), which were listed in Table 119 above. These transcript(s) encode for protein(s) which are variant(s) of protein Trefoil factor 3 precursor. A description of each variant protein according to the present invention is now provided.

Variant protein HUMTREF AC_PEA_2_P7 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HUMTREF AC_PEA_2_T5. The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans- membrane region prediction program predicts that this protein has a trans -membrane region.

Variant protein HUMTREFAC_PEA_2_P7 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 125, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMTREF AC_PEA_2_P7 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 125 - Amino acid mutations

Variant protein HUMTREFAC_PEA_2_P7 is encoded by the following transcript(s): HUMTREF AC_PEA_2_T5, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HUMTREFAC_PEA_2_T5 is shown in bold; this coding portion starts at position 278 and ends at position 688. The transcript also has the following SNPs as listed in Table 126 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMTREFAC_PEA_2_P7 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 126 - Nucleic acid SNPs

Variant protein HUMTREF AC PEA 2 P8 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HUMTREFAC_PEA_2_T4. An alignment is given to the known protein (Trefoil factor 3 precursor) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between HUMTREFAC_PEA_2_P8 and TFF3_HUMAN: 1.An isolated chimeric polypeptide encoding for HUMTREF AC_PEA_2_P8, comprising a first amino acid sequence being at least 90 % homologous to MAARALCMLGLVLALLSSSSAEEYVGL corresponding to amino acids 1 - 27 of TFF3_HUMAN, which also corresponds to amino acids 1 - 27 of HUMTREFAC_PEA_2_P8, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence WKVHLPKGEGFSSG corresponding to amino acids 28 - 41 of HUMTREF AC_PEA_2_P8, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HUMTREF AC_PEA_2_P8, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence WKVHLPKGEGFSSG in HUMTREFAC_PEA_2_P8.

The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans -membrane region prediction program predicts that this protein has a trans -membrane region. Variant protein HUMTREFACJPEA_2_P8 also has the following non-silent SNPs

(Single Nucleotide Polymorphisms) as listed in Table 127, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMTREF AC PEA 2 P8 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 127 - Amino acid mutations

Variant protein HUMTREF AC_PEA_2_P8 is encoded by the following transcript(s): HUMTREF AC_PEA_2_T4, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HUMTREFAC_PEA_2_T4 is shown in bold; this coding portion starts at position 278 and ends at position 400. The transcript also has the following SNPs as listed in Table 128 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMTREFAC_PEA_2_P8 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 128 - Nucleic acid SNPs

As noted above, cluster HUMTREFAC features 7 segment(s), which were listed in Table

2 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.

Segment cluster HUMTREF AC_PEA_2jnode_0 according to the present invention is supported by 188 libraries. The number of libraries was determined as previously described.

This segment can be found in the following transcript(s): HUMTREFACJPEA_2_T4 and HUMTREFAC_PEA_2_T5. Table 129 below describes the starting and ending position of this segment on each transcript.

Table 129 - Segment location on transcripts

Segment cluster HUMTREF AC_PEA_2_node_9 according to the present invention is supported by 150 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMTREFAC_PEA_2_T4 and HUMTREFAC_PEA_2_T5. Table 130 below describes the starting and ending position of this segment on each transcript. Table 130 - Segment location on transcripts

Segment cluster HUMTREF AC_PEA_2_node_2 according to the present invention is supported by 4 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMTREFACJPEA_2_T4. Table 131 below describes the starting and ending position of this segment on each transcript.

Table 131 - Segment location on transcripts

Segment cluster HUMTREF AC_PEA_2_node_3 according to the present invention is supported by 10 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMTREFACJPEA_2_T4 and HUMTREFAC_PEA_2_T5. Table 132 below describes the starting and ending position of this segment on each transcript.

Table 132 - Segment location on transcripts

Segment cluster HUMTREF AC_PEA_2_node_4 according to the present invention is supported by 197 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMTREFAC_PEA_2_T4 and HUMTREF AC_PEA_2_T5. Table 133 below describes the starting and ending position of this segment on each transcript.

Table 133 - Segment location on transcripts

Segment cluster HUMTREF AC_PEA_2_node_5 according to the present invention is supported by 187 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMTREFAC_PEA_2_T4 and HUMTREFAC_PEA_2_T5. Table 134 below describes the starting and ending position of this segment on each transcript. Table 134 - Segment location on transcripts

Segment cluster HUMTREF AC_PEA_2_node_8 according to the present invention can be found in the following trans cript(s): HUMTREFAC_PEA_2_T4 and HUMTREFAC_PEA_2_T5. Table 135 below describes the starting and ending position of this segment on each transcript. Table 135 - Segment location on transcripts

Variant protein alignment to the previously known protein:

Sequence name: TFF3_HUMAN

Sequence documentation:

Alignment of: HUMTREFAC_PEA_2_P8 x TFF3_HUMAN

Alignment segment 1/1:

Quality: 246.00 Escore: 0

Matching length: 27 Total length: 27

Gaps: 0

Alignment:

1 MAARALCMLGLVLALLSSSSAEEYVGL 27 1 MAARALCMLGLVLALLSSSSAEEYVGL 27

DESCRIPTION FOR CLUSTER HSCOC4

Cluster HSCOC4 features 19 transcript(s) and 79 segment(s) of interest, the names for which are given in Tables 136 and 137, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 138.

Table 136 - Transcripts of interest

Table 137 - Segments of interest

Table 138 -Proteins of interest

These sequences axe variants of the known protein Complement C4 precursor [Contains: C4a anaphylatoxin] (SwissProt accession identifier CO4_HUMAN), SEQ ID NO: 388, referred to herein as the previously known protein. Protein Complement C4 precursor [Contains: C4a anaphylatoxin] is known or believed to have the following function(s): C4 plays a central role in the activation of the classical pathway of the complement system. It is processed by activated Cl which remove from the alpha chain the C4a anaphylatoxin;Derived from proteolytic degradation of complement C4, C4a anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes. The sequence for protein Complement C4 precursor [Contains: C4a anaphylatoxin] is given at the end of the application, as "Complement C4 precursor [Contains: C4a anaphylatoxin] amino acid sequence". Known polymorphisms for this sequence are as shown in Table 139. Table 139 - Amino acid mutations for Known Protein

The following GO Annotation(s) apply to the previously known protein. The following annotation(s) were found: muscle contraction regulation; inflammatory response; complement activation; complement activation, classical pathway, which are annotation(s) related to Biological Process; complement component; proteinase inhibitor, which are annotation(s) related to Molecular Function; and extracellular; extracellular space, which are annotation(s) related to Cellular Component.

Cluster HSCOC4 can be used as a diagnostic marker according to overexpression of transcripts of this cluster in cancer. Expression of such transcripts in normal tissues is also given according to the previously described methods. The term "number" in the left hand column of the table and the numbers on the yaxis of Figure 12 refer to weighted expression of ESTs in each category, as "parts per million" (ratio of the expression of ESTs for a particular cluster to the expression of all ESTs in that category, according to parts per million).

Overall, the following results were obtained as shown with regard to the histograms in Figure 12 and Table 140. This cluster is overexpressed (at least at a minimum level) in the following pathological conditions: brain malignant tumors, a mixture of malignant tumors from different tissues, breast malignant tumors, pancreas carcinoma and prostate cancer.

Table 140 - Normal tissue distribution

Table 141 - P values and ratios for expression in cancerous tissue

As noted above, cluster HSCOC4 features 19 transcript(s), which were listed in Table 136 above. These transcript(s) encode for protein(s) which are variant(s) of protein Complement C4 precursor [Contains: C4a anaphylatoxin]. A description of each variant protein according to the present invention is now provided.

Variant protein HSCOC4 PEA 1 P3 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA_1_T1. An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between HSCOC4_PEA_1_P3 and C04_HUMAN: 1.An isolated chimeric polypeptide encoding for HSCOC4_PEA_1_P3, comprising a first amino acid sequence being at least 90 % homologous to

MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQWKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTMQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQΓVTMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL

RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTV corresponding to amino acids 1 - 865 of CO4_HUMAN, which also corresponds to amino acids 1 - 865 of HSCOC4_PEA_1_P3, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence RPHRSLSIQELGEPGPSEGWGG corresponding to amino acids 866 - 887 of HSCOC4_PEA_1_P3, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order. 2.An isolated polypeptide encoding for a tail of HSCOC4_PEA_1_P3, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence RPHRSLSIQELGEPGPSEGWGG in HSCOC4_PEA_1_P3.

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

Variant protein HSCOC4_PEA_1_P3 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 142, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P3 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 142- Amino acid mutations

The glycosylation sites of variant protein HSCOC4_PEA_1_P3, as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 143 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the glycosylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).

Table 143 - Glycosylation site(s)

The phosphorylation sites of variant protein HSCOC4 PEA 1 P3, as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 144 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the phosphorylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).

Table 144 - Phosphorylation site(s)

Variant protein HSCOC4_PEA_1_P3 is encoded by the following transcript(s): HSCOC4_PEA_1_T1, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA_1_T1 is shown in bold; this coding portion starts at position 501 and ends at position 3161. The transcript also has the following SNPs as listed in

Table 145 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P3 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 145 -Nucleic acid SNPs

Variant protein HSCOC4_PEA_1_P5 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA_1_T3. An alignment is given to the known protein (Complement C4 precursor

[Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between HSCOC4_PEA_1_P5 and CO4_HUMAN: LAn isolated chimeric polypeptide encoding forHSCOC4_PEA_l_P5, comprising a first amino acid sequence being at least 90 % homologous to

MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQWKGSVFLR NPSRNNWCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTMQGMLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAΠESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID

EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKG corresponding to amino acids 1 - 818 of CO4JHUMAN, which also corresponds to amino acids 1 - 818 of

HSCOC4_PEA_1_P5, and a second amino acid sequence being at least 70%, optionally at least

80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence DVTLSGPQVTLLPFPCTPAPCSLCS corresponding to amino acids 819 - 843 of HSCOC4JPEA_1_P5, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSCOC4_PEA_1_P5, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DVTLSGPQVTLLPFPCTPAPCSLCS in HSCOC4_PEA_1_P5. The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans -membrane region.

Variant protein HSCOC4_PEA_1_P5 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 146, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P5 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 146 - Amino acid mutations

The glycosylation sites of variant protein HSCOC4_PEA_1_P5, as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 147 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the glycosylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).

Table 147 - Glycosylation site(s)

The phosphorylation sites of variant protein HSCOC4_PEA_1_P5, as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 148 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the phosphorylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).

Table 148 - Phosphorylation site(s)

Variant protein HSCOC4_PEA_1_P5 is encoded by the following transcript(s): HSCOC4_PEA_1_T3, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA_1_T3 is shown in bold; this coding portion starts at position 501 and ends at position 3029. The transcript also has the following SNPs as listed in Table 149 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P5 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 149 - Nucleic acid SNPs

Variant protein HSCOC4_PEA_1_P6 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4 PEA 1 T4. An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between HSCOC4_PEA_1_P6 and CO4_HUMAN:

LAn isolated chimeric polypeptide encoding for HSCOC4_PEA_1_P6, comprising a first amino acid sequence being at least 90 % homologous to

MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQWKGSVFLR

NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYTYGKPVQGVAYVRFGLLDEDGICKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSP ASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSWPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKG corresponding to amino acids 1 - 1052 of CO4 HUMAN, which also corresponds to amino acids 1 - 1052 of HSCOC4_PEA_1_P6, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence

SGCKGKQEGGQERTVTGRWTAQEATEGKKGGP corresponding to amino acids 1053 - 1084 of HSCOC4_PEA_1_P6, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSCOC4_PEA_1_P6, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SGCKGKQEGGQERTVTGRWTAQEATEGKKGGP in HSCOC4_PEA_1_P6.

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

Variant protein HSCOC4_PEA_1_P6 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 150, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P6 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 150 - Amino acid mutations

The glycosylation sites of variant protein HSCOC4 PEA 1 P6, as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 151 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the glycosylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).

Table 151 - Glycosylation site(s)

The phosphorylation sites of variant protein HSCOC4 PEA 1 P6, as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 152 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the phosphorylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).

Table 152 - Phosphorylation site(s)

Variant protein HSCOC4_PEA_1_P6 is encoded by the following transcript(s): HSCOC4_PEA_1_T4, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA_1_T4 is shown in bold; this coding portion starts at position 501 and ends at position 3752. The transcript also has the following SNPs as listed in Table 153 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P6 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 153 - Nucleic acid SNPs

Variant protein HSCOC4 PEA 1 P12 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA_1_T11. An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: Comparison report between HSCOC4_PEA_1_P12 and CO4_HUMAN_V1 (SEQ ID NO:

389):

LAn isolated chimeric polypeptide encoding for HSCOC4_PEA_1_P12, comprising a first amino acid sequence being at least 90 % homologous to

MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQWKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYΓYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMLSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKILLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKPVCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSWPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMTYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNΛVLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKV corresponding to amino acids 1 - 1380 of CO4_HUMAN_V1, which also corresponds to amino acids 1 - 1380 of HSCOC4_PEA_1_P12, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence RAREGVGPGTGGGEGVE corresponding to amino acids 1381 - 1397 of HSCOC4_PEA_1JP12, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSCOC4 PEA 1 P12, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence RAREGVGPGTGGGEGVE in HSCOC4_PEA_1_P12.

It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1. These changes were previously known to occur and are listed in the table below.

Table 154 - Changes to CO4_HUMAN_V1

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

Variant protein HSCOC4_PEA_1_P12 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 155, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P12 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 155 -Amino acid mutations

Variant protein HSCOC4_PEA_1_P12 is encoded by the following transcript(s): HSCOC4_PEA_1_T11, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4 PEA 1 T11 is shown in bold; this coding portion starts at position 501 and ends at position 4691. The transcript also has the following SNPs as listed in Table 156 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P12 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 156 - Nucleic acid SNPs

Variant protein HSCOC4JPEA 1 P15 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA_1_T14. An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: Comparison report between HSCOC4_PEA_1_P15 and CO4_HUMAN_V1:

1.An isolated chimeric polypeptide encoding for HSCOC4_PEA_1_P15, comprising a first amino acid sequence being at least 90 % homologous to

MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQWKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKJRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQΓVTMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSWPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTECAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQ corresponding to amino acids 1 - 1359 of CO4_HUMAN_V1, which also corresponds to amino acids 1 - 1359 of HSCOC4_PEA_1_P15, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence VNHSLVNHSLAWVARTPGPRGQARSRPQPPTRGIPAALLPGVFGGRLTSWLRDLEL corresponding to amino acids 1360 - 1415 of HSCOC4 PEA 1 P15, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSCOC4_PEA_1_P15, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence

VNHSLVNHSLAWVARTPGPRGQARS RPQPPTRGIPAALLPGVFGGRLTSWLRDLEL in HSCOC4 PEA 1 P15.

It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN__V1. These changes were previously known to occur and are listed in the table below.

Table 157 - Changes to CO4_HUMAN_V1

Variant protein HSCOC4_PEA_1_P15 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 158, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P15 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 158 - Amino acid mutations

Variant protein HSCOC4_PEA_1_P15 is encoded by the following transcript(s): HSCOC4_PEA_1_T14, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA_1_T14 is shown in bold; this coding portion starts at position 501 and ends at position 4745. The transcript also has the following SNPs as listed in Table 159 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P15 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 159 - Nucleic acid SNPs

Variant protein HSCOC4_PEA_1_P16 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA_1_T15. An alignment is given to the known protein (Complement C4 precursor

Comparison report between HSCOC4_PEA_1_P16 and CO4_HUMAN_V1 : 1.An isolated chimeric polypeptide encoding for HSCOC4_PEA_1_P16, comprising a first amino acid sequence being at least 90 % homologous to

MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQWKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYΓYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSΠΉPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQΓVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSVWTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIEVTVKGHVE

YTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNRRRREAPK corresponding to amino acids 1 - 1457 of CO4_HUMAN_V1, which also corresponds to amino acids 1 - 1457 of HSCOC4 PEA 1 P16, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence

AERQGGAVWHGHRGRHPPEWIPRPAC corresponding to amino acids 1458 - 1483 of HSCOC4_PEA_1_P16, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSCOC4_PEA_1_P16, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence AERQGGAVWHGHRGRHPPEWIPRPAC in HSCOC4_PEA_1_P16.

Table 160- Changes to CO4_HUMAN_V1

The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because of manual inspection of known protein localization and/or gene structure.

Variant protein HSCOC4_PEA_1_P16 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 161, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P16 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 161 -Amino acid mutations

Variant protein HSCOC4_PEA_1_P16 is encoded by the following transcript(s): HSCOC4 PEA 1 T15, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA_1_T15 is shown in bold; this coding portion starts at position 501 and ends at position 4949. The transcript also has the following SNPs as listed in Table 162 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P16 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 162 - Nucleic acid SNPs

Variant protein HSCOC4_PEA_1_P20 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA_1_T20. An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: Comparison report between HSCOC4_PEA_1_P20 and CO4_HUMAN_V1 :

1.An isolated chimeric polypeptide encoding for HSCOC4_PEA_1_P20, comprising a first amino acid sequence being at least 90 % homologous to

MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ WKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPΠIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQΓVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTPXKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSWPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR

QGSFQGGFRSTQ corresponding to amino acids 1 - 1303 of CO4_HUMAN_V1, which also corresponds to amino acids 1 - 1303 of HSCOC4_PEA_1_P20, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence VGAVPGLWRGWVVLRPRACLSPGSTSLGHGDCPGCPVCLLDCLPHH corresponding to amino acids 1304 - 1349 of HSCOC4_PEA_1_P20, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order. 2.An isolated polypeptide encoding for a tail of HSCOC4_PEA_1_P20, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VGAVPGLWRGWWLRPRACLSPGSTSLGHGDCPGCPVCLLDCLPHH in HSCOC4_PEA_1_P20. It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1. These changes were previously known to occur and are listed in the table below.

Table 163 - Changes to CO4_HUMAN_V1

Variant protein HSCOC4_PEA_1_P20 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 164 (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P20 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 164 - Amino acid mutations

Variant protein HSCOC4_PEA_1_P20 is encoded by the following transcript(s): HSCOC4_PEA_1_T20, for which the sequence(s) is/are given at the end of the application. The 60

276 coding portion of transcript HSCOC4JPEA_1_T20 is shown in bold; this coding portion starts at position 501 and ends at position 4547. The transcript also has the following SNPs as listed in Table 165 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4 PEA 1 P20 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 165 - Nucleic acid SNPs

Variant protein HSCOC4_PEA_1_P9 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA_1_T21. An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: Comparison report between HSCOC4_PEA_1_P9 and CO4_HUMAN_V1 :

1.An isolated chimeric polypeptide encoding for HSCOC4_PEA_1_P9, comprising a first amino acid sequence being at least 90 % homologous to

MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQWKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKΈVYMPSSIFQDDFVIPDISEPGIWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRA VGSGATFSHYYYMILSRGQΓVFMNREPKRTLTSVSVFVDHHLA

PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKΈKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSWPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIEVTVKGHVE YTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNRRRREAPKWEEQESRV HYTVCIWRNGKVGLSGMAIADVTLLSGFHALRADLEKLTSLSDRYVSHFETEGPHVLL

YFDSV corresponding to amino acids 1 - 1529 of CO4_HUMAN_V1, which also corresponds to amino acids 1 - 1529 of HSCOC4_PEA_1_P9, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at feast 90% and most preferably at least 95% homologous to a polypeptide having the sequence SGER corresponding to amino acids 1530 - 1533 of HSCOC4 PEA 1 P9, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSCOC4_PEA_1_P9, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SGER in HSCOC4_PEA_1_P9.

It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1. These changes were previously known to occur and are listed in the table below. 05/002560

280

Table 166 - Changes to CO4_HUMAN_V1

The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans -membrane region prediction program predicts that this protein has a trans-membrane region. Variant protein HSCOC4_PEA_1_P9 also has the following non-silent SNPs (Single

Nucleotide Polymorphisms) as listed in Table 167, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P9 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 167 - Amino acid mutations

Variant protein HSCOC4_PEA_1_P9 is encoded by the following transcript(s):

HSCOC4_PEA_1_T21, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA_1_T21 is shown in bold; this coding portion starts at position 501 and ends at position 5099. The transcript also has the following SNPs as listed in

Table 168 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4 PEA 1 P9 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 168 - Nucleic acid SNPs

Variant protein HSCOC4 PEA 1JP22 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA_1_T25. An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the \ariant protein according to the present invention to each such aligned protein is as follows: Comparison report between HSCOC4_PEA_1_P22 and CO4_HUMAN_V1 :

LAn isolated chimeric polypeptide encoding for HSCOC4_PEA_1_P22, comprising a first amino acid sequence being at least 90 % homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQWKGSVFLR NPSRNNWCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSWPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMΓYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIEVTVKGHVE YTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNRRRREAPKVVEEQESRV HYTVCIWRNGKVGLSGMAIADVTLLSGFHALRADLEKLTSLSDRYVSHFETEGPHVLL YFDSVPTSRECVGFEAVQEVPVGLVQP ASATLYDYYNPERRCSVFYGAPSKSRLLATLC SAEVCQCAEGKCPRQRRALERGLQDEDGYRMKFACYYPRVEYGFQVKVLREDSRAAF RLFETKITQVLHF corresponding to amino acids 1 - 1653 of CO4_HUMAN_V1, which also corresponds to amino acids 1 - 1653 of HSCOC4_PEA_1_P22, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SMKQTGEAGRAGGRQGG corresponding to amino acids 1654 - 1670 of HSCOC4_PEA_1_P22, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSCOC4_PEA_1_P22, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SMKQTGEAGRAGGRQGG in HSCOC4_PEA_1_P22.

Table 169 - Changes to CO4_HUMAN_V1

Variant protein HSCOC4_PEA_1_P22 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 170 (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P22 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 170 -Amino acid mutations

Variant protein HSCOC4_PEA_1_P22 is encoded by the following transcript(s):

HSCOC4_PEA_1_T25, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA_1_T25 is shown in bold; this coding portion starts at position 501 and ends at position 5510. The transcript also has the following SNPs as listed in

Table 171 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P22 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 171 -Nucleic acid SNPs

Variant protein HSCOC4_PEA_1_P23 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA_1_T28. An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: Comparison report between HSCOC4_PEA_1_P23 and CO4_HUMAN_V1 :

1.An isolated chimeric polypeptide encoding for HSCOC4_PEA_1_P23, comprising a first amino acid sequence being at least 90 % homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQWKGSVFLR NPSRNTSTVTCSPKVDFTLSSERDFALLSLQWLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKIILSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSWPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIEVTVKGHVE YTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNRRRREAPKVVEEQESRV HYTVCIWRNGKVGLSGMAIADVTLLSGFHALRADLEKLTSLSDRYVSHFETEGPHVLL YFDSVPTSRECVGFEAVQEVPVGLVQPASATLYDYYNPERRCSVFYGAPSKSRLLATLC SAEVCQCAEGKCPRQRRALERGLQDEDGYRMKFACYYPRVEYG corresponding to amino acids 1 - 1626 of CO4_HUMAN_V1, which also corresponds to amino acids 1 - 1626 of HSCOC4_PEA_1_P23, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence

QSSHRGPGLTLPRGP AVLVSLGVACSSYRSCTQPVCSDTNFLPSQPQSNSPFPLLLTPS corresponding to amino acids 1627 - 1685 of HSCOC4_PEA_1_P23, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSCOC4_PEA_1_P23, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence QSSHRGPGLTLPRGP AVLVSLGVACSSYRSCTQPVCSDTNFLPSQPQSNSPFPLLLTPS in HSCOC4 PEA 1 P23.

It should be noted that the known protein sequence (C04_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1. These changes were previously known to occur and are listed in the table below.

Table 172 - Changes to CO4_HUMAN_V1

The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard b the cell: secreted. The protein localization is believed to be secreted because of manual inspection of known protein localization and/or gene structure.

Variant protein HSCOC4_PEA_1JP23 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 173, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P23 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 173 -Amino acid mutations

Variant protein HSCOC4_PEA_1_P23 is encoded by the following transcript(s): HSCOC4_PEA_1_T28, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA_1_T28 is shown in bold; this coding portion starts at position 501 and ends at position 5555. The transcript also has the following SNPs as listed in Table 174 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P23 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 174 - Nucleic acid SNPs

Variant protein HSCOC4JPEA 1JP24 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA_1_T30. An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between HSCOC4_PEA_1_P24 and CO4_HUMAN_V1: 1.An isolated chimeric polypeptide encoding for HSCOC4_PEA_1_P24, comprising a first amino acid sequence being at least 90 % homologous to

MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGYPLSVGVQLQDVPRGQWKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYΓYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQΓVTMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSWPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVΈASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIEVTVKGHVE YTMEANEDYEDYEYDELP AKDDPDAPLQPVTPLQLFEGRRNRRRREAPKWEEQESRV HYTVCIWRNGKVGLSGMAIADVTLLSGFHALRADLEKLTSLSDRYVSHFETEGPHVLL

YFDS corresponding to amino acids 1 - 1528 of CO4 JHUMANM/ 1, which also corresponds to amino acids 1 - 1528 of HSCOC4_PEA_1_P24, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence

SADVLCFTGHQVRADSWPPCVLLKSASVLRGSALASVAPWSGVCRTRMATG corresponding to amino acids 1529 - 1579 of HSCOC4_PEA_1_P24, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSCOC4_PEA_1_P24, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SADVLCFTGHQVRADSWPPCVLLKSASVLRGSALASVAPWSGVCRTRMATG in HSCOC4_PEA_1_P24.

It should be noted that the known protein sequence (CO4JHUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1. These changes were previously known to occur and are listed in the table below. Table 175 - Changes to CO4 JJUMAN JVl

The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans -membrane region prediction program predicts that this protein has a trans -membrane region. Variant protein HSCOC4_PEA_1_P24 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 176, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P24 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 176 - Amino acid mutations

Variant protein HSCOC4_PEA_1_P24 is encoded by the following transcript(s): HSCOC4_PEA_1_T30, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA_1_T30 is shown in bold; this coding portion starts at position 501 and ends at position 5237. The transcript also has the following SNPs as listed in Table 177 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P24 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 177 - Nucleic acid SNPs

Variant protein HSCOC4_PEA_1_P25 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA_1_T31. An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between HSCOC4_PEA_1_P25 and CO4_HUMAN_V1: 1.An isolated chimeric polypeptide encoding for HSCOC4_PEA_1_P25, comprising a first amino acid sequence being at least 90 % homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQWKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKD AKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSfflSLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLWGAPFLLQALVREMSGSPASGPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIUPQTISELQLSVSAGSPHPALARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSWPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIEVTVKGHVE YTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNRRRREAPKWEEQESRV HYTVCIWRNGKVGLSGMAIADVTLLSGFHALRADLEKLTSLSDRYVSHFETEGPHVLL YFDSVPTSRECVGFEAVQEVPVGLVQPASATLYDYYNPERRCSVFYGAPSKSRLLATLC SAEVCQCAEG corresponding to amino acids 1 - 1593 of CO4_HUMAN_V1, which also corresponds to amino acids 1 - 1593 of HSCOC4_PEA_1_P25, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence ETEGLGRGSGGGMAGAPPTLSDGFPNFRE VPSPASRPGAGSAGRGWLQDEVCLLLPPC GVRLPG corresponding to amino acids 1594 - 1657 of HSCOC4_PEA_1_P25, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order. 2.An isolated polypeptide encoding for a tail of HSCOC4 PEA 1JP25, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence

ETEGLGRGSGGGMAGAPPTLSDGFPNFREVPSPASRPGAGSAGRGWLQDEVCLLLPPC GVRLPG in HSCOC4_PEA_1_P25.

It should be noted that the known protein sequence (CO4JHUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1. These changes were previously known to occur and are listed in the table below.

Table 178 - Changes to CO4_HUMAN_V1

Variant protein HSCOC4_PEA_1_P25 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 179, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P25 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 179 -Amino acid mutations

Variant protein HSCOC4_PEA_1_P25 is encoded by the following transcript(s): HSCOC4JPEA_1_T31, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA_1_T31 is shown in bold; this coding portion starts at position 501 and ends at position 5471. The transcript also has the following SNPs as listed in Table 180 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P25 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 180 - Nucleic acid SNPs

Variant protein HSCOC4 PEA 1JP26 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA_1_T32. An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: Comparison report between HSCOC4_PEA_1_P26 and CO4_HUMAN_V1 :

1.An isolated chimeric polypeptide encoding for HSCOC4_PEA_1_P26, comprising a first amino acid sequence being at least 90 % homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQWKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRK-KEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL

PNFEVKITPGKPYILTWGHLDEMQLDIQARYIYGKPVQGVAWRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAΠESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQΓVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSWPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIEVTVKGHVE YTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNRRRREAPKWEEQESRV HYTVCIWRNGKVGLSGMAIADVTLLSGFHALRADLEKLTSLSDRYVSHFETEGPHVLL YFDSVPTSRECVGFEAVQEVPVGLVQPASATLYDYYNPERRCSVFYGAPSKSRLLATLC

SAEVCQCAEG corresponding to amino acids 1 - 1593 of CO4_HUMAN_V1, which also corresponds to amino acids 1 - 1593 of HSCOC4JPEA_1_P26, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence ETEGLGRGSGGGMAGAPPTLSDGFPNFREVPSPASRPGAGSAGRGWLQDEVCLLLPPC GVRSVFPPRPWPDPPSGTGCFGLSGCSLLLLQVMHAACLL corresponding to amino acids 1594 - 1691 of HSCOC4_PEA_1_P26, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order. 2.An isolated plypeptide encoding for a tail of HSCOC4_PEA_1_P26, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence

ETEGLGRGSGGGMAGAPPTLSDGFPNFREVPSPASRPGAGSAGRGWLQDEVCLLLPPC GVRSVFPPRPWPDPPSGTGCFGLSGCSLLLLQVMHAACLL in HSCOC4_PEA_1_P26.

It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4JHUMAN V1. These changes were previously known to occur and are listed in the table below. Table 181 - Changes to CO4 JIUMAN JVl

Variant protein HSCOC4_PEA_1_P26 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 182, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P26 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 182 -Amino acid mutations

Variant protein HSCOC4_PEA_1_P26 is encoded by the following transcript(s): HSCOC4_PEA_1_T32, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA_1_T32 is shown in bold; this coding portion starts at position 501 and ends at position 5573. The transcript also has the following SNPs as listed in Table 183 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P26 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 183 - Nucleic acid SNPs

Variant protein H3COC4_PEA_1_P30 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4JPEA_1_T40. An alignment is given to the known protein (Complement C4 precursor

Comparison report between HSCOC4_PEA_1_P30 and CO4_HUMAN_V3 SEQ ID NO: 390): 1.An isolated chimeric polypeptide encoding for HSCOC4_PEA_1_P30, comprising a first amino acid sequence being at least 90 % homologous to

MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQWKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYΎHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG

LAFSDGDQWTLSRKPVLSCPKΈKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR

LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSWPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVΉALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGS corresponding to amino acids 1 - 1232 of CO4_HUMAN_V3, which also corresponds to amino acids 1 - 1232 of HSCOC4_PEA_1_P30, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence RNPVRLLQPRAQMFCVLRGTK corresponding to amino acids 1233 - 1253 of HSCOC4_PEA_1_P30, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSCOC4_PEA_1_P30, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence RNPVRLLQPRAQMFCVLRGTK in HSCOC4_PEA_1_P30.

It should be noted that the known protein sequence (CO4_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V3. These changes were previously known to occur and are listed in the table below.

Table 184 - Changes to CO4_HUMAN_V3

Variant protein HSCOC4_PEA_1_P30 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 185, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P30 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 185 -Amino acid mutations

Variant protein HSCOC4 PEA 1 P30 is encoded by the following transcript(s): HSCOC4_PEA_1_T40, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA_1_T40 is shown in bold; this coding portion starts at position 501 and ends at position 4259. The transcript also has the following SNPs as listed in Table 186 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4 PEA 1 P30 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 186 - Nucleic acid SNPs

Variant protein HSCOC4_PEA_1_P38 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA_1_T2. An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: Comparison report between HSCOC4_PEA_1_P38 and CO4_HUMAN:

1.An isolated chimeric polypeptide encoding for HSCOC4_PEA_1_P38, comprising a first amino acid sequence being at least 90 % homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQWKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRK-KEVYMPSSIFQDDFVPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL

PNFEVKITPGKPYILTVPGHLDEMQLDIQARYΓYGKPVQGVAYVRFGLLDEDGKKTFFR

GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE

LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYΎMILSRGQΓVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKENVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID

EDDPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKG corresponding to amino acids 1 - 818 of C04_HUMAN, which also corresponds to amino acids 1 - 818 of HSCOC4_PEA_1_P38, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence DVTLSGPQVTLLPFPCTPAPCSLCS corresponding to amino acids 819 - 843 of HSCOC4_PEA_1_P38, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSCOC4_PEA_1_P38, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DVTLSGPQVTLLPFPCTPAPCSLCS in HSCOC4_PEA_1_P38.

Variant protein HSCOC4_PEA_1_P38 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 187, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P38 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 187 - Amino acid mutations

The glycosylation sites of variant protein HSCOC4_PEA_1_P38, as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 188 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the glycosylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).

Table 188 - Glycosylation site(s)

The phosphorylation sites of variant protein HSCOC4_PEA_1_P38, as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table

189 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the phosphorylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).

Table 189 - Phosphorylation site(s)

Variant protein HSCOC4_PEA_1_P38 is encoded by the following transcript(s): HSCOC4_PEA_1_T2, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA_1_T2 is shown in bold; this coding portion starts at position 501 and ends at position 3029. The transcript also has the following SNPs as listed in Table 190 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P38 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 190 - Nucleic acid SNPs

Variant protein HSCOC4_PEA_1_P39 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA_1_T5. An alignment is given to the known protein (Complement C4 precursor

[Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or 2560

326 more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between HSCOC4_PEA_1_P39 and C04_HUMAN: 1.An isolated chimeric polypeptide encoding for HSCOC4_PEA_1_P39, comprising a first amino acid sequence being at least 90 % homologous to

MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQWKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTMQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYΓYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE

LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQ corresponding to amino acids 1 - 387 of CO4_HUMAN, which also corresponds to amino acids 1 - 387 of HSCOC4_PEA_1_P39, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homobgous to a polypeptide having the sequence VSSRGEG corresponding to amino acids 388 - 394 of HSCOC4_PEA_1_P39, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order. 2.An isolated polypeptide encoding for a tail of HSCOC4_PEA_1_P39, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VSSRGEG in HSCOC4_PEA_1_P39.

The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans- membrane region prediction program predicts that this protein has a trans -membrane region. Variant protein HSCOC4_PEA_1_P39 also has the following non-silent SNPs (Single

Nucleotide Polymorphisms) as listed in Table 191, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P39 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 191 - Amino acid mutations

The glycosylation sites of variant protein HSCOC4 PEA 1 P39, as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table

192 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the glycosylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).

Table 192 - Glycosylation site(s)

The phosphorylation sites of variant protein HSCOC4JPEA_1 JP39, as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 193 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the phosphorylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).

Table 193 - Phosphorylation sιte(s)

Variant protein HSCOC4 PEA 1 P39 is encoded by the following transcript(s): HSCOC4_PEA_1_T5, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA_1_T5 is shown in bold; this coding portion starts at position 501 and ends at position 1682. The transcript also has the following SNPs as listed in

Table 194 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P39 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 194 -Nucleic acid SNPs

2005/002560

330

Variant protein HSCOC4_PEA_1_P40 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA_1_T7. An alignment is given to the known protein (Complement C4 precursor

Comparison report between HSCOC4_PEA_1_P40 and C04_HUMAN: 1.An isolated chimeric polypeptide encoding for HSCOC4_PEA_1_P40, comprising a first amino acid sequence being at least 90 % homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQWKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTMQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKY corresponding to amino acids 1 - 236 of CO4_HUMAN, which also corresponds to amino acids 1 - 236 of HSCOC4_PEA_1_P40, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence AGEWTEPHFPLKGRVPGRPGEAEYGHY corresponding to amino acids 237 - 263 of HSCOC4_PEA_1_P40, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSCOC4_PEA_1_P40, comprising a polypeptide being at least 70%, optimally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence AGEWTEPHFPLKGRVPGRPGEAEYGHY in HSCOC4_PEA_1_P40.

Variant protein HSCOC4_PEA_1_P40 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 195, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P40 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 195 -Amino acid mutations

The glycosylation sites of variant protein HSCOC4_PEA_1_P40, as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table 196 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the glycosylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein). Table 196 - Glycosylation site(s)

The phosphorylation sites of variant protein HSCOC4_PEA_1_P40, as compared to the known protein Complement C4 precursor [Contains: C4a anaphylatoxin], are described in Table

197 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the phosphorylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein). Table 197 - Phosphorylation site(s)

Variant protein HSCOC4_PEA_1_P40 is encoded by the following transcript(s): HSCOC4_PEA_1_T7, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA_1_T7 is shown in bold; this coding portion starts at position 501 and ends at position 1289. The transcript also has the following SNPs as listed in Table 198 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P40 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 198 - Nucleic acid SNPs

Variant protein HSCOC4_PEA_1_P41 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA_1_T8. An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: Comparison report between HSCOC4_PEA_1_P41 and CO4_HUMAN_V1:

1.An isolated chimeric polypeptide encoding for HSCOC4_PEA_1_P41, comprising a first amino acid sequence being at least 90 % homologous to MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQWKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAΠESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQ QVLVPAGSARPVAFSWPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIEVTVKGHVE YTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNRRRREAPKWEEQESRV HYTVCIWRNGKVGLSGMAIADVTLLSGFHALRADLEKLTSLSDRYVSHFETEGPHVLL

YFDSV corresponding to amino acids 1 - 1529 of CO4_HUMAN_V1, which also corresponds to amino acids 1 - 1529 of HSCOC4_PEA_1_P41, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SGER corresponding to amino acids 1530 - 1533 of HSCOC4 PEA 1 P41, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2An isolated polypeptide encoding for a tail of HSCOC4_PEA_1_P41, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SGER in HSCOC4_PEA_1_P41. It should be noted that the known protein sequence (CO4JHUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for CO4_HUMAN_V1. These changes were previously known to occur and are listed in the table below.

Table 199 - Changes to CO4_HUMAN_V1

The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard t> the cell: secreted. The protein localization is believed to be secreted because of manual inspection of known protein localization and/or gene structure.

Variant protein HSCOC4_PEA_1_P41 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 200, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4 PEA 1 P41 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 200 - Amino acid mutations

Variant protein HSCOC4_PEA_1JP41 is encoded by the following transcript(s): HSCOC4_PEA_1_T8, for which the) sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA_1_T8 is shown in bold; this coding portion starts at position 501 and ends at position 5099. The transcript also has the following SNPs as listed in Table 201 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P41 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 201 - Nucleic acid SNPs

Variant protein HSCOC4_PEA_1_P42 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSCOC4_PEA_1_T12. An alignment is given to the known protein (Complement C4 precursor [Contains: C4a anaphylatoxin]) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: Comparison report between HSCOC4_PEA_1_P42 and CO4_HUMAN_V1 :

1.An isolated chimeric polypeptide encoding for HSCOC4_PEA_1_P42, comprising a first amino acid sequence being at least 90 % homologous to

MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQWKGSVFLR NPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLK DSLSRTTMQGESΠ.LFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMV ENSHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVL PNFEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFR GLESQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAE LTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVP EVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPD SRPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPK-RTLTSVSVFVDHHLA PSFYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDS LALVALGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAG LAPSDGDQWTLSRKIU-,SCPKEKTTRKK-R]S^V^SffQKAINEKLGQYASPTAKRCCQDGVTR LPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLID EDDIPVRSFFPENWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQL RVFREFHLHLRLPMSVRRFEQ LELRPVLYNΎLDKNLTVSVHVSPVEGLCLAGGGGLAQ

QVLVPAGSARPVAFSWPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREEL VYELNPLDHRGRTLEPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASL LRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRK ADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQ DPCPVLDRSMQGGLVGNDETVALTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKASS FLGEKASAGLLGAHAAAITAYALTLTKAPADLRGVAHNNLMAMAQETGDNLYWGSV TGSQSNAVSPTPAPRNPSDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTR QGSFQGGFRSTQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIEVTVKGHVE YTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNRRRREAPKWEEQESRV HYTVCIW corresponding to amino acids 1 - 1473 of CO4_HUMAN_V1, which also corresponds to amino acids 1 - 1473 of HSCOC4_PEA_1_P42, a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence WAPGAALGQGREGRTQAGAGLLEPAQAEPGRQLTRLHR corresponding to amino acids 1474 - 1511 of HSCOC4_PEA_1_P42, a third amino acid sequence being at least 90 % homologous to RNGKVGLSGMAIADVTLLSGFHALRADLEK corresponding to amino acids 1474 - 1503 of CO4_HUMAN_V1, which also corresponds to amino acids 1512 - 1541 of HSCOC4_PEA_1_P42, and a fourth amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence VWSATQGNPLCPRY corresponding to amino acids 1542 - 1555 of HSCOC4_PEA_1_P42, wherein said first amino acid sequence, second amino acid sequence, third amino acid sequence and fourth amino acid sequence are contiguous and in a sequential order. 2.An isolated polypeptide encoding for an edge portion of HSCOC4_PEA_1_P42, comprising an amino acid sequence being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence encoding for

WAPGAALGQGREGRTQAGAGLLEPAQAEPGRQLTRLHR, corresponding to

HSCOC4_PEA_1_P42.

3.An isolated polypeptide encoding for a tail of HSCOC4_PEA_1_P42, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VWSATQGNPLCPRY in HSCOC4_PEA_1_P42.

Table 202 - Changes to CO4_HUMAN_V1

The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans- membrane region prediction program predicts that this protein has a trans -membrane region. Variant protein HSCOC4_PEA_1_P42 also has the following non-silent SNPs (Single

Nucleotide Polymorphisms) as listed in Table 203, (given according to their positions) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P42 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 203 -Amino acid mutations

Variant protein HSCOC4 PEA 1 P42 is encoded by the following transcript(s): HSCOC4_PEA_1_T12, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSCOC4_PEA_1_T12 is shown in bold; this coding portion starts at position 501 and ends at position 5165. The transcript also has the following SNPs as listed in Table 204 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSCOC4_PEA_1_P42 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 204 - Nucleic acid SNPs

As noted above, cluster HSCOC4 features 79 segment(s), which were- listed in Table 2 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.

Segment cluster HSCOC4_PEA_l_node_l according to the present invention is supported by 24 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4JPEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and HSCOC4_PEA_1_T40. Table 205 below describes the starting and ending position of this segment on each transcript.

Table 205 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_5 according to the present invention is supported by 29 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEAJ_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and HSCOC4_PEA_1_T40. Table 206 below describes the starting and ending position of this segment on each transcript.

Table 206 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_7 according to the present invention is supported by 35 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 207 below describes the starting and ending position of bis segment on each transcript.

Table 207 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_30 according to the present invention is supported by 35 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_rT15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 208 below describes the starting and ending position of this segment on each transcript.

Table 208 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_33 according to the present invention is supported by 30 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_ 1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4JPEA_1_T20,

HSCOC4JPEA 1 T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4JPEA 1 T40. Table 209 below describes the starting and ending position of this segment on each transcript.

Table 209 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_35 according to the present invention is supported by 31 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4J^>EA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T40. Table 210 below describes the starting and ending position of this segment on each transcript.

Table 210 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_37 according to the present invention is supported by 33 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 211 below describes the starting and ending position of this segment on each transcript.

Table 211 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_39 according to the present invention is supported by 35 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4__PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4JPEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4J^»EA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 212 below describes the starting and ending position of this segment on each transcript. Table 212 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_43 according to the present invention is supported by 34 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20, HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 213 below describes the starting and ending position of this segment on each transcript.

Table 213 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_48 according to the present invention is supported by 2 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4JPEA_1_T2 and

HSCOC4_PEA_1_T3. Table 214 below describes the starting and ending position of this segment on each transcript.

Table 214 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_49 according to the present invention is supported by 37 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4JPEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1JT31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 215 below describes the starting and ending position of this segment on each transcript. Table 215 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_51 according to the present invention is supported by 40 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T40. Table 216 below describes the starting and ending position of this segment on each transcript.

Table 216 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_nodeJ58 according to the present invention is supported by 52 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1JT7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1JT14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1JT21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1JT30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 217 below describes the starting and ending position of this segment on each transcript.

Table 217 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_59 according to the present invention is supported by 8 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T4. Table 218 below describes the starting and ending position of this segment on each transcript.

Table 218 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_62 according to the present invention is supported by 61 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4JPEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4JPEA_1_T31, HSCOC4_PEA_1_T32 and HSCOC4_PEA_1_T40. Table 219 below describes the starting and ending position of this segment on each transcript.

Table 219 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_66 according to the present invention is supported by 65 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4JPEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T40. Table 220 below describes the starting and ending position of this segment on each transcript.

Table 220 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_72 according to the present invention is supported by 65 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4JPEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_T32. Table 221below describes the starting and ending position of this segment on each transcript.

Table 221 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_77 according to the present invention is supported by 2 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T14 and HSCOC4_PEA_1_T20. Table 222 below describes the starting and ending position of this segment on each transcript.

Table 222 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_79 according to the present invention is supported by 6 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T11. Table 223 below describes the starting and ending position of this segment on each transcript.

Table 223 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_93 according to the present invention is supported by 25 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T12 and HSCOC4_PEA_1JT21. Table 224 below describes the starting and ending position of this segment on each transcript.

Table 224 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_100 according to the present invention is supported by 13 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T21. Table 225 below describes the starting and ending position of this segment on each transcript.

Table 225 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_105 according to the present invention is supported by 9 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T28 and HSCOC4_PEA_1_T32. Table 226 below describes the starting and ending position of this segment on each transcript.

Table 226 - Segment location on transcripts

Segment cluster HSCOC4_PEA_ l_node_107 according to the present invention is supported by 27 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28 and HSCOC4_PEA_1_T32. Table 227 below describes the starting and ending position of this segment on each transcript.

Table 227- Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_108 according to the present invention is supported by 120 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20, HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 228 below describes the starting and ending position of this segment on each transcript.

Table 228 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_109 according to the present invention is supported by 12 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T25 and

HSCOC4_PEA_1_T28. Table 229 below describes the starting and ending position of this segment on each transcript.

Table 229 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_110 according to the present invention is supported by 97 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and HSCOC4_PEA_1_T40. Table 230 below describes the starting and ending position of this segment on each transcript.

Table 230 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_l 12 according to the present invention is supported by 71 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4JPEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4JPEA_1_T40. Table 231 below describes the starting and ending position of this segment on each transcript.

Table 231 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_113 according to the present invention is supported by 19 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28 and HSCOC4_PEA_1_T32. Table 232 below describes the starting and ending position of this segment on each transcript.

Table 232 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_2 according to the present invention is supported by 25 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 233 below describes the starting and ending position of this segment on each transcript. Table 233 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_8 according to the present invention is supported by 35 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA__1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4JPEA_1_T40. Table 234 below describes the starting and ending position of this segment on each transcript.

Table 234 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_10 according to the present invention is supported by 33 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T40. Table 235 below describes the starting and ending position of this segment on each transcript.

Table 235 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_12 according to the present invention is supported by 33 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4JPEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 236 below describes the starting and ending position of this segment on each transcript.

Table 236 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_14 according to the present invention is supported by 30 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T40. Table 237 below describes the starting and ending position of this segment on each transcript. Table 237 - Segment location on transcripts

Segment cluster HSCOC4JPEA_l_node_17 according to the present invention is supported by 28 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T8, HSCOC4JPEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20, HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30,

HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and HSCOC4_PEA_1_T40. Table 238 below describes the starting and ending position of this segment on each transcript.

Table238 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_19 according to the present invention is supported by 27 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T8, HSCOC4__PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20, HSCOC4_PEA_1_T21,

HSCOC4_PEA_1_T25, HSCOC4JPEA_1_T28, HSCOC4_PEA_1_T30,

HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and HSCOC4_PEA_1_T40. Table 239 below describes the starting and ending position of this segment on each transcript.

Table 239 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_21 according to the present invention is supported by 26 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4JPEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4JPEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 240 below describes the starting and ending position of this segment on each transcript.

Table 240 - Segment location on transcripts

Segment cluster HSCOC4_PEA_ljtiode_22 according to the present invention is supported by 26 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA__1_T2, HSCOC4_PEA_1JT3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 241 below describes the starting and ending position of this segment on each transcript.

Table 241 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_28 according to the present invention is supported by 34 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1__T40. Table 242 below describes the starting and ending position of this segment on each transcript.

Table 242 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_29 according to the present invention is supported by 5 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T5. Table 243 below describes the starting and ending position of this segment on each transcript.

Table 243 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_41 according to the present invention is supported by 32 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1JT1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 244 below describes the starting and ending position of this segment on each transcript. Table 244 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_45 according to the present invention is supported by 31 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1JT3, HSCOC4_PEA_1_T4, HSCOC4JPEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20, HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 245 below describes the starting and ending position of this segment on each transcript.

Table 245 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_47 according to the present invention is supported by 32 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20, HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 246 below describes the starting and ending position of this segment on each transcript.

Table 246- Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_50 according to the present invention is supported by 5 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1 and HSCOC4_PEA_1_T3. Table 247 below describes the starting and ending position of this segment on each transcript.

Table 247- Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_53 according to the present invention is supported by 38 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4 PEA 1 T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4JPEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4JPEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 248 below describes the starting and ending position of this segment on each transcript.

Table 248 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_55 according to the present invention is supported by 40 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1JT3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T40. Table 249below describes the starting and ending position of this segment on each transcript.

Table 249- Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_57 according to the present invention is supported by 42 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4J^>EA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4JPEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T40. Table 250 below describes the starting and ending position of this segment on each transcript.

Table 250 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_60 according to the present invention is supported by 50 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4JPEA_1_T7, HSCOC4JPEA 1 T8, HSCOC4JPEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4__PEA__1_T31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 251 below describes the starting and aiding position of this segment on each transcript.

Table 251 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_64 according to the present invention is supported by 65 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1JT3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEAJ_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEAJ_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and HSCOC4_PEA_1_T40. Table 252 below describes the starting and ending position of this segment on each transcript.

Table 252 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_69 according to the present invention can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7,

HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1JT12, HSCOC4_PEA_1_T14,

HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20, HSCOC4_PEA_1_T21,

HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30,

HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and HSCOC4_PEA_1_T40. Table 253 below describes the starting and ending position of this segment on each transcript.

Table 253 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_70 according to the present invention is supported by 58 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4JPEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_T32. Table 254 below describes the starting and ending position of this segment on each transcript.

Table 254 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_71 according to the present invention is supported by 58 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4JPEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_T32. Table 255 below describes the starting and ending position of this segment on each transcript.

Table 255 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_73 according to the present invention is supported by 1 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcripts): HSCOC4_PEA_1_T20. Table 256below describes the starting and ending position of this segment on each transcript.

Table 256- Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_74 according to the present invention can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20, HSCOC4JPEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30,

HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_T32. Table 257 below describes the starting and ending position of this segment on each transcript.

Table 257- Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_75 according to the present invention is supported by 65 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4J^»EA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_T32. Table 258 below describes the starting and ending position of this segment on each transcript.

Table 258 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_76 according to the present invention is supported by 66 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4JPEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4JPEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_J_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_T32. Table 259 below describes the starting and ending position of this segment on each transcript.

Table 259- Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_78 according to the present invention is supported by 71 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4JPEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_T32. Table 260 below describes the starting and ending position of this segment on each transcript.

Table 260 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_80 according to the present invention is supported by 75 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1__T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4JPEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4JPEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4__PEA_1_T30, HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_T32. Table 261 below describes the starting and ending position of this segment on each transcript. Table 261 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_82 according to the present invention can be found in the following transcript(s): HSCOC4_PEAJ_T1, HSCOC4JPEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7,

HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14,

HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20, HSCOC4_PEA_1_T21,

HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30,

HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_T32. Table 262below describes the starting and ending position of this segment on each transcript.

Table 262 - Segment location on transcripts

Segment cluster HSCOC4 PEA 1 node_83 according to the present invention is supported by 77 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_T32. Table 263 below describes the starting and ending position of this segment on each transcript.

Table 263 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_84 according to the present invention can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7,

HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1JT12, HSCOC4_PEA_1_T14,

HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20, HSCOC4_PEA_1_T21,

HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30,

HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_132. Table 264 below describes the starting and ending position of this segment on each transcript.

Table 264 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l__node_85 according to the present invention is supported by 68 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4__PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T20, HSCOC4_PEA_1_T21,

HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_T32. Table 265 below describes the starting and ending position of this segment on each transcript.

Table 265 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_86 according to the present invention is supported by 7 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4JPEA_1_T12. Table 266 below describes the starting and ending position of this segment on each transcript.

Table 266 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_87 according to the present invention is supported by 74 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4JPEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_T32. Table 267 below describes the starting and ending position of this segment on each transcript.

Table 267 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_88 according to the present invention is supported by 2 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T12. Table 268below describes the starting and ending position of this segment on each transcript.

Table 268 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_89 according to the present invention can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20, HSCOC4_PEA_1_T21,

HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30,

HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_T32. Table 269 below describes the starting and ending position of this segment on each transcript.

Table 269 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_90 according to the present invention can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEAJ_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20, HSCOC4_PEA_1_T21,

HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30,

HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_T32. Table 270 below describes the starting and ending position of this segment on each transcript.

Table 270 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_91 according to the present invention is supported by 78 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_T32. Table 271 below describes the starting and ending position of this segment on each transcript.

Table 271 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_92 according to the present invention can be found in the following transcripts): HSCOC4_PEA_1_T1, HSCOC4_PEA_J_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA__1_T7,

HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14,

HSCOC4JPEA_1_T15, HSCOC4_PEA_1_T20, HSCOC4_PEA_1_T21,

HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T30,

HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_T32. Table 272 below describes the starting and ending position of this segment on each transcript.

Table 272- Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_94 according to the present invention can be found in the following transcript(s): HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T12 and HSCOC4_PEA_1_T21. Table 273below describes the starting and ending position of this segment on each transcript.

Table 273 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_96 according to the present invention can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4JPEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20, HSCOC4_PEA_1_T21, HSCOC4JPEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T31 and

HSCOC4_PEA_1_T32. Table 274 below describes the starting and ending position of this segment on each transcript.

Table 21 A - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_97 according to the present invention can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4__PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEAJ_T20, HSCOC4_PEA_1_T21,

HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T31 and

HSCOC4_PEA_1_T32. Table 275 below describes the starting and ending position of this segment on each transcript.

Table 275 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_98 according to the present invention is supported by 93 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_T32. Table 276 below describes the starting and ending position of this segment on each transcript.

Table 276 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_99 according to the present invention is supported by 93 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4J?EA_1_T4, HSCOC4JPEA_1_T5,

HSCOC4JPEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12,

HSCOC4JPEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28, HSCOC4_PEA_1_T31, HSCOC4J?EA_1_T32 and HSCOC4_PEA_1_T40. Table 277 below describes the starting and ending position of this segment on each transcript.

Table 211 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_101 according to the present invention is supported by 116 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4JPEA_1_T31, HSCOC4_PEA_1_T32 and HSCOC4_PEA_1_T40. Table 278 below describes the starting and ending position of this segment on each transcript.

Table 278 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_102 according to the present invention is supported by 3 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T31 and HSCOC4_PEA_1_T32. Table 279 below describes the starting and ending position of this segment on each transcript.

Table 279 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_103 according to the present invention is supported by 106 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 280 below describes the starting and ending position of this segment on each transcript.

Table 280 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_104 according to the present invention is supported by 101 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1,

HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5,

HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4J^>EA_1_T12,

HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T40. Table 281 below describes the starting and ending position of this segment on each transcript.

Table 281- Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_106 according to the present invention is supported by 110 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1JT5, HSCOC4JPEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T11, HSCOC4_PEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T21, HSCOC4_PEA_1_T25, HSCOC4_PEA_1_T28,

HSCOC4_PEA_1_T30, HSCOC4_PEA_1_T31, HSCOC4_PEA_1_T32 and

HSCOC4_PEA_1_T40. Table 282 below describes the starting and ending position of this segment on each transcript.

Table 282 - Segment location on transcripts

Segment cluster HSCOC4_PEA_l_node_l 11 according to the present invention is supported by 77 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSCOC4_PEA_1_T1, HSCOC4_PEA_1_T2, HSCOC4_PEA_1_T3, HSCOC4_PEA_1_T4, HSCOC4_PEA_1_T5, HSCOC4_PEA_1_T7, HSCOC4_PEA_1_T8, HSCOC4_PEA_1_T1 1, HSCOC4JPEA_1_T12, HSCOC4_PEA_1_T14, HSCOC4_PEA_1_T15, HSCOC4_PEA_1_T20,

HSCOC4_PEA_1_T40. Table 283 below describes the starting and ending position of this segment on each transcript.

Table 283 - Segment location on transcripts

Variant protein alignment to the previously known protein: Sequence name: CO4_HUMAN

Sequence documentation:

Alignment of: HSCOC4_PEA_1_P3 x C04_HUMAN

Alignment segment 1/1:

Quality: 8438.00 Escore: 0

Matching length: 870 Total length: 870

Matching Percent Similarity: 99.66 Matching Percent Identity: 99.66 Total Percent Similarity: 99.66 Total Percent Identity: 99.66

Gaps: 0

Alignment:

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

M M I I I I M M I I I I M I II M I I M M I I I I I M M I I I I I I I I I I M

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

I I I I l M I I M I l I I M I l I I I M I I I I l I M I l I M I I l I I l M M I I I

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

I I I l I M I M I I l I I l I l I I I I M I M I l I M I M M M M M I I l I l I l

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150 151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

I I I I I I I I I I I I I I I I I I I Il I I I I I I I I I I Il I I I I I I I I I I I I I I I I I

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200 . . . . .

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

I I I Il I Il I I Il I I Il Il Il I Il Il I I Il I Il Il I Il I I Il Il I I I I I Il

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

I I I I I I I I I I I I I I I I I I I I I Il I I I I I I I I Il I I I I I I I I I I I I I I Il I

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350 I I I I I I M I I I I I I I M I I I I M I I I I I Il I I I I I I I I I I I I I I I M I Il

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

I I I I I Il I I I I I I I I I I I I I I Il I I I I I I I I I I Il Il I I I I I I I I Il I I I 351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

I I I I I Il I I I I I I I I I I I Il I I I I I I Il I I I I I I I I I I I I I I I Il I I I I I 401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450 . . . . .

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

I MI I I I M I M I I I M M I I I I I M I I I I I M I M I M I I M I I M M I

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550 501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

I I I I I I I I I Il I I I Il I I I I I I I I I I I I I I Il I I I I I I Il Il I I Il Il Il 551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

II I Il I Il III I I Il I I I Il Il Il I I I I I Il I I Il Il Il I Il I I I Il I Il

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650 . . . . .

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

I I I Il I I I Il I I I I I I I I I I I I I I I I I I I Il I I Il III I I I I Il I I I I Il

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

I I I I I Il I I I I I I I I I I I Il I I I I I I I I I I I I I I I I Il I I I I I I Il I I I I

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800 M I I M I I M I I I I I I I I I M M M M I I M I M M I I I M I I I I M I I I

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

I I M Il I I I M M M I Il I M M M M I I M Il M I I M M I Il I Il I M 801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

851 LRPVLYNYLDKNLTVRPHRS 870

I M I I I I I I M Il I I I I

851 LRPVLYNYLDKNLTVSVHVS 870

Sequence name: CO4 HUMAN

Sequence documentation:

Alignment of: HSCOC4 PEA 1 P5 x CO4 HUMAN

Alignment segment 1/1:

Quality: 7969.00

Escore: 0

Matching length 818 Total length: 818

Matching Percent Similarity 100.00 Matching Percent

Identity: 100.00

Total Percent Similarity: 100.00 Total Percent

Identity: 100.00

Gaps:

Alignment:

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

I I I I I Il I Il I I I I I I I Il I Il I I I I I I I Il I I I I Il I I I Il I Il I I I I I

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQ 50

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

I I Il I I I I I Il Il Il Il Il I I I I Il I I I I I I Il I I Il Il I I I I I I I I I Il 51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100 101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150 M M M I M II M I M I I M I I I I I I M M I I IIIII I I!

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150 . . . . .

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

I I I I I I I I I I I M M I I M I M I I M I M I I I I I M M I I I M M I I I I I

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

I I I I I I M M M I M I I I M I I M I M I I I I I I I M I Il I I M I M M M

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300 I M M I I I I I M I M M I M I I I I I M M M M I Il I I Il I I M I I I M I

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

I I I I I M M I I M I I I I M M M M I Il I I I I I Il I M I M M I M Il M 301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

II I I I I I I M M Il M M M I I I I I I I M M M I I M I I M I I M M Il I

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400 . . . . .

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

Il I Il M M I I I Il I I M I I I M M I M I I I I M M I M M I M I I M I I

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500 451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

Il Il I I I Il I I Il Il I I I I Il Il Il Il I I Il Il Il Il Il Il Il Il I Il I I 551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600 . . . . .

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

M Il I I Il I Il I M M M I Il Il M I Il I M I Il Il I Il M M I Il Il I I

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

Il M I Il Il I M M I I M I I Il I M Il I I Il Il I Il I Il M Il I M Il Il

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750 Il I Il I M I M I M I I M I I I M M M M Il I M I M M I M Il I M I M

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

I I I I M I Il M M Il I M I Il Il I M M I M I I MM Il M Il I I I Il M 751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

801 DSLTTWEIHGLSLSKTKG 818

II Il I M M Il I I I M M

801 DSLTTWEIHGLSLSKTKG 818

Sequence name: CO4 HUMAN

Sequence documentation:

Alignment of: HSCOC4 PEA 1 P6 x CO4 HUMAN

Alignment segment 1/1:

Quality: 10211.00

Escore: 0

Matching length 1052 Total length: 1052

Matching Percent Similarity 100.00 Matching Percent

Identity: 100.00

Total Percent Similarity: 100.00 Total Percent

Identity: 100.00

Gaps:

Alignment:

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

I I I Il Il I I I I I Il I Il I Il I I I I I I I I I I I I I Il I I I I I I Il I I I I I I I

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

I I I I I I I Il I I I 11 Il I Il I Il I I I Il I Il Il Il I Il I I I I Il I Il I Il I

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100 101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

I I Il I I I Il I I I I I I I I I I I I I I Il I I I Il I I I Il Il I I Il I Il Il I I I I

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150 . . . . .

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

M I M I M I I I M M I M M II I I I I I I M M I I I I M M I I I I I I I M I

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

I M I I I Il I Il I M Il M M M I M Il I M I M I I I I I Il I M Il M M I

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300 I I I I I I I I M Il M M M M I I I I I I Il M I M I I I I I Il I I I I Il M M

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

I I I I I I Il M I I I I M Il M M I Il I Il M I I Il I I M M I I I I I I M I I 301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

I I I Il I Il M I I M M M M M I I I I Il M I Il Il I M I M I Il Il Il I I

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400 . . . . .

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

I Il M I M I I I I M Il M I I M I I Il Il M I I M I M M I M M M M M

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

I I I Il Il I I I I I I I I I I I I Il I I Il Il I I Il I I I I I I I Il Il I I Il I I Il 501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

IMM MI III M M IM M IM M I I I I I I MI MII I I M I I M I MI

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600 . . . . .

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650^'

I M M Il M I I I M Il I I M I I Il M M Il M M M Il I I I Il I Il M Il

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

M III I I M I I I I I I M M M I M M Il I Il Il Il Il Il I Il Il Il I I I I

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750 M M M I I M M I I I M I M I M M I Il I M M M Il M I Il I I Il I I M

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

II M Il M I M M M M Il III M M I Il I Il M Il I M M Il Il I I I M 751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

I M M I I M Il I M Il I I Il M Il M Il Il M M Il I M M M I Il M Il

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850 . . . . .

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900 Il I I I I I 111 I I I I I I I I I Il I I I I I I I Il I I I I I I I I I Il I I I I Il I I I

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

901 WPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950 I M M I I MI M M I M M M I M I I I I I I I I I I I M I M I I M M M M

901 WPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

M I M I I l I I l I M M M I I M I I l I M I l I M I l M M M I l I M M M 951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050

I I l M I I M M I l I l I l I l M M I I I l I l I l I I M M I M I l M I l I I M

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050

1051 KG 1052

I I 1051 KG 1052

Sequence name: CO4_HUMAN_V1

Sequence documentation:

Alignment of: HSCOC4_PEA_1_P12 x CO4_HUMAN_V1

Alignment segment 1/1: Quality: 13367.00 Escore: 0

Matching length: 1380 Total length: 1380

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00 Gaps: 0

Alignment:

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

I I I I I I I I I I I I I I I Il I I I l I I I I i I I l I l I l I l I I I I I I I I I I I I Il I

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

51 VVKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

M M I M M I I I I I M I I I I I M I I I I I I I I I I I I I M M I M I M I I M

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

M I I I M I I l I l I M I I I I I I I M I M M I l I I M I I I I I I I I I M I M I

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

I I I I M I I I I I I M M M M I I I I M M I I M I l I I M M M I I I I I I M

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250 201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

M MIIII M I I I I I I II I M M IM I M I I I II I I M I M II M II I M 251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

I I I M I I I I I I M Il I I M I I I I Il M I M M I I M M M I M M I I I M

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350 . . . . .

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

I I I I M I M I M M I Il I I I I M I I I I M M I I I I I I M I I I I I M I I M

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

I Il I M I I I M I I I I I M Il M I I I M M I I I I M M M M Il M M I M

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500 I M Il I I M I I I M Il I I M M I I I I I M M I I M M I M I I M I I I I M

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

I I M I I I I I I I I M M M I I I M M I I I I M I I M M M I M I I I Il I I I 501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

I I I I M I I I I I Il I I M I M I M I M M I I M M I I M I I I I I M M I M

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600 . . . . .

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650 M I M IM I I IM M M I I M M I I I I M I M I I M MI M I I I M I M I

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700 M I M I I M I I M M I Il M I I I M Il Il I I I M Il I M M M M M M I

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

I M M I M Il M Il Il I I I M M Il M M I M I I I Il I I M Il I I M I Il 701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

M I Il I I I Il M M Il I M I M M M I I I M M M M I Il I Il I M I I M

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800 . . . . .

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

M I Il I I I Il M Il I I I M M I M Il Il I I I I I I M M I Il I I I M I I M

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

I M M I I M Il Il I M I Il I Il I Il M Il I I I I M I M Il M Il M I I M

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

901 WPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950 I M M I I I M I I I Il I M M I M I I M M I Il I I I I M I I M I I M I I M

901 WPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

I M Il I I M M I Il M I M Il I M I M M M I I Il I M I I M I I M I I M 951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000 1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050

I I I I I I Il Il Il I I I Il I Il I I I I I I I I I Il Il Il I I I I I I I I I Il I I I I

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050

1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100

I I I I I I I I Il Il I I Il I I I I I Il I Il i I I I I I I I I I I Il I I I I Il I I I I I

1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100

• • • • •

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150 M I M I I I I I M I Il I I I I I Il I I I I Il Il I I I I I Il Il I I I I Il I Il Il

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

I M M M M M MI M M M M I M I I M I I I I M M I M I I I IM M M 1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250

M I M I I M I I I I M I M Il M M I M I M M I M I M M M Il I I M M

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250 . . . . .

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

I I M M M I I I M I M M I M I I M M M M I M M I M I M M I M Il I

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350

M I I M M I I I MM M I I I I I M I M M M M I M I I I M M M I M M

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350

1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKV 1380 M I Il M M I M I I M M M Il Il I M M I

1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKV 1380

Sequence name: CO4_HUMAN_V1

Sequence documentation:

Alignment of: HSCOC4_PEA_1_P15 x CO4_HUMAN_V1

Alignment segment 1/1:

Quality: 13174.00

Escore: 0

Matching length: 1359 Total length: 1359

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent

Identity: 100.00

Gaps: 0

Alignment:

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQ 50

I I I I l I l I I I l I I I I l I I l I I I I I I l I l I l I I I I I I l I I I l I I I I I I I I I

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50 . . . . .

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100 I I I I I I Il I I I I I I I I I I I I I I I I I I I I I Il I I I I I I I I I I I I I I Il I I I 51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150 I I I I I I I I I I I I Il Il I I Il Il I I I I I Il Il I Il I I Il Il I I I I I I I I Il

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

I I I I I I I I I I I I I I I I Il Il Il I I I I I I I I I I I Il I I I I I I I Il Il Il I I 151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

I I I I I I I I I Il I I Il I I I I I I I I Il Il I I Il I I I I I Il I I I I I I I I I I I I

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250 . . . . .

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

I I I I I I I I I I I Il I I I I I Il Il I I Il I I I I I I I I I I I I I I I I Il I I I I Il 251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

I Il I I I I I I I I I I I I I I I I I I I Il I I I I Il I I I I I I I I I I I I Il I I I Il I 301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400 I I I I I I I I I 11 I I I I I I I I I I I I I I I M I I I I I I I I I I I I I I I I I I I I I I

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

I I I I I I I I I I I I I I Il I I I I I I I I I I I I I I I I I I I I Il I I I I I I I I I I I I 401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450 451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

M I I M I M M I I I I I M I I I I I I M I I I I I I I M I I M I I M I I M I I I

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

M M I M I I M I IM M M I I M Il Il I M I M I IM I I M Il M I M Il

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600 M Il I M I I Il I I M M I M M I Il M M I M I I I I I M M Il I M I M I

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

M Il I I I MM I I I I I M M I I I M M I Il M M I M M M I I I M M M 601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

MMMMMMMMMIMMMMIMMMMMMMMMMM

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700 . . . . .

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

I I Il I I M I I I Il M I Il I I Il I Il M M I I I I M M I I I I M M I I I M

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

• • • • • 751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

M M M I M M I M I M M Il I I Il I I I I M I M Il M I M I M I I M I I

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

• • • • •

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850 I M M I Il I M M I I I I Il M M M I M M I I I M M I M M I Il I I I M

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850 60

440

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

I I I I Il Il I I I I I I I Il I Il I I I I I I I I I I I I I I I I Il I I I I Il I I I I I I

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900 . . . . .

901 VVPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

M M I I I I I I I I I I I II M M I I I IM I I I M I I I M I M I I I M I M I I

901 WPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

• > • • • 951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

I I Il Il Il Il Il I I Il I Il Il Il Il I Il Il Il Il Il Il I Il I I Il Il I Il 951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050 M M I I I M M I M M Il Il Il Il M M M Il M Il I M M M I M M M

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050

1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100

I Il M M I M Il Il M Il Il Il Il M Il M Il M M M M M I M I M M 1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150

M I I M M M Il I I M Il Il M M M Il M Il M M M I M I M Il Il M

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150 . . . . .

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

M M M M M Il Il I M Il Il Il M Il M Il Il M M M Il M Il I Il Il

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250 1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

I I I Il I I I I I I I I I I I I I I I I I I I I I I I I I I Il I I I I I I I I I I I I I Il Il 1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350

M I I I I I M M I M I I M I I I I M I I I M I M I M I M M I I I M I I I M

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350

1351 IRGLEEELQ 1359

IMMIIII

1351 IRGLEEELQ 1359

Sequence name: CO4_HUMAN_V1

Sequence documentation:

Alignment of: HSCOC4_PEA_1_P16 x CO4_HUMAN_V1

Alignment segment 1/1:

Quality: 14137.00

Escore: 0 Matching length: 1457 Total length: 1457 Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent

Identity: 100.00 Gaps: 0

Alignment:

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50 I M M I I I I M Il M I I I I I I I I I I I I I I I I I I I I M I I I I I I I I I I I I I

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

I Il I Il I Il I Il Il I I I I I Il I I I Il I Il I Il I I I I I Il Il I Il I Il Il I 51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

I Il Il Il I Il I I I I I Il Il Il I I Il I I Il I I I I Il III Il Il I I I Il I I I 101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150 . . . . .

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

M M I I M M I M M M M M M M I I M I M M M I M I M M M I I M

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

I I Il M M Il M I I M I I M M M I M M M I M I M M M M I M I Il I

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300 M M I I M M I I M M M M Il I M I M I M M M Il I I M Il M I M M

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300 301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

I I Il I I I I I I I I I Il I I I I I Il I I I I I I I I I Il I I I Il I I I I I I Il I I I I 301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350 . . . . .

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

I I I I I I I I I I Il Il Il I Il I I Il I I I Il Il Il I I I I I Il I I I Il Il I I Il

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500 M M I I I I I I I Il M M M I I I M M M I I M M I M I M M I I I I Il M

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

M M I M I M I I I I M M I Il I M M M Il Il I M M M I Il I M M I M 501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

M M M I I M I I I I M M M I I Il I M I M I I I I I Il I M I M M M M I

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600 . . . . .

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

M I Il M M I I Il M M M M I M I M I M I I I I I I I I I I I M M I M I I

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

_* • • • • 651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700 651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

I I I I I I I I I Il I I I I I Il I I I I I I Il I I Il I I I Il I Il I Il I Il i I Il I I 701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

I I Il I Il I I Il Il I I III I I I I I Il I I Il Il I Il Il I I I I Il I I I I I Il I

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800 . . . . .

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

II I I Il Il Il Il Il Il Il I Il I I I I Il I Il Il I Il I Il I I Il Il I I I I I I

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

I l I l I I l I I l I l I l I l I I I I I I I I l I I l I I I l I l I I I I I I I I I I l I I I I I 851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

901 WPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950 I I M M I I I I M I I I M I l I I I l I l I l I I l I I I I I I I I I I I I I I I I I l I I

901 VVPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

I Il Il I Il I Il I Il III I Il I I Il Il I I Il I Il I Il I Il I Il I Il Il I I I 951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050

II I I I I I I I I I Il I III Il I I Il Il Il I I I I Il Il I I I I I Il I I I I I I I I 1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050 . . . . .

1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100 I Il I I I I I I I I Il I I I Il I I I I I I I I I I I I I I I I I I I I I I I I I I I I Il I I 1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150 M I I I I I I M M I I I I M M M I I M I M I I M M I I M I I I M I I I M I

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

I M M Il Il I I I I M M I I I Il M I Il Il M Il I I M I M M M M M M 1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250

M I I M M I I M I M M I I M M M I M I I M M I I Il M M I M I I I Il

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250 . . . . .

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

M Il I I I I M I M M Il I M I I M I M I I Il I I I M I M I Il M I I M I I

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350

II I I M M I I Il I I I I M I I I M I I I M I I I M M I M I M M I I M I M

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350

1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIE 1400 M M I I I M M M M M I I M I I M M I Il M Il I M I M Il I M Il M I

1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIE 1400

1401 VTVKGHVEYTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNR 1450

M I M M Il I M M M M M I M I Il I I I Il I I I M I M I I I M I I I I M 1401 VTVKGHVEYTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNR 1450 1451 RRREAPK 1457

1451 RRREAPK 1457

Sequence name: CO4 HUMAN Vl

Sequence documentation:

Alignment of: HSCOC4 PEA 1 P20 x C04 HUMAN Vl

Alignment segment 1/1:

Quality: 12641.00 Escore: 0 Matching length: 1303 Total length: 1303

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps: 0

Alignment:

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

I I I I I I I I I I I I I I I I I I I I I I I I Il I I Il I I I I I I I I I I I I I I I Il I I I 1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

I Il I I Il I I I I Il I I I I I Il I I I I Il I I I I I I I I I I Il I I I Il I I I Il I I 51 VVKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

I I I I I Il I I Il I I I I I Il Il Il I I I I Il I I Il Il I Il Il I I I I I I I Il I I

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150 . . . . .

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

I I I I I I Il Il I I Il I I I Il I Il Il I I I I Il Il Il I Il I Il I I Il I I Il I I

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

II I I l I l I I l 11 I I I l I I I I I I I l I I l I I I I l I I I I I I I l I I I l I I I l I l

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300 M I M I I I M I I M I I I I I I M I I I M I I M M M M M I M M I I M M

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

I Il M I M M I I I M I I I M M I I M M I M M M I M I M I M M M M 301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

M M I M I M I I M I I I I M I M I M M I M M I I Il M I I M I Il I I M

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400 . . . . .

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450 I I I Il Il I I I I Il I I Il I I Il I I I I Il I I I I I I I I I I I i I I I I I I I I I I I 401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500 M I I I I I I I I I I I I I I I M I M M Il Il I M I I I M M I I M M I M I I I

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

Il Il I I Il I I I I Il I I I Il Il I Il Il I Il Il Il I I Il I I I I I I I I Il I Il 501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

I M M I I M M I I M I M M I M I M M M I M I I I I M M I M I I M M

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600 . . . . .

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

M I I M M M Il I M I M M Il I M I I I Il I M M M Il M I M I M I M

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

I I M Il I I I M M M M I I I M M I M M I M I M M M I M I I M M M

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750 M M M I M M M M M I M M M M M Il M I I M M M M M M M M

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

II M I M M I I M M Ml M M I M M M M M M I M M M M Il M M 751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800 801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

M I I I I I I I I I M I M I I I M I I I I I M I I I I I I I I I M I I M I M M I I

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

I M I Il I Il M I M I M I Il I I M Il I I I M M Il I I I M M M M M M

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

901 WPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950 I I M M Il Il I I Il I I Il I Il M I M I Il I M M M I M I I M I M M M

901 WPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

II M M I M M I M I I Il I I I I M M I I M I M I M M I M M I I M I M 951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050

I M I Il I M I I M I I I M M M Il I M I Il I I Il M I I M M Il M Il Il

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050 . . . . .

1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100

M I I M Il I M M M M Il I I M I I I M M I M M M Il I M M I I I I M

1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150

I M I M Il I M I I MM M M I M M I I Il M I M I Il M I M I I I I M I

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200 M I M Il I I M M M M M Il I I M I M Il Il I I I M Il I I M I I I M I I

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200 1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250

I M I I I MIII II I I I I I M I I I I I I II II I MI II M I I MII M I I I I

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

I Il Il I I M I M I I I Il I M M Il Il I I I M M M I I M I Il M M I I M

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

1301 STQ 1303

I I I 1301 STQ 1303

Sequence name: CO4_HUMAN_V1

Sequence documentation:

Alignment of: HSCOC4_PEA_1_P9 x CO4_HUMAN_Vl

Alignment segment 1/1:

Quality: 14831.00

Escore: 0

Matching length: 1529 ^' Total length: 1529 Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent

Identity: 100.00 Gaps: 0

Alignment:

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50 M I M II M IM IIIIM II I I M I I M I I M II MI I M M IIM IIM

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

M I I I M I M M M I I M M I I M Il I M I M I M I I I I I Il M I I Il I I 51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

I I I I I I I Il I I M I I I I M M I I I M I I I I M M M Il I I I Il Il I I I M

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150 . . . . .

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

II I M I M I I Il I I I I I I M M I M I Il I I M I Il M M M I I M M I M

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

M M I M I M M I I Il I Il I I I M I I M I Il I Il Il I M I I M I M I Il I

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300 I I I M Il Il I I Il I I M M Il I M I I I I M M I Il M I I I Il I I M M M

M I M I I M I M I I I MI I M I I I M M M M M I M M I I I I I I I I I M

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350 . . . . .

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

M I M M I I M I M M I I M Il I M Il I M M Il M I M M Il I M Il M

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

Il I Il I M I Il Il M M I M M M I I M M M M I M I Il I I M I Il I M

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500 I I M I I Il I M M M M Il I M M Il M M M M I I M M Il I M Il I Il

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

M M I Il I M Il M M M Il I I M M M I M M I M I M M Il Il M M I 501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

I IM I I M I I I M I I M I I M Il I M I I I M I Il M Il Il M M Il Il M

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600 . . . . .

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

I Il I I I M I Il I M Il I I M I Il M M I M I Il I I M I Il M I M M M I

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

M Il M I I I M Il I I I Il M Il M I Il Il I M I I Il Il Il I M M M Il I 651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

IiI MIIII M M I I I I II MI I II I IIII II M I I I I I I I M M I I I II 701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

I I I I I I I I I I I I I I I I M I I I I I I I I I Ml M I I I I I M I M I I I I M I I

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800 . . . . .

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

I Il M I I I I Il I I I M I M Il M M I I M I I M Il I I I I M M M I I I M

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

I I I I I M Il I Il I I I I I I I I I I I I I I M Il I I I I I I I M I I I I I I I I I I I

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

901 VVPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950 I I M I I I I I M I M M I M I I I I I M I M I I I I Il M M I I M I M I I M

901 WPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

M I I I M I I I I I I I I I I Il I M M I I I I I I M M M I I M I M I M I M I 951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

• • • • •

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050

M I I M M I I M I I I I I I I M I I I I I I I I I I I I I I I I I I I I I I M M I I I

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050 . . . . .

1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100 I I I I Il I I I I I Il I I I I I I I I I Il I I I Il I I I I I I Il I I Il Il I I I I I I I 1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100

• • » • •

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150 I I I I I I I I I M I M I I I I I I Il I Il Il I I I I I I M I M I Il I I I I I I I I I

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

I I I I I Il I I Il Il I I I I I I I I I I I I I I I I I I I I I I I I I Il I I I I Il I I I I 1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250

M I M M I I I I I I I M I I M M I I M I M I I I I I I M I I M M M I I M I

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250 . . . . .

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

I M M I M I II M I M M M M M M M M M M M M M M M I M I M

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350

M Il I M I I I Il I M Il I Il I Il I Il Il I Il I M I I Il I Il Il M I Il M

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350

1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIE 1400 I M I Il M M I Il I M M M I M I M Il Il M I Il I M I M I M Il I I I I

1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIE 1400

1401 VTVKGHVEYTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNR 1450

M M Il I I I I M I Il Il I Il Il I I I Il M Il I I Il Il Il I Il I Il I Il Il 1401 VTVKGHVEYTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNR 1450 1451 RRREAPKWEEQESRVHYTVCIWRNGKVGLSGMAIADVTLLSGFHALRAD 1500

I I I Il I I I I I I I I I I I I I Il I I I I I I I I I I I I I I I Il I I I I I I I I I Il I I

1451 RRREAPKWEEQESRVHYTVCIWRNGKVGLSGMAIADVTLLSGFHALRAD 1500

1501 LEKLTSLSDRYVSHFETEGPHVLLYFDSV 1529

I M M I I M I I M M M M I M M M I M

1501 LEKLTSLSDRYVSHFETEGPHVLLYFDSV 1529

Sequence name: CO4_HUMAN_V1

Sequence documentation:

Alignment of: HSCOC4_PEA_1_P22 x CO4_HUMAN_V1

Alignment segment 1/1:

Quality: 16066.00

Escore: 0

Matching length: 1654 Total length: 1654

Matching Percent Similarity: 100.00 Matching Percent Identity: 99.94

Total Percent Similarity: 100.00 Total Percent

Identity: 99.94 Gaps: 0 Alignment:

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

I I I I I Il I I I I I I I I I I Il I I I I Il I I I I I I I Il I I I I I I I I I I I I I I I I 1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

• _* • • •

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

Il Il I I I Il Il Il I I Il Il I I Il Il I I Il Il I Il I Il I Il I Il Il I Il I I

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100 . . . . .

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

I I I Il I I I I I I I I I I I Il I I I I I I I I I I I I I I I Il Il Il I I I I I I I I I I I

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

I I Il I I I Il I I I Il I Il I Il I I I I I I I I I Il I I I Il Il I I I I I I I I I I I I

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250 I I I M I I I I I I I I I I I I M I M I I I I M Il I Il I I I I Il I I I I I I I I I Il

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

II Il I I I Il I I I I I I I Il I I I I I I I I Il I I I Il Il I Il Il Il Il Il I Il I 251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

I I I I I III I I I I I I I I I I I Il I I I I I I Il I I I I I I I I I I Il I I I I I I I I I

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350 . . . . .

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400 I I I I I I I I I I I I I I Il I I I I I I I I I Il I Il I I I I I I I I I I Il I I I I I I Il

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450 Il I I Il M I Il I I Il I I I I M Il Il Il Il Il Il I Il I I I Il I I I I I Il Il

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

M M IIM I I I I IM M M I I I M M I M I M M I I M M I M I I I I I I I 451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

II Il M M M M M M Il I I M I I I Il Il M M I Il I I I M Il M Il I M

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550 . . . . .

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

Il M I I Il I I I M I Il Il Il I I Il M M M M M Il M Il M M I M I M

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

Il M I I Il Il I I I I I Il M M I M I M M I M M I I M Il Il I Il M I M

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700 M M I I M M Il I I I Il I M Il M M M Il M I I I I M I I Il I I Il M M

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

Il I I M M I I I I I Il M M I M M I M I M M I I I M Il I M M Il M I I 701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750 751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

I I Il I I I I I I I I I I I I I I Il I I I I I I I Il I I I I I I Il I Il I Il I I I I I Il

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

• • • • • 801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

I I I I I I I I Il Il I I Il I I I Il I I Il I I I Il I Il Il I I Il Il Il III I I Il

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900 I I M I I I I I I I I I I I I I I I I I l I I l I I I M I I I I I I I I I I l I l I M I I I l

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

901 WPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

I I I Il I I Il I I Il I I I I I I I I I I I I I I Il I I I I I I Il I I I I Il Il I I Il I 901 VVPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

I Il Il I I I Il I I I I I Il I I I I I I I I I I I I Il I I I I Il Il I Il I I I I Il I I

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000 . . . . .

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050

I I I I I I Il I Il I I I Il Il I Il Il Il Il I Il I I I I I I I I I Il I I I I Il I Il

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050

1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100

I I I Il I Il I I I I I I I I I I I I I I Il I I I I I I I I I I I I Il Il I I I I I I I Il I

1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150 1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

I I I I I Il I I I I I I I I I Il I I I I I I I i I I I I I I I Il i I I I I Il I I I I I Il I

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200 . . . . .

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250

MIIMMMMIMIIIMMIIIIMIIMIIIIIMMMIIIIMI

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

M M M Il I M M M M I M I I M I M I M M M M I M M M I M M M

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350 M M M I I I M I M M M M M M M M M I M Il M M M M I M M I I

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350

1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIE 1400

M M M I M Il M M M M M I Il M M M M M M I I M I M I M M I I 1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIE 1400

1401 VTVKGHVEYTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNR 1450

M M M M Il M Il I M M I M Il M I M M M M M M M M M M M I

1401 VTVKGHVEYTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNR 1450 . . . . .

1451 RRREAPKWEEQESRVHYTVCIWRNGKVGLSGMAIADVTLLSGFHALRAD 1500

M M M I I M Il Il M I M M M M M I I I M M Il M M M M I M I M

1451 RRREAPKVVEEQESRVHYTVCIWRNGKVGLSGMAIADVTLLSGFHALRAD 1500

1501 LEKLTSLSDRYVSHFETEGPHVLLYFDSVPTSRECVGFEAVQEVPVGLVQ 1550 1501 LEKLTSLSDRYVSHFETEGPHVLLYFDSVPTSRECVGFEAVQEVPVGLVQ 1550

1551 PASATLYDYYNPERRCSVFYGAPSKSRLLATLCSAEVCQCAEGKCPRQRR 1600

I I I i I I I I I I I I Il I I I I I I I I Il Il I Il I I Il I I I I I I I I Il I I I I I I I 1551 PASATLYDYYNPERRCSVFYGAPSKSRLLATLCSAEVCQCAEGKCPRQRR 1600

1601 ALERGLQDEDGYRMKFACYYPRVEYGFQVKVLREDSRAAFRLFETKITQV 1650

I I I I I I I I I I I I Il I Il I Il I I I Il I I I Il Il I Il I I I Il Il Il I Il I I I

1601 ALERGLQDEDGYRMKFACYYPRVEYGFQVKVLREDSRAAFRLFETKITQV 1650

1651 LHFS 1654

III: 1651 LHFT 1654

Sequence name: CO4_HUMAN_V1

Sequence documentation:

Alignment of: HSCOC4_PEA_1_P23 x CO4_HUMAN_V1

Alignment segment 1/1:

Quality: 15806.00

Escore: 0 Matching length: 1626 Total length: 1626 Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent

Identity: 100.00 Gaps: 0

Alignment:

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50 MI I M M I I I I M M I M I I I I M I I M M I M I M M M I I I M M M

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

M M I I M Il M Il I I I M M I M I M Il M Il Il I I I M M I Il I I I M 51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

I Il M I I I I M I M Il I M M M Il I M I Il I I M M I I M Il I I Il I M

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150 . . . . .

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

M I I Il I I I M M I M M M I Il Il I Il Il I Il M Il Il I Il Il I M I I I

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

M Il I I I I M I Il M M M I I I I I I M I I I M I M M Il I Il Il I I M M

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300 I I Il I M I M Il M M I M M M I M I I Il M I M Il I I I Il M M Il M

M M M M I I M M M I M I I M I M I M M M I M I I I I I M I M I M I

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350 . . . . .

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

I I I I M M I I I M I M I I I I I I I M I I M M I M I I I M Il I I I Il I M I

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

MMMMMMMMMMMMMMMMMMMMMMMMM

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500 Il I I M M Il I I I I M I I I I I I I I I Il I Il I Il I M M I I M M M M M

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

I M M M M M M I I I M M M M M I I M I M M I I I I I I I M I M M I 501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

M I I M I I I I M M M M I I I M I M I I Il I M I I I M I I I I M M Il M

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600 . . . . .

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

M I I M M I I I I I M M M I I Il I M I I M M I I I I I I I I M M M M M

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700 651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

I I I I I I Il I I I I Il I I I I I I I I I Il I I I Il I I I I I I Il I I Il I I I I I I I I 701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

751 QAGLQRALETLQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

I I I I I I I Il I I Il I Il I I Il I I Il I Il I I I I I I I Il Il I I Il I Il Il I Il

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800 . . . . .

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

I I I I I I Il I Il I Il I Il I I I I I Il I Il I I I I I I I I I I I I I Il Il Il I Il I

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

M M M M M M I I II IM IMM III M I I M M I I M II III M I II I

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

901 WPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950 Il Il Il I Il I I M M Il I M M Il Il Il Il M Il I M Il I M M M Il Il

901 WPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

M Il Il M I I I M M M M Il I M M M Il I M M M M M Il Il I M M 951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050

II Il I l I I l I I M M M I M I M M I l M M M M M M M Il M M I Il

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050 . . . . .

1051 KGYMRIQQFRKADGSYAAWLSR^'DSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100 I I Il Il I I I I Il I I I I I I I I I I I I I I I I Il Il Il I I I I Il I I I Il I I I I I 1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150 I I I I I M I M I M I I Il I I I I I M M M I I I I I Il I I I I I I I I I Il I Il I

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

I M M I M M I I I M M M I M I I M I MI I M M M M I I I M I I M M 1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250

I I M Il Il I M M Il I I Il M Il Il M I Il M Il M M M M M M M Il

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250 . . . . .

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

I I Il M I M M Il M I M M I M M M I Il M Il M M M M M M M Il

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350

I M Il M Il M Il I Il I Il M Il Il M I Il M Il I M I M I M M I M Il

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350

1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIE 1400 Il Il M I Il I I M M I M M M M I M M I M M Il I M I I I M M M Il

1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIE 1400

1401 VTVKGHVEYTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNR 1450

I M I M M M Il M Il M M I M I I M I Il I I I M I Il Il M I M M I M 1401 VTVKGHVEYTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNR 1450 1451 RRREAPKWEEQESRVHYTVCIWRNGKVGLSGMAIADVTLLSGFHALRAD 1500

I I I I I l I I M i l I l I I I I I I l I I I I I I I I I I I I I I I I l I I I l I I I I I I l I 1451 RRREAPKWEEQESRVHYTVCIWRNGKVGLSGMAIADVTLLSGFHALRAD 1500

1501 LEKLTSLSDRYVSHFETEGPHVLLYFDSVPTSRECVGFEAVQEVPVGLVQ 1550

II I I Il I I I I Il I Il Il I I I Il Il I I I I I I I I I I I I Il Il Il I I I I Il Il

1501 LEKLTSLSDRYVSHFETEGPHVLLYFDSVPTSRECVGFEAVQEVPVGLVQ 1550

1551 PASATLYDYYNPERRCSVFYGAPSKSRLLATLCSAEVCQCAEGKCPRQRR 1600 I I I I I M I I I M M I I I I M I I Il I I I I I I M I I I I I M I Il M M M Il

1551 PASATLYDYYNPERRCSVFYGAPSKSRLLATLCSAEVCQCAEGKCPRQRR 1600

1601 ALERGLQDEDGYRMKFACYYPRVEYG 1626

I Il I I Il I I I₁I I Il I I I Il I I I I I I I 1601 ALERGLQDEDGYRMKFACYYPRVEYG 1626

Sequence name: CO4_HUMAN_V1

Sequence documentation:

Alignment of: HSCOC4_PEA_1_P24 x CO4_HUMAN_V1

Alignment segment 1/1:

Quality: 14823.00

Escore: 0 Matching length: 1528 Total length: 1528

Identity: 100.00

Gaps: 0

Alignment: . . . . .

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQ 50

I I I I I I I I I I I I I I I I I I I I Il I Il I I I Il I I I I I I I I I I I I I I I I I i I I

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

I I I I Il Il I Il I I I Il Il I I I Il Il I I I I I Il I Il I Il I I Il I I I I I Il I

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150 I I I M I I I I I I I I I I M I I I I M Il I Il I I I Il I I Il Il Il Il I Il I I Il

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

I I I I I I Il I I I I I Il Il I I I I I I I I I I I Il I I I Il I I I Il I I I Il I I Il I 151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

I I I I Il Il I I I I I I I I I I I I I Il I I Il I I I Il I I Il I I I I I I Il I Il I I I 201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250 . . . . .

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300 I Il I I I I Il I I I I I I I I I I I Il I I I I I I I I I I I I I I I I I I I I Il I I I I I I

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350 I I I I I I M I I I I I I I M I I I M I I I I I I I I I I I I I I I M I I I M I I I I Il

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

I M M I I I M M M M I I I M M M M M M I M M M I M M I M I I M 351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

II I Il Il Il Il Il Il I I I Il Il Il M Il I Il Il Il Il Il Il Il Il Il Il I

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450 . . . . .

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

M M I Il M M M I M M M I M M I Il Il I M I M M I Il Il I I Il M I

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

M M M M I M Il Il M M I M M Il M M Il I Il Il M Il M I M I M I

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600 M I M M M M Il M M Il M M Il M I M Il M M M M M M Il M Il

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

M M I I M Il M M I I M M M I M M M M M I Il M M M I Il Il M I 601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650 651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

I I I Il Il I I I I I I I I I I I I I I I Il I I I I I I I I I I I Il I I I I I I I I I I I I I

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

I I I I I I Il Il I I I I I I I I I I Il I I I I I I I I Il I Il Il I I I I I I I I I I I I I

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800 M M MI I II I M M I I I I I I M I M M I I IM I MI I M I I I M M I M

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

I I I I I I M I M I I I I M I I I Il I M I I M M I I M M I I I M I I I I M I I 801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

I I I I I I IM I I M I I M M Il I I M I I I M I I M Il I M M I I I I Il M I

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900 . . . . .

901 WPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

I I M I I Il M I I I I Il Il I M M I M I M I I I Il I I Il I Il I M I I Il I I

901 VVPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

I I Il M I I I I M I M I Il I I MM I I I M M I Il M I M I Il I I I I I I M

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050 M I I I I I Il I I Il I I M I I M I I I I I I I M I M I I Il I I M I I I I M M I

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050 1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100

I I I I I I I Il I I I I I I I I I I I I I Il I Il I I Il I I I I Il Il Il Il I I I I I I I

1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100 . . . . .

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150

M I I I M I I I M M I I M M I M M I M M I I I I M I II M M I I M I M

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

M M Il Il Il M Il M Il I M Il M M M Il M M M M M I Il M Il M

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250 I M M M I I I M Il Il M M M I Il M M M Il I M Il M I Il Il M M I

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

M Il Il Il I III M I M M M M M I M M Il Il M Il M I Il Il M I M 1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350

M M Il Il M I I M Il Il I M I M M I Il M Il M M I Il I I Il Il Il Il

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350 . . . . .

1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIE 1400

II M M I I I I I I M I I M I M I M M I M M Il Il Il M M I M Il Il Il

1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIE 1400

1401 VTVKGHVEYTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNR 1450 1401 VTVKGHVEYTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNR 1450

1451 RRREAPKWEEQESRVHYTVCIWRNGKVGLSGMAIADVTLLSGFHALRAD 1500

1451 RRREAPKVVEEQESRVHYTVCIWRNGKVGLSGMAIADVTLLSGFHALRAD 1500

1501 LEKLTSLSDRYVSHFETEGPHVLLYFDS 1528

Sequence name: CO4 HUMAN Vl

Sequence documentation:

Alignment of: HSCOC4_PEA_1_P25 x CO4_HUMAN_V1

Alignment segment 1/1:

Quality: 15464.00 Escore: 0

Matching length: 1593 Total length: 1593

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00 Total Percent Similarity: 100.00 Total Percent Identity: 100.00 Gaps: 0

Alignment:

• • • • • 1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

M I I I I I i M M M I I I I M M I I I I I I M I I I I I I M I I I M M M I I I

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQ 50

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100 I M I Il M Il M I M I I I Il M I M I M Il Il M Il Il Il I I Il Il I M I

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

I I I Il Il I M M I I I I Il Il M I I M I Il M M M M I Il I M M M Il I 101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

^'151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

M M Il Il M I Il M M M Il I M I I I M M I M I M I M I I M Il Il I I

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200 . . . . .

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

M M M M I M I M I M I M M I Il I M Il I M Il I M M M I Il I M M

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

I I I I Il I Il I M I I I I I M M Il Il Il Il Il M Il I I M I I Il I Il M I I 251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350 Il M Il I M M Il M I Il Il I M I Il Il M I Il I M I Il I I Il Il I M I I

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350 351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

I M I M M I I M M I I I M I I I I M I I I I I M I II I I I I I M I I M M M

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400 . . . . .

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

M I M M I I I M M I I M M I Il I M M I I Il I I I I I I I I I I M M M M

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

I I M M I I I M I M I M M I I M M I I M M Il I I Il I I I M I I M M M

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550 I I I I M M I M I I I M I I M M M I I I M M I I I I I I I I I M I M I M M

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

M I I I M I M I I I I M I I M M I M I I M I I Il M M I M M M M M M 551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

M Il I I I I Il I M I Il I I M M M M I M M I I M M I M I M I I M M I

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650 . . . . .

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

M Il I I I I I I Il I I M I M I I M I M I M Il I I I I I M M I I I I Il I M I

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750 701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

M I M I I MI I MMIMI MM M I M M II M I I M M M MII M M 751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

M I M M I I M III I M Il M M I M M I M I I I M I I Il M M III Il I

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850 . . . . .

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

M M I M I M M M Il M M M I M M M M I M I I M I I M I M M Il I

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

901 WPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

Il M M Il I I I I I I I I Il Il I M M Il Il M I M I M M I Il I M I Il Il

901 WPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV .1000 I Il M M M I I M M I Il I I I I I M M I I I M I Il Il M I Il I I I M Il I

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050

I I M I M M M I M I M M M I I I I Il I Il M M M I I M I I I I I I M M 1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050

1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100

I I M I M M M M M I I M I M I I M I I Il I M M Il I I M I I I I M M I

1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100 . . . . .

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150 I I I I i I I I I Il I I I I I I I I Il Il I I I I Il Il I I i I I I I I I I I I Il I Il Il

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200 I I I I M I I Il I I M Il M I I I I I I M Il Il I I Il I I I I Il I Il I I I I I I I

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250

I I I I I I I I I I I I I I I I Il I I I I I I I I I I I Il I I I I Il I I Il I I I I I I I Il 1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAΞMADQAAAWLTRQGSFQGGFR 1300

Il Il I I I I I Il Il I I I I I I I I Il I I Il I I I Il I I I I I I I Il I I I Il I I I I

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300 . . . . .

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350

I I I I I I I Il I I I I I Il I I I I I I I I I I I I Il Il I I I Il I I Il Il I I I I Il I

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350

1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIE 1400

I I I I I I I I I Il I Il I Il I I I Il I I I I I Il I I I I Il Il I I Il I I I I I I Il I 1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIE 1400

1401 VTVKGHVEYTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNR 1450 I M I I I I I I I I I I M I I I I M I M M I I I I M I I I I I I I I I I M M I I I I

1401 VTVKGHVEYTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNR 1450

• • • • _"

1451 RRREAPKWEEQESRVHYTVCIWRNGKVGLSGMAIADVTLLSGFHALRAD 1500

I I Il I I I I I I I I I I Il Il I I I I I I Il I Il I Il Il I I I Il I I I I Il I Il Il 1451 RRREAPKVVEEQESRVHYTVCIWRNGKVGLSGMAIADVTLLSGFHALRAD 1500 1501 LEKLTSLSDRYVSHFETEGPHVLLYFDSVPTSRECVGFEAVQEVPVGLVQ 1550

I III I I I i Il I I I I I I I I I I I I Il i I I I I I I I I I I I I Il I I I I I I I 1 I I I

1501 LEKLTSLSDRYVSHFETEGPHVLLYFDSVPTSRECVGFEAVQEVPVGLVQ 1550

1551 PASATLYDYYNPERRCSVFYGAPSKSRLLATLCSAEVCQCAEG 1593

I Il Il I I I I I I Il I Il I I I Il Il I Il Il I I I I I I I I I Il I I Il 1551 PASATLYDYYNPERRCSVFYGAPSKSRLLATLCSAEVCQCAEG 1593

Sequence name: CO4_HUMAN_V1

Sequence documentation:

Alignment of: HSCOC4_PEA_1_P26 x CO4_HUMAN_V1

Alignment segment 1/1:

Quality: 15464.00

Escore: 0

Matching length: 1593 Total length: 1593

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent

Identity: 100.00 Gaps: 0 Alignment:

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

I MIM I I IIM I IM I I MII M I I I III M M M M I I III MI M M 1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

M I M M M IM M M M M M M M I M M I I I M M M M MM M M

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100 . . . . .

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

I M I I M M I M I M Il M M Il M I I Il Il Il I M M M Il Il Il M M

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

I I M M I M I M I I I Il Il I M I M M Il Il Il I Il Il M Il Il Il I M I

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250 I I M I M M I Il M Il Il M Il I M I I I M M Il M I M M M M M M I

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

I I M I I M M I M Il I I M Il Il M Il M M M I M I I I I M Il Il M I I 251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

M Il Il I Il M I I M M I Il Il I Il M M M M Il I Il Il I M I I I M I I

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350 . . . . .

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400 M M I I I I I I M I I I i I I M I I I I I I I M I I I M I I M I I I M M I M I I

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450 M I I I M I I I M M I I Il Il I I I M M I M I I I M I I Il Il I Ml I M I I

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

I I I M I I I M M Il M I M I M M I I I M M I I M I I I I M M Il I Il M 451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

I I M M I M I I I I I I I I I M I I I M M I I I I M M I I I I M M I I M I M

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550 . . . . .

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

M Il I I I M M M I I I I I M I Il I I I I I M M Il I M I M I M M I M I I

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

I Il Il I I I I I M M M M I I M I M M I Ml Il M I Il I M I I I I I I I I I

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700 M M I I M M I I M M M Il I I I I I M I I I M M I I M I I M I I M M M

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

I I Il M M Il Il M Il I I I I I I I I I I M I I I Il M I I Il M I M I I M M 701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750 751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

I I Il Il I Il I I I I I I I Il I I I I I I I I I I I I I I I I I I I I I I I I I I I I I Il I

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

I I Il Il Il I Il I I I I I I Il I I Il I I I I I Il Il I Il I Il I I I I I I I Il Il I

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900 I I I I M Il I I I I I I I I ll I I I I Il Il I I I I I Il I I I I I I I I I Il I I I I I I

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

901 WPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

I I I I l I l I l I I I l I l I I I I I l I I I I I I I I I l I I l I I I I I I l I I I I I I I l I 901 WPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

I Il I I I Il I I I Il I Il I I I Il I I I Il I I Il I I Il I I I I I I Il Il I I I Il I

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000 . . . . .

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050

I Il Il I Il I I I I Il I I Il I Il I I Il I I Il I I I I I I Il I I I Il I I I I I I I I 1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050

1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100

I I I I I Il I I I I Il I I I I I Il I I I I Il I I I I I Il I I I I I Il I I I I I I I I Il 1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150 I I I I I M M I I I I I I I I I I I I I I I I M I I I M I M I I I I I I I I M Il I I I

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150 • • • • >

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

I I I I Il I I I I I Il Il Il I I I I I I I I I I I I I I I I Il I Il I I I I I I Il I I I I

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200 . . . . .

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250

I I I I I I Il I Il I I I Il I I I I I I I Il I Il I I I I I Il Il Il I I Il I I I I Il I 1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

I I I Il I Il I Il I I I I I Il I I Il I I Il I I I I I Il I Il Il I Il I Il I I I I I I 1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350 I M M I M I I M I I I I I I M M I I M M I I M M M M I M I M I I I I I I

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350

1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIE 1400

M I I M I Il Il I I I M M I M I I I I M I Il I M M I M I Il I M I I M I I 1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIE 1400

1401 VTVKGHVEYTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNR 1450

I I I I I I I I I M M I I M I M I I I I I M Il Il I I I M I M M I M Il M M

1401 VTVKGHVEYTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNR 1450 . . . . .

1451 RRREAPKVVEEQESRVHYTVCIWRNGKVGLSGMAIADVTLLSGFHALRAD 1500

I M Il I I I M M I I I I I I M M I M I M M Il I I I M I I M Il M I I I M 1451 RRREAPKWEEQESRVHYTVCIWRNGKVGLSGMAIADVTLLSGFHALRAD 1500

1551 PASATLYDYYNPERRCSVFYGAPSKSRLLATLCSAEVCQCAEG 1593

Sequence name: CO4_HUMAN_V3

Sequence documentation:

Alignment of: HSCOC4_PEA_1_P30 x CO4_HUMAN_V3

Alignment segment 1/1:

Quality: 11940.00

Escore: 0

Matching length: 1232 Total length: 1232

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps: 0

Alignment: 1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQ 50

I I I I I Il I I Il I I I I i I Il I I I Il I I I I I I I I I I I Il I I I Il I I I Il I I I

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQ 50

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

I I Il Il Il Il I I I I I I I Il Il I I I Il Il I I Il I I I I Il Il I I Il I I I I I I 51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150 I I M I I I I I I I M M M I M I Il Il I I I I I I Il I I I Il I I I I I I Il I I Il

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

I I I Il Il I I I I Il I I I I Il I Il I I I I I I I I Il Il Il I Il I I I I I Il I I Il 151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

I I I I I Il I I I I I I I I I I Il Il I I I I Il I I I I I I I I Il I I I Il I I I I I I I I 201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250 . . . . .

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

M M I I I I I M M M I I I M I I I I I M M I I I I I M M I I M M I I M I I

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

I I I Il M I Il M I Il Il M M Il M M M Il Il Il I M M Il Il Il M M

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400 I I M I I I I Il I Il M M I Il I I M M M I Il Il M Il Il I M I M M Il I

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400 401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

I I I Il I Il I Il I I I III I I i I I I I I I I I I Il I I I Il I I I I I I Il I I I I I I

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450 . . . . .

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

I I I I I I Il I I Il Il I I Il I I Il I Il I I I I Il I Il I Il I Il I I I Il I Il Il 451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

I I Il I I I Il I Il I I I Il Il I I I Il I I I I I I Il I I Il Il Il Il I I I I I I I I 501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

• • > • •

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600 I I I I I I I I I I I I I I I I I I M I M I I I I M I I I I M I I I I I I I I I I I I I I I

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

I I I I I I Il Il Il I Il I I I Il Il I I I I I I Il I I Il Il I Il I I I Il Il I Il I 601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

M M M I I I I I M M M M I I I I I I M I I I I I M I M I I I I I M M I I I I

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700 . . . . .

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

I M I M M I I I M M I M M I M M M M M M M M I M M I M I M I I

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800 751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

I I I I I I Il Il Il I I I I Il I I Il I I I I I i I Il I I Il I Il I I I I I I I I Il I I 801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

Il Il I I Il Il Il I I I Il I I I Il I I Il I Il I Il Il I I I I Il Il I I Il I I I I 851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900 . . . . .

901 WPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

II I Il I Il Il Il Il I Il I Il I I I I I I I I I I I Il Il I Il I Il Il Il Il I I I

901 VVPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

I I I I I Il Il I Il I I I Il I Il I Il I I Il I I Il I I I I Il I I I I I I I Il I Il I

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050 I I I I I M I I I I I I I I Il Il I I I I I I I I Il I Il Il Il Il Il Il I I I I I Il I

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050

1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100

II I Il I I I Il Il I I Il Il Il I Il I I I Il I I I Il I I I I I I I I I I I Il I I Il 1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100

• • • • •

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150

I I I I I I I I I I I I I I I I I I Il I I I I I I Il Il I I I I Il I Il I I I I I Il I I Il 1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150 . . . . .

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGS 1232

Sequence name: CO4 HUMAN

Sequence documentation :

Alignment of: HSCOC4 PEA 1_P38 x CO4_HUMAN

Alignment segment 1/1:

Quality: 7969.00

Escore: 0

Matching length: 818 Total length: 818 Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps:

Alignment: 1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

I Il I I I I I I I.I I I I I I Il Il I I I I I I I I I I I I I I I I I I I I I I I Il I I I I I

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50 . . . . .

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

M I I M I I I I I M I I I M M I I I I M M I I I I M I I I I I I I I I I I M M I

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

I Il M I M M I Il I I M M I I I I I I M I I M I I M M M I I Il M I M Il

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200 M I I I I M M M I I I I M M I I I I M I M M I I M M I Il I I I I I I I I M

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

I M I M M M.I M I I I I M I I I I I M M I I I I I I I M I Il I M I M I I I I 201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

M I I M M M M I I I I I I I I I I I M M I I I M I I Il I I M I I M I I I I M

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300 . . . . .

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

I I I I I I M I I I M I I I I M I I I I I I I I I M I I Il M M M M I I M I I I I

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400 351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450 MIIIMMIIIIMIMIMIIIIIMIIM 401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

I I Il I I I I Il Il I Il Il I Il I Il I I Il Il Il I I I I I Il I I I Il Il I Il I I 451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500 . . . . .

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

I M M M M I Il Il I I I I M I M I I I Il I I I I Il I I I M I M I M I M I I

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

I I I I I I I I M I M I I I I Il I I I I Il M I I I M I M I M I I M I M M I I I

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650 M M I M I I I I I I I M M I Il I M Il I M M I I I I I I I I I I I I M M I I I

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

M I I Il I M I I I M I I I I I M I I I I I M I I I I I I I M I I I I Il M I I M I 651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

M I I I I I I I I M M I I M I M I I I I I M I I I M Il M I I I I I I I I M I I I

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750 . . . . .

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

801 DSLTTWEIHGLSLSKTKG 818

Sequence name: CO4JHUMAN

Sequence documentation:

Alignment of: HSCOC4_PEA_1_P39 x CO4_HUMAN

Alignment segment 1/1:

Quality: 3766.00

Escore: 0

Matching length: 387 Total length: 387 Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps:

Alignment: 1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

Il Il I I Il I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I Il I I i I Il I I I I

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50 . . . . .

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

M M M II M I M I M M I I I I I I M I I I I M M I M M M I I I M I M I

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

M Il M I I M M I Il Il M Il Il Il Il Il M M I M M Il I I Il I M I M

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200 I M M Il M M M I M Il M M Il M Il M M I M M M Il I M M M Il

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

Il Il I Il I M Il M Il I Il I M M M M M I M Il M Il M Il Il M I M 201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

• • • • •

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

M Il Il M I M M Il Il M Il Il I I M Il I I Il M M I Il Il I M Il M I

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300 . . . . .

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

M M I M Il Il I M M I M I M I M Il M M M Il I Il Il M Il Il M Il

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQ 387 351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQ 387

Sequence name: CO4_HUMAN

Sequence documentation:

Alignment of: HSCOC4_PEA_1_P40 x CO4_HUMAN

Alignment segment 1/1:

Quality: 2309.00

Escore:

Matching length: 236 Total length: 236 Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps:

Alignment:

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQ 50

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQ 50 51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

I Il I I I Il I I i I I I I I I Il I I Il I I I I I Il I I I I I I I I Il I I I I I I I I I I

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

I I I I I I I I I Il I I I Il III Il I I I I I I Il I Il I I I I I Il I Il I I I I I I Il

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200 I I I I I I I M I I I I M M I I I I Il I I I I Il I I I I I I I I I I M I I I I I I Il I

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKY 236

I I I I Il I I I I I I I Il I I I I Il Il I I I I I I I I I I I I I 201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKY 236

Sequence name: CO4_HUMAN_V1

Sequence documentation:

Alignment of: HSCOC4_PEA_1_P41 x CO4_HUMAN_V1

Alignment segment 1/1:

Quality: 14831.00

Escore: 0 Matching length: 1529 Total length: 1529

Identity: 100.00

Gaps: 0

Alignment: . . . . .

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQ 50

I I I I I I I I I I Il I I I I I I I I I I I I I I I I I I I I I I I Il I Il I I I I I I I I Il

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

I I Il Il I I I I I Il Il Il Il I Il Il Il I I I I I Il I I I Il Il I I I I I I Il Il

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150 I I M M I I I M I I I I M I I M I M M I I M M I M I M I I M I I I I I I I I

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200 I I I Il Il Il I I I I I I I I Il I I I Il I I Il Il I I I I Il I I I Il I I I I I I I I I 151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250 I I I Il Il I I Il I I I Il Il Il I I Il I I Il Il I I Il Il I I I Il I I Il I I Il I

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250 . . . . .

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300 MII MIIMMM I M I MII MI M IM I MI III i I I II I M M MI

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350 M I M I I M M I I M I M M M I M I M M I M M Il Il M Il Il I M I I

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

Il I Il I M I M M M I I M I M I I M M I I Il I Il I M M Il I Il I I I I I 351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

I I I Il I I Il Il I M Il I M I M Il M I I I I M M M Il I Il I I M M M I

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450 . . . . .

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

M M Il Il Il M M M M I M M I I I Il M Il Il M Il I M Il M M I Il

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

I I I M M M M Il I M I Il Il M M M M M Il Il I M M M Il Il Il I I

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600 I I Il M I Il I I M I M I I Il I M Il I Il M Il I M Il I Il I Il I I I Il Il

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

I I M Il Il M M Il I I M Il I I Il I M M I Il I Il Ii M M Il I Il M Il 601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650 651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700 651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

M M I I I I Il M I M M I I I I M Ml M I M M I I I I M M M M I M M

701 RCCQDGVTRLPMMRSCEQRAARVQQPDCREPFLSCCQFAESLRKKSRDKG 750

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800 M M I I I M I I M I I M M M M I M M M I M I I M I M I I M Il I I M

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

M M I I I M I I I I M I M I I M I M M Il I M I M M M I I M M M I M 801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

M M M M M I I I I I I I I M M I M I I I M M M I M Il Il I M I M M I

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900 . . . . .

901 WPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

M M I I I I I I I Il M I I M I I M I I M I M I M I M M M Il M I Il I Il

901 VVPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

I M Il I M M M M I I M M I I Il I M M M I I M I I I I I M I I I I I M I

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050 I I I I M Il M M I M M I I M M M I I I I I M M Il Il M M Il I I I I Il

I I I I I Il I I I Il I I I I Il I I I I I I I I I I I I I I I I I I I I Il I I I I I I I I I I 1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100 . . . . .

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150

I I Il I I I I I I I I I Il Il I I Il I I I Il Il I I I I I I I I I Il I I Il I I I I Il I

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150

• • • > • 1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

I M M M M MI I M I I M M M M I M I I I M M I I I I I M M I I I I M

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

• • • • •

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250 Il M Il M I M M I I I M Il M M M M M Il M Il Il M M M Il M M

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

II I I Il M I M I I M M M Il M Il I M M M I M Il I M Il Il I Il M I 1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350

Il M Il I I M I M M M M Il Il Il I Il M M Il I Il M Il Il I M M M

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350 . . . . .

1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIE 1400

I M I M M I I I Il M I M M Il M Il Il I M Il Il M M I I I M M M M

1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIE 1400

1451 RRREAPKWEEQESRVHYTVCIWRNGKVGLSGMAIADVTLLSGFHALRAD 1500

1451 RRREAPKVVEEQESRVHYTVCIWRNGKVGLSGMAIADVTLLSGFHALRAD 1500

1501 LEKLTSLSDRYVSHFETEGPHVLLYFDSV 1529

Sequence name: CO4_HUMAN_V1

Sequence documentation:

Alignment of: HSCOC4_PEA_1_P42 x CO4_HUMAN_V1

Alignment segment 1/1:

Quality: 14480.00 Escore: 0

Matching length: 1506 Total length: 1544

Matching Percent Similarity: 99.93 Matching Percent Identity: 99.87 Total Percent Similarity: 97.47 Total Percent Identity: 97.41

Gaps: 1

Alignment:

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

I Il I I I I I I I I I I I I Il I I I I Il Il I I I I I I I I Il I Il I I Il I I I I I Il I

1 MRLLWGLIWASSFFTLSLQKPRLLLFSPSWHLGVPLSVGVQLQDVPRGQ 50

• • • • •

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100 M I I I I I I I I I M M I I I I I Il I Il I I I I I I I Il I I M M M I I Il Il I I

51 WKGSVFLRNPSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLH 100

101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

I M I I I I I M I I I I M I I M M M I M I I I I M I I M I I I I I I I I I I I M 101 QLLRGPEVQLVAHSPWLKDSLSRTTNIQGINLLFSSRRGHLFLQTDQPIY 150

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200

II M I M I I M M M M IM M I M Il M M M M M M M M I M Il M

151 NPGQRVRYRVFALDQKMRPSTDTITVMVENSHGLRVRKKEVYMPSSIFQD 200 . . . . .

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

Il M M I M M Il M M I M Il M M Il M Il M M M Il I I M M M M

201 DFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPNFEVKITPGKP 250

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

M M M I I M M M M M Il Il Il M M M M M Il M Il I I III Il I M

251 YILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE 300

301 SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGG 350 M M Il Il M M I M M I M M M I M M Il I M M M Il I M I M Il M

I I I I I Il I I I I Il I I Il I Il I I I I I I I I I I I I I I I I I I I I Il I I I I I I I I

351 EMEEAELTSWYFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASG 400 . . . . .

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

I I I Il I Il I I Il Il I I Il I Il Il I I I I I I Il I I I Il I Il I I Il I I Il Il I

401 IPVKVSATVSSPGSVPEVQDIQQNTDGSGQVSIPIIIPQTISELQLSVSA 450

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

I I I Il I I I I I I I Il I Il I I I I I I Il I I I I Il Il I I I Il Il Il Il I I I I I I

451 GSPHPAIARLTVAAPPSGGPGFLSIERPDSRPPRVGDTLNLNLRAVGSGA 500

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550 M M M I I I M I I M I M I M I I M M I I M I I I I M I I I I I I I M M M

501 TFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPSFYFVAFYYHG 550

551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

II Il M M I Il M I I Il I I III Il M I I M I I I M M I I M M I I I Il Il 551 DHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA 600

• > • • •

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650

I Il M M Il M Il I M Il I Il Il I I I M I Il I I M Il M Il M I I Il Il I

601 LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAA 650 . . . . .

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

II Il I M I I M M I M Il I I Il M I M Il I I I I M M M M I Il I Il Il I

651 GLAFSDGDQWTLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAK 700

751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

I I Il I I I I I I I I I Il I I I I I I I I Il I Il I I I I I I I I I I I I I I I I I I I I I I 751 QAGLQRALEILQEEDLIDEDDIPVRSFFPENWLWRVETVDRFQILTLWLP 800

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850

II I I Il I I Il I Il I I I Il Il I I I I I Il I I I I Il I Il I I I Il I Il I I I Il I

801 DSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLPMSVRRFEQLE 850 . . . . .

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

M I M M M I M I I I I I I M M I M I M I I I I I I M I M I I M I M I I M

851 LRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS 900

901 WPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

M M M M M Il Il I Il I I Il I M M I I I M M M M M Il M M I M Il

901 WPTAAAAVSLKWARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNP 950

• • • • •

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000 Il Il M I I M M M M I M I I I M I M I M I M I M I M I M Il M M M

951 LDHRGRTLEIPGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGV 1000

1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050

I M Il I M Il M I M I M M I M M Il M M I M M I M I M I M I I I M 1001 ASLLRLPRGCGEQTMIYLAPTLAASRYLDKTEQWSTLPPETKDHAVDLIQ 1050

• • • • •

1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100

I M I I M I I M I M Il M I I M M I I I I M Il M M M I I M I M M I M

1051 KGYMRIQQFRKADGSYAAWLSRDSSTWLTAFVLKVLSLAQEQVGGSPEKL 1100 . . . . .

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150 M M M I I I I I I M M I I I M I I M I M I I I I I I M I M I M M I I I I I I

1101 QETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVALTAFVTIALH 1150

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

S Il I M M I M M M M M Il M Il M I Il Il Il M M I M M M Il I I M

1151 HGLAVFQDEGAEPLKQRVEASISKASSFLGEKASAGLLGAHAAAITAYAL 1200

1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250

I M M M M I M M I I I Il M Il I Il I Il Il M Il M M M I M Il I I I I 0 1201 TLTKAPADLRGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNP 1250

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300

M Il Il I M Il M M M M M I I M M I I M I I M M I M I M I M M I I

1251 SDPMPQAPALWIETTAYALLHLLLHEGKAEMADQAAAWLTRQGSFQGGFR 1300 5 . . . . .

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350

M Il Il I M I I I M I M M M I M I Il M I M M Il Il M M Il M I M I

1301 STQDTVIALDALSAYWIASHTTEERGLNVTLSSTGRNGFKSHALQLNNRQ 1350

0 1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIE 1400

II I Il Il I M M Il I M M M I Il M I I Il Il M Il M Il M I M I I M I

1351 IRGLEEELQFSLGSKINVKVGGNSKGTLKVLRTYNVLDMKNTTCQDLQIE 1400

1401 VTVKGHVEYTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNR 1450 5 Il I M M I I I I M Il M M I I I I Il M Il Il I I M I M M I M I M M M

1401 VTVKGHVEYTMEANEDYEDYEYDELPAKDDPDAPLQPVTPLQLFEGRRNR 1450

1451 RRREAPKWEEQESRVHYTVCIWWAPGAALGQGREGRTQAGAGLLEPAQA 1500

I l I l I l I I M I I l M I l M I I l I 0 1451 RRREAPKWEEQESRVHYTVCIW 1473 1501 EPGRQLTRLHRRNGKVGLSGMAIADVTLLSGFHALRADLEKVWS 1544

1474 RNGKVGLSGMAIADVTLLSGFHALRADLEKLTS 1506

DESCRIPTION FOR CLUSTER HSSTROL3

Cluster HSSTROL3 features 6 transcript(s) and 16 segment(s) of interest, the names for which are given in Tables 284 and 285, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 286.

Table 284 - Transcripts of interest

Table 286 - Proteins of interest

These sequences are variants of the known protein Stromelysin-3 precursor (SwissProt accession identifier MM11_HUMAN; known also according to the synonyms EC 3.4.24.-; Matrix metalloproteinase-11; MMP-I l; ST3; SLr 3), SEQ ID NO: 391) referred to herein as the previously known protein.

Protein Stromelysin-3 precursor is known or believed to have the following function(s): May play an important role in the progression of epithelial malignancies. The sequence for protein Stromelysin-3 precursor is given at the end of the application, as "Stromelysin-3 precursor amino acid sequence". The following GO Annotation(s) apply to the previously known protein. The following annotation(s) were found: proteolysis and peptidolysis; developmental processes; morphogenesis, which are annotation(s) related to Biological Process; stromelysin 3; calcium binding; zinc binding; hydrolase, which are annotation(s) related to Molecular Function; and extracellular matrix, which are annotation(s) related to Cellular Component.

Cluster HSSTROL3 can be used as a diagnostic marker according to overexpression of transcripts of this cluster in cancer. Expression of such transcripts in normal tissues is also given according to the previously described methods. The term "number" in the left hand column of the table and the numbers on the y-axis of Figure 13 refer to weighted expression of ESTs in each category, as "parts per million" (ratio of the expression of ESTs for a particular cluster to the expression of all ESTs in that category, according to parts per million).

Overall, the following results were obtained as shown with regard to the histograms in Figure 13 and Table 287. This cluster is overexpressed (at least at a rriinimum level) in the following pathological conditions: transitional cell carcinoma, epithelial malignant tumors, a mixture of malignant tumors from different tissues and pancreas carcinoma.

Table 287 - Normal tissue distribution

Table 288 - P values and ratios for expression in cancerous tissue

As noted above, cluster HSSTROL3 features 6 transcript(s), which were listed in Table 284 above. These transcript(s) encode for protein(s) which are variant(s) of protein Stromelysin- 3 precursor. A description of each variant protein according to the present invention is now provided.

Variant protein HSSTROL3 P4 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSSTROL3_T5. An alignment is given to the known protein (Stromelysin-3 precursor) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: Comparison report between HSSTROL3_P4 and MM 1 IJHUMAN:

1.An isolated chimeric polypeptide encoding for HSSTROL3 P4, comprising a first amino acid sequence being at least 90 % homologous to MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS PAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVLSGGRWEKTDLTYRILRFP WQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMIDFARYW corresponding to amino acids 1 - 163 of MM11_HUMAN, which also corresponds to amino acids 1 - 163 of HSSTROL3_P4, a bridging amino acid H corresponding to amino acid 164 of HSSTROL3JP4, a second amino acid sequence being at least 90 % homologous to GDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWTIGDDQGTDLLQVAAHEFGHVLG LQHTTAAKALMSAFYTFRYPLSLSPDDCRGVQHLYGQPWPTVTSRTPALGPQAGIDTN EIAPLEPDAPPDACEASFDAVSTIRGELFFFKAGFVWRLRGGQLQPGYPALASRHWQGL PSPVDAAFEDAQGHIWFFQGAQYWV YDGEKPVLGPAPLTELGLVRFPVHAALVWGPE KNKIYFFRGRDYWRFHPSTRRVDSPVPRRATDWRGVPSEIDAAFQDADG corresponding to amino acids 165 - 445 of MM11_HUMAN, which also corresponds to amino acids 165 - 445 of HSSTROL3 P4, and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence

ALGVRQLVGGGHSSRFSHLWAGLPHACHRKSGSSSQVLCPEPSALLSVAG corresponding to amino acids 446 - 496 of HSSTROL3_P4, wherein said first amino acid sequence, bridging amino acid, second amino acid sequence and third amino acid sequence are contiguous and in a sequential order. 2.An isolated polypeptide encoding for a tail of HSSTROL3 P4, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence ALGVRQLVGGGHSSRFSHLWAGLPHACHRKSGSSSQVLCPEPSALLSVAG in HSSTROL3 P4.

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

Variant protein HSSTROL3_P4 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 289, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P4 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 289 -Amino acid mutations

Variant protein HSSTROL3_P4 is encoded by the following transcript(s): HSSTROL3_T5, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSSTROL3 JT5 is shown in bold; this coding portion starts at position 24 and ends at position 1511. The transcript also has the following SNPs as listed in Table 290 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P4 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 290 - Nucleic acid SNPs

Variant protein HSSTROL3_P5 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSSTROL3_T8 and HSSTROL3_T9. An alignment is given to the known protein (Stromelysin-3 precursor) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: Comparison report between HSSTROL3_P5 and MMl 1_HUMAN: 1.An isolated chimeric polypeptide encoding for HSSTROL3_P5, comprising a first amino acid sequence being at least 90 % homologous to MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS PAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVLSGGRWEKTDLTYRILRFP WQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMIDFARYW corresponding to amino acids 1 - 163 of MMl IJHUMAN, which also corresponds to amino acids 1 - 163 of HSSTROL3_P5, a bridging amino acid H corresponding to amino acid 164 of HSSTROL3JP5, a second amino acid sequence being at least 90 % homologous to GDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWTIGDDQGTDLLQVAAHEFGHVLG LQHTTAAKALMSAFYTFRYPLSLSPDDCRGVQHLYGQPWPTVTSRTPALGPQAGIDTN EIAPLEPDAPPDACEASFDAVSTIRGELFFFKAGFVWRLRGGQLQPGYPALASRHWQGL PSPVDAAFEDAQGHIWFFQ corresponding to amino acids 165 - 358 of MMl 1_HUMAN, which also corresponds to amino acids 165 - 358 of HSSTROL3_P5, and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence ELGFPSSTGRDESLEHCRCQGLHK corresponding to amino acids 359 - 382 of HSSTROL3_P5, wherein said first amino acid sequence, bridging amino acid, second amino acid sequence and third amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSSTROL3_P5, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence ELGFPSSTGRDESLEHCRCQGLHK in HSSTROL3_P5. The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans -membrane region prediction program predicts that this protein has a trans -membrane region.

Variant protein HSSTROL3_P5 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 291, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P5 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 291 -Amino acid mutations

Variant protein HSSTROL3_P5 is encoded by the following transcript(s): HSSTROL3JT8 and HSSTROL3_T9, for which the sequence(s) is/are given at the end of the application.

The coding portion of transcript HSSTROL3_T8 is shown in bold; this coding portion starts at position 24 and ends at position 1169. The transcript also has the following SNPs as listed in Table 292 (given according to their psition on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P5 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 292 -Nucleic acid SNPs

The coding portion of transcript HSSTROL3 T9 is shown iα bold; this coding portion starts at position 24 and ends at position 1169. The transcript also has the following SNPs as listed in Table 293 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P5 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 293 -Nucleic acid SNPs

Variant protein HSSTROL3_P7 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSSTROL3_T10. An alignment is given to the known protein (Stromelysin-3 precursor) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: Comparison report between HSSTROL3JP7 and MMl 1_HUMAN: 1.An isolated chimeric polypeptide encoding for HSSTROL3_P7, comprising a first amino acid sequence being at least 90 % homologous to MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS PAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVLSGGRWEKTDLTYRILRFP WQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMIDFARYW corresponding to amino acids 1 - 163 of MM11_HUMAN, which also corresponds to amino acids 1 - 163 of HSSTROL3_P7, a bridging amino acid H corresponding to amino acid 164 of HSSTROL3_P7, a second amino acid sequence being at least 90 % homologous to GDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWTIGDDQGTDLLQVAAHEFGHVLG LQHTTAAKALMSAFYTFRYPLSLSPDDCRGVQHLYGQPWPTVTSRTPALGPQAGIDTN EIAPLEPDAPPDACEASFDAVSTIRGELFFFKAGFVWRLRGGQLQPGYPALASRHWQGL PSPVDAAFEDAQGHIWFFQG corresponding to amino acids 165 - 359 of MM11_HUMAN, which also corresponds to amino acids 165 - 359 of HSSTROL3 P7, and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence TTGVSTPAPGV corresponding to amino acids 360 - 370 of HSSTROL3__P7, wherein said first amino acid sequence, bridging amino acid, second amino acid sequence and third amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSSTROL3_P7, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TTGVSTPAPGV in HSSTROL3_P7.

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

Variant protein HSSTROL3_P7 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 294, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P7 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 294 - Amino acid mutations

Variant protein HSSTROL3_P7 is encoded by the following transcript(s): HSSTROL3_T10, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSSTROL3_T10 is shown in bold; this coding portion starts at position 24 and ends at position 1133. The transcript also has the following SNPs as listed in Table 295 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3 P7 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 295 - Nucleic acid SNPs

Variant protein HSSTROL3_P8 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSSTROL3_T11. An alignment is given to the known protein (Stromelysin-3 precursor) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between HSSTROL3_P8 and MMl IJHUMAN: 1.An isolated chimeric polypeptide encoding for HSSTROL3_P8, comprising a first amino acid sequence being at least 90 % homologous to MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS PAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVLSGGRWEKTDLTYRILRFP WQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMroFARYW corresponding to amino acids 1 - 163 of MMl 1_HUMAN, which also corresponds to amino acids 1 - 163 of HSSTROL3_P8, a bridging amino acid H corresponding to amino acid 164 of HSSTROL3JP8, a second amino acid sequence being at least 90 % homologous to GDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWTIGDDQGTDLLQVAAHEFGHVLG LQHTTAAKALMSAFYTFRYPLSLSPDDCRGVQHLYGQPWPTVTSRTPALGPQAGIDTN EIAPLE corresponding to amino acids 165 - 286 of MMl IJHUMAN, which also corresponds to amino acids 165 - 286 of HSSTROL3_P8, and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence VRPCLPVPLLLCWPL corresponding to amino acids 287 - 301 of HSSTROL3_P8, wherein said first amino acid sequence, bridging amino acid, second amino acid sequence and third amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSSTROL3_P8, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VRPCLPVPLLLCWPL in HSSTROL3_P8.

Variant protein HSSTROL3_P8 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 296, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P8 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 296 -Amino acid mutations

Variant protein HSSTROL3_P8 is encoded by the following transcript(s): HSSTROL3_T11, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSSTROL3_T11 is shown in bold; this coding portion starts at position 24 and ends at position 926. The transcript also has the following SNPs as listed in Table 297 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P8 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 297 - Nucleic acid SNPs

Variant protein HSSTROL3 P9 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSSTROL3_T12. An alignment is given to the known protein (Stromelysin-3 precursor) at the end of the application.. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: Comparison report between HSSTROL3_P9 and MMl 1_HUMAN: 1.An isolated chimeric polypeptide encoding for HSSTROL3_P9, comprising a first amino acid sequence being at least 90 % homologous to MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS PAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQK corresponding to amino acids 1 - 96 of MMl IJHUMAN, which also corresponds to amino acids 1 - 96 of HSSTROL3_P9, a second amino acid sequence being at least 90 % homologous to RILRFPWQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMIDFARYW corresponding to amino acids 113 - 163 of MM11_HUMAN, which also corresponds to amino acids 97 - 147 of HSSTROL3_P9, a bridging amino acid H corresponding to amino acid 148 of HSSTROL3JP9, a third amino acid sequence being at least 90 % homologous to GDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWTIGDDQGTDLLQVAAHEFGHVLG LQHTTAAKALMSAFYTFRYPLSLSPDDCRGVQHLYGQPWPTVTSRTPALGPQAGIDTN EIAPLEPDAPPDACEASFDAVSTIRGELFFFKAGFVWRLRGGQLQPGYPALASRHWQGL PSPVDAAFEDAQGHIWFFQG corresponding to amino acids 165 - 359 of MM11_HUMAN, which also corresponds to amino acids 149 - 343 of HSSTROL3_P9, and a fourth amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence TTGVSTPAPGV corresponding to amino acids 344 - 354 of HSSTROL3_P9, wherein said first amino acid sequence, second amino acid sequence, bridging amino acid, third amino acid sequence and fourth amino acid sequence are contiguous and in a sequential order.

2.An isolated chimeric polypeptide encoding for an edge portion of HSSTROL3_P9, comprising a polypeptide having a length "n", wherein n is at least about 10 amino acids in length, optionally at least about 20 amino acids in length, preferably at least about 30 amino acids in length, more preferably at least about 40 amino acids in length and most preferably at least about 50 amino acids in length, wherein at least two amino acids comprise KR, having a structure as follows: a sequence starting from any of amino acid numbers 96-x to 96; and ending at any of amino acid numbers 97+ ((n-2) - x), in which x varies from 0 to n-2.

3.An isolated polypeptide encoding for a tail of HSSTROL3_P9, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TTGVSTPAPGV in HSSTROL3_P9.

The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans- membrane region prediction program predicts that this protein has a trans -membrane region. Variant protein HSSTROL3JP9 also has the following non-silent SNPs (Single

Nucleotide Polymorphisms) as listed in Table 298, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3_P9 sequence provides support for tie deduced sequence of this variant protein according to the present invention). Table 298 - Amino acid mutations

Variant protein HSSTROL3_P9 is encoded by the following transcript(s): HSSTROL3_T12, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSSTROL3_T12 is shown in bold; this coding portion starts at position 24 and ends at position 1085. The transcript also has the following SNPs as listed in Table 299 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSSTROL3 P9 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 299 - Nucleic acid SNPs

As noted above, cluster HSSTROL3 features 16 segment(s), which were listed in Table 2 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.

Segment cluster HSSTROL3_node_6 according to the present invention is supported by

14 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3JT5, HSSTROL3_T8, HSSTROL3_T9, HSSTROL3_T10, HSSTROL3_T11 and HSSTROL3JT12. Table 300 below describes the starting and ending position of this segment on each transcript.

Table 300 - Segment location on transcripts

Segment cluster HSSTROL3_node_10 according to the present invention is supported by 21 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5, HSSTROL3_T8, HSSTROL3_T9, HSSTROL3_T10, HSSTROL3JT11 and HSSTROL3_T12. Table 301 below describes the starting and ending position of this segment on each transcript.

Table 301 - Segment location on transcripts

Segment cluster HSSTROL3_node_13 according to the present invention is supported by 36 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3 T5, HSSTROL3JT8, HSSTROL3JT9,

HSSTROL3_T10, HSSTROL3JT11 and HSSTROL3JT12. Table 302 below describes the starting and ending position of this segment on each transcript.

Table 302 - Segment location on transcripts

Segment cluster HSSTROL3_node_15 according to the present invention is supported by 47 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5, HSSTROL3_T8, HSSTROL3JT9, HSSTROL3JT10, HSSTROL3JU1 and HSSTROL3_T12. Table 303 below describes the starting and ending position of this segment on each transcript.

Table 303 - Segment location on transcripts

Segment cluster HSSTROL3_node_19 according to the present invention is supported by 63 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5, HSSTROL3_T8, HSSTROL3_T9, HSSTROL3_T10, HSSTROL3_T11 and HSSTROL3_T12. Table 304 below describes the starting and ending position of this segment on each transcript.

Table 304 - Segment location on transcripts

Segment cluster HSSTROL3_node_21 according to the present invention is supported by 61 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5, HSSTROL3_T8, HSSTROL3_T9, HSSTROL3_T10, HSSTROL3_T11 and HSSTROL3_T12. Table 305 below describes the starting and ending position of this segment on each transcript.

Table 305 - Segment location on transcripts

Segment cluster HSSTROL3_node_24 according to the present invention is supported by 7 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T8 and HSSTROL3_T9. Table 306 below describes the starting and ending position of this segment on each transcript. Table 306 - Segment location on transcripts

Segment cluster HSSTROL3_node_25 according to the present invention is supported by 13 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T8. Table 307 below describes the starting and ending position of this segment on each transcript.

Table 307- Segment location on transcripts

Segment cluster HSSTROL3_node_26 according to the present invention is supported by

55 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5, HSSTROL3 JT8, HSSTROL3JT9 and HSSTROL3JT11. Table 308 below describes the starting and ending position of this segment on each transcript. Table 308 - Segment location on transcripts

Segment cluster HSSTROL3_node_28 according to the present invention is supported by 10 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5, HSSTROL3_T9 and HSSTROL3_T10. Table 309 below describes the starting and ending position of this segment on each transcript.

Table 309 - Segment location on transcripts

Segment cluster HSSTROL3_node_29 according to the present invention is supported by 109 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5, HSSTROL3_T8, HSSTROL3JT9, HSSTROL3JT10, HSSTROL3_T11 and HSSTROL3_T12. Table 310 below describes the starting and ending position of this segment on each transcript.

Table 310 - Segment location on transcripts

According to an optional embodiment of the present invention, short segments related to the above cluster are also provided. These segments are up to about 120 bp in length, and so are included in a separate description. Segment cluster HSSTROL3_node_ll according to the present invention is supported by 25 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5, HSSTROL3_T8, HSSTROL3_T9, HSSTROL3_T10 and HSSTROL3JT11. Table 311 below describes the starting and ending position of this segment on each transcript.

Table 311 - Segment location on transcripts

Segment cluster HSSTROL3_node_17 according to the present invention is supported by

45 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3JT5, HSSTROL3_T8, HSSTROL3_T9, HSSTROL3JT10, HSSTROL3_T11 and HSSTROL3JT12. Table 312below describes the starting and ending position of this segment on each transcript. Table 312 - Segment location on transcripts

Segment cluster HSSTROL3_node_18 according to the present invention can be found in the following transcript(s): HSSTROL3JT5, HSSTROL3JT8, HSSTROL3_T9, HSSTROL3_T10, HSSTROL3_T11 and HSSTROL3_T12. Table 313 below describes the starting and ending position of this segment on each transcript.

Table 313 - Segment location on transcripts

Segment cluster HSSTROL3_node_20 according to the present invention is supported by 1 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T11. Table 314 below describes the starting and ending position of this segment on each transcript.

Table 314 - Segment location on transcripts

Segment cluster HSSTROL3_node_27 according to the present invention is supported by 50 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSSTROL3_T5, HSSTROL3_T8, HSSTROL3JT9, HSSTROL3_T10, HSSTROL3_T11 and HSSTROL3JU2. Table 315 below describes the starting and ending position of this segment on each transcript.

Table 315 - Segment location on transcripts

Variant protein alignment to the previously known protein: Sequence name: MMll_HUMAN

Sequence documentation:

Alignment of: HSSTROL3 P4 x MMIl HUMAN

Alignment segment 1/1:

Quality: 4444.00 Escore: 0

Matching length: 445 Total length: 445

Matching Percent Similarity: 99.78 Matching Percent Identity: 99.78 Total Percent Similarity: 99.78 Total Percent Identity: 99.78

Gaps: 0

Alignment:

1 MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQP 50

I M I I IM I I I I I I I M M I I I I I I I I I i I I I I I I M I I I I M I I I I I I I

1 MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQP 50 . . . . .

51 WHAALPSSPAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVL 100

I I I M M I M M M M I M I I M I M I M M I I M M I I M M I I I I I I I

51 WHAALPSSPAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVL 100

101 SGGRWEKTDLTYRILRFPWQLVQEQVRQTMAEALKVWSDVTPLTFTEVHE 150

M M I I M M I I M M I M I I M I M M I M I I M I M M I M I M I I M

101 SGGRWEKTDLTYRILRFPWQLVQEQVRQTMAEALKVWSDVTPLTFTEVHE 150

151 GRADIMIDFARYWHGDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWT 200 M Il I I I I Il I M M I M I I M M M I I I M I M I I Il M M I M I M I

^• 151 GRADIMIDFARYWDGDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWT 200

201 IGDDQGTDLLQVAAHEFGHVLGLQHTTAAKALMSAFYTFRYPLSLSPDDC 250

I I I M I I I M M I Il I I I M I M I I M M I I M M I I Il I I I I I I M I I I 201 IGDDQGTDLLQVAAHEFGHVLGLQHTTAAKALMSAFYTFRYPLSLSPDDC 250

251 RGVQHLYGQPWPTVTSRTPALGPQAGIDTNEIAPLEPDAPPDACEASFDA 300

I I I I M M Il I I I I I I I I I M I I M I M M I M I I I I I M M I I M I M I

251 RGVQHLYGQPWPTVTSRTPALGPQAGIDTNEIAPLEPDAPPDACEASFDA 300 . . . . .

301 VSTIRGELFFFKAGFVWRLRGGQLQPGYPALASRHWQGLPSPVDAAFEDA 350 I I I I I M I I Il I I I Il I I I I I I Il I I Il I I Il I I Il I I I I Il I I I I I I Il 301 VSTIRGELFFFKAGFVWRLRGGQLQPGYPALASRHWQGLPSPVDAAFEDA 350

351 QGHIWFFQGAQYWVYDGEKPVLGPAPLTELGLVRFPVHAALVWGPEKNKI 400 M I I I I I M I I I Il I I Il M Il I Il I I I Il I I I M I I I Il Il I I I I I I M

351 QGHIWFFQGAQYWVYDGEKPVLGPAPLTELGLVRFPVHAALVWGPEKNKI 400

401 YFFRGRDYWRFHPSTRRVDSPVPRRATDWRGVPSEIDAAFQDADG 445

I I Il I Il Il Il I I Il Il Il I Il Il Il I I I I I I I I Il I Il I I I I Il 401 YFFRGRDYWRFHPSTRRVDSPVPRRATDWRGVPSEIDAAFQDADG 445

Sequence name: MM11_HUMAN

Sequence documentation:

Alignment of: HSSTROL3_P5 x MMll_HUMAN

Alignment segment 1/1:

Quality: 3566.00

Escore: 0

Matching length: 358 Total length: 358

Matching Percent Similarity: 99.72 Matching Percent Identity: . 99.72 Total Percent Similarity: 99.72 Total Percent Identity: 99.72

Gaps: 0

Alignment:

1 MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQP 50

M II M M I M I II M IM MI I I II I I M I I M I I I II M I III I MI I

1 MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQP 50 . . . . .

51 WHAALPSSPAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVL 100

M Il M M Il I I I I Il M I I I I I I I I M M I M I I I M I I I M I M I I I I

51 WHAALPSSPAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVL 100

101 SGGRWEKTDLTYRILRFPWQLVQEQVRQTMAEALKVWSDVTPLTFTEVHE 150

M I I Il I I I I I I I I M I I I I I I I I I I M I I M I M I M I I M M I M M I

101 SGGRWEKTDLTYRILRFPWQLVQEQVRQTMAEALKVWSDVTPLTFTEVHE 150

151 GRADIMIDFARYWHGDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWT 200 M I I I I M I M I I M I I M I Il I I I Il I I M M Il M I I M I M I I I I I

151 GRADIMIDFARYWDGDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWT 200

201 IGDDQGTDLLQVAAHEFGHVLGLQHTTAAKALMSAFYTFRYPLSLSPDDC 250

M M M I M M M I I I I M I M I Il M I Il M M M Il I M I I I M M I I 201 IGDDQGTDLLQVAAHEFGHVLGLQHTTAAKALMSAFYTFRYPLSLSPDDC 250

251 RGVQHLYGQPWPTVTSRTPALGPQAGIDTNEIAPLEPDAPPDACEASFDA 300

I I I I Il M I M I M M I I I M M I I I I M I I M I I M I I M M I I I I I M

251 RGVQHLYGQPWPTVTSRTPALGPQAGIDTNEIAPLEPDAPPDACEASFDA 300 . . . . .

301 VSTIRGELFFFKAGFVWRLRGGQLQPGYPALASRHWQGLPSPVDAAFEDA 350

351 QGHIWFFQ 358

Sequence name: MMIl HUMAN

Sequence documentation:

Alignment of: HSSTROL3_P7 x MMlIJHUMAN

Alignment segment 1/1:

Quality: 3575.00 Escore: 0

Matching length: 359 Total length: 359 Matching Percent Similarity: 99.72 Matching Percent Identity: 99.72

Total Percent Similarity: 99.72 Total Percent Identity: 99.72

Gaps:

Alignment: 1 MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQP 50

I I I I I I I Il I I I I Il I I I I I I I I Il I I I I I I I I I I I I I I I I I I I I I I I I I

1 MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQP 50 . . . . .

51 WHAALPSSPAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVL 100

II I Il I I I Il I Il I I I I I I I Il Il I I Il Il I I I I Il I I III I Il I I I I I I

51 WHAALPSSPAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVL 100

101 SGGRWEKTDLTYRILRFPWQLVQEQVRQTMAEALKVWSDVTPLTFTEVHE 150

I I I Il I I I I Il I I I I Il I I I Il I I I I Il I I Il Il I Il I I I I I I I I I I III

101 SGGRWEKTDLTYRILRFPWQLVQEQVRQTMAEALKVWSDVTPLTFTEVHE 150

151 GRADIMIDFARYWHGDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWT 200 I M I I I I I I M I I I I I I I I I I I I M I I I I I I I I I I I M I Il I I I I M I I

151 GRADIMIDFARYWDGDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWT 200

201 IGDDQGTDLLQVAAHEFGHVLGLQHTTAAKALMSAFYTFRYPLSLSPDDC 250

M I I IIMII I M M I I I I M M M I I I I I I II III I III MIII I I II I 201 IGDDQGTDLLQVAAHEFGHVLGLQHTTAAKALMSAFYTFRYPLSLSPDDC 250

251 RGVQHLYGQPWPTVTSRTPALGPQAGIDTNEIAPLEPDAPPDACEASFDA 300

M M I I I M I I Il I I I M I I I I I I I I I M M I I Il I M I I Il I I I Il I I I

251 RGVQHLYGQPWPTVTSRTPALGPQAGIDTNEIAPLEPDAPPDACEASFDA 300 . . . . .

301 VSTIRGELFFFKAGFVWRLRGGQLQPGYPALASRHWQGLPSPVDAAFEDA 350

M Il M I I I M I I I I I I I Il I I M I I Il M I I M M Il M I I I I I M I I I

301 VSTIRGELFFFKAGFVWRLRGGQLQPGYPALASRHWQGLPSPVDAAFEDA 350

351 QGHIWFFQG 359 351 QGHIWFFQG 359

Sequence name: MM11_HUMAN

Sequence documentation:

Alignment of: HSSTROL3_P8 x MMll_HϋMAN

Alignment segment 1/1:

Quality: 2838.00 Escore: 0

Matching length: 286 Total length: 286 Matching Percent Similarity: 99.65 Matching Percent Identity: 99.65

Total Percent Similarity: 99.65 Total Percent Identity: 99.65

Gaps:

Alignment:

1 MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQP 50

1 MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQP 50 51 WHAALPSSPAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVL 100 51 WHAALPSSPAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVL 100

101 SGGRWEKTDLTYRILRFPWQLVQEQVRQTMAEALKVWSDVTPLTFTEVHE 150 I I I I Il I I M Il I M Il M I M I M I I I I I I M M I I I Il I Il I I I M M

101 SGGRWEKTDLTYRILRFPWQLVQEQVRQTMAEALKVWSDVTPLTFTEVHE 150

151 GRADIMIDFARYWHGDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWT 200 Il Il I I I I I I I I I I I I I I I I I M M I I I I I M M I M I I I I I M Il M I

151 GRADIMIDFARYWDGDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWT 200

• > • > •

201 IGDDQGTDLLQVAAHEFGHVLGLQHTTAAKALMSAFYTFRYPLSLSPDDC 250

I M Il I Il I I Il I M M M I I I I I M I I M I I M Il I I M M I Il I M M 201 IGDDQGTDLLQVAAHEFGHVLGLQHTTAAKALMSAFYTFRYPLSLSPDDC 250

251 RGVQHLYGQPWPTVTSRTPALGPQAGIDTNEIAPLE 286

I I I I I I I I M I M I I I I M I I I I M I Il Il I I I I I I

251 RGVQHLYGQPWPTVTSRTPALGPQAGIDTNEIAPLE 286

Sequence name: MM11_HUMAN

Sequence documentation:

Alignment of: HSSTROL3_P9 x MM11_HUMAN Alignment segment 1/1:

Quality: 3316.00

Escore: 0 Matching length: 343 Total length: 359

Matching Percent Similarity: 99.71 Matching Percent

Identity: 99.71

Total Percent Similarity: 95.26 Total Percent Identity: 95.26

Gaps: 1

Alignment:

1 MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQP 50

51 WHAALPSSPAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQK.... 96

51 WHAALPSSPAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVL 100

97 RILRFPWQLVQEQVRQTMAEALKVWSDVTPLTFTEVHE 134

101 SGGRWEKTDLTYRILRFPWQLVQEQVRQTMAEALKVWSDVTPLTFTEVHE 150

135 GRADIMIDFARYWHGDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWT 184

151 GRADIMIDFARYWDGDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWT 200

185 IGDDQGTDLLQVAAHEFGHVLGLQHTTAAKALMSAFYTFRYPLSLSPDDC 234 I I I I i I I I I I I I I I I I I I I I Il I I I I I Il I I I I I I Il I I Il I Il I Il I I I 201 IGDDQGTDLLQVAAHEFGHVLGLQHTTAAKALMSAFYTFRYPLSLSPDDC 250

235 RGVQHLYGQPWPTVTSRTPALGPQAGIDTNEIAPLEPDAPPDACEASFDA 284 I I I I I M M Il I M M I M I I I Il I I Il Il I I M M I I Il Il Il Il Il I I

251 RGVQHLYGQPWPTVTSRTPALGPQAGIDTNEIAPLEPDAPPDACEASFDA 300

285 VSTIRGELFFFKAGFVWRLRGGQLQPGYPALASRHWQGLPSPVDAAFEDA 334

I I I I I I I I I I I I I Il I I I Il I Il Il I Il I I I I Il I Il I Il I I I I Il Il Il 301 VSTIRGELFFFKAGFVWRLRGGQLQPGYPALASRHWQGLPSPVDAAFEDA 350

335 QGHIWFFQG 343

I I I Il I I Il 351 QGHIWFFQG 359

Expression of Stromelysin-3 precursor (EC 3.4.24.-) (Matrix metalloproteinase-11) (MMP-Il) (ST3) (SL-3HSSTROL3) transcripts which are detectable by amplicon as depicted in sequence name HSSTROL3 seg24 in normal and cancerous Prostate tissues

Expression of Stromelysin-3 precursor (EC 3.4.24.-) (Matrix metalloproteinase-11) (MMP-I l) (ST3) (SL-3) transcripts detectable by or according to seg24, HSSTROL3 seg24 amplicon(s) and HSSTROL3 seg24F and HSSTROL3 seg24R primers was measured by real time PCR. In parallel the expression of four housekeeping genes -PBGD (GenBank Accession No. BC019323; amplicon - PBGD-amplicon), HPRTl (GenBank Accession No. NM_000194; amplicon - HPRTl -amplicon), SDHA (GenBank Accession No. NM_004168; amplicon - SDHA-amplicon), and RPL19 (GenBank Accession No. NM_000981; RPL19 amplicon) was measured similarly. For each RT sample, the expression of the above amplicon was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal post-mortem (PM) samples (Sample Nos. 42, 48-53, 59-63, Table 1, "Tissue samples in testing panel", above), to obtain a value of fold up-regulation for each sample relative to median of the normal PM samples. Figure 14 is a histogram showing over expression of the above -indicated Stromelysin-3 precursor transcripts in cancerous Prostate samples relative to the normal samples. Values represent the average of duplicate experiments. Error bars indicate the minimal and maximal values obtained.) As is evident from Figure 14, the expression of Stromelysin-3 precursor transcripts detectable by the above amplicon(s) in cancer samples was higher than in several non-cancerous samples (Sample Nos. 42, 48-53, 59-63, Table 1, "Tissue samples in testing panel"). Notably an over- expression of at least 3 fold was found in 4 out of 19 adenocarcinoma samples.

The P value for the difference in the expression levels of Stromelysin-3 precursor transcripts detectable by the above amplicon(s) in Prostate cancer samples versus the normal tissue samples was determined by T test as 2.34E-03.

The above value demonstrate statistical significance of the results. Primer pairs are also optionally and preferably encompassed within the present invention; for example, for the above experiment, the following primer pair was used as a non- limiting illustrative example only of a suitable primer pair: HSSTROL3 seg24F forward primer; and HSSTROL3 seg24R reverse primer.

The present invention also preferably encompasses any amplicon obtained through the use of any suitable primer pair; for example, for the above experiment, the following amplicon was obtained as a non- limiting illustrative example only of a suitable amplicon: HSSTROL seg24.

HSSTROL seg24 Forward primer (SEQ ID NO:497): ATTTCCATCCTCAACTGGCAGA HSSTROL seg24 Reverse primer (SEQ ID NO:498): TGCCCTGGAACCCACG

HSSTROL seg24 Amplicon (SEQ ID NO:499):

ATTTCCATCCTCAACTGGCAGAGATGAGAGCCTGGAGCATTGCAGATGCCAGGGAC TTCACAAATGAAGGCACAGCATGGGAAACCTGCGTGGGTTCCAGGGCA Expression of Stromelysin-3 precursor transcripts which are detectable by amplicon as depicted in sequence name HSSTROL3 seg24 in different normal tissues

Expression of Stromelysin-3 precursor transcripts detectable by or according to HSSTROL3 seg24 amplicon(s) and HSSTROL3 seg24F and HSSTROL3 seg24R was measured by real time PCR. In parallel the expression of four housekeeping genes Ubiquitin (GenBank Accession No. BC000449; amplicon - Ubiquitin-amplicon) and SDHA (GenBank Accession No. NM_004168; amplicon - SDHA-amplicon), RPL19 (GenBank Accession No. NM_000981; RPLl 9 amplicon), TATA box (GenBank Accession No. NM_003194; TATA amplicon) was measured similarly. For each RT sample, the expression of the above amplicon was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the lung samples (Sample Nos. 15-17, Table 2 "Tissue samples in normal panel", above), to obtain a value of relative expression of each sample relative to median of the lung samples.

The results are shown in Figure 15, demonstrating the expression of Stromelysin-3 transcripts which are detectable by amplicon as depicted in sequence name HSSTROL3 seg24 in different normal tissues.

DESCRIPTION FOR CLUSTER HUMF5A

Cluster HUMF5A features 3 transcript(s) and 33 segments) of interest, the names for which are given in Tables 316and 317, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 318.

Table 316 - Transcripts of interest

Table 318- Proteins of interest

These sequences are variants of the known protein Coagulation factor V precursor (SwissProt accession identifier FA5_HUMAN; known also according to the synonyms Activated protein C cofactor), SEQ ID NO: 392, referred to herein as the previously known protein.

Protein Coagulation factor V precursor is known or believed to have the following function(s): Coagulation factor V is a cofactor that participates with factor Xa to activate prothrombin to thrombin. The sequence for protein Coagulation factor V precursor is given at the end of the application, as "Coagulation factor V precursor amino acid sequence". Known polymorphisms for this sequence are as shown in Table 319.

Table 319 -Amino acid mutations for Known Protein

The following GO Annotation(s) apply to the previously known protein. The following annotation(s) were found: cell adhesion; blood coagulation, which are annotation(s) related to Biological Process; and blood coagulation factor; copper binding, which are annotation(s) related to Molecular Function.

The GO assignment relies on information from one or more of the SwissProt/TremBl Protein knowledgebase, available from <http://www.expasy.ch/sprot/>; or Locuslink, available from <http://www.ncbi.nkn.nih.gov/projects/LocusLink/>.

As noted above, cluster HUMF5A features 3 transcript(s), which were listed in Table 316 above. These transcript(s) encode for protein(s) which are variant(s) of protein Coagulation factor V precursor. A description of each variant protein according to the present invention is now provided.

Variant protein HUMF5A_PEA_1_P3 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HUMF5A_PEA_1_T1. An alignment is given to the known protein (Coagulation factor V precursor) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: Comparison report between HUMF5A_PEA_1_P3 and FA5_HUMAN_V1 (SEQ ID

NO:393):

1.An isolated chimeric polypeptide encoding for HUMF5A_PEA_1_P3, comprising a first amino acid sequence being at least 90 % homologous to

MFPGCPRLWVLWLGTSWVGWGSQGTEAAQLRQFYVAAQGISWSYRPEPTNSSLNLS VTSFKKIVYREYEPYFKKEKPQSTISGLLGPTLYAEVGDIIKVHFKNKADKPLSIHPQGIR YSKLSEGASYLDHTFPAEKMDDAVAPGREYTYEWSISEDSGPTHDDPPCLTHIYYSHEN LIEDFNSGLIGPLLICKKGTLTEGGTQKTFDKQIVLLFAVFDESKSWSQSSSLMYTVNGY VNGTMPDITVCAHDHISWHLLGMSSGPELFSIHFNGQVLEQNHHKVSAITLVSATSTTA NMTVGPEGKWIISSLTPKHLQAGMQAYIDIKNCPKKTRNLKKITREQRRHMKRWEYFI AAEEVΓWDYAPVIPANMDKKYRSQHLDNFSNQIGKHYKKVMYTQYEDESFTKHTVNP NMKEDGILGPΠRAQVRDTLKIVFKNMASRPYSIYPHGVTFSPYEDEVNSSFTSGRNNTM IRAVQPGETYTYKWNILEFDEPTENDAQCLTRPYYSDVDIMRDIASGLIGLLLICKSRSL DRRGIQRAADIEQQAWAWDENKSWLEDNINKFCENPDEVKRDDPKFYESNIMSTIN GYVPESITTLGFCFDDTVQWHFCSVGTQNEILTIHFTGHSFIYGKRHEDTLTLFPMRGES VTVTMDISRVGTWMLTSMNSSPRSKKLRLKTRDVKCIPDDDEDSYEIFEPPESTVMATRK MHDRLEPEDEESDADYDYQNRLAAALGIRSFRNSSLNQEEEEFNLTALALENGTEFVSS NTDIIVGSNYSSPSNISKFTVNNLAEPQKAPSHQQATTAGSPLRHLIGKNSVLNSSTAEHS SPYSEDPIEDPLQPDVTGIRLLSLGAGEFRSQEHAKRKGPKVERDQAAKHRFSWMKLLA HKVGRHLSQDTGSPSGMRPWEDLPSQDTGSPSRMRPWKDPPSDLLLLKQSNSSKILVG RWHLASEKGSYEΠQDTDEDTAVNNWLISPQNASRAWGESTPLANKPGKQSGHPKFPR VRHKSLQVRQDGGKSRLKKSQFLIKTRKKKKEKHTHHAPLSPRTFHPLRSEAYNTFSER RLKHSLVLHKSNETSLPTDLNQTLPSMDFGWIASLPDHNQNSSNDTGQASCPPGLYQTV PPEEHYQTFPIQDPDQMHSTSDPSHRSSSPELSEMLEYDRSHKSFPTDISQMSPSSEHEV WQTVISPDLSQVTLSPELSQTNLSPDLSHTTLSPELIQRNLSPALGQMPISPDLSHTTLSPD LSHTTLSLDLSQTNLSPELSQTNLSPALGQMPLSPDLSHTTLSLDFSQTNLSPELSHMTLS PELSQTNLSPALGQMPISPDLSHTTLSLDFSQTNLSPELSQTNLSPALGQMPLSPDPSHTT LSLDLSQTNLSPELSQTNLSPDLSEMPLFADLSQPLTPDLDQMTLSPDLGETDLSPNFGQ MSLSPDLSQVTLSPDISDTTLLPDLSQISPPPDLDQIFYPSESSQSLLLQEFNESFPYPDLGQ MPSPSSPTLNDTFLSKEFNPLVIVGLSKDGTDYIEIIPKEEVQSSEDDYAEIDYVPYDDPY KTDVRTNINSSRDPDNIAAWYLRSNNGNRRNYYIAAEEISWDYSEFVQRETDIEDSDDIP EDTTYKK corresponding to amino acids 1 - 1617 of FA5_HUMAN_V1, which also corresponds to amino acids 1 - 1617 of HUMF5A_PEA_1_P3, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence GSMKSISEFLVLLSELKWMMLSKFVLKI corresponding to amino acids 1618 - 1645 of HUMF5A_PEA_1_P3, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HUMF5A_PEA_1_P3, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence GSMKSISEFLVLLSELKWMMLSKFVLKI in HUMF5AJPEA_1_P3. It should be noted that the known protein sequence (FA5_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for FA5_HUMAN_V1. These changes were previously known to occur and are listed in the table below.

Table 320 - Changes to FA5_HUMAN_V1

Variant protein HUMF5A_PEA_1_P3 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 321, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMF5A_PEA_1_P3 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 321 - Amino acid mutations

Variant protein HUMF5A_PEA_1_P3 is encoded by the following transcript(s): HUMF5A_PEA_1_T1, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HUMF5A_PEA_1_T1 is shown in bold; this coding portion starts at position 183 and ends at position 5117. The transcript also has the following SNPs as listed in Table 322 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMF5A_PEA_1_P3 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 322 - Nucleic acid SNPs

Variant protein HUMF5A_PEA_1_P4 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HUMF5A_PEA_1_T3. An alignment is given to the known protein (Coagulation factor V precursor) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between HUMF5A_PEA_1_P4 and FA5_HUMAN_V1: 1.An isolated chimeric polypeptide encoding for HUMF5A_PEA_1_P4, comprising a first amino acid sequence being at least 90 % homologous to MFPGCPRLWVLWLGTSWVGWGSQGTEAAQLRQFYVAAQGISWSYRPEPTNSSLNLS VTSFKKWYREYEPYFKKEKPQSTISGLLGPTLYAEVGDIIKVHFKNKADKPLSIHPQGIR YSKLSEGASYLDHTFPAEKMDDAVAPGREYTYEWSISEDSGPTHDDPPCLTHIYYSHEN LIEDFNSGLIGPLLICKKGTLTEGGTQKTFDKQIVLLFAVFDESKSWSQSSSLMYTVNGY VNGTMPDITVCAHDHISWHLLGMSSGPELFSIHFNGQVLEQNHHKVSAITLVSATSTTA NMTVGPEGKWIISSLTPKHLQAGMQAYIDIKNCPKKTRNLKKITREQRR[IMKRWEYFI

AAEEVΓWDYAPVIPANMDKKYRSQHLDNFSNQIGKHYKKVMYTQYEDESFTKHTVNP NMKEDGILGPΠRAQVRDTLKIVFKNMASRPYSIYPHGVTFSPYEDEVNSSFTSGRNNTM IRAVQPGETYTYKWNILEFDEPTENDAQCLTRPYYSDVDIMRDIASGLIGLLLICKSRSL DRRGIQRAADIEQQ AVFAVFDENKSWYLEDNINKFCENPDEVKRDDPKFYESNIMSTIN GYVPESITTLGFCFDDTVQWHFCSVGTQNEILTIHFTGHSFIYGKRHEDTLTLFPMRGES VTVTMDNVGTWMLTSMNSSPRSKKLRLKFRDVKCIPDDDEDSYEIFEPPESTVMATRK MHDRLEPEDEESDADYDYQNRLAAALGIRSFRNSSLNQEEEEFNLTALALENGTEFVSS NTDΠVGSNYSSPSNISKFTVNNLAEPQKAPSHQQATTAGSPLRHLIGKNSVLNSSTAEHS SPYSEDPIEDPLQPDVTGIRLLSLGAGEFRSQEHAKRKGPKVERDQAAKHRFSWMKLLA HKVGRHLSQDTGSPSGMRPWEDLPSQDTGSPSRMRPWKDPPSDLLLLKQSNSSKILVG RWHLASEKGSYEIIQDTDEDTAVNNWLISPQNASRAWGESTPLANKPGKQSGHPKFPR VRHKSLQVRQDGGKSPVLKKSQFLIKTRKKKKEKHTHHAPLSPRTFHPLRSEAYNTFSER RLKHSLVLHKSNETSLPTDLNQTLPSMDFGWIASLPDHNQNSSNDTGQASCPPGLYQTV PPEEHYQTFPIQDPDQMHSTSDPSHRSSSPELSEMLEYDRSHKSFPTDISQMSPSSEHEV WQTVISPDLSQVTLSPELSQTNLSPDLSHTTLSPELIQRNLSPALGQMPISPDLSHTTLSPD LSHTTLSLDLSQTNLSPELSQTNLSPALGQMPLSPDLSHTTLSLDFSQTNLSPELSHMTLS PELSQTNLSPALGQMPISPDLSHTTLSLDFSQTNLSPELSQTNLSPALGQMPLSPDPSHTT LSLDLSQTNLSPELSQTNLSPDLSEMPLFADLSQIPLTPDLDQMTLSPDLGETDLSPNFGQ MSLSPDLSQVTLSPDISDTTLLPDLSQISPPPDLDQIFYPSESSQSLLLQEFNESFPYPDLGQ MPSPSSPTLNDTFLSKEFNPLVΓVGLSKDGTDYIEΠPKEEVQSSEDDYAEIDYVPYDDPY KTDVRTNINSSRDPDNIAAWYLRSNNGNMINYYIAAEEISWDYSEFVQRETDIEDSDDIP EDTTYKKWFRKYLDSTFTKRDPRGEYEEHLGILGPIIRAEVDDVIQVRFKNLASRPYSL HAHGLSYEKSSEGKTYEDDSPEWFKEDNAVQPNSSYTYVWHATERSGPESPGSACRA WAYYSAVNPEKDIHSGLIGPLLICQKGILHKDSNMPVDMREFVLLFMTFDEKKSWYYE KKSRSSWRLTSSEMKKSHEFHAMGMYSLPGLKMYEQEWVRLHLLNIGGSQDIHVVH FHGQTLLENGNKQHQLGVWPLLPGSFKTLEMKASKPGWWLLNTEVGENQRAGMQTP FLIMDRDCRMPMGLSTGΠSDSQIKASEFLGYWEPRLARLNNGGSYNAWSVEKLAAEFA SKPWIQVDMQKEVIITGIQTQGAKHYLKSCYTTEFYVAYSSNQINWQIFKGNSTRNVMY

FNGNSDASTIKENQFDPPIVARYIRISPTRAYNRPTLRLELQGCE corresponding to amino acids 1 - 2062 of FA5_HUMAN_V1, which also corresponds to amino acids 1 - 2062 of HUMF5A_PEA_1_P4, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence DVPHPWVWKMER corresponding to amino acids 2063 - 2074 of HUMF5AJPEA_1_P4, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HUMF5A_PEA_1_P4, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DVPHPWVWKMER in HUMF5A_PEA_1_P4.

It should be noted that the known protein sequence (FA5_HUMAN) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence £>r FA5_HUMAN_V1. These changes were previously known to occur and are listed in the table below. Table 323 - Changes to FA5_HUMAN_V1

Variant protein HUMF5A_PEA_1_P4 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 324, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMF5A_PEA_1_P4 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 324 - Amino acid mutations

Variant protein HUMF5A_PEA_1_P4 is encoded by the following transcript(s): HUMF5A_PEA_1_T3, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HUMF5A_PEA_1_T3 is shown in bold; this coding portion starts at position 183 and ends at position 6404. The transcript also has the following SNPs as listed in Table 325 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMF5A_PEA_1_P4 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 325 - Nucleic acid SNPs

Variant protein HUMF5A_PEA_1_P8 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HUMF5A_PEA_1_T7. An alignment is given to the known protein (Coagulation factor V precursor) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between HUMF5A_PEA_1_P8 and FA5_HUMAN: 1.An isolated chimeric polypeptide encoding for HUMF5A_PEA_1_P8, comprising a first amino acid sequence being at least 90 % homologous to

MFPGCPRLWVLVVLGTSWVGWGSQGTEAAQLRQFYVAAQGISWSYRPEPTNSSLNLS VTSFKKΓVΎREYEPYFKEΈKPQSTISGLLGPTLYAEVGDIIKVHFKNKADKPLSIHPQGIR YSKLSEGASYLDHTFPAEKMDDAVAPGREYTYEWSISEDSGPTHDDPPCLTHΓYYSHEN LIEDFNSGLIGPLLICKKGTLTEGGTQKTFDKQIVLLFAVFDESKSWSQSSSLMYTVNGY VNGTMPDITVCAHDHISWHLLGMSSGPELFSIHFNGQVLEQNHHKVSAITLVSATSTTA NMTVGPEGKWIISSLTPKHLQAGMQAYIDIKNCPKKTRNLKKITREQRRHMKRWEYFI AAEEVIWDYAPVEPANMDKKYRSQHLDNFSNQIGKHYKKVMYTQYEDESFTKHTVNP NMKEDGrLGPIIRAQVRDTLKIVFKNMASPJ¹YSnTHGVTFSPYEDEVNSSFTSGRNNTM IRAVQPGETYTYKWNILEFDEPTENDAQCLTRPYYSDVDMRDIASGLIGLLLICKSRSL DRRGIQRAADIEQQAWAWDENKSWYLEDNINKFCENPDEVKRDDPKFYESNIMS corresponding to amino acids 1 - 587 of FA5 HUMAN, which also corresponds to amino acids 1 - 587 of HUMF5A_PEA_1_P8, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SKSEYYFCSSVFHSCG corresponding to amino acids 588 - 603 of HUMF5A_PEA_1_P8, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HUMF5A_PEA_1_P8, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence SKSEYYFCSSWHSCG in HUMF5A_PEA_1 JP8.

The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signatpeptide prediction programs predict that this protein has a signal peptide, and neither trans -membrane region prediction program predicts that this protein has a trans -membrane region. Variant protein HUMF5A_PEA_1_P8 also has the following non-silent SNPs (Single

Nucleotide Polymorphisms) as listed in Table 326, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMF5A_PEA_1_P8 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 326 -Amino acid mutations

The glycosylation sites of variant protein HUMF5A_PEA_1_P8, as compared to the known protein Coagulation factor V precursor, are described in Table 327 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the glycosylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).

Table 327 - Glycosylation site(s)

The phosphorylation sites of variant protein HUMF5A_PEA_1_P8, as compared to the known protein Coagulation factor V precursor, are described in Table 328 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the phosphorylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).

Table 328 - Phosphorylation site(s)

Variant protein HUMF5A_PEA_1_P8 is encoded by the following transcript(s): HUMF5A_PEA_1_T7, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HUMF5A_PEA_1_T7 is shown in bold; this coding portion starts at position 183 and ends at position 1991. The transcript also has the following SNPs as listed in Table 329 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HUMF5A_PEA_1_P8 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 329 - Nucleic acid SNPs

As noted above, cluster HUMF5A features 33 segment(s), which were listed in Table 2 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.

Segment cluster HUMF5A_PEA_l_node_0 according to the present invention is supported by 9 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1, HUMF5AJPEA_1_T3 and HUMF5A_PEA_1_T7. Table 330 below describes the starting and ending position of this segment on each transcript.

Table 330 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_4 according to the present invention is supported by 7 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1, HUMF5A_PEA_1_T3 and HUMF5A_PEA_1_T7. Table 331 below describes the starting and ending position of this segment on each transcript.

Table 331 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_6 according to the present invention is supported by 11 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1, HUMF5A_PEA_1_T3 and HUMF5A_PEA_1_T7. Table 332 below describes the starting and ending position of this segment on each transcript.

Table 332 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_8 according to the present invention is supported by 8 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1, HUMF5A_PEA_1_T3 and HUMF5A_PEA_1_T7. Table 333 below describes the starting and ending position of this segment on each transcript.

Table 333 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_10 according to the present invention is supported by 7 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1, HUMF5A_PEA_1_T3 and HUMF5A_PEA_1_T7. Table 334 below describes the starting and ending position of this segment on each transcript.

Table 334- Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_12 according to the present invention is supported by 10 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1, HUMF5A_PEA_1_T3 and HUMF5A_PEA_1_T7. Table 335 below describes the starting and ending position of this segment on each transcript.

Table 335- Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_14 according to the present invention is supported by 9 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1,

HUMF5AJPEA_1_T3 and HUMF5A_PEA_1_T7. Table 336 below describes the starting and ending position of this segment on each transcript.

Table 336 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_18 according to the present invention is supported by 10 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1, HUMF5A_PEA_1_T3 and HUMF5A_PEA_1_T7. Table 337 below describes the starting and ending position of this segment on each transcript.

Table 337 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_21 according to the present invention is supported by 12 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5AJPEA_1_T1, HUMF5A_PEA_1_T3 and HUMF5AJPEA_1_T7. Table 338 below describes the starting and ending position of this segment on each transcript.

Table 338 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_22 according to the present invention is supported by 1 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T7. Table 339 below describes the starting and ending position of this segment on each transcript.

Table 339 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_24 according to the present invention is supported by 13 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1 and HUMF5A_PEA_1_T3. Table 340 below describes the starting and ending position of this segment on each transcript. Table 340 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_26 according to the present invention is supported by 33 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1 and HUMF5A_PEA_1_T3. Table 341 below describes the starting and ending position of this segment on each transcript.

Table 341 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_27 according to the present invention is supported by 12 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1 and HUMF5A_PEA_1_T3. Table 342 below describes the starting and ending position of this segment on each transcript.

Table 342 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_29 according to the present invention is supported by 22 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1 and

HUMF5A_PEA_1_T3. Table 343 below describes the starting and ending position of this segment on each transcript.

Table 343 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_35 according to the present invention is supported by 7 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1 and HUMF5A_PEA_1_T3. Table 344 below describes the starting and ending position of this segment on each transcript.

Table 344 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_37 according to the present invention is supported by 9 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1 and HUMF5A_PEA_1_T3. Table 345 below describes the starting and ending position of this segment on each transcript.

Table 345 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_39 according to the present invention is supported by 10 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1 and HUMF5A_PEA_1_T3. Table 346 below describes the starting and ending position of this segment on each transcript.

Table 346 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_47 according to the present invention is supported by 14 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1 and HUMF5A_PEA_1_T3. Table 347 below describes the starting and ending position of this segment on each transcript.

Table 347 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_50 according to the present invention is supported by 20 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5AJPEA_1_T1 and HUMF5A_PEA_1_T3. Table 348 below describes the starting and ending position of this segment on each transcript. Table 348 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_53 according to the present invention is supported by 29 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1 and HUMF5A_PEA_1_T3. Table 349 below describes the starting and ending position of this segment on each transcript.

Table 349 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_56 according to the present invention is supported by 24 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1 and HUMF5A_PEA_1_T3. Table 350 below describes the starting and ending position of this segment on each transcript.

Table 350 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_60 according to the present invention is supported by 24 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1 and HUMF5A_PEA_1_T3. Table 351 below describes the starting and ending position of this segment on each transcript.

Table 351- Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_2 according to the present invention is supported by 6 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1, HUMF5A_PEA_1_T3 and HUMF5A_PEA_1_T7. Table 352 below describes the starting and ending position of this segment on each transcript. Table 352- Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_16 according to the present invention is supported by 10 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1, HUMF5AJPEA_1_T3 and HUMF5A_PEA_1_T7. Table 353 below describes the starting and ending position of this segment on each transcript.

Table 353 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_31 according to the present invention is supported by 3 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1 and HUMF5A_PEA_1_T3. Table 354 below describes the starting and ending position of this segment on each transcript. Table 354 - Segment location on transcripts

Segment cluster HUMF5A_PEA__l_node_32 according to the present invention is supported by 2 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T3. Table 355 below describes the starting and ending position of this segment on each transcript. Table 355 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_33 according to the present invention is supported by 4 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A JPEA_1_T1 and HUMF5A_PEA_1_T3. Table 356 below describes the starting and ending position of this segment on each transcript.

Table 356 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_41 according to the present invention is supported by 8 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1 and HUMF5AJPEA_1_T3. Table 357 below describes the starting and ending position of this segment on each transcript.

Table 357- Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_43 according to the present invention is supported by 6 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1 and HUMF5A_PEA_1_T3. Table 358 below describes the starting and ending position of this segment on each transcript.

Table 358 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_45 according to the present invention is supported by 12 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1 and HUMF5A_PEA_1_T3. Table 359 below describes the starting and ending position of this segment on each transcript. Table 359 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_51 according to the present invention can be found in the following transcript(s): HUMF5A_PEA_1_T1. Table 360below describes the starting and ending position of this segment on each transcript.

Table 360 - Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_57 according to the present invention is supported by 18 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HUMF5A_PEA_1_T1 and HUMF5A_PEA_1_T3. Table 361 below describes the starting and ending position of this segment on each transcript.

Table 361- Segment location on transcripts

Segment cluster HUMF5A_PEA_l_node_59 according to the present invention can be found in the following transcript(s): HUMF5A_PEA_1_T1 and HUMF5A_PEA_1_T3. Table 362 below describes the starting and ending position of this segment on each transcript.

Table 362- Segment location on transcripts

Variant protein alignment to the previously known protein: Sequence name: FA5_HUMAN_V1

Sequence documentation:

Alignment of: HUMF5A_PEA_1_P3 x FA5_HUMAN_V1

Alignment segment 1/1:

Quality: 16060.00 Escore: 0

Matching length: 1617 Total length: 1617

Identity: 100.00

Gaps:

Alignment:

1 MFPGCPRLWVLWLGTSWVGWGSQGTEAAQLRQFYVAAQGISWSYRPEPT 50

IMI I MMM I I M I I M M I I I I MI MIII MI I I I M I MM I II I

1 MFPGCPRLWVLWLGTSWVGWGSQGTEAAQLRQFYVAAQGI SWSYRPEPT 50

51 NSSLNLSVTSFKKIVYREYEPYFKKEKPQSTISGLLGPTLYAEVGDIIKV 100

I I M I l I l M I l M I I l I l I M M I I l M M M M I I I M I I l I M M I l

51 NSSLNLSVTSFKKIVYREYEPYFKKEKPQSTISGLLGPTLYAEVGDIIKV 100

101 HFKNKADKPLSIHPQGIRYSKLSEGASYLDHTFPAEKMDDAVAPGREYTY 150

I I M Il Il M M M I I M I Il M M I I M I Il I M I I I M I Il I M M Il

101 HFKNKADKPLSIHPQGIRYSKLSEGASYLDHTFPAEKMDDAVAPGREYTY 150 151 EWSISEDSGPTHDDPPCLTHIYYSHENLIEDFNSGLIGPLLICKKGTLTE 200

I I Il I I I I Il I I Il I I Il Il I I Il I I I I I I I I I I I I I Il Il I Il I I I Il I

151 EWSISEDSGPTHDDPPCLTHIYYSHENLIEDFNSGLIGPLLICKKGTLTE 200 . . . . .

201 GGTQKTFDKQIVLLFAVFDESKSWSQSSSLMYTVNGYVNGTMPDITVCAH 250

I I I Il I I I I I I I I I I Il I I Il Il I I I Il I I I I I Il I Il I I I I I I I I Il Il 201 GGTQKTFDKQIVLLFAVFDESKSWSQSSSLMYTVNGYVNGTMPDITVCAH 250

251 DHISWHLLGMSSGPELFSIHFNGQVLEQNHHKVSAITLVSATSTTANMTV 300

I I I I Il I I I Il I I Il I I I I I Il I I I I I I I I I Il I I I I I Il Il I I Il I Il I 251 DHISWHLLGMSSGPELFSIHFNGQVLEQNHHKVSAITLVSATSTTANMTV 300

301 GPEGKWIISSLTPKHLQAGMQAYIDIKNCPKKTRNLKKITREQRRHMKRW 350 I I I M I Il I I I I I I I I I I I I I I I M I M I I I I M I I I I I I I I I I I M I I I

301 GPEGKWIISSLTPKHLQAGMQAYIDIKNCPKKTRNLKKITREQRRHMKRW 350

351 EYFIAAEEVIWDYAPVIPANMDKKYRSQHLDNFSNQIGKHYKKVMYTQYE 400

I I I Il I I I Il Il I Il I I I I I I Il I Il I I I I Il I I I Il I I I I I I Il Il I Il 351 EYFIAAEEVIWDYAPVIPANMDKKYRSQHLDNFSNQIGKHYKKVMYTQYE 400

401 DESFTKHTVNPNMKEDGILGPIIRAQVRDTLKIVFKNMASRPYSIYPHGV 450

I I Il I I I I I I I Il I I I I I I I I I Il I I I Il I I I I I I I I I I I I I Il Il I I I I

401 DESFTKHTVNPNMKEDGILGPIIRAQVRDTLKIVFKNMASRPYSIYPHGV 450 . . . . .

451 TFSPYEDEVNSSFTSGRNNTMIRAVQPGETYTYKWNILEFDEPTENDAQC 500

I I I I I I I I I Il I I Il I I I I I I I I I I Il Il I I I Il I I Il I I I I I I I I I I I I 451 TFSPYEDEVNSSFTSGRNNTMIRAVQPGETYTYKWNILEFDEPTENDAQC 500

501 LTRPYYSDVDIMRDIASGLIGLLLICKSRSLDRRGIQRAADIEQQAVFAV 550 501 LTRPYYSDVDIMRDIASGLIGLLLICKSRSLDRRGIQRAADIEQQAVFAV 550

551 FDENKSWYLEDNINKFCENPDEVKRDDPKFYESNIMSTINGYVPESITTL 600

I I I I I I I I I I I I I Il I I I I I I Il I Il Il I I I I I I I I I I I I I I I I I I I I I I 551 FDENKSWYLEDNINKFCENPDEVKRDDPKFYESNIMSTINGYVPESITTL 600

601 GFCFDDTVQWHFCSVGTQNEILTIHFTGHSFIYGKRHEDTLTLFPMRGES 650

IM I I I M MM M MI MII M I M I IM I M M I III M IMM M M

601 GFCFDDTVQWHFCSVGTQNEILTIHFTGHSFIYGKRHEDTLTLFPMRGES 650 . . . . .

651 VTVTMDNVGTWMLTSMNSSPRSKKLRLKFRDVKCIPDDDEDSYEIFEPPE 700

II I M M I M I M M M I I M M M M M Il M Il M M M I Il I M I M

651 VTVTMDNVGTWMLTSMNSSPRSKKLRLKFRDVKCIPDDDEDSYEIFEPPE 700

701 STVMATRKMHDRLEPEDEESDADYDYQNRLAAALGIRSFRNSSLNQEEEE 750

M M M Il M I M I M I Il I M M M I Il M I M Il M M Il M M M M

701 STVMATRKMHDRLEPEDEESDADYDYQNRLAAALGIRSFRNSSLNQEEEE 750

751 FNLTALALENGTEFVSSNTDIIVGSNYSSPSNISKFTVNNLAEPQKAPSH 800 M I M Il I M I M M I I I M M Il I M M M M M I I I M M M M M Il

751 FNLTALALENGTEFVSSNTDIIVGSNYSSPSNISKFTVNNLAEPQKAPSH 800

801 QQATTAGSPLRHLIGKNSVLNSSTAEHSSPYSEDPIEDPLQPDVTGIRLL 850

Il I M I M III M MM M I M I M Il I I M M M Il I Il Il Il I M M I 801 QQATTAGSPLRHLIGKNSVLNSSTAEHSSPYSEDPIEDPLQPDVTGIRLL 850

851 SLGAGEFRSQEHAKRKGPKVERDQAAKHRFSWMKLLAHKVGRHLSQDTGS 900

M M M M I I I M M I I I I M M M M I M I M M I M M M M I M I I I

851 SLGAGEFRSQEHAKRKGPKVERDQAAKHRFSWMKLLAHKVGRHLSQDTGS 900 . . . . .

901 PSGMRPWEDLPSQDTGSPSRMRPWKDPPSDLLLLKQSNSSKILVGRWHLA 950 I I I I I I I I I I I I I I I I I Il I I I I I I I Il Il I I I I I I I I I I I I I I I I I I Il 901 PSGMRPWEDLPSQDTGSPSRMRPWKDPPSDLLLLKQSNSSKILVGRWHLA 950

951 SEKGSYEIIQDTDEDTAVNNWLISPQNASRAWGESTPLANKPGKQSGHPK 1000 I I Il I I I I I Il M Il I M Il Il Il I Il I I I Il Il I I I Il I I I I Il I I I Il

951 SEKGSYEIIQDTDEDTAVNNWLISPQNASRAWGESTPLANKPGKQSGHPK 1000

1001 FPRVRHKSLQVRQDGGKSRLKKSQFLIKTRKKKKEKHTHHAPLSPRTFHP 1050

I I I I I I I Il I I I I Il I I I I I I I I I I I I I I I I I I I Il I Il I I Il I Il I I I I 1001 FPRVRHKSLQVRQDGGKSRLKKSQFLIKTRKKKKEKHTHHAPLSPRTFHP 1050

1051 LRSEAYNTFSERRLKHSLVLHKSNETSLPTDLNQTLPSMDFGWIASLPDH 1100

IMMI I M M M M I MI I M MII M M M MM IIIM I MI I I I M

1051 LRSEAYNTFSERRLKHSLVLHKSNETSLPTDLNQTLPSMDFGWIASLPDH 1100 . . . . .

1101 NQNSSNDTGQASCPPGLYQTVPPEEHYQTFPIQDPDQMHSTSDPSHRSSS 1150

M M M I M M M I I M M I Il M I I M I I M M I M I I I Il I I M M I I

1101 NQNSSNDTGQASCPPGLYQTVPPEEHYQTFPIQDPDQMHSTSDPSHRSSS 1150

1151 PELSEMLEYDRSHKSFPTDISQMSPSSEHEVWQTVISPDLSQVTLSPELS 1200

M M M I Il M M M M I M I M Il I M M M M M I I I M M I Il I I I I

1151 PELSEMLEYDRSHKSFPTDISQMSPSSEHEVWQTVISPDLSQVTLSPELS 1200

1201 QTNLSPDLSHTTLSPELIQRNLSPALGQMPISPDLSHTTLSPDLSHTTLS 1250 M I M M I M Il Il I Il M I M M M I M Il I I I I M I I M I M M I M I

1201 QTNLSPDLSHTTLSPELIQRNLSPALGQMPISPDLSHTTLSPDLSHTTLS 1250

1251 LDLSQTNLSPELSQTNLSPALGQMPLSPDLSHTTLSLDFSQTNLSPELSH 1300

M M M Il I M M Il M I M I M M M M M M M M M M Il I I M M I 1251 LDLSQTNLSPELSQTNLSPALGQMPLSPDLSHTTLSLDFSQTNLSPELSH 1300 1301 MTLSPELSQTNLSPALGQMPISPDLSHTTLSLDFSQTNLSPELSQTNLSP 1350

Il I I I Il I Il I I I Il I Il I I I Il I I I I I I I Il I I I I I I I I Il I I I I I I I I

1301 MTLSPELSQTNLSPALGQMPISPDLSHTTLSLDFSQTNLSPELSQTNLSP 1350

1351 ALGQMPLSPDPSHTTLSLDLSQTNLSPELSQTNLSPDLSEMPLFADLSQI 1400

I I Il I I Il I I I Il I I Il I I Il I Il I I I Il I Il I I Il I I I I I Il I I I Il I I 1351 ALGQMPLSPDPSHTTLSLDLSQTNLSPELSQTNLSPDLSEMPLFADLSQI 1400

1401 PLTPDLDQMTLSPDLGETDLSPNFGQMSLSPDLSQVTLSPDISDTTLLPD 1450 M M I I M Il Il Il Il Il I I I Il I I I I I I Il Il I I I Il I I I I I I I Il I Il

1401 PLTPDLDQMTLSPDLGETDLSPNFGQMSLSPDLSQVTLSPDISDTTLLPD 1450

1451 LSQISPPPDLDQIFYPSESSQSLLLQEFNESFPYPDLGQMPSPSSPTLND 1500

I I I I I I Il Il Il I Il Il I Il Il Il Il I Il I I Il Il I Il Il I Il I I I I I I I ' 1451 LSQISPPPDLDQIFYPSESSQSLLLQEFNESFPYPDLGQMPSPSSPTLND 1500

1501 TFLSKEFNPLVIVGLSKDGTDYIEIIPKEEVQSSEDDYAEIDYVPYDDPY 1550

Il Il I I I I I I Il I I Il I I I I I Il Il I Il I Il Il I I I I I I Il Il I I Il I Il

1501 TFLSKEFNPLVIVGLSKDGTDYIEIIPKEEVQSSEDDYAEIDYVPYDDPY 1550 . . . . .

1551 KTDVRTNINSSRDPDNIAAWYLRSNNGNRRNYYIAAEEISWDYSEFVQRE 1600

I I Il I I Il I Il I Il Il Il Il Il I I I I I Il I I Il I Il I I I Il Il I Il I I Il

1551 KTDVRTNINSSRDPDNIAAWYLRSNNGNRRNYYIAAEEISWDYSEFVQRE 1600

1601 TDIEDSDDIPEDTTYKK 1617

I I I I III I I I I I I Il I I

1601 TDIEDSDDIPEDTTYKK 1617 Sequence name: FA5_HUMAN_V1

Sequence documentation:

Alignment of: HUMF5A__PEA_1_P4 x FA5_HUMAN_V1

Alignment segment 1/1:

Quality: 20532.00

Escore: 0

Matching length: 2062 Total length: 2062 Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps: 0

Alignment:

1 MFPGCPRLWVLVVLGTSWVGWGSQGTEAAQLRQFYVAAQGISWSYRPEPT 50

M M M M I I M M I M I I M I M M I M I M I I M I I M M M I I I M I 1 MFPGCPRLWVLWLGTSWVGWGSQGTEAAQLRQFYVAAQGI SWSYRPEPT 50

51 NSSLNLSVTSFKKIVYREYEPYFKKEKPQSTISGLLGPTLYAEVGDIIKV 100

I l I M I I I I I M M M I I Il I M I M M I I M I I I M M I I I I M I M M

51 NSSLNLSVTSFKKIVYREYEPYFKKEKPQSTISGLLGPTLYAEVGDIIKV 100 . . . . .

101 HFKNKADKPLSIHPQGIRYSKLSEGASYLDHTFPAEKMDDAVAPGREYTY 150 I Il I I I Il I I I I I I I I I Il I I Il I I I Il I I I I I I I Il I I I I I Il I I I I Il ioi HFKNKADKPLSIHPQGIRYSKLSEGΆSYLDHTFPAEKMDDΆVΆPGREYTY 150

151 EWSISEDSGPTHDDPPCLTHIYYSHENLIEDFNSGLIGPLLICKKGTLTE 200 I M II M I I I I MM I MM II I IM I M IM II I I MII M MI I I II I

151 EWSISEDSGPTHDDPPCLTHIYYSHENLIEDFNSGLIGPLLICKKGTLTE 200

201 GGTQKTFDKQIVLLFAVFDESKSWSQSSSLMYTVNGYVNGTMPDITVCAH 250

M Il M Il I I M I M Il I Il Il Il Il M I Il M I M Il Il M Il M Il Il 201 GGTQKTFDKQIVLLFAVFDESKSWSQSSSLMYTVNGYVNGTMPDITVCAH 250

251 DHISWHLLGMSSGPELFSIHFNGQVLEQNHHKVSAITLVSATSTTANMTV 300

II M M M M M I Il III M Il Il M M M I M Il Il I M M M Il Il Il

251 DHISWHLLGMSSGPELFSIHFNGQVLEQNHHKVSAITLVSATSTTANMTV 300 . . . . .

301 GPEGKWIISSLTPKHLQAGMQAYIDIKNCPKKTRNLKKITREQRRHMKRW 350

M Il I I M I I I I Il I Il Il M M Il I M M M Il M M Il M M M I M I

301 GPEGKWIISSLTPKHLQAGMQAYIDIKNCPKKTRNLKKITREQRRHMKRW 350

351 EYFIAAEEVIWDYAPVIPANMDKKYRSQHLDNFSNQIGKHYKKVMYTQYE 400

M Il M M I I I M M M I M I M Il M M M M Il I M M I M I M Il Il

351 EYFIAAEEVIWDYAPVIPANMDKKYRSQHLDNFSNQIGKHYKKVMYTQYE 400

401 DESFTKHTVNPNMKEDGILGPIIRAQVRDTLKIVFKNMASRPYSIYPHGV 450 I M M I M I I I M I M I Il Il I M M M Il M Il M Il M M I M I I Il I

401 DESFTKHTVNPNMKEDGILGPIIRAQVRDTLKIVFKNMASRPYSIYPHGV 450

451 TFSPYEDEVNSSFTSGRNNTMIRAVQPGETYTYKWNILEFDEPTENDAQC 500

M M I I M M M Il I I I Il M M M I M Il M Il M Il M M I M Il Il I 451 TFSPYEDEVNSSFTSGRNNTMIRAVQPGETYTYKWNILEFDEPTENDAQC 500 501 LTRPYYSDVDIMRDIASGLIGLLLICKSRSLDRRGIQRAADIEQQAVFAV 550

I I I i Il I I I I I I I Il I I I I I I Il I I I I I I I Il I I I I I I I I I I I I I I Il I I

501 LTRPYYSDVDIMRDIASGLIGLLLICKSRSLDRRGIQRAADIEQQAVFAV 550

551 FDENKSWYLEDNINKFCENPDEVKRDDPKFYESNIMSTINGYVPESITTL 600

MMIIM MM I I M I I IIM M M I I M M M MM I I I M I M M I I

551 FDENKSWYLEDNINKFCENPDEVKRDDPKFYESNIMSTINGYVPESITTL 600

601 GFCFDDTVQWHFCSVGTQNEILTIHFTGHSFIYGKRHEDTLTLFPMRGES 650 Il Il Il M M Il I M M M M M Il M M M Il I M I M M I M M M I I

601 GFCFDDTVQWHFCSVGTQNEILTIHFTGHSFIYGKRHEDTLTLFPMRGES 650

651 VTVTMDNVGTWMLTSMNSSPRSKKLRLKFRDVKCIPDDDEDSYEIFEPPE 700

II Il Il M M M I M Il M I I I M I M M I M Il M Il I M Il M M I M 651 VTVTMDNVGTWMLTSMNSSPRSKKLRLKFRDVKCIPDDDEDSYEIFEPPE 700

701 STVMATRKMHDRLEPEDEESDADYDYQNRLAAALGIRSFRNSSLNQEEEE 750

I M M Il I M M I I M I Il I M M M MM M I M M M I I M Il M I M

701 STVMATRKMHDRLEPEDEESDADYDYQNRLAAALGIRSFRNSSLNQEEEE 750 . . . . .

751 FNLTALALENGTEFVSSNTDIIVGSNYSSPSNISKFTVNNLAEPQKAPSH 800

M M M Il I I M I M M M M M M Il Il M M Il I M M I M M Il M I

751 FNLTALALENGTEFVSSNTDIIVGSNYSSPSNISKFTVNNLAEPQKAPSH 800

801 QQATTAGSPLRHLIGKNSVLNSSTAEHSSPYSEDPIEDPLQPDVTGIRLL 850

M M M M I M I M Il M M M Il M Il Il Il M M I M I M I M M I I I

801 QQATTAGSPLRHLIGKNSVLNSSTAEHSSPYSEDPIEDPLQPDVTGIRLL 850

851 SLGAGEFRSQEHAKRKGPKVERDQAAKHRFSWMKLLAHKVGRHLSQDTGS 900 I M Il M M Il M I M I I M M M I M M M M M M Il Il Il Il Il I M

851 SLGAGEFRSQEHAKRKGPKVERDQAAKHRFSWMKLLAHKVGRHLSQDTGS 900 901 PSGMRPWEDLPSQDTGSPSRMRPWKDPPSDLLLLKQSNSSKILVGRWHLA 950

I I I I I I I I I I I Il I I I I I I I I I I I Il I I I I I I I I Il I I I I I I I I Il Il I I

901 PSGMRPWEDLPSQDTGSPSRMRPWKDPPSDLLLLKQSNSSKILVGRWHLA 950 . . . . .

951 SEKGSYEIIQDTDEDTAVNNWLISPQNASRAWGESTPLANKPGKQSGHPK 1000

I I I Il I I Il I Il I I I I I I I I I I I Il I I I Il I I Il I I I I Il I I Il I Il I I I

951 SEKGSYEIIQDTDEDTAVNNWLISPQNASRAWGESTPLANKPGKQSGHPK 1000

1001 FPRVRHKSLQVRQDGGKSRLKKSQFLIKTRKKKKEKHTHHAPLSPRTFHP 1050

I M M M I I M M I M M M I I M M M I I M M I I I M M M I I I M M

1001 FPRVRHKSLQVRQDGGKSRLKKSQFLIKTRKKKKEKHTHHAPLSPRTFHP 1050

1051 LRSEAYNTFSERRLKHSLVLHKSNETSLPTDLNQTLPSMDFGWIASLPDH 1100 I I I Il I M M Il M I M Il Il M M Il Il M M I M M Il I Il I M I I M

1051 LRSEAYNTFSERRLKHSLVLHKSNETSLPTDLNQTLPSMDFGWIASLPDH 1100

1101 NQNSSNDTGQASCPPGLYQTVPPEEHYQTFPIQDPDQMHSTSDPSHRSSS 1150

II M M I M I I I M Il M M M M M M Il I M M M Il M M M I M M 1101 NQNSSNDTGQASCPPGLYQTVPPEEHYQTFPIQDPDQMHSTSDPSHRSSS 1150

• • • • •

1151 PELSEMLEYDRSHKSFPTDISQMSPSSEHEVWQTVISPDLSQVTLSPELS 1200

Il M I M Il M Il M I Il I M M M M M M M M M M Il M M I M I I

1151 PELSEMLEYDRSHKSFPTDISQMSPSSEHEVWQTVISPDLSQVTLSPELS 1200 . . . . .

1201 QTNLSPDLSHTTLSPELIQRNLSPALGQMPISPDLSHTTLSPDLSHTTLS 1250

Il Il I M M M M M I I M M Il M Il I M III I I I M Il M Il M M M

1201 QTNLSPDLSHTTLSPELIQRNLSPALGQMPISPDLSHTTLSPDLSHTTLS 1250

1251 LDLSQTNLSPELSQTNLSPALGQMPLSPDLSHTTLSLDFSQTNLSPELSH 1300 1251 LDLSQTNLSPELSQTNLSPALGQMPLSPDLSHTTLSLDFSQTNLSPELSH 1300

1301 MTLSPELSQTNLSPALGQMPISPDLSHTTLSLDFSQTNLSPELSQTNLSP 1350

I I I Il I I Il I Il I I Il I I I I I I I I I I I Il I I I I I I Il I I I I Il M I I I I I 1301 MTLSPELSQTNLSPALGQMPISPDLSHTTLSLDFSQTNLSPELSQTNLSP 1350

1351 ALGQMPLSPDPSHTTLSLDLSQTNLSPELSQTNLSPDLSEMPLFADLSQI 1400

II I I I I I Il Il Il I I Il Il I Il I Il I I I I I I Il Il Il Il Il I Il Il I Il I 1351 ALGQMPLSPDPSHTTLSLDLSQTNLSPELSQTNLSPDLSEMPLFADLSQI 1400 . . . . .

1401 PLTPDLDQMTLSPDLGETDLSPNFGQMSLSPDLSQVTLSPDISDTTLLPD 1450

M M I I I M I M M I I I I M M M I I M M M I M M M M M I M M M

1401 PLTPDLDQMTLSPDLGETDLSPNFGQMSLSPDLSQVTLSPDISDTTLLPD 1450

1451 LSQISPPPDLDQIFYPSESSQSLLLQEFNESFPYPDLGQMPSPSSPTLND 1500

M Il M M Il I I I M I I M M M M M M M Il M M M M M M M I M

1451 LSQISPPPDLDQIFYPSESSQSLLLQEFNESFPYPDLGQMPSPSSPTLND 1500

1501 TFLSKEFNPLVIVGLSKDGTDYIEIIPKEEVQSSEDDYAEIDYVPYDDPY 1550 M I l M M I l I M M I l M I M M I M M M M M I l I I M I l M M I M

1501 TFLSKEFNPLVIVGLSKDGTDYIEIIPKEEVQSSEDDYAEIDYVPYDDPY 1550

1551 KTDVRTNINSSRDPDNIAAWYLRSNNGNRRNYYIAAEEISWDYSEFVQRE 1600

M M M M M I MM M I l M M M M M I M M M M M Il M M M M 1551 KTDVRTNINSSRDPDNIAAWYLRSNNGNRRNYYIAAEEISWDYSEFVQRE 1600

1601 TDIEDSDDIPEDTTYKKWFRKYLDSTFTKRDPRGEYEEHLGILGPIIRA 1650

M M M I M M M I M M M I l M M M M I l M M M I M M M I M M

1601 TDIEDSDDIPEDTTYKKWFRKYLDSTFTKRDPRGEYEEHLGILGPIIRA 1650 . . . . .

1651 EVDDVIQVRFKNLASRPYSLHAHGLSYEKSSEGKTYEDDSPEWFKEDNAV 1700 I i M I M I M M M I I I M I I I I I I I M M I I I I M I l I I I M I I M I M

1651 EVDDVIQVRFKNLASRPYSLHAHGLSYEKSSEGKTYEDDSPEWFKEDNAV 1700

1701 QPNSSYTYVWHATERSGPESPGSACRAWAYYSAVNPEKDIHSGLIGPLLI 1750 1 M I M M Il Il Il I I Il I Il I Il I Il Il Il Il Il I Il I Il Il Il Il I Il

1701 QPNSSYTYVWHATERSGPESPGSACRAWAYYSAVNPEKDIHSGLIGPLLI 1750

1751 CQKGILHKDSNMPVDMREFVLLFMTFDEKKSWYYEKKSRSSWRLTSSEMK 1800

I M I Il I I I Il I M Il Il Il I Il I I I Il Il I M I I I Il Il I I I M I I I M 1751 CQKGILHKDSNMPVDMREFVLLFMTFDEKKSWYYEKKSRSSWRLTSSEMK 1800

1801 KSHEFHAINGMIYSLPGLKMYEQEWVRLHLLNIGGSQDIHWHFHGQTLL 1850

I Il I Il Il I Il Il Il I I Il M I I I M M M I I I M I M Il M M I I M I I

1801 KSHEFHAINGMIYSLPGLKMYEQEWVRLHLLNIGGSQDIHWHFHGQTLL 1850 . . . . . .

1851 ENGNKQHQLGVWPLLPGSFKTLEMKASKPGWWLLNTEVGENQRAGMQTPF 1900

I M I I M I I I I M Il I M M Il I Il Il I I M M M I Il M Il I Il I Il M

1851 ENGNKQHQLGVWPLLPGSFKTLEMKASKPGWWLLNTEVGENQRAGMQTPF 1900

1901 LIMDRDCRMPMGLSTGIISDSQIKASEFLGYWEPRLARLNNGGSYNAWSV 1950

M I M I I M M I I III I I Il I M M Il I M M M M I M M I M M Il M

1901 LIMDRDCRMPMGLSTGIISDSQIKASEFLGYWEPRLARLNNGGSYNAWSV 1950

1951 EKLAAEFASKPWIQVDMQKEVIITGIQTQGAKHYLKSCYTTEFYVAYSSN 2000 I Il I M M M I I I M M I I Il I Il M M Il I I I I I M M M I M M I Il I

1951 EKLAAEFASKPWIQVDMQKEVIITGIQTQGAKHYLKSCYTTEFYVAYSSN 2000

2001 QINWQIFKGNSTRNVMYFNGNSDASTIKENQFDPPIVARYIRISPTRAYN 2050

I I M M M I M I M M Il I Il M I I Ml Il M M I I I I M M Il I M I Il 2001 QINWQIFKGNSTRNVMYFNGNSDASTIKENQFDPPIVARYIRISPTRAYN 2050 2051 RPTLRLELQGCE 2062

2051 RPTLRLELQGCE 2062

Sequence name: FA5_HUMAN

Sequence documentation:

Alignment of: HUMF5A PEA 1 P8 x FA5 HUMAN

Alignment segment 1/1:

Quality: 5863.00 Escore: 0 Matching length: 588 Total length: 588

Matching Percent Similarity: 100.00 Matching Percent Identity: 99.83

Total Percent Similarity: 100.00 Total Percent Identity: 99.83

Gaps: 0

Alignment:

1 MFPGCPRLWVLVVLGTSWVGWGSQGTEAAQLRQFYVAAQGISWSYRPEPT 50 1 MFPGCPRLWVLWLGTSWVGWGSQGTEAAQLRQFYVAAQGISWSYRPEPT 50

51 NSSLNLSVTSFKKIVYREYEPYFKKEKPQSTISGLLGPTLYAEVGDIIKV 100

I I I Il I I Il I I I I I I I I I I I I I I I Il I I I I I I Il I Il I I I I I Il I I I I I I 51 NSSLNLSVTSFKKIVYREYEPYFKKEKPQSTISGLLGPTLYAEVGDIIKV 100

101 HFKNKADKPLSIHPQGIRYSKLSEGASYLDHTFPAEKMDDAVAPGREYTY 150

IMIIMIIIMIIMMMIMIIIMMMIMMMIMMIMIM

101 HFKNKADKPLSIHPQGIRYSKLSEGASYLDHTFPAEKMDDAVAPGREYTY 150 . . . . .

151 EWSISEDSGPTHDDPPCLTHIYYSHENLIEDFNSGLIGPLLICKKGTLTE 200

M M I I M M M M I I Il M M I M Il I I M M M I Il I M Il M M I I I

151 EWSISEDSGPTHDDPPCLTHIYYSHENLIEDFNSGLIGPLLICKKGTLTE 200

201 GGTQKTFDKQIVLLFAVFDESKSWSQSSSLMYTVNGYVNGTMPDITVCAH 250

I M I I I M M I I M M I I I I Il M I I I I Il I I Il M I M I I I M I M I M

201 GGTQKTFDKQIVLLFAVFDESKSWSQSSSLMYTVNGYVNGTMPDITVCAH 250

251 DHISWHLLGMSSGPELFSIHFNGQVLEQNHHKVSAITLVSATSTTANMTV 300 M I I I I I I Il M I M M M I Il M I I I M I I M I M M Il M M M M M

251 DHISWHLLGMSSGPELFSIHFNGQVLEQNHHKVSAITLVSATSTTANMTV 300

301 GPEGKWIISSLTPKHLQAGMQAYIDIKNCPKKTRNLKKITREQRRHMKRW 350

M I I I I M I I M I Il M I M I I Il M M M I I I I Il I Il I M M I M I M 301 GPEGKWIISSLTPKHLQAGMQAYIDIKNCPKKTRNLKKITREQRRHMKRW 350

351 EYFIAAEEVIWDYAPVIPANMDKKYRSQHLDNFSNQIGKHYKKVMYTQYE 400

M I I M M I I M I Il Il I M I I Il M M I I I I I M Il Il I M M I M M I

351 EYFIAAEEVIWDYAPVIPANMDKKYRSQHLDNFSNQIGKHYKKVMYTQYE 400 . . . . .

401 DESFTKHTVNPNMKEDGILGPIIRAQVRDTLKIVFKNMASRPYSIYPHGV 450 Il Il I I Il I I I I I I I I Il I I I I I I I I Il I I I Il I I I I Il I I I I I I I I I I I

401 DESFTKHTVNPNMKEDGILGPIIRAQVRDTLKIVFKNMASRPYSIYPHGV 450

451 TFSPYEDEVNSSFTSGRNNTMIRAVQPGETYTYKWNILEFDEPTENDAQC 500 I I I I M I I M M M Il M M I Il I M I M M Il I I I I Il I M I I M M Il

451 TFSPYEDEVNSSFTSGRNNTMIRAVQPGETYTYKWNILEFDEPTENDAQC 500

501 LTRPYYSDVDIMRDIASGLIGLLLICKSRSLDRRGIQRAADIEQQAVFAV 550

M M I I I M I IM M I I M I I I M I M I I M M I I I I I M M M M I I M 501 LTRPYYSDVDIMRDIASGLIGLLLICKSRSLDRRGIQRAADIEQQAVFAV 550

551 FDENKSWYLEDNINKFCENPDEVKRDDPKFYESNIMSS 588

I M IMM MIM MIM IMIM MMM M I M II:

551 FDENKSWYLEDNINKFCENPDEVKRDDPKFYESNIMST 588

DESCRIPTION FOR CLUSTER Z40511

Cluster Z40511 features 1 transcript(s) and 14 segment(s) of interest, the names for which are given in Tables 363 and 364, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 365.

Table 363 - Transcripts of interest

Table 364 - Segments of interest

Table 365 - Proteins of interest

These sequences are variants of the known protein Hypothetical protein (SwissProt accession identifier Q96DV8), SEQ ID NO:394, referred to herein as the previously known protein.

The sequence for protein Hypothetical protein is given at the end of the application, as "Hypothetical protein amino acid sequence".

As noted above, cluster Z40511 έatures 1 transcript(s), which were listed in Table 363 above. These transcript(s) encode for protein(s) which are variant(s) of protein Hypothetical protein. A description of each variant protein according to the present invention is now provided.

Variant protein Z40511_P5 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) Z40511_T8. An alignment is given to the known protein (Hypothetical protein) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between Z40511_P5 and Q9Y4S1_V2 SEQ ID NO: 396: 1.An isolated chimeric polypeptide encoding for Z40511_P5, comprising a first amino acid sequence being at least 90 % homologous to

MVYKTLFALCILTAGWRVQSLPTSAPLSVSLPTNIVPPTTIWTSSPQNTDADTASPSNGT ^■ HNNSVLPVTASAPTSLLPKNISIESREEEITSPGSNWEGTNTDPSPSGFSSTSGGVHLTTTL EEHSSGTPEAGVAATLSQSAAEPPTLISPQAPASSPSSLSTSPPEVFSASVTTNHSSTVTST QPTGAPTAPESPTEESSSDHTPTSHATAEPVPQEKTPPTTVSGKVMCELIDMET corresponding to amino acids 1 - 238 of Q9Y4S1 V2, which also corresponds to amino acids 1 - 238 of Z40511 P5, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence

TTTFPRVIMQEVEHALSSGPPMEDFWTTMTTGPGETTTTLCTMTPNNGIWPGMRINCS LFISAYPVELIST corresponding to amino acids 239 - 310 of Z40511JP5, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of Z40511 P5, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TTTFPRVIMQEVEHALSSGPPMEDFWTTMTTGPGETTTTLCTMTPNNGIWPGMRTNCS LFISAYPVELIST in Z40511_P5.

Comparison report between Z40511_P5 and Q96DV8JV1 (SEQ ID NO: 395): 1.An isolated chimeric polypeptide encoding for Z40511_P5, comprising a first amino acid sequence being at least 90 % homologous to

MVYKTLFALCILTAGWRVQSLPTSAPLSVSLPTNΓVTPTTIWTSSPQNTDADTASPSNGT HNNSVLPVTASAPTSLLPKNISIESREEEITSPGSNWEGTNTDPSPSGFSSTSGGVHLTTTL EEHSSGTPEAGVAATLSQSAAEPPTLISPQAPASSPSSLSTSPPEVFSASVTTNHSSTVTST QPTGAPTAPESPTEESSSDHTPTSHATAEPWQEKTPPTTVSGKVMCELIDMETTTTFPR VIMQEVEHALSSG corresponding to amino acids 1 - 257 of Q96DV8JV1, which also corresponds to amino acids 1 - 257 of Z40511_P5, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence PPMEDFWTTMTTGPGETTTTLCTMTPNNGIWPGMRINCSLFISAYPVELIST corresponding to amino acids 258 - 310 of Z40511_P5, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of Z40511_P5, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence

IPPMEDFWTTMTTGPGETTTTLCTMTPNNGIWPGMRINCSLFISAYPVELIST in Z40511_P5.

It should be noted that the known protein sequence (Q96DV8) has one or more changes than the sequence given at the end of the application and named as being the amino acid sequence for Q96DV8_V1. These changes were previously known to occur and are listed in the table below.

Table 366 - Changes to Q96DV8_V1

Comparison report between Z40511_P5 and AAQ89137 (SEQ ID NO: 397): 1.An isolated chimeric polypeptide encoding for Z40511_P5, comprising a first amino acid sequence being at least 90 % homologous to

MVYKTLFALCILTAGWRVQSLPTSAPLSVSLPTNIVPPTTIWTSSPQNTDADTASPSNGT HNNSVLPVTASAPTSLLPKNISIESREEEITSPGSNWEGTNTDPSPSGFSSTSGGVHLTTTL EEHSSGTPEAGVAATLSQSAAEPPTLISPQAPASSPSSLSTSPPEVFSASVTTNHSSTVTST QPTGAPTAPESPTEESSSDHTPTSHATAEPVPQEKTPPTTVSGKVMCELIDMETTTTFPR VIMQEVEHALSSG corresponding to amino acids 1 - 257 of AAQ89137, which also corresponds to amino acids 1 - 257 of Z40511_P5, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence IPPMEDFWTTMTTGPGETTTTLCTMTPNNGIWPGMRINCSLFISAYPVELIST corresponding to amino acids 258 - 310 of Z40511_P5, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of Z40511_P5, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence ffPMEDFWTTMTTGPGETTTTLCTMTPNNGIWPGMRINCSLFISAYPVELIST in

Z40511 P5.

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

Variant protein Z40511JP5 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 367, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein Z40511_P5 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 367 - Amino acid mutations

Variant protein Z40511_P5 is ercoded by the following transcript(s): Z40511JT8, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript Z40511_T8 is shown in bold; this coding portion starts at position 275 and ends at position 1204. The transcript also has the following SNPs as listed in Table 368 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein Z40511_P5 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 368- Nucleic acid SNPs

As noted above, cluster Z40511 features 14 segment(s), which were listed in Table 2 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.

Segment cluster Z40511_node_4 according to the present invention is supported by 40 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8. Table 369below describes the starting and ending position of this segment on each transcript.

Table 369 - Segment location on transcripts

Segment cluster Z40511_node_10 according to the present invention is supported by 49 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8. Table 370 below describes the starting and ending position of this segment on each transcript.

Table 370- Segment location on transcripts

Segment cluster Z40511_node_ll according to the present invention is supported by 76 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8. Table 371 below describes the starting and ending position of this segment on each transcript.

Table 371 - Segment location on transcripts

Segment cluster Z40511_node_15 according to the present invention is supported by 75 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8. Table 372 below describes the starting and ending position of this segment on each transcript.

Table 372 - Segment location on transcripts

Segment cluster Z40511_node_17 according to the present invention is supported by 57 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8. Table 373 below describes the starting and ending position of this segment on each transcript.

Table 373 - Segment location on transcripts

Segment cluster Z40511_node_18 according to the present invention is supported by 88 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8. Table 374 below describes the starting and ending position of this segment on each transcript.

Table 374 - Segment location on transcripts

Segment cluster Z40511_node_19 according to the present invention is supported by 92 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8. Table 375 below describes the starting and ending position of this segment on each transcript.

Table 375 - Segment location on transcripts

Segment cluster Z40511_node_20 according to the present invention is supported by 115 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8. Table 376 below describes the starting and ending position of this segment on each transcript.

Table 376- Segment location on transcripts

Segment cluster Z40511_node_21 according to the present invention is supported by 72 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8. Table 377 below describes the starting and ending position of this segment on each transcript.

Table 311 - Segment location on transcripts

Segment cluster Z40511_node_23 according to the present invention is supported by 96 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8. Table 378 below describes the starting and ending position of this segment on each transcript. Table 378 - Segment location on transcripts

Segment cluster Z40511_node_25 according to the present invention is supported by 89 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8. Table 379 below describes the starting and ending position of this segment on each transcript.

Table 379- Segment location on transcripts

Segment cluster Z40511_node_16 according to the present invention is supported by 41 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8. Table 380below describes the starting and ending position of this segment on each transcript.

Table 380 - Segment location on transcripts

Segment cluster Z40511_node_22 according to the present invention is supported by 43 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8. Table 381 below describes the starting and ending position of this segment on each transcript. Table 381 - Segment location on transcripts

Segment cluster Z40511_node_24 according to the present invention is supported by 61 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): Z40511_T8. Table 382 below describes the starting and ending position of this segment on each transcript.

Table 382 - Segment location on transcripts

Variant protein alignment to the previously known protein: Sequence name: Q9Y4S1_V2

Sequence documentation:

Alignment of: Z40511 P5 x Q9Y4S1 V2

Alignment segment 1/1:

Quality: 2321.00

Escore: Matching length: 243 Total length: 243

Matching Percent Similarity: 98.77 Matching Percent Identity: 98.77 Total Percent Similarity: 98.77 Total Percent Identity: 98.77

Gaps: 0

Alignment: . . . . .

1 MVYKTLFALCILTAGWRVQSLPTSAPLSVSLPTNIVPPTTIWTSSPQNTD 50

I I Il Il I I I Il I I I I Il I III I I I Il I I I I I I I I I I I I I I I I Il I I I Il I

1 MVYKTLFALCILTAGWRVQSLPTSAPLSVSLPTNIVPPTTIWTSSPQNTD 50

51 ADTASPSNGTHNNSVLPVTASAPTSLLPKNISIESREEEITSPGSNWEGT 100

II I I I I I I I Il I I I I I I I I Kl I I I I I Il Il Il I Il I Il I I I I I Il I I I Il

51 ADTASPSNGTHNNSVLPVTASAPTSLLPKNISIESREEEITSPGSNWEGT 100

101 NTDPSPSGFSSTSGGVHLTTTLEEHSSGTPEAGVAATLSQSAAEPPTLIS 150 I I I M I I I I M I I I I I I I I M M M M I I I I I M I I M I I I I I I M I I M

101 NTDPSPSGFSSTSGGVHLTTTLEEHSSGTPEAGVAATLSQSAAEPPTLIS 150

151 PQAPASSPSSLSTSPPEVFSASVTTNHSSTVTSTQPTGAPTAPESPTEES 200

I I Il Il I I I I I I I Il Il I Il I I I I I I I I I Il I Il I I I I I I I I I I I I I Il I 151 PQAPASSPSSLSTSPPEVFSASVTTNHSSTVTSTQPTGAPTAPESPTEES 200

201 SSDHTPTSHATAEPVPQEKTPPTTVSGKVMCELIDMETTTTFP 243

I I I I I I I I I I I I I I I I I I I I I I I I I Il I I I Il I I I I I I Il

201 SSDHTPTSHATAEPVPQEKTPPTTVSGKVMCELIDMETPPPFP 243

Sequence name: Q96DV8_V1

Sequence documentation:

Alignment of: Z40511_P5 x Q96DV8_V1

Alignment segment 1/1:

Quality: 2493.00 Escore: 0 Matching length: 257 Total length: 257

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps: 0

Alignment:

1 MVYKTLFALCILTAGWRVQSLPTSAPLSVSLPTNIVPPTTIWTSSPQNTD 50

51 ADTASPSNGTHNNSVLPVTASAPTSLLPKNISIESREEEITSPGSNWEGT 100

51 ADTASPSNGTHNNSVLPVTASAPTSLLPKNISIESREEEITSPGSNWEGT 100 101 NTDPSPSGFSSTSGGVHLTTTLEEHSSGTPEAGVAATLSQSAAEPPTLIS 150

I I Il I I I I Il I Il I I Il Il I I I I Il I I I Il I I I I I I Il I I I Il I I I I I Il

101 NTDPSPSGFSSTSGGVHLTTTLEEHSSGTPEAGVAATLSQSAAEPPTLIS 150 . . . . .

151 PQAPASSPSSLSTSPPEVFSASVTTNHSSTVTSTQPTGAPTAPESPTEES 200

I Il I Il I I Il Il Il Il I Il I Il I Il Il Il I Il I Il Il Il I I Il I I I Il I I 151 PQAPASSPSSLSTSPPEVFSASVTTNHSSTVTSTQPTGAPTAPESPTEES 200

201 SSDHTPTSHATAEPVPQEKTPPTTVSGKVMCELIDMETTTTFPRVIMQEV 250

I I III Il Il I I I I I I I I I I Il I I I I I I I I I I Il I I I I Il I I Il I I Il I I I

201 SSDHTPTSHATAEPVPQEKTPPTTVSGKVMCELIDMETTTTFPRVIMQEV 250

251 EHALSSG 257 IMIIII

251 EHALSSG 257

Sequence name: AAQ89137

Sequence documentation:

Alignment of: Z40511_P5 x AAQ89137

Alignment segment 1/1: Quality: 2493.00

Escore: 0

Matching length: 257 Total length: 257 Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent

Identity: 100.00

Gaps: 0

Alignment:

1 MVYKTLFALCILTAGWRVQSLPTSAPLSVSLPTNIVPPTTIWTSSPQNTD 50

I I I I I I I Il I I Il I Il I Il I I I I I I Il I I I I I I I I I Il I I I I I I Il I I I I 1 MVYKTLFALCILTAGWRVQSLPTSAPLSVSLPTNIVPPTTIWTSSPQNTD 50

51 ADTASPSNGTHNNSVLPVTASAPTSLLPKNISIESREEEITSPGSNWEGT 100

Il Il I I Il Il I I Il I I Il Il I Il I I I Il I I I I I I I I Il Il I Il Il I I I Il

51 ADTASPSNGTHNNSVLPVTASAPTSLLPKNISIESREEEITSPGSNWEGT 100 . . . . .

101 NTDPSPSGFSSTSGGVHLTTTLEEHSSGTPEAGVAATLSQSAAEPPTLIS 150

II I I I I I I I I Il Il I I Il Il I I I I I I Il I I I I I I Il I I Il I I I Il I I I I I

101 NTDPSPSGFSSTSGGVHLTTTLEEHSSGTPEAGVAATLSQSAAEPPTLIS 150

151 PQAPASSPSSLSTSPPEVFSASVTTNHSSTVTSTQPTGAPTAPESPTEES 200

Il Il I I Il Il Il I Il Il I Il I I I I I Il I Il I I I I I I I Il I I I Il Il Il Il 151 PQAPASSPSSLSTSPPEVFSASVTTNHSSTVTSTQPTGAPTAPESPTEES 200

201 SSDHTPTSHATAEPVPQEKTPPTTVSGKVMCELIDMETTTTFPRVIMQEV 250 I I I I Il I I M I I Il I Il M I M I I M I I I I I I I I I I I Il I I Il I I I I I I I

201 SSDHTPTSHATAEPVPQEKTPPTTVSGKVMCELIDMETTTTFPRVIMQEV 250 251 EHALSSG 257

251 EHALSSG 257

DESCRIPTION FOR CLUSTER H53626

Cluster H53626 features 2 transcript(s) and 20 segment(s) of interest, the names for which are given in Tables 383 and 384, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 385.

Table 383 - Transcripts of interest

Cluster H53626 can be used as a diagnostic marker according to overexpression of transcripts of this cluster in cancer. Expression of such transcripts in normal tissues is also given according to the previously described methods. The term "number" in the left hand column of the table and the numbers on the y-axis of Figure 16 refer to weighted expression of ESTs in each category, as "parts per million" (ratio of the expression of ESTs for a particular cluster to the expression of all ESTs in that category, according to parts per million).

Overall, the following results were obtained as shown with regard to the histograms in Figure 16 and Table 386. This cluster is overexpressed (at least at a minimum level) in the following pathological conditions: epithelial malignant tumors, a mixture of malignant tumors from different tissues and myosarcoma.

Table 386 - Normal tissue distribution

Table 387 - P values and ratios for expression in cancerous tissue

As noted above, cluster H53626 features 2 transcript(s), which were listed in Table 1 above. A description of each variant protein according to the present invention is now provided.

Variant protein H53626_PEA_1_P4 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) H53626 PEA 1 T15. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: Comparison report between H53626_PEA_1_P4 and Q8N441 (SEQ ID NO:500): 1.An isolated chimeric polypeptide encoding for H53626_PEA_1_P4, comprising a first amino acid sequence being at least 90 % homologous to MTPSPLLLLLLPPLLLGAFPPAAAARGPPKMADKVVPRQVARLGRTVRLQCPVEGDPPP LTMWTKDGRTIHSGWSRFRVLPQGLKVKQVEREDAGVYVCKATNGFGSLSVNYTLW LDDISPGKESLGPDSSSGGQEDPASQQWARPRFTQPSKMRRRVIARPVGSSVRLKCVAS GHPRPDITWMKDDQALTRPEAAEPRKKKWTLSLKNLRPEDSGKYTCRVSNRAGAINAT YKVDVIQRTRSKPVLTGTHPVNTTVDFGGTTSFQCKVRSDVKPVIQWLKRVEYGAEGR HNSTIDVGGQKFWLPTGDVWSRPDGSYLNKLLITRARQDDAGMYICLGANTMGYSFR SAFLTVLP corresponding to amino acids 1 - 357 of Q8N441, which also corresponds to amino acids 1 - 357 of H53626_PEA_1_P4, second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence

GARLPRHATPCWCPDPPPGPGVPPTGWGPTLPSRAVLARSSAEGGQPRGTVSTAPGMG LGCSPGLCVGVPLPTSFPLALA corresponding to amino acids 358 - 437 of H53626_PEA_1_P4, and a third amino acid sequence being at least 90 % homologous to DPKPPGPPVASSSSATSLPWPWIGIPAGAVFILGTLLLWLCQAQKKPCTPAPAPPLPGH RPPGTARDRSGDKDLPSLAALSAGPGVGLCEEHGSPAAPQHLLGPGPVAGPKLYPKLY TDIHTHTHTHSHTHSHVEGKVHQHIHYQC corresponding to amino acids 358 - 504 of Q8N441, which also corresponds to amino acids 438 - 584 of H53626_PEA_1_P4, wherein said first, second and third amino acid sequences are contiguous and in a sequential order. 2.An isolated polypeptide encoding for an edge portion of H53626_PEA_1_P4, comprising an amino acid sequence being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence encoding for

GARLPRHATPCWCPDPPPGPGVPPTGWGPTLPSRAVLARSSAEGGQPRGTVSTAPGMG LGCSPGLCVGVPLPTSFPLALA, corresponding to H53626_PEA_1_P4.

The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: membrane. The protein localization is believed to be membrane because although both signal peptide prediction programs agree that this protein has a signal peptide, both trans -membrane region prediction programs predict that this protein has a trans-membrane region downstream of this signal peptide..

Variant protein H53626_PEA_1_P4 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 388, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein H53626_PEA_1_P4 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 388 - Amino acid mutations

Variant protein H53626_PEA_1_P4 is encoded by the following transcript(s): H53626_PEA_1_T15, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript H53626JPEA_1_T15 is shown in bold; this coding portion starts at position 17 and ends at position 1768. The transcript also has the following SNPs as listed in Table 389 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein H53626_PEA_1_P4 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 389 - Nucleic acid SNPs

Variant protein H53626_PEA_1_P5 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) H53626_PEA_1_T16. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: Comparison report between H53626_PEA_1_P5 and Q9H4D7 (SEQ ID NO:501): 1.An isolated chimeric polypeptide encoding for H53626_PEA_1_P5, comprising a first amino acid sequence being at least 90 % homologous to MTPSPLLLLLLPPLLLGAFPPAAAARGPPKMADKVVPRQVARLGRTVRLQCPVEGDPPP LTMWTKDGRTIHSGWSRFRVLPQGLKVKQVEREDAGVYVCKATNGFGSLSVNYTLW LDDISPGKESLGPDSSSGGQEDPASQQWARPRFTQPSKMRRRVIARPVGSSVRLKCVAS GHPRPDITWMKDDQALTRPEAAEPRKKKWTLSLKNLRPEDSGKYTCRVSNRAGAINAT YKVDVTQRTRSKPVLTGTHPVNTTVDFGGTTSFQCK corresponding to amino acids 1 - 269 of Q9H4D7, which also corresponds to amino acids 1 - 269 of H53626_PEA_1_P5, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence

TQNRQGHLWPPRPRPLACRGPWSSASQPALSSSWAPCSCGFARPRRSRAPPRLPLPCLG TARRGRPATAAETRTFPRWPPSALALVWGCVRSMGLRQPPSTYWAQAQLLALSCTPNS TQTSTHTHTHTLTHTHTWRARSTSTSTISARRHRICSGHGGAGQTGRLGGWRTELQTKA GDPWRGGMASTPGSLCVRHSPWTHTHRHTHYLDACMHTHARTRAP corresponding to amino acids 270 - 490 of H53626_PEA_1_P5, wherein said first and second amino acid sequences are contiguous and in a sequential order. 2.An isolated polypeptide encoding for a tail of H53626_PEA_1_P5, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TQNRQGHLWPPRPRPLACRGPWSSASQPALSSSWAPCSCGFARPRRSRAPPRLPLPCLG TARRGRPATAAETRTFPRWPPSALALVWGCVRSMGLRQPPSTYWAQAQLLALSCTPNS TQTSTHTHTHTLTHTHTWRARSTSTSTISARRHRICSGHGGAGQTGRLGGWRTELQTKA GDPWRGGMASTPGSLCVRHSPWTHTHRHTHYLDACMHTHARTRAP in

H53626_PEA_1_P5.

Comparison report between H53626_PEA_1_P5 and Q8N441: 1.An isolated chimeric polypeptide encoding for H53626_PEA_1_P5, comprising a first amino acid sequence being at least 90 % homologous to MTPSPLLLLLLPPLLLGAFPPAAAARGPPKMADKVVPRQVARLGRTVRLQCPVEGDPPP LTMWTKDGRTIHSGWSRFRVLPQGLKVKQVEREDAGVYVCKATNGFGSLSVNYTLW LDDISPGKESLGPDSSSGGQEDPASQQWARPRFTQPSKMRRRVIARPVGSSVRLKCVAS GHPRPDITWMKI)DQALTRPEAAEPRKKKWTLSLKNLRPEDSGKYTCRVSNRAGAINAT YKVDVIQRTRSKPVLTGTHPVNTTVDFGGTTSFQCK corresponding to amino acids 1 - 269 of Q8N441, which also corresponds to amino acids 1 - 269 of H53626_PEA_1_P5, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence

TQNRQGHLWPPRPRPLACRGPWSSASQPALSSSWAPCSCGFARPRRSRAPPRLPLPCLG TARRGRPATAAETRTFPRWPPSALALVWGCVRSMGLRQPPSTYWAQAQLLALSCTPNS TQTSTHTHTHTLTHTHTWRARSTSTSTISARRHRICSGHGGAGQTGRLGGWRTELQTKA GDPWRGGMASTPGSLCVRHSPWTHTHRHTHYLDACMHTHARTRAP corresponding to amino acids 270 - 490 of H53626 PEA 1 P5, wherein said first and second amino acid sequences are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of H53626_PEA_1_P5, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TQNRQGHLWPPRPRPLACRGPWSSASQPALSSSWAPCSCGFARPRRSRAPPRLPLPCLG TARRGRPATAAETRTFPRWPPSALALVWGCVRSMGLRQPPSTYWAQAQLLALSCTPNS TQTSTHTHTHTLTHTHTWRARSTSTSTISARRHRICSGHGGAGQTGRLGGWRTELQTKA GDPWRGGMASTPGSLCVRHSPWTHTHRHTHYLDACMHTHARTRAP in

H53626_PEA_1_P5.

Variant protein H53626_PEA_1_P5 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 390, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein H53626_PEA_1_P5 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 390 -Amino acid mutations

Variant protein H53626_PEA_1_P5 is encoded by the following transcript(s): H53626_PEA_1_T16, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript H53626_PEA_1_T16 is shown in bold; this coding portion starts at position 17 and ends at position 1486. The transcript also has the following SNPs as listed in Table 391 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein H53626_PEA_1_P5 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 391 - Nucleic acid SNPs

As noted above, cluster H53626 features 20 segment(s), which were listed in Table 2 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.

Segment cluster H53626_PEA_l_rrode_15 according to the present invention is supported by 25 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA_1_T15 and H53626_PEA__1_T16. Table 392 below describes the starting and ending position of this segment on each transcript.

Table 392 - Segment location on transcripts

Segment cluster H53626_PEA_l_node_22 according to the present invention is supported by 42 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA_1_T15 and H53626_PEA__1_T16. Table 393 below describes the starting and ending position of this segment on each transcript.

Table 393 - Segment location on transcripts

Segment cluster H53626_PEA_l_node_25 according to the present invention is supported by 41 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA_1_T15. Table 394 below describes the starting and ending position of this segment on each transcript.

Table 394 - Segment location on transcripts

Segment cluster H53626_PEA_l_node_26 according to the present invention is supported by 5 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA_1_T15. Table 395 below describes the starting and ending position of this segment on each transcript.

Table 395 - Segment location on transcripts

Microarray (chip) data is also available for this segment as follows. As described above with regard to the cluster itself, various oligonucleotides were tested for being differentially expressed in various disease conditions, particularly cancer. The following oligonucleotides were found to hit this segment (with regard to prostate cancer), shown in Table 396.

Table 396 - Oligonucleotides related to this segment

Segment cluster H53626_PEA_l_node_27 according to the present invention is supported by 106 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA_1JT15 and H53626_PEA_1_T16. Table 397 below describes the starting and ending position of this segment on each transcript.

Table 397 - Segment location on transcripts

Segment cluster H53626_PEA_l_node_34 according to the present invention is supported by 121 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA_1_T15 and H53626_PEA_1_T16. Table 398 below describes the starting and ending position of this segment on each transcript.

Table 398- Segment location on transcripts

Segment cluster H53626_PEA_l_node_35 according to the present invention is supported by 85 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA_1_T15 and H53626_PEA_1_T16. Table 399 below describes the starting and ending position of this segment on each transcript.

Table 399- Segment location on transcripts

Segment cluster H53626_PEA_l_node_36 according to the present invention is supported by 69 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA_1_T15 and H53626_PEA_1_T16. Table 400 below describes the starting and ending position of this segment on each transcript.

Table 400 - Segment location on transcripts

Segment cluster H53626_PEA_ljαode_ll according to the present invention is supported by 12 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA_1_T15 and H53626JPEA_1_T16. Table 401 below describes the starting and ending position of this segment on each transcript.

Table 401 - Segment location on transcripts

Segment cluster H53626_PEA_l_node_12 according to the present invention is supported by 11 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA_1_T15 and H53626_PEA_1_T16. Table 402 below describes the starting and ending position of this segment on each transcript.

Table 402- Segment location on transcripts

Segment cluster H53626_PEA_l_node_16 according to the present invention can be found in the following transcript(s): H53626_PEA_1_T15 and H53626_PEA_1_T16. Table 403 below describes the starting and ending position of this segment on each transcript.

Table 403 - Segment location on transcripts

Segment cluster H53626_PEA_l_node_19 according to the present invention is supported by 25 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA_1_T15 and H53626_PEA_1_T16. Table 404 below describes the starting and ending position of this segment on each transcript.

Table 404 - Segment location on transcripts

Segment cluster H53626_PEA_l_node_20 according to the present invention is supported by 27 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626JPEA_1_T15 and H53626JPEA_1_T16. Table 405 below describes the starting and ending position of this segment on each transcript.

Table 405 - Segment location on transcripts

Segment cluster H53626_PEA_l_node_24 according to the present invention is supported by 34 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA_1_T15 and H53626_PEA_1_T16. Table 406 below describes the starting and ending position of this segment on each transcript.

Table 406- Segment location on transcripts

Segment cluster H53626_PEA_l_node_28 according to the present invention is supported by 66 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA_1_T15 and H53626_PEA_1_T16. Table 407 below describes the starting and ending position of this segment on each transcript.

Table 407 - Segment location on transcripts

Segment cluster H53626_PEA_l_node_29 according to the present invention is supported by 73 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA_1_T15 and H53626_PEA_1JT16. Table 408 below describes the starting and ending position of this segment on each transcript.

Table 408- Segment location on transcripts

Segment cluster H53626_PEA_l_node_30 according to the present invention is supported by 71 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA_1_T15 and H53626_PEA_1JT16. Table 409 below describes the starting and ending position of this segment on each transcript.

Table 409- Segment location on transcripts

Segment cluster H53626_PEA_l_node_31 according to the present invention is supported by 67 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA_1_T15 and H53626_PEA_1_T16. Table 410 below describes the starting and ending position of this segment on each transcript.

Table 410 - Segment location on transcripts

Segment cluster H53626_PEA_l_node_32 according to the present invention is supported by 65 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): H53626_PEA_1__T15 and H53626_PEA_1_T16. Table 410 below describes the starting and ending position of this segment on each transcript.

Table 410 - Segment location on transcripts

Segment cluster H53626_PEA_l_node_33 according to the present invention can be found in the following transcript(s): H53626_PEA_1_T15 and H53626_PEA_1_T16. Table 411 below describes the starting and ending position of this segment on each transcript.

Table 411 - Segment location on transcripts

Expression of Homo sapiens fibroblast growth factor receptor- like 1 (FGFRLl) H53626 transcripts which are detectable by amplicon as depicted in sequence name H53626 junc24-

27Fl R3 in different normal tissues

Expression of Homo sapiens fibroblast growth factor receptor- like 1 (FGFRLl) transcripts detectable by or according to H53626 junc24-27FlR3 amplicon(s) and H53626 junc24-27Fl and H53626 junc24-27R3 was measured by real time PCR (these sequences relate to the known protein ("WT") sequence). In parallel the expression of four housekeeping genes - RPLl 9 (GenBank Accession No. NM_000981; RPLl 9 amplicon), TATA box (GenBank Accession No. NM_003194; TATA amplicon), UBC (GenBank Accession No. BC000449; amplicon - Ubiquitin-amplicon) and SDHA (GenBank Accession No. NM_004168; amplicon - SDHA-amplicon) was measured similarly. For each RT sample, the expression of the above amplicon was normalized to the geometric mean of the quantities of the housekeeping genes.

H53626 junc24-27 Forward primer (SEQ ID NO:502): GTCCTTCCAGTGCAAGACCCA H53626 junc24-27 Reverse primer (SEQ ID NO:503): TGGGCCTGGCAAAGCC H53626 junc24-27 Amplicon (SEQ ID NO:504):

GTCCTTCCAGTGCAAGACCCAAAACCGCCAGGGCCACCTGTGGCCTCCTCGTCCTC GGCCACTAGCCTGCCGTGGCCCGTGGTCATCGGCATCCCAGCCGGCGCTGTCTTCAT CCTGGGCACCCTGCTCCTGTGGCTTTGCCAGGCCCA

Expression of Homo sapiens fibroblast growth factor receptor- like 1 (FGFRLl) H53626 transcripts, which are detectable by amplicon as depicted in sequence name H53626 seg25 in different normal tissues.

Expression of Homo sapiens fibroblast growth factor receptor- like 1 (FGFRLl) transcripts detectable by or according to H53626 seg25 amplicon(s) and H53626 seg25F and

H53626 seg25R was measured by real time PCR. In parallel the expression of four housekeeping genes: RPL19 (GenBank Accession No. NM_000981; RPL19 amplicon), TATA box (GenBank Accession No. NM_003194; TATA amplicon), UBC (GenBank Accession No.

BC000449; amplicon - Ubiquitin-amplicon) and SDHA (GenBank Accession No. NM_004168; amplicon - SDHA-amplicon) was measured similarly. For each RT sample, the expression of the above amplicon was normalized to the geometric mean of the quantities of the housekeeping genes.

H53626 seg25 Forward primer (SEQ ID NO:505): CCGACGGCTCCTACCTCAA H53626 seg25 Reverse primer (SEQ ID NO:506): GGAAGCTGTAGCCCATGGTGT H53626 seg25 Amplicon (SEQ ID NO:507):

CCGACGGCTCCTACCTCAATAAGCTGCTCATCACCCGTGCCCGCCAGGACGATGCG GGCATGTACATCTGCCTTGGCGCCAACACCATGGGCTACAGCTTCC Variant protein alignment to the previously known protein:

Sequence name: /tmp/KlMec2ReKO/eglEUS2AXY:Q8N441

Sequence documentation:

Alignment of: H53626_PEA_1_P4 x Q8N441

Alignment segment 1/1:

Quality: 4882.00

Escore: 0

Matching length: 504 Total length: 584

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 86.30 Total Percent Identity: 86.30

Gaps: 1

Alignment:

1 MTPSPLLLLLLPPLLLGAFPPAAAARGPPKMADKWPRQVARLGRTVRLQ 50

1 MTPSPLLLLLLPPLLLGAFPPAAAARGPPKMADKVVPRQVARLGRTVRLQ 50

51 CPVEGDPPPLTMWTKDGRTIHSGWSRFRVLPQGLKVKQVEREDAGVYVCK 100

101 ATNGFGSLSVNYTLWLDDISPGKESLGPDSSSGGQEDPASQQWARPRFT 150 /

621

101 ATNGFGSLSWYTLWLDDISPGKESLGPDSSSGGQEDPASQQWARPRFT 150

151 QPSKMRRRVIARPVGSSVRLKCVASGHPRPDITWMKDDQALTRPEAAEPR 200

I I I I I I I I I I I I I I I Ml I I I I I I I I I I Il I I I I I Il I Il I I I I I I Il I I 151 QPSKMRRRVIARPVGSSVRLKCVASGHPRPDITWMKDDQALTRPEAAEPR 200

> • • • •

201 KKKWTLSLKNLRPEDSGKYTCRVSNRAGAINATYKVDVIQRTRSKPVLTG 250

I MM M M M I I M I I M M I I MI I I M I I I I I I M I I M M I I I M I

201 KKKWTLSLKNLRPEDSGKYTCRVSNRAGAINATYKVDVIQRTRSKPVLTG 250 . . . . .

251 THPVNTTVDFGGTTSFQCKVRSDVKPVIQWLKRVEYGAEGRHNSTIDVGG 300

I I M I Il M I M Il Il I I M I I I I M I Il Il M M I M I Il Il I I Il Il I

251 THPVNTTVDFGGTTSFQCKVRSDVKPVIQWLKRVEYGAEGRHNSTIDVGG 300

301 QKFWLPTGDVWSRPDGSYLNKLLITRARQDDAGMYICLGANTMGYSFRS 350

M I I I M I l M I l M M I M I M M I I M I l M I M M I I l I l I l I I l I I

301 QKFWLPTGDVWSRPDGSYLNKLLITRARQDDAGMYICLGANTMGYSFRS 350

351 AFLTVLPGARLPRHATPCWCPDPPPGPGVPPTGWGPTLPSRAVLARSSAE 400 I Il M M

351 AFLTVLP 357

401 GGQPRGTVSTAPGMGLGCSPGLCVGVPLPTSFPLALADPKPPGPPVASSS 450

I I M I M M I M I 358 DPKPPGPPVASSS 370

451 SATSLPWPWIGIPAGAVFILGTLLLWLCQAQKKPCTPAPAPPLPGHRPP 500

I I I l I M I l I l M I I I I l I M M I I I I M I I M I M I I l I I l I M I I I M

371 SATSLPWPWIGIPAGAVFILGTLLLWLCQAQKKPCTPAPAPPLPGHRPP 420 . . . . .

501 GTARDRSGDKDLPSLAALSAGPGVGLCEEHGSPAAPQHLLGPGPVAGPKL 550

421 GTARDRSGDKDLPSLAALSAGPGVGLCEEHGSPAAPQHLLGPGPVAGPKL 470

551 YPKLYTDIHTHTHTHSHTHSHVEGKVHQHIHYQC 584

471 YPKLYTDIHTHTHTHSHTHSHVEGKVHQHIHYQC 504

Sequence name: /tmp/oSUZaRW3WK/oSh3fN5ZtO:Q9H4D7

Sequence documentation:

Alignment of: H53626_PEA_1_P5 x Q9H4D7

Alignment segment 1/1:

Quality: 2644.00

Escore: 0

Matching length: 269 Total length: 269 Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps:

Alignment: 1 MTPSPLLLLLLPPLLLGAFPPAAAARGPPKMADKWPRQVARLGRTVRLQ 50

I I Il I I I I I I I I I I I I I I Il I I I I I Il I I I I I I I I I I I I I I I I I I I I Il I l MTPSPLLLLLLPPLLLGAFPPAAAARGPPKMADKWPRQVARLGRTVRLQ 50 . . . . .

51 CPVEGDPPPLTMWTKDGRTIHSGWSRFRVLPQGLKVKQVEREDAGVYVCK 100

I I I I Il Il Il Il Il I Il Il I Il Il I I I Il I I I I Il I I I I I I I Il I I Il I I

51 CPVEGDPPPLTMWTKDGRTIHSGWSRFRVLPQGLKVKQVEREDAGVYVCK 100

101 ATNGFGSLSVNYTLWLDDISPGKESLGPDSSSGGQEDPASQQWARPRFT 150

I I I I I I I Il I I I I I I I I I Il Il I Il I Il I I I I I I I I I I I I I I Il Il I I Il

101 ATNGFGSLSVNYTLWLDDISPGKESLGPDSSSGGQEDPASQQWARPRFT 150

151 QPSKMRRRVIARPVGSSVRLKCVASGHPRPDITWMKDDQALTRPEAAEPR 200 M M I II M I I I M M M II I I I I I I I I M I M M I I I M I M I I I MM

151 QPSKMRRRVIARPVGSSVRLKCVASGHPRPDITWMKDDQALTRPEAAEPR 200

201 KKKWTLSLKNLRPEDSGKYTCRVSNRAGAINATYKVDVIQRTRSKPVLTG 250

II Il I M Il M I M Il M M M I I M I M Il M I I M M M M M M Il I 201 KKKWTLSLKNLRPEDSGKYTCRVSNRAGAINATYKVDVIQRTRSKPVLTG 250

251 THPVNTTVDFGGTTSFQCK 269

I I I M Il Il I M I M M Il

251 THPVNTTVDFGGTTSFQCK 269

Sequence name: /tmp/oSUZaRW3WK/oSh3fN5ZtO:Q8N441 Sequence documentation:

Alignment of: H53626_PEA_1_P5 x Q8N441

Alignment segment 1/1:

Quality: 2644.00 Escore: 0 Matching length: 269 Total length: 269

Matching Percent Similarity: 100.00 Matching Percent Identity: 100.00

Total Percent Similarity: 100.00 Total Percent Identity: 100.00

Gaps: 0

Alignment:

1 MTPSPLLLLLLPPLLLGAFPPAAAARGPPKMADKVVPRQVARLGRTVRLQ 50

1 MTPSPLLLLLLPPLLLGAFPPAAAARGPPKMADKWPRQVARLGRTVRLQ 50

51 CPVEGDPPPLTMWTKDGRTIHSGWSRFRVLPQGLKVKQVEREDAGVYVCK 100

I I I I I I I l I I I I I l I I I l I I I M I I I I I I I I l I I I I I I I I I I I I l I I I I I

51 CPVEGDPPPLTMWTKDGRTIHSGWSRFRVLPQGLKVKQVEREDAGVYVCK 100

101 ATNGFGSLSVNYTLWLDDISPGKESLGPDSSSGGQEDPASQQWARPRFT 150

101 ATNGFGSLSVNYTLWLDDISPGKESLGPDSSSGGQEDPASQQWARPRFT 150 151 QPSKMRRRVIARPVGSSVRLKCVASGHPRPDITWMKDDQALTRPEAAEPR 200

151 QPSKMRRRVIARPVGSSVRLKCVASGHPRPDITWMKDDQALTRPEAAEPR 200

201 KKKWTLSLKNLRPEDSGKYTCRVSNRAGAINATYKVDVIQRTRSKPVLTG 250

251 THPVNTTVDFGGTTSFQCK 269

DESCRIPTION FOR CLUSTER HSMUClA

Cluster HSMUClA features 14 transcript(s) and 22 segment(s) of interest, the names for which are given in Tables 412 and 413, respectively, the sequences themselves are given at the end of the application. The selected protein variants are given in table 414.

Table 412 - Transcripts of interest

Table 414- Proteins of interest

These sequences are variants of the known protein Mucin 1 precursor (SwissProt accession identifier MUC1_HUMAN; known also according to the synonyms MUC-I; Polymorphic epithelial mucin; PEM; PEMT; Episialin; Tumor- associated mucin; Carcinoma- associated mucin; Tumor- associated epithelial membrane antigen; EMA; H23AG; Peanut- reactive urinary mucin; PUM; Breast carcinoma- associated antigen DF3; CD227 antigen), SEQ ID NO: 398, referred to herein as the previously known protein.

Protein Mucin 1 precursor is known or believed to have the following function(s): May play a role in adhesive functions and in cell-cell interactions, metastasis and signaling. May provide a protective layer on epithelial surfaces. Direct or indirect interaction with actin cytoskeleton;Isoform 7 behaves as a receptor and binds the secreted isoform 5. The binding induces the phosphorylation of the isoform 7, alters cellular morphology and initiates cell signaling. Can bind to GRB2 adapter protein. The sequence for protein Mucin 1 precursor is given at the end of the application, as "Mucin 1 precursor amino acid sequence". Known polymorphisms for this sequence are as shown in Table 415.

Table 415 -Amino acid mutations for Known Protein

Protein Mucin 1 precursor localization is believed to be Type I membrane protein. Two secreted forms (5 and 9) are also produced.

The previously known protein also has the following indication(s) and/or potential therapeutic use(s): Cancer, breast; Cancer, lung, non-small cell; Cancer, ovarian; Cancer, prostate; Cancer. It has been investigated for clinical/therapeutic use in humans, for example as a target for an antibody or small molecule, and/or as a direct therapeutic; available information related to these investigations is as follows. Potential pharmaceutically related or therapeutically related activity or activities of the previously known protein are as follows: CD8 agonist; DNA antagonist; Immunostimulant; Interferon gamma agonist; MUC-I inhibitor. A therapeutic role for a protein represented by the cluster has been predicted. The cluster was assigned this field because there was information in the drug database or the public databases (e.g., described herein above) that this protein, or part thereof, is used or can be used for a potential therapeutic indication: Anticancer; Monoclonal antibody, murine; Immunotoxin; Immunostimulant;

Immunoconjugate.

The following GO Annotation(s) apply to the previously known protein. The following annotation(s) were found: actin binding, which are annotation(s) related to Molecular Function; and cytoskeleton; integral plasma membrane protein, which are annotation(s) related to Cellular Component.

Cluster HSMUClA can be used as a diagnostic marker according to overexpression of transcripts of this cluster in cancer. Expression of such transcripts in normal tissues is also given according to the previously described methods. The term "number" in the left hand column of the table and the numbers on the y-axis of Figure 17 refer to weighted expression of ESTs in each category, as "parts per million" (ratio of the expression of ESTs for a particular cluster to the expression of all ESTs in that category, according to parts per million).

Overall, the following results were obtained as shown with regard to the histograms in Figure 17 and Table 416. This cluster is overexpressed (at least at a minimum level) in the following pathological conditions: a mixture of malignant tumors from different tissues, breast malignant tumors, pancreas carcinoma and prostate cancer.

Table 416 - Normal tissue distribution

Table All - P values and ratios for expression in cancerous tissue

As noted above, cluster HSMUClA features 14 transcript(s), which were listed in Table 1 above. These transcript(s) encode for protein(s) which are variant(s) of protein Mucin 1 precursor. A description of each variant protein according to the present invention is now provided.

Variant protein HSMUCl A_PEA_1_P25 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s)

HSMUC1A_PEA_1_T26. The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from

SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide.

Variant protein HSMUC 1A_PEA_1_P25 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 418, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA_1_P25 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 418- Amino acid mutations

Variant protein HSMUC1A_PEA_1_P25 is encoded by the following transcript(s): HSMUCl A_PEA_1_T26, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1A_PEA_1_T26 is shown in bold; this coding portion starts at position 507 and ends at position 1115. The transcript also has the following SNPs as listed in Table 419 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUCl A_PEA_1_P25 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 419 - Nucleic acid SNPs

Variant protein HSMUCl A_PEA_1_P29 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA_1_T33. The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans-membrane region prediction program predicts that this protein has a trans -membrane region.

Variant protein HSMUC 1A_PEA_1_P29 is encoded by the following transcript(s): HSMUC1A_PEA_1_T33, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1A_PEA_1_T33 is shown in bold; this coding portion starts at position 507 and ends at position 953. The transcript also has the following SNPs as listed in Table 420 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUCl A_PEA_1_P29 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 420 - Nucleic acid SNPs

Variant protein HSMUC1A_PEA_1_P3O according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1AJPEA_1_T34. The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signatpeptide prediction programs predict that this protein has a signal peptide.

Variant protein HSMUClA_PEA_l_P30 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 421, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUClA_PEA_l_P30 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 421 -Amino acid mutations

Variant protein HSMUClA_PEA_l_P30 is encoded by the following transcript(s): HSMUC1A_PEA_1_T34, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUCl A_PEA_1_T34 is shown in bold; this coding portion starts at position 507 and ends at position 1004. The transcript also has the following SNPs as listed in Table 422 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC 1A_PEA_1_P3O sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table All - Nucleic acid SNPs

Variant protein HSMUCl A_PEA_1_P32 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA_1_T36. The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict mat this protein has a signal peptide.

Variant protein HSMUCl A_PEA_1_P32 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 423, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA_1_P32 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 423 - Amino acid mutations

Variant protein HSMUC1A_PEA_1_P32 is encoded by the following transcript(s): HSMUCl A_PEA_1_T36, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUCl A_PEA_1_T36 is shown in bold; this coding portion starts at position 507 and ends at position 977. The transcript also has the following SNPs as listed in Table 424 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUCl A_PEA_1_P32 sequence provides support for the deduced sequence of this variant protein according to the present invention). ,

Table 424 - Nucleic acid SNPs

Variant protein HSMUC1A_PEA_1_P36 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA_1_T4O. The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans- membrane region prediction program predicts that this protein has a trans -membrane region.

Variant protein HSMUC1A_PEA_1_P36 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 425, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA_1_P36 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 425 - Amino acid mutations

Variant protein HSMUC1A_PEA_1_P36 is encoded by the following transcripts): HSMUC1A_PEA_1_T4O, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC 1A_PEA_1_T4O is shown in bold; this coding portion starts at position 507 and ends at position 983. The transcript also has the following SNPs as listed in Table 426 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA_1_P36 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 426 - Nucleic acid SNPs

Variant protein HSMUC1A_PEA_1_P39 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC 1A_PEA_1_T43. The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans- membrane region prediction program predicts that this protein has a trans -membrane region. Variant protein HSMUC1A_PEA_1_P39 also has the following non-silent SNPs (Single

Nucleotide Polymorphisms) as listed in Table 427, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA_1_P39 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 427 -Amino acid mutations

Variant protein HSMUC1A_PEA_1_P39 is encoded by the following transcript(s): HSMUC1A_PEA_1_T43, for which the sequence(s) is/are given at the end of the application.

The coding portion of transcript HSMUC 1A_PEA_1_T43 is shown in bold; this coding portion starts at position 507 and ends at position 914. The transcript also has the following SNPs as listed in Table 428 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA_1_P39 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 428 - Nucleic acid SNPs

Variant protein HSMUC1A_PEA_1_P45 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA_1_T29. The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans- membrane region prediction program predicts that this protein has a trans -membrane region.

Variant protein HSMUC1A_PEA_1_P45 is encoded by the following transcript(s): HSMUC 1A_PEA_1_T29, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1A_PEA_1_T29 is shown in bold; this coding portion starts at position 507 and ends at position 746. The transcript also has the following SNPs as listed in Table 429 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUCl A_PEA_1_P45 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 429 - Nucleic acid SNPs

Variant protein HSMUCl A_PEA_1_P49 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA_1_T12. The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans- membrane region prediction program predicts that this protein has a trans -membrane region.

Variant protein HSMUC1A_PEA_1_P49 is encoded by the following transcript(s):

HSMUC1A_PEA_1_T12, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1AJPEA_1_T12 is shown in bold; this coding portion starts at position 507 and ends at position 884. The transcript also has the following SNPs as listed in Table 430 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC 1A PEA 1JP49 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 430 - Nucleic acid SNPs

Variant protein HSMUC1A_PEA_1_P52 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUClA_PEA_l_T30. The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans- membrane region prediction program predicts that this protein has a trans -membrane region.

Variant protein HSMUC1A_PEA_1_P52 is encoded by the following transcript(s): HSMUC 1A_PEA_1_T3O, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1A_PEA_1_T3O is shown in bold; this coding portion starts at position 507 and ends at position 719. The transcript also has the following SNPs as listed in Table 431 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA_1_P52 sequence provides support for the deduced sequence of this variant protein according to the present invention). Table 431 - Nucleic acid SNPs

Variant protein HSMUC1A_PEA_1_P53 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA_1_T31. The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans- membrane region prediction program predicts that this protein has a trans -membrane region.

Variant protein HSMUC 1A_PEA_1_P53 is encoded by the following transcript(s): HSMUC1A_PEA_1_T31, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUCl A_PEA_1_T31 is shown in bold; this coding portion starts at position 507 and ends at position 665. The transcript also has the following SNPs as listed in Table 432 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUCl A_PEA_1_P53 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 432 - Nucleic acid SNPs

Variant protein HSMUC1A_PEA_1_P56 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA_1_T42. The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans- membrane region prediction program predicts that this protein has a trans -membrane region.

Variant protein HSMUC 1A_PEA_1_P56 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 433, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA_1_P56 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 433 - Amino acid mutations

Variant protein HSMUC1A_PEA_1_P56 is encoded by the following transcript(s): HSMUCl A_PEA_1_T42, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUCl A_PEA_1_T42 is shown in bold; this coding portion starts at position 507 and ends at position 890. The transcript also has the following SNPs as listed in Table 434 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUCl A_PEA_1_P56 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 434 - Nucleic acid SNPs

Variant protein HSMUC1A_PEA_1_P58 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC1A_PEA_1_T35. The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signal-peptide prediction programs predict that this protein has a signal peptide, and neither trans- membrane region prediction program predicts that this protein has a trans-membrane region.

Variant protein HSMUC1A_PEA_1_P58 also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 435, (given according to their position(s) on the amino acid sequence, with the alternative amino acid(s) listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC1A_PEA_1_P58 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 435 -Amino acid mutations

Variant protein HSMUC1A_PEA_1_P58 is encoded by the following transcripts): HSMUCl A_PEA_1_T35, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUCl A_PEA_1_T35 is shown in bold; this coding portion starts at position 507 and ends at position 980. The transcript also has the following SNPs as listed in Table 436 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC 1A_PEA_1_P58 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 436 - Nucleic acid SNPs

Variant protein HSMUC1A_PEA_1_P59 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC 1A_PEA_1_T28. The location of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: secreted. The protein localization is believed to be secreted because both signalr-peptide prediction programs predict that this protein has a signal peptide, and neither trans- membrane region prediction program predicts that this protein has a trans -membrane region.

Variant protein HSMUC1A_PEA_1_P59 is encoded by the following transcript(s): HSMUC1A_PEA_1_T28, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUC1A_PEA_1_T28 is shown in bold; this coding portion starts at position 507 and ends at position 794. The transcript also has the following SNPs as listed in Table 437 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUC 1A_PEA_1_P59 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 437 - Nucleic acid SNPs

Variant protein HSMUC1A_PEA_1_P63 according to the present invention has an amino acid sequence as given at the end of the application; it is encoded by transcript(s) HSMUC 1A_PEA_1_T47. An alignment is given to the known protein (Mucin 1 precursor) at the end of the application. One or more alignments to one or more previously published protein sequences are given at the end of the application. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows:

Comparison report between HSMUC 1A_PEA_1_P63 and MUCIJHUMAN: 1.An isolated chimeric polypeptide encoding for HSMUCl A PEA 1 P63, comprising a first amino acid sequence being at least 90 % homologous to MTPGTQSPFFLLLLLTVLTWTGSGHASSTPGGEKETSATQRSSV corresponding to amino acids 1 - 45 of MUC1_HUMAN, which also corresponds to amino acids 1 - 45 of HSMUC 1A_PEA_1_P63, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence

EEEVSADQVSVGASGVLGSFKEARNAPSFLSWSFSMGPSK corresponding to amino acids 46 - 85 of HSMUC1A_PEA_1_P63, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.

2.An isolated polypeptide encoding for a tail of HSMUC 1A_PEA_1_P63, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence EEEVSADQVSVGASGVLGSFKEARNAPSFLSWSFSMGPSK in HSMUC1A_PEA_1_P63.

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

The glycosylation sites of variant protein HSMUCl A_PEA_1_P63, as compared to the known protein Mucin 1 precursor, are described in Table 438 (given according to their position(s) on the amino acid sequence in the first column; the second column indicates whether the glycosylation site is present in the variant protein; and the last column indicates whether the position is different on the variant protein).

Table 438 - Glycosylation site(s)

Variant protein HSMUC 1AJPEA_1_P63 is encoded by the following transcript(s): HSMUCl A_PEA_1_T47, for which the sequence(s) is/are given at the end of the application. The coding portion of transcript HSMUCl A_PEA_1_T47 is shown in bold; this coding portion starts at position 507 and ends at position 761. The transcript also has the following SNPs as listed in Table 439 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed; the last column indicates whether the SNP is known or not; the presence of known SNPs in variant protein HSMUCl A_PEA_1_P63 sequence provides support for the deduced sequence of this variant protein according to the present invention).

Table 439 - Nucleic acid SNPs

As noted above, cluster HSMUClA features 22 segment(s), which were listed in Table 2 above and for which the sequence(s) are given at the end of the application. These segment(s) are portions of nucleic acid sequence(s) which are described herein separately because they are of particular interest. A description of each segment according to the present invention is now provided.

Segment cluster HSMUC lA_PEA_l_node_0 according to the present invention is supported by 31 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA_1_T12, HSMUC1A_PEA_1_T26, HSMUC1A_PEA_1_T28, HSMUC1A_PEA_1_T29,

HSMUC1A_PEA_1_T3O, HSMUCl A_PEA_1_T31, HSMUCl A_PEA_1_T33,

HSMUC 1A_PEA_1_T34, HSMUCl A_PEA_1_T35, HSMUCl A_PEA_1_T36,

HSMUC1A_PEA_1_T4O, HSMUC1A_PEA_1_T42, HSMUC1A_PEA_1_T43 and HSMUC1A_PEA_1_T47. Table 440 below describes the starting and ending position of this segment on each transcript.

Table 440 - Segment location on transcripts

Segment cluster HSMUClA_PEA_l_node_14 according to the present invention is supported by 55 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC 1A_PEA_1_T12. Table 441 below describes the starting and ending position of this segment on each transcript.

Table 441 - Segment location on transcripts

Segment cluster HSMUC lA_PEA_l_node_24 according to the present invention is supported by 135 libraries. The number of libraries was determined as previously described. This segment can be found in the fellowing transcript(s): HSMUC1AJPEA_1_T12. Table 442 below describes the starting and ending position of this segment on each transcript.

Table 442 - Segment location on transcripts

Segment cluster HSMUClA_PEA_l_node_29 according to the present invention is supported by 156 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA_1_T12, HSMUC1A_PEA_1_T26, HSMUC1A_PEA_1_T28, HSMUC1A_PEA_1_T29,

HSMUCl A_PEA_l_T30, HSMUCl A_PEA_1_T31, HSMUCl A_PEA_1_T33,

HSMUC1A_PEA_1_T34, HSMUC1A_PEA_1_T35, HSMUC1A_PEA_1_T36,

HSMUC1A_PEA_1_T4O, HSMUC1A_PEA_1_T42 and HSMUC1A_PEA_1_T43. Table 443 below describes the starting and ending position of this segment on each transcript.

Table 443 - Segment location on transcripts

Segment cluster HSMUClA_PEA_l_node_35 according to the present invention is supported by 51 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA_1_T47. Table 444 below describes the starting and ending position of this segment on each transcript. Table 444 - Segment location on transcripts

Segment cluster HSMUClA_PEA_l_node_38 according to the present invention is supported by 140 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA_1_T12, HSMUC1A_PEA_1_T26, HSMUC1AJPEA_1_T28, HSMUC1A_PEA_1_T29,

HSMUClA_PEA_l_T30, HSMUC1A_PEA_1_T31, HSMUCl A_PEA_1_T33,

HSMUC1A_PEA_1_T34, HSMUC1A_PEA_ 1_T35, HSMUC1A_PEA_1_T36,

HSMUC1A_PEAJ_T4O, HSMUC1A_PEA_1_T42, HSMUC 1A_PEA_1_T43 and HSMUC1A_PEA_1_T47. Table 446 below describes the starting and ending position of this segment on each transcript.

Table 446 - Segment location on transcripts

Segment cluster HSMUClA_PEA_l_node_3 according to the present invention is supported by 17 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA_1_T29, HSMUC1A_PEA_1_T34, HSMUC1A_PEA_1_T4O and HSMUC 1A_PEA_1_T43. Table 447 below describes the starting and ending position of this segment on each transcript. Table 447 - Segment location on transcripts

Segment cluster HSMUC lA_PEA_l_node_4 according to the present invention can be found in the following transcript(s): HSMUC1A_PEA__1_T12, HSMUC1A_PEA_1_T26, HSMUC 1A_PEA_1_T28, HSMUC 1A_PEA_1_T29, HSMUClA_PEA_l_T30,

HSMUC1A_PEA_1_T31, HSMUC1A_PEA_1_T33, HSMUC 1A_PEA_1_T34,

HSMUC1A_PEA_1_T35, HSMUC1A_PEA_1_T36, HSMUC 1A_PEA_1_T4O,

HSMUC1A_PEA_1_T42, HSMUC 1A_PEA_1_T43 and HSMUC 1A_PEA_1_T47. Table 448 below describes the starting and ending position of this segment on each transcript. Table 448 - Segment location on transcripts

Segment cluster HSMUC lA_PEA_l_node_5 according to the present invention is supported by 34 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA_1_T12, HSMUC1A_PEA_1_T26, HSMUC1A_PEA_1_T28, HSMUC1A_PEA_1_T29,

HSMUClA_PEA_l_T30, HSMUCl A_PEA_1_T31, HSMUC1A_PEA_1_T33,

HSMUCl A_PEA_1_T34, HSMUCl A_PEA_1_T35, HSMUC 1A_PEA_1_T36,

HSMUC1A_PEA_1_T4O, HSMUC 1A_PEA_1_T42, HSMUC1A_PEA_1_T43 and HSMUC1A_PEA_1_T47. Table 449 below describes the starting and ending position of this segment on each transcript.

Table 449 - Segment location on transcripts

Segment cluster HSMUClA_PEA_l_node_6 according to the present invention is supported by 35 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA_1_T12,

HSMUC1A_PEA_1_T26, HSMUC1A_PEA_1_T28, HSMUC1A_PEA_1_T29,

HSMUCl A_PEA_l_T30, HSMUC1A_PEA_1_T31, HSMUCl A_PEA_1_T33,

HSMUC1A_PEA_1_T34, HSMUC1A_PEA_1_T35, HSMUC1A_PEA_1_T36,

HSMUC1A_PEA_1_T4O, HSMUC1A_PEA_1_T42, HSMUC1A_PEA_1_T43 and HSMUC1A_PEA_1_T47. Table 450 below describes the starting and ending position of this segment on each transcript.

Table 450 - Segment location on transcripts

Segment cluster HSMUC 1A_PEA_1 node_7 according to the present invention is supported by 32 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA_1_T12, HSMUC1A_PEA_1_T26, HSMUC1A_PEA_1_T28, HSMUC1A_PEA_1_T29,

HSMUC1A_PEA_1_T3O, HSMUCl A_PEA_1_T31, HSMUC1A_PEA_1_T33,

HSMUC1A_PEA_1_T34, HSMUC1A_PEA_1_T35, HSMUC1A_PEA_1_T36,

HSMUC 1A_PEA_1_T4O, HSMUC 1A_PEA_1_T42 and HSMUC1A_PEA_1_T43. Table 451 below describes the starting and ending position of this segment on each transcript. Table 451 - Segment location on transcripts

Segment cluster HSMUClA_PEA_l_node_17 according to the present invention can be found in the following transcript(s): HSMUC 1A_PEA_1_T28, HSMUC1A_PEA_1_T33 and HSMUC1A_PEA_1_T4O. Table 452 below describes the starting and ending position of this segment on each transcript.

Table 452 - Segment location on transcripts

Segment cluster HSMUCl A_PEA_l_node_l 8 according to the present invention is supported by 90 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1AJPEA_1_T12,

HSMUC1A_PEA_1_T26, HSMUC1A_PEA_1_T28, HSMUC1A_PEA_1_T29,

HSMUClA_PEA_l__T30, HSMUC1A_PEA_1_T33, HSMUCl AJPE A_1_T35, HSMUC1A_PEA_1_T4O and HSMUC1A_PEA_1_T42. Table 453 below describes the starting and ending position of this segment on each transcript.

Table 453 - Segment location on transcripts

Segment cluster HSMUC lA_PEA_l_node_20 according to the present invention can be found in the following transcript(s): HSMUC1A_PEA_1_T12, HSMUC1A_PEA_1_T26, HSMUC1A_PEA_1_T28, HSMUC1A_PEA_1_T33, HSMUC1A_PEA_1_T35 and HSMUC1A_PEA_1_T42. Table 454 below describes the starting and ending position of this segment on each transcript.

Table 454 - Segment location on transcripts

Segment cluster HSMUCl A_PEA_ljtiode_21 according to the present invention is supported by 97 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA_1_T12, HSMUC1A_PEA_1_T26, HSMUC1AJPEA_1_T28, HSMUC1A_PEA_1_T33,

HSMUC1A_PEA_1_T35 and HSMUC 1A_PEA_1_T42. Table 455 below describes the starting and ending position of this segment on each transcript.

Table 455 - Segment location on transcripts

Segment cluster HSMUC lA_PEA_l_node_23 according to the present invention can be found in the following transcript(s): HSMUC1A_PEA_1_T12. Table 456 below describes the starting and ending position of this segment on each transcript. Table 456 - Segment location on transcripts

Segment cluster HSMUC lA_PEA_l_node_26 according to the present invention is supported by 129 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA_1_T12, HSMUC1A_PEA_1_T26, HSMUC1A_PEA_1_T28, HSMUC1A_PEA_1_T29,

HSMUCl A_PEA_l_T30 and HSMUC1A_PEA_1_T31. Table 457 below describes the starting and ending position of this segment on each transcript.

Table 457 - Segment location on transcripts

Segment cluster HSMUClA_PEA_l_node_27 according to the present invention is supported by 140 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA_1_T12, HSMUC1A_PEA_1_T26, HSMUC1A_PEA_1_T28, HSMUC1A_PEA_1_T29,

HSMUC 1A_PEA_1_T3O, HSMUC 1A_PEA_1_T31, HSMUC1A_PEA_1_T33, HSMUCl A_PEA_1_T34, HSMUCl A_PEA_1_T35 and HSMUC1A_PEA_1_T36. Table 458 below describes the starting and ending position of this segment on each transcript.

Table 458- Segment location on transcripts

Segment cluster HSMUCl A_PEA_l_node_31 according to the present invention can be found in the following transcript(s): HSMUC1A_PEA_1_T12, HSMUC1A_PEA_1_T26, HSMUC1A_PEA_1_T28, HSMUC 1A_PEA_1_T29, HSMUC1A_PEA_1_T3O,

HSMUC1A_PEA_1_T31, HSMUC1A_PEA_1_T33, HSMUC1A_PEA_1_T34,

HSMUC1A_PEA_1_T35, HSMUC1A_PEA_1_T36, HSMUC 1A_PEA_1_T4O,

HSMUC1A_PEA_1_T42 and HSMUC 1A_PEA_1_T43. Table 459 below describes the starting and ending position of this segment on each transcript. Table 459 - Segment location on transcripts

Segment cluster HSMUC lA_PEA_l_node_34 according to the present invention is supported by 24 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA_1_T47. Table 460 below describes the starting and ending position of this segment on each transcript.

Table 460 - Segment location on transcripts

Segment cluster HSMUClA_PEA_l_node_36 according to the present invention is supported by 135 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA_1_T12, HSMUC1A_PEA_1_T26, HSMUC1A_PEA_1_T28, HSMUC1A_PEA_1_T29,

HSMUClA_PEA_l_T30, HSMUC1A_PEA_1_T31, HSMUC1A_PEA_1_T33, HSMUC1A_PEA_1_T34, HSMUC1A_PEA_1_T35, HSMUC1A_PEA_1_T36,

HSMUC1A_PEA_1_T4O, HSMUC1A_PEA_1_T42, HSMUC1A_PEA_1_T43 and HSMUC1A_PEA_1_T47. Table 461 below describes the starting and ending position of this segment on each transcript.

Table 461- Segment location on transcripts

Segment cluster HSMUClA_PEA_ljtiode_37 according to the present invention is supported by 146 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcript(s): HSMUC1A_PEA_1_T12,

HSMUC1A_PEA_1_T26, HSMUC1A_PEA_1_T28, HSMUC1A_PEA_1_T29,

HSMUClA_PEA_l_T30, HSMUC1A_PEA_1_T31, HSMUC1A_PEA_1_T33,

HSMUC1A_PEA_1_T34, HSMUC1A_PEA_1_T35, HSMUC 1A_PEA_1_T36,

HSMUC1A_PEA_1_T4O, HSMUC 1A_PEA_1_T42, HSMUC1A_PEA_1_T43 and HSMUC1A_PEA_1_T47. Table 462 below describes the starting and ending position of this segment on each transcript.

Table 462- Segment location on transcripts

Variant protein alignment to the previously known protein:

Sequence name: MUC1_HUMAN

Sequence documentation:

Alignment of: HSMUC1A_PEA_1_P63 x MUC1JHUMAN

Alignment segment 1/1:

Quality: 429.00 Escore: 0

Matching length: 59 Total length: 59

Matching Percent Similarity: 86.44 Matching Percent Identity: 81.36 Total Percent Similarity: 86.44 Total Percent Identity: 81.36 Gaps : 0

Alignment:

1 MTPGTQSPFFLLLLLTVLTWTGSGHASSTPGGEKETSATQRSSVEEEVS 50

M I M I I I M I M I I I I I I I I I I I M M I I I I M I I I M I I I I M

1 MTPGTQSPFFLLLLLTVLTWTGSGHASSTPGGEKETSATQRSSVPSSTE 50

51 ADQVSVGAS 59 : Il : : I

51 KNAVSMTSS 59

Expression of AA315457 transcripts which are detectable by SEQ ID NO:413 in normal, benign and cancerous prostate tissues Expression of AA315457 transcripts detectable by SEQ ID NO:413 (e.g., variant no.1

SEQ ID NO: 415) was measured by real time PCR. AA315457 is a non- limiting example of a marker according to the present invention. In parallel the expression of four housekeeping genes - PBGD (GenBank Accession No. BCOl 9323; amplicon - SEQ ID NO:404), HPRTl (GenBank Accession No. NM_000194; amplicon - SEQ ID NO: 402), RPL19 (GenBank Accession No. NM_000981; amplicon - SEQ ID NO:410) and SDHA (GenBank Accession No. NM_004168; amplicon - SEQ ID NO:407), was measured similarly. For each RT sample, the expression of SEQ ID NO:413 was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal post-mortem (PM) samples (Sample Nos.42, 48-53, 59-63, Table 2, above), to obtain a value of fold up -regulation for each sample relative to median of the normal PM samples. Figures 18A and 18B are histograms showing over expression of the above- indicated AA315457 transcripts in cancerous and benign (BPH) prostate samples relative to the normal samples. The number and percentage of cancer samples that exhibit at least 3 fold over- expression, out of the total number of samples tested is indicated in the bottom. As is evident from Figures 18A and 18B, the expression of AA315457 transcripts detectable by SEQ ID NO:413 in cancer samples was significantly higher than in the non¬ cancerous samples (Sample Nos. 33-35, 43-47- BPH samples, 40-41 - normal matched samples and 42, 48-53, 59-63 - normal post mortem samples, Table 2). Notably an over- expression of at least 3 fold was found in 9 out of 19 adenocarcinoma samples. However, when an additional duplicate experiment was performed, the expression of SEQ ID NO:413 was weaker so just 5 out of 19 cancer samples showed overexpression of at least 3 fold, as shown with regard to Figure 18B.

Statistical analysis was applied to verify the significance of these results, as described below. The P value for the difference in the expression levels of AA315457 transcripts detectable by SEQ ID NO:413 in prostate cancer samples versus the normal prostate samples was determined by T test as 7.33E-02.

Threshold of 3 fold overexpression was found to differentiate between cancer and normal samples with P value of 4.58E-03 as checked by exact fisher test.

The P value for the difference between the expression levels of AA315457 transcripts detectable by SEQ ID NO:413 in the prostate cancer samples versus the BPH prostate samples was determined by T test as 8.04E-02.

Threshold of 3 fold overexpression was found to differentiate between cancer and BPH sample with P value of 1.97E-02 as checked by exact fisher test.

The P value for the difference between the expression levels of AA315457 transcripts detectable by SEQ ID NO:413 in the prostate cancer samples versus the BPH and normal prostate samples was determined by T test as 7.60E-02. Threshold of 3 fold overexpression was found to differentiate between cancer sample and BPH and normal sample with P value of 4.36E-04 as checked by exact fisher test. All the above values demonstrate statistical significance of the results.

According to the present invention, AA315457 is a non- limiting example of a marker for diagnosing prostate cancer. The AA315457 marker of the present invention can be used alone or in combination, for various uses, including but not limited to, prognosis, prediction, screening, early diagnosis, therapy selection and treatment monitoring of prostate cancer. Although optionally any method may be used to detect overexpression and/or differential expression of this marker, preferably a NAT-based technology is used. Therefore, optionally and preferably, any nucleic acid molecule capable of selectively hybridizing to AA315457 as previously defined is also encompassed within the present invention. Primer pairs are also optionally and preferably encompassed within the present invention; for example, for the above experiment, the following primer pair was used as a non- limiting illustrative example only of a suitable primer pair: AA315457- forward primer (SEQ ID NO: 411): CATGGACCCCAGGCAAGTC; and AA315457-Reverse primer (SEQ ID NO: 412): CTGTTTAGGGTCGAGGCTGTG.

The present invention also preferably encompasses any amplicon obtained through the use of any suitable primer pair; for example, for the above experiment, the following amplicon was obtained as a non- limiting illustrative example only of a suitable amplicon: AA315457 amplicon (SEQ ID NO: 413):

CATGGACCCCAGGCAAGTCCCCCCACCCACGCATTTCTAATCATCTGCCCTG GTTTTGCCTCCTGAGTCTGTTAAGGCTGTGTGCCCCTCATCGAGGCCCGTCACAGCC TCGACCCTAAACAG.

According to other preferred embodiments of the present invention, AA315457 or a fragment thereof comprises a biomarker for detecting prostate cancer. Optionally and more preferably, the fragment of AA315457 comprises AA315457_segment_8 (SEQ ID NO: 414). Also optionally and more preferably, any suitable method may be used for detecting a fragment such as AA315457_segment_8 for example. Most preferably, NAT-based technology used, such as any nucleic acid molecule capable of specifically hybridizing with the fragment. Optionally and most preferably, a primer pair is used for obtaining the fragment.

According to still other preferred embodiments, the present invention optionally and preferably encompasses any amino acid sequence or fragment thereof encoded by a nucleic acid sequence corresponding to AA315457 as described above, including but not limited to SEQ ID NOs: 414 and 415. Any oligopeptide or peptide relating to such an amino acid sequence or fragment thereof may optionally also (additionally or alternatively) be used as a biomarker. The present invention also optionally encompasses antibodies capable of recognizing, and/or being elicited by, such an oligopeptide or peptide.

The present invention also optionally and preferably encompasses any nucleic acid sequence or fragment thereof, or amino acid sequence or fragment thereof, corresponding to AA315457 as described above, optionally for any application.

Expression ofThrombospondin 1 (THBSl) transcripts which are detectable by SEQID NO:421 in normal, benign and cancerous prostate tissues

Expression of Thrombospondin 1 (THBSl) transcripts detectable by SEQ ID NO:421, segment 24 (e.g., variants no. 10,11 and 30; SEQ ID NOs: 441, 442, and 451) was measured by real time PCR, according to the exemplary marker HUMTHROM- segment 24 (SEQ ID NO:425) . In parallel the expression of four housekeeping genes - PBGD (GenBank Accession No. BC019323; amplicon - SEQ ID NO:404), HPRTl (GenBank Accession No. NM_000194; amplicon - SEQ ID NO:401), RPL19 (GenBank Accession No. NM_000981 ; amplicon - SEQ ID NO:410) and SDHA (GenBank Accession No. NM_004168; amplicon - SEQ ID NO:407), was measured similarly. For each RT sample, the expression of SEQ ID NO:421 was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal post-mortem (PM) samples (Sample Nos. 42, 48-53, 59-63, Table 2, above), to obtain a value of fold up- regulation for each sample relative to median of the normal PM samples.

Figure 19 is a histogram showing over expression of the above -indicated Thrombospondin 1 (THBSl) transcripts in cancerous and benign (BPH) prostate samples relative to the normal samples. The number and percentage of cancer samples that exhibit at least 3 fold over- expression, out of the total number of samples tested is indicated in the bottom. As is evident from Figure 19, the expression of Thrombospondin 1 (THBSl) transcripts detectable by SEQ ID NO:421 in cancer samples was significantly higher than in the normal PM samples (Sample Nos. 42, 48-53, 59-63, Table 2). Notably an over-expression of at least 3 fold was found in 10 out of 19 adenocarcinoma samples. Over expression of at least 3 fold was observed also in 7 out of the 8 BPH samples, and in the 2 matched normal samples. Since matched samples are histologically non-cancerous tissue that surrounds the tumor, such samples could have been contaminated with cancer or pre-cancer cells.

Statistical analysis was applied to verify the significance of these results, as described below. The P value for the difference in the expression levels of Thrombospondin 1 (THBSl) transcripts detectable by SEQ ID NO:421 in prostate cancer samples versus the normal prostate samples was determined by T test as 9.92E-03.

Threshold of 3 fold overexpression was found to differentiate between cancer and normal samples with P value of 2.08E-03 as checked by exact fisher test. The above value demonstrates statistical significance of the results.

According to the present invention, HUMTHROM is a non- limiting example of a marker for diagnosing prostate cancer. The HUMTHROM marker of the present invention, can be used alone or in combination, for prognosis, prediction, screening, early diagnosis, therapy selection and treatment monitoring of prostate cancer. Although optionally any method may be used to detect overexpression and/or differential expression of this marker, preferably a NAT-based technology is used. Therefore, optionally and preferably, any nucleic acid molecule capable of selectively hybridizing to HUMTHROM as previously defined is also encompassed within the present invention. Primer pairs are also optionally and preferably encompassed within the present invention; for example, for the above experiment, the following primer pair was used as a non- limiting illustrative example only of a suitable primer pair: HUMTHROM- seg24- forward (SEQ ID NO:419): CTGCAGGCTCAGCAACTTCTT; and HUMTHROM- seg24-reverse (SEQ ID NO:420): TTTCAAATCCCTCCCTTGTCA.

The present invention also preferably encompasses any amplicon obtained through the use of any suitable primer pair; for example, for the above experiment, the following amplicon was obtained as a non- limiting illustrative example only of a suitable amplicon: Amplicon from seg 24: CTGCAGGCTCAGCAACTTCTTTTAATGAAAAACAAACTCACCCTCTTCCCCA GCATTCTTTCCATGTGTCAGAGAAGCAGAGGTTTCTTGAACGGGCTTAGGAGAGTCT ATGACAAGGGAGGGATTTGAAA.

According to other preferred embodiments of the present invention, HUMTHROM or a fragment thereof comprises a biomarker for detecting prostate cancer. Optionally and more preferably, the fragment of HUMTHROM comprises HUMTHROM- seg24 (SEQ ID NO:425).

Also optionally and more preferably, any suitable method may be used for detecting a fragment such as HUMTHROM- seg24 for example. Most preferably, NAT-based technology used, such as any nucleic acid molecule capable of specifically hybridizing with the fragment. Optionally and most preferably, a primer pair is used for obtaining the fragment.

Optionally the HUMTHROM transcript could (additionally or alternatively) comprise any one or more of the following sequences: SEQ ID NOs : 435-440; 443-445; 447-450. .

According to still other preferred embodiments, the present invention optionally and preferably encompasses any amino acid sequence or fragment thereof encoded by a nucleic acid sequence corresponding to HUMTHROM as described above or below. Any oligopeptide or peptide relating to such an amino acid sequence or fragment thereof may optionally also (additionally or alternatively) be used as a biomarker. The present invention also optionally encompasses antibodies capable of recognizing, and/or being elicited by, such an oligopeptide or peptide. Also, optionally and preferably HUMTHROM could be detected by detection of an amino acid sequence according to any of SEQ ID NOs 452-463, for which the unique regions relating to the splice variants are given separately and additionally in SEQ ID NOs 464-472. The present invention also encompasses these amino acid sequences as a biomarker for detecting prostate cancer. The present invention also optionally and preferably encompasses any nucleic acid sequence or fragment thereof, or amino acid sequence or fragment thereof, corresponding to HUMTHROM as described above or below, optionally for any application. Expression ofThrombospondin 1 (THBSl) transcripts which are detectable by SEQID NO:418 in normal, benign and cancerous prostate tissues

Expression of Thrombospondin 1 (THBSl) transcripts detectable by SEQ ID NO:418, segment 19 (e.g., variant no. 18; SEQ ID NO: 446) was measured by real time PCR, according to the exemplary, illustrative marker HUMTHROM-segment 19 (SEQ ID NO: 423). In parallel the expression of four housekeeping genes - PBGD (GenBank Accession No. BC019323; amplicon - SEQ ID NO:404), HPRTl (GenBank Accession No. NM_OOO194; amplicon - SEQ ID NO:401), RPL19 (GenBank Accession No. NM_000981; amplicon - SEQ ID NO:410) and SDHA (GenBank Accession No. NM_004168; amplicon - SEQ ID NO:407), was measured similarly. For each RT sample, the expression of SEQ ID NO:418 was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal post-mortem (PM) samples (Sample Nos. 42, 48-53, 59-63, Table 2, above), to obtain a value of fold up-regulation for each sample relative to median of the normal PM samples.

Figure 20 is a histogram showing over expression of the above -indicated Thrombospondin 1 (THBSl) transcripts in cancerous and benign (BPH) prostate samples relative to the normal samples. The number and percentage of cancer samples that exhibit at least 3 fold over- expression, out of the total number of samples tested is indicated in the bottom. As is evident from Figure 20, the expression of Thrombospondin 1 (THBSl) transcripts detectable by SEQ ID NO: 418 in cancer samples was significantly higher than in the normal PM samples (Sample Nos. 42, 48-53, 59-63, Table 2). Notably an over- expression of at least 3 fold was found in 17 out of 19 adenocarcinoma samples. Over expression of at least 3 fold was observed also in 6 out of the 8 BPH samples, and in the 2 matched normal samples. Since matched samples are histologically non-cancerous tissue that surrounds the tumor, such samples could have been contaminated with cancer or pre-cancer cells. These samples were purchased commercially with the matching non-cancerous tissue samples, as described above.

Statistical analysis was applied to verify the significance of these results, as described below. The P value for the difference in the expression levels of Thrombospondin 1 (THBSl) transcripts detectable by SEQ ID NO: 418 in prostate cancer samples versus the normal prostate samples was determined by T test as 1.17E-04.

Threshold of 3 fold overexpression was found to differentiate between cancer and normal samples with P value of 1.00E-05 as checked by exact fisher test.

The P value for the difference between the expression levels of Thrombospondin 1 (THBSl) transcripts detectable by SEQ ID NO: 418 in the prostate cancer samples versus the BPH and normal prostate samples was determined by T test as 7.36E-02. Threshold of 3 fold overexpression was found to differentiate between cancer sample and BPH and normal sample with P value of 5.42E- 04 as checked by exact fisher test. AU the above values demonstrate statistical significance of the results.

According to the present invention, HUMTHROM is a non- limiting example of a marker for diagnosing prostate cancer. Although optionally any method may be used to detect overexpression and/or differential expression of this marker, preferably a NAT-based technology is used. Therefore, optionally and preferably, any nucleic acid molecule capable of selectively hybridizing to HUMTHROM as previously defined is also encompassed within the present invention. Primer pairs are also optionally and preferably encompassed within the present invention; for example, for the above experiment, the following primer pair was used as a non- limiting illustrative example only of a suitable primer pair:HUMTHROM-segl 9- forward (SEQ ID NO:416): AAAGCATCCGATTACCCCACT andHUMTHROM-segl9-reverse (SEQ ID NO:417): CCGGCACAAAGTTGCAGTTA.

The present invention also preferably encompasses any amplicon obtained through the use of any suitable primer pair; for example, for the above experiment, the following amplicon was obtained as a non- limiting illustrative example only of a suitable amplicon: Amplicon from seg 19: AAAGGGCGAGGAGATGAATGTACGGTCTAGTTTTAGAAACGTGATTAGAAA ATCCATGGTAAATCCTGCAGGGGAAAAACAGTCTTCCATATTTAAAAATGCTGCTCT GGAATAAGTTGTGAGCAGATGGACTTGTAAACGCCTAGGTGCTGAGCA.

According to other preferred embodiments of the present invention, HUMTHROM or a fragment thereof comprises a biomarker for detecting prostate cancer. Optionally and more preferably, the fragment of HUMTHROM comprises HUMTHROM- seg 19 (SEQ ID NO: 423).

Also optionally and more preferably, any suitable method may be used for detecting a fragment such as HUMTHROM- seg 19 for example. Most preferably, NAT-based technology used, such as any nucleic acid molecule capable of specifically hybridizing with the fragment. Optionally and most preferably, a primer pair is used for obtaining the fragment.

Comparison of expression of 3 sequences (SEQ ID NO: 413, 418 and 421) in normal, benign and cancerous prostate tissues

Expression of transcripts detectable by SEQ ID NO: 413, 418 and 421 was measured by real time PCR (the expression of each SEQ ID was checked separately). These transcripts correspond to markers described with Examples above. In parallel the expression of four housekeeping genes - PBGD (GenBank Accession No. BCO 19323; amplicon - SEQ ID NO:404), HPRTl (GenBank Accession No. NM_000194; amplicon - SEQ ID NO:401), RPL19 (GenBank Accession No. NM_000981 ; amplicon - SEQ ID NO:410) and SDHA (GenBank Accession No. NM_004168; amplicon - SEQ ID NO:407), was measured similarly. For each RT sample, the expression was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal post-mortem (PM) samples (Sample Nos. 42, 48-53, 59- 63, Table 2, above), to obtain a value of fold up-regulation for each sample relative to median of the normal PM samples.

Figure 21 is a histogram showing over expression of the above- indicated transcripts in cancerous and benign (BPH) prostate samples relative to the normal samples. The number and percentage of cancer samples that exhibit at least 3 fold over- expression of at least one marker according to the present invention, out of the total number of samples tested, is indicated in the bottom.

As is evident from Figure 21, over- expression of at least 3 fold of at least one of the SEQ

ID NO: 413, 418 and 421 was found in 18 out of 19 adenocarcinoma samples taken from prostate tissue (almost all prostate cancers are adenocarcinomas). Overexpression of at least 3 fold of at least one marker according to the present invention was observed in 7 out of the 8

BPH samples, and in the 2 matched normal samples. Since matched samples are histologically non- cancerous tissue that surrounds the tumor, such samples could have been contaminated with cancer or pre- cancer cells. However, at least certain markers were shown to be capable of differentiating between BPH and prostate cancer, such as AA315457 for example.

Statistical analysis was applied to verify the significance of these results, as described below. Threshold of 3 fold overexpression of at least one of the amplicons as depicted in SEQ ID NO: 413, 418 and 421 was found to differentiate between cancer and normal samples with P value of 1.62E-06 as checked by exact fisher test.

Expression ofDD3/PCA3 transcript which are detectable by SEQ ID NO: 475 in normal, benign and cancerous prostate tissues Expression of DD3/PCA3 transcripts detectable by the amplicon of SEQ ID NO:475

(e.g., variant no. 0; SEQ ID NO: 476; SEQ ID NO:483 is the forward primer, SEQ ID NO:474 is the reverse primer), related to cluster AA578773, segments 1 and 6, was measured by real time PCR. In parallel the expression of four housekeeping genes - PBGD (GenBank Accession No. BC019323; amplicon - SEQ ID NO:404), HPRTl (GenBank Accession No. NM_000194; amplicon - SEQ ID NO:401), RPLl 9 (GenBank Accession No. NM_000981 ; amplicon - SEQ ID NO:410) and SDHA (GenBank Accession No. NM_004168; amplicon - SEQ ID NO:407), was measured similarly. For each RT sample, the expression was normalized to the geometric mean of the quantities of the housekeeping genes. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal post-mortem (PM) samples (Sample Nos. 42, 48-53, 59-63, Table 2, above), to obtain a value of fold up-regulation for each sample relative to median of the normal PM samples. Figure 22 is a histogram showing over expression of the above -indicated DD3/PCA3 transcripts in cancerous and benign (BPH) prostate samples relative to the normal samples. The number and percentage of cancer samples that exhibit at least 3 fold over- expression, out of the total number of samples tested is indicated in the bottom. As is evident from Figure 22, an over-expression of at least 3 fold was found in 12 out of

19 adenocarcinoma (prostate cancer) samples. Over expression of at least 3 fold was observed also in 4 out of the 12 normal PM samples.

Thus, clearly DD3 may optionally be used as a biomarker in combination with any previously described biomarker according to the present invention. The DD3 marker of the present invention, can be used alone or in combination, for prognosis, prediction, screening, early diagnosis, therapy selection and treatment monitoring of prostate cancer.

Expression ofThrombospondin 1 (THBSl) transcripts which are detectable by SEQIDs NOs:477-482 in normal, benign and cancerous prostate tissues

Expression ofThrombospondin 1 (THBSl) transcripts detectable by SEQ ID NOs: 477- 482 (e.g., variants nos. 4, 6, 8, 11, 14, 15, 26, 27, 28, 30 (SEQ ID No.: 435, 437, 439, 442, 444, 445, 448, 449, 450, 451) was measured with oligonucleotide-based micro-arrays. The results of image intensities for each feature were normalized according to the ninetieth percentile of the image intensities of all the features on the chip. Then, feature image intensities for replicates of the same oligonucleotide on the chip and replicates of the same sample were averaged. Outlying results were discarded.

For every oligonucleotide (SEQ ID NOs: 477-482) the averaged intensity determined for every sample was divided by the averaged intensity of all the normal samples (Sample Nos. 48- 52, Table 2, above), to obtain a value of fold up-regulation for each sample relative to the averaged normal samples. These data are presented in a histogram in Figure 23. As is evident from Figure 23, the expression of Thrombospondin 1 (THBSl) transcripts detectable with oligonucleotides according to SEQ ID NOs: 477-482 in cancer samples was significantly higher than in the normal samples.

According to the present invention, Thrombospondin 1 (THBSl) transcripts detectable by oligonucleotides as depicted in SEQ ID NOs: 477-482 are non- limiting examples of markers for diagnosing lung cancer. The Thrombospondin 1 (THBSl) markers of the present invention can be used alone or in combination, for a number of uses, including but not limited to, prognosis, prediction, screening, early diagnosis, therapy selection and treatment monitoring of prostate cancer. Although optionally any method may be used to detect overexpression and/or differential expression of this marker, preferably a NAT-based technology is used. Therefore, optionally and preferably, any nucleic acid molecule capable of selectively hybridizing to Thrombospondin 1 (THBSl) transcripts as previously defined is also encompassed within the present invention. Oligonucleotides are also optionally and preferably encompassed within the present invention; for example, for the above experiment, the following oligonucleotides were used as a non- limiting illustrative example only of a suitable oligonucleotides: SEQ ID NOs: 477-482

According to other preferred embodiments of the present invention, Thrombospondin 1 (THBSl) transcripts detectable by SEQ ID NOs: 477-482, or a fragment thereof comprises biomarkers for detecting prostate cancer. Optionally and more preferably, Thrombospondin 1 (THBSl) splice variants, as depicted in SEQ ID NO: 435, 437, 439, 442, 444, 445, 448, 449, 450, 451 (e.g., variant no. 4, 6, 8, 11, 14, 15, 26, 27, 28, 30), or a fragment thereof comprise a biomarker for detecting prostate cancer. Optionally and more preferably, any suitable method may be used for detecting a fragment such as Thrombospondin 1 (THBSl) transcripts as depicted in SEQ ID NOs: .: 435, 437, 439, 442, 444, 445, 448, 449, 450, 45 lor fragments thereof. Most preferably, NAT-based technology used, such as any nucleic acid molecule capable of specifically hybridizing with the fragment. Optionally and most preferably, a primer pair is used for obtaining the fragment.

According to other preferred embodiments of the present invention, Thrombospondin 1 (THBSl) splice variants containing the unique segments as depicted in SEQ ID NOs: 422, 424- 427, 431-433 (unique segments), for example as these included in variants 4, 6, 8, 11, 14, 15, 26, 27, 28, 30 (SEQ ID NOs: 435, 437, 439, 442, 444, 445, 448, 449, 450, 451 , respectively), are useful as biomarkers for detecting prostate cancer.

Proteins containing unique amino acid sequences are 2, 3, 4, 5, 7, 10, 16, 17, and 18. The SEQ ID Nos for those proteins are: 452-456, 458, 461-463. The amino acid unique sequences are SEQ ID NO.s: 464-472 for variants P2, P3, P4, P5, P7, PlO, P16, P17 and P18 (all from the cluster HUMTHROM as described in this example). The present invention also encompasses these amino acid sequences as a biomarker for detecting prostate cancer.

The present invention also optionally and preferably encompasses any nucleic acid sequence or fragment thereof, or amino acid sequence or fragment thereof, corresponding to Thrombospondin 1 (THBSl) variants as described above, optionally for any application.

A table is provided below with additional information concerning sequences according to the present invention.

Kits and Diagnostic Assays and Methods The markers described with regard to any of Examples 1-6 above can be used alone, in combination with other markers described above, and/or with other entirely different markers (including but not limited to DD3, PSA or prostate specific membrane antigen) to aid in the diagnosis of prostate cancer, benign prostate hyperplasia or a negative diagnosis. These markers can be used in combination with other markers for a number of uses, including but not limited to, prognosis, prediction, screening, early diagnosis, therapy selection and treatment monitoring of prostate cancer, and also optionally including staging of the disease. Used together, they tend to provide more information for the diagnostician, increasing the percentage of true positive and true negative diagnoses and decreasing the percentage of false positive or false negative diagnoses, than a single marker alone. Assays and methods according to the present invention, as described above, include but are not limited to, immunoassays, hybridization assays and NAT-based assays. The combination of the markers of the present invention with other markers described above, and/or with other entirely different markers to aid in the diagnosis of prostate cancer could be carried out as a mix of NAT-based assays, immunoassays and hybridization assays. According to preferred embodiments of the present invention, the assays are NAT-based assays, as described for example with regard to the Examples above. In yet another aspect, the present invention provides kits for aiding a diagnosis of prostate cancer, wherein the kits can be used to detect the markers of the present invention. For example, the kits can be used to detect any one or combination of markers described above, which markers are differentially present in samples of a prostate cancer patient, BPH and normal patients. The kits of the invention have many applications. For example, the kits can be used to differentiate if a subject has prostate cancer, BPH or has a negative diagnosis, thus aiding a prostate cancer diagnosis. In another example, the kits can be used to identify compounds that modulate expression of the markers in in vitro prostate cells or in vivo animal models for prostate cancer.

In one embodiment, a kit comprises: (a) a substrate comprising an adsorbent thereon, wherein the adsorbent is suitable for binding a marker, and (b) a washing solution or instructions for making a washing solution, wherein the combination of the adsorbent and the washing solution allows detection of the marker as previously described.

Optionally, the kit can further comprise instructions for suitable operational parameters in the form of a label or a separate insert. For example, the kit may have standard instructions informing a consumer/kit user how to wash the probe after a sample of seminal plasma or other tissue sample is contacted on the probe.

In another embodiment, a kit comprises (a) an antibody that specifically binds to a marker; and (b) a detection reagent. Such kits can be prepared from the materials described above. In either embodiment, the kit may optionally further comprise a standard or control information, and/or a control amount of material, so that the test sample can be compared with the control information standard and/or control amount to determine if the test amount of a marker detected in a sample is a diagnostic amount consistent with a diagnosis of prostate cancer.

Therapeutic applications of splice variants of the present invention Splice variants described herein (including any polynucleotide, oligonucleotide, polypeptide, peptide or fragments thereof) or antibodies that specifically bind thereto may optionally be used for therapeutic applications, for example to treat the diseases described herein with regard to diagnostic applications thereof. A "variant- treatable" disease refers to any disease that is treatable by using a splice variant of any of the therapeutic proteins according to the present invention. "Treatment" also encompasses prevention, amelioration, elimination and control of the disease and/or pathological condition. The diseases for which such variants may be useful therapeutic agents are described in greater detail below for each of the variants. The variants themselves are described by "cluster" or by gene, as these variants are splice variants of known proteins. Therefore, a "cluster-related disease" or a "variant-related disease" refers to a disease that may be treated by a particular protein, with regard to the description of such diseases below a therapeutic protein variant according to the present invention.

The term "biologically active", as used herein, refers to a protein having structural, regulatory, or biochemical functions of a naturally occurring molecule. Likewise, "immunologically active" refers to the capability of the natural, recombinant, or synthetic ligand, or any oligopeptide thereof, to induce a specific immune response in appropriate animals or cells and to bind with specific antibodies.

The term "modulate", as used herein, refers to a change in the activity of at least one receptor mediated activity. For example, modulation may cause an increase or a decrease in protein activity, binding characteristics, or any other biological, functional or immunological properties of a ligand.

METHODS OF TREATMENT As mentioned hereinabove the novel therapeutic protein variants of the present invention and compositions derived therefrom (i.e., peptides, oligonucleotides) can be used to treat cluster-related diseases.

Thus, according to an additional aspect of the present invention there is provided a method of treating cluster-related disease in a subject. The subject according to the present invention is a mammal, preferably a human which has at least one type of the cluster-related diseases described hereinabove. As mentioned hereinabove, the biomolecular sequences of the present invention can be used to treat subjects with the above-described diseases.

The subject according to the present invention is a mammal, preferably a human which is diagnosed with one of the diseases described hereinabove, or alternatively is predisposed to having one of the diseases described hereinabove.

As used herein the term "treating" refers to preventing, curing, reversing, attenuating, alleviating, minimizing, suppressing or halting the deleterious effects of the above-described diseases.

Treating, according to the present invention, can be effected by specifically upregulating or alternatively downregulating the expression of at least one of the polypeptides of the present invention in the subject.

Optionally, upregulation may be effected by administering to the subject at least one of the polypeptides of the present invention (e.g., recombinant or synthetic) or an active portion thereof, as described herein. However, since the bioavailability of large polypeptides may potentially be relatively small due to high degradation rate and low penetration rate, administration of polypeptides is preferably confined to small peptide fragments (e.g., about 100 amino acids). The polypeptide or peptide may optionally be administered in a pharmaceutical composition, described in more detail below.

It will be appreciated that treatment of the above-described diseases according to the present invention may be combined with other treatment methods known in the art (i.e., combination therapy). Thus, treatment of malignancies using the agents of the present invention may be combined with, for example, radiation therapy, antibody therapy and/or chemotherapy.

Alternatively or additionally, an upregulating method may optionally be effected by specifically upregulating the amount (optionally expression) in the subject of at least one of the polypeptides of the present invention or active portions thereof.

As is mentioned hereinabove and in the Examples section which follows, the biomolecular sequences of this aspect of the present invention may be used as valuable therapeutic tools in the treatment of diseases in which altered activity or expression of the wild- type gene product is known to contribute to disease onset or progression. For example in case a disease is caused by overexpression of a membrane bound receptor, a soluble variant thereof 2

687 may be used as an antagonist which competes with the receptor for binding the ligand, to thereby terminate signaling from the receptor.

Examples of such diseases are listed in the Examples section which follows. It will be appreciated that the polypeptides of the present invention may also have agonistic properties. These include increasing the stability of the ligand (e.g., IL-4), protection from proteolysis and modification of the pharmacokinetic properties of the ligand (i.e., increasing the half- life of the ligand, while decreasing the clearance thereof). As such, the biomolecular sequences of this aspect of the present invention may be used to treat conditions or diseases in which the wild-type gene product plays a favorable role, for example, increasing angiogenesis in cases of diabetes or ischemia.

Upregulating expression of the therapeutic protein variants of the present invention may be effected via the administration of at least one of the exogenous polynucleotide sequences of the present invention, ligated into a nucleic acid expression construct designed for expression of coding sequences in eukaryotb cells (e.g., mammalian cells), as described above. Accordingly, the exogenous polynucleotide sequence may be a DNA or RNA sequence encoding the variants of the present invention or active portions thereof.

It will be appreciated that the nucleic acid construct can be administered to the individual employing any suitable mode of administration, described hereinbelow (i.e., in-vivo gene therapy). Alternatively, the nucleic acid construct is introduced into a suitable cell via an appropriate gene delivery vehicle/method (transfection, transduction, homologous recombination, etc.) and an expression system as needed and then the modified cells are expanded in culture and returned to the individual (i.e., ex- vivo gene therapy). Nucleic acid constructs are described in greater detail above.

It will be appreciated that the present methodology may also be effected by specifically upregulating the expression of the variants of the present invention endogenously in the subject.

Agents for upregulating endogenous expression of specific splice variants of a given gene include antisense oligonucleotides, which are directed at splice sites of interest, thereby altering the splicing pattern of the gene. This approach has been successfully used for shifting the balance of expression of the two isoforms of Bctx [Taylor (1999) Nat. Biotechnol. 17:1097- 1100; and Mercatante (2001) J. Biol. Chem. 276:16411-16417]; IL-5R [Karras (2000) MoI.

Pharmacol. 58:380-387]; and c-myc [Giles (1999) Antisense Acid Drug Dev. 9:213-220]. For example, interleukin 5 and its receptor play a critical role as regulators of hematopoiesis and as mediators in some inflammatory diseases such as allergy and asthma. Two alternatively spliced isoforms are generated from the IL-5R gene, which include (i.e., long form) or exclude (i.e., short form) exon 9. The long form encodes for the intact membrane- bound receptor, while the shorter form encodes for a secreted soluble non- functional receptor. Using 2'-O-MOE-oligonucleotides specific to regions of exon 9, Karras and co-workers (supra) were able to significantly decrease the expression of the wild type receptor and increase the expression of the shorter isoforms. Design and synthesis of oligonucleotides which can be used according to the present hvention are described hereinbelow and by Sazani and KoIe (2003) Progress in Moleclular and Subcellular Biology 31 :217-239.

Upregulating expression of the polypeptides of the present invention in a subject may be effected via the administration of at least one of the exogenous polynucleotide sequences of the present invention (e.g., SEQ ID NOs: 3, 7, 11, 15, 19, 23, 27, 31, 35, 39 or 43) ligated into a nucleic acid expression construct designed for expression of coding sequences in eukaryotic cells (e.g., mammalian cells). Accordingly, the exogenous polynucleotide sequence may be a

DNA or RNA sequence encoding the variants of the present invention or active portions thereof.

It will be appreciated that the nucleic acid construct can be administered to the individual employing any suitable mode of administration, described hereinbelow (i.e., in-vivo gene therapy). Alternatively, the nucleic acid construct is introduced into a suitable cell via an appropriate gene delivery vehicle/method (transfection, transduction, homologous recombination, etc.) and an expression system as needed and then the modified cells are expanded in culture and returned to the individual (i.e., ex- vivo gene therapy).

Preferably, the promoter utilized by the nucleic acid construct of the present invention is active in the specific cell population transformed. Examples of cell type- specific and/or tissue- specific promoters include promoters, such as albumin that is liver specific [Pinkert et al., (1987) Genes Dev. 1:268-277], lymphoid specific promoters [Calame et al., (1988) Adv. Immunol. 43:235-275]; in particular promoters of T-cell receptors [Winoto et al., (1989) EMBO J. 8:729-733] and immunoglobulins; [Banerji et al. (1983) Cell 33729-740], neuron- specific promoters such as the neurofilament promoter [Byrne et al. (1989) Proc. Natl. Acad. Sci. USA 86:5473-5477], pancreas- specific promoters [Edlunch et al. (1985) Science 230:912-916] or mammary gland- specific promoters such as the milk whey promoter (U.S. Pat. No. 4,873,316 and European Patent Application No. EP 264,166).

Examples of suitable constructs include, but are not limited to, pcDNA3, pcDNA3.1 (+/- ), pGL3, PzeoSV2 (+/-), pDisplay, pEF/myc/cyto, pCMV/myc/cyto each of which is commercially available from Invitrogen Co. (www.invitrogen.com). Examples of retroviral vector and packaging systems are those sold by Clontech, San Diego, Calif., including Retro-X vectors pLNCX and pLXSN, which permit cloning into multiple cloning sites and the trasgene is transcribed from CMV promoter. Vectors derived from Mo-MuLV are also included such as pBabe, where the transgene will be transcribed from the 5'LTR promoter. Currently preferred in vivo nucleic acid transfer techniques include transfection with viral or non- viral constructs, such as adenovirus, lentivirus, Herpes simplex I virus, or adeno- associated virus (AAV) and lipid-based systems. Useful lipids for lipid- mediated transfer of the gene are, for example, DOTMA, DOPE, and DC-Choi [Tonkinson et al., Cancer Investigation, 14(1): 54-65 (1996)]. The most preferred constructs for use in gene therapy are viruses, most preferably adenoviruses, AAV, lentiviruses, or retroviruses. A viral construct such as a retroviral construct includes at least one transcriptional promoter/enhancer or locus-defining elements), or other elements that control gene expression by other means such as alternate splicing, nuclear RNA export, or post-translational modification of messenger. Such vector constructs also include a packaging signal, long terminal repeats (LTRs) or portions thereof, and positive and negative strand primer binding sites appropriate to the virus used, unless it is already present in the viral construct. In addition, such a construct typically includes a signal sequence for secretion of the peptide from a host cell in which it is placed. Preferably the signal sequence for this purpose is a mammalian signal sequence or the signal sequence of the polypeptide variants of the present invention. Optionally, the construct may also include a signal that directs polyadenylation, as well as one or more restriction sites and a translation termination sequence. By way of example, such constructs will typically include a 5' LTR, a tRNA binding site, a packaging signal, an origin of second-strand DNA synthesis, and a 3' LTR or a portion thereof. Other vectors can be used that are non-viral, such as cationic lipids, polylysine, and dendrimers. It will be appreciated that the present methodology may also be performed by specifically upregulating the expression of the splice variants of the present invention endogenously in the subject. Agents for upregulating endogenous expression of specific splice variants of a given gene include antisense oligonucleotides, which are directed at splice sites of interest, thereby altering the splicing pattern of the gene. This approach has been successfully used for shifting the balance of expression of the two isoforms of Bcl-x [Taylor (1999) Nat. Biotechnol. 17:1097-1100; and Mercatante (2001) J. Biol. Chem. 276:16411-16417]; II_^5R [Karras (2000) MoI. Pharmacol. 58:380-387]; and c-myc [Giles (1999) Antisense Acid Drug Dev. 9:213-220].

For example, interleukin 5 and its receptor play a critical role as regulators of hematopoiesis and as mediators in some inflammatory diseases such as allergy and asthma. Two alternatively spliced isoforms are generated from the IL-5R gene, which include (Le., long form) or exclude (i.e., short form) exon 9. The long form encodes for the intact membrane- bound receptor, while the shorter form encodes for a secreted soluble non- functional receptor. Using 2'-0-MOE-oligonucleotides specific to regions of exon 9, Karras and co-workers (supra) were able to significantly decrease the expression of the wild type receptor and increase the expression of the shorter isoforms. Design and synthesis of oligonucleotides which can be used according to the present invention are described hereinbelow and by Sazani and KoIe (2003) Progress in Moleclular and Subcellular Biology 31:217-239.

Treatment can preferably effected by agents which are capable of specifically downregulating expression (or activity) of at least one of the polypeptide variants of the present invention.

Down regulating the expression of the therapeutic protein variants of the present invention may be achieved using oligonucleotide agents such as those described in greater detail below.

SiRNA molecules - Small interfering RNA (siRNA) molecules can be used to down- regulate expression of the therapeutic protein variants of the present invention. RNA interference is a two-step process. The first step, which is termed as the initiation step, input dsRNA is digested into 21-23 nucleotide (nt) small interfering RNAs (siRNA), probably by the action of Dicer, a member of the RNase III family of dsRNA- specific ribonucleases, which processes (cleaves) dsRNA (introduced directly or via a transgene or a virus) in an ATP- dependent manner. Successive cleavage events degrade the RNA to 19-21 bp duplexes (siRNA), each with 2- nucleotide 3' overhangs [Hutvagner and Zamore Curr. Opin. Genetics and

Development 12:225-232 (2002); and Bernstein Nature 409:363-366 (2001)].

In the effector step, the siRNA duplexes bind to a nuclease complex to from the RNA- induced silencing complex (RISC). An ATP-dependent unwinding of the siRNA duplex is required for activation of the RISC. The active RISC then targets the homologous transcript by base pairing interactions and cleaves the niRNA into 12 nucleotide fragments from the 3' terminus of the siRNA [Hutvagner and Zamore Curr. Opin. Genetics and Development 12:225- 232 (2002); Hammond et al. (2001) Nat. Rev. Gen. 2:110-119 (2001); and Sharp Genes. Dev. 15:485-90 (2001)]. Although the mechanism of cleavage is still to be elucidated, research indicates that each RISC contains a single siRNA and an RNase [Hutvagner and Zamore Curr. Opin. Genetics and Development 12:225-232 (2002)].

Because of the remarkable potency of RNAi, an amplification step within the RNAi pathway has been suggested. Amplification could occur by copying of the input dsRNAs which would generate more siRNAs, or by replication of the siRNAs formed. Alternatively or additionally, amplification could be effected by multiple turnover events of the RISC [Hammond et al. Nat. Rev. Gen. 2:110-119 (2001), Sharp Genes. Dev. 15:485-90 (2001); Hutvagner and Zamore Curr. Opin. Genetics and Development 12:225-232 (2002)]. For more information on RNAi see the following reviews Tuschl ChemBiochem. 2:239-245 (2001); CullenNat. Immunol. 3:597-599 (2002); and Brantl Biochem. Biophys. Act. 1575:15-25 (2002). Synthesis of RNAi molecules suitable for use with the present invention can be effected as follows. First, the mRNA sequence is scanned downstream of the AUG start codon for AA dinucleotide sequences. Occurrence of each AA and the 3' adjacent 19 nucleotides is recorded as potential siRNA target sites. Preferably, siRNA target sites are selected from the open reading frame, as untranslated regions (UTRs) are richer in regulatory protein binding sites. UTR-binding proteins and/or translation initiation complexes may interfere with binding of the siRNA endonuclease complex [Tuschl ChemBiochem. 2:239-245]. It will be appreciated though, that siRNAs directed at untranslated regions may also be effective, as demonstrated for GAPDH wherein siRNA directed at the 5' UTR mediated about 90 % decrease in cellular GAPDH mRNA and completely abolished protein level (www.ambion.com/techlib/tn/91/912.html). Second, potential target sites are compared to an appropriate genomic database (e.g., human, mouse, rat etc.) using any sequence alignment software, such as the BLAST software available from the NCBI server (www.ncbi.nhn.nih.gov/BLAST/). Putative target sites which exhibit significant homology to other coding sequences are filtered out. Qualifying target sequences are selected as template for siRNA synthesis.

Preferred sequences are those including low G/C content as these have proven to be more effective in mediating gene silencing as compared to those with GC content higher than 55 %. Several target sites are preferably selected along the length of the target gene for evaluation. Target sites are selected from the unique nucleotide sequences of each of the polynucleotides of the present invention, such that each polynucleotide is specifically down regulated. For better evaluation of the selected siRNAs, a negative control is preferably used in conjunction. Negative control siRNA preferably include the same nucleotide composition as the siRNAs but lack significant homology to the genome. Thus, a scrambled nucleotide sequence of the siRNA is preferably used, provided it does not display any significant homology to any other gene. DNAzyme molecules - Another agent capable of downregulating expression of the polypeptides of the present invention is a DNAzyme molecule capable of specifically cleaving an mRNA transcript or DNA sequence of the polynucleotides of the present invention. DNAzymes are single -stranded polynucleotides which are capable of cleaving both single and double stranded target sequences (Breaker, R.R. and Joyce, G. Chemistry and Biology 1995;2:655; Santoro, S.W. & Joyce, G.F. Proc. Natl, Acad. Sci. USA 1997;943:4262) A general model (the "10-23" model) for the DNAzyme has been proposed. "10-23" DNAzymes have a catalytic domain of 15 deoxyribonucleotides, flanked by two substrate-recognition domains of seven to nine deoxyribonucleotides each. This type of DNAzyme can effectively cleave its substrate RNA at purine:pyrimidine junctions (Santoro, S.W. & Joyce, G.F. Proc. Natl, Acad. Sci. USA 199; for rev of DNAzymes see Khachigian, LM [Curr Opin MoI Ther 4:119-21 (2002)].

Target sites for DNAzymes are selected from the unique nucleotide sequences of each of the polynucleotides of the present invention, such that each polynucleotide is specifically down regulated. Examples of construction and amplification of synthetic, engineered DNAzymes recognizing single and double- stranded target cleavage sites have been disclosed in U.S. Pat. No. 6,326,174 to Joyce et al. DNAzymes of similar design directed against the human Urokinase receptor were recently observed to inhibit Urokinase receptor expression, and successfully inhibit colon cancer cell metastasis in vivo (Itoh et al , 20002, Abstract 409, Ann Meeting Am Soc Gen Ther www.asgt.org). In another application, DNAzymes complementary to bcr-abl oncogenes were successful in inhibiting the oncogenes expression in leukemia cells, and lessening relapse rates in autologous bone marrow transplant in cases of CML and ALL.

Antisense molecules - Downregulation of the polynucleotides of the present invention can also be effected by using an antisense polynucleotide capable of specifically hybridizing with an mRNA transcript encoding the polypeptide variants of the present invention.

The term "antisense", as used herein, refers to any composition containing nucleotide sequences, which are complementary to a specific DNA or RNA sequence.

The term "antisense strand" is used in reference to a nucleic acid strand that is complementary to the "sense" strand. Antisense molecules also include peptide nucleic acids and may be produced by any method including synthesis or transcription. Once introduced into a cell, the complementary nucleotides combine with natural sequences produced by the cell to form duplexes and block either transcription or translation. The designation "negative" is sometimes used in reference to the antisense strand, and "positive" is sometimes used in reference to the sense strand. Antisense oligonucleotides are also used for modulation of alternative splicing in vivo and for diagnostics in vivo and in vitro (Khelifϊ C. et al., 2002,

Current Pharmaceutical Design 8:451-1466; Sazani, P., and KoIe. R. Progress in Molecular and

Cellular Biology, 2003, 31:217-239).

Design of antisense molecules which can be used to efficiently downregulate expression of the polypeptides of the present invention must be effected while considering two aspects important to the antisense approach. The first aspect is delivery of the oligonucleotide into the cytoplasm of the appropriate cells, while the second aspect is design of an oligonucleotide which specifically binds the designated mRNA within cells in a way which inhibits translation thereof.

The prior art teaches of a number of delivery strategies which can be used to efficiently deliver oligonucleotides into a wide variety of cell types [see, for example, Luft J MoI Med 76:

75-6 (1998); Kronenwett et al. Blood 91: 852-62 (1998); Rajur et al. Bioconjug Chem 8: 935-40 (1997); Lavigne et al. Biochem Biophys Res Commun 237: 566-71 (1997) and Aoki et al. (1997) Biochem Biophys Res Commun 231: 540-5 (1997)].

In addition, algorithms for identifying those sequences with the highest predicted binding affinity for their target mRNA based on a thermodynamic cycle that accounts for the energetics of structural alterations in both the target mRNA and the oligonucleotide are also available [see, for example, Walton et al. Biotechnol Bioeng 65: 1-9 (1999)].

Such algorithms have been successfully used to implement an antisense approach in cells. For example, the algorithm developed by Walton et al. enabled scientists to successfully design antisense oligonucleotides for rabbit beta-globin (RBG) and mouse tumor necrosis factor- alpha (TNF alpha) transcripts. The same research group has more recently reported that the antisense activity of rationally selected oligonucleotides against three model target mRNAs (human lactate dehydrogenase A and B and rat gpl30) in cell culture as evaluated by a kinetic PCR technique proved effective in almost all cases, including tests against three different targets in two cell types with phosphodiester and phosphorothioate oligonucleotide chemistries. In addition, several approaches for designing and predicting efficiency of specific oligonucleotides using an in vitro system were also published (Matveeva et al., Nature Biotechnology 16: 1374 - 1375 (1998)].

Several clinical trials have demonstrated safety, feasibility and activity of antisense oligonucleotides. For example, antisense oligonucleotides suitable for the treatment of cancer have been successfully used [Holmund et al., Curr Opin MoI Ther 1:372-85 (1999)], while treatment of hematological malignancies via antisense oligonucleotides targeting c-myb gene, p53 and Bcl-2 had entered clinical trials and had been shown to be tolerated by patients [Gerwitz Curr Opin MoI Ther 1:297-306 (1999)].

More recently, antisense- mediated suppression of human heparanase gene expression has been reported to inhibit pleural dissemination of human cancer cells in a mouse model [Uno et al., Cancer Res 61:7855-60 (2001)].

Thus, the current consensus is that recent developments in the field of antisense technology which, as described above, have led to the generation of highly accurate antisense design algorithms and a wide variety of oligonucleotide delivery systems, enable an ordinarily skilled artisan to design and implement antisense approaches suitable for downregulating expression of known sequences without having to resort to undue trial and error experimentation.

Target sites for antisense molecules are selected from the unique nucleotide sequences of each of the polynucleotides of the present invention, such that each polynucleotide is specifically down regulated.

Ribo2ymes - Another agent capable of downregulating expression of the polypeptides of the present invention is a ribozyme molecule capable of specifically cleaving an mRNA transcript encoding the polypeptide variants of the present invention. Ribozymes are being increasingly used for the sequence-specific inhibition of gene expression by the cleavage of mRNAs encoding proteins of interest [Welch et al., Curr Opin Biotechnol. 9:486-96 (1998)]. The possibility of designing ribozymes to cleave any specific target RNA has rendered them valuable tools in both basic research and therapeutic applications. In therapeutics area, ribo2ymes have been exploited to target viral RNAs in infectious diseases, dominant oncogenes in cancers and specific somatic mutations in genetic disorders [Welch et al., Clin Diagn Virol. 10:163-71 (1998)]. Most notably, several ribozyme gene therapy protocols for HIV patients are already in Phase 1 trials. More recently, ribozymes have been used for transgenic animal research, gene target validation and pathway elucidation. Several ribozymes are in various stages of clinical trials. ANGIOZYME was the first chemically synthesized ribozyme to be studied in human clinical trials. ANGIOZYME specifically inhibits formation of the VEGF-r (Vascular Endothelial Growth Factor receptor), a key component in the angiogenesis pathway. Ribozyme Pharmaceuticals, Inc., as well as other firms have demonstrated the importance of anti- angiogenesis therapeutics in animal models. HEPTAZYME, a ribozyme designed to selectively destroy Hepatitis C Virus (HCV) RNA, was found effective in decreasing Hepatitis C viral RNA in cell culture assays (Ribozyme Pharmaceuticals, Incorporated - WEB home page).

Alternatively, down regulation of the polypeptide variants of the present invention may be achieved at the polypeptide level using downregulating agents such as antibodies or antibody fragments capabale of specifically binding the polypeptides of the present invention and inhibiting the activity thereof (i.e., neutralizing antibodies). Such antibodies can be directed for example, to the heterodimerizing domain on the variant, or to a putative ligand binding domain. Further description of antibodies and methods of generating same is provided below. PHARMACEUTICAL COMPOSITIONS AND DELIVERY THEREOF

The present invention features a pharmaceutical composition comprising a therapeutically effective amount of a therapeutic agent according to the present invention, which is preferably a therapeutic protein variant as described herein. Optionally and alternatively, the therapeutic agent could be an antibody or an oligonucleotide that specifically recognizes and binds to the therapeutic protein variant, but not to the corresponding full length known protein.

Alternatively, the pharmaceutical composition of the present invention includes a therapeutically effective amount of at least an active portion of a therapeutic protein variant polypeptide.

The pharmaceutical composition according to the present invention is preferably used for the treatment of cluster-related diseases.

"Treatment" refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented. Hence, the mammal to be treated herein may have been diagnosed as having the disorder or may be predisposed or susceptible to the disorder.

"Mammal" for purposes of treatment refers to any animal classified as a mammal, hcluding humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, etc. Preferably, the mammal is human. A "disorder" is any condition that would benefit from treatment with the agent according to the present invention. This includes chronic and acute disorders or diseases including those pathological conditions which predispose the mammal to the disorder in question. Non- limiting examples of disorders to be treated herein are described with regard to specific examples given herein. The term "therapeutically effective amount" refers to an amount of agent according to the present invention that is effective to treat a disease or disorder in a mammal. In the case of cancer, the therapeutically effective amount of the agent may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer. To the extent the agent may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy, efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR).

The therapeutic agents of the present invention can be provided to the subject per se, or as part of a pharmaceutical composition where they are mixed with a pharmaceutically acceptable carrier.

As used herein a "pharmaceutical composition" refers to a preparation of one or more of the active ingredients described herein with other chemical components such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

Herein the term "active ingredient" refers to the preparation accountable for the biological effect.

Hereinafter, the phrases "physiologically acceptable carrier" and "pharmaceutically acceptable carrier" which may be interchangeably used refer to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. An adjuvant is included under these phrases. One of the ingredients included in the pharmaceutically acceptable carrier can be for example polyethylene glycol (PEG), a biocompatible polymer with a wide range of solubility in both organic and aqueous media (Mutter et al. (1979). Herein the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

Techniques for formulation and administration of drugs may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition, which is incorporated herein by reference.

Suitable routes of administration may, for example, include oral, rectal, transmucosal, especially transnasal, intestinal or parenteral delivery, including intramuscular, subcutaneous and intramedullary injections as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. Alternately, one may administer a preparation in a local rather than systemic manner, for example, via injection of the preparation directly into a specific region of a patient's body.

Pharmaceutical compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.

For injection, the active ingredients of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient. Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl- cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross- linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical compositions, which can be used orally, include push- fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push- fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or Hquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

For administration by nasal inhalation, the active ingredients for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in a dispenser may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The preparations described herein may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative. The compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active ingredients may be prepared as appropriate oily or water based injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the active ingredients to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen- free water based solution, before use.

The preparation of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides. Pharmaceutical compositions suitable for use in context of the present invention include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a therapeutically effective amount means an amount of active ingredients effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.

For any preparation used in the methods of the invention, the therapeutically effective amount or dose can be estimated initially from in vitro assays. For example, a dose can be formulated in animal models and such information can be used to more accurately determine useful doses in humans.

Toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, in cell cultures or experimental animals. The data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl, et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1

P-I)-

Depending on the severity and responsiveness of the condition to be treated, dosing can be of a single or a plurality of administrations, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved. The amount of a composition to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.

Compositions including the preparation of the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

Pharmaceutical compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accommodated by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.

IMMUNOGENIC COMPOSITIONS

A therapeutic agent according to the present invention may optionally be a molecule, which promotes a specific immunogenic response against at least one of the polypeptides of the present invention in the subject. The molecule can be polypeptide variants of the present invention, a fragment derived therefrom or a nucleic acid sequence encoding thereof. Although such a molecule can be provided to the subject per se, the agent is preferably administered with an immunostimulant in an immunogenic composiiton. An immunostimulant may be any substance that enhances or potentiates an immune response (antibody and/or cell- mediated) to an exogenous antigen. Examples of immunostimulants include adjuvants, biodegradable microspheres (e.g., polylactic galactide) and liposomes into which the compound is incorporated (see e.g., U.S. Pat. No. 4,235,877). Vaccine preparation is generally described in, for example, M. F. Powell and M. J. Newman, eds., "Vaccine Design (the subunit and adjuvant approach)," Plenum Press (NY, 1995). Illustrative immunogenic compositions may contain DNA encoding one or more of the polypeptides as described above, such that the polypeptide is generated in situ. The DNA may be present within any of a variety of delivery systems known to those of ordinary skill in the art, including nucleic acid expression systems (see below), bacteria and viral expression systems. Numerous gene delivery techniques are well known in the art, such as those described by Rolland, Crit. Rev. Therap. Drag Carrier Systems 15:143-198, 1998, and references cited therein. Appropriate nucleic acid expression systems contain the necessary DNA sequences for expression in the subject (such as a suitable promoter and terminating signal). Bacterial delivery systems involve the administration of a bacterium (such as Bacillus-Calmette-Guerrin) that expresses an immunogenic portion of the polypeptide on its cell surface or secretes such an epitope. In a preferred embodiment, the DNA may be introduced using a viral expression system (e.g., vaccinia or other pox virus, retrovirus, or adenovirus), which may involve the use of a non-pathogenic (defective), replication competent virus. Suitable systems are disclosed, for example, in Fisher-Hoch et al., Proc. Natl. Acad. Sd. USA 86:317-321, 1989; Flexner et al., Ann. N.Y Acad. Sci. 569:86-103, 1989; Flexner et al., Vaccine 8:17-21, 1990; U.S. Pat. Nos. 4,603,112, 4,769,330, and 5,017,487; WO 89/01973; U.S. Pat. No. 4,777,127; GB 2,200,651; EP 0,345,242; WO 91/02805; Berkner, Biotechniques 6:616-627, 1988; Rosenfeld et al., Science 252:431-434, 1991; Kolls et al., Proc. Natl. Acad. Sci. USA 91:215-219, 1994; Kass- Eisler et al., Proc. Natl. Acad. Sci. USA 90:11498-11502, 1993; Guzman et al., Circulation 88:2838-2848, 1993; and Guzman et al., Cir. Res. 73:1202-1207, 1993. Techniques for incorporating DNA into such expression systems are well known to those of ordinary skill in the art. The DNA may also be "naked," as described, for example, in Ulmer et al., Science 259:1745-1749, 1993 and reviewed by Cohen, Science 259:1691-1692, 1993. The uptake of naked DNA may be increased by coating the DNA onto biodegradable beads, which are efficiently transported into the cells.

It will be appreciated that an immunogenic composition may comprise both a polynucleotide and a polypeptide component. Such immunogenic compositions may provide for an enhanced immune response.

Any of a variety of immunostimulants may be employed in the immunogenic compositions of this invention. For example, an adjuvant may be included. Most adjuvants contain a substance designed to protect the antigen from rapid catabolism, such as aluminum hydroxide or mineral oil, and a stimulator of immune responses, such as lipid A, Bortadella pertussis or Mycobacterium tuberculosis derived proteins. Suitable adjuvants are commercially available as, for example, Freund's Incomplete Adjuvant and Complete Adjuvant (Difco Laboratories, Detroit, Mich.); Merck Adjuvant 65 (Merck and Company, Inc., Rahway, N. J.); AS-2 (SmithKline Beecham, Philadelphia, Pa.); aluminum salts such as aluminum hydroxide gel (alum) or aluminum phosphate; salts of calcium, iron or zinc; an insoluble suspension of acylated tyrosine; acylated sugars; cationically or anionically derivatized polysaccharides; polyphosphazenes; biodegradable microspheres; monophosphoryl lipid A and quil A. Cytokines, such as GM-CSF or interleukin-2,-7, or -12, may also be used as adjuvants. The adjuvant composition may be designed to induce an immune response predominantly of the ThI type. High levels of ThI -type cytokines (e.g., IFN-.gamma., TNF.alpha., IL-2 and IL- 12) tend to favor the induction of cell mediated immune responses to an administered antigen. In contrast, high levels of Th2-type cytokines (e.g., IL-4, IL-5, IL-6 and IL-10) tend to favor the induction of humoral immune responses. Following application of an immunogenic composition as provided herein, the subject will support an immune response that includes ThI- and Th2-type responses. The levels of these cytokines may be readily assessed using standard assays. For a review of the families of cytokines, see Mosmann and Coffinan, Ann. Rev. Immunol. 7:145-173, 1989.

Preferred adjuvants for use in eliciting a predominantly ThI -type response include, for example, a combination of monophosphoryl lipid A, preferably 3-de-O-acylated monophosphoryl lipid A (3D-MPL), together with an aluminum salt. MPL adjuvants are available from Corixa Corporation (Seattle, Wash.; see U.S. Pat. Nos. 4436,727; 4,877,611; 4,866,034 and 4,912,094). CpG-containing oligonucleotides (in which the CpG dinucleotide is unmethylated) also induce a predominantly ThI response. Such oligonucleotides are well known and are described, for example, in WO 96/02555, WO 99/33488 and U.S. Pat. Nos. 6,008,200 and 5,856,462. Immunostimulatory DNA sequences are also described, for example, by Sato et al., Science 273:352, 1996. Another preferred adjuvant is a saponin, preferably QS21 (Aquila Biophaπnaceuticals Inc., Framingham, Mass.), which may be used alone or in combination with other adjuvants. For example, an enhanced system involves the combination of a monophosphoryl lipid A and saponin derivative, such as the combination of QS21 and 3D-MPL as described in WO 94/00153, or a less reactogenic composition where the QS21 is quenched with cholesterol, as described in WO 96/33739. Other preferred formulations comprise an oil- in- water emulsion and tocopherol. A particularly potent adjuvant formulation involving QS21, 3D-MPL and tocopherol in an oil- in- water emulsion is described in WO 95/17210.

Other preferred adjuvants include Montanide ISA 720 (Seppic, France), SAF (Chiron, Calif., United States), ISCOMS (CSL), MF-59 (Chiron), the SBAS series of adjuvants (e.g., SBAS-2 or SBAS-4, available from SmithKline Beecham, Rixensart, Belgium), Detox (Corixa, Hamilton, Mont.), RC-529 (Corixa, Hamilton, Mont.) and other aminoalkyl glucosaminide 4- phosphates (AGPs), such as those described in pending U.S. patent application Ser. Nos. 08/853,826 and 09/074,720. A delivery vehicle may be employed within the immunogenic composition of the present invention to facilitate production of an antigen-specific immune response that targets tumor cells. Delivery vehicles include antigen presenting cells (APCs), such as dendritic cells, macrophages, B cells, monocytes and other cells that may be engineered to be efficient APCs. Such cells may be genetically modified to increase the capacity for presenting the antigen, to improve activation and/or maintenance of the T cell response, to have anti- tumor effects per se and/or to be immunologically compatible with the receiver (i.e., matched HLA haplotype). APCs may generally be isolated from any of a variety of biological fluids and organs, including tumor and peritumoral tissues, and may be autologous, allogeneic, syngeneic or xenogeneic cells. Dendritic cells are highly potent APCs (Banchereau and Steinman, Nature 392:245-251,

1998) and have been shown to be effective as a physiological adjuvant for eliciting prophylactic or therapeutic antitumor immunity (see Timmernan and Levy, Ann. Rev. Med. 50:507-529, 1999). In general, dendritic cells may be identified based on their typical shape (stellate in situ, with marked cytoplasmic processes (dendrites) visible in vitro), their ability to take up, process and present antigens with high efficiency and their ability to activate naive T cell responses. Dendritic cells may, of course, be engineered to express specific cell- surface receptors or ligands that are not commonly found on dendritic cells in vivo or ex vivo, and such modified dendritic cells are contemplated by the present invention. As an alternative to dendritic cells, secreted vesicles antigen-loaded dendritic cells (called exosomes) may be used within an immunogenic composition (see Zitvogel et al., Nature Med. 4:594-600, 1998). W

705

Dendritic cells and progenitors may be obtained from peripheral blood, bone marrow, tumor- infiltrating cells, peritumoral tissues- infiltrating cells, lymph nodes, spleen, skin, umbilical cord blood or any other suitable tissue or fluid. For example, dendritic cells may be differentiated ex vivo by adding a combination of cytokines such as GM-CSF, IL-4, IL- 13 and/or TNF.alpha. to cultures of monocytes harvested from peripheral blood. Alternatively, CD34 positive cells harvested from peripheral blood, umbilical cord blood or bone marrow may be differentiated into dendritic cells by adding to the culture medium combinations of GM-CSF, IL-3, TNF.alpha., CD40 ligand, LPS, flt3 ligand and/or other compound(s) that induce differentiation, maturation and proliferation of dendritic cells. Dendritic cells are categorized as "immature" and "mature" cells, which allows a simple way to discriminate between two well characterized phenotypes. Immature dendritic cells are characterized as APC with a high capacity for antigen uptake and processing, which correlates with the high expression of Fey receptor and mannose receptor. The mature phenotype is typically characterized by a lower expression of these markers, but a high expression of cell surface molecules responsible for T cell activation such as class I and class II MHC, adhesion molecules (e.g., CD54 and CDI l) and costimulatory molecules (e.g., CD40, CD80, CD86 and 4- IBB).

APCs may generally be transfected with at least one polynucleotide encoding- a polypeptide of the present invention, such that variant II, or an immunogenic portion thereof, is expressed on the cell surface. Such transfection may take place ex vivo, and a composition comprising such transfected cells may then be used for therapeutic purposes, as described herein. Alternatively, a gene delivery vehicle that targets a dendritic or other antigen presenting cell may be administered to the subject, resulting in transfection that occurs in vivo. In vivo and ex vivo transfection of dendritic cells, for example, may generally be performed using any methods known in the art, such as those described in WO 97/24447, or the gene gun approach described by Mahvi et al., Immunology and cell Biology 75:456-460, 1997. Antigen loading of dendritic cells may be achieved by incubating dendritic cells or progenitor cells with a polypeptide of the present inventio, DNA (naked or within a plasmid vector) or RNA; or with antigen- expressing recombinant bacterium or viruses (e.g., vaccinia, fowlpox, adenovirus or lentivirus vectors). Prior to loading, the polypeptide may be covalently conjugated to an immunological partner that provides T cell help (e.g., a carrier molecule) such as described above. Alternatively, a dendritic cell may be pulsed with a non- conjugated immunological partner, separately or in the presence of the polypeptide.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

Claims

WHAT IS CLAIMED IS:

1. An isolated polynucleotide comprising a polynucleotide having a sequence selected from the group consisting of: R11723_PEA_1_T15, R11723_PEA_1_T17, Rl 1723_PEA_1_T19, Rl 1723_PEA_l_T20, Rl 1723_PEA_1_T5, or Rl 1723_PEA__1_T6.

2. An isolated polynucleotide comprising a node having a sequence selected from the group consisting of : R11723_PEA_l_node_13, R11723_PEA_l_node_16, Rl 1723_PEA_l_node_l 9, RIl 723_PEA_l_node_2, Rl 1723_PEA_l_node_22, Rl 1723_PEA_l_node_31, Rl 1723_PEA_l_node_10, Rl 1723_PEA_l_node_l 1, Rl 1723_PEA_l_node_15, Rl 1723_PEA_l_node_18, Rl 1723_PEA_l_node_20, Rl 1723_PEA_l_node_21, Rl 1723JPEA_l_node_23, Rl 1723_PEA_l_node_24, Rl 1723_PEA_l_node_25, Rl 1723_PEA_l_node_26, Rl 1723_PEA_l_node_27, Rl 1723_PEA_l_node_28, Rl 1723_PEA_l_node_29, Rl 1723_PEA_l_node_3, Rl 1723_PEA_l_node_30, Rl 1723_PEA_l_node_4, Rl 1723_PEA_l_node_5, R11723_PEA_l_node_6, R11723_PEA_l_node_7 or Rl 1723_PEA_l_node_8.

3. An isolated polypeptide comprising a polypeptide having a sequence selected from the group consisting of : R11723_PEA_1JP2, R11723_PEA_1_P6, R11723_PEA_1_P7, R11723_PEA_1_P13, or R11723_PEA_l_P10.

4. An isolated chimeric polypeptide encoding for Rl 1723_PEA_1_P6, comprising a first amino acid sequence being at least 70% homologous to a polypeptide having the sequence MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAGIMYRKSCASSAACLIASAGSPCRGLAPGREEQRALHKAGAVGGGVR corresponding to amino acids 1 - 110 of Rl 1723_PEA_1_P6, and a second amino acid sequence being at least 90 % homologous to MYAQALLWGVLQRQAAAQHLHEHPPKLLRGHRVQERVDDRAEVEKRLREGEEDHV RPEVGPRPVVLGFGRSHDPPNLVGHPAYGQCHNNQPWADTSRRERQRKEKHSMRTQ corresponding to amino acids 1 - 112 of Q8IXM0, which also corresponds to amino acids 111 - 222 of R11723_PEA_1_P6, wherein said first and second amino acid sequences are contiguous and in a sequential order.

5. An isolated polypeptide encoding for a head of Rl 1723_PEA_1_P6, comprising a polypeptide being at least about 70% homologous to the sequence MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAGIMYRKSCASSAACLIASAGSPCRGLAPGREEQRALHKAGAVGGGVR of R11723_PEA_1_P6.

6. An isolated chimeric polypeptide encoding for Rl 1723_PEA_1_P6, comprising a first amino acid sequence being at least 90 % homologous to

MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFΓVNCTVNVQDMCQKEV

MEQSAGIMYRKSCASSAACLIASAG corresponding to amino acids 1 - 83 of Q96AC2, which also corresponds to amino acids 1 - 83 of R11723 PEA 1 P6, and a second amino acid sequence being at least about 70% homologous to a polypeptide having the sequence SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLWGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPVVLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ corresponding to amino acids 84 - 222 of Rl 1723_PEA_1_P6, wherein said first and second amino acid sequences are contiguous and in a sequential order.

7. An isolated polypeptide encoding for a tail of R11723_PEA_1_P6, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence

SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLWGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPWLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ in R11723_PEA_1_P6.

8. An isolated chimeric polypeptide encoding for Rl 1723 PEA 1 P6, comprising a first amino acid sequence being at least 90 % homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAGIMYRKSCASSAACLIASAG corresponding to amino acids 1 - 83 of Q8N2G4, which also corresponds to amino acids 1 - 83 of R11723_PEA_1_P6, and a second amino acid sequence being at least about 70% homologous to a polypeptide having the sequence SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLWGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPWLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ corresponding to amino acids 84 - 222 of R11723_PEA_1_P6, wherein said first and second amino acid sequences are contiguous and in a sequential order.

9. An isolated polypeptide encoding for a tail of R11723_PEA_1_P6, comprising a polypeptide being at least about 70% homologous to the sequence SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLWGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRP WLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ in R11723_PEA_1_P6.

10. An isolated chimeric polypeptide encoding for Rl 1723_PEA_1_P6, comprising a first amino acid sequence being at least 90 % homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAGIMYRKSCASSAACLIASAG corresponding to amino acids 24 - 106 of BAC85518, which also corresponds to amino acids 1 - 83 of Rl 1723_PEA_1_P6, and a second amino acid sequence being at least about 70% homologous to a polypeptide having the sequence SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLWGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPWLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ corresponding to amino acids 84 - 222 of R11723_PEA_1_P6, wherein said first and second amino acid sequences are contiguous and in a sequential order.

11. An isolated polypeptide encoding for a tail of Rl 1723 PEA 1 P6, comprising a polypeptide being at least about 70% homologous to the sequence SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLWGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPWLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ in R11723_PEA_1_P6.

12. An isolated chimeric polypeptide encoding for Rl 1723_PEA_1_P7, comprising a first amino acid sequence being at least 90 % homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAG corresponding to amino acids 1 - 64 of Q96AC2, which also corresponds to amino acids 1 - 64 of Rl 1723_PEA_1_P7, and a second amino acid sequence being at least about 70% homologous to a polypeptide having the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT corresponding to amino acids 65 - 93 of R11723_PEA_1_P7, wherein said first and second amino acid sequences are contiguous and in a sequential order.

13. An isolated polypeptide encoding for a tail of R11723_PEA_1_P7, comprising a polypeptide being at least about 70% homologous to the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT in R11723_PEA_1_P7.

14. An isolated chimeric polypeptide encoding for Rl 1723_PEA_1_P7, comprising a first amino acid sequence being at least 90 % homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSAG corresponding to amino acids 1 - 64 of Q8N2G4, which also corresponds to amino acids 1 - 64 of Rl 1723_PEA_1_P7, and a second amino acid sequence being at least about 70% homologous to a polypeptide having the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT corresponding to amino acids 65 - 93 of R11723_PEA_1_P7, wherein said first and second amino acid sequences are contiguous and in a sequential order.

15. An isolated polypeptide encoding for a tail of R11723_PEA_1_P7, comprising a polypeptide being at least about 70% homologous to the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT in R11723_PEA_1_P7.

16. An isolated chimeric polypeptide encoding for Rl 1723_PEA_1_P7, comprising a first amino acid sequence being at least about 70% homologous to a polypeptide having the sequence MWVLG corresponding to amino acids 1 - 5 of R11723_PEA_1_P7, second amino acid sequence being at least 90 % homologous to

IAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFΓVNCTVNVQDMCQKEVMEQSAG corresponding to amino acids 22 - 80 of BAC85273, which also corresponds to amino acids 6 - 64 of Rl 1723_PEA_1_P7, and a third amino acid sequence being at least about 70% homologous to a polypeptide having the sequence

SHCVTRLECSGTISAHCNLCLPGSNDHPT corresponding to amino acids 65 - 93 of Rl 1723_PEA_1_P7, wherein said first, second and third amino acid sequences are contiguous and in a sequential order.

17. An isolated polypeptide encoding for a head of R11723_PEA_1_P7, comprising a polypeptide being at least about 70% homologous to the sequence MWVLG of R11723_PEA_1_P7.

18. An isolated polypeptide encoding for a tail of R11723_PEA_1_P7, comprising a polypeptide being at least about 70% homologous to the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT in R11723_PEA_1_P7.

19. An isolated chimeric polypeptide encoding for Rl 1723_PEA_1_P7, comprising a first amino acid sequence being at least 90 % homologous to

MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFΓVNCTVNVQDMCQKEV

MEQSAG corresponding to amino acids 24 - 87 of BAC85518, which also corresponds to amino acids 1 - 64 of R11723_PEA_1_P7, and a second amino acid sequence being at least about 70% homologous to a polypeptide having the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT corresponding to amino acids 65 - 93 of R11723_PEA_1_P7, wherein said first and second amino acid sequences are contiguous and in a sequential order.

20. An isolated polypeptide encoding for a tail of R11723_PEA_1_P7, comprising a polypeptide being at least about 70% homologous to the sequence SHCVTRLECSGTISAHCNLCLPGSNDHPT in R11723_PEA_1_P7.

21. An isolated chimeric polypeptide encoding for R11723_PEA_1_P13, comprising a first amino acid sequence being at least 90 % homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSA corresponding to amino acids 1 - 63 of Q96AC2, which also corresponds to amino acids 1 - 63 of R11723_PEA_1_P13, and a second amino acid sequence being at least about 70% homologous to a polypeptide having the sequence DTKRTNTLLFEMRHFAKQLTT corresponding to amino acids 64 - 84 of R11723JPEA_1_P13, wherein said first and second amino acid sequences are contiguous and in a sequential order.

22. An isolated polypeptide encoding for a tail of R11723_PEA_1_P13, comprising a polypeptide being at least about 70% homologous to the sequence DTKRTNTLLFEMRHFAKQLTT in Rl 1723_PEA_1_P13.

23. An isolated chimeric polypeptide encoding for R11723_PEA_l_P10, comprising a first amino acid sequence being at least 90 % homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSA corresponding to amino acids 1 - 63 of Q96AC2, which also corresponds to amino acids 1 - 63 of R11723JPEA_l_P10, and a second amino acid sequence being at least about 70% homologous to a polypeptide having the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK corresponding to amino acids 64 - 90 of Rl 1723_PEA_l_P10, wherein said first and second amino acid sequences are contiguous and in a sequential order.

24. An isolated polypeptide encoding for a tail of R11723_PEA_l_P10, comprising a polypeptide being at least about 70% homologous to the sequence DRVSLCHEAGVQWNNPSTLQPLPPRLK in R11723_PEA_l_P10.

25. An isolated chimeric polypeptide encoding for R11723_PEA_l_P10, comprising a first amino acid sequence being at least 90 % homologous to MWVLGLAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSA corresponding to amino acids 1 - 63 of Q8N2G4, which also corresponds to amino acids 1 - 63 of R11723_PEA_l_P10, and a second amino acid sequence being at least about 70% homologous to a polypeptide having the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK corresponding to amino acids 64 - 90 of Rl 1723_PEA_l_P10, wherein said first and second amino acid sequences are contiguous and in a sequential order.

26. An isolated polypeptide encoding for a tail of Rl 1723_PEA_l_P10, comprising a polypeptide being at least about 70% homologous to the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK in R11723_PEA_l_P10.

27. An isolated chimeric polypeptide encoding for R11723_PEA_l_P10, comprising a first amino acid sequence being at least about 70% homologous to a polypeptide having the sequence MWVLG corresponding to amino acids 1 - 5 of R11723_PEA_l_P10, second amino acid sequence being at least 90 % homologous to IAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEVMEQSA corresponding to amino acids 22 - 79 of BAC85273, which also corresponds to amino acids 6 - 63 of R11723_PEA_l_P10, and a third amino acid sequence being at least about 70% homologous to a polypeptide having the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK corresponding to amino acids 64 - 90 of R11723_PEA_l_P10, wherein said first, second and third amino acid sequences are contiguous and in a sequential order.

28. An isolated polypeptide encoding for a head of Rl 1723_PEA_l_P10, comprising a polypeptide being at least about 70% homologous to the sequence MWVLG of R11723_PEA_l_P10.

29. An isolated polypeptide encoding for a tail of R11723_PEA_l_P10, comprising a polypeptide being at least about 70% homologous to the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK in R11723_PEA_l_P10.

30. An isolated chimeric polypeptide encoding for R11723_PEA_l_P10, comprising a first amino acid sequence being at least 90 % homologous to

MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV

MEQSA corresponding to amino acids 24 - 86 of BAC85518, which also corresponds to amino acids 1 - 63 of R11723_PEA_l_P10, and a second amino acid sequence being a at least about 70% homologous to a polypeptide having the sequence

DRVSLCHEAGVQWNNFSTLQPLPPRLK corresponding to amino acids 64 - 90 of Rl 1723_PEA_l_P10, wherein said first and second amino acid sequences are contiguous and in a sequential order.

31. An isolated polypeptide encoding for a tail of R11723_PEA_l_P10, comprising a polypeptide being at least about 70% homologous to the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK in R11723_PEA_l_P10.

32. An isolated oligonucleotide, comprising an amplicon selected from the group consisting of SEQ ID NOs: 891 or 894.

33. A primer pair, comprising a pair of isolated oligonucleotides capable of amplifying said amplicon of claim 32.

34. The primer pair of claim 33, comprising a pair of isolated oligonucleotides selected from the group consisting of: SEQ NOs 889 and 890; or 892 and 893.

35. An antibody capable of specifically binding to an epitope of an amino acid sequence of any of claims 3-31.

36. The antibody of claim 35, wherein said amino acid sequence comprises said tail of claims 4-31.

37. The antibody of claims 35 or 36, wherein said antibody is capable of differentiating between a splice variant having said epitope and a corresponding known protein PSEC.

38. A kit for detecting prostate cancer, comprising a kit detecting overexpression of a splice variant according to any of the above claims.

39. The kit of claim 38, wherein said kit comprises a NAT-based technology.

40. The kit of claim 39, wherein said kit further comprises at least one primer pair capable of selectively hybridizing to a nucleic acid sequence according to claims 1 or 2.

41. The kit of claim 38, wherein said kit further comprises at least one oligonucleotide capable of selectively hybridizing to a nucleic acid sequence according to claims 1 or 2.

42. The kit of claim 38, wherein said kit comprises an antibody according to any of claims 35-37.

43. The kit of claim 42, wherein said kit further comprises at least one reagent for performing an ELISA or a Western blot.

44. A method for detecting prostate cancer, comprising detecting overexpression of a splice variant according to any of the above claims.

45. The method of claim 44, wherein said detecting overexpression is performed with a NAT-based technology.

46. The method of claim 44, wherein said detecting overexpression is performed with an immunoassay.

47. The method of claim 46, wherein said immunoassay comprises an antibody according to any of the above claims.

48. A biomarker capable of detecting prostate cancer, comprising any of the above nucleic acid sequences or a fragment thereof, or any of the above amino acid sequences or a fragment thereof.

49. A method for screening for prostate cancer, comprising detecting prostatecancer cells with a biomarker or an antibody or a method or assay according to any of the above claims.

50. A method for diagnosing prostate cancer, comprising detecting prostate cancer cells with a biomarker or an antibody or a method or assay according to any of the above claims.

51. A method for monitoring disease progression and/or treatment efficacy and/or relapse of prostate cancer, comprising detecting prostate cancer cells with a biomarker or an antibody or a method or assay according to any of the above claims.

52. A method of selecting a therapy for prostate cancer, comprising detecting prostate cancer cells with a biomarker or an antibody or a method or assay according to any of the above claims and selecting a therapy according to said detection.