CA2440747A1 - Novel nucleic acids and polypeptides - Google Patents

Abstract

The present invention provides novel nucleic acids, novel polypeptide sequences encoded by these nucleic acids and uses thereof.

Description

NOVEL NUCLEIC ACIDS AND POLYPEPTIDES
1. BACKGROUND OF THE INVENTION
S 1.1 TECHNICAL FIELD
The present invention provides novel polynucleotides and proteins encoded by such polynucleotides, along with uses for these polynucleotides and proteins, for example in therapeutic, diagnostic and research methods.
1.2 BACKGROUND
Technology aimed at the discovery of protein factors (including e.g., cytokines, such as lymphokines, interferons, CSFs, chemokines, and interleukins) has matured rapidly over the past decade. The now routine hybridization cloning and expression cloning techniques clone novel polynucleotides "directly" in the sense that they rely on information directly related to the discovered protein (i.e., partial DNA/amino acid sequence of the protein in the case of hybridization cloning; activity of the protein in the case of expression cloning). More recent "indirect" cloning techniques such as signal sequence cloning, which isolates DNA sequences based on the presence of a now well-recognized secretory leader sequence motif, as well as various PCR-based or low stringency hybridization-based cloning techniques, have advanced the state of the art by making available large numbers of DNA/amino acid sequences for proteins that are known to have biological activity, for example, by virtue of their secreted nature in the case of leader sequence cloning, by virtue of their cell or tissue source in the case of PCR-based techniques, or by virtue of structural similarity to other genes of known biological activity.
Identified polynucleotide and polypeptide sequences have numerous applications in, for example, diagnostics, forensics, gene mapping; identification of mutations responsible for genetic disorders or other traits, to assess biodiversity, and to produce many other types of data and products dependent on DNA and amino acid sequences.

2. SUMMARY OF THE INVENTION

The compositions of the present invention include novel isolated polypeptides, novel isolated polynucleotides encoding such polypeptides, including recombinant DNA
molecules, cloned genes or degenerate variants thereof, especially naturally occurring variants such as allelic variants, antisense polynucleotide molecules, and antibodies that specifically recognize one or more epitopes present on such polypeptides, as well as hybridomas producing such antibodies.
The compositions of the present invention additionally include vectors, including expression vectors, containing the polynucleotides of the invention, cells genetically engineered to contain such polynucleotides and cells genetically engineered to express such polynucleotides.
The present invention relates to a collection or library of at least one novel nucleic acid sequence assembled from expressed sequence tags (ESTs) isolated mainly by sequencing by hybridization (SBH), and in some cases, sequences obtained from one or more public databases. The invention relates also to the proteins encoded by such polynucleotides, along with therapeutic, diagnostic and research utilities for these polynucleotides and proteins. These nucleic acid sequences are designated as SEQ ID NO:
1- 526. The polypeptide sequences are designated SEQ )D NOS: 527 - 1052. The nucleic acids and polypeptides are provided in the Sequence Listing. In the nucleic acids provided in the Sequence Listing, A is adenine; C is cytosine; G is guanine; T is thymine; and N is any of the four bases. In the amino acids provided in the Sequence Listing, *
corresponds to the stop codon.
The nucleic acid sequences of the present invention also include, nucleic acid sequences that hybridize to the complement of SEQ ID NO: 1 - 526 under stringent hybridization conditions; nucleic acid sequences which are allelic variants or species homologues of any of the nucleic acid sequences recited above, or nucleic acid sequences that encode a peptide comprising a specific domain or truncation of the peptides encoded by SEQ >D NO: 527 - 1052. A polynucleotide comprising a nucleotide sequence having at least 90% identity to an identifying sequence of SEQ B7 NO: 1 - 526 or a degenerate variant or fragment thereof. The identifying sequence can be 100 base pairs in length.
The nucleic acid sequences of the present invention also include the sequence information from the nucleic acid sequences of SEQ >D NO: 1 - 526. The sequence inforniation can be a segment of any one of SEQ >D NO: 1- 526 that uniquely identifies or represents the sequence information of SEQ ID NO: 1 - 526.
A collection as used in this application can be a collection of only one polynucleotide. The collection of sequence information or identifying information of each sequence can be provided on a nucleic acid array. In one embodiment, segments of sequence information are provided on a nucleic acid array to detect the polynucleotide that contains the segment. The array can be designed to detect full-match or mismatch to the polynucleotide that contains the segment. The collection can also be provided in a computer-readable format.
This invention also includes the reverse or direct complement of any of the nucleic acid sequences recited above; cloning or expression vectors containing the nucleic acid sequences; and host cells or organisms transformed with these expression vectors. Nucleic acid sequences (or their reverse or direct complements) according to the invention have numerous applications in a variety of techniques known to those skilled in the art of molecular biology, such as use as hybridization probes, use as primers for PCR, use in an array, use in computer-readable media, use in sequencing full-length genes, use for chromosome and gene mapping, use in the recombinant production of protein, and use in the generation of anti-sense DNA or RNA, their chemical analogs and the like.
In a preferred embodiment, the nucleic acid sequences of SEQ ~ NO: 1-526 or novel segments or parts of the nucleic acids of the invention are used as primers in expression assays that are well lrnown in the art. In a particularly preferred embodiment, the nucleic acid sequences of SEQ m NO: 1-526 or novel segments or parts of the nucleic acids provided herein are used in diagnostics for identifying expressed genes or, as well known in the art and exemplified by Vollrath et al., Science 258:52-59 (1992), as expressed sequence tags for physical mapping of the human genome.
The isolated polynucleotides of the invention include, but are not limited to, a polynucleotide comprising any one of the nucleotide sequences set forth in SEQ
~ NO: 1-526; a polynucleotide comprising any of the full length protein coding sequences of SEQ >D
NO: 1-526; and a polynucleotide comprising any of the nucleotide sequences of the mature protein coding sequences of SEQ >D NO: 1-526. The polynucleotides of the present invention also include, but are not limited to, a polynucleotide that hybridizes under stringent hybridization conditions to (a) the complement of any one of the nucleotide sequences set forth in SEQ )D NO: 1-526; (b) a nucleotide sequence encoding any one of the amino acid sequences set forth in the Sequence Listing; (c) a polynucleotide which is an allelic variant of any polynucleotides recited above; (d) a polynucleotide which encodes a species homolog (e.g. orthologs) of any of the proteins recited above; or (e) a polynucleotide that encodes a polypeptide comprising a specific domain or truncation of any of the polypeptides comprising an amino acid sequence set forth in the Sequence Listing.
The isolated polypeptides of the invention include, but are not limited to, a polypeptide comprising any of the amino acid sequences set forth in the Sequence Listing;
or the corresponding full length or mature protein. Polypeptides of the invention also include polypeptides with biological activity that are encoded by (a) any of the polynucleotides having a nucleotide sequence set forth in SEQ >D NO: 1-526; or (b) polynucleotides that hybridize to the complement of the polynucleotides of (a) under stringent hybridization conditions. Biologically or immunologically active variants of any of the polypeptide sequences in the Sequence Listing, and "substantial equivalents" thereof (e.g., with at least about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% amino acid sequence identity) that preferably retain biological activity are also contemplated. The polypeptides of the invention may be wholly or partially chemically synthesized but are preferably produced by recombinant means using the genetically engineered cells (e.g. host cells) of the invention.
The invention also provides compositions comprising a polypeptide of the invention. Polypeptide compositions of the invention may further comprise an acceptable Garner, such as a hydrophilic, e.g., pharmaceutically acceptable, carrier.
The invention also provides host cells transformed or transfected with a polynucleotide of the invention.
The invention also relates to methods for producing a polypeptide of the invention comprising growing a culture of the host cells of the invention in a suitable culture medium under conditions permitting expression of the desired polypeptide, and purifying the polypeptide from the culture or from the host cells. Preferred embodiments include those in which the protein produced by such process is a mature form of the protein.
Polynucleotides according to the invention have numerous applications in a variety of techniques known to those skilled in the art of molecular biology.
These techniques include use as hybridization probes, use as oligomers, or primers, for PCR, use for chromosome and gene mapping, use in the recombinant production of protein, and use in generation of anti-sense DNA or RNA, their chemical analogs and the like.
For example, when the expression of an mRNA is largely restricted to a particular cell or S tissue type, polynucleotides of the invention can be used as hybridization probes to detect the presence of the particular cell or tissue mRNA in a sample using, e.g., in situ hybridization.
In other exemplary embodiments, the polynucleotides are used in diagnostics as expressed sequence tags for identifying expressed genes or, as well known in the art and exemplified by Vollrath et al., Science 258:52-59 (1992), as expressed sequence tags for physical mapping of the human genome.
The polypeptides according to the invention can be used in a variety of conventional procedures and methods that are currently applied to other proteins. For example, a polypeptide of the invention can be used to generate an antibody that specifically binds the polypeptide. Such antibodies, particularly monoclonal antibodies, are useful for detecting or quantitating the polypeptide in tissue. The polypeptides of the invention can also be used as molecular weight markers, and as a food supplement.
Methods are also provided for preventing, treating, or ameliorating a medical condition which comprises the step of administering to a mammalian subject a therapeutically effective amount of a composition comprising a polypeptide of the present invention and a pharmaceutically acceptable carrier.
In particular, the polypeptides and polynucleotides of the invention can be utilized, for example, in methods for the prevention andlor treatment of disorders involving aberrant protein expression or biological activity.
The present invention further relates to methods for detecting the presence of the polynucleotides or polypeptides of the invention in a sample. Such methods can, for example, be utilized as part of prognostic and diagnostic evaluation of disorders as recited herein and for the identification of subjects exhibiting a predisposition to such conditions. The invention provides a method for detecting the polynucleotides of the invention in a sample, comprising contacting the sample with a compound that binds to and forms a complex with the polynucleotide of interest for a period sufficient to form the complex and under conditions sufficient to form a complex and detecting the complex such that if a complex is detected, the polynucleotide of interest is detected. The invention also provides a method for detecting the polypeptides of the invention in a sample comprising contacting the sample with a compound that binds to and forms a complex with the polypeptide under conditions and for a period sufficient to form the complex and detecting the formation of the complex such that if a complex is formed, the polypeptide is detected.
The invention also provides kits comprising polynucleotide probes and/or monoclonal antibodies, and optionally quantitative standards, for carrying out methods of the invention. Furthermore, the invention provides methods for evaluating the efficacy of drugs, and monitoring the progress of patients, involved in clinical trials for the treatment of disorders as recited above.
The invention also provides methods for the identification of compounds that modulate (i.e., increase or decrease) the expression or activity of the polynucleotides and/or polypeptides of the invention. Such methods can be utilized, for example, for the identification of compounds that can ameliorate symptoms of disorders as recited herein.
Such methods can include, but are not limited to, assays for identifying compounds and other substances that interact with (e.g., bind to) the polypeptides of the invention. The invention provides a method for identifying a compound that binds to the polypeptides of the invention comprising contacting the compound with a polypeptide of the invention in a cell for a time sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a reporter gene sequence in the cell; and detecting the complex by detecting the reporter gene sequence expression such that if expression of the reporter gene is detected the compound that binds to a polypeptide of the invention is identified.
The methods of the invention also provides methods for treatment which involve the administration of the polynucleotides or polypeptides of the invention to individuals exhibiting symptoms or tendencies. In addition, the invention encompasses methods for treating diseases or disorders as recited herein comprising administering compounds and other substances that modulate the overall activity of the target gene products.

Compounds and other substances can effect such modulation either on the level of target gene/protein expression or target protein activity.
The polypeptides of the present invention and the polynucleotides encoding them are also useful for the same functions known to one of skill in the art as the polypeptides and polynucleotides to which they have homology (set forth in Table 2); for which they have a signature region (as set forth in Table 3); or for which they have homology to a gene family (as set forth in Table 4). If no homology is set forth for a sequence, then the polypeptides and polynucleotides of the present invention are useful for a variety of applications, as described herein, including use in arrays for detection.
3. DETAILED DESCRIPTION OF THE INVENTION
3.1 DEFINITIONS
It must be noted that as used herein and in the appended claims, the singular 1 S forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise.
The term "active" refers to those forms of the polypeptide which retain the biologic and/or immunologic activities of any naturally occurring polypeptide.
According to the invention, the terms "biologically active" or "biological activity"
refer to a protein or peptide having structural, regulatory or biochemical functions of a naturally occurring molecule. Likewise "immunologically active" or "immunological activity" refers to the capability of the natural, recombinant or synthetic polypeptide to induce a specific immune response in appropriate animals or cells and to bind with specific antibodies.
The term "activated cells" as used in this application are those cells which are engaged in extracellular or intracellular membrane trafficking, including the export of secretory or enzymatic molecules as part of a normal or disease process.
The terms "complementary" or "complementarity" refer to the natural binding of polynucleotides by base pairing. For example, the sequence 5'-AGT-3' binds to the complementary sequence 3'-TCA-S'. Complementarity between two single-stranded molecules may be "partial" such that only some of the nucleic acids bind or it may be "complete" such that total complementarity exists between the single stranded molecules.

The degree of complementarity between the nucleic acid strands has significant effects on the efficiency and strength of the hybridization between the nucleic acid strands.
The term "embryonic stem cells (ES)" refers to a cell that can give rise to many differentiated cell types in an embryo or an adult, including the germ cells.
The term S "germ line stem cells (GSCs)" refers to stem cells derived from primordial stem cells that provide a steady and continuous source of germ cells for the production of gametes. The term "primordial germ cells (PGCs)" refers to a small population of cells set aside from other cell lineages particularly from the yolk sac, mesenteries, or gonadal ridges during embryogenesis that have the potential to differentiate into germ cells and other cells.
PGCs are the source from which GSCs and ES cells are derived The PGCs, the GSCs and the ES cells are capable of self renewal. Thus these cells not only populate the germ line and give rise to a plurality of terminally differentiated cells that comprise the adult specialized organs, but are able to regenerate themselves.
The term "expression modulating fragment," EMF, means a series of nucleotides which modulates the expression of an operably linked ORF or another EMF.
As used herein, a sequence is said to "modulate the expression of an operably linked sequence" when the expression of the sequence is altered by the presence of the EMF. EMFs include, but are not limited to, promoters, and promoter modulating sequences (inducible elements). One class of EMFs are nucleic acid fragments which induce the expression of an operably linked ORF in response to a specific regulatory factor or physiological event.
The terms "nucleotide sequence" or "nucleic acid" or "polynucleotide" or "oligonucleotide" are used interchangeably and refer to a heteropolymer of nucleotides or the sequence of these nucleotides. These phrases also refer to DNA or RNA of genomic or synthetic origin which may be single-stranded or double-stranded and may represent the sense or the antisense strand, to peptide nucleic acid (PNA) or to any DNA-like or RNA-like material. In the sequences herein A is adenine, C is cytosine, T is thymine, G
is guanine and N is A, C, G or T (U). It is contemplated that where the polynucleotide is RNA, the T (thymine) in the sequences provided herein is substituted with U
(uracil).
Generally, nucleic acid segments provided by this invention may be assembled from fragments of the genome and short oligonucleotide linkers, or from a series of oligonucleotides, or from individual nucleotides, to provide a synthetic nucleic acid which is capable of being expressed in a recombinant transcriptional unit comprising regulatory elements derived from a microbial or viral operon, or a eukaryotic gene.
The terms "oligonucleotide fragment" or a "polynucleotide fragment", "portion,"
or "segment" or "probe" or "primer" are used interchangeably and refer to a sequence of nucleotide residues which are at least about S nucleotides, more preferably at least about 7 nucleotides, more preferably at least about 9 nucleotides, more preferably at least about 11 nucleotides and most preferably at least about 17 nucleotides. The fragment is preferably less than about 500 nucleotides, preferably less than about 200 nucleotides, more preferably less than about 100 nucleotides, more preferably less than about 50 nucleotides and most preferably less than 30 nucleotides. Preferably the probe is from about 6 nucleotides to about 200 nucleotides, preferably from about 1 S to about 50 nucleotides, more preferably from about 17 to 30 nucleotides and most preferably from about 20 to 25 nucleotides. Preferably the fragments can be used in polymerase chain reaction (PCR), various hybridization procedures or microarray procedures to identify or amplify identical or related parts of mRNA or DNA molecules. A fragment or segment may uniquely identify each polynucleotide sequence of the present invention.
Preferably the fragment comprises a sequence substantially similar to any one of SEQ ID
NOs: l-526.
Probes may, for example, be used to determine whether specific mRNA
molecules are present in a cell or tissue or to isolate similar nucleic acid sequences from chromosomal DNA as described by Walsh et al. (Walsh, P.S. et al., 1992, PCR
Methods Appl 1:241-250). They may be labeled by nick translation, Klenow fill-in reaction, PCR, or other methods well known in the art. Probes of the present invention, their preparation and/or labeling are elaborated in Sambrook, J. et al., 1989, Molecular Cloning: A
Laboratory Manual, Cold Spring Harbor Laboratory, NY; or Ausubel, F.M. et al., 1989, Current Protocols in Molecular Biology, John Wiley & Sons, New York NY, both of which are incorporated herein by reference in their entirety.
The nucleic acid sequences of the present invention also include the sequence information from the nucleic acid sequences of SEQ ID NOs: 1-526. The sequence information can be a segment of any one of SEQ >D NOs: 1-526 that uniquely identifies or represents the sequence information of that sequence of SEQ ID NO: 1-526.
One such segment can be a twenty-mer nucleic acid sequence because the probability that a twenty-mer is fully matched in the human genome is 1 in 300. In the human genome, there are three billion base pairs in one set of chromosomes. Because 4z°
possible twenty-mers exist, there are 300 times more twenty-mers than there are base pairs in a set of human chromosomes. Using the same analysis, the probability for a seventeen-mer to be fully matched in the human genome is approximately 1 in S. When these segments are used in arrays for expression studies, fifteen-mer segments can be used. The probability that the fifteen-mer is fully matched in the expressed sequences is also approximately one in five because expressed sequences comprise less than approximately S% of the entire genome sequence.
Similarly, when using sequence information for detecting a single mismatch, a segment can be a twenty-f ve mer. The probability that the twenty-five mer would appear in a human genome with a single mismatch is calculated by multiplying the probability for a full match (1-425) times the increased probability for mismatch at each nucleotide position (3 x 25). The probability that an eighteen mer with a single mismatch can be detected in an array for expression studies is approximately one in five. The probability that a twenty-mer with a single mismatch can be detected in a human genome is approximately one in five.
The term "open reading frame," ORF, means a series of nucleotide triplets coding for amino acids without any termination codons and is a sequence translatable into protein.
The terms "operably linked" or "operably associated" refer to functionally related nucleic acid sequences. For example, a promoter is operably associated or operably linked with a coding sequence if the promoter controls the transcription of the coding sequence. While operably linked nucleic acid sequences can be contiguous and in the same reading frame, certain genetic elements e.g. repressor genes are not contiguously linked to the coding sequence but still control transcription/translation of the coding sequence.
The term "pluripotent" refers to the capability of a cell to differentiate into a number of differentiated cell types that are present in an adult organism. A
pluripotent cell is restricted in its differentiation capability in comparison to a totipotent cell.

The terms "polypeptide" or "peptide" or "amino acid sequence" refer to an oligopeptide, peptide, polypeptide or protein sequence or fragment thereof and to naturally occurring or synthetic molecules. A polypeptide "fragment,"
"portion," or "segment" is a stretch of amino acid residues of at least about 5 amino acids, preferably at least about 7 amino acids, more preferably at least about 9 amino acids and most preferably at least about 17 or more amino acids. The peptide preferably is not greater than about 200 amino acids, more preferably less than 150 amino acids and most preferably less than 100 amino acids. Preferably the peptide is from about 5 to about 200 amino acids. To be active, any polypeptide must have sufficient length to display biological and/or immunological activity.
The term "naturally occurring polypeptide" refers to polypeptides produced by cells that have not been genetically engineered and specifically contemplates various polypeptides arising from post-translational modifications of the polypeptide including, but not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation and acylation.
The term "translated protein coding portion" means a sequence which encodes for the full length protein which may include any leader sequence or any processing sequence.
The term "mature protein coding sequence" means a sequence which encodes a peptide or protein without a signal or leader sequence. The "mature protein portion"
means that portion of the protein which does not include a signal or leader sequence. The peptide may have been produced by processing in the cell which removes any leader/signal sequence. The mature protein portion may or may not include the initial methionine residue. The methionine residue may be removed from the protein during processing in the cell. The peptide may be produced synthetically or the protein may have been produced using a polynucleotide only encoding for the mature protein coding sequence.
The term "derivative" refers to polypeptides chemically modified by such techniques as ubiquitination, labeling (e.g., with radionuclides or various enzymes), covalent polymer attachment such as pegylation (derivatization with polyethylene glycol) and insertion or substitution by chemical synthesis of amino acids such as ornithine, which do not normally occur in human proteins.
The term "variant"(or "analog") refers to any polypeptide differing from naturally occurring polypeptides by amino acid insertions, deletions, and substitutions, created using, a g., recombinant DNA techniques. Guidance in determining which amino acid residues may be replaced, added or deleted without abolishing activities of interest, may be found by comparing the sequence of the particular polypeptide with that of homologous peptides and minimizing the number of amino acid sequence changes made in regions of high homology (conserved regions) or by replacing amino acids with consensussequence.
Alternatively, recombinant variants encoding these same or similar polypeptides may be synthesized or selected by making use of the "redundancy" in the genetic code.
Various codon substitutions, such as the silent changes which produce various restriction sites, may be introduced to optimize cloning into a plasmid or viral vector or expression in a particular prokaryotic or eukaryotic system. Mutations in the polynucleotide sequence may be reflected in the polypeptide or domains of other peptides added to the polypeptide to modify the properties of any part of the polypeptide, to change characteristics such as ligand-binding affinities, interchain affinities, or degradation/turnover rate.
Preferably, amino acid "substitutions" are the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, i.e., conservative amino acid replacements. "Conservative" amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved. For example, nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine; polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine; positively charged (basic) amino acids include arginine, lysine, and histidine; and negatively charged (acidic) amino acids include aspartic acid and glutamic acid. "Insertions" or "deletions" are preferably in the range of about 1 to 20 amino acids, more preferably 1 to 10 amino acids. The variation allowed may be experimentally determined by systematically making insertions, deletions, or substitutions of amino acids in a polypeptide molecule using recombinant DNA techniques and assaying the resulting recombinant variants for activity.
Alternatively, where alteration of function is desired, insertions, deletions or non-conservative alterations can be engineered to produce altered polypeptides. Such alterations can, for example, alter one or more of the biological functions or biochemical characteristics of the polypeptides of the invention. For example, such alterations may change polypeptide characteristics such as ligand-binding affinities, interchain affinities, or degradation/turnover rate. Further, such alterations can be selected so as to generate polypeptides that are better suited for expression, scale up and the like in the host cells chosen for expression. For example, cysteine residues can be deleted or substituted with another amino acid residue in order to eliminate disulfide bridges.
The terms "purified" or "substantially purified" as used herein denotes that the indicated nucleic acid or polypeptide is present in the substantial absence of other biological macromolecules, e.g., polynucleotides, proteins, and the like. In one embodiment, the polynucleotide or polypeptide is purified such that it constitutes at least 95% by weight, more preferably at least 99% by weight, of the indicated biological macromolecules present (but water, buffers, and other small molecules, especially molecules having a molecular weight of less than 1000 daltons, can be present).
The term "isolated" as used herein refers to a nucleic acid or polypeptide separated from at least one other component (e.g., nucleic acid or polypeptide) present with the nucleic acid or polypeptide in its natural source. In one embodiment, the nucleic acid or polypeptide is found in the presence of (if anything) only a solvent, buffer, ion, or other component normally present in a solution of the same. The terms "isolated" and "purified" do not encompass nucleic acids or polypeptides present in their natural source.
The term "recombinant," when used herein to refer to a polypeptide or protein, means that a polypeptide or protein is derived from recombinant (e.g., microbial, insect, or mammalian) expression systems. "Microbial" refers to recombinant polypeptides or proteins made in bacterial or fungal (e.g., yeast) expression systems. As a product, "recombinant microbial" defines a polypeptide or protein essentially free of native endogenous substances and unaccompanied by associated native glycosylation.
Polypeptides or proteins expressed in most bacterial cultures, e.g., E. coli, will be free of glycosylation modifications; polypeptides or proteins expressed in yeast will have a glycosylation pattern in general different from those expressed in mammalian cells.
The term "recombinant expression vehicle or vector" refers to a plasmid or phage or virus or vector, for expressing a polypeptide from a DNA (RNA) sequence. An S expression vehicle can comprise a transcriptional unit comprising an assembly of (1) a genetic element or elements having a regulatory role in gene expression, for example, .
promoters or enhancers, (2) a structural or coding sequence which is transcribed into mRNA and translated into protein, and (3) appropriate transcription initiation and termination sequences. Structural units intended for use in yeast or eukaryotic expression systems preferably include a leader sequence enabling extracellular secretion of translated protein by a host cell. Alternatively, where recombinant protein is expressed without a leader or transport sequence, it may include an amino terminal methionine residue. This residue may or may not be subsequently cleaved from the expressed recombinant protein to provide a final product.
The term "recombinant expression system" means host cells which have stably integrated a recombinant transcriptional unit into chromosomal DNA or carry the recombinant transcriptional unit extrachromosomally. Recombinant expression systems as defined herein will express heterologous polypeptides or proteins upon induction of the regulatory elements linked to the DNA segment or synthetic gene to be expressed.
This term also means host cells which have stably integrated a recombinant genetic element or elements having a regulatory role in gene expression, for example, promoters or enhancers. Recombinant expression systems as defined herein will express polypeptides or proteins endogenous to the cell upon induction of the regulatory elements linked to the endogenous DNA segment or gene to be expressed. The cells can be prokaryotic or eukaryotic.
The term "secreted" includes a protein that is transported across or through a membrane, including transport as a result of signal sequences in its amino acid sequence when it is expressed in a suitable host cell. "Secreted" proteins include without limitation proteins secreted wholly (e.g., soluble proteins) or partially (e.g., receptors) from the cell in which they are expressed. "Secreted" proteins also include without limitation proteins that are transported across the membrane of the endoplasmic reticulum.
"Secreted"

proteins are also intended to include proteins containing non-typical signal sequences (e.g. Interleukin-1 Beta, see Kxasney, P.A. and Young, P.R. (1992) Cytokine 4(2):134 -143) and factors released from damaged cells (e.g. Interleukin-1 Receptor Antagonist, see Arend, W.P. et. al. (1998) Annu. Rev. Immunol. 16:27-55) Where desired, an expression vector may be designed to contain a "signal or leader sequence" which will direct the polypeptide through the membrane of a cell. Such a sequence may be naturally present on the polypeptides of the present invention or provided from heterologous protein sources by recombinant DNA techniques.
The term "stringent" is used to refer to conditions that are commonly understood in the art as stringent. Stringent conditions can include highly stringent conditions (i.e., hybridization to filter-bound DNA in 0.5 M NaHP04, 7% sodium dodecyl sulfate (SDS), 1 mM EDTA at 65°C, and washing in O.1X SSC/0.1% SDS at 68°C), and moderately stringent conditions (i.e., washing in 0.2X SSC/0.1% SDS at 42°C).
Other exemplary hybridization conditions are described herein in the examples.
In instances of hybridization of deoxyoligonucleotides, additional exemplary stringent hybridization conditions include washing in 6X SSC/0.05% sodium pyrophosphate at 37°C (for 14-base oligonucleotides), 48°C (for 17-base-oligos), 55°C
(for 20-base oligonucleotides), and 60°C (for 23-base oligonucleotides).
As used herein, "substantially equivalent" or "substantially similar" can refer both to nucleotide and amino acid sequences, for example a mutant sequence, that varies from a reference sequence by one or more substitutions, deletions, or additions, the net effect of which does not result in an adverse functional dissimilarity between the reference and subject sequences. Typically, such a substantially equivalent sequence varies from one of those listed herein by no more than about 35% (i.e., the number of individual residue substitutions, additions, and/or deletions in a substantially equivalent sequence, as compared to the corresponding reference sequence, divided by the total number of residues in the substantially equivalent sequence is about 0.35 or less). Such a sequence is said to have 65% sequence identity to the listed sequence. In one embodiment, a substantially equivalent, e.g., mutant, sequence of the invention varies from a listed sequence by no more than 30% (70% sequence identity); in a variation of this embodiment, by no more than 25% (75% sequence identity); and in a further variation of this embodiment, by no more than 20% (80% sequence identity) and in a further variation of this embodiment, by no more than 10% (90% sequence identity) and in a further variation of this embodiment, by no more that 5% (95% sequence identity).
Substantially equivalent, e.g., mutant, amino acid sequences according to the invention preferably have at least 80% sequence identity with a listed amino acid sequence, more preferably at least 85% sequence identity, more preferably at least 90% sequence identity, more preferably at least 95% sequence identity, more preferably at least 98% sequence identity, and most preferably at least 99% sequence identity. Substantially equivalent nucleotide sequence of the invention can have lower percent sequence identities, taking into account, for example, the redundancy or degeneracy of the genetic code. Preferably, the nucleotide sequence has at least about 65% identity, more preferably at least about 75%
identity, more preferably at least about 80% sequence identity, more preferably at least 85%
sequence identity, more preferably at least 90% sequence identity, more preferably at least about 95% sequence identity, more preferably at least 98% sequence identity, and 1 S most preferably at least 99% sequence identity. For the purposes of the present invention, sequences having substantially equivalent biological activity and substantially equivalent expression characteristics are considered substantially equivalent.
For the purposes of determining equivalence, truncation of the mature sequence (e.g., via a mutation which creates a spurious stop codon) should be disregarded. Sequence identity may be determined, e.g., using the Jotun Hein method (Hero, J. (1990) Methods Enzymol. 183:626-645). Identity between sequences can also be determined by other methods known in the art, e.g. by varying hybridization conditions.
The term "totipotent" refers to the capability of a cell to differentiate into all of the cell types of an adult organism.
The term "transformation" means introducing DNA into a suitable host cell so that the DNA is replicable, either as an extrachromosomal element, or by chromosomal integration. The term "transfection" refers to the taking up of an expression vector by a suitable host cell, whether or not any coding sequences are in fact expressed.
The term "infection" refers to the introduction of nucleic acids into a suitable host cell by use of a virus or viral vector.

As used herein, an "uptake modulating fragment," UMF, means a series of nucleotides which mediate the uptake of a linked DNA fragment into a cell.
UMFs can be readily identified using known IJMFs as a target sequence or target motif with the computer-based systems described below. The presence and activity of a LJMF
can be confirmed by attaching the suspected UMF to a marker sequence. The resulting nucleic acid molecule is then incubated with an appropriate host under appropriate conditions and the uptake of the marker sequence is determined. As described above, a IJMF
will increase the frequency of uptake of a linked marker sequence.
Each of the above terms is meant to encompass all that is described for each, unless the context dictates otherwise.
3.2 NUCLEIC ACIDS OF THE INVENTION
Nucleotide sequences of the invention are set forth in the Sequence Listing.
The isolated polynucleotides of the invention include a polynucleotide comprising the nucleotide sequences of SEQ ID NO: 1 - 526; a polynucleotide encoding any one of the peptide sequences of SEQ ID NO: 527 - 1052; and a polynucleotide comprising the nucleotide sequence encoding the mature protein coding sequence of the.polynucleotides of any one of SEQ ID NO: 1 - 526. The polynucleotides of the present invention also include, but are not limited to, a polynucleotide that hybridizes under stringent conditions to (a) the complement of any of the nucleotides sequences of SEQ ID NO: 1 -526; (b) nucleotide sequences encoding any one of the amino acid sequences set forth in the Sequence Listing as SEQ ID NO: 527 - 1052; (c) a polynucleotide which is an allelic variant of any polynucleotide recited above; (d) a polynucleotide which encodes a species homolog of any of the proteins recited above; or (e) a polynucleotide that encodes a polypeptide comprising a specific domain or truncation of the polypeptides of SEQ ID
NO: 527 - 1052. Domains of interest may depend on the nature of the encoded polypeptide; e.g., domains in receptor-like polypeptides include ligand-binding, extracellular, transmembrane, or cytoplasmic domains, or combinations thereof;
domains in immunoglobulin-like proteins include the variable immunoglobulin-like domains;
domains in enzyme-like polypeptides include catalytic and substrate binding domains;
and domains in ligand polypeptides include receptor-binding domains.

The polynucleotides of the invention include naturally occurring or wholly or partially synthetic DNA, e.g., cDNA and genomic DNA, and RNA, e.g., mRNA. The polynucleotides may include all of the coding region of the cDNA or may represent a portion of the coding region of the cDNA.
The present invention also provides genes corresponding to the cDNA sequences disclosed herein. The corresponding genes can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include the preparation of probes or primers from the disclosed sequence information for identification and/or amplification of genes in appropriate genomic libraries or other sources of genomic materials. Further 5' and 3' sequence can be obtained using methods known in the art. For example, full length cDNA or genomic DNA that corresponds to any of the polynucleotides of SEQ ID NO: 1 - 526 can be obtained by screening appropriate cDNA or genomic DNA
libraries under suitable hybridization conditions using any of the polynucleotides of SEQ ID
NO: 1 - 526 or a portion thereof as a probe. Alternatively, the polynucleotides of SEQ ID
NO: 1 - 526 may be used as the basis for suitable primers) that allow identification and/or amplification of genes in appropriate genomic DNA or cDNA libraries.
The nucleic acid sequences of the invention can be assembled from ESTs and sequences (including cDNA and genomic sequences) obtained from one or more public databases, such as dbEST, gbpri, and UniGene. The EST sequences can provide identifying sequence information, representative fragment or segment information, or novel segment information for the full-length gene.
The polynucleotides of the invention also provide polynucleotides including nucleotide sequences that are substantially equivalent to the polynucleotides recited above. Polynucleotides according to the invention can have, e.g., at least about 65%, at least about 70%, at least about 75%, at least about 80%, 81%, 82%, 83%, 84%, more typically at least about 85%, 86%, 87%, 88%, 89%, more typically at least about 90%, 91%, 92%, 93%, 94%, and even more typically at least about 95%, 96%, 97%, 98%, 99%
sequence identity to a polynucleotide recited above.
Included within the scope of the nucleic acid sequences of the invention are nucleic acid sequence fragments that hybridize under stringent conditions to any of the nucleotide sequences of SEQ ID NO: 1 - 526, or complements thereof, which fragment is greater than about 5 nucleotides, preferably 7 nucleotides, more preferably greater than 9 nucleotides and most preferably greater than 17 nucleotides. Fragments of, e.g. 15, 17, or 20 nucleotides or more that are selective for (i.e. specifically hybridize to) any one of the polynucleotides of the invention are contemplated. Probes capable of specifically hybridizing to a polynucleotide can differentiate polynucleotide sequences of the invention from other polynucleotide sequences in the same family of genes or can differentiate human genes from genes of other species, and are preferably based on unique nucleotide sequences.
The sequences falling within the scope of the present invention are not limited to these specific sequences, but also include allelic and species variations thereof. Allelic and species variations can be routinely determined by comparing the sequence provided in SEQ
>D NO: 1 - 526, a representative fragment thereof, or a nucleotide sequence at least 90%
identical, preferably 95% identical, to SEQ >D NOs: 1 - 526 with a sequence from another isolate of the same species. Furthermore, to accommodate codon variability, the invention includes nucleic acid molecules coding for the same amino acid sequences as do the specific ORFs disclosed herein. In other words, in the coding region of an ORF, substitution of one codon for another codon that encodes the same amino acid is expressly contemplated.
The nearest neighbor or homology result for the nucleic acids of the present invention, including SEQ m NOs: 1 - 526, can be obtained by searching a database using an algorithm or a program. Preferably, a BLAST which stands for Basic Local Alignment Search Tool is used to search for local sequence alignments (Altshul, S.F. J
Mol. Evol. 36 290-300 (1993) and Altschul S.F. et al. J. Mol. Biol. 21:403-410 (1990)).
Alternatively a FASTA version 3 search against Genpept, using Fastxy algorithm.
Species homologs (or orthologs) of the disclosed polynucleotides and proteins are also provided by the present invention. Species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source from the desired species.
The invention also encompasses allelic variants of the disclosed polynucleotides or proteins; that is, naturally-occurring alternative forms of the isolated polynucleotide which also encode proteins which are identical, homologous or related to that encoded by the polynucleotides.

The nucleic acid sequences of the invention are further directed to sequences which encode variants of the described nucleic acids. These amino acid sequence variants may be prepared by methods known in the art by introducing appropriate nucleotide changes into a native or variant polynucleotide. There are two variables in the construction of amino acid sequence variants: the location of the mutation and the nature of the mutation. Nucleic acids encoding the amino acid sequence variants are preferably constructed by mutating the polynucleotide to encode an amino acid sequence that does not occur in nature. These nucleic acid alterations can be made at sites that differ in the nucleic acids from different species (variable positions) or in highly conserved regions (constant regions). Sites at such locations will typically be modified in series, e.g., by substituting first with conservative choices (e.g., hydrophobic amino acid to a different hydrophobic amino acid) and then with more distant choices (e.g., hydrophobic amino acid to a charged amino acid), and then deletions or insertions may be made at the target site. Amino acid sequence deletions generally range from about 1 to 30 residues, 1 S preferably about 1 to 10 residues, and are typically contiguous. Amino acid insertions include amino- and/or carboxyl-terminal fusions ranging in length from one to one hundred or more residues, as well as intrasequence insertions of single or.
multiple amino acid residues. Intrasequence insertions may range generally from about 1 to 10 amino residues, preferably from 1 to 5 residues. Examples of terminal insertions include the heterologous signal sequences necessary for secretion or for intracellular targeting in different host cells and sequences such as FLAG or poly-histidine sequences useful for purifying the expressed protein.
In a preferred method, polynucleotides encoding the novel amino acid sequences are changed via site-directed mutagenesis. This method uses oligonucleotide sequences to alter a polynucleotide to encode the desired amino acid variant, as well as sufficient adjacent nucleotides on both sides of the changed amino acid to form a stable duplex on either side of the site of being changed. In general, the techniques of site-directed mutagenesis are well known to those of skill in the art and this technique is exemplified by publications such as, Edelman et al., DNA 2:183 (1983). A versatile and efficient method for producing site-specific changes in a polynucleotide sequence was published by Zoller and Smith, Nucleic Acids Res. 10:6487-6500 (1982). PCR may also be used to create amino acid sequence variants of the novel nucleic acids. When small amounts of template DNA are used as starting material, primers) that differs slightly in sequence from the corresponding region in the template DNA can generate the desired amino acid variant. PCR amplification results in a population of product DNA fragments that differ from the polynucleotide template encoding the polypeptide at the position specified by the primer. The product DNA fragments replace the corresponding region in the plasmid and this gives a polynucleotide encoding the desired amino acid variant.
A further technique for generating amino acid variants is the cassette mutagenesis technique described in Wells et al., Gene 34:315 (1985); and other mutagenesis techniques well known in the art, such as, for example, the techniques in Sambrook et al., supra, and Current Protocols in Molecular Biology, Ausubel et al. Due to the inherent degeneracy of the genetic code, other DNA sequences which encode substantially the same or a functionally equivalent amino acid sequence may be used in the practice of the invention for the cloning and expression of these novel nucleic acids. Such DNA
sequences include those which are capable of hybridizing to the appropriate novel nucleic acid sequence under stringent conditions.
Polynucleotides encoding preferred polypeptide truncations of the invention can be used to generate polynucleotides encoding chimeric or fusion proteins comprising one or more domains of the invention and heterologous protein sequences.
The polynucleotides of the invention additionally include the complement of any of the polynucleotides recited above. The polynucleotide can be DNA (genomic, cDNA, amplified, or synthetic) or RNA. Methods and algorithms for obtaining such polynucleotides are well known to those of skill in the art and can include, for example, methods for determining hybridization conditions that can routinely isolate polynucleotides of the desired sequence identities.
In accordance with the invention, polynucleotide sequences comprising the mature protein coding sequences corresponding to any one of SEQ >D NO: 1-526, or functional equivalents thereof, may be used to generate recombinant DNA
molecules that direct the expression of that nucleic acid, or a functional equivalent thereof, in appropriate host cells. Also included are the cDNA inserts of any of the clones identified herein.

A polynucleotide according to the invention can be joined to any of a variety of other nucleotide sequences by well-established recombinant DNA techniques (see Sambrook J et al. (1989) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, NY). Useful nucleotide sequences for joining to polynucleotides include an assortment of vectors, e.g., plasmids, cosmids, lambda phage derivatives, phagemids, and the like, that are well known in the art. Accordingly, the invention also provides a vector including a polynucleotide of the invention and a host cell containing the polynucleotide.
In general, the vector contains an origin of replication functional in at least one organism, convenient restriction endonuclease sites, and a selectable marker for the host cell.
Vectors according to the invention include expression vectors, replication vectors, probe generation vectors, and sequencing vectors. A host cell according to the invention can be a prokaryotic or eukaryotic cell and can be a unicellular organism or part of a multicellular organism.
The present invention further provides recombinant constructs comprising a 1 S nucleic acid having any of the nucleotide sequences of SEQ ID NOs: 1 - 526 or a fragment thereof or any other polynucleotides of the invention. In one embodiment, the recombinant constructs of the present invention comprise a vector, such as a plasmid or viral vector, into which a nucleic acid having any of the nucleotide sequences of SEQ ID
NOs: 1 - 526 or a fragment thereof is inserted, in a forward or reverse orientation. In the case of a vector comprising one of the ORFs of the present invention, the vector may further comprise regulatory sequences, including for example, a promoter, operably linked to the ORF. Large numbers of suitable vectors and promoters are known to those of skill in the art and are commercially available for generating the recombinant constructs of the present invention. The following vectors are provided by way of example. Bacterial: pBs, phagescript, PsiX174, pBluescript SK, pBs KS, pNHBa, pNHl6a, pNHl8a, pNH46a (Stratagene); pTrc99A, pKK223-3, pKK233-3, pDR540, pRITS (Pharmacia). Eukaryotic: pWLneo, pSV2cat, pOG44, PXTI, pSG (Stratagene) pSVK3, pBPV, pMSG, pSVL (Pharmacia).
The isolated polynucleotide of the invention may be operably linked to an expression control sequence such as the pMT2 or pED expression vectors disclosed in Kaufinan et al., Nucleic Acids Res. 19, 4485-4490 (1991), in order to produce the protein recombinantly. Many suitable expression control sequences are known in the art.
General methods of expressing recombinant proteins are also known and are exemplified in R. Kaufman, Methods in Enzymology 185, 537-566 (1990). As defined herein "operably linked" means that the isolated polynucleotide of the invention and an expression control sequence are situated within a vector or cell in such a way that the protein is expressed by a host cell which has been transformed (transfected) with the ligated polynucleotide/expression control sequence.
Promoter regions can be selected from any desired gene using CAT
(chloramphenicol transferase) vectors or other vectors with selectable markers. Two appropriate vectors are pKK232-8 and pCM7. Particular named bacterial promoters include lacI, lacZ, T3, T7, gpt, lambda PR, and trc. Eukaryotic promoters include CMV
immediate early, HSV thymidine kinase, early and late SV40, LTRs from retrovirus, and mouse metallothionein-I. Selection of the appropriate vector and promoter is well within the level of ordinary skill in the art. Generally, recombinant expression vectors will include origins of replication and selectable markers permitting transformation of the host cell, e.g., the ampicillin resistance gene ofE. coli and S. cerevisiae TRP1 gene, and a promoter derived from a highly-expressed gene to direct transcription of a downstream structural sequence. Such promoters can be derived from operons encoding glycolytic enzymes such as 3-phosphoglycerate kinase (PGK), a-factor, acid phosphatase, or heat shock proteins, among others. The heterologous structural sequence is assembled in appropriate phase with translation initiation and termination sequences, and preferably, a leader sequence capable of directing secretion of translated protein into the periplasmic space or extracellular medium. Optionally, the heterologous sequence can encode a fusion protein including an amino terminal identification peptide imparting desired characteristics, e.g., stabilization or simplified purification of expressed recombinant product. Useful expression vectors for bacterial use are constructed by inserting a structural DNA sequence encoding a desired protein together with suitable translation initiation and termination signals in operable reading phase with a functional promoter.
The vector will comprise one or more phenotypic selectable markers and an origin of replication to ensure maintenance of the vector and to, if desirable, provide amplification within the host. Suitable prokaryotic hosts for transformation include E.
coli, Bacillus subtilis, Salmonella typhirrrurium and various species within the genera Pseudomonas, Streptomyces, and Staphylococcus, although others may also be employed as a matter of choice.
As a representative but non-limiting example, useful expression vectors for bacterial use can comprise a selectable marker and bacterial origin of replication derived from commercially available plasmids comprising genetic elements of the well known cloning vector pBR322 (ATCC 37017). Such commercial vectors include, for example, pKK223-3 (Pharmacia Fine Chemicals, Uppsala, Sweden) and GEM 1 (Promega Biotech, Madison, WI, USA). These pBR322 "backbone" sections are combined with an appropriate promoter and the structural sequence to be expressed. Following transformation of a suitable host strain and growth of the host strain to an appropriate cell density, the selected promoter is induced or derepressed by appropriate means (e.g., temperature shift or chemical induction) and cells are cultured for an additional period.
Cells are typically harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract retained for further purification.
Polynucleotides of the invention can also be used to induce immune responses.
For example, as described in Fan et al., Nat. Biotech. 17:870-872 (1999);
incorporated herein by reference, nucleic acid sequences encoding a polypeptide may be used to generate antibodies against the encoded polypeplide following topical administration of naked plasmid DNA or following injection, and preferably intra-muscular injection of the DNA. The nucleic acid sequences are preferably inserted in a recombinant expression vector and may be in the form of naked DNA.
3.3 ANTISENSE
Another aspect of the invention pertains to isolated antisense nucleic acid molecules that are hybridizable to or complementary to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 1 - 526, or fragments, analogs or derivatives thereof. An "antisense" nucleic acid comprises a nucleotide sequence that is complementary to a "sense" nucleic acid encoding a protein, e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA
sequence. In specific aspects, antisense nucleic acid molecules are provided that comprise a sequence complementary to at least about 10, 25, 50, 100, 250 or nucleotides or an entire coding strand, or to only a portion thereof. Nucleic acid molecules encoding fragments, homologs, derivatives and analogs of a protein of any of SEQ ID NO: 527 -1052 or antisense nucleic acids complementary to a nucleic acid sequence of SEQ ID NO: 1 - 526 are additionally provided.
In one embodiment, an antisense nucleic acid molecule is antisense to a "coding region" of the coding strand of a nucleotide sequence of the invention. The term "coding region" refers to the region of the nucleotide sequence comprising codons which are translated into amino acid residues. In another embodiment, the antisense nucleic acid molecule is antisense to a "noncoding region" of the coding strand of a nucleotide sequence of the invention. The term "noncoding region" refers to 5' and 3' sequences that flank the coding region that are not translated into amino acids (i.e., also referred to as 5' and 3' untranslated regions).
Given the coding strand sequences encoding a nucleic acid disclosed herein (e.g., SEQ ID NO: 1 - 526, antisense nucleic acids of the invention can be designed according to the rules of Watson and Crick or Hoogsteen base pairing. The antisense nucleic acid molecule can be complementary to the entire coding region of an mRNA, but more preferably is an oligonucleotide that is antisense to only a portion of the coding or noncoding region of an mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of an mRNA.
An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides in length. An antisense nucleic acid of the invention can be constructed using chemical synthesis or enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used.
Examples of modified nucleotides that can be used to generate the antisense nucleic acid include: 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, S-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, S-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, S-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-S-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following 1 S subsection).
The antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA
and/or genomic DNA encoding a protein according to the invention to thereby inhibit expression of the protein, e.g., by inhibiting transcription and/or translation. The hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA
duplexes, through specific interactions in the major groove of the double helix. An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically.
For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface, e.g., by linking the antisense nucleic acid molecules to peptides or antibodies that bind to cell surface receptors or antigens. The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To achieve sufficient intracellular concentrations of antisense molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III
promoter are preferred.
In yet another embodiment, the antisense nucleic acid molecule of the invention is an a-anomeric nucleic acid molecule. An a-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual a-units, the strands run parallel to each other (Gaultier et al. (1987) Nucleic Acids Res 15:
6625-6641). The antisense nucleic acid molecule can also comprise a 2'-o-methylribonucleotide (moue et al. (1987) Nucleic Acids Res 15: 6131-6148) or a chimeric RNA -DNA analogue (moue et al. (1987) FEBS Lett 215: 327-330).
3.4 RIBOZYMES AND PNA MOIETIES
In still another embodiment, an antisense nucleic acid of the invention is a ribozyme. Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and Gerlach (1988) Nature 334:585-591)) can be used to catalytically cleave mRNA transcripts to thereby inhibit translation of an mRNA. A ribozyme having specificity for a nucleic acid of the invention can be designed based upon the nucleotide sequence of a DNA disclosed herein (i.e., SEQ ID NO: 1 - 526). For example, a derivative of Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a mRNA. See, e.g., Cech et al. U.5. Pat. No. 4,987,071; and Cech et al. U.5.
Pat. No.
5,116,742. Alternatively, mRNA of the invention can be used to select a catalytic RNA
having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., (1993) Science 261:1411-1418.
Alternatively, gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region (e.g., promoter and/or enhancers) to form triple helical structures that prevent transcription of the gene in target cells. See generally, Helene. (1991) Anticancer Drug Des. 6: 569-84; Helene. et al. (1992) Ann. N Y.
Acad.
Sci. 660:27-36; and Maher (1992) Bioassays 14: 807-15.

In various embodiments, the nucleic acids of the invention can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see Hyrup et al. (1996) Bioorg Med Chem 4: 5-23). As used herein, the terms "peptide nucleic acids" or "PNAs" refer to nucleic acid mimics, e.g., DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength.
The synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described in Hyrup et al. (1996) above; Perry-O'Keefe et al. (1996) PNAS 93: 14670-675.
PNAs of the invention can be used in therapeutic and diagnostic applications.
For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. PNAs of the invention can also be used, e.g., in the analysis of single base pair mutations in a gene by, e.g., PNA directed PCR clamping; as artificial restriction enzymes when used in combination with other enzymes, e.g., S 1 nucleases (Hyrup B. (1996) above); or as probes or primers for DNA sequence and hybridization (Hyrup et al. (1996), above; Perry-O'Keefe (1996), above).
In another embodiment, PNAs of the invention can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA-DNA chimeras can be generated that may combine the advantageous properties of PNA and DNA. Such chimeras allow DNA
recognition enzymes, e.g., RNase H and DNA polymerases, to interact with the DNA
portion while the PNA portion would provide high binding affinity and specificity.
PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleobases, and orientation (Hyrup (1996) above). The synthesis of PNA-DNA chimeras can be performed as described in Hyrup (1996) above and Finn et al. (1996) Nucl Acids Res 24: 3357-63. For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry, and modified nucleoside analogs, e.g., 5'-(4-methoxytrityl)amino-5'-deoxy-thymidine phosphoramidite, can be used between the PNA and the 5' end of DNA (Mag et al. (1989) Nucl Acid Res 17: 5973-88). PNA
monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5' PNA segment and a 3' DNA segment (Finn et al. (1996) above). Alternatively, chimeric molecules can be synthesized with a 5' DNA segment and a 3' PNA
segment.
See, Petersen et al. (1975) BioorgMed Chem Lett 5: 1119-11124.
In other embodiments, the oligonucleotide may include other appended.groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger et al., 1989, Proc.
Natl. Acad. Sci.
U.S.A. 86:6553-6556; Lemaitre et al., 1987, Proc. Natl. Acad. Sci. 84:648-652;
PCT
Publication No. W088/09810) or the blood-brain barrier (see, e.g., PCT
Publication No.
W089/10134). In addition, oligonucleotides can be modified with hybridization triggered cleavage agents (See, e.g., Krol et al., 1988, BioTechnigues 6:958-976) or intercalating agents. (See, e.g., Zon, 1988, Pharm. Res. 5: 539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, a hybridization triggered cross-linking agent, a transport agent, a hybridization-triggered cleavage agent, etc.
3.5 HOSTS
The present invention further provides host cells genetically engineered to contain the polynucleotides of the invention. For example, such host cells may contain nucleic acids of the invention introduced into the host cell using known transformation, transfection or infection methods. The present invention still further provides host cells genetically engineered to express the polynucleotides of the invention, wherein such polynucleotides are in operative association with a regulatory sequence heterologous to the host cell which drives expression of the polynucleotides in the cell.
Knowledge of nucleic acid sequences allows for modification of cells to permit, or increase, expression of endogenous polypeptide. Cells can be modified (e.g., by homologous recombination) to provide increased polypeptide expression by replacing, in whole or in part, the naturally occurnng promoter with all or part of a heterologous promoter so that the cells express the polypeptide at higher levels. The heterologous promoter is inserted in such a manner that it is operatively linked to the encoding sequences. See, for example, PCT International Publication No. W094/12650, PCT
International Publication No. W092/20808, and PCT International Publication No.
W091/09955. It is also contemplated that, in addition to heterologous promoter DNA, amplifiable marker DNA (e.g., ada, dhfr, and the multifunctional CAD gene which encodes carbamyl phosphate synthase, aspartate transcarbamylase, and dihydroorotase) and/or intron DNA may be inserted along with the heterologous promoter DNA. If linked to the coding sequence, amplification of the marker DNA by standard selection methods results in co-amplification of the desired protein coding sequences in the cells.
The host cell can be a higher eukaryotic host cell, such as a mammalian cell, a lower eukaryotic host cell, such as a yeast cell, or the host cell can be a prokaryotic cell, such as a bacterial cell. Introduction of the recombinant construct into the host cell can be effected by calcium phosphate transfection, DEAE, dextran mediated transfection, or electroporation (Davis, L. et al., Basic Methods in Molecular Biology (1986)).
The host cells containing one of the polynucleotides of the invention, can be used in conventional manners to produce the gene product encoded by the isolated fragment (in the case of an ORF) or can be used to produce a heterologous protein under the control of the EMF.
Any host/vector system can be used to express one or more of the ORFs of the present invention. These include, but are not limited to, eukaryotic hosts such as HeLa cells, Cv-1 cell, COS cells, 293 cells, and Sf~ cells, as well as prokaryotic host such as E.
coli and B. subtilis. The most preferred cells are those which do not normally express the particular polypeptide or protein or which expresses the polypeptide or protein at low natural level. Mature proteins can be expressed in mammalian cells, yeast, bacteria, or other cells under the control of appropriate promoters. Cell-free translation systems can also be employed to produce such proteins using RNAs derived from the DNA
constructs of the present invention. Appropriate cloning and expression vectors for use with prokaryotic and eukaryotic hosts are described by Sambrook, et al., in Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor, New York (1989), the disclosure of which is hereby incorporated by reference.

Various mammalian cell culture systems can also be employed to express recombinant protein. Examples of mammalian expression systems include the COS-lines of monkey kidney fibroblasts, described by Gluzman, Cell 23:175 (1981).
Other cell lines capable of expressing a compatible vector are, for example, the C127, monkey COS cells, Chinese Hamster Ovary (CHO) cells, human kidney 293 cells, human epidermal A431 cells, human Co1o205 cells, 3T3 cells, CV-1 cells, other transformed primate cell lines, normal diploid cells, cell strains derived from in vitro culture of primary tissue, primary explants, HeLa cells, mouse L cells, BHK, HL-60, U937, HaK or Jurkat cells. Mammalian expression vectors will comprise an origin of replication, a suitable promoter and also any necessary ribosome binding sites, polyadenylation site, splice donor and acceptor sites, transcriptional termination sequences, and S' flanking nontranscribed sequences. DNA sequences derived from the SV40 viral genome, for example, SV40 origin, early promoter, enhancer, splice, and polyadenylation sites may be used to provide the required nontranscribed genetic elements. Recombinant polypeptides and proteins produced in bacterial culture are usually isolated by initial extraction from cell pellets, followed by one or more salting-out, aqueous ion exchange or size exclusion chromatography steps. Protein refolding steps can be used, as necessary, in completing configuration of the mature protein. Finally, high performance liquid chromatography (HPLC) can be employed for final purification steps. Microbial cells employed in ,20 expression of proteins can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents.
Alternatively, it may be possible to produce the protein in lower eukaryotes such as yeast or insects or in prokaryotes such as bacteria. Potentially suitable yeast strains include Saccharomyces cerevisiae, Schizosaccharomyces pombe, Kluyveromyces strains, Candida, or any yeast strain capable of expressing heterologous proteins.
Potentially suitable bacterial strains include Escherichia coli, Bacillus subtilis, Salmonella typhimurium, or any bacterial strain capable of expressing heterologous proteins. If the protein is made in yeast or bacteria, it may be necessary to modify the protein produced therein, for example by phosphorylation or glycosylation of the appropriate sites, in order to obtain the functional protein. Such covalent attachments may be accomplished using known chemical or enzymatic methods.

In another embodiment of the present invention, cells and tissues may be engineered to express an endogenous gene comprising the polynucleotides of the invention under the control of inducible regulatory elements, in which case the regulatory sequences of the endogenous gene may be replaced by homologous recombination.
As described herein, gene targeting can be used to replace a gene's existing regulatory region with a regulatory sequence isolated from a different gene or a novel regulatory sequence synthesized by genetic engineering methods. Such regulatory sequences may be comprised of promoters, enhancers, scaffold-attachment regions, negative regulatory elements, transcriptional initiation sites, regulatory protein binding sites or combinations of said sequences. Alternatively, sequences which affect the structure or stability of the RNA or protein produced may be replaced, removed, added, or otherwise modified by targeting. These sequence include polyadenylation signals, mRNA stability elements, splice sites, leader sequences for enhancing or modifying transport or secretion properties of the protein, or other sequences which alter or improve the function or stability of protein or RNA molecules.
The targeting event may be a simple insertion of the regulatory sequence, placing the gene under the control of the new regulatory sequence, e.g., inserting a new promoter or enhancer or both upstream of a gene. Alternatively, the targeting event may be a simple deletion of a regulatory element, such as the deletion of a tissue-specific negative regulatory element. Alternatively, the targeting event may replace an existing element;
for example, a tissue-specific enhancer can be replaced by an enhancer that has broader or different cell-type specificity than the naturally occurring elements.
Here, the naturally occurnng sequences are deleted and new sequences are added. In all cases, the identification of the targeting event may be facilitated by the use of one or more selectable marker genes that are contiguous with the targeting DNA, allowing for the selection of cells in which the exogenous DNA has integrated into the host cell genome.
The identification of the targeting event may also be facilitated by the use of one or more marker genes exhibiting the property of negative selection, such that the negatively selectable marker is linked to the exogenous DNA, but configured such that the negatively selectable marker flanks the targeting sequence, and such that a correct homologous recombination event with sequences in the host cell genome does not result in the stable integration of the negatively selectable marker. Markers useful for this purpose include the Herpes Simplex Virus thymidine kinase (TK) gene or the bacterial xanthine-guanine phosphoribosyl-transferase (gpt) gene.
The gene targeting or gene activation techniques which can be used in accordance with this aspect of the invention are more particularly described in U.S.
Patent No.
5,272,071 to Chappel; U.S. Patent No. 5,578,461 to Sherwin et al.;
International Application No. PCT/LTS92/09627 (W093/09222) by Selden et al.; and International Application No. PCT/US90/06436 (W091/06667) by Skoultchi et al., each of which is incorporated by reference herein in its entirety.
3.6 POLYPEPTIDES OF THE INVENTION
The isolated polypeptides of the invention include, but are not limited to, a polypeptide comprising: the amino acid sequences set forth as any one of SEQ
ID NO:
527 -1052 or an amino acid sequence encoded by any one of the nucleotide sequences SEQ ID NOs: 1 - 526 or the corresponding full length or mature protein.
Polypeptides of the invention also include polypeptides preferably with biological or immunological activity that are encoded by: (a) a polynucleotide having any one of the nucleotide sequences set forth in SEQ ID NOs: 1 - 526 or (b) polynucleotides encoding any one of the amino acid sequences set forth as SEQ ID NO 527 -1052 or (c) polynucleotides that hybridize to the complement of the polynucleotides of either (a) or (b) under stringent hybridization conditions. The invention also provides biologically active or immunologically active variants of any of the amino acid sequences set forth as SEQ ID
NO: 527 -1052 or the corresponding full length or mature protein; and "substantial equivalents" thereof (e.g., with at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, 86%, 87%, 88%, 89%, at least about 90%, 91%, 92%, 93%, 94%, typically at least about 95%, 96%, 97%, more typically at least about 98%, or most typically at least about 99% amino acid identity) that retain biological activity. Polypeptides encoded by allelic variants may have a similar, increased, or decreased activity compared to polypeptides comprising SEQ ID
NO: 527 -1052.

Fragments of the proteins of the present invention which are capable of exhibiting biological activity are also encompassed by the present invention. Fragments of the protein may be in linear form or they may be cyclized using known methods, for example, as described in H. U. Saragovi, et al., Bio/Technology 10, 773-778 (1992) and S in R. S. McDowell, et al., J. Amer. Chem. Soc. 114, 9245-9253 (1992), both of which are incorporated herein by reference. Such fragments may be fused to Garner molecules such as immunoglobulins for many purposes, including increasing the valency of protein binding sites.
The present invention also provides both full-length and mature forms (for example, without a signal sequence or precursor sequence) of the disclosed proteins. The protein coding sequence is identified in the sequence listing by translation of the disclosed nucleotide sequences. The mature form of such protein may be obtained by expression of a full-length polynucleotide in a suitable mammalian cell or other host cell.
The sequence of the mature form of the protein is also determinable from the amino acid sequence of the full-length form. Where proteins of the present invention are membrane bound, soluble forms of the proteins are also provided. In such forms, part or all of the regions causing the proteins to be membrane bound are deleted so that the proteins are fully secreted from the cell in which they are expressed.
Protein compositions of the present invention may further comprise an acceptable carrier, such as a hydrophilic, e.g., pharmaceutically acceptable, carrier.
The present invention further provides isolated polypeptides encoded by the nucleic acid fragments of the present invention or by degenerate variants of the nucleic acid fragments of the present invention. By "degenerate variant" is intended nucleotide fragments which differ from a nucleic acid fragment of the present invention (e.g., an ORF) by nucleotide sequence but, due to the degeneracy of the genetic code, encode'an identical polypeptide sequence. Preferred nucleic acid fragments of the present invention are the ORFs that encode proteins.
A variety of methodologies known in the art can be utilized to obtain any one of the isolated polypeptides or proteins of the present invention. At the simplest level, the amino acid sequence can be synthesized using commercially available peptide synthesizers. The synthetically-constructed protein sequences, by virtue of sharing primary, secondary or tertiary structural and/or conformational characteristics with proteins may possess biological properties in common therewith, including protein activity. This technique is particularly useful in producing small peptides and fragments of larger polypeptides. Fragments are useful, for example, in generating antibodies against the native polypeptide. Thus, they may be employed as biologically active or immunological substitutes for natural, purified proteins in screening of therapeutic compounds and in immunological processes for the development of antibodies.
The polypeptides and proteins of the present invention can alternatively be purified from cells which have been altered to express the desired polypeptide or protein.
As used herein, a cell is said to be altered to express a desired polypeptide or protein when the cell, through genetic manipulation, is made to produce a polypeptide or protein which it normally does not produce or which the cell normally produces at a lower level.
One skilled in the art can readily adapt procedures for introducing and expressing either recombinant or synthetic sequences into eukaryotic or prokaryotic cells in order to generate a cell which produces one of the polypeptides or proteins of the present invention.
The invention also relates to methods for producing a polypeptide comprising growing a culture of host cells of the invention in a suitable culture medium, and purifying the protein from the cells or the culture in which the cells are grown. For example, the methods of the invention include a process for producing a polypeptide in which a host cell containing a suitable expression vector that includes a polynucleotide of the invention is cultured under conditions that allow expression of the encoded polypeptide. The polypeptide can be recovered from the culture, conveniently from the culture medium, or from a lysate prepared from the host cells and further purified.
Preferred embodiments include those in which the protein produced by such process is a full length or mature form of the protein.
In an alternative method, the polypeptide or protein is purified from bacterial cells which naturally produce the polypeptide or protein. One skilled in the art can readily follow known methods for isolating polypeptides and proteins in order to obtain one of the isolated polypeptides or proteins of the present invention. These include, but are not limited to, immunochromatography, HPLC, size-exclusion chromatography, ion-exchange chromatography, and immuno-affinity chromatography. See, e.g., Scopes, Protein Purification: Principles and Practice, Springer-Verlag (1994);
Sambrook, et al., in Molecular Cloning: A Laboratory Manual; Ausubel et al., Current Protocols in Molecular Biology. Polypeptide fragments that retain biological/immunological activity include fragments comprising greater than about 100 amino acids, or greater than about 200 amino acids, and fragments that encode specific protein domains.
The purified polypeptides can be used in in vitro binding assays which are well known in the art to identify molecules which bind to the polypeptides. These molecules include but are not limited to, for e.g., small molecules, molecules from combinatorial libraries, antibodies or other proteins. The molecules identified in the binding assay are then tested for antagonist or agonist activity in in vivo tissue culture or animal models that are well known in the art. In brief, the molecules are titrated into a plurality of cell cultures or animals and then tested for either cell/animal death or prolonged survival of the animal/cells.
1 S In addition, the peptides of the invention or molecules capable of binding to the peptides may be complexed with toxins, e.g., ricin or cholera, or with other compounds that are toxic to cells. The toxin-binding molecule complex is then targeted to a tumor or other cell by the specificity of the binding molecule for SEQ ID NO: 527 -1052.
The protein of the invention may also be expressed as a product of transgenic animals, e.g., as a component of the milk of transgenic cows, goats, pigs, or sheep which are characterized by somatic or germ cells containing a nucleotide sequence encoding the protein.
The proteins provided herein also include proteins characterized by amino acid sequences similar to those of purified proteins but into which modification are naturally provided or deliberately engineered. For example, modifications, in the peptide or DNA
sequence, can be made by those skilled in the art using known techniques.
Modifications of interest in the protein sequences may include the alteration, substitution, replacement, insertion or deletion of a selected amino acid residue in the coding sequence.
For example, one or more of the cysteine residues may be deleted or replaced with another amino acid to alter the conformation of the molecule. Techniques for such alteration, substitution, replacement, insertion or deletion are well known to those skilled in the art (see, e.g., U.S. Pat. No. 4,518,584). Preferably, such alteration, substitution, replacement, insertion or deletion retains the desired activity of the protein. Regions of the protein that are important for the protein function can be determined by various methods known in the art including the alanine-scanning method which involved systematic substitution of single or strings of amino acids with alanine, followed by testing the resulting alanine-containing variant for biological activity. This type of analysis determines the importance of the substituted amino acids) in biological activity. Regions of the protein that are important for protein function may be determined by the eMATRIX
program.
Other fragments and derivatives of the sequences of proteins which would be expected to retain protein activity in whole or in part and are useful for screening or other immunological methodologies may also be easily made by those skilled in the art given the disclosures herein. Such modifications are encompassed by the present invention.
The protein may also be produced by operably linking the isolated polynucleotide of the invention to suitable control sequences in one or more insect expression vectors, and employing an insect expression system. Materials and methods for baculovirus/insect cell expression systems are commercially available in kit form from, e.g., Invitrogen, San Diego, Calif., U.S.A. (the MaxBatTM kit), and such methods are well known in the art, as described in Summers and Smith, Texas Agricultural Experiment Station Bulletin No. 1555 (1987), incorporated herein by reference. As used herein, an insect cell capable of expressing a polynucleotide of the present invention is "transformed."
The protein of the invention may be prepared by culturing transformed host cells under culture conditions suitable to express the recombinant protein. The resulting expressed protein may then be purified from such culture (i.e., from culture medium or cell extracts) using known purification processes, such as gel filtration and ion exchange chromatography. The purification of the protein may also include an affinity column containing agents which will bind to the protein; one or more column steps over such affinity resins as concanavalin A-agarose, heparin-toyopearlTM or Cibacrom blue 3GA
SepharoseTM; one or more steps involving hydrophobic interaction chromatography using such resins as phenyl ether, butyl ether, or propyl ether; or immunoaffinity chromatography.

Alternatively, the protein of the invention may also be expressed in a form which will facilitate purification. For example, it may be expressed as a fusion protein, such as those of maltose binding protein (MBP), glutathione-S-transferase (GST) or thioredoxin (TRX), or as a His tag. Kits for expression and purification of such fusion proteins are S commercially available from New England BioLab (Beverly, Mass.), Pharmacia (Piscataway, N.J.) and Invitrogen, respectively. The protein can also be tagged with an epitope and subsequently purified by using a specific antibody directed to such epitope.
One such epitope ("FLAG~") is commercially available from Kodak (New Haven, Conn.).
Finally, one or more reverse-phase high performance liquid chromatography (RP-HPLC) steps employing hydrophobic RP-HPLC media, e.g., silica gel having pendant methyl or other aliphatic groups, can be employed to further purify the protein. Some or all of the foregoing purification steps, in various combinations, can also be employed to provide a substantially homogeneous isolated recombinant protein. The protein thus purified is substantially free of other mammalian proteins and is defined in accordance with the present invention as an "isolated protein."
The polypeptides of the invention include analogs (variants). This embraces fragments, as well as peptides in which one or more amino acids has been deleted, inserted, or substituted. Also, analogs of the polypeptides of the invention embrace fusions of the polypeptides or modifications of the polypeptides of the invention, wherein the polypeptide or analog is fused to another moiety or moieties, e.g., targeting moiety or another therapeutic agent. Such analogs may exhibit improved properties such as activity and/or stability. Examples of moieties which may be fused to the polypeptide or an analog include, for example, targeting moieties which provide for the delivery of polypeptide to pancreatic cells, e.g., antibodies to pancreatic cells, antibodies to immune cells such as T-cells, monocytes, dendritic cells, granulocytes, etc., as well as receptor and ligands expressed on pancreatic or immune cells. Other moieties which may be fused to the polypeptide include therapeutic agents which are used for treatment, for example, immunosuppressive drugs such as cyclosporin, SK506, azathioprine, CD3 antibodies and steroids. Also, polypeptides may be fused to immune modulators, and other cytokines such as alpha or beta interferon.

3.6.1 DETERMINING POLYPEPTIDE AND POLYNUCLEOTIDE
IDENTITY AND SIMILARITY
Preferred identity and/or similarity are designed to give the largest match between the sequences tested. Methods to determine identity and similarity are codified in computer programs including, but are not limited to, the GCG program package, including GAP (Devereux, J., et al., Nucleic Acids Research 12(1):387 (1984);
Genetics Computer Group, University of Wisconsin, Madison, WI), BLASTP, BLASTN, BLASTX, FASTA (Altschul, S.F. et al., J. Molec. Biol. 215:403-410 (1990), PSI-BLAST
(Altschul S.F. et al., Nucleic Acids Res. vol. 25, pp. 3389-3402, herein incorporated by reference), eMatrix software (Wu et al., J. Comp. Biol., Vol. 6, pp. 219-235 (1999), herein incorporated by reference), eMotif software (Nevill-Manning et al, ISMB-97, Vol.
4, pp. 202-209, herein incorporated by reference), pFam software (Sonnhammer et al., Nucleic Acids Res., Vol. 26(1), pp. 320-322 (1998), herein incorporated by reference) and the Kyte-Doolittle hydrophobocity prediction algorithm (J. Mol Biol, 157, pp. 105-31 (1982), incorporated herein by reference). The BLAST programs are publicly available from the National Center for Biotechnology Information (NCBI) and other sources (BLAST Manual, Altschul, S., et al. NCB NLM NIH Bethesda, MD 20894; Altschul, S., et al., J. Mol. Biol. 215:403-410 (1990).
3.7 CHIMERIC AND FUSION PROTEINS
The invention also provides chimeric or fusion proteins. As used herein, a "chimeric protein" or "fusion protein" comprises a polypeptide of the invention operatively linked to another polypeptide. Within a fusion protein the polypeptide according to the invention can correspond to all or a portion of a protein according to the invention. In one embodiment, a fusion protein comprises at least one biologically active portion of a protein according to the invention. In another embodiment, a fusion protein comprises at least two biologically active portions of a protein according to the invention.
Within the fusion protein, the term "operatively linked" is intended to indicate that the polypeptide according to the invention and the other polypeptide are fused in-frame to each other. The polypeptide can be fused to the N-terminus or C-terminus, or to the middle.

For example, in one embodiment a fusion protein comprises a polypeptide according to the invention operably linked to the extracellular domain of a second protein.
In another embodiment, the fusion protein is a GST-fusion protein in which the polypeptide sequences of the invention are fused to the C-terminus of the GST
(i.e., glutathione S-transferase) sequences.
In another embodiment, the fusion protein is an immunoglobulin fusion protein in which the polypeptide sequences according to the invention comprise one or more domains fused to sequences derived from a member of the immunoglobulin protein family. The immunoglobulin fusion proteins of the invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between a ligand and a protein of the invention on the surface of a cell, to thereby suppress signal transduction in vivo. The immunoglobulin fusion proteins can be used to affect the bioavailability of a cognate ligand. Inhibition of the ligand/protein interaction may be useful therapeutically for both the treatment of proliferative and differentiative disorders, e.g., cancer as well as modulating (e.g., promoting or inhibiting) cell survival.
Moreover, the immunoglobulin fusion proteins of the invention can be used as immunogens to produce antibodies in a subject, to purify ligands, and in screening assays to identify molecules that inhibit the interaction of a polypeptide of the invention with a ligand.
A chimeric or fusion protein of the invention can be produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, e.g., by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR
amplification of gene fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive gene fragments that can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, for example, Ausubel et al. (eds.) CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide). A nucleic acid encoding a polypeptide of the invention can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the protein of the invention.
3.8 GENE THERAPY
Mutations in the polynucleotides of the invention gene may result in loss of normal function of the encoded protein. The invention thus provides gene therapy to restore normal activity of the polypeptides of the invention; or to treat disease states involving polypeptides of the invention. Delivery of a functional gene encoding polypeptides of the invention to appropriate cells is effected ex vivo, in situ, or in vivo by use of vectors, and more particularly viral vectors (e.g., adenovirus, adeno-associated virus, or a retrovirus), or ex vivo by use of physical DNA transfer methods (e.g., liposomes or chemical treatments). See, for example, Anderson, Nature, supplement to vol. 392, no. 6679, pp.25-20 (1998). For additional reviews of gene therapy technology see Friedmann, Science, 244: 1275-1281 (1989); Verma, Scientific American: 68-(1990); and Miller, Nature, 357: 455-460 (1992). Introduction of any one of the nucleotides of the present invention or a gene encoding the polypeptides of the present invention can also be accomplished with extrachromosomal substrates (transient expression) or artificial chromosomes (stable expression). Cells may also be cultured ex vivo in the presence of proteins of the present invention in order to proliferate or to produce a desired effect on or activity in such cells. Treated cells can then be introduced in vivo for therapeutic purposes. Alternatively, it is contemplated that in other human disease states, preventing the expression of or inhibiting the activity of polypeptides of the invention will be useful in treating the disease states. It is contemplated that antisense therapy or gene therapy could be applied to negatively regulate the expression of polypeptides of the invention.
Other methods inhibiting expression of a protein include the introduction of antisense molecules to the nucleic acids of the present invention, their complements, or their translated RNA sequences, by methods known in the art. Further, the polypeptides of the present invention can be inhibited by using targeted deletion methods, or the insertion of a negative regulatory element such as a silencer, which is tissue specific.
The present invention still further provides cells genetically engineered in vivo to express the polynucleotides of the invention, wherein such polynucleotides are in operative association with a regulatory sequence heterologous to the host cell which drives expression of the polynucleotides in the cell. These methods can be used to increase or decrease the expression of the polynucleotides of the present invention.
Knowledge of DNA sequences provided by the invention allows for modification of cells to permit, increase, or decrease, expression of endogenous polypeptide.
Cells can be modified (e.g., by homologous recombination) to provide increased polypeptide expression by replacing, in whole or in part, the naturally occurnng promoter with all or part of a heterologous promoter so that the cells express the protein at higher levels.
The heterologous promoter is inserted in such a manner that it is operatively linked to the desired protein encoding sequences. See, for example, PCT International Publication No. WO
94/12650, PCT International Publication No. WO 92/20808, and PCT International Publication No.
WO 91/09955. It is also contemplated that, in addition to heterologous promoter DNA, amplifiable marker DNA (e.g., ada, dhfr, and the multifunctional CAD gene which encodes carbamyl phosphate synthase, aspartate transcarbamylase, and dihydroorotase) and/or intron DNA may be inserted along with the heterologous promoter DNA. If linked to the desired protein coding sequence, amplification of the marker DNA by standard selection methods results in co-amplification of the desired protein coding sequences in the cells.
In another embodiment of the present invention, cells and tissues may be engineered to express an endogenous gene comprising the polynucleotides of the invention under the control of inducible regulatory elements, in which case the regulatory sequences of the endogenous gene may be replaced by homologous recombination. As described herein, gene targeting can be used to replace a gene's existing regulatory region with a regulatory sequence isolated from a different gene or a novel regulatory sequence synthesized by genetic engineering methods. Such regulatory sequences may be comprised of promoters, enhancers, scaffold-attachment regions, negative regulatory elements, transcriptional initiation sites, regulatory protein binding sites or combinations of said sequences.
Alternatively, sequences which affect the structure or stability of the RNA or protein produced may be replaced, removed, added, or otherwise modified by targeting.
These sequences include polyadenylation signals, mRNA stability elements, splice sites, leader sequences for enhancing or modifying transport or secretion properties of the protein, or other sequences which alter or improve the function or stability of protein or RNA
molecules.
The targeting event may be a simple insertion of the regulatory sequence, placing the gene under the control of the new regulatory sequence, e.g., inserting a new promoter or enhancer or both upstream of a gene. Alternatively, the targeting event may be a simple deletion of a regulatory element, such as the deletion of a tissue-specific negative regulatory element. Alternatively, the targeting event may replace an existing element;
for example, a tissue-specific enhancer can be replaced by an enhancer that has broader or different cell-type specificity than the naturally occurnng elements. Here, the naturally occurring sequences are deleted and new sequences are added. In all cases, the identification of the targeting event may be facilitated by the use of one or more selectable marker genes that are 1 S contiguous with the targeting DNA, allowing for the selection of cells in which the exogenous DNA has integrated into the cell genome. The identification of the targeting event may also be facilitated by the use of one or more marker genes exhibiting the property of negative selection, such that the negatively selectable marker is linked to the exogenous DNA, but configured such that the negatively selectable marker flanks the targeting sequence, and such that a correct homologous recombination event with sequences in the host cell genome does not result in the stable integration of the negatively selectable marker.
Markers useful for this purpose include the Herpes Simplex Virus thymidine kinase (TK) gene or the bacterial xanthine-guanine phosphoribosyl-transferase (gpt) gene.
The gene targeting or gene activation techniques which can be used in accordance with this aspect of the invention are more particularly described in U.S.
Patent No.
5,272,071 to Chappel; U.S. Patent No. 5,578,461 to Sherwin et al.;
International Application No. PCT/US92/09627 (W093/09222) by Selden et al.; and International Application No.
PCT/LTS90/06436 (W091/06667) by Skoultchi et aL, each ofwhich is incorporated by reference herein in its entirety.
3.9 TRANSGENIC ANIMALS

In preferred methods to determine biological functions of the polypeptides of the invention in vivo, one or more genes provided by the invention are either over expressed or inactivated in the germ line of animals using homologous recombination [Capecchi, Science 244:1288-1292 (1989)]. Animals in which the gene is over expressed, under the regulatory control of exogenous or endogenous promoter elements, are known as transgenic animals. Animals in which an endogenous gene has been inactivated by homologous recombination are referred to as "knockout" animals. Knockout animals, preferably non-human mammals, can be prepared as described in U.S. Patent No.
5,557,032, incorporated herein by reference. Transgenic animals are useful to determine the roles polypeptides of the invention play in biological processes, and preferably in disease states. Transgenic animals are useful as model systems to identify compounds that modulate lipid metabolism. Transgenic animals, preferably non-human mammals, are produced using methods as described in U.S. Patent No 5,489,743 and PCT
Publication No. W094/28122, incorporated herein by reference.
Transgenic animals can be prepared wherein all or part of a promoter of the polynucleotides of the invention is either activated or inactivated to alter the level of expression of the polypeptides of the invention. Inactivation can be carried out using homologous recombination methods described above. Activation can be achieved by supplementing or even replacing the homologous promoter to provide for increased protein expression. The homologous promoter can be supplemented by insertion of one or more heterologous enhancer elements known to confer promoter activation in a particular tissue.
The polynucleotides of the present invention also make possible the development, through, e.g., homologous recombination or knock out strategies, of animals that fail to express polypeptides of the invention or that express a variant polypeptide.
Such animals are useful as models for studying the in vivo activities of polypeptide as well as for studying modulators of the polypeptides of the invention.
In preferred methods to determine biological functions of the polypeptides of the invention in vivo, one or more genes provided by the invention are either over expressed or inactivated in the germ line of animals using homologous recombination [Capecchi, Science 244:1288-1292 (1989)]. Animals in which the gene is over expressed, under the regulatory control of exogenous or endogenous promoter elements, are known as transgenic animals. Animals in which an endogenous gene has been inactivated by homologous recombination are referred to as "knockout" animals. Knockout animals, preferably non-human mammals, can be prepared as described in U.S. Patent No.
5,557,032, incorporated herein by reference. Transgenic animals are useful to determine the roles polypeptides of the invention play in biological processes, and preferably in disease states. Transgenic animals are useful as model systems to identify compounds that modulate lipid metabolism. Transgenic animals, preferably non-human mammals, are produced using methods as described in U.S. Patent No 5,489,743 and PCT
Publication No. W094/28122, incorporated herein by reference.
Transgenic animals can be prepared wherein all or part of the polynucleotides of the invention promoter is either activated or inactivated to alter the level of expression of the polypeptides of the invention. Inactivation can be earned out using homologous recombination methods described above. Activation can be achieved by supplementing or even replacing the homologous promoter to provide for increased protein expression. The homologous promoter can be supplemented by insertion of one or more heterologous enhancer elements known to confer promoter activation in a particular tissue.
3.10 USES AND BIOLOGICAL ACTIVITY
The polynucleotides and proteins of the present invention are expected to exhibit one or more of the uses or biological activities (including those associated with assays cited herein) identified herein. Uses or activities described for proteins of the present invention may be provided by administration or use of such proteins or of polynucleotides encoding such proteins (such as, for example, in gene therapies or vectors suitable for introduction of DNA). The mechanism underlying the particular condition or pathology will dictate whether the polypeptides of the invention, the polynucleotides of the invention or modulators (activators or inhibitors) thereof would be beneficial to the subject in need of treatment. Thus, "therapeutic compositions of the invention" include compositions comprising isolated polynucleotides (including recombinant DNA molecules, cloned genes and degenerate variants thereof) or polypeptides of the invention (including full length protein, mature protein and truncations or domains thereof), or compounds and other substances that modulate the overall activity of the target gene products, either at the level of target gene/protein expression or target protein activity. Such modulators include polypeptides, analogs, (variants), including fragments and fusion proteins, antibodies and other binding proteins;
chemical compounds that directly or indirectly activate or inhibit the polypeptides of the invention (identified, e.g., via drug screening assays as described herein);
antisense polynucleotides and polynucleotides suitable for triple helix formation; and in particular antibodies or other binding partners that specifically recognize one or more epitopes of the polypeptides of the invention.
The polypeptides of the present invention may likewise be involved in cellular activation or in one of the other physiological pathways described herein.
3.10.1 RESEARCH USES AND UTILITIES
The polynucleotides provided by the present invention can be used by the research community for various purposes. The polynucleotides can be used to express recombinant protein for analysis, characterization or therapeutic use; as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in disease states); as molecular weight markers on gels; as chromosome markers or tags (when labeled) to identify chromosomes or to map related gene positions; to compare with endogenous DNA sequences in patients to identify potential genetic disorders;
as probes to hybridize and thus discover novel, related DNA sequences; as a source of information to derive PCR primers for genetic fingerprinting; as a probe to "subtract-out"
known sequences in the process of discovering other novel polynucleotides; for selecting and making oligomers for attachment to a "gene chip" or other support, including for examination of expression patterns; to raise anti-protein antibodies using DNA
immunization techniques; and as an antigen to raise anti-DNA antibodies or elicit another immune response. Where the polynucleotide encodes a protein which binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction), the polynucleotide can also be used in interaction trap assays (such as, for example, that described in Gyuris et al., Cell 75:791-803 (1993)) to identify polynucleotides encoding the other protein with which binding occurs or to identify inhibitors of the binding interaction.
The polypeptides provided by the present invention can similarly be used in assays to determine biological activity, including in a panel of multiple proteins for high-throughput screening; to raise antibodies or to elicit another immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the protein (or its receptor) in biological fluids; as markers for tissues in which the corresponding polypeptide is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state); and, of course, to isolate correlative receptors or ligands. Proteins involved in these binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction.
Any or all of these research utilities are capable of being developed into reagent grade or kit format for commercialization as research products.
Methods for performing the uses listed above are well known to those skilled in the art. References disclosing such methods include without limitation "Molecular Cloning: A Laboratory Manual", 2d ed., Cold Spring Harbor Laboratory Press, Sambrook, J., E. F. Fritsch and T. Maniatis eds., 1989, and "Methods in Enzymology:
Guide to Molecular Cloning Techniques", Academic Press, Berger, S. L. and A.
R.
Kimmel eds., 1987.
3.10.2 NUTRITIONAL USES
Polynucleotides and polypeptides of the present invention can also be used as nutritional sources or supplements. Such uses include without limitation use as a protein or amino acid supplement, use as a carbon source, use as a nitrogen source and use as a source of carbohydrate. In such cases the polypeptide or polynucleotide of the invention can be added to the feed of a particular organism or can be administered as a separate solid or liquid preparation, such as in the form of powder, pills, solutions, suspensions or capsules. In the case of microorganisms, the polypeptide or polynucleotide of the invention can be added to the medium in or on which the microorganism is cultured.

3.10.3 CYTOKINE AND CELL PROLIFERATION/DIFFERENTIATION
ACTIVITY
A polypeptide of the present invention may exhibit activity relating to cytokine, cell proliferation (either inducing or inhibiting) or cell differentiation (either inducing or S inhibiting) activity or may induce production of other cytokines in certain cell populations. A polynucleotide of the invention can encode a polypeptide exhibiting such attributes. Many protein factors discovered to date, including all known cytokines, have exhibited activity in one or more factor-dependent cell proliferation assays, and hence the assays serve as a convenient confirmation of cytokine activity. The activity of therapeutic compositions of the present invention is evidenced by any one of a number of routine factor dependent cell proliferation assays for cell lines including, without limitation, 32D, DA2, DA1G, T10, B9, B9/11, BaF3, MC9/G, M+(preB M+), 2E8, RBS, DA1, 123, T1165, HT2, CTLL2, TF-1, Mo7e, CMK, HLJVEC, and Caco. Therapeutic compositions of the invention can be used in the following:
Assays for T-cell or thytnocyte proliferation include without limitation those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M.
Kruisbeek, D.
H. Margulies, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19;
Chapter 7, Immunologic studies in Humans); Takai et al., J. Immunol. 137:3494-3500, 1986; Bertagnolli et al., J. Immunol. 145:1706-1712, 1990; Bertagnolli et al., Cellular Immunology 133:327-341, 1991; Bertagnolli, et al., I. Immunol. 149:3778-3783, 1992;
Bowman et al., I. Immunol. 152:1756-1761, 1994.
Assays for cytokine production and/or proliferation of spleen cells, lymph node cells or thymocytes include, without limitation, those described in:
Polyclonal T cell stimulation, Kruisbeek, A. M. and Shevach, E. M. In Current Protocols in Immunology.
J. E. e.a. Coligan eds. Vol 1 pp. 3.12.1-3.12.14, John Wiley and Sons, Toronto. 1994; and Measurement of mouse and human interleukin-y, Schreiber, R. D. In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol 1 pp. 6.8.1-6.8.8, John Wiley and Sons, Toronto.
1994.
Assays for proliferation and differentiation of hematopoietic and lymphopoietic cells include, without limitation, those described in: Measurement of Human and Murine Interleukin 2 and Interleukin 4, Bottomly, K., Davis, L. S. and Lipsky, P. E.
In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol 1 pp. 6.3.1-6.3.12, John Wiley and Sons, Toronto. 1991; deVries et al., J. Exp. Med. 173:1205-1211, 1991; Moreau et al., Nature 336:690-692, 1988; Greenberger et al., Proc. Natl. Acad. Sci. U.S.A.
S 80:2931-2938, 1983; Measurement of mouse and human interleukin 6--Nordan, R.
In Current Protocols in Immunology. J. E. Coligan eds. Vol 1 pp. 6.6.1-6.6.5, John Wiley and Sons, Toronto. 1991; Smith et al., Proc. Natl. Aced. Sci. U.S.A. 83:1857-1861, 1986;
Measurement of human Interleukin 11--Bennett, F., Giannotti, J., Clark, S. C.
and Turner, K. J. In Current Protocols in Immunology. J. E. Coligan eds. Vol 1 pp. 6.15.1 John Wiley and Sons, Toronto. 1991; Measurement of mouse and human Interleukin 9--Ciarletta, A., Giannotti, J., Clark, S. C. and Turner, K. J. In Current Protocols in Immunology. J. E. Coligan eds. Vol 1 pp. 6.13.1, John Wiley and Sons, Toronto.
1991.
Assays for T-cell clone responses to antigens (which will identify, among others, proteins that affect APC-T cell interactions as well as direct T-cell effects by measuring proliferation and cytokine production) include, without limitation, those described in:
Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H.
Margulies, E. M. Shevach, W Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function;
Chapter 6, Cytokines and their cellular receptors; Chapter 7, Immunologic studies in Humans);
Weinberger et al., Proc. Natl. Acad. Sci. USA 77:6091-6095, 1980; Weinberger et al., Eur. J. Immun. 11:405-411, 1981; Takai et al., J. Immunol. 137:3494-3500, 1986; Takai et al., J. Immunol. 140:508-512, 1988.
3.10.4 STEM CELL GROWTH FACTOR ACTIVITY
2~ A polypeptide of the present invention may exhibit stem cell growth factor activity and be involved in the proliferation, differentiation and survival of pluripotent and totipotent stem cells including primordial germ cells, embryonic stem cells, hematopoietic stem cells and/or germ line stem cells. Administration of the polypeptide of the invention to stem cells in vivo or ex vivo is expected to maintain and expand cell populations in a totipotential or pluripotential state which would be useful for re-engineering damaged or diseased tissues, transplantation, manufacture of bio-pharmaceuticals and the development of bio-sensors. The ability to produce large quantities of human cells has important working applications for the production of human proteins which currently must be obtained from non-human sources or donors, implantation of cells to treat diseases such as Parkinson's, Alzheimer's and other S neurodegenerative diseases; tissues for grafting such as bone marrow, skin, cartilage, tendons, bone, muscle (including cardiac muscle), blood vessels, cornea, neural cells, gastrointestinal cells and others; and organs for transplantation such as kidney, liver, pancreas (including islet cells), heart and lung.
It is contemplated that multiple different exogenous growth factors and/or cytokines may be administered in combination with the polypeptide of the invention to achieve the desired effect, including any of the growth factors listed herein, other stem cell maintenance factors, and specifically including stem cell factor (SCF), leukemia inhibitory factor (LIF), Flt-3 ligand (Flt-3L), any of the interleukins, recombinant soluble IL-6 receptor fused to IL-6, macrophage inflammatory protein 1-alpha (MIP-1-alpha), G-CSF, GM-CSF, thrombopoietin (TPO), platelet factor 4 (PF-4), platelet-derived growth factor (PDGF), neural growth factors and basic fibroblast growth factor (bFGF).
Since totipotent stem cells can give rise to virtually any mature cell type, expansion of these cells in culture will facilitate the production of large quantities of mature cells. Techniques for culturing stem cells are known in the art and administration of polypeptides of the invention, optionally with other growth factors and/or cytokines, is expected to enhance the survival and proliferation of the stem cell populations. This can be accomplished by direct administration of the polypeptide of the invention to the culture medium. Alternatively, stroma cells transfected with a polynucleotide that encodes for the polypeptide of the invention can be used as a feeder layer for the stem cell populations in culture or in vivo. Stromal support cells for feeder layers may include embryonic bone marrow fibroblasts, bone marrow stromal cells, fetal liver cells, or cultured embryonic fibroblasts (see U.S. Patent No. 5,690,926).
Stem cells themselves can be transfected with a polynucleotide of the invention to induce autocrine expression of the polypeptide of the invention. This will allow for generation of undifferentiated totipotential/pluripotential stem cell lines that are useful as is or that can then be differentiated into the desired mature cell types.
These stable cell lines can also serve as a source of undifferentiated totipotential/pluripotential mRNA to create cDNA libraries and templates for polymerase chain reaction experiments.
These studies would allow for the isolation and identification of differentially expressed genes in stem cell populations that regulate stem cell proliferation and/or maintenance.
S Expansion and maintenance of totipotent stem cell populations will be useful in the treatment of many pathological conditions. For example, polypeptides of the present invention may be used to manipulate stem cells in culture to give rise to neuroepithelial cells that can be used to augment or replace cells damaged by illness, autoimmune disease, accidental damage or genetic disorders. The polypeptide of the invention may be useful for inducing the proliferation of neural cells and for the regeneration of nerve and brain tissue, i.e. for the treatment of central and peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders which involve degeneration, death or trauma to neural cells or nerve tissue. In addition, the expanded stem cell populations can also be genetically altered for gene therapy purposes and to decrease host rejection of replacement tissues after grafting or implantation.
Expression of the polypeptide of the invention and its effect on stem cells can also be manipulated to achieve controlled differentiation of the stem cells into more differentiated cell types. A broadly applicable method of obtaining pure populations of a specific differentiated cell type from undifferentiated stem cell populations involves the use of a cell-type specific promoter driving a selectable marker. The selectable marker allows only cells of the desired type to survive. For example, stem cells can be induced to differentiate into cardiomyocytes (Wobus et al., Differentiation, 48: 173-182, (1991);
Klug et al., J. Clin. Invest., 98(1): 216-224, (1998)) or skeletal muscle cells (Browder, L.
W. In: Principles of Tissue Engineering eds. Lanza et al., Academic Press (1997)).
Alternatively, directed differentiation of stem cells can be accomplished by culturing the stem cells in the presence of a differentiation factor such as retinoic acid and an antagonist of the polypeptide of the invention which would inhibit the effects of endogenous stem cell factor activity and allow differentiation to proceed.
In vitro cultures of stem cells can be used to determine if the polypeptide of the invention exhibits stem cell growth factor activity. Stem cells are isolated from any one of various cell sources (including hematopoietic stem cells and embryonic stem cells) and cultured on a feeder layer, as described by Thompson et al. Proc. Natl. Acad.
Sci, U.S.A., 92: 7844-7848 (1995), in the presence of the polypeptide of the invention alone or in combination with other growth factors or cytokines. The ability of the polypeptide of the invention to induce stem cells proliferation is determined by colony formation on semi-s solid support e.g. as described by Bernstein et al., Blood, 77: 2316-2321 (1991).
3.10.5 HEMATOPOIESIS REGULATING ACTIVITY
A polypeptide of the present invention may be involved in regulation of hematopoiesis and, consequently, in the treatment of myeloid or lymphoid cell disorders.
Even marginal biological activity in support of colony forming cells or of factor-dependent cell lines indicates involvement in regulating hematopoiesis, e.g. in supporting the growth and proliferation of erythroid progenitor cells alone or in combination with other cytokines, thereby indicating utility, for example, in treating various anemias or for use in conjunction with irradiation/chemotherapy to stimulate the 1 S production of erythroid precursors and/or erythroid cells; in supporting the growth and proliferation of myeloid cells such as granulocytes and monocytes/macrophages (i.e., traditional CSF activity) useful, for example, in conjunction with chemotherapy to prevent or treat consequent myelo-suppression; in supporting the growth and proliferation of megakaryocytes and consequently of platelets thereby allowing prevention or treatment of various platelet disorders such as thrombocytopenia, and generally for use in place of or complimentary to platelet transfusions; and/or in supporting the growth and proliferation of hematopoietic stem cells which are capable of maturing to any and all of the above-mentioned hematopoietic cells and therefore find therapeutic utility in various stem cell disorders (such as those usually treated with transplantation, including, without limitation, aplastic anemia and paroxysmal nocturnal hemoglobinuria), as well as in repopulating the stem cell compartment post irradiation/chemotherapy, either in-vivo or ex-vivo (i.e., in conjunction with bone marrow transplantation or with peripheral progenitor cell transplantation (homologous or heterologous)) as normal cells or genetically manipulated for gene therapy.
Therapeutic compositions of the invention can be used in the following:

Suitable assays for proliferation and differentiation of various hematopoietic lines are cited above.
Assays for embryonic stem cell differentiation (which will identify, among others, proteins that influence embryonic differentiation hematopoiesis) include, without S limitation, those described in: Johansson et al. Cellular Biology 15:141-151, 1995; Keller et al., Molecular and Cellular Biology 13:473-486, 1993; McClanahan et al., Blood 81:2903-291 S, 1993.
Assays for stem cell survival and differentiation (which will identify, among others, proteins that regulate lympho-hematopoiesis) include, without limitation, those described in: Methylcellulose colony forming assays, Freshney, M. G. In Culture of Hematopoietic Cells. R. I. Freshney, et al. eds. Vol pp. 265-268, Wiley-Liss, Inc., New York, N.Y. 1994; Hirayama et al., Proc. Natl. Acad. Sci. USA 89:5907-5911, 1992;
Primitive hematopoietic colony forming cells with high proliferative potential, McNiece, I. K. and Briddell, R. A. In Culture of Hematopoietic Cells. R. I. Freshney, et al. eds. Vol pp. 23-39, Wiley-Liss, Inc., New York, N.Y. 1994; Neben et al., Experimental Hematology 22:353-359, 1994; Cobblestone area forming cell assay, Ploemacher, R. E.
In Culture of Hematopoietic Cells. R. I. Freshney, et al. eds. Vol pp. 1-2-1, Wiley-Liss, Inc., New York, N.Y. 1994; Long term bone marrow cultures in the presence of stromal cells, Spooncer, E., Dexter, M. and Allen, T. In Culture of Hematopoietic Cells. R. I.
Freshney, et al. eds. Vol pp. 163-179, Wiley-Liss, Inc., New York, N.Y. 1994;
Long term culture initiating cell assay, Sutherland, H. J. In Culture of Hematopoietic Cells. R. I.
Freshney, et al. eds. Vol pp. 139-162, Wiley-Liss, Inc., New York, N.Y. 1994.
3.10.6 TISSUE GROWTH ACTIVITY
A polypeptide of the present invention also may be involved. in bone, cartilage, tendon, ligament and/or nerve tissue growth or regeneration, as well as in wound healing and tissue repair and replacement, and in healing of burns, incisions and ulcers.
A polypeptide of the present invention which induces cartilage and/or bone growth in circumstances where bone is not normally formed, has application in the healing of bone fractures and cartilage damage or defects in humans and other animals.
Compositions of a polypeptide, antibody, binding partner, or other modulator of the invention may have prophylactic use in closed as well as open fracture reduction and also in the improved fixation of artificial joints. De novo bone formation induced by an osteogenic agent contributes to the repair of congenital, trauma induced, or oncologic resection induced craniofacial defects, and also is useful in cosmetic plastic surgery.
A polypeptide of this invention may also be involved in attracting bone-forming cells, stimulating growth of bone-forming cells, or inducing differentiation of progenitors of bone-forming cells. Treatment of osteoporosis, osteoarthritis, bone degenerative disorders, or periodontal disease, such as through stimulation of bone and/or cartilage repair or by blocking inflammation or processes of tissue destruction (collagenase activity, osteoclast activity, etc.) mediated by inflammatory processes may also be possible using the composition of the invention.
Another category of tissue regeneration activity that may involve the polypeptide of the present invention is tendon/ligament formation. Induction of tendon/ligament-like tissue or other tissue formation in circumstances where such tissue is not normally formed, has application in the healing of tendon or ligament tears, deformities and other tendon or ligament defects in humans and other animals. Such a preparation employing a tendon/ligament-like tissue inducing protein may have prophylactic use. in preventing damage to tendon or ligament tissue, as well as use in the improved fixation of tendon or ligament to bone or other tissues, and in repairing defects to tendon or ligament tissue.
De novo tendon/ligament-like tissue formation induced by a composition of the present invention contributes to the repair of congenital, trauma induced, or other tendon or ligament defects of other origin, and is also useful in cosmetic plastic surgery for attachment or repair of tendons or ligaments. The compositions of the present invention may provide environment to attract tendon- or ligament-forming cells, stimulate growth of tendon- or ligament-forming cells, induce differentiation of progenitors of tendon- or ligament-forming cells, or induce growth of tendon/ligament cells or progenitors ex vivo for return in vivo to effect tissue repair. The compositions of the invention may also be useful in the treatment of tendinitis, carpal tunnel syndrome and other tendon or ligament defects. The compositions may also include an appropriate matrix and/or sequestering agent as a carrier as is well known in the art.

The compositions of the present invention may also be useful for proliferation of neural cells and for regeneration of nerve and brain tissue, i.e. for the treatment of central and peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders, which involve degeneration, death or trauma to neural cells or nerve tissue. More specifically, a composition may be used in the treatment of diseases of the peripheral nervous system, such as peripheral nerve injuries, peripheral neuropathy and localized neuropathies, and central nervous system diseases, such as Alzheimer's, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome. Further conditions which may be treated in accordance with the present invention include mechanical and traumatic disorders, such as spinal cord disorders, head trauma and cerebrovascular diseases such as stroke. Peripheral neuropathies resulting from chemotherapy or other medical therapies may also be treatable using a composition of the invention.
Compositions of the invention may also be useful to promote better or faster closure of non-healing wounds, including without limitation pressure ulcers, ulcers associated with vascular insufficiency, surgical and traumatic wounds, and the like.
Compositions of the present invention may also be involved in the generation or regeneration of other tissues, such as organs (including, for example, pancreas, liver, intestine, kidney, skin, endothelium), muscle (smooth, skeletal or cardiac) and vascular (including vascular endothelium) tissue, or for promoting the growth of cells comprising such tissues. Part of the desired effects may be by inhibition or modulation of fibrotic scarnng may allow normal tissue to regenerate. A polypeptide of the present invention may also exhibit angiogenic activity.
A composition of the present invention may also be useful for gut protection or regeneration and treatment of lung or liver fibrosis, reperfusion injury in various tissues, and conditions resulting from systemic cytokine damage.
A composition of the present invention may also be useful for promoting or inhibiting differentiation of tissues described above from precursor tissues or cells; or for inhibiting the growth of tissues described above.
Therapeutic compositions of the invention can be used in the following:
SS

Assays for tissue generation activity include, without limitation, those described in: International Patent Publication No. W095/16035 (bone, cartilage, tendon);
International Patent Publication No. W095/05846 (nerve, neuronal);
International Patent Publication No. W091/07491 (skin, endothelium).
Assays for wound healing activity include, without limitation, those described in:
Winter, Epidermal Wound Healing, pps. 71-112 (Maibach, H. I. and Rovee, D. T., eds.), Year Book Medical Publishers, Inc., Chicago, as modified by Eaglstein and Mertz, J.
Invest. Dermatol 71:382-84 (1978).
3.10.7 IMMUNE STIMULATING OR SUPPRESSING ACTIVITY
A polypeptide of the present invention may also exhibit immune stimulating or immune suppressing activity, including without limitation the activities for which assays are described herein. A polynucleotide of the invention can encode a polypeptide exhibiting such activities. A protein may be useful in the treatment of various immune deficiencies and disorders (including severe combined immunodeficiency (SCID)), e.g., in regulating (up or down) growth and proliferation of T and/or B lymphocytes, as well as effecting the cytolytic activity of NK cells and other cell populations. These immune deficiencies may be genetic or be caused by viral (e.g., HIV) as well as bacterial or fungal infections, or may result from autoimmune disorders. More specifically, infectious diseases causes by viral, bacterial, fungal or other infection may be treatable using a protein of the present invention, including infections by HIV, hepatitis viruses, herpes viruses, mycobacteria, Leishmania spp., malaria spp. and various fungal infections such as candidiasis. Of course, in this regard, proteins of the present invention may also be useful where a boost to the immune system generally may be desirable, i.e., in the treatment of cancer.
Autoimmune disorders which may be treated using a protein of the present invention include, for example, connective tissue disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, autoimmune pulmonary inflammation, Guillain-Barre syndrome, autoimmune thyroiditis, insulin dependent diabetes mellitis, myasthenia gravis, graft-versus-host disease and autoimmune inflammatory eye disease.
Such a protein (or antagonists thereof, including antibodies) of the present invention may also to be useful in the treatment of allergic reactions and conditions (e.g., anaphylaxis, serum sickness, drug reactions, food allergies, insect venom allergies, mastocytosis, allergic rhinitis, hypersensitivity pneumonitis, urticaria, angioedema, eczema, atopic dermatitis, allergic contact dermatitis, erythema multiforme, Stevens-Johnson syndrome, allergic conjunctivitis, atopic keratoconjunctivitis, venereal keratoconjunctivitis, giant papillary conjunctivitis and contact allergies), such as asthma (particularly allergic asthma) or other respiratory problems. Other conditions, in which immune suppression is desired (including, for example, organ transplantation), may also be treatable using a protein (or antagonists thereof) of the present invention. The therapeutic effects of the polypeptides or antagonists thereof on allergic reactions can be evaluated by in vivo animals models such as the cumulative contact enhancement test (Lastbom et al., Toxicology 125: 59-66, 1998), skin prick test (Hoffmann et al., Allergy 54:
446-54, 1999), guinea pig skin sensitization test (Vohr et al., Arch. Toxocol. 73: 501-9), and murine local lymph node assay (Kimber et al., J. Toxicol. Environ. Health 53:
563-79).
Using the proteins of the invention it may also be possible to modulate immune responses, in a number of ways. Down regulation may be in the form of inhibiting or blocking an immune response already in progress or may involve preventing the induction of an immune response. The functions of activated T cells may be inhibited by suppressing T cell responses or by inducing specific tolerance in T cells, or both.
Immunosuppression of T cell responses is generally an active, non-antigen-specific, process which requires continuous exposure of the T cells to the suppressive agent.
Tolerance, which involves inducing non-responsiveness or anergy in T cells, is distinguishable from immunosuppression in that it is generally antigen-specific and persists after exposure to the tolerizing agent has ceased. Operationally, tolerance can be demonstrated by the lack of a T cell response upon reexposure to specific antigen in the absence of the tolerizing agent.
Down regulating or preventing one or more antigen functions (including without limitation B lymphocyte antigen functions (such as, for example, B7)), e.g., preventing high level lymphokine synthesis by activated T cells, will be useful in situations of tissue, skin and organ transplantation and in graft-versus-host disease (GVHD). For example, blockage of T cell function should result in reduced tissue destruction in tissue transplantation. Typically, in tissue transplants, rejection of the transplant is initiated through its recognition as foreign by T cells, followed by an immune reaction that destroys the transplant. The administration of a therapeutic composition of the invention may prevent cytokine synthesis by immune cells, such as T cells, and thus acts as an immunosuppressant. Moreover, a lack of costimulation may also be sufficient to anergize the T cells, thereby inducing tolerance in a subject. Induction of long-term tolerance by B
lymphocyte antigen-blocking reagents may avoid the necessity of repeated administration of these blocking reagents. To achieve sufficient immunosuppression or tolerance in a subject, it may also be necessary to block the function of a combination of B
lymphocyte antigens.
The efficacy of particular therapeutic compositions in preventing organ transplant rejection or GVHD can be assessed using animal models that are predictive of efficacy in humans. Examples of appropriate systems which can be used include allogeneic cardiac grafts in rats and xenogeneic pancreatic islet cell grafts in mice, both of which have been used to examine the immunosuppressive effects of CTLA4Ig fusion proteins in vivo as described in Lenschow et al., Science 257:789-792 (1992) and Turka et al., Proc. Natl.
Acad. Sci USA, 89:11102-11105 (1992). In addition, murine models of GVHD (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp. 846-847) can be used to determine the effect of therapeutic compositions of the invention on the development of that disease.
Blocking antigen function may also be therapeutically useful for treating autoimmune diseases. Many autoimmune disorders are the result of inappropriate activation of T cells that are reactive against self tissue and which promote the production of cytokines and autoantibodies involved in the pathology of the diseases.
Preventing the activation of autoreactive T cells may reduce or eliminate disease symptoms.
Administration of reagents which block stimulation of T cells can be used to inhibit T
cell activation and prevent production of autoantibodies or T cell-derived cytokines which may be involved in the disease process. Additionally, blocking reagents may induce antigen-specific tolerance of autoreactive T cells which could lead to long-term relief from the disease. The efficacy of blocking reagents in preventing or alleviating autoimmune disorders can be determined using a number of well-characterized animal models of human autoimmune diseases. Examples include murine experimental autoimmune encephalitis, systemic lupus erythmatosis in MRL/lpr/lpr mice or NZB
hybrid mice, murine autoimmune collagen arthritis, diabetes mellitus in NOD
mice and BB rats, and murine experimental myasthenia gravis (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp. 840-856).
Upregulation of an antigen function (e.g., a B lymphocyte antigen function), as a means of up regulating immune responses, may also be useful in therapy.
Upregulation of immune responses may be in the form of enhancing an existing immune response or eliciting an initial immune response. For example, enhancing an immune response may be useful in cases of viral infection, including systemic viral diseases such as influenza, the common cold, and encephalitis.
Alternatively, anti-viral immune responses may be enhanced in an infected patient by removing T cells from the patient, costimulating the T cells in vitro with viral antigen-pulsed APCs either expressing a peptide of the present invention or together with a stimulatory form of a soluble peptide of the present invention and reintroducing the in vitro activated T cells into the patient. Another method of enhancing anti-viral immune responses would be to isolate infected cells from a patient, transfect them with a nucleic acid encoding a protein of the present invention as described herein such that the cells express all or a portion of the protein on their surface, and reintroduce the transfected cells into the patient. The infected cells would now be capable of delivering a costimulatory signal to, and thereby activate, T cells in vivo.
A polypeptide of the present invention may provide the necessary stimulation signal to T cells to induce a T cell mediated immune response against the transfected tumor cells. In addition, tumor cells which lack MHC class I or MHC class II
molecules, or which fail to reexpress sufficient mounts of MHC class I or MHC class II
molecules, can be transfected with nucleic acid encoding all or a portion of (e.g., a cytoplasmic-domain truncated portion) of an MHC class I alpha chain protein and (3z microglobulin protein or an MHC class II alpha chain protein and an MHC class II beta chain protein to thereby express MHC class I or MHC class II proteins on the cell surface. Expression of the appropriate class I or class II MHC in conjunction with a peptide having the activity of a B lymphocyte antigen (e.g., B7-1, B7-2, B7-3) induces a T cell mediated immune response against the transfected tumor cell.
Optionally, a gene encoding an antisense construct which blocks expression of an MHC class II
associated protein, such as the invariant chain, can also be cotransfected with a DNA
encoding a peptide having the activity of a B lymphocyte antigen to promote presentation of tumor associated antigens and induce tumor specific immunity. Thus, the induction of a T cell mediated immune response in a human subject may be sufficient to overcome tumor-specific tolerance in the subject.
The activity of a protein of the invention may, among other means, be measured by the following methods:
Suitable assays for thymocyte or splenocyte cytotoxicity include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E.
Coligan, A.
M. Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Herrmann et al., Proc.
Natl. Acad. Sci. USA 78:2488-2492, 1981; Hemnann et al., J. Immunol. 128:1968-1974, 1982; Handa et al., J. Immunol. 135:1564-1572, 1985; Takai et al., I. Immunol.
137:3494-3500, 1986; Takai et al., J. Immunol. 140:508-512, 1988; Bowman et al., J.
Virology 61:1992-1998; Bertagnolli et al., Cellular Immunology 133:327-341, 1991;
Brown et al., J. Immunol. 153:3079-3092, 1994.
Assays for T-cell-dependent immunoglobulin responses and isotype switching (which will identify, among others, proteins that modulate T-cell dependent antibody responses and that affect Thl/Th2 profiles) include, without limitation, those described in: Maliszewski, J. Immunol. 144:3028-3033, 1990; and Assays for B cell function: In vitro antibody production, Mond, J. J. and Brunswick, M. In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol 1 pp. 3.8.1-3.8.16, John Wiley and Sons, Toronto. 1994.
Mixed lymphocyte reaction (MLR) assays (which will identify, among others, proteins that generate predominantly Thl and CTL responses) include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A.
M.
Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Takai et al., J.
Immunol.
137:3494-3500, 1986; Takai et al., J. >lnmunol. 140:508-512, 1988; Bertagnolli et al., J.
Immunol. 149:3778-3783, 1992.
Dendritic cell-dependent assays (which will identify, among others, proteins expressed by dendritic cells that activate naive T-cells) include, without limitation, those described in: Guery et al., J. Immunol. 134:536-544, 1995; Inaba et al., Journal of Experimental Medicine 173:549-559, 1991; Macatonia et al., Journal of Immunology 154:5071-5079, 1995; Porgador et al., Journal of Experimental Medicine 182:255-260, 1995; Nair et al., Journal of Virology 67:4062-4069, 1993; Huang et al., Science 264:961-965, 1994; Macatonia et al., Journal of Experimental Medicine 169:1255-1264, 1989; Bhardwaj et al., Journal of Clinical Investigation 94:797-807, 1994; and Inaba et al., Journal of Experimental Medicine 172:631-640, 1990.
Assays for lymphocyte survival/apoptosis (which will identify, among others, proteins that prevent apoptosis after superantigen induction and proteins that regulate lymphocyte homeostasis) include, without limitation, those described in:
Darzynkiewicz et al., Cytometry 13:795-808, 1992; Gorczyca et al., Leukemia 7:659-670, 1993;
Gorczyca et al., Cancer Research 53:1945-1951, 1993; Itoh et al., Cell 66:233-243, 1991;
Zacharchuk, Journal of Immunology 145:4037-4045, 1990; Zamai et al., Cytometry 14:891-897, 1993; Gorczyca et al., International Journal of Oncology 1:639-648, 1992.
Assays for proteins that influence early steps of T-cell commitment and development include, without limitation, those described in: Antica et al., Blood 84:111-117, 1994; Fine et al., Cellular Immunology 155:111-122, 1994; Galy et al., Blood 85:2770-2778, 1995; Toki et al., Proc. Nat. Acad Sci. USA 88:7548-7551, 1991.
3.10.8 ACTIVIN/INHIBIN ACTIVITY
A polypeptide of the present invention may also exhibit activin- or inhibin-related activities. A polynucleotide of the invention may encode a polypeptide exhibiting such characteristics. Inhibins are characterized by their ability to inhibit the release of follicle stimulating hormone (FSH), while activins and are characterized by their ability to stimulate the release of follicle stimulating hormone (FSH). Thus, a polypeptide of the present invention, alone or in heterodimers with a member of the inhibin family, may be useful as a contraceptive based on the ability of inhibins to decrease fertility in female mammals and decrease spermatogenesis in male mammals. Administration of sufficient amounts of other inhibins can induce infertility in these mammals.
Alternatively, the polypeptide of the invention, as a homodimer or as a heterodimer with other protein subunits of the inhibin group, may be useful as a fertility inducing therapeutic, based upon the ability of activin molecules in stimulating FSH release from cells of the anterior pituitary. See, for example, U.S. Pat. No. 4,798,885. A polypeptide of the invention may also be useful for advancement of the onset of fertility in sexually immature mammals, so as to increase the lifetime reproductive performance of domestic animals such as, but not limited to, cows, sheep and pigs.
The activity of a polypeptide of the invention may, among other means, be measured by the following methods.
Assays for activin/inhibin activity include, without limitation, those described in:
Vale et al., Endocrinology 91:562-572, 1972; Ling et al., Nature 321:779-782, 1986; Vale et al., Nature 321:776-779, 1986; Mason et al., Nature 318:659-663, 1985;
Forage et al., Proc. Natl. Acad. Sci. USA 83:3091-3095, 1986.
3.10.9 CHEMOTACTIC/CHEMOKINETIC ACTIVITY
A polypeptide of the present invention may be involved in chemotactic or chemokinetic activity for mammalian cells, including, for example, monocytes, fibroblasts, neutrophils, T-cells, mast cells, eosinophils, epithelial and/or endothelial cells. A polynucleotide of the invention can encode a polypeptide exhibiting such attributes. Chemotactic and chemokinetic receptor activation can be used to mobilize or attract a desired cell population to a desired site of action. Chemotactic or chemokinetic compositions (e.g. proteins, antibodies, binding partners, or modulators of the invention) provide particular advantages in treatment of wounds and other trauma to tissues, as well as in treatment of localized infections. For example, attraction of lymphocytes, monocytes or neutrophils to tumors or sites of infection may result in improved immune responses against the tumor or infecting agent.
A protein or peptide has chemotactic activity for a particular cell population if it can stimulate, directly or indirectly, the directed orientation or movement of such cell population. Preferably, the protein or peptide has the ability to directly stimulate directed movement of cells. Whether a particular protein has chemotactic activity for a population of cells can be readily determined by employing such protein or peptide in any known assay for cell chemotaxis.
Therapeutic compositions of the invention can be used in the following:
Assays for chemotactic activity (which will identify proteins that induce or prevent chemotaxis) consist of assays that measure the ability of a protein to induce the migration of cells across a membrane as well as the ability of a protein to induce the adhesion of one cell population to another cell population. Suitable assays for movement and adhesion include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Marguiles, E. M.
Shevach, W.
Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 6.12, Measurement of alpha and beta Chemokines 6.12.1-6.12.28; Taub et al. J. Clin.
Invest.
95:1370-1376, 1995; Lind et al. APMIS 103:140-146, 1995; Muller et al Eur. J.
Immunol. 25:1744-1748; Gruber et al. J. of Immunol. 152:5860-5867, 1994;
Johnston et al. J. of Immunol. 153:1762-1768, 1994.
3.10.10 HEMOSTATIC AND THROMBOLYTIC ACTIVITY
A polypeptide of the invention may also be involved in hemostatis or thrombolysis or thrombosis. A polynucleotide of the invention can encode a polypeptide exhibiting such attributes. Compositions may be useful in treatment of various coagulation disorders (including hereditary disorders, such as hemophilias) or to enhance coagulation and other hemostatic events in treating wounds resulting from trauma, surgery or other causes. A composition of the invention may also be useful for dissolving or inhibiting formation of thromboses and for treatment and prevention of conditions resulting therefrom (such as, for example, infarction of cardiac and central nervous system vessels (e.g., stroke).
Therapeutic compositions of the invention can be used in the following:
Assay for hemostatic and thrombolytic activity include, without limitation, those described in: Linet et al., J. Clin. Pharmacol. 26:131-140, 1986; Burdick et al., Thrombosis Res. 45:413-419, 1987; Humphrey et al., Fibrinolysis 5:71-79 (1991);
Schaub, Prostaglandins 35:467-474, 1988.
~ 3.10.11 CANCER DIAGNOSIS AND THERAPY
Polypeptides of the invention may be involved in cancer cell generation, proliferation or metastasis. Detection of the presence or amount of polynucleotides or polypeptides of the invention may be useful for the diagnosis and/or prognosis of one or more types of cancer. For example, the presence or increased expression of a polynucleotide/polypeptide of the invention may indicate a hereditary risk of cancer, a precancerous condition, or an ongoing malignancy. Conversely, a defect in the gene or absence of the polypeptide may be associated with a cancer condition.
Identification of single nucleotide polymorphisms associated with cancer or a predisposition to cancer may also be useful for diagnosis or prognosis.
Cancer treatments promote tumor regression by inhibiting tumor cell proliferation, inhibiting angiogenesis (growth of new blood vessels that is necessary to support tumor growth) andlor prohibiting metastasis by reducing tumor cell motility or invasiveness. Therapeutic compositions of the invention may be effective in adult and pediatric oncology including in solid phase tumors/malignancies, locally advanced tumors, human soft tissue sarcomas, metastatic cancer, including lymphatic metastases, blood cell malignancies including multiple myeloma, acute and chronic leukemias, and lymphomas, head and neck cancers including mouth cancer, larynx cancer and thyroid cancer, lung cancers including small cell carcinoma and non-small cell cancers, breast cancers including small cell carcinoma and ductal carcinoma, gastrointestinal cancers including esophageal cancer, stomach cancer, colon cancer, colorectal cancer and polyps associated with colorectal neoplasia, pancreatic cancers, liver cancer, urologic cancers including bladder cancer and prostate cancer, malignancies of the female genital tract including ovarian carcinoma, uterine (including endometrial) cancers, and solid tumor in the ovarian follicle, kidney cancers including renal cell carcinoma, brain cancers including intrinsic brain tumors, neuroblastoma, astrocytic brain tumors, gliomas, metastatic tumor cell invasion in the central nervous system, bone cancers including osteomas, skin cancers including malignant melanoma, tumor progression of human skin keratinocytes, squamous cell carcinoma, basal cell carcinoma, hemangiopericytoma and Karposi's sarcoma.
Polypeptides, polynucleotides, or modulators of polypeptides of the invention (including inhibitors and stimulators of the biological activity of the polypeptide of the invention) may be administered to treat cancer. Therapeutic compositions can be administered in therapeutically effective dosages alone or in combination with adjuvant cancer therapy such as surgery, chemotherapy, radiotherapy, thermotherapy, and laser therapy, and may provide a beneficial effect, e.g. reducing tumor size, slowing rate of tumor growth, inhibiting metastasis, or otherwise improving overall clinical condition, without necessarily eradicating the cancer.
The composition can also be administered in therapeutically effective amounts as a portion of an anti-cancer cocktail. An anti-cancer cocktail is a mixture of the polypeptide or modulator of the invention with one or more anti-cancer drugs in addition to a pharmaceutically acceptable carrier for delivery. The use of anti-cancer cocktails as 1 S a cancer treatment is routine. Anti-cancer drugs that are well known in the art and can be used as a treatment in combination with the polypeptide or modulator of the invention include: Actinomycin D, Aminoglutethimide, Asparaginase, Bleomycin, Busulfan, Carboplatin, Carmustine, Chlorambucil, Cisplatin (cis-DDP), Cyclophosphamide, Cytarabine HC1 (Cytosine arabinoside), Dacarbazine, Dactinomycin, Daunorubicin HCI, Doxorubicin HC1, Estramustine phosphate sodium, Etoposide (V 16-213), Floxuridine, S-Fluorouracil (5-Fu), Flutamide, Hydroxyurea (hydroxycarbamide), Ifosfamide, Interferon Alpha-2a, Interferon Alpha-2b, Leuprolide acetate (LHRH-releasing factor analog), Lomustine, Mechlorethamine HCl (nitrogen mustard), Melphalan, Mercaptopurine, Mesna, Methotrexate (MTX), Mitomycin, Mitoxantrone HCI, Octreotide, Plicamycin, Procarbazine HCI, Streptozocin, Tamoxifen citrate, Thioguanine, Thiotepa, Vinblastine sulfate, Vincristine sulfate, Amsacrine, Azacitidine, Hexamethylmelamine, Interleukin-2, Mitoguazone, Pentostatin, Semustine, Teniposide, and Vindesine sulfate.
In addition, therapeutic compositions of the invention may be used for prophylactic treatment of cancer. There are hereditary conditions and/or environmental situations (e.g. exposure to carcinogens) known in the art that predispose an individual to developing cancers. Under these circumstances, it may be beneficial to treat these individuals with therapeutically effective doses of the polypeptide of the invention to reduce the risk of developing cancers.
In vitro models can be used to determine the effective doses of the polypeptide of the invention as a potential cancer treatment. These in vitro models include proliferation assays of cultured tumor cells, growth of cultured tumor cells in soft agar (see Freshney, (1987) Culture of Animal Cells: A Manual of Basic Technique, Wily-Liss, New York, NY Ch 18 and Ch 21), tumor systems in nude mice as described in Giovanella et al., J.
Natl. Can. Inst., 52: 921-30 (1974), mobility and invasive potential of tumor cells in Boyden Chamber assays as described in Pilkington et al., Anticancer Res., 17:

(1997), and angiogenesis assays such as induction of vascularization of the chick chorioallantoic membrane or induction of vascular endothelial cell migration as described in Ribatta et al., Intl. J. Dev. Biol., 40: 1189-97 (1999) and Li et al., Clin. Exp.
Metastasis, 17:423-9 (1999), respectively. Suitable tumor cells lines are available, e.g.
from American Type Tissue Culture Collection catalogs.
3.10.12 RECEPTOR/LIGAND ACTIVITY
A polypeptide of the present invention may also demonstrate activity as receptor, receptor ligand or inhibitor or agonist of receptor/ligand interactions. A
polynucleotide of the invention can encode a polypeptide exhibiting such characteristics.
Examples of such receptors and ligands include, without limitation, cytokine receptors and their ligands, receptor kinases and their ligands, receptor phosphatases and their ligands, receptors involved in cell-cell interactions and their ligands (including without limitation, cellular adhesion molecules (such as selectins, integrins and their ligands) and receptor/ligand pairs involved in antigen presentation, antigen recognition and development of cellular and humoral immune responses. Receptors and ligands are also useful for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction. A protein of the present invention (including, without limitation, fragments of receptors and ligands) may themselves be useful as inhibitors of receptor/ligand interactions.
The activity of a polypeptide of the invention may, among other means, be measured by the following methods:

Suitable assays for receptor-ligand activity include without limitation those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M.
Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley- Interscience (Chapter 7.28, Measurement of Cellular Adhesion under static conditions 7.28.1- 7.28.22), Takai et al., Proc. Natl. Acad. Sci. USA 84:6864-6868, 1987;
Bierer et al., J. Exp. Med. 168:1145-1156, 1988; Rosenstein et al., J. Exp.
Med.
169:149-160 1989; Stoltenborg et al., J. Immunol. Methods 175:59-68, 1994;
Stitt et al., Cell 80:661-670, 1995.
By way of example, the polypeptides of the invention may be used as a receptor for a ligand(s) thereby transmitting the biological activity of that ligand(s). Ligands may be identified through binding assays, affinity chromatography, dihybrid screening assays, BIAcore assays, gel overlay assays, or other methods known in the art.
Studies characterizing drugs or proteins as agonist or antagonist or partial agonists or a partial antagonist require the use of other proteins as competing ligands. The polypeptides of the present invention or ligand(s) thereof may be labeled by being coupled to radioisotopes, colorimetric molecules or a toxin molecules by conventional methods. ("Guide to Protein Purification" Murray P. Deutscher (ed) Methods in Enzymology Vol. 182 (1990) Academic Press, Inc. San Diego). Examples of radioisotopes include, but are not limited to, tritium and carbon-14 .
Examples of colorimetric molecules include, but are not limited to, fluorescent molecules such as fluorescamine, or rhodamine or other colorimetric molecules. Examples of toxins include, but are not limited, to ricin.
3.10.13 DRUG SCREENING
This invention is particularly useful for screening chemical compounds by using the novel polypeptides or binding fragments thereof in any of a variety of drug screening techniques. The polypeptides or fragments employed in such a test may either be free in solution, affixed to a solid support, borne on a cell surface or Located intracellularly. One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the polypeptide or a fragment thereof. Drugs are screened against such transformed cells in competitive binding assays.

Such cells, either in viable or fixed form, can be used for standard binding assays. One may measure, for example, the formation of complexes between polypeptides of the invention or fragments and the agent being tested or examine the diminution in complex formation between the novel polypeptides and an appropriate cell line, which are well known in the art.
Sources for test compounds that may be screened for ability to bind to or modulate (i.e., increase or decrease) the activity of polypeptides of the invention include (1) inorganic and organic chemical libraries, (2) natural product libraries, and (3) combinatorial libraries comprised of either random or mimetic peptides, oligonucleotides or organic molecules.
Chemical libraries may be readily synthesized or purchased from a number of commercial sources, and may include structural analogs of known compounds or compounds that are identified as "hits" or "leads" via natural product screening.
The sources of natural product libraries are microorganisms (including bacteria and fungi), animals, plants or other vegetation, or marine organisms, and libraries of mixtures for screening may be created by: (1) fermentation and extraction of broths from soil, plant or marine microorganisms or (2) extraction of the organisms themselves.
Natural product libraries include polyketides, non-ribosomal peptides, and (non-naturally occurring) variants thereof. For a review, see Science 282:63-68 (1998).
Combinatorial libraries are composed of large numbers of peptides, oligonucleotides or organic compounds and can be readily prepared by traditional automated synthesis methods, PCR, cloning or proprietary synthetic methods. Of particular interest are peptide and oligonucleotide combinatorial libraries.
Still other libraries of interest include peptide, protein, peptidomimetic, multiparallel synthetic collection, recombinatorial, and polypeptide libraries. For a review of combinatorial chemistry and libraries created therefrom, see Myers, Curr. Opin. Biotechnol.
8:701-707 (1997). For reviews and examples of peptidomimetic libraries, see Al-Obeidi et al., Mol.
Biotechnol, 9(3):205-23 (1998); Hruby et al., Curr Opin Chem Biol, 1(1):114-19 (1997);
Dorner et al., BioorgMed Chem, 4(5):709-15 (1996) (alkylated dipeptides).
Identification of modulators through use of the various libraries described herein permits modification of the candidate "hit" (or "lead") to optimize the capacity of the "hit" to bind a polypeptide of the invention. The molecules identified in the binding assay are then tested for antagonist or agonist activity in in vivo tissue culture or animal models that are well known in the art. In brief, the molecules are titrated into a plurality of cell cultures or animals and then tested for either cell/animal death or prolonged survival of S the animal/cells.
The binding molecules thus identified may be complexed with toxins, e.g., ricin or cholera, or with other compounds that are toxic to cells such as radioisotopes. The toxin-binding molecule complex is then targeted to a tumor or other cell by the specificity of the binding molecule for a polypeptide of the invention. Alternatively, the binding molecules may be complexed with imaging agents for targeting and imaging purposes.
3.10.14 ASSAY FOR RECEPTOR ACTIVITY
The invention also provides methods to detect specific binding of a polypeptide e.g. a ligand or a receptor. The art provides numerous assays particularly useful for 1 S identifying previously unknown binding partners for receptor polypeptides of the invention. For example, expression cloning using mammalian or bacterial cells, or dihybrid screening assays can be used to identify polynucleotides encoding-binding partners. As another example, affinity chromatography with the appropriate immobilized polypeptide of the invention can be used to isolate polypeptides that recognize and bind polypeptides of the invention. There are a number of different libraries used for the identification of compounds, and in particular small molecules, that modulate (i.e., increase or decrease) biological activity of a polypeptide of the invention.
Ligands for receptor polypeptides of the invention can also be identified by adding exogenous ligands, or cocktails of ligands to two cells populations that are genetically identical except for the expression of the receptor of the invention: one cell population expresses the receptor of the invention whereas the other does not. The response of the two cell populations to the addition of ligands(s) are then compared. Alternatively, an expression library can be co-expressed with the polypeptide of the invention in cells and assayed for an autocrine response to identify potential ligand(s). As still another example, BIAcore assays, gel overlay assays, or other methods known in the art can be used to identify binding partner polypeptides, including, (1) organic and inorganic chemical libraries, (2) natural product libraries, and (3) combinatorial libraries comprised of random peptides, oligonucleotides or organic molecules.
The role of downstream intracellular signaling molecules in the signaling cascade of the polypeptide of the invention can be determined. For example, a chimeric protein in which the cytoplasmic domain of the polypeptide of the invention is fused to the extracellular portion of a protein, whose ligand has been identified, is produced in a host cell. The cell is then incubated with the ligand specific for the extracellular portion of the chimeric protein, thereby activating the chimeric receptor. Known downstream proteins involved in intracellular signaling can then be assayed for expected modifications i.e.
phosphorylation. Other methods known to those in the art can also be used to identify signaling molecules involved in receptor activity.
3.10.15 ANTI-INFLAMMATORY ACTIVITY
Compositions of the present invention may also exhibit anti-inflammatory activity. The anti-inflammatory activity may be achieved by providing a stimulus to cells involved in the inflammatory response, by inhibiting or promoting cell-cell interactions (such as, for example, cell adhesion), by inhibiting or promoting chemotaxis of cells involved in the inflammatory process, inhibiting or promoting cell extravasation, or by stimulating or suppressing production of other factors which more directly inhibit or promote an inflammatory response. Compositions with such activities can be used to treat inflammatory conditions including chronic or acute conditions), including without limitation intimation associated with infection (such as septic shock, sepsis or systemic inflammatory response syndrome (SIRS)), ischemia-reperfusion injury, endotoxin lethality, arthritis, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine-induced lung injury, inflammatory bowel disease, Crohn's disease or resulting from over production of cytokines such as TNF or IL-1. Compositions of the invention may also be useful to treat anaphylaxis and hypersensitivity to an antigenic substance or material. Compositions of this invention may be utilized to prevent or treat conditions such as, but not limited to, sepsis, acute pancreatitis, endotoxin shock, cytokine induced shock, rheumatoid arthritis, chronic inflammatory arthritis, pancreatic cell damage from diabetes mellitus type 1, graft versus host disease, inflammatory bowel disease, inflamation associated with pulmonary disease, other autoimmune disease or inflammatory disease, an antiproliferative agent such as for acute or chronic mylegenous leukemia or in the prevention of premature labor secondary to intrauterine infections.
3.10.16 LEUKEMIAS
Leukemias and related disorders may be treated or prevented by administration of a therapeutic that promotes or inhibits function of the polynucleotides and/or polypeptides of the invention. Such leukemias and related disorders include but are not limited to acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia, chronic leukemia, chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia (for a review of such disorders, see Fishman et al., 1985, Medicine, 2d Ed., J.B.
Lippincott Co., Philadelphia).
3.10.17 NERVOUS SYSTEM DISORDERS
Nervous system disorders, involving cell types which can be tested for efficacy of intervention with compounds that modulate the activity of the polynucleotides and/or polypeptides of the invention, and which can be treated upon thus observing an indication of therapeutic utility, include but are not limited to nervous system injuries, and diseases or disorders which result in either a disconnection of axons, a diminution or degeneration of neurons, or demyelination. Nervous system lesions which may be treated in a patient (including human and non-human mammalian patients) according to the invention include but are not limited to the following lesions of either the central (including spinal cord, brain) or peripheral nervous systems:
(i) traumatic lesions, including lesions caused by physical injury or associated with surgery, for example, lesions which sever a portion of the nervous system, or compression injuries;
(ii) ischemic lesions, in which a lack of oxygen in a portion of the nervous system results in neuronal injury or death, including cerebral infarction or ischemia, or spinal cord infarction or ischemia;

(iii) infectious lesions, in which a portion of the nervous system is destroyed or injured as a result of infection, for example, by an abscess or associated with infection by human immunodeficiency virus, herpes zoster, or herpes simplex virus or with Lyme disease, tuberculosis, syphilis;
S (iv) degenerative lesions, in which a portion of the nervous system is destroyed or injured as a result of a degenerative process including but not limited to degeneration associated with Parkinson's disease, Alzheimer's disease, Huntington's chorea, or amyotrophic lateral sclerosis;
(v) lesions associated with nutritional diseases or disorders, in which a portion of the nervous system is destroyed or injured by a nutritional disorder or disorder of metabolism including but not limited to, vitamin B12 deficiency, folic acid deficiency, Wernicke disease, tobacco-alcohol amblyopia, Marchiafava-Bignami disease (primary degeneration of the corpus callosum), and alcoholic cerebellar degeneration;
(vi) neurological lesions associated with systemic diseases including but not limited to diabetes (diabetic neuropathy, Bell's palsy), systemic lupus erythematosus, carcinoma, or sarcoidosis;
(vii) lesions caused by toxic substances including alcohol, lead, or particular neurotoxins; and (viii) demyelinated lesions in which a portion of the nervous system is destroyed or injured by a demyelinating disease including but not limited to multiple sclerosis, human immunodeficiency virus-associated myelopathy, transverse myelopathy or various etiologies, progressive multifocal leukoencephalopathy, and central pontine myelinolysis.
Therapeutics which are useful according to the invention for treatment of a nervous system disorder may be selected by testing for biological activity in promoting the survival or differentiation of neurons. For example, and not by way of limitation, therapeutics which elicit any of the following effects may be useful according to the invention:
(i) increased survival time of neurons in culture;
(ii) increased sprouting of neurons in culture or in vivo;

WO 02/074961 , PCT/US02/05109 (iii) increased production of a neuron-associated molecule in culture or in vivo, e.g., choline acetyltransferase or acetylcholinesterase with respect to motor neurons; or (iv) decreased symptoms of neuron dysfunction in vivo.
Such effects may be measured by any method known in the art. In preferred, S non-limiting embodiments, increased survival of neurons may be measured by the method set forth in Arakawa et al. (1990, J. Neurosci. 10:3507-3515);
increased sprouting of neurons may be detected by methods set forth in Pestronk et al. (1980, Exp.
Neurol.
70:b5-82) or Brown et al. (1981, Ann. Rev. Neurosci. 4:17-42); increased production of neuron-associated molecules may be measured by bioassay, enzymatic assay, antibody binding, Northern blot assay, etc., depending on the molecule to be measured;
and motor neuron dysfunction may be measured by assessing the physical manifestation of motor neuron disorder, e.g., weakness, motor neuron conduction velocity, or functional disability.
In specific embodiments, motor neuron disorders that may be treated according to the invention include but are not limited to disorders such as infarction, infection, exposure to toxin, trauma, surgical damage, degenerative disease or malignancy that may affect motor neurons as well as other components of the nervous system, as well as disorders that selectively affect neurons such as amyotrophic lateral sclerosis, and including but not limited to progressive spinal muscular atrophy, progressive bulbar palsy, primary lateral sclerosis, infantile and juvenile muscular atrophy, progressive bulbar paralysis of childhood (Fazio-Londe syndrome), poliomyelitis and the post polio syndrome, and Hereditary Motorsensory Neuropathy (Charcot-Marie-Tooth Disease).
3.10.18 OTHER ACTIVITIES
A polypeptide of the invention may also exhibit one or more of the following additional activities or effects: inhibiting the growth, infection or function of, or killing, infectious agents, including, without limitation, bacteria, viruses, fungi and other parasites; effecting (suppressing or enhancing) bodily characteristics, including, without limitation, height, weight, hair color, eye color, skin, fat to lean ratio or other tissue pigmentation, or organ or body part size or shape (such as, for example, breast augmentation or diminution, change in bone form or shape); effecting biorhythms or circadian cycles or rhythms; effecting the fertility of male or female subjects; effecting the metabolism, catabolism, anabolism, processing, utilization, storage or elimination of dietary fat, lipid, protein, carbohydrate, vitamins, minerals, co-factors or other nutritional factors or component(s); effecting behavioral characteristics, including, without limitation, appetite, libido, stress, cognition (including cognitive disorders), depression (including depressive disorders) and violent behaviors; providing analgesic effects or other pain reducing effects; promoting differentiation and growth of embryonic stem cells in lineages other than hematopoietic lineages; hormonal or endocrine activity;
in the case of enzymes, correcting deficiencies of the enzyme and treating deficiency-related diseases; treatment of hyperproliferative disorders (such as, for example, psoriasis);
immunoglobulin-like activity (such as, for example, the ability to bind antigens or complement); and the ability to act as an antigen in a vaccine composition to raise an immune response against such protein or another material or entity which is cross-reactive with such protein.
3.10.19 IDENTIFICATION OF POLYMORPHISMS
The demonstration of polymorphisms makes possible the identification of such polymorphisms in human subjects and the pharmacogenetic use of this information for diagnosis and treatment. Such polymorphisms may be associated with, e.g., differential predisposition or susceptibility to various disease states (such as disorders involving inflammation or immune response) or a differential response to drug administration, and this genetic information can be used to tailor preventive or therapeutic treatment appropriately. For example, the existence of a polymorphism associated with a predisposition to inflammation or autoimmune disease makes possible the diagnosis of this condition in humans by identifying the presence of the polymorphism.
Polymorphisms can be identified in a variety of ways known in the art which all generally involve obtaining a sample from a patient, analyzing DNA from the sample, optionally involving isolation or amplification of the DNA, and identifying the presence of the polymorphism in the DNA. For example, PCR may be used to amplify an appropriate fragment of genomic DNA which may then be sequenced.
Alternatively, the DNA may be subjected to allele-specific oligonucleotide hybridization (in which appropriate oligonucleotides are hybridized to the DNA under conditions permitting detection of a single base mismatch) or to a single nucleotide extension assay (in which an oligonucleotide that hybridizes immediately adjacent to the position of the polymorphism is extended with one or more labeled nucleotides). In addition, traditional restriction fragment length polymorphism analysis (using restriction enzymes that provide differential digestion of the genomic DNA depending on the presence or absence of the polymorphism) may be performed. Arrays with nucleotide sequences of the present invention can be used to detect polymorphisms. The array can comprise modified nucleotide sequences of the present invention in order to detect the nucleotide sequences of the present invention. In the alternative, any one of the nucleotide sequences of the present invention can be placed on the array to detect changes from those sequences.
Alternatively a polymorphism resulting in a change in the amino acid sequence could also be detected by detecting a corresponding change in amino acid sequence of the protein, e.g., by an antibody specific to the variant sequence.
3.10.20 ARTHRITIS AND INFLAMMATION
The immunosuppressive effects of the compositions of the invention against rheumatoid arthritis is determined in an experimental animal model system. The experimental model system is adjuvant induced arthritis in rats, and the protocol is described by J. Holoshitz, et at., 1983, Science, 219:56, or by B. Waksman et al., 1963, Int. Arch. Allergy Appl. Immunol., 23:129. Induction of the disease can be caused by a single injection, generally intradermally, of a suspension of killed Mycobacterium tuberculosis in complete Freund's adjuvant (CFA). The route of injection can vary, but rats may be injected at the base of the tail with an adjuvant mixture. The polypeptide is administered in phosphate buffered solution (PBS) at a dose of about 1-5 mg/kg. The control consists of administering PBS only.
The procedure for testing the effects of the test compound would consist of intradermally injecting killed Mycobacterium tuberculosis in CFA followed by immediately administering the test compound and subsequent treatment every other day until day 24. At 14, 15, 18, 20, 22, and 24 days after injection of Mycobacterium CFA, an overall arthritis score may be obtained as described by J. Holoskitz above. An analysis of the data would reveal that the test compound would have a dramatic affect on the swelling of the joints as measured by a decrease of the arthritis score.
3.11 THERAPEUTIC METHODS
The compositions (including polypeptide fragments, analogs, variants and antibodies or other binding partners or modulators including antisense polynucleotides) of the invention have numerous applications in a variety of therapeutic methods.
Examples of therapeutic applications include, but are not limited to, those exemplified herein.
3.11.1 EXAMPLE
One embodiment of the invention is the administration of an effective amount of the polypeptides or other composition of the invention to individuals affected by a disease or disorder that can be modulated by regulating the peptides of the invention.
While the mode of administration is not particularly important, parenteral administration is preferred. An exemplary mode of administration is to deliver an intravenous bolus.
The dosage of the polypeptides or other composition of the invention will normally be determined by the prescribing physician. It is to be expected that the dosage will vary according to the age, weight, condition and response of the individual patient. Typically, the amount of polypeptide administered per dose will be in the range of about 0.01 ~g/kg to 100 mg/kg of body weight, with the preferred dose being about 0.1 pg/kg to 10 mg/kg of patient body weight. For parenteral administration, polypeptides of the invention will be formulated in an injectable form combined with a pharmaceutically acceptable parenteral vehicle. Such vehicles are well known in the art and examples include water, saline, Ringer's solution, dextrose solution, and solutions consisting of small amounts of the human serum albumin. The vehicle may contain minor amounts of additives that maintain the isotonicity and stability of the polypeptide or other active ingredient. The preparation of such solutions is within the skill of the art.

3.12 PHARMACEUTICAL FORMULATIONS AND ROUTES OF
ADMINISTRATION
A protein or other composition of the present invention (from whatever source derived, including without limitation from recombinant and non-recombinant sources and including antibodies and other binding partners of the polypeptides of the invention) may be administered to a patient in need, by itself, or in pharmaceutical compositions where it is mixed with suitable carriers or excipient(s) at doses to treat or ameliorate a variety of disorders. Such a composition may optionally contain (in addition to protein or other active ingredient and a Garner) diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The term "pharmaceutically acceptable"
means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s). The characteristics of the Garner will depend on the route of administration. The pharmaceutical composition of the invention may also contain cytokines, lymphokines, or other hematopoietic factors such as M-CSF, GM-CSF, TNF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IFN, TNFO, TNF1, TNF2, G-CSF, Meg-CSF, thrombopoietin, stem cell factor, and erythropoietin. In further compositions, proteins of the invention may be combined with other agents beneficial to the treatment of the disease or disorder in question. These agents include various growth factors such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factors (TGF-a and TGF-(3), insulin-like growth factor (IGF), as well as cytokines described herein.
The pharmaceutical composition may further contain other agents which either enhance the activity of the protein or other active ingredient or complement its activity or use in treatment. Such additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with protein or other active ingredient of the invention, or to minimize side effects. Conversely, protein or other active ingredient of the present invention may be included in formulations of the particular clotting factor, cytokine, Iymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or anti- inflammatory agent to minimize side effects of the clotting factor, cytokine, lymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or anti-inflammatory agent (such as IL-lRa, IL-1 Hyl, IL-1 Hy2, anti-TNF, corticosteroids, immunosuppressive agents). A protein of the present invention may be active in multimers (e.g., heterodimers or homodimers) or complexes with itself or other proteins. As a result, pharmaceutical compositions of the invention may comprise a protein of the invention in such multimeric or complexed form.
As an alternative to being included in a pharmaceutical composition of the invention including a first protein, a second protein or a therapeutic agent may be concurrently administered with the first protein (e.g., at the same time, or at differing times provided that therapeutic concentrations of the combination of agents is achieved at the treatment site). Techniques for formulation and administration of the compounds of the instant application may be found in "Remington's Pharmaceutical Sciences,"
Mack Publishing Co., Easton, PA, latest edition. A therapeutically effective dose further refers to that amount of the compound sufficient to result in amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions.
1 S When applied to an individual active ingredient, administered alone, a therapeutically effective dose refers to that ingredient alone. When applied to a combination, a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
In practicing the method of treatment or use of the present invention, a therapeutically effective amount of protein or other active ingredient of the present invention is administered to a mammal having a condition to be treated.
Protein or other active ingredient of the present invention may be administered in accordance with the method of the invention either alone or in combination with other therapies such as treatments employing cytokines, lymphokines or other hematopoietic factors.
When co-administered with one or more cytokines, lymphokines or other hematopoietic factors, protein or other active ingredient of the present invention may be administered either simultaneously with the cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolvtic or anti-thrombotic factors, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering protein or other active ingredient of the present invention in combination with cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors.
3.12.1 ROUTES OF ADMINISTRATION
Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
Administration of protein or other active ingredient of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be earned out in a variety of conventional ways, such as oral ingestion, inhalation, topical application or cutaneous, subcutaneous, intraperitoneal, parenteral or intravenous injection.
Intravenous administration to the patient is preferred.
Alternately, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into a arthritic joints or in fibrotic tissue, often in a depot or sustained release formulation. In order to prevent the scarring process frequently occurnng as complication of glaucoma surgery; the compounds may be administered topically, for example, as eye drops.
Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with a specific antibody, targeting, for example, arthritic or fibrotic tissue. The liposomes will be targeted to and taken up selectively by the afflicted tissue.
The polypeptides of the invention are administered by any route that delivers an effective dosage to the desired site of action. The determination of a suitable route of administration and an effective dosage for a particular indication is within the level of skill in the art. Preferably for wound treatment, one administers the therapeutic compound directly to the site. Suitable dosage ranges for the polypeptides of the invention can be extrapolated from these dosages or from similar studies in appropriate animal models. Dosages can then be adjusted as necessary by the clinician to provide maximal therapeutic benefit.
3.12.2 COMPOSITIONS/FORMULATIONS

Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
These pharmaceutical compositions may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen. When a therapeutically effective amount of protein or other active ingredient of the present invention is administered orally, protein or other active ingredient of the present invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the pharmaceutical composition of the invention may additionally contain a solid Garner such as a gelatin or an adjuvant. The tablet, capsule, and powder contain from about 5 to 95%
protein or other active ingredient of the present invention, and preferably from about 25 to 90% protein or other active ingredient of the present invention. When administered in liquid form, a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils may be added. The liquid form of the pharmaceutical composition may further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol. When administered in liquid form, the pharmaceutical composition contains from about 0.5 to 90% by weight of protein or other active ingredient of the present invention, and preferably from about 1 to 50%
protein or other active ingredient of the present invention.
When a therapeutically effective amount of protein or other active ingredient of the present invention is administered by intravenous, cutaneous or subcutaneous injection, protein or other active ingredient of the present invention will be in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable protein or other active ingredient solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A
preferred pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to protein or other active ingredient of the present invention, an isotonic vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, or other vehicle as known in the art. The pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art. For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barner 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 Garners 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 to be treated. Pharmaceutical preparations for oral use can be obtained from a solid excipient, optionally grinding a 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 carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the 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, and/or 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 preparations 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 can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for S oral administration should be in dosages suitable for such administration.
For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. 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 an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative.
The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions.
Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or 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 compounds 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, before use.
The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
A pharmaceutical earner for the hydrophobic compounds of the invention is a co-solvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The co-solvent system may be the VPD
co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:SW) consists of VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or earners for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.

Various types of sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein or other active ingredient stabilization may be employed.
The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Many of the active ingredients of the invention may be provided as salts with pharmaceutically compatible counter ions. Such pharmaceutically acceptable base addition salts are those salts which retain the biological effectiveness and properties of the free acids and which are obtained by reaction with inorganic or organic bases such as sodium hydroxide, magnesium hydroxide, ammonia, trialkylamine, dialkylamine, monoalkylamine, dibasic amino acids, sodium acetate, potassium benzoate, triethanol amine and the like.
The pharmaceutical composition of the invention may be in the form of a complex of the proteins) or other active ingredients) of present invention along with protein or peptide antigens. The protein and/or peptide antigen will deliver a stimulatory signal to both B and T lymphocytes. B lymphocytes will respond to antigen through their surface immunoglobulin receptor. T lymphocytes will respond to antigen through the T
cell receptor (TCR) following presentation of the antigen by MHC proteins. MHC
and structurally related proteins including those encoded by class I and class II
MHC genes on host cells will serve to present the peptide antigens) to T lymphocytes.
The antigen components could also be supplied as purified MHC-peptide complexes alone or with co-stimulatory molecules that can directly signal T cells. Alternatively antibodies able to bind surface immunoglobulin and other molecules on B cells as well as antibodies able to bind the TCR and other molecules on T cells can be combined with the pharmaceutical composition of the invention.
The pharmaceutical composition of the invention may be in the form of a liposome in which protein of the present invention is combined, in addition to other pharmaceutically acceptable earners, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution. Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithins, phospholipids, saponin, bile acids, and the like. Preparation of such liposomal formulations is within the level of skill in the S art, as disclosed, for example, in U.S. Patent Nos. 4,235,871; 4,501,728;
4,837,028; and 4,737,323, all of which are incorporated herein by reference.
The amount of protein or other active ingredient of the present invention in the pharmaceutical composition of the present invention will depend upon the nature and severity of the condition being treated, and on the nature of prior treatments which the patient has undergone. Ultimately, the attending physician will decide the amount of protein or other active ingredient of the present invention with which to treat each individual patient. Initially, the attending physician will administer low doses of protein or other active ingredient of the present invention and observe the patient's response.
Larger doses of protein or other active ingredient of the present invention may be administered until the optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further. It is contemplated that the various pharmaceutical compositions used to practice the method of the present invention should contain about 0.01 pg to about 100 mg (preferably about 0.1 pg to about 10 mg, more preferably about 0.1 pg to about 1 mg) of protein or other active ingredient of the present invention per kg body weight. For compositions of the present invention which are useful for bone, cartilage, tendon or ligament regeneration, the therapeutic method includes administering the composition topically, systematically, or locally as an implant or device. When administered, the therapeutic composition for use in this invention is, of course, in a pyrogen-free, physiologically acceptable form. Further, the composition may desirably be encapsulated or injected in a viscous form for delivery to the site of bone, cartilage or tissue damage. Topical administration may be suitable for wound healing and tissue repair. Therapeutically useful agents other than a protein or other active ingredient of the invention which may also optionally be included in the composition as described above, may alternatively or additionally, be administered simultaneously or sequentially with the composition in the methods of the invention. Preferably for bone and/or cartilage formation, the composition would include a matrix capable of delivering the protein-containing or other active ingredient-containing composition to the site of bone and/or cartilage damage, providing a structure for the developing bone and cartilage and optimally capable of being resorbed into the body. Such matrices may be formed of materials presently in use for other implanted medical applications.
The choice of matrix material is based on biocompatibility, biodegradability, mechanical properties, cosmetic appearance and interface properties. The particular application of the compositions will define the appropriate formulation.
Potential matrices for the compositions may be biodegradable and chemically defined calcium sulfate, tricalcium phosphate, hydroxyapatite, polylactic acid, polyglycolic acid and polyanhydrides. Other potential materials are biodegradable and biologically well-defined, such as bone or dermal collagen. Further matrices are comprised of pure proteins or extracellular matrix components. Other potential matrices are nonbiodegradable and chemically defined, such as sintered hydroxyapatite, bioglass, aluminates, or other ceramics. Matrices may be comprised of combinations of any of the above mentioned types of material, such as polylactic acid and hydroxyapatite or collagen and tricalcium phosphate. The bioceramics may be altered in composition, such as in calcium-aluminate-phosphate and processing to alter pore size, particle size, particle shape, and biodegradability. Presently preferred is a 50:50 (mole weight) copolymer of lactic acid and glycolic acid in the form of porous particles having diameters ranging from 1 SO to 800 microns. In some applications, it will be useful to utilize a sequestering agent, such as carboxymethyl cellulose or autologous blood clot, to prevent the protein compositions from disassociating from the matrix.
A preferred family of sequestering agents is cellulosic materials such as alkylcelluloses (including hydroxyalkylcelluloses), including methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl-methylcellulose, and carboxymethylcellulose, the most preferred being cationic salts of carboxymethylcellulose (CMC). Other preferred sequestering agents include hyaluronic acid, sodium alginate, polyethylene glycol), polyoxyethylene oxide, carboxyvinyl polymer and polyvinyl alcohol). The amount of sequestering agent useful herein is 0.5-20 wt %, preferably 1-10 wt % based on total formulation weight, which represents the amount necessary to prevent desorption of the protein from the polymer matrix and to provide appropriate handling of the composition, yet not so much that the progenitor cells are prevented from infiltrating the matrix, thereby providing the protein the opportunity to assist the osteogenic activity of the progenitor cells. In further compositions, proteins or other active ingredients of the invention may be combined with other agents beneficial to the treatment of the bone and/or cartilage defect, wound, or tissue in question. These agents include various growth factors such as epidermal growth factor (EGF), platelet derived growth factor (PDGF), transforming growth factors (TGF-a and TGF-~3), and insulin-like growth factor (IGF).
The therapeutic compositions are also presently valuable for veterinary applications. Particularly domestic animals and thoroughbred horses, in addition to humans, are desired patients for such treatment with proteins or other active ingredients of the present invention. The dosage regimen of a protein-containing pharmaceutical composition to be used in tissue regeneration will be determined by the attending physician considering various factors which modify the action of the proteins, e.g., 1 S amount of tissue weight desired to be formed, the site of damage, the condition of the damaged tissue, the size of a wound, type of damaged tissue (e.g., bone), the patient's age, sex, and diet, the severity of any infection, time of administration and other clinical factors. The dosage may vary with the type of matrix used in the reconstitution and with inclusion of other proteins in the pharmaceutical composition. For example, the addition of other known growth factors, such as IGF I (insulin like growth factor I), to the final composition, may also effect the dosage. Progress can be monitored by periodic assessment of tissue/bone growth and/or repair, for example, X-rays, histomorphometric determinations and tetracycline labeling.
Polynucleotides of the present invention can also be used for gene therapy.
Such polynucleotides can be introduced either in vivo or ex vivo into cells for expression in a mammalian subject. Polynucleotides of the invention may also be administered by other known methods for introduction of nucleic acid into a cell or organism (including, without limitation, in the form of viral vectors or naked DNA). Cells may also be cultured ex vivo in the presence of proteins of the present invention in order to proliferate or to produce a desired effect on or activity in such cells. Treated cells can then be introduced in vivo for therapeutic purposes.

3.12.3 EFFECTIVE DOSAGE
Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from appropriate in vitro assays.
For example, a dose can be formulated in animal models to achieve a circulating concentration range that can be used to more accurately determine useful doses in humans. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the ICSO as determined in cell culture (i.e., the concentration of the test compound which achieves a half maximal inhibition of the protein's biological activity). Such information can be used to more accurately determine useful doses in humans.
A therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms or a prolongation of survival in a patient.
Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LDSO (the dose lethal to 50% of the population) and the EDSO (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LDso and EDSO.
Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the EDSO with little or no toxicity.
The dosage may vary within this range 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.1 . Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the desired effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data.
S Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
Dosage intervals can also be determined using MEC value. Compounds should be administered using a regimen which maintains plasma levels above the MEC
for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
An exemplary dosage regimen for polypeptides or other compositions of the invention will be in the range of about 0.01 ~glkg to 100 mg/kg of body weight daily, with the preferred dose being about 0.1 ~g/kg to 25 mg/kg of patient body weight daily, varying in adults and children. Dosing may be once daily, or equivalent doses may be delivered at longer or shorter intervals.
The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's age and weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
3.12.4 PACKAGING
The compositions may, if desired, be presented in a pack or dispenser device 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.
Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
3.13 ANTIBODIES

Also included in the invention are antibodies to proteins, or fragments of proteins of the invention. The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen-binding site that specifically binds (immunoreacts with) an antigen. Such antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, Fab, Fab' and F~ab~~2 fragments, and an Fab expression library. In general, an antibody molecule obtained from humans relates to any of the classes IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature of the heavy chain present in the molecule. Certain classes have subclasses as well, such as IgG~, IgGZ, and others. Furthermore, in humans, the light chain may be a kappa chain or a lambda chain.
Reference herein to antibodies includes a reference to all such classes, subclasses and types of human antibody species.
An isolated related protein of the invention may be intended to serve as an antigen, or a portion or fragment thereof, and additionally can be used as an immunogen 1~ to generate antibodies that immunospecifically bind the antigen, using standard techniques for polyclonal and monoclonal antibody preparation. The full-length protein can be used or, alternatively, the invention provides antigenic peptide fragments of the antigen for use as immunogens. An antigenic peptide fragment comprises at least 6 amino acid residues of the amino acid sequence of the full length protein, such as an amino acid sequence shown in SEQ )D NO: 527 -1052, and encompasses an epitope thereof such that an antibody raised against the peptide forms a specific immune complex with the full length protein or with any fragment that contains the epitope.
Preferably, the antigenic peptide comprises at least 10 amino acid residues, or at least 15 amino acid residues, or at least 20 amino acid residues, or at least 30 amino acid residues. Preferred epitopes encompassed by the antigenic peptide are regions of the protein that are located on its surface; commonly these are hydrophilic regions.
In certain embodiments of the invention, at least one epitope encompassed by the antigenic peptide is a surface region of the protein, e.g., a hydrophilic region. A
hydrophobicity analysis of the human related protein sequence will indicate which ti regions of a related protein are particularly hydrophilic and, therefore, are likely to encode surface residues useful for targeting antibody production. As a means for targeting antibody production, hydropathy plots showing regions of hydrophilicity and hydrophobicity may be generated by any method well known in the art, including, for example, the Kyte Doolittle or the Hopp Woods methods, either with or without Fourier transformation. See, e.g., Hopp and Woods, 1981, Proc. Nat. Acad. Sci. USA 78:

3828; Kyte and Doolittle 1982, J. Mol. Biol. 157: 105-142, each of which is incorporated herein by reference in its entirety. Antibodies that are specific for one or more domains within an antigenic protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein.
A protein of the invention, or a derivative, fragment, analog, homolog or ortholog thereof, may be utilized as an immunogen in the generation of antibodies that immunospecifically bind these protein components.
The term "specific for" indicates that the variable regions of the antibodies of the invention recognize and bind polypeptides of the invention exclusively (i.e., able to distinguish the polypeptide of the invention from other similar polypeptides despite 1 S sequence identity, homology, or similarity found in the family of polypeptides), but may also interact with other proteins (for example, S. aureus protein A or other antibodies in ELISA techniques) through interactions with sequences outside the variable region of the antibodies, and in particular, in the constant region of the molecule.
Screening assays to determine binding specificity of an antibody of the invention are well known and routinely practiced in the art. For a comprehensive discussion of such assays, see Harlow et al. (Eds), Antibodies A Laboratory Manual; Cold Spring Harbor Laboratory;
Cold Spring Harbor, NY (1988), Chapter 6. Antibodies that recognize and bind fragments of the polypeptides of the invention are also contemplated, provided that the antibodies are first and foremost specific for, as defined above, full-length polypeptides of the invention. As with antibodies that are specific for full length polypeptides of the invention, antibodies of the invention that recognize fragments are those which can distinguish polypeptides from the same family of polypeptides despite inherent sequence identity, homology, or similarity found in the family of proteins.
Antibodies of the invention are useful for, for example, therapeutic purposes (by modulating activity of a polypeptide of the invention), diagnostic purposes to detect or quantitate a polypeptide of the invention, as well as purification of a polypeptide of the invention. Kits comprising an antibody of the invention for any of the purposes described herein are also comprehended. In general, a kit of the invention also includes a control antigen for which the antibody is immunospecific. The invention further provides a hybridoma that produces an antibody according to the invention. Antibodies of the invention are useful for detection and/or purification of the polypeptides of the invention.
Monoclonal antibodies binding to the protein of the invention may be useful diagnostic agents for the immunodetection of the protein. Neutralizing monoclonal antibodies binding to the protein may also be useful therapeutics for both conditions associated with the protein and also in the treatment of some forms of cancer where abnormal expression of the protein is involved. In the case of cancerous cells or leukemic cells, neutralizing monoclonal antibodies against the protein may be useful in detecting and preventing the metastatic spread of the cancerous cells, which may be mediated by the protein.
The labeled antibodies of the present invention can be used for in vitro, in vivo, 1 S and in situ assays to identify cells or tissues in which a fragment of the polypeptide of interest is expressed. The antibodies may also be used directly in therapies or other diagnostics. The present invention further provides the above-described antibodies immobilized on a solid support. Examples of such solid supports include plastics such as polycarbonate, complex carbohydrates such as agarose and Sepharose~, acrylic resins and such as polyacrylamide and latex beads. Techniques for coupling antibodies to such solid supports are well known in the art (Weir, D.M. et al., "Handbook of Experimental Immunology" 4th Ed., Blackwell Scientific Publications, Oxford, England, Chapter 10 (1986); Jacoby, W.D. et al., Meth. Enzym. 34 Academic Press, N.Y. (1974)). The immobilized antibodies of the present invention can be used for in vitro, in vivo, and in situ assays as well as for immuno-affinity purification of the proteins of the present invention.
Various procedures known within the art may be used for the production of polyclonal or monoclonal antibodies directed against a protein of the invention, or against derivatives, fragments, analogs homologs or orthologs thereof (see, for example, Antibodies: A Laboratory Manual, Harlow E, and Lane D, 1988, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, incorporated herein by reference).
Some of these antibodies are discussed below.
3.13.1 POLYCLONAL ANTIBODIES
S For the production of polyclonal antibodies, various suitable host animals (e.g., rabbit, goat, mouse or other mammal) may be immunized by one or more injections with the native protein, a synthetic variant thereof, or a derivative of the foregoing. An appropriate immunogenic preparation can contain, for example, the naturally occurring immunogenic protein, a chemically synthesized polypeptide representing the immunogenic protein, or a recombinantly expressed immunogenic protein.
Furthermore, the protein may be conjugated to a second protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. The preparation can further include an adjuvant.
Various adjuvants used to increase the immunological response include, but are not limited to, Freund's (complete and incomplete), mineral gels (e.g., aluminum hydroxide), surface-active substances (e.g., lysolecithin, pluronic polyols, polyanions, peptides;
oil emulsions, dinitrophenol, etc.), adjuvants usable in humans such as Bacille Calmette-Guerin and Corynebacterium parvum, or similar immunostimulatory agents. Additional examples of adjuvants that can be employed include MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).
The polyclonal antibody molecules directed against the immunogenic protein can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as affinity chromatography using protein A or protein G, which provide primarily the IgG fraction of immune serum. Subsequently, or alternatively, the specific antigen which is the target of the immunoglobulin sought, or an epitope thereof, may be immobilized on a column to purify the immune specific antibody by immunoaffinity chromatography. Purification of immunoglobulins is discussed, for example, by D.
Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia PA, Vol. 14, No.
8 (April 17, 2000), pp. 25-28).

3.13.2 MONOCLONAL ANTIBODIES
The term "monoclonal antibody" (MAb) or "monoclonal antibody composition", as used herein, refers to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product. In particular, the complementarity determining regions (CDRs) of the monoclonal antibody are identical in all the molecules of the population. MAbs thus contain an antigen-binding site capable of immunoreacting with a particular epitope of the antigen characterized by a unique binding affinity for it.
Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975). In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes can be immunized in vitro.
The immunizing agent will typically include the protein antigen, a fragment thereof or a fusion protein thereof. Generally, either peripheral blood lymphocytes are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-103). Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells can be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine ("HAT medium"), which substances prevent the growth of HGPRT-deficient cells.
Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, California and the American Type Culture Collection, Manassas, Virginia. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies (Kozbor, J.
Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. S1-63).
The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the antigen.
Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107:220 (1980). Preferably, antibodies having a high degree of specificity and a high binding affinity for the target antigen are isolated.
After the desired hybridoma cells are identified, the clones can be subcloned by limiting dilution procedures and grown by standard methods. Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal.
The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
The monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Patent No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells of the invention serve as a preferred source of such DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences (U.5. Patent No. 4,816,567; Morrison, Nature 368, 812-13 (1994)) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.
3.13.3 HUMANIZED ANTIBODIES
The antibodies directed against the protein antigens of the invention can further comprise humanized antibodies or human antibodies. These antibodies are suitable for administration to humans without engendering an immune response by the human against the administered immunoglobulin. Humanized forms of antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab')2 or other antigen-binding subsequences of antibodies) that are principally comprised of the sequence of a human immunoglobulin, and contain minimal sequence derived from a non-human immunoglobulin. Humanization can be performed following the method of Winter and co-workers (Jones et al., Nature, 321:522-525 (1986);
Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. (See also U.S. Patent No. 5,225,539). In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies can also comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al., 1986; Riechmann et al., 1988; and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992)).
3.13.4 HUMAN ANTIBODIES
Fully human antibodies relate to antibody molecules in which essentially the entire sequences of both the light chain and the heavy chain, including the CDRs, arise from human genes. Such antibodies are termed "human antibodies", or "fully human antibodies" herein. Human monoclonal antibodies can be prepared by the trioma technique; the human B-cell hybridoma technique (see Kozbor, et al., 1983 Immunol Today 4: 72) and the EBV hybridoma technique to produce human monoclonal antibodies (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER
THERAPY, Alan R. Liss, Inc., pp. 77-96). Human monoclonal antibodies may be utilized in the practice of the present invention and may be produced by using human hybridomas (see Cote, et al., 1983. Proc Natl Acad Sci USA 80: 2026-2030) or by transforming human B-cells with Epstein Barr Virus in vitro (see Cole, et al., 1985 In:
MONOCLONAL
ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96).
In addition, human antibodies can also be produced using additional techniques, including phage display libraries (Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)). Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S.
Patent Nos.
5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et al.
(Bio/Technolo~y 10, 779-783 (1992)); Lonberg et al. (Nature 368 856-859 (1994));
Morrison (Nature 368, 812-13 (1994)); Fishwild et al, (Nature Biotechnolo~y 14, 845-51 (1996)); Neuberger (Nature Biotechnolo~y 14, 826 (1996)); and Lonberg and Huszar (Intern. Rev. Immunol. 13 65-93 (1995)).

Human antibodies may additionally be produced using transgenic nonhuman animals that are modified so as to produce fully human antibodies rather than the animal's endogenous antibodies in response to challenge by an antigen. (See PCT
publication W094/02602). The endogenous genes encoding the heavy and light immunoglobulin chains in the nonhuman host have been incapacitated, and active loci encoding human heavy and light chain immunoglobulins are inserted into the host's genome. The human genes are incorporated, for example, using yeast artificial chromosomes containing the requisite human DNA segments. An animal which provides all the desired modifications is then obtained as progeny by crossbreeding intermediate transgenic animals containing fewer than the full complement of the modifications. The preferred embodiment of such a nonhuman animal is a mouse, and is termed the XenomouseTM as disclosed in PCT publications WO 96/33735 and WO 96/34096. This animal produces B cells that secrete fully human immunoglobulins. The antibodies can be obtained directly from the animal after immunization with an immunogen of interest, as, for example, a preparation of a polyclonal antibody, or alternatively from immortalized B cells derived from the animal, such as hybridomas producing monoclonal antibodies. Additionally, the genes encoding the immunoglobulins with human variable regions can be recovered and expressed to obtain the antibodies directly, or can be further modified to obtain analogs of antibodies such as, for example, single chain Fv molecules.
An example of a method of producing a nonhuman host, exemplified as a mouse, lacking expression of an endogenous immunoglobulin heavy chain is disclosed in U.S.
Patent No. 5,939,598. It can be obtained by a method including deleting the J
segment genes from at least one endogenous heavy chain locus in an embryonic stem cell to prevent rearrangement of the locus and to prevent formation of a transcript of a rearranged immunoglobulin heavy chain locus, the deletion being effected by a targeting vector containing a gene encoding a selectable marker; and producing from the embryonic stem cell a transgenic mouse whose somatic and germ cells contain the gene encoding the selectable marker.
A method for producing an antibody of interest, such as a human antibody, is disclosed in U.S. Patent No. 5,916,771. It includes introducing an expression vector that contains a nucleotide sequence encoding a heavy chain into one mammalian host cell in culture, introducing an expression vector containing a nucleotide sequence encoding a light chain into another mammalian host cell, and fusing the two cells to form a hybrid cell. The hybrid cell expresses an antibody containing the heavy chain and the light chain.
In a further improvement on this procedure, a method for identifying a clinically relevant epitope on an immunogen, and a correlative method for selecting an antibody that binds immunospecifically to the relevant epitope with high affinity, are disclosed in PCT publication WO 99/53049.
3.13.5 FAB FRAGMENTS AND SINGLE CHAIN ANTIBODIES
According to the invention, techniques can be adapted for the production of single-chain antibodies specific to an antigenic protein of the invention (see e.g., U.S.
Patent No. 4,946,778). In addition, methods can be adapted for the construction of Fan expression libraries (see e.g., Huse, et al., 1989 Science 246: 1275-1281) to allow rapid and effective identification of monoclonal Fab fragments with the desired specificity for a protein or derivatives, fragments, analogs or homologs thereof. Antibody fragments that contain the idiotypes to a protein antigen may be produced by techniques known in the art including, but not limited to: (i) an F~ab~~z fragment produced by pepsin digestion of an antibody molecule; (ii) an Fab fragment generated by reducing the disulfide bridges of an F~ab')2 fragment; (iii) an Fab fragment generated by the treatment of the antibody molecule with papain and a reducing agent and (iv) F,, fragments.
3.13.6 BISPECIFIC ANTIBODIES
Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for an antigenic protein of the invention. The second binding target is any other antigen, and advantageously is a cell-surface protein or receptor or receptor subunit.
Methods for making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature, 305:537-539 (1983)).
Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO 93/08829, published 13 May 1993, and in Traunecker et al., 1991 EMBO J., 10:3655-3659.
Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences.
The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region (CH1) containing the site necessary for light-chain binding present in at least one of the fusions. DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymologw, 121:210 (1986).
According to another approach described in WO 96/2701 l, the interface between a pair of antibody molecules can be engineered to maximize the percentage of , heterodimers that are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH3 region of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g. tyrosine or tryptophan).
Compensatory "cavities" of identical or similar size to the large side chains) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers.
Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g. F(ab')2 bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al., Science 229:81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab')Z fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab' fragments generated are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab'-TNB derivatives is then reconverted to the Fab'-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab'-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.
Additionally, Fab' fragments can be directly recovered from E. coli and chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med.
175:217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab')Z molecule. Each Fab' fragment was separately secreted from E. coli and subjected 1 S to directed chemical coupling in vitro to form the bispecific antibody.
The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.
Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al., J.
Immunol.
148(5):1547-1553 (1992). The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab' portions of two different antibodies by gene fusion.
The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers. The "diabody" technology described by Hollinger et al., Proc.
Natl. Acad. Sci. USA 90:6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments. The fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the V,-~
and VL domains of one fragment are forced to pair with the complementary VL
and VN

domains of another fragment, thereby forming two antigen-binding sites.
Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See, Gruber et al., J. Immunol. 152:5368 (1994).
Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991).
Exemplary bispecific antibodies can bind to two different epitopes, at least one of which originates in the protein antigen of the invention. Alternatively, an anti-antigenic arm of an immunoglobulin molecule can be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g.
CD2, CD3, CD28, or B7), or Fc receptors for IgG (Fc~yR), such as Fc~yRI (CD64), Fc~yRII
(CD32) and Fc~yRIII (CD16) so as to focus cellular defense mechanisms to the cell expressing the particular antigen. Bispecific antibodies can also be used to direct cytotoxic agents to cells which express a particular antigen. These antibodies possess an antigen-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. Another bispecific antibody of interest binds the protein antigen described herein and further binds tissue factor (TF).
3.13.7 HETEROCONJUGATE ANTIBODIES
Heteroconjugate antibodies are also within the scope of the present invention.
Heteroconjugate antibodies are composed of two covalently joined antibodies.
Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Patent No. 4,676,980), and for treatment of HIV infection (WO
91/00360;
WO 92/200373; EP 03089). It is contemplated that the antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S. Patent No. 4,676,980.
3.13.8 EFFECTOR FUNCTION ENGINEERING

It can be desirable to modify the antibody of the invention with respect to effector function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer. For example, cysteine residues) can be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated can have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et al., J. Exp Med., 176: 1191-1195 (1992) and Shopes, J. Immunol., 148: 2918-(1992). Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers as described in Wolff et al. Cancer Research, 53:
2560-2565 (1993). Alternatively, an antibody can be engineered that has dual Fc regions and can thereby have enhanced complement lysis and ADCC capabilities.
See Stevenson et al., Anti-Cancer Drug Design, 3: 219-230 (1989).
3.13.9 IMMUNOCONJUGATES
The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).
Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above. Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, croon; sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include 2~2Bi, 13~I, 131In, 9oY, and ~ s6Re.
Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987).
Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See W094/11026.
In another embodiment, the antibody can be conjugated to a "receptor" (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a "ligand"
(e.g., avidin) that is in turn conjugated to a cytotoxic agent.
3.14 COMPUTER READABLE SEQUENCES
In one application of this embodiment, a nucleotide sequence of the present invention can be recorded on computer readable media. As used herein, "computer readable media" refers to any medium which can be read and accessed directly by a computer. Such media include, but are not limited to: magnetic storage media, such as floppy discs, hard disc storage medium, and magnetic tape; optical storage media such as CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media. A skilled artisan can readily appreciate how any of the presently known computer readable mediums can be used to create a manufacture comprising computer readable medium having recorded thereon a nucleotide sequence of the present invention. As used herein, "recorded"
refers to a process for storing information on computer readable medium. A skilled artisan can readily adopt any of the presently known methods for recording information on computer readable medium to generate manufactures comprising the nucleotide sequence information of the present invention.

A variety of data storage structures are available to a skilled artisan for creating a computer readable medium having recorded thereon a nucleotide sequence of the present invention. The choice of the data storage structure will generally be based on the means chosen to access the stored information. In addition, a variety of data processor programs and formats can be used to store the nucleotide sequence information of the present invention on computer readable medium. The sequence information can be represented in a word processing text file, formatted in commercially-available software such as WordPerfect and Microsoft Word, or represented in the form of an ASCII f 1e, stored in a database application, such as DB2, Sybase, Oracle, or the like. A skilled artisan can readily adapt any number of data processor structuring formats (e.g. text file or database) in order to obtain computer readable medium having recorded thereon the nucleotide sequence information of the present invention.
By providing any of the nucleotide sequences SEQ ID NOs: 1 - 526 or a representative fragment thereof; or a nucleotide sequence at least 95°/a identical to any of the nucleotide sequences of SEQ ID NOs: 1 - 526 in computer readable form, a skilled artisan can routinely access the sequence information for a variety of purposes.
Computer software is publicly available which allows a skilled artisan to access sequence information provided in a computer readable medium. The examples which follow demonstrate how software which implements the BLAST (Altschul et al., J. Mol.
Biol.
215:403-410 (1990)) and BLAZE (Brutlag et al., Comp. Chem. 17:203-207 (1993)) search algorithms on a Sybase system is used to identify open reading frames (ORFs) within a nucleic acid sequence. Such ORFs may be protein encoding fragments and may be useful in producing commercially important proteins such as enzymes used in fermentation reactions and in the production of commercially useful metabolites.
As used herein, "a computer-based system" refers to the hardware means, software means, and data storage means used to analyze the nucleotide sequence information of the present invention. The minimum hardware means of the computer-based systems of the present invention comprises a central processing unit (CPLI), input means, output means, and data storage means. A skilled artisan can readily appreciate that any one of the currently available computer-based systems are suitable for use in the present invention. As stated above, the computer-based systems of the present invention comprise a data storage means having stored therein a nucleotide sequence of the present invention and the necessary hardware means and software means for supporting and implementing a search means. As used herein, "data storage means"
refers to memory which can store nucleotide sequence information of the present invention, or a memory access means which can access manufactures having recorded thereon the nucleotide sequence information of the present invention.
As used herein, "search means",refers to one or more programs which are implemented on the computer-based system to compare a target sequence or target structural motif with the sequence information stored within the data storage means.
Search means are used to identify fragments or regions of a known sequence which match a particular target sequence or target motif. A variety of known algorithms are disclosed publicly and a variety of commercially available software for conducting search means are and can be used in the computer-based systems of the present invention.
Examples of such software includes, but is not limited to, Smith-Waterman, MacPattern (EMBL), BLASTN and BLASTA (NPOLYPEPTIDEIA). A skilled artisan can readily recognize that any one of the available algorithms or implementing software packages for conducting homology searches can be adapted for use in the present computer-based systems. As used herein, a "target sequence" can be any nucleic acid or amino acid sequence of six or more nucleotides or two or more amino acids. A skilled artisan can readily recognize that the longer a target sequence is, the less likely a target sequence will be present as a random occurrence in the database. The most preferred sequence length of a target sequence is from about 10 to 300 amino acids, more preferably from about 30 to 100 nucleotide residues. However, it is well recognized that searches for commercially important fragments, such as sequence fragments involved in gene expression and protein processing, may be of shorter length.
As used herein, "a target structural motif," or "target motif," refers to any rationally selected sequence or combination of sequences in which the sequences) are chosen based on a three-dimensional configuration which is formed upon the folding of the target motif. There are a variety of target motifs known in the art.
Protein target motifs include, but are not limited to, enzyme active sites and signal sequences. Nucleic acid target motifs include, but are not limited to, promoter sequences, hairpin structures and inducible expression elements (protein binding sequences).
3.15 TRIPLE HELIX FORMATION
In addition, the fragments of the present invention, as broadly described, can be used to control gene expression through triple helix formation or antisense DNA or RNA, both of which methods are based on the binding of a polynucleotide sequence to DNA or RNA. Polynucleotides suitable for use in these methods are preferably 20 to 40 bases in length and are designed to be complementary to a region of the gene involved in transcription (triple helix - see Lee et al., Nucl. Acids Res. 6:3073 (1979);
Cooney et al., Science 15241:456 (1988); and Dervan et al., Science 251:1360 (1991)) or to the mRNA
itself (antisense - Olmno, J. Neurochem. 56:560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, FL (1988)).
Triple helix-formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA hybridization blocks translation of an mRNA molecule into polypeptide.
Both techniques have been demonstrated to be effective in model systems.
Information contained in the sequences of the present invention is necessary for the design of an antisense or triple helix oligonucleotide.
3.16 DIAGNOSTIC ASSAYS AND KITS
The present invention further provides methods to identify the presence or expression of one of the ORFs of the present invention, or homolog thereof, in a test sample, using a nucleic acid probe or antibodies of the present invention, optionally conjugated or otherwise associated with a suitable label.
In general, methods for detecting a polynucleotide of the invention can comprise contacting a sample with a compound that binds to and forms a complex with the polynucleotide for a period sufficient to form the complex, and detecting the complex, so that if a complex is detected, a polynucleotide of the invention is detected in the sample.
Such methods can also comprise contacting a sample under stringent hybridization conditions with nucleic acid primers that anneal to a polynucleotide of the invention under such conditions, and amplifying annealed polynucleotides, so that if a polynucleotide is amplified, a polynucleotide of the invention is detected in the sample.
In general, methods for detecting a polypeptide of the invention can comprise contacting a sample with a compound that binds to and forms a complex with the S polypeptide for a period sufficient to form the complex, and detecting the complex, so that if a complex is detected, a polypeptide of the invention is detected in the sample.
In detail, such methods comprise incubating a test sample with one or more of the antibodies or one or more of the nucleic acid probes of the present invention and assaying for binding of the nucleic acid probes or antibodies to components within the test sample.
Conditions for incubating a nucleic acid probe or antibody with a test sample vary. Incubation conditions depend on the format employed in the assay, the detection methods employed, and the type and nature of the nucleic acid probe or antibody used in the assay. One skilled in the art will recognize that any one of the commonly available hybridization, amplification or immunological assay formats can readily be adapted to employ the nucleic acid probes or antibodies of the present invention.
Examples of such assays can be found in Chard, T., An Introduction to Radioimmunoassay and Related Techniques, Elsevier Science Publishers, Amsterdam, The Netherlands (1986);
Bullock, G.R. et al., Techniques in Immunocytochemistry, Academic Press, Orlando, FL
Vol. 1 (1982), Vol. 2 (1983), Vol. 3 (1985); Tijssen, P., Practice and Theory of immunoassays:
Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers, Amsterdam, The Netherlands ( 1985). The test samples of the present invention include cells, protein or membrane extracts of cells, or biological fluids such as sputum, blood, serum, plasma, or urine. The test sample used in the above-described method will vary based on the assay format, nature of the detection method and the tissues, cells or extracts used as the sample to be assayed. Methods for preparing protein extracts or membrane extracts of cells are well known in the art and can be readily be adapted in order to obtain a sample which is compatible with the system utilized.
In another embodiment of the present invention, kits are provided which contain the necessary reagents to carry out the assays of the present invention.
Specifically, the invention provides a compartment kit to receive, in close confinement, one or more containers which comprises: (a) a first container comprising one of the probes or antibodies of the present invention; and (b) one or more other containers comprising one or more of the following: wash reagents, reagents capable of detecting presence of a bound probe or antibody.
In detail, a compartment kit includes any kit in which reagents are contained in separate containers. Such containers include small glass containers, plastic containers or strips of plastic or paper. Such containers allows one to efficiently transfer reagents from one compartment to another compartment such that the samples and reagents are not cross-contaminated, and the agents or solutions of each container can be added in a quantitative fashion from one compartment to another. Such containers will include a container which will accept the test sample, a container which contains the antibodies used in the assay, containers which contain wash reagents (such as phosphate buffered saline, Tris-buffers, etc.), and containers which contain the reagents used to detect the bound antibody or probe. Types of detection reagents include labeled nucleic acid probes, labeled secondary antibodies, or in the alternative, if the primary antibody is labeled, the enzymatic, or antibody binding reagents which are capable of reacting with the labeled antibody. One skilled in the art will readily recognize that the disclosed probes and antibodies of the present invention can be readily incorporated into one of the established kit formats which are well known in the art.
3.17 MEDICAL IMAGING
The novel polypeptides and binding partners of the invention are useful in medical imaging of sites expressing the molecules of the invention (e.g., where the polypeptide of the invention is involved in the immune response, for imaging sites of inflammation or infection). See, e.g., Kunkel et al., U.S. Pat. NO. 5,413,778.
Such methods involve chemical attachment of a labeling or imaging agent, administration of the labeled polypeptide to a subject in a pharmaceutically acceptable earner, and imaging the labeled polypeptide in vivo at the target site.
3.18 SCREENING ASSAYS
Using the isolated proteins and polynucleotides of the invention, the present invention further provides methods of obtaining and identifying agents which bind to a polypeptide encoded by an ORF corresponding to any of the nucleotide sequences set forth in SEQ ID NOs: 1 - 526, or bind to a specific domain of the polypeptide encoded by the nucleic acid. In detail, said method comprises the steps of:
(a) contacting an agent with an isolated protein encoded by an ORF of the present invention, or nucleic acid of the invention; and (b) determining whether the agent binds to said protein or said nucleic acid.
In general, therefore, such methods for identifying compounds that bind to a polynucleotide of the invention can comprise contacting a compound with a polynucleotide of the invention for a time sufficient to form a polynucleotide/compound complex, and detecting the complex, so that if a polynucleotide/compound complex is detected, a compound that binds to a polynucleotide of the invention is identified.
Likewise, in general, therefore, such methods for identifying compounds that bind to a polypeptide of the invention can comprise contacting a compound with a polypeptide of the invention for a time sufficient to form a polypeptide/compound complex, and detecting the complex, so that if a polypeptide/compound complex is detected, a compound that binds to a polynucleotide of the invention is identified.
Methods for identifying compounds that bind to a polypeptide of the invention can also comprise contacting a compound with a polypeptide of the invention in a cell for a time sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a receptor gene sequence in the cell, and detecting the complex by detecting reporter gene sequence expression, so that if a polypeptide/compound complex is detected, a compound that binds a polypeptide of the invention is identified.
Compounds identified via such methods can include compounds which modulate the activity of a polypeptide of the invention (that is, increase or decrease its activity, relative to activity observed in the absence of the compound). Alternatively, compounds identified via such methods can include compounds which modulate the expression of a polynucleotide of the invention (that is, increase or decrease expression relative to expression levels observed in the absence of the compound). Compounds, such as compounds identified via the methods of the invention, can be tested using standard assays well known to those of skill in the art for their ability to modulate activity/expression.

The agents screened in the above assay can be, but are not limited to, peptides, carbohydrates, vitamin derivatives, or other pharmaceutical agents. The agents can be selected and screened at random or rationally selected or designed using protein modeling techniques.
For random screening, agents such as peptides, carbohydrates, pharmaceutical agents and the like are selected at random and are assayed for their ability to bind to the protein encoded by the ORF of the present invention. Alternatively, agents may be rationally selected or designed. As used herein, an agent is said to be "rationally selected or designed" when the agent is chosen based on the configuration of the particular protein. For example, one skilled in the art can readily adapt currently available procedures to generate peptides, pharmaceutical agents and the like, capable of binding to a specific peptide sequence, in order to generate rationally designed antipeptide peptides, for example see Hurby et al., Application of Synthetic Peptides: Antisense Peptides," In Synthetic Peptides, A User's Guide, W.H. Freeman, NY (1992), pp. 289-307, and Kaspczak et al., Biochemistry 28:9230-8 (1989), or pharmaceutical agents, or the like.
In addition to the foregoing, one class of agents of the present invention, as broadly described, can be used to control gene expression through binding to one of the ORFs or EMFs of the present invention. As described above, such agents can be randomly screened or rationally designed/selected. Targeting the ORF or EMF
allows a skilled artisan to design sequence specific or element specific agents, modulating the expression of either a single ORF or multiple ORFs which rely on the same EMF
for expression control. One class of DNA binding agents are agents which contain base residues which hybridize or form a triple helix formation by binding to DNA or RNA.
Such agents can be based on the classic phosphodiester, ribonucleic acid backbone, or can be a variety of sulfhydryl or polymeric derivatives which have base attachment capacity.
Agents suitable for use in these methods preferably contain 20 to 40 bases and are designed to be complementary to a region of the gene involved in transcription (triple helix - see Lee et al., Nucl. Acids Res. 6:3073 (1979); Cooney et al., Science 241:456 (1988); and Dervan et al., Science 251:1360 (1991)) or to the mRNA itself (antisense -Okano, J. Neurochem. 56:560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, FL (1988)). Triple helix-formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA
hybridization blocks translation of an mRNA molecule into polypeptide. Both techniques have been demonstrated to be effective in model systems. Information contained in the sequences of the present invention is necessary for the design of an antisense or triple helix oligonucleotide and other DNA binding agents.
Agents which bind to a protein encoded by one of the ORFs of the present invention can be used as a diagnostic agent. Agents which bind to a protein encoded by one of the ORFs of the present invention can be formulated using known techniques to generate a pharmaceutical composition.
3.19 USE OF NUCLEIC ACIDS AS PROBES
Another aspect of the subject invention is to provide for polypeptide-specific nucleic acid hybridization probes capable of hybridizing with naturally occurnng nucleotide sequences. The hybridization probes of the subject invention may be derived from any of the nucleotide sequences SEQ ID NOs: 1 - 526. Because the corresponding gene is only expressed in a limited number of tissues, a hybridization prohe derived from any of the nucleotide sequences SEQ ID NOs: 1 - 526 can be used as an indicator of the presence of RNA of cell type of such a tissue in a sample.
Any suitable hybridization technique can be employed, such as, for example, in situ hybridization. PCR as described in US Patents Nos. 4,683,195 and 4,965,188 provides additional uses for oligonucleotides based upon the nucleotide sequences. Such probes used in PCR may be of recombinant origin, may be chemically synthesized, or a mixture of both. The probe will comprise a discrete nucleotide sequence for the detection of identical sequences or a degenerate pool of possible sequences for identification of closely related genomic sequences.
Other means for producing specific hybridization probes for nucleic acids include the cloning of nucleic acid sequences into vectors for the production of mRNA
probes.
Such vectors are known in the art and are commercially available and may be used to synthesize RNA probes in vitro by means of the addition of the appropriate RNA
polymerise as T7 or SP6 RNA polymerise and the appropriate radioactively labeled nucleotides. The nucleotide sequences may be used to construct hybridization probes for mapping their respective genomic sequences. The nucleotide sequence provided herein may be mapped to a chromosome or specific regions of a chromosome using well known genetic and/or chromosomal mapping techniques. These techniques include in situ S hybridization, linkage analysis against known chromosomal markers, hybridization screening with libraries or flow-sorted chromosomal preparations specific to known chromosomes, and the like. The technique of fluorescent in situ hybridization of chromosome spreads has been described, among other places, in Verma et al (1988) Human Chromosomes: A Manual of Basic Techniques, Pergamon Press, New York NY.
Fluorescent in situ hybridization of chromosomal preparations and other physical chromosome mapping techniques may be correlated with additional genetic map data.
Examples of genetic map data can be found in the 1994 Genome Issue of Science (265:1981fj. Correlation between the location of a nucleic acid on a physical chromosomal map and a specific disease (or predisposition to a specific disease) may help delimit the region of DNA associated with that genetic disease. The nucleotide sequences of the subject invention may be used to detect differences in gene sequences between normal, carrier or affected individuals.
3.20 PREPARATION OF SUPPORT BOUND OLIGONUCLEOTIDES
Oligonucleotides, i.e., small nucleic acid segments, may be readily prepared by, for example, directly synthesizing the oligonucleotide by chemical means, as is commonly practiced using an automated oligonucleotide synthesizer.
Support bound oligonucleotides may be prepared by any of the methods known to those of skill in the art using any suitable support such as glass, polystyrene or Teflon. One strategy is to precisely spot oligonucleotides synthesized by standard synthesizers.
Immobilization can be achieved using passive adsorption (Inouye & Hondo, (1990) J. Clin.
Microbiol. 28(6).1469-72); using LJV light (Nagata et al., 1985; Dahlen et al., 1987;
Morrissey & Collins, (1989) Mol. Cell Probes 3(2) 189-207) or by covalent binding of base modified DNA (Keller et al., 1988; 1989); all references being specifically incorporated herein.
Another strategy that may be employed is the use of the strong biotin-streptavidin interaction as a linker. For example, Broude et al. (1994) Proc. Natl. Acad.
Sci. USA 91 (8) 3072-6, describe the use of biotinylated probes, although these are duplex probes, that are immobilized on streptavidin-coated magnetic beads. Streptavidin-coated beads may be purchased from Dynal, Oslo. Of course, this same linking chemistry is applicable to coating any surface with streptavidin. Biotinylated probes may be purchased from various sources, S such as, e.g., Operon Technologies (Alameda, CA).
Nunc Laboratories (Naperville, IL) is also selling suitable material that could be used. Nunc Laboratories have developed a method by which DNA can be covalently bound to the microwell surface termed Covalink NH. CovaLink NH is a polystyrene surface grafted with secondary amino groups (>NH) that serve as bridge-heads for further covalent coupling. CovaLink Modules may be purchased from Nunc Laboratories. DNA
molecules may be bound to CovaLink exclusively at the 5'-end by a phosphoramidate bond, allowing immobilization of more than 1 pmol of DNA (Rasmussen et al., (1991) Anal.
Biochem.
198(1) 138-42).
The use of CovaLink NH strips for covalent binding of DNA molecules at the 5'-end has been described (Rasmussen et al., (1991). In this technology, a phosphoramidate bond is employed (Chu et al., (1983) Nucleic Acids Res. 11(8) 6513-29). This is beneficial as immobilization using only a single covalent bond is preferred. The phosphoramidate bond joins the DNA to the CovaLink NH secondary amino groups that are positioned at the end of spacer arms covalently grafted onto the polystyrene surface through a 2 nm long spacer arm. To link an oligonucleotide to CovaLink NH via an phosphoramidate bond, the oligonucleotide terminus must have a 5'-end phosphate group. It is, perhaps, even possible for biotin to be covalently bound to CovaLink and then streptavidin used to bind the probes.
More specifically, the linkage method includes dissolving DNA in water (7.5 ng/ul) and denaturing for 10 min. at 95°C and cooling on ice for 10 min. Ice-cold 0.1 M
1-methylimidazole, pH 7.0 (1-MeIm7), is then added to a final concentration of 10 mM
1-MeIm7. A ss DNA solution is then dispensed into CovaLink NH strips (75 ul/well) standing on ice.
Carbodiimide 0.2 M I-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), dissolved in 10 mM 1-MeIm7, is made fresh and 25 u1 added per well. The strips are incubated for 5 hours at SO°C. After incubation the strips are washed using, e.g., Nunc-Immuno Wash; first the wells are washed 3 times, then they are soaked with washing solution for 5 min., and finally they are washed 3 times (where in the washing solution is 0.4 N NaOH, 0.25% SDS heated to 50°C).
It is contemplated that a further suitable method for use with the present invention is that described in PCT Patent Application WO 90/03382 (Southern & Maskos), incorporated herein by reference. This method of preparing an oligonucleotide bound to a support involves attaching a nucleoside 3'-reagent through the phosphate group by a covalent phosphodiester link to aliphatic hydroxyl groups earned by the support. The oligonucleotide is then synthesized on the supported nucleoside and protecting groups removed from the synthetic oligonucleotide chain under standard conditions that do not cleave the oligonucleotide from the support. Suitable reagents include nucleoside phosphoramidite and nucleoside hydrogen phosphorate.
An on-chip strategy for the preparation of DNA probe for the preparation of DNA
probe arrays may be employed. For example, addressable laser-activated photodeprotection may be employed in the chemical synthesis of oligonucleotides directly on a glass surface, as described by Fodor et al. (1991) Science 251(4995) 767-73, incorporated herein by reference. Probes may also be immobilized on nylon supports as described by Van Ness et al. (1991) Nucleic Acids Res. 19(12) 3345-S0; or linked to Teflon using the method of Duncan & Cavalier (1988) Anal. Biochem. 169(1) 104-8; all references being specifically incorporated herein.
To link an oligonucleotide to a nylon support, as described by Van Ness et al.
(1991), requires activation of the nylon surface via alkylation and selective activation of the 5'-amine of oligonucleotides with cyanuric chloride.
One particular way to prepare support bound oligonucleotides is to utilize the light-generated synthesis described by Pease et al., (1994) PNAS USA 91(11) 5022-6, incorporated herein by reference). These authors used current photolithographic techniques to generate arrays of immobilized oligonucleotide probes (DNA chips). These methods, in which light is used to direct the synthesis of oligonucleotide probes in high-density, miniaturized arrays, utilize photolabile S'-protected N acyl-deoxynucleoside phosphoramidites, surface linker chemistry and versatile combinatorial synthesis strategies.
A matrix of 256 spatially defined oligonucleotide probes may be generated in this manner.

3.21 PREPARATION OF NUCLEIC ACID FRAGMENTS
The nucleic acids may be obtained from any appropriate source, such as cDNAs, genomic DNA, chromosomal DNA, microdissected chromosome bands, cosmid or YAC
inserts, and RNA, including mRNA without any amplification steps. For example, Sambrook et al. (1989) describes three protocols for the isolation of high molecular weight DNA from mammalian cells (p. 9.14-9.23).
DNA fragments may be prepared as clones in M13, plasmid or lambda vectors and/or prepared directly from genomic DNA or cDNA by PCR or other amplification methods. Samples may be prepared or dispensed in multiwell plates. About 100-1000 ng of DNA samples may be prepared in 2-S00 ml of final volume.
The nucleic acids would then be fragmented by any of the methods known to those of skill in the art including, for example, using restriction enzymes as described at 9.24-9.28 of Sambrook et al. (1989), shearing by ultrasound and NaOH treatment.
Low pressure shearing is also appropriate, as described by Schriefer et al.
(1990) Nucleic Acids Res. 18(24) 7455-6, incorporated herein by reference). In this method, DNA
samples are passed through a small French pressure cell at a variety of low to intermediate pressures. A lever device allows controlled application of low to intermediate pressures to the cell. The results of these studies indicate that low-pressure shearing is a useful alternative to sonic and enzymatic DNA fragmentation methods.
One particularly suitable way for fragmenting DNA is contemplated to be that using the two base recognition endonuclease, CviJI, described by Fitzgerald et al.
(1992) Nucleic Acids Res. 20(14) 3753-62. These authors described an approach for the rapid fragmentation and fractionation of DNA into particular sizes that they contemplated to be suitable for shotgun cloning and sequencing.
The restriction endonuclease CviJI normally cleaves the recognition sequence PuGCPy between the G and C to leave blunt ends. Atypical reaction conditions, which alter the specificity of this enzyme (CviJI**), yield a quasi-random distribution of DNA
fragments form the small molecule pUCl9 (2688 base pairs). Fitzgerald et al.
(1992) quantitatively evaluated the randomness of this fragmentation strategy, using a CviJI**
digest of pUC 19 that was size fractionated by a rapid gel filtration method and directly ligated, without end repair, to a lac Z minus M13 cloning vector. Sequence analysis of 76 clones showed that CviJI** restricts pyGCPy and PuGCPu, in addition to PuGCPy sites, and that new sequence data is accumulated at a rate consistent with random fragmentation.
As reported in the literature, advantages of this approach compared to sonication and agarose gel fractionation include: smaller amounts of DNA are required (0.2-0.5 ug instead of 2-5 ug); and fewer steps are involved (no preligation, end repair, chemical extraction, or agarose gel electrophoresis and elution are needed Irrespective of the manner in which the nucleic acid fragments are obtained or prepared, it is important to denature the DNA to give single stranded pieces available for hybridization. This is achieved by incubating the DNA solution for 2-S minutes at 80-90°C.
The solution is then cooled quickly to 2°C to prevent renaturation of the DNA fragments before they are contacted with the chip. Phosphate groups must also be removed from genomic DNA by methods known in the art.
3.22 PREPARATION OF DNA ARRAYS
Arrays may be prepared by spotting DNA samples on a support such as a nylon membrane. Spotting may be performed by using arrays of metal pins (the positions of which correspond to an array of wells in a microtiter plate) to repeated by transfer of about 20 n1 of a DNA solution to a nylon membrane. By offset printing, a density of dots higher than the density of the wells is achieved. One to 25 dots may be accommodated in 1 mm2, depending on the type of label used. By avoiding spotting in some preselected number of rows and columns, separate subsets (subarrays) may be formed. Samples in one subarray may be the same genomic segment of DNA (or the same gene) from different individuals, or may be different, overlapped genomic clones. Each of the subarrays may represent replica spotting of the same samples. In one example, a selected gene segment may be amplified from 64 patients. For each patient, the amplified gene segment may be in one 96-well plate (all 96 wells containing the same sample). A plate for each of the 64 patients is prepared. By using a 96-pin device, all samples may be spotted on one 8 x 12 cm membrane.
Subarrays may contain 64 samples, one from each patient. Where the 96 subarrays are identical, the dot span may be 1 mm2 and there may be a 1 mm space between subarrays.
Another approach is to use membranes or plates (available from NUNC, Naperville, Illinois) which may be partitioned by physical spacers e.g. a plastic grid molded over the membrane, the grid being similar to the sort of membrane applied to the bottom of multiwell plates, or hydrophobic strips. A fixed physical spacer is not preferred for imaging by exposure to flat phosphor-storage screens or x-ray films.
The present invention is illustrated in the following examples. Upon consideration of the present disclosure, one of skill in the art will appreciate that many other embodiments S and variations may be made in the scope of the present invention.
Accordingly, it is intended that the broader aspects of the present invention not be limited to the disclosure of the following examples. The present invention is not to be limited in scope by the exemplified embodiments which are intended as illustrations of single aspects of the invention, and compositions and methods which are functionally equivalent are within the scope of the invention. Indeed, numerous modifications and variations in the practice of the invention are expected to occur to those skilled in the art upon consideration of the present preferred embodiments. Consequently, the only limitations which should be placed upon the scope of the invention are those which appear in the appended claims.
All references cited within the body of the instant specification are hereby incorporated by reference in their entirety.
4.0 EXAMPLES
4.1 EXAMPLE 1 Novel Nucleic Acid Seguences Obtained From Various Libraries A plurality of novel nucleic acids were obtained from cDNA libraries prepared from various human tissues and in some cases isolated from a genomic library derived from human chromosome using standard PCR, SBH sequence signature analysis and Sanger sequencing techniques. The inserts of the library were amplified with PCR
using primers specific for the vector sequences which flank the inserts. Clones from cDNA
libraries were spotted on nylon membrane filters and screened with oligonucleotide probes (e.g., 7-mers) to obtain signature sequences. The clones were clustered into groups of similar or identical sequences. Representative clones were selected for sequencing.
In some cases, the S' sequence of the amplified inserts was then deduced using a typical Sanger sequencing protocol. PCR products were purified and subjected to fluorescent dye terminator cycle sequencing. Single pass gel sequencing was done using a 377 Applied Biosystems (ABI) sequencer to obtain the novel nucleic acid sequences. In some cases RACE (Random Amplification of cDNA Ends) was performed to further extend the sequence in the 5' direction.
4.2 EXAMPLE 2 Novel Nucleic Acids The novel nucleic acids of the present invention of the invention were assembled from sequences that were obtained from a cDNA library by methods described in Example 1 above, and in some cases sequences obtained from one or more public databases. The nucleic acids were assembled using an EST sequence as a seed. Then a recursive algorithm was used to extend the seed EST into an extended assemblage, by pulling additional sequences from different databases (i.e., Hyseq's database containing EST
sequences, dbEST version 119, gb pri 119, and UniGene version 119) that belong to this assemblage.
The algorithm terminated when there was no additional sequences from the above databases that would extend the assemblage. Inclusion of component sequences into the assemblage was based on a BLASTN hit to the extending assemblage with BLAST score greater than 300 and percent identity greater than 95%.
Using PIIRAP (Univ. of Washington) or CAP4 (Paracel), a full length gene cDNA
sequence and its corresponding protein sequence were generated from the assemblage. Any frame shifts and incorrect stop codons were corrected by hand editing. During editing, the sequence was checked using FASTY and/or BLAST against Genbank (i.e., dbEST
version 121, gb pri 121, UniGene version 121, Genpept release 121) and the amino acid version of Genseq released February 15, 2001. Other computer programs which may have been used in the editing process were phredPhrap and Consed (University of Washington) and ed-ready, ed-ext and cg-zip-2 (Hyseq, Inc.). The full-length nucleotide and amino acid sequences, including splice variants resulting from these procedures are shown in the Sequence Listing as SEQ ID NOS: 1- 526.
Table 1 shows the various tissue sources of SEQ ID NO: 1-526.
The nearest neighbor results for polypeptides encoded by SEQ ID NO: 1-526 (i.e.
SEQ 1D NO: 527 - 1052) were obtained by a BLASTP (version 2.0a1 19MP-WashU) search against Genpept, Geneseq and SwissProt databases using BLAST algorithm.
The nearest neighbor result showed the closest homologue with functional annotation for SEQ
ID NO: 527 - 1052. The translated amino acid sequences for which the nucleic acid sequence encodes are shown in the Sequence Listing. The homologues with identifiable functions for SEQ ID NO: 527 - 1052 are shown in Table 2 below.Using eMatrix software package (Stanford University, Stanford, CA) (Wu et al., J. Comp.
Biol., Vol. 6 pp. 219-235 (1999) herein incorporated by reference), polypeptides encoded by SEQ ID
NO: 1-526 (i.e. SEQ ID NO: 527 - 1052) were examined to determine whether they had identifiable signature regions. Table 3 shows the signature region found in the indicated polypeptide sequences, the description of the signature, the eMatrix p-values) and the positions) of the signature within the polypeptide sequence.
Using the Pfam software program (Sonnhammer et al., Nucleic Acids Res., Vol.
26(1) pp. 320-322 (1998) herein incorporated by reference) polypeptides encoded by SEQ ID NO: 1-526 (i.e. SEQ )D NO: 527 - 1052) were examined for domains with homology to certain peptide domains. Table 4 shows the name of the domain found, the description, the product of all the e-value of similar domains found, the pFam score for the identified domain within the sequence, number of similar domains found, and the position of the domain in the SEQ ID NO: being interrogated.
The GeneAtlasT"' software package (Molecular Simulations Inc. (MSI), San Diego, CA) was used to predict the three-dimensional structure models for the polypeptides encoded by SEQ 117 NO: 1-526 (i.e. SEQ ID NO: 527 - 1052). Models were generated by (1) PSI-BLAST which is a multiple alignment sequence profile-based searching developed by Altschul et al, (Nucl. Acids. Res. 25, 3389-3408 (1997)), (2) High Throughput Modeling (HTM) (Molecular Simulations Inc. (MSI) San Diego, CA,) which is an automated sequence and structure searching procedure (http://www.msi.comn, and (3) SeqFoldT"' which is a fold recognition method described by Fischer and Eisenberg (J. Mol. Biol. 209, 779-791 (1998)). This analysis was carried out, in part, by comparing the polypeptides of the invention with the known NMR
(nuclear magnetic resonance) and x-ray crystal three-dimensional structures as templates.
Table 5 shows, "PDB ID", the Protein DataBase (PDB) identifier given to template structure; "Chain ID", identifier of the subcomponent of the PDB template structure;
"Compound Information", information of the PDB template structure and/or its subcomponents; "PDB Function Annotation" gives function of the PDB template as annotated by the PDB files (http:/www.resb.or~ DBE; start and end amino acid position of the protein sequence aligned; PSI-BLAST score, the verify score, the SeqFold score, and the Potentials) of Mean Force (PMF). The verify score produced by GeneAtlasTM
software (MSI), is based on Dr. Eisenberg's Profile-3D threading program developed in Dr. David Eisenberg's laboratory (US patent no. 5,436,850 and Luthy, Bowie, and Eisenberg, Nature, 356:83-85 (1992)) and a publication by R. Sanchez and A.
Sali, Proc.
Natl. Acad. Sci. USA, 95:12502-13597. The verify score produced by GeneAtlas normalizes the verify score for proteins with different lengths so that a unified cutoff can be used to select good models as follows:
Verify score (normalized) _ (raw score - 1/2 high score)/(1/2 high score) The PMF score, produced by GeneAtlasTM software (MSI), is a composite scoring function that depends in part on the compactness of the model, sequence identity in the alignment used to build the model, pairwise and surface mean force potential (MFP). As given in Table 5, a verify score between 0 to 1.0, with 1 being the best, represents a good model. Similarly, a PMF score between 0 to 1.0, with 1 being the best, represents a good model. A SeqFoldT"' score of more than SO is considered significant. A good model may also be determined by one of skill in the art based on all the information in Table 5 taken in totality.
The nucleotide sequence within the sequences that codes for signal peptide sequences and their cleavage sites can be determined from using Neural Network SignalP
V 1.1 program (from Center for Biological Sequence Analysis, The Technical University of Denmark). The process for identifying prokaryotic and eukaryotic signal peptides and their cleavage sites are also disclosed by Henrik Nielson, Jacob Engelbrecht, Soren Brunak, and Gunnar von Heijne in the publication " Identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites" Protein Engineering, Vol. 10, no. 1, pp. 1-6 (1997), incorporated herein by reference. A maximum S
score and a mean S score, as described in the Nielson et al., as reference, were obtained for the polypeptide sequences. Table 6 shows the position of the last amino acid of the signal peptide in each of the polypeptides and the maximum score and mean score associated with that signal peptide.

Table 7 correlates each of SEQ ID NO: 1-526 to a specific chromosomal location.
Table 8 is a correlation table of the novel polynucleotide sequences SEQ ID
NO:
1-526, novel polypeptide sequences SEQ ID NO: 527 - 1052, and their corresponding priority nucleotide sequences in the priority application USSN 09/810,173, herein incorporated by reference in its entirety.

Table 1 Tissue )RNA/TissueLibrarySEQ ID NO:
Origin Source Name adipocytesStratageneADP001 39 49 68 84 103-104 117 124 186 188-189 adrenal Clontech ADR002 11 14 25 30 39 83 90 92 100 108 111 131 gland 133 137 144 148 155 164 adult brainBioChain ABR012 47 262 adult brainBioChain ABR013 60 205 adult brainClontech ABR001 17 39 55 61 95 124 137 153 186 233 247 adult brainClontech ABR006 9 17 26 32 38 41 61 77 81 83 87 95 106 adult brainClontech ABR008 2 4 7 12 17-18 24-25 28-29 32 35-38 44 adult brainClontech ABRO 394 adult brainGIBCO AB3001 9 13 21 32 34 49 58 61 77 92 98 124 138-141 adult brainGIBCO ABD003 9 15-16 18 24 26 32 34 39 54 60-61 66 adult brainInvitro ABR014 65 125 184 247 307 338 467 490 509 513 en adult brainInvitro ABR015 12 34 60 73 127 140 287 417 445 en adult brainInvitro ABR016 3 24 34 136 177 248 307 452 474 en adult brainInvitrogenABT004 29 39 47 65-66 83 87 97 107 143 151-152 adult heartGIBCO AHR001 5-6 11 15-16 18-20 23 34 39 41 48 50 62-63 adult kidneyGIBCO AKD001 5-6 11-12 14-16 19 22 24 27 32 34 39 41 482 489 495-498 509-5l 1 adult kidneyInvitrogenAKT002 1 18 27 34 58 66 77 101 107 124 129 131 adult liverClontech ALV003 32 74-75 94 137 247 420 516 Table 1 Tissue RNA/TissueLibrarySEQ ID NO:
Origin Source Name adult liverInvitrogenALV002 6 12 18 23 25 34 49 65 74-75 80 87 94 370 383 387 399 4I2-4 t4 452 456 460 adult lungGIBCO ALG001 15-16 18 27 34 47 65 72 74-75 83 92 127 adult lungInvitrogenLGT002 5 11-12 14 16 18-19 24 26 30 32 34-36 adult spleenClontech SPLc01 17 22 25 54 71 108 117 121 130 133 153 adult spleenGIBCO ASP001 15-16 22 24 26 34 41 77 96 103-104 107 bladder InvitrogenBLD001 35-36 77 103-104 124 144 218 281 287 bone marrowClonetech BMD007 32 bone marrowClontech BMD001 2 5 9 12 15 17-18 20 24-25 27 30 34 38 bone marrowClontech BMD004 346 460 bone marrowGF BMD002 4 17-18 23-25 27-28 30 32 35-36 38 47 cervix BioChain CVX001 5-6 18 20 24 30 32 42 44 55-56 66 68 colon InvitrogenCLN001 11 13 34 81 100 105 126 184 186 196 254 dia hra BioChain DIA002-226-227 m endothelialStrategeneEDT001 2 13-14 16-19 22 24 26-27 30-31 34-36 cells 80 83 85-86 92 96 98 100 102 106-108 fetal brainClontech FBR001 39 87 247 353 375 452 460 513 fetal brainClontech FBR004 181 205 393 fetal brainClontech FBR006 1 7-8 12 17-19 24 27 29-30 32 34-36 46-49 Table 1 Tissue 1ZNA/TissueLibrary SEQ ID NO:
Origin Source Name fetal brainGIBCO HFB001 5 11-12 1 S-16 18 20 24 27-28 30 34-36 fetal brainInvitrogenFBT002 13 15 18-19 25 37 42 46 60 65-66 74-75 fetal heartInvitrogenFHR001 6 15 18-19 24 26 29 37 46 57-S8 74-75 fetal kidneClontech FKD001 17 39 92 97 99 133 193 203-205 318 326 fetal kidneyClontech FKD002 27-28 46 48-49 53 69-70 81 94 105 117 fetal liverClontech FLV002 19 170-173 223 298 401 fetal liverClontech FLV004 4 19 25-26 29 32 37-38 46 53 80-81 92 fetal liverInvitrogenFLV001 12 16 25 32 44 60 77 80 117 137 144 188 fetal liver-Soares FLS001 2-21 23-43 45-55 58 65 67 69-70 72-81 spleen 103-108 110 115 120 124-12S 131 133 137 fetal liver-Soares FLS002 2-3 5-6 9 11-12 15-16 18-20 23-28 31 spleen 65 68 73-75 77 80 83 90 93 97-98 100-101 fetal liver-Soares FLS003 6 16 21 48 65 72 84 98 110 114 124 208 spleen 307 317 336-337 356 366 370 397 401 405-408 fetal lun Clontech FLG001 65 137 237 247 281 312 334 434 510 fetal lungInvitrogenFLG003 49 66 77 lOS 121 182 246-248 281 294 fetal muscleInvitrogenFMS001 9 23 53 84 95 118 281 322-323 331 336 fetal muscleInvitro FMS002 23 25 28-29 48 58 92 103-104 124 127 en 131-132 201 217 247 255 257 Table 1 Tissue RNA/TissueLibrary SEQ ID NO:
Origin Source Name fetal skinInvitrogenFSK001 5 9 15-16 18 24 26 28 30 32 35-36 40 fetal skinInvitrogenFSK002 4 24-26 31 46 48 53 68 71 74-75 77 81 fibroblastJulio_m EPM001 357 a ile s fibroblastJulio_m EPM004 357 a ile s fibroblastsJulio BAC001 484 m infant NULL IBM002 13 42 48 61 77 170-173 184 190 308 444 brain 456 467 infant NULL IBS001 26 60 84 100 137 143 170-173 175 184 brain 281 315 366 376 397 489 507 infant Soares IB2002 9 13 16 18 20 22 24 26 30-31 34 37-38 brain 45 47-48 54 60-63 66 69 77 infant Soares IB2003 2 13-14 17 24-25 30 38 49 61 66 77 87 brain 95 107 130 137 140 143-144 353 3? 1 383-384 397 411 442 456 458 leukoc Clontech LUC003 5 77 112 137 165 181-182 272 307 376 tes 416 453 508-509 512 leukocytesGIBCO LUC001 5 13-15 18-20 24-25 27 32 34 37 39 43 lung StrategeneLFBOOI 6 11 13 15 41 46 56 84 92 112 143 154 1 h node Clontech ALN001 18 71 122 155 176-177 202 326 338 411 lymphocyteATCC LPC001 5 1S 24-2S 29 39 44 53-55 70-71 87 92 macro ha Invitro HMP001 24 69 113 129 137 144 287 326 389 396 a en 398 406 467 510 mammary InvitrogenMMG001 15-18 24-26 30 32 35-37 39 44 49 62-63 gland 101 103-105 107 109 112 114 117 131-132 Table 1 Tissue RNA/TissueLibrarySEQ ID NO:
Origin Source Name melanoma Clontech MEL004 18 39 50 73 92 118 124 127 208 212 247 *Mixture Various CGd010 60 77 94 322 338 473 478-479 496 S 19 of 16 tissues Vendors -mRNA

*Mixture Various CGd011 39 77 243 247 352 401 412-414 471 480 of 16 500 tissues Vendors -mRNA

*Mixture Various CGd012 13 18 20 25-26 30 39 46 50 56 59 65 72 of 16 77 80-81 95 99 108 110 124 tissues Vendors 144 148 189 194 215-216 225 232 241 243 mRNA 337 351-352 368 380 390-391 401 412-414 *Mixture Various CGd013 26 58 81 105 127 284 331 of 16 tissues Vendors -mRNA

*Mixture Various CGd015 4 18 34 39 60 67 71 106 147 180 207 254 of 16 331 367 370-371 401 456 tissues Vendors 497 501 503 507-509 512 -mRNA

*Mixture Various CGd016 2 29-30 77 112 131 143 175 184 248 259 of 16 307 33S 359 397 401 409 tissues Vendors 505-506 524 -mRNA

neuron StrategeneNTD001 3 8 11-13 45 69 77 79 81 131 137 139-140 neuron StrategeneNTR001 77 81 95 103-104 111 163 181-182 342 353 neuronal StrategeneNTU001 17 39 79 95 11 I 117 140 151-152 182 266 cells 305-306 358 369 373 375 ovary InvitrogenAOV001 2 5-6 8-9 12 15-16 18 20 24-25 27-28 30 153 155-15b 162 164-165 ituita Clontech PIT004 12 14 137 151-152 164 189 266 380 461 land 467 513 516 521 placenta Clontech PLA003 24 71 84 92 96 103-104 178 182 184 246 lacenta Invitro APL001 151-152 182 215-216 247 340 en lacenta Invitro APL002 24 34 49 80 83 107 112 125 153 190 247 en 353 397 400 510 prostate Clontech PRT001 15 28 53 80 96 105 112 124-125 141 181 rectum InvitrogenREC001 18 78 80 83 105 196 226-227 248 266 275 saliva Clontech SALS03 482 land salivary Clontech SAL001 25 39 41 124 202 268 299 338 340 353 355 gland 365 381 411 418 430 489-skeletal Clontech SKM001 11 23 182 186 217 226-227 247 353 378 muscle 386 411 498 513 525 skin fibroblastATCC SFB001 16 small intestineClontech S1N001 12 18 20 24 26 30 35-36 39 48 S3 62-63 Table 1 Tissue RNA/TissueLibrarySEQ ID NO:
Origin Source Name spinal Clontech SPC001 22 34 41 51 66 88 121 124 133 137 155 cord 158 178 181-182 196 Z14-216 stomach Clontech STO001 9 16 55 86 165 251 254 274 282 323 355 testis GIBCO ATS001 13-15 17-18 24 41 46 66 77 80 107-108 thalamus Clontech THA002 32 39 60 68 126 137 144 154 185 190 247 thymus Clonetech THM001 14 17 25 28 30 34 39 49 53-54 61 76 87 thymus Clontech THMc02 4 18 25 27 34-36 38 46-47 53-54 64 71 thyroid Clontech THR001 5 9 11-12 14 16-19 24-25 27 29-30 34 42 gland 46-48 55 57-58 61 67 69 77 trachea Clontech TRC001 18 24 70 126 174 215-216 238 251 286 365 umbilical BioChain FUC001 9 15 17-18 22 26 29-30 34 39 41 47 58 cord 70 72 96 99 103-104 112 I 14 uterus Clontech UTR001 47 84 111 114 197 211 246-247 273 281 young liverGIBCO ALV001 15-16 23 38 67 92 96 101 114 120 130 137 *The 16 tissue/mRNAs and their vendor sources are as follows: 1) Norntal adult brain mRNA (Invitrogen), 2) Norn~al adult kidney mRNA (Invitrogen), 3) Normal fetal brain mRNA
(Invitrogen), 4) Normal adult liver mRNA
(Invitrogen), 5) Normal fetal kidney mRNA (Invitrogen), 6) Normal fetal liver ntRNA (Invitrogen), 7) normal fetal skin mRNA (Invitrogen), 8) human adrenal gland mRNA (Clontech), 9) Human bone marrow mRNA (Clontech), 10) Human leukemia lymphoblastic mRNA (Clontech), 11 ) Human thymus mRNA
(Clontech), 12) human lymph node mRNA (Clontech), 13) human so\spinal cord mRNA (Clontech), 14) human thyroid mRNA (Clontech), 15) human esophagus mRNA (BioChain), 16) human coneeptional.umbilical cord mRNA
(BioChain).

Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit 527 gi9798452Homo SapiensmRNA for putative capacitative4470 100 calcium channel ( 7 ene .

527 15326854 Mus musculusrece tor-activated calcium4392 98 channel 527 g12295903Homo SapiensHuman putative calcium 3529 81 influx channel (h 3) mRNA, com fete cds.

528 AAG89238 Homo sapiensGEST Human secreted protein,545 100 SEQ ID

NO: 358.

528 AAG93320 Homo sa NISC- Human rotein HP 545 100 iens 10515.

528 g113620915Homo SapiensbMRP63 mRNA for mitochondrial545 100 ribosomal protein bMRP63, complete cds.

529 AAW78211 Homo SapiensHUMA- Human secreted 333 88 protein encoded b ene 86 clone HTWCT03.

529 17294596 alt 2 CG4300 ene roduct Droso 65 31 hila 529 17294595 alt 1 CG4300 ene roduct Droso 65 31 hila 530 AAB95369 Homo SapiensHELI- Human protein sequence2361 100 SEQ

ID N0:17686.

530 g110435142Homo sapienscDNA FLJ13215 fis, clone2361 100 NT2RP4001447.

530 g1 I 6041164Macaca hypothetical protein 1576 89 fascicularis 531 113625172Homo sa 5-HT rece for mRNA, co 1615 93 iens fete cds.

531 110503978Homo sa clone SP329 unknown mRNA.1615 100 iens 531 g17300419DrosophilaCG17796 gene product 96 27 melano aster 532 110438219Homo sa cDNA: FLJ21986 fis, clone1425 99 iens HEP06248.

532 AA013496 Homo SapiensHYSE- Human polypeptide 1125 99 SEQ ID

NO 27388.

532 ABB I Homo SapiensHYSE- Human novel protein,725 97 N0:2090.

533 14929685 Homo sa CGI-108 rotein mRNA, 269 98 iens com fete cds.

533 112838900Mus musculusutative 269 98 533 AAY65253 Homo SapiensGEST Human 5' EST related265 96 of a tide SEQ ID N0:1414.

534 1220500 Mus musculusNDPP-1 rotein 65 29 534 g16679028Mus NPC derived proline rich65 29 protein 1 musculus]
>

[Mus musculus 535 AAG02210 Homo SapiensGEST Human secreted protein,397 98 SEQ ID

NO: 6291.

536 g17573295Homo sapiensHuman DNA sequence from 389 75 clone RPI-238023 on chromosome 6.

Contains part of the gene for a novel protein similar to PIGR
(polymeric immunoglobulin receptor), part of the gene for a novel protein similar to rat SAC (soluble adenylyl cyclase), ESTs, STSs and GSS, com fete se uence.

536 g14140400Rattus soluble adenylyl cyclase176 47 norve icus 536 AAB81929 Homo sapiensSTRD Human soluble adenylyl172 45 c claw.

Table 2 SEQ ID Accession Species Description Score NO: No.

Identit 537 AAY10830 Homo SapiensHUMA- Amino acid sequence246 100 of a human secreted rotein.

537 g113815145SulfolobusHypothetical protein 68 37 solfataricus 537 g115898682SulfolobusHypothetical protein 68 37 solfataricus]
>

[Sulfolobus solfataricus 538 112841269 Mus musculusutative 503 84 538 AAY13186 Homo SapiensGEST Human secreted protein406 97 encoded b 5' EST SE ID NO: 200.

538 AAW67825 Homo SapiensHUMA- Human secreted 369 100 protein encoded b ene 19 clone HELBW38.

539 AAS15817 Homo SapiensSAAT/ Human cDNA encoding730 94 as 1 rostate s ecific rotein SSH9.

539 AAU10191 Homo sapiensSAAT/ Human prostate 730 94 specific protein SSH9.

539 AAB58298 Homo SapiensROSE/ Lung cancer associated730 94 of a tide se uence SEQ
ID 636.

540 AAB43589 Homo SapiensHUMA- Human cancer associated913 100 rotein se uence SEQ ID
N0:1034.

540 g15817181 Homo SapiensmRNA; cDNA DKFZp566E104 745 99 (from clone DKFZ 566E104);
artial cds.

540 g17512814 Homo Sapienshypothetical protein 745 99 DKFZp566E104.1 - human (fra ment) >

541 AAB58235 Homo SapiensROSE/ Lung cancer associated1480 100 of a tide se uence SEQ
ID 573.

541 g15410296 Homo Sapienshomeobox prox 1 mRNA, 1267 100 complete cds.

541 14929667 Homo sa CGI-99 rotein mRNA, com 1267 100 iens lete cds.

542 g17108913 Homo Sapiensglucocorticoid receptor 1818 100 coactivator-1 mRNA, artial cds.

542 AAM66710 Homo SapiensMOLE- Human bone marrow 513 66 expressed probe encoded protein SEQ

ID NO: 27016.

542 AAM54312 Homo SapiensMOLE- Human brain expressed513 66 single exon probe encoded protein SEQ ID

NO: 26417.

543 AAA61620 Homo SapiensMITO- cDNA encoding human275 100 as 1 ubi uitin-con'u atin enz a ra UBC.

543 AAZ10849_asHomo SapiensDAND TIA-1 binding protein275 100 1 (TIABP1) ene.

543 AAV51398 Homo SapiensDAND Human TIABP1 genomic275 100 as 1 DNA.

544 AAB43887 Homo SapiensHUMA- Human cancer associated1183 100 rotein se uence SEQ ID
N0:1332.

544 g1533111 Canis signal peptidase complex1130 95 25 kDa familiarissubunit 544 112856773 Mus musculusutative 1129 95 545 16841242 Homo sa HSPC296 567 99 iens 545 112842164 Mus musculusutative 564 97 545 g17293870 DrosophilaCG6884 gene product 236 45 melano aster Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit 546 gi3043652Homo SapiensmRNA for KIAA0564 protein,5065 100 partial cds.

546 gi3875726Caenorhabditissimilar to nir like gene1447 34 involved in elegans denitrification-cDNA
EST yk12a1.3 comes from this gene~cDNA
EST

yk7e7.3 comes from this gene~cDNA

EST yk7e7.5 comes from this gene~cDNA EST yk34c7.3 comes from this gene~cDNA EST yk12a1.5 comes from this gene~cDNA EST
yk24f12.5 comes from this gene~cDNA
EST

yk34c7.5 comes from this gene~cDNA

EST yk154e5.3 comes from this gene~cDNA EST yk212d10.3 comes from this gene~cDNA EST
yk212d10.5 comes from this gene~cDNA
EST

yk225b7.3 comes from this gene~cDNA EST yk225b7.5 comes from this gene~cDNA EST
yk243b7.5 comes from this gene~cDNA
EST

yk349d4.5 comes from this gene~cDNA EST yk367e8.3 comes from this gene~cDNA EST
yk367e8.5 comes from this gene-cDNA
EST

yk420f3.3 comes from this gene--cDNA EST yk420f3.5 comes from this gene~cDNA EST
yk529f9.5 comes from this gene-cDNA
EST

k565d10,5 comes from this ene 546 gi10728542Drosophilac12.2 gene product 1005 56 melano aster 547 gi12052936Homo SapiensmRNA; cDNA DKFZp566E2324955 100 (from clone DKFZp566E2324);

com lete cds.

547 gi 10439692Homo SapienscDNA: FLJ23112 fis, clone580 100 LNG07874.

547 gi6692513Hepatitis large S protein 81 32 B

virus 548 AAY07902 Homo SapiensHUMA- Human secreted 322 88 protein fra ment encoded from ene 51.

548 gi4008342Caenorhabditispredicted using Genefinder~contains66 39 elegans similarity to Pfam domain:

(V-type ATPase 116kDa subunit family), Score=925.6, E-value=4.6e-275, N=l~cDNA EST yk15f10.3 comes from this gene~cDNA
EST

yk15f10.5 comes from this gene~cDNA EST yk224h11,3 comes from this gene~cDNA EST
yk223d1,3 comes from this gene~cDNA
EST

yk287c7.3 comes from this gene~cDNA EST yk321h11.3 comes from this ene~cDNA EST
k224h11.5 Table 2 SEQ ID Accession Species Description Score NO: No.

Identit comes from this gene~cDNA
EST

yk223d1.5 comes from this gene~cDNA EST yk287c7.5 comes from this gene-cDNA EST
yk321h11.5 comes from this ene 548 g17496564 Unknown hypothetical protein 66 39 C26H9A.1 -Caenorhabditis ele ans >

549 g117389834Homo SapiensSimilar to RIKEN cDNA 1024 100 gene, clone MGC:23953 IMAGE:4292862, mRNA, complete cds.

549 112844552 Mus musculusutative 906 89 549 AAM93823 Homo SapiensHELI- Human polypeptide,727 46 SEQ ID

NO: 3881.

550 AAH26493 Homo SapiensBOST- Human low density 697 94 as lipoprotein 1 bindin rotein 1 (LBP-1 ene.

550 AAH26492 Homo SapiensBOST- Human low density 697 94 as lipoprotein 1 b indin rotein 1 LBP-1 cDNA.

550 AAB82802 Homo SapiensBOST- Human low density 697 94 lipoprotein bindin rotein 1 LBP-1).

551 g112698332Homo SapiensC/EBP-induced protein 2084 100 mRNA, com lete cds.

551 114150747 Mus musculusGIG18 641 43 551 g15739567 Homo SapiensBAC clone RP11-505D17 635 44 from 7p22-21, com fete se uence.

552 g111761611Homo Sapienskinesin-like protein 6087 99 RBKINI (RBKIN) mRNA, complete cds, alternatively s liced.

552 g111761613Homo Sapienskinesin-like protein 5852 96 RBKIN2 (RBKIN) mRNA, complete cds, alternatively s liced.

552 g112054030Homo SapiensmRNA for KINESIN-13A1 5771 95 (KIN13A

ene).

553 g117391063Homo SapiensSimilar to RIKEN cDNA 1311 100 gene, clone MGC:21379 IMAGE:4509694, mRNA, complete cds.

553 112837824 Mus musculusutative 1083 83 553 g17292416 DrosophilaCG14985 gene product 383 35 melano aster 554 112857727 Mus musculusutative 1260 94 554 g16851256 Mus musculusprotein tyrosine phosphatase-like1242 93 rotein PTPLB

554 AAB59515 Homo SapiensHUMA- Human secreted 1092 100 protein BLAST search protein SEQ ID NO:

104.

555 AAM93439 Homo SapiensHELI- Human polypeptide,1266 100 SEQ ID

NO: 3078.

555 g116741367Homo Sapiensclone MGC:17276 IMAGE:4180160,1266 100 mRNA, com lete cds.

555 g115079907Homo SapiensSimilar to secretory 1266 100 carrier membrane protein 4, clone MGC:19661 IMAGE:3161979, mRNA, com lete Table 2 SEQ ID Accession Species Description Score NO: No.

Identit cds.

556 gi16507984Human putative env 430 48 endogenous retrovirus 556 gi4185944 Human env protein 429 47 endogenous retrovirus K

556 gi3150438 Human pol-env 429 47 endogenous retrovirus K

557 AAB98212 Homo SapiensNANF- Human early endosome1129 100 antigen 1 isomer (hEEAI-iso) SEQ ID N0:7.

557 19963835 Homo sa AD024 mRNA, com lete 1129 100 iens cds.

557 112834062 Mus musculusutative 717 78 558 112847029 Mus musculusutative 1082 76 558 AAY60569 Homo SapiensMETA- Human normal bladder1073 100 tissue EST encoded rotein 241.

558 112854670 Mus musculusutative 525 80 559 115824269 Homo sa NEDD4-like ubi uitin 64 34 iens ligase 3 559 12662159 Homo sa KIAA0439 64 34 iens 560 AAB43895 Homo SapiensHUMA- Human cancer associated814 100 rotein se uence SEQ ID
N0:1340.

560 g15231141 Homo Sapienssin3 associated polypeptide804 100 (SAP 18) mRNA, com lete cds.

560 g12108210 Homo Sapienssin3 associated polypeptide804 100 p18 (SAP I 8) mRNA, com lete cds.

561 g117061811Homo SapiensC21orf57 isoformA protein1102 80 (C21orf57) mRNA, partial cds, alternatively s liced.

561 AAM25823 Homo SapiensHYSE- Human protein sequence938 97 SEQ

ID N0:1338.

561 g117061813Homo SapiensC21orf57 isoformB protein804 64 (C21orf57) mRNA, partial cds, alternatively s liced.

562 g117061811Homo sapiensC21orf57 isoform A protein818 75 (C21orf57) mRNA, partial cds, alternatively s liced.

562 AAM25823 Homo SapiensHYSE- Human protein sequence687 97 SEQ

ID N0:1338.

562 AAY48371 Homo SapiensMETA- Human prostate 674 96 cancer-associated rotein 68.

563 AAB93239 Homo SapiensHELI- Human protein sequence1630 100 SEQ

ID N0:12243.

563 g115928956Homo Sapiensclone MGC:22951 IMAGE:4872309,1630 100 mRNA, com fete cds.

563 g114042582Homo sapienscDNA FLJ14798 fis, clone1630 100 NT2RP4001313, weakly similar to MITOCHONDRIAL IMPORT

RECEPTOR SUBUNIT TOM40.

564 AAB94479 Homo SapiensHELI- Human protein sequence1521 100 SEQ

ID N0:15153.

564 110434979 Homo sa cDNA FLJ13111 fis, clone1521 100 iens Table 2 SEQ ID Accession Species Description Score NO: No.

Identit NT2RP3002566.

564 gi14043295Homo Sapiensclone IMAGE:3534358, 1448 100 mRNA, artial cds.

565 gi15620831Homo SapiensmRNA for KIAA1886 protein,1420 99 partial cds.

565 gi13276647Homo SapiensmRNA; cDNA DKFZp761I21231420 99 (from clone DKFZ 761I2123 ;
com fete cds.

565 AAY86184 Homo SapiensHELI- Nuclear transport 1364 99 protein clone hfi~2007 rotein se uence.

566 14321787 Mus musculus6- vo 1-tetrah dro term 156 42 s thaw 566 112832727 Mus musculusutative 156 42 566 g1202561 Rattus 6-pyruvoyl-tetrahydropterin148 41 synthase norve icus 567 g113477179Homo Sapienshypothetical protein 1036 100 FLJ10342, clone MGC:12937 IMAGE:2820292, mRNA, com fete cds.

567 g112804363Homo Sapienshypothetical protein 1036 100 FLJ10342, clone MGC:4366 IMAGE:2822886, mRNA, com lete cds.

567 g112653941Homo Sapienshypothetical protein 1036 100 FLJ10342, clone MGC:2740 IMAGE:2822886, mRNA, com lete cds.

568 g19280047 Macaca unname dprotein product 596 97 fascicularis 568 g114532556ArabidopsisATSg57360/MSF19 2 91 33 thaliana 568 g113487068ArabidopsisAdagio 1 91 33 thaliana 569 AAY87333 Homo SapiensINCY- Human signal peptide543 93 containing protein HSPP-110 SEQ ID

NO:110.

569 AAY12883 Homo SapiensGEST Human 5' EST secreted226 86 protein SEQ ID N0:473.

569 AAY12868 Homo SapiensGEST Human 5' EST secreted168 81 protein SEQ ID N0:458.

570 g117389322Homo SapiensSimilar to NICE-5 protein,130 65 clone MGC:21212 IMAGE:3907760, mRNA, com lete cds.

570 AAY73387 Homo Sapiens1NCY- HTRM clone 3340290122 75 protein se uence.

570 AAG73684 Homo SapiensHUMA- Human colon cancer76 45 antigen rotein SEQ ID N0:4448.

571 g19280156 Macaca unnamed protein product 168 82 fascicularis 571 AA011992 Homo SapiensHYSE- Human polypeptide 76 50 SEQ ID

NO 25884.

571 AA008245 Homo SapiensHYSE- Human polypeptide 70 43 SEQ ID

NO 22137.

572 g112666208Homo SapiensHuman DNA sequence from 490 100 clone RP11-103J18 on chromosome Contains ESTs, STSs, GSSs and a CpG

island. Contains two novel genes and the 3' art of a novel ene similar to Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit mouse M025, com lete se uence.

572 AAU09964 Homo SapiensMILL- Human cytidine 425 100 deaminase-like rotein from clone 26934.

572 AAG04055 Homo SapiensGEST Human secreted protein,425 100 SEQ ID

NO: 8136.

573 g112654927Homo Sapiensclone MGC:5509 IMAGE:3453623,1201 100 mRNA, com lete cds.

573 g113905264Mus musculusSimilar to hypothetical 1034 85 protein 573 g19022437Xenopus ashwin 241 41 laevis 574 g113477177Homo SapiensSimilar to RIKEN cDNA 1128 100 gene, clone MGC:12936 IMAGE:2820022, mRNA, complete cds.

574 112851027Mus musculusutative 1012 89 574 AAG04038 Homo SapiensGEST Human secreted protein,506 92 SEQ ID

NO: 8119.

575 AAG93293 Homo sa NISC- Human rotein HP 1343 100 iens 10659.

575 g115929856Homo SapiensSimilar to RIKEN cDNA 1343 100 gene, clone MGC:21397 IMAGE:3852440, mRNA, complete cds.

575 113097141Mus musculusRIKEN cDNA 0610011N22 1156 82 ene 576 AA007956 Homo SapiensHYSE- Human polypeptide 74 38 SEQ ID

NO 21848.

576 15917666 Zea ma extensin-like rotein 74 40 s 576 g13980411Arabidopsisputative proline-rich 74 39 protein thaliana 577 AAG89212 Homo SapiensGEST Human secreted protein,324 100 SEQ ID

NO: 332.

577 gi49808I6Thermotogahypothetical protein 72 36 maritima 577 g19294037Arabidopsis 67 45 thaliana 578 g113324963CaenorhabditisHypothetical protein 73 41 F37B4.9 ele ans 578 16677927 Mus musculuss hin osine hos hate 65 30 1 ase 1 579 112856429Mus musculusutative 869 66 579 g116549784Homo SapienscDNA FLJ30562 fis, clone763 99 BRAWH2004731.

579 112848379Mus musculusutative 659 62 580 AAY94526 Homo SapiensINCY- Human lysine-rich 342 96 statherin rotein.

580 g1438731 Mesomys cytochrome b 75 39 his idus 580 11478112 Sciurus c ochrome b 73 38 aberti 581 AAY73460 Homo SapiensGEMY Human secreted protein416 100 clone ykl4_1 protein sequence SEQ ID

N0:142.

582 AAY07790 Homo SapiensHUMA- Human secreted 294 100 protein fra ment encoded from ene 47.

582 g17107077Porcine envelo a 1 co rotein 63 55 Table 2 SEQ ID Accession Species Description Score NO: No.

Identit reproductive and respiratory syndrome virus 582 gi15231798Arabidopsisputative protein 63 34 thaliana 583 gi6331397 Homo SapiensmRNA for KIAA1287 protein,6081 99 partial cds.

583 gi12053113Homo SapiensmRNA; cDNA DKFZp434H12206081 99 (from clone DKFZp434H
1220);

com lete cds.

583 112850252 Mus musculusutative 1511 93 584 g113623583Homo Sapiensclone IMAGE:3939163, 610 99 mRNA, artial cds.

584 AAG01516 Homo SapiensGEST Human secreted protein,522 98 SEQ ID

NO: 5597.

584 g1 12654201Homo Sapiensclone IMAGE:3449838, 458 100 mRNA, artial cds.

585 g116519031Homo Sapiensputative tetracycline 535 99 transporter-like rotein mlZNA, com lete cds.

585 12506078 Mus musculustetrac cline trans orter-like535 99 rotein 585 1128 Mus musculusutative 535 99 586 _ Homo SapienscDNA FLJ30760 fis, clone2043 100 g116550027 FEBRA2000536, weakly similar to Homo Sapiens paraneoplastic cancer-testis-brain anti en MAS) mRNA.

586 g114043275Homo Sapiensclone MGC:15827 IMAGE:3507248,2043 100 mRNA, com lete cds.

586 AAB 12529 Homo SapiensSLOK Human Ma5 protein 754 46 SEQ ID

N0:13.

587 g19929997 Macaca hypothetical protein 856 93 fascicularis 587 AAB45027 Homo SapiensHUMA- Human secreted 76 52 protein encoded b ene 3.

587 g113359187Homo SapiensmRNA for KIAA1657 protein,73 44 partial cds.

588 g113559239Homo sapiensHuman DNA sequence from 815 100 clone RP5-84266 on chromosome 20.

Contains the 3' end of a novel gene, the 3' end of the gene for a novel protein similar to SEL1L (sel-1 (suppressor of 11n-12, C.elegans)-like), ESTs, STSs and GSSs, com lete se uence.

588 AAY38477 Homo SapiensHUMA- Human secreted 712 75 protein encoded b ene No. 23.

588 g116769652DrosophilaLD45826p 618 54 melano aster 589 g19971051 Homo SapiensHuman DNA sequence from 585 100 clone RP11-526K24 on chromosome 20.

Contains a novel gene, the 5' end of a novel gene, two CpG islands, ESTs, GSSs and STSs, com lete se uence.

589 AAG01028 Homo sa GEST Human secreted rotein,579 96 iens SEQ ID

Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit NO: 5109.

589 gi6782267CaenorhabditiscDNA EST yk536g11.3 comes222 51 from elegans this gene~cDNA EST yk532d11.5 comes from this gene~cDNA
EST

yk536g11.5 comes from this gene--cDNA EST yk642c12.5 comes from this ene 590 ABB 12373Homo SapiensHYSE- Human bone marrow 587 88 expressed rotein SE ID NO: 128.

590 gi12698103Macaca hypothetical protein 505 96 fascicular7s 590 AAG02711 Homo SapiensGEST Human secreted protein,411 97 SEQ ID

N0: 6792.

591 114336677Homo sa 16 13.3 se uence section673 100 iens 1 of 8.

591 g114327922Homo Sapienshypothetical protein 673 100 FLJ22940, clone MGC:14880 IMAGE:3946937, mRNA, com lete cds.

591 g112655063Homo Sapienspolymerise (RNA) III 673 100 (DNA directed) polypeptide K (12.3 kDa), clone MGC:668 IMAGE:3051476, mRNA, com lete cds.

592 g19651111Macaca hypothetical protein 495 74 fascicularis 592 AA006794 Homo SapiensHYSE- Human polypeptide 110 37 SEQ ID

NO 20686.

592 g13882271Homo SapiensmRNA for KIAA0775 protein,101 29 com lete cds.

593 112848554Mus musculusutative 1362 96 593 g18655657Homo SapiensmRNA; cDNA DKFZp7620076 1041 100 (from clone DKFZ 7620076 .

593 g112804029Homo Sapiensclone IMAGE:3940519, 754 51 mRNA, artial cds.

594 g12190184Homo SapiensmRNA for zinc finger 616 100 protein, com lete cds.

594 giI2803507Homo Sapienszinc finger protein, 616 I00 clone MGC:717 IMAGE:3143091, mRNA, complete cds.

594 AAB58863 Homo SapiensHUMA- Breast and ovarian599 97 cancer associated antigen protein sequence SEQ ID 571.

595 g115080543Homo SapiensSimilar to RIKEN cDNA 1254 100 gene, clone MGC:21579 IMAGE:4473003, mRNA, complete cds.

595 AAY35940 Homo SapiensGEST Extended human secreted1051 99 rotein se uence, SEQ
ID NO. 189.

595 112860261Mus musculusutative 1007 78 596 AA843377 Homo sapiensCURA- Human ORFX ORF3141807 99 polypeptide sequence SEQ ID

N0:6282.

596 g116877603Homo SapiensSimilar to SNARE Vtila-beta711 100 protein, clone MGC:9292 IMAGE:3885564, mRNA, com fete cds.

Table 2 SEQ ID Accession Species Description Score NO: No.

Identit 596 13421062 Mus musculus29-kDa Gol i SNARE 700 98 597 g113384259Homo Sapiensapolipoprotein L6 mRNA, 1550 99 complete cds.

597 AAM93925 Homo SapiensHELI- Human polypeptide,1341 100 SEQ ID

NO: 4091.

597 g16562077 Homo SapiensHuman DNA sequence from 1251 100 clone SC22CB-33F2 on chromosome Contains part of the gene for a novel protein similar to C-terminal parts of APOL (apolipoprotein L) and TNF-inducible protein CG12-1.
Contains GSSs, com lete se uence.

598 AAG01189 Homo SapiensGEST Human secreted protein,301 98 SEQ ID

NO: 5270.

598 AAM40924 Homo SapiensHYSE- Human polypeptide 106 41 SEQ ID

NO 5855.

598 ABB 11379 Homo SapiensHYSE- Human secreted 106 41 protein homologue, SEQ ID N0:1749.

599 112848031 Mus musculusutative 504 76 599 g112718388Neurosporaconserved hypothetical 186 37 protein crassa 599 g19758240 Arabidopsis 141 27 thaliana 600 AAG04048 Homo SapiensGEST Human secreted protein,553 100 SEQ ID

NO: 8129.

600 AAM25836 Homo SapiensHYSE- Human protein sequence501 73 SEQ

ID N0:1351.

600 ABB15766 Homo SapiensHUMA- Human nervous system365 80 related of a tide SEQ ID NO 4423.

601 AAM25836 Homo SapiensHYSE- Human protein sequence645 77 SEQ

ID N0:1351.

601 AAG04048 Homo SapiensGEST Human secreted protein,553 100 SEQ ID

NO: 8129.

601 AAG02274 Homo SapiensGEST Human secreted protein,276 96 SEQ ID

NO: 6355.

602 g117133695Nostoc WD-40 repeat-protein 65 45 Sp.

603 g17243278 Homo SapiensmRNA for KIAA 1440 protein,2003 100 partial cds.

603 g17291723 DrosophilaCG3173 gene product 1815 34 melano aster 603 g113279125Homo Sapiensclone IMAGE:3618123, 1779 100 mRNA, artial cds.

604 AAY12244 Homo SapiensGEST Human 5' EST secreted378 87 protein SE ID NO: 557.

604 AAY59717 Homo SapiensGEST Secreted protein 378 87 FLl.

604 g12291129 CaenorhabditisHypothetical protein 78 30 C02A12.5 ele ans 605 g115074866Tuber protein kinase C homologue82 32 ma natum 605 17110512 Gallus TGF-beta s1 nal transducer79 37 anus Smad8 605 AAM93694 Homo sa HELI- Human of a tide, 75 63 iens SEQ ID

Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit NO: 3606.

606 AAU16929 Homo SapiensHUMA- Human novel secreted1118 99 protein, SEQ ID 170.

606 AAU17002 Homo SapiensHUMA- Human novel secreted1117 100 protein, SEQ ID 243.

606 g113623247Homo SapiensSimilar to RIKEN cDNA 1082 100 gene, clone MGC:11275 IMAGE:3944355, mRNA, complete cds.

607 g112698049Homo SapiensmRNA for KIAA1752 protein,2706 99 partial cds.

607 16103000 Mus musculusfatso rotein 2384 86 607 112855822Mus musculusutative 463 80 608 AAB93514 Homo SapiensHELI- Human protein sequence312 100 SEQ

ID N0:12846.

608 AAG01489 Homo SapiensGEST Human secreted protein,312 100 SEQ ID

NO: 5570.

608 AAW61552 Homo sa ABBO Human endosulfine 312 100 iens B rotein.

609 g115341686Homo Sapiensclone MGC:20522 IMAGE:4578480,1695 100 mRNA, com lete cds.

609 g114349357Homo Sapienshypothetical protein 1695 100 FLJ22501, clone MGC:14897 IMAGE:3939754, mRNA, com fete cds.

609 g110438914Homo SapienscDNA: FLJ22501 fis, clone1695 100 HRC 11368.

610 AAM93816 Homo SapiensHELI- Human polypeptide,1051 95 SEQ ID

NO: 3867.

610 g19280104Macaca unnamed protein product 1035 48 fascicularis 610 AAE07112 Homo SapiensHUMA- Human gene 6 encoded1033 49 secreted protein fragment, SEQ ID

N0:129.

611 AAG93313 Homo sa NISC- Human rotein HP 365 100 iens 10569.

611 g117389971Homo Sapiensclone IMAGE:4251653, 365 100 mRNA, artial cds.

611 AAG02098 Homo SapiensGEST Human secreted protein,300 100 SEQ ID

NO: 6179.

612 g112654899Homo SapiensSimilar to x 006 protein,1110 100 clone MGC:5294 IMAGE:3452502, mRNA, com lete cds.

612 AAB41932 Homo SapiensCURA- Human ORFX ORF16961091 100 polypeptide sequence SEQ ID

N0:3392.

612 19437345 Homo sa x 006 rotein mRNA, com 1022 97 iens lete cds.

613 g1 11611571Macaca hypothetical protein 220 89 fascicularis 613 g19280196Macaca unnamed protein product 111 34 fascicularis 613 112846582Mus musculusutative 88 28 614 AAG02925 Homo SapiensGEST Human secreted protein,275 96 SEQ ID

NO: 7006.

614 g1402177 Candida Fatty acid synthase subunit65 41 beta albicans Table 2 SE(~ ID AccessionSpecies Description Score NO: No.

Identit 614 g11592041Methanococcuconserved hypothetical 65 31 protein s 'annaschii 615 g115787978Homo sapiensnuclear export factor 2824 100 3 (NXF3) mRNA, corn lete cds.

615 g111230440Homo SapiensmRNA for nuclear RNA 2824 100 export factor 3 (NXF3 ene).

615 g112053833Homo Sapienspartial mRNA for nuclear1794 99 RNA export factor 3 (NXF3 ene .

616 17770141 Homo sa PR01728 662 100 iens 616 g1169156 Pisumsativumribulosel,5-bisphosphatecarboxylase73 25 small subunit ro a tide 616 g117862888DrosophilaSD01663p 72 31 melano aster 617 AAY27630 Homo SapiensHUMA- Human secreted 220 100 protein encoded b ene No. 64.

618 g115487240Homo SapiensmRNA for putative autophagy-related2138 99 cysteine endopeptidase 2 (AUTL2 ene).

618 g14176500Homo SapiensHuman DNA sequence from 2123 100 clone 889N15 on chromosome Xq22.1-22.3.

Contains part of the gene for a novel protein similar to X.
laevis Cortical Thymocyte Marker CTX, the possibly alternatively spliced gene for 26S

PrOteasome subunit p28 (Ankyrin repeat protein), a novel gene and exons 36 through 45 of the COL4A6 for Collagen Alpha 6(IV).
Contains ESTs, STSs, GSSs and a putative CpG island, corn fete se uence.

618 g115487242Homo SapiensmRNA for putative autophagy-related1446 73 cysteine endopeptidase 2, short splice variant (AUTL2 ene).

619 g12558947Bacillus ParC 89 23 subtilis 619 g12634193Bacillus DNA gyrase-like protein 88 23 (subunit A) subtilis 619 g1 1405462Bacillus GrIA 88 23 subtilis 620 g112583981Homo Sapienstransmembrane 6 superfamily1386 90 member 2 TM6SF2 mRNA, artial cds.

620 g112583979Homo Sapienstransmembrane 6 superfamily830 54 member 1 (TM6SF1) mRNA, corn lete cds.

620 AAG89336 Homo SapiensGEST Human secreted protein,828 54 SEQ ID

NO: 456.

621 g117384428Homo SapiensHuman DNA sequence from 4928 100 clone RP11-100C15 on chromosome 9q34.2-34.3 Contains the 3' end of a novel gene for a protein similar to KIAA1543 protein, the gene for a novel potassium channel subunit protein (KIAA1422), part of a novel gene, the 5' end of a ene for a novel 1i ocalin/c osolic Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit fatty-acid binding protein and CpG

islands, com lete se uence.

621 gi15215360Homo Sapiensclone IMAGE:3939659, 3270 99 mRNA, artial cds.

621 gi14714974Homo Sapiensclone IMAGE:3865907, 1090 100 mRNA, artial cds.

622 AAB66590 Homo sa UYBR- Human KARP-1 rotein.932 91 iens 622 gi307094 Homo sapiensHuman Ku (p70/p80) subunit923 92 mRNA, com lete cds.

622 gi307093 Homo SapiensHuman Ku autoinunune 923 92 antigen gene, com fete cds.

623 AAY73468 Homo sapiensGEMY Human secreted protein601 91 clone yd88_1 protein sequence SEQ ID

N0:158.

623 gi7292183DrosophilaCG12361 gene product 75 32 melano aster 623 gi5911822Homo SapiensHuman DNA sequence from 74 33 clone RP3-526I14 on chromosome Contains the BZRP gene for peripheral benzodiazapine receptor (PBR, PKBS, mitochondrial benzodiazepine, MBR), the KIAA0153 gene, and the gene for a novel CUB and EGF-like domains containing protein. Contains ESTs, STSs, GSSs, genomic marker D22S 1179, a ca repeat polymorphism and a putative CpG island, complete se uence.

624 gi15788454Mus musculusgrowth hormone-inducible409 92 soluble rotein 624 gi7298358DrosophilaCG6115 gene product 215 50 melano aster 624 gi7529571Homo SapiensHuman DNA sequence from 93 34 clone RP1-12208 on chromosome 6q14.2-16.1. Contains the 3' part of a novel gene partially coded for by KIAA0301, a novel gene and the 3' part of the gene KIAA0957. Contains ESTs, STSs, GSSs and a putative CpG
island, co lete se uence.

625 gi9967224Macaca hypothetical protein 337 98 fascicularis 625 gi577220 SaccharomyceStt4p: Phosphatidylinositol-4-kinase68 42 s cerevisiae 625 gi454207 Saccharomycehomologous protein to 68 42 PI3-kinase s cerevisiaeSTT4 626 gi7291693DrosophilaCG16787 gene product 233 36 melano aster 626 gi4966353ArabidopsisESTs gb~T76348, gb~N65615110 26 and thaliana b 218119 come from this ene.

626 gi17104753Arabidopsisunknown protein 99 26 thaliana 627 gi12856787Mus musculusputative ~ 785 98 ~

Table 2 SEQ ID Accession Species Description Score NO: No.

Identit 627 AAG02618 Homo SapiensGEST Human secreted protein,319 100 SEQ ID

NO: 6699.

627 gi4218005 Arabidopsisputative vicilin storage101 23 protein thaliana lobulin-like) 628 112834588 Mus musculusutative 420 65 628 g17299316 DrosophilaCG12816 gene product 99 40 melano aster G28 AAM83343 Homo SapiensHUMA- Human 82 34 immune/haematopoietic antigen SEQ

ID N0:10936.

629 AAB50865 Homo SapiensUNIW Modified human annexin,565 99 SEQ

ID NO: 6.

629 AAB50864 Homo sapiensUNIW Modified human annexin,565 99 SEQ

ID NO: 4.

629 AAB50863 Homo SapiensUNIW Modified human annexin,565 99 SEQ

ID NO: 2.

630 AAB50865 Homo SapiensUNIW Modified human annexin,163 96 SEQ

ID NO: 6.

630 AAB50864 Homo SapiensUNIW Modified human annexin,163 96 SEQ

ID NO: 4.

630 AAB50863 Homo SapiensUNIW Modified human annexin,163 96 SEQ

ID NO: 2.

631 AAE04909 Homo SapiensINCY- Human transporter 3324 100 and ion channel-22 (TRICH-22 rotein.

631 AAB24281 Homo SapiensUROG- Prostate tumour 3320 99 associated gene 24P4C12 protein sequence SEQ

ID N0:2.

631 AAB93981 Homo SapiensHELI- Human protein sequence3313 99 SEQ

ID N0:14063.

632 AAG81401 Homo SapiensZYMO Human AFP protein 229 100 sequence SEQ ID N0:320.

632 AAG93300 Homo sa NISC- Human rotein HP104I7.229 100 iens 632 AAG00912 Homo SapiensGEST Human secreted protein,229 100 SEQ ID

NO: 4993.

633 AAG89339 Homo SapiensGEST Human secreted protein,861 100 SEQ ID

NO: 459.

633 113397925 Mus musculush othetical rotein 815 94 633 112850449 Mus musculusutative 814 94 634 AAB94808 Homo SapiensHELI- Human protein sequence708 100 SEQ

ID N0:15947.

634 g110436192Homo SapienscDNA FLJ13912 fis, clone708 100 Y79AA 1000230.

634 g115680180Homo Sapiensclone MGC:22939 IMAGE:4870865,404 91 mRNA, com lete cds.

635 114091315 Mus musculusADMP 371 85 635 g116877066Homo Sapiensclone MGC:24447 IMAGE:4077762,173 45 mRNA, com lete cds.

635 g116877059Homo Sapiensclone MGC:24437 IMAGE:4075637,173 45 mRNA, com lete cds.

636 g110442725Homo Sapienspellino related intracellular2273 100 signalling molecule (PRISM) mRNA, complete cds.

636 110242359 Homo sa ellino 1 PELI1) mRNA, 2273 100 iens com fete Table 2 SEQ ID Accession Species Description Score NO: No.

Identit cds.

636 1167 Mus musculusellino Droso hila) homolo2268 99 637 _ human ORFI 77 32 g1330178 he esvirus 637 AAY17406 Homo SapiensUYHU- Human atrophin-1 76 35 related rotein.

637 18096340 Homo sa mRNA for RERE, com lete 76 35 iens cds.

638 AAB42962 Homo SapiensCURA- Human ORFX ORF27261099 100 polypeptide sequence SEQ ID

N0:5452.

638 g13342738 Homo Sapienschromosome 19, cosmid 358 93 826660, co lete se uence.

638 AAG03426 Homo sapiensGEST Human secreted protein,315 100 SEQ ID

NO: 7507.

639 AAY00293 Homo SapiensHUMA- Human secreted 645 86 protein encoded b ene 36.

639 AAM23891 Homo SapiensHYSE- Human EST encoded 394 97 protein SEQ ID NO: 1416.

639 AAY12138 Homo SapiensGEST Human 5' EST secreted217 100 protein SEQ ID NO: 451.

640 g115341790Homo SapiensSimilar to RIKEN cDNA 1484 100 gene, clone MGC:17347 IMAGE:2901027, mRNA, complete cds.

640 112837626 Mus musculusutative 1414 96 640 AAG74211 Homo SapiensHUMA- Human colon cancer400 64 antigen rotein SEQ ID N0:4975.

641 g114017855Homo SapiensmRNA for KIAA1819 protein,2032 99 partial cds.

641 g114017849Homo SapiensmRNA for KIAA1816 protein,253 25 partial cds.

641 16979930 Homo sa Maml mRNA, artial cds. 195 24 iens 642 110439151 Homo sa cDNA: FLJ22671 fis, clone1445 100 iens HSI08712.

642 AAE07108 Homo SapiensHUMA- Human gene 3 encoded881 98 secreted protein fragment, SEQ ID

N0:125.

642 AAE07053 Homo SapiensHUMA- Human gene 3 encoded768 99 secreted protein HWHS013, SEQ ID

N0:70.

643 AAB94047 Homo SapiensHELI- Human protein sequence1038 100 SEQ

ID N0:14209.

643 g114327927Homo Sapienshypothetical protein 1038 100 FLJ12474, clone MGC:15036 IMAGE:3678268, mRNA, com fete cds.

643 g110433982Homo SapienscDNA FLJ12474 fis, clone1038 100 NT2RM 1000927.

644 AAU00784 Homo SapiensINCY- Human apoptosis 1941 100 protein, APOP-4.

644 g113544020Homo SapiensSimilar to RIKEN cDNA 1941 100 gene, clone MGC:13096 IMAGE:3944994, mRNA, complete cds.

644 112833947 Mus musculusutative 1382 69 Table 2 SEQ ID Accession Species Description Score NO: No.

Identit 645 gi387048 Cricetus DHFR-coamplified protein1037 85 cricetus 645 AAU19758 Homo SapiensHUMA- Human novel extracellular538 100 matrix rotein, Se ID
No 408.

645 AAU21495 Homo SapiensHUMA- Human novel foetal538 100 antigen, SEQ ID NO 1739.

646 gi16565963Homo SapiensSAM-dependent methyltransferase1076 90 gene, exon 11 and complete cds; and SAM-dependent methyltransferase gene, complete cds, alternatively s liced.

646 gi15342055Homo Sapienshypothetical protein 1076 90 MGC2454, clone MGC:4132 IMAGE:2961526, mRNA, com lete cds.

646 gi13278783Homo Sapiensclone MGC:2454 IMAGE:2961526,1076 90 mRNA, com lete cds.

647 AAG03651 Homo SapiensGEST Human secreted protein,199 76 SEQ ID

NO: 7732.

647 gi8927662 Unknown Contains similarity to 84 39 extensin (atExtl) from Arabidopsis thaliana gb~L143627 and is rich 647 gi7294152 DrosophilaCG13048 gene product 83 41 melanogaster 648 AAY12550 Homo SapiensGEST Human 5' EST secreted163 100 protein SEQ ID NO: 215 from WO
9906553.

648 gi9759124 Arabidopsissalt-inducible protein-like66 37 thaliana 648 gi15237345Arabidopsissalt-inducible protein-like66 37 thaliana]
>

[Arabidopsis thaliana 649 11262852 Mus musculusM17 rotein 413 55 649 g113874586Macaca hypothetical protein 150 34 fascicularis 649 g115150696CaenorhabditisHypothetical protein 80 32 Y55BIBR.3 ele ans 650 g112862482Homo SapiensALS2CR3 mRNA for amyotrophic2969 99 lateral sclerosis 2, candidate 3, com lete cds.

650 g112862664Homo SapiensALS2CR3 gene for amyotrophic2963 99 lateral sclerosis 2, candidate 3, exon 16 and com lete cds.

650 AAY92241 Homo SapiensLUDW- Human cancer associated2962 99 anti en recursor (MO-REN-46).

651 g114043592Homo Sapienshypothetical protein 1401 100 FLJ13154, clone MGC:13154 IMAGE:4302289, mRNA, com lete cds.

651 g113623389Homo sapienshypothetical protein 1401 100 FLJ13154, clone MGC:10683 IMAGE:4025993, mRNA, com lete cds.

651 g113325194Homo Sapienshypothetical protein 1401 100 FLJ13154, clone MGC:11014 IMAGE:3641317, mRNA, com fete cds.

Table 2 SEQ ID Accession Species Description Score NO: No.

Identit 652 112841092 Mus musculusutative 1442 90 652 AAB43804 Homo SapiensHUMA- Human cancer associated531 85 rotein se uence SEQ ID
N0:1249.

652 g1466475 Geobacillusputative phospho-beta-glucosidase261 33 stearothermop hilus 653 g116550394Homo SapienscDNA FLJ31056 fis, clone1412 99 HSYRA2000760.

653 g116648324DrosophilaLD29159p 265 42 melano aster 653 g17295644 DrosophilaCG14613 gene product 265 42 melano aster 654 AAY53056 Horno GEMY Human secreted protein479 100 sapiens clone my340_1 protein sequence SEQ ID

N0:118.

655 g17293719 DrosophilaCG14182 gene product 480 51 melano aster 655 g116648454DrosophilaSD01285p 79 22 melano aster 655 g17291881 DrosophilaCG3770 gene product 79 22 melano aster 656 g115146320ArabidopsisAt2g27260/F12K2.16 79 34 thaliana 656 g113272403Arabidopsisunknown protein 79 34 thaliana 656 g13608135 Arabidopsisputative G-box-binding 74 26 bZIP

thaliana transcri tion factor 657 g110439656Homo SapienscDNA: FLJ23082 fis, clone1960 99 LNG06451.

657 AAB95383 Homo SapiensHELI- Human protein sequence1222 100 SEQ

ID N0:17715.

657 g110435167Homo SapienscDNA FLJ13231 fis, clone1222 100 OVARC1000145.

658 g117046389Homo SapiensC21orf70 isoform B protein606 100 (C21orf70) mRNA, complete cds, alternatively s liced.

658 g117046387HomosapiensC21orf70isoformAprotein(C21orf70)606 100 mRNA, complete cds, alternatively s liced.

658 g114424633Homo Sapiensclone MGC:16722 IMAGE:4128732,606 100 mRNA, co lete cds.

659 AA009511 Homo SapiensHYSE- Human polypeptide 98 38 SEQ ID

NO 23403.

659 AA009309 Homo SapiensHYSE- Human polypeptide 92 56 SEQ ID

NO 23201.

659 1220579 Mus musculuso en readin frame ( 196 88 57 AA

660 AAB94146 Homo SapiensHELI- Human protein sequence2585 100 SEQ

m N0:14423.

660 g113325430Homo Sapienshypothetical protein 2585 100 FLJ12584, clone MGC:11212 IMAGE:3929097, mRNA, corn fete cds.

660 g110434160Homo SapienscDNA FLJ12584 fis, clone2585 100 NT2RM4001187.

Table 2 SEQ 1D Accession Species Description Score NO: No.

Identit 661 AAY59708 Homo SapiensGEST Secreted protein 196 95 FL1.

661 AAB43261 Homo SapiensCURA- Human ORFX ORF3025184 97 polypeptide sequence SEQ ID

N0:6050.

661 gi15451283Macaca hypothetical protein 179 97 fascicularis 662 i t 2834045Mus musculusutative 309 57 662 AAM79478 Homo SapiensHYSE- Human protein SEQ 306 52 ID NO

3124.

662 AAM78494 Homo SapiensHYSE- Human protein SEQ 306 52 ID NO

1156.

663 AAB87406 Homo SapiensHUMA- Human gene 32 encoded1862 91 secreted protein HELHN47, SEQ ID

N0:147.

663 AAY86456 Homo SapiensHUMA- Human gene 46-encoded1862 91 rotein fra ment, SEQ
ID N0:371.

663 AAY86260 Homo SapiensHUMA- Human secreted 1862 91 protein HELHN47, SEQ ID N0:175.

664 AAW75222 Homo SapiensHUMA- Human secreted 208 100 protein encoded b ene 27 clone H2MBT68.

664 gi3874864 CaenorhabditisC38C6.4 70 36 ele ans 664 gi7497178 Caenorhabditishypothetical protein 70 36 C38C6.4 -ele ans Caenorhabditis ele ans >

665 gi9929941 Macaca hypothetical protein 486 89 fascicularis 665 AAM99916 Homo SapiensHUMA- Human polypeptide 70 36 SEQ ID

NO 32.

665 gi9929941 Macaca hypothetical protein 486 89 fascicularis 666 gi10438496Homo SapienscDNA: FL722202 fis, clone915 100 HRC01333.

666 11946267 Or za m b 80 31 sativa 666 AAB64815 Homo SapiensHUMA- Human secreted 79 30 protein sequence encoded by gene NO:101.

667 AAG03788 Homo SapiensGEST Human secreted protein,113 34 SEQ ID

NO: 7869.

667 AAM24321 Homo SapiensHYSE- Human EST encoded 107 56 protein SEQ ID NO: 1846.

667 AAY65066 Homo SapiensGEST Human 5' EST related88 50 of a tide SEQ ID N0:1227.

668 g111611585Macaca hypohtetical protein 1798 90 fascicularis 668 g112698180Macaca hypothetical protein 1789 89 fascicularis 668 g113279047Homo Sapiensclone MGC:10761 IMAGE:3606108,1446 100 mRNA, com fete cds.

669 g17417266 Homo Sapienschromosome X map Xp11.234039 99 L-type calcium channel alpha-1 subunit (CACNA1F) gene, complete cds;

HSP27 seudo ene, com fete Table 2 SEQ ID Accession Species Description Score NO: No.

Identit sequence; and JM1 protein, rotein, and Hb2E eves, com lete cds.

669 113559955 Mus musculusDXImx48e rotein 3034 79 669 g1165693 Oryctolagusprotein phosphatase regulatory220 28 subunit cuniculus 670 AAB43283 Homo SapiensCURA- Human ORFX ORF3047715 100 polypeptide sequence SEQ ID

N0:6094.

670 g114250579Homo Sapienshypothetical protein 715 100 PP1628, clone MGC:3072 IMAGE:3346334, mRNA, com lete cds.

670 110441903 Homo sa clone Pl'1628 unknown 715 100 iens mRNA.

671 g115082451Homo Sapiensclone MGC:20253 IMAGE:4647654,1107 98 mRNA, com lete cds.

671 AAB98620 Homo SapiensSHAN- Human vacuolar 1105 98 H~+-ATPase C subunit 42.

671 g113277864Mus musculusSimilar to ATPase, H+ 1016 90 transporting, lysosomal (vacuolar proton pump) 42kD

672 AAB73533 Homo SapiensINCY- Human transferase 150 96 HTFS-40, SEQ ID N0:40.

672 AAM40557 Homo SapiensHYSE- Human polypeptide 150 96 SEQ ID

NO 5488.

672 AAM38771 Homo SapiensHYSE- Human polypeptide 150 96 SEQ ID

NO 1916.

673 AAE 12563 Homo SapiensISIS- Human CITEDX (HCITEDX)994 100 rotein.

673 114495276 Homo sa MRG2 ene, com lete cds. 994 100 iens 673 15002200 Mus musculusmsgl-related rotein 2 712 77 674 g14590448 LeishmaniaL6 ribosomal protein 80 34 braziliensis 674 AAY30681 Homo SapiensGENO- Splice variant 71 60 ZAP-1B protein of the human tumor suppressor gene ZAP-1.

674 AAY30680 Homo SapiensGENO- Splice variant 71 60 ZAP-lA protein of the human tumor suppressor gene ZAP-1.

675 g1995537 Homo SapiensH.sapiens gp70 region 707 100 of endogenous retrovirus erv-4.

675 g1995542 Homo SapiensH.sapiens gp70 region 698 99 of endogenous retrovirus erv-6.

675 g1995529 Homo SapiensH.sapiens gp70 region 690 97 of endogenous retrovirus erv-16.

676 g113816301SulfolobusSecond ORF in transposon86 45 solfataricus 676 g113815862SulfolobusTransposaseISCl234 86 45 solfataricus 676 g11707705 Sulfolobusorf c06026 86 45 solfataricus 677 g16470334 Homo Sapiensprotein translocase, 914 100 ~ JM26 protein, UDP-galactose translocator, pim-2 protooncogene homolog pim-2h, and shal- a otassium channel enes, Table 2 SEQ ID Accession Species Description Score NO: No.

Identit complete cds; JM 12 protein and transcription factor IGHM enhancer 3 genes, partial cds; and unknown gene, com lete se uence.

677 gi3258629 Homo Sapiensinner mitochondria) membrane914 100 translocase Timl7b mRNA, nuclear gene encoding mitochondria) protein, com lete cds.

677 gi3114824 Homo SapiensmRNA for (JM3) preprotein914 100 translocase, complete CDS (clone IMAGE 345224 and LLOXNC01U138D3 (Baylor Colle e)).

678 gi6470334 Homo Sapiensprotein translocase, 852 77 JM26 protein, UDP-galactose translocator, pim-2 protooncogene homolog pim-2h, and shal-type potassium channel genes, complete cds; JM12 protein and transcription factor IGHM enhancer 3 genes, partial cds; and unknown gene, com lete se uence.

678 gi3258629 Homo Sapiensinner mitochondria) membrane852 77 translocase Timl7b mRNA, nuclear gene encoding mitochondria) protein, com lete cds.

678 gi3114824 Homo SapiensmRNA for (JM3) preprotein852 77 translocase, complete CDS (clone IMAGE 345224 and LLOXNCOlU138D3 (Baylor Colle a ).

679 AAB95758 Homo SapiensHELI- Human protein sequence685 100 SEQ

ID N0:18678.

679 gi14042475Homo SapienscDNA FLJ14739 fis, clone685 100 NT2RP3002402.

679 AAG02020 Homo SapiensGEST Human secreted protein,480 98 SEQ ID

NO: 6101.

680 AAY48565 Homo SapiensMETA- Human breast tumour-336 96 associated rotein 26.

680 gi9967248 Maraca hypothetical protein 318 88 fascicularis 680 gi3834384 Homo Sapiensnuclear localization 66 32 signal containing protein deleted in Velo-Cardio-Facial syndrome (Nlvcfj mRNA, complete cds.

681 gi10437387Homo sapienscDNA: FLJ21308 fis, clone2600 99 COL02131.

681 AAG73603 Homo SapiensHUMA- Human colon cancer2016 100 antigen rotein SEQ ID N0:4367.

681 gi6102903 Homo SapiensmRNA; cDNA DKFZp566D244 1492 68 (from clone DKFZ 566D244 ;
artial cds.

682 AA009836 Homo SapiensHYSE- Human polypeptide 265 100 SEQ ID

NO 23728.

682 AAU39010 Homo sa GEMY Human secreted rotein265 100 iens Table 2 SEQ ID Accession Species Description Score NO: No.

Identit bf377 1.

682 gi1695241 CaenorhabditisHypothetical protein 67 43 F20D6.8 ele ans 683 AAG03386 Homo SapiensGEST Human secreted protein,343 98 SEQ ID

NO: 7467.

683 gi16504195Salmonellahypothetical protein 78 28 enterica subsp.

enterica serovar T hi 683 gi 12328592Heterodoxuscytochrome b 66 37 macro us 684 gi14250495Homo SapiensSimilar to RIKEN cDNA 1677 100 gene, clone MGC:9740 IMAGE:3853707, mRNA, complete cds.

684 gi 15489134Homo sapiensRIKEN cDNA 0610006H 10 1159 69 gene, clone MGC:17267 IMAGE:4155233, mRNA, com lete cds.

684 114789807 Mus musculusRIKEN cDNA 0610006H10 1159 69 ene 685 AAG73989 Homo SapiensHUMA- Human colon cancer717 100 antigen rotein SEQ ID N0:4753.

685 AAB58998 Homo SapiensHUMA- Breast and ovarian717 100 cancer associated antigen protein sequence SEQ ID 706.

685 AAM89100 Homo SapiensHUMA- Human 247 61 immune/haematopoietic antigen SEQ

ID N0:16693.

686 AAY04295 Homo SapiensHUMA- Human secreted 478 97 protein encoded b ene 3.

686 1211447 Gallus rece for osine kinase 75 35 allus 686 g11749624 Schizosaccharsimilar to Saccharomyces69 43 cerevisiae omyces hypothetical 48.OKD protein pombe in CDC28-ARL1 intergenic region precursor, SWISS-PROT
Accession Number P38288 687 AAY02726 Homo SapiensHUMA- Human secreted 158 100 protein encoded b ene 77 clone HE2EC79.

688 g19967194 Macaca hypotheticalprotein 269 94 fascicularis 688 g19948233 Pseudomonasprobable MFS transporter69 43 aeru inosa 688 g115026548ClostridiumPredicted membrane protein68 32 acetobutylicu m 689 AAY02923 Homo sapiensHUMA- Fragment of human 235 100 secreted rotein encoded b ene 99.

690 AAG73811 Homo SapiensHUMA- Human colon cancer1099 96 antigen rotein SEQ ID N0:4575.

690 g117028339Homo sapiensclone MGC:10198 IMAGE:3909581,966 99 mRNA, com lete cds.

690 116740631 Mus musculusUnknown rotein for MGC:27606)900 90 691 AAG02438 Homo SapiensGEST Human secreted protein,360 100 SEQ ID

NO: 6519.

Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit 692 116553914Homo sa cDNA FLJ25202 fis, clone2486 87 iens REC05350.

692 g113445910Homo Sapiensradial spoke protein 1771 86 3 (RSP3) mRNA, com lete cds.

692 g116553419Homo SapienscDNA FLJ33093 fis, clone1566 88 TRACH2000675, weakly similar to RADIAL SPOKE PROTEIN
3.

693 116553914Homo sa cDNA FLJ25202 fis, clone2921 99 iens REC05350.

693 g113445910Homo Sapiensradial spoke protein 2144 100 3 (RSP3) mRNA, com lete cds.

693 g113874516Macaca hypothetical protein 1799 94 fascicularis 694 AAY13135 Homo SapiensGEST Human secreted protein355 100 encoded b 5' EST SEQ ID NO: 149.

694 g116420959Salmonellaregulator for XapA (LysR74 35 family) typhimurium 694 g116503639Salmonellaxanthosine operon transcriptional74 35 enterica regulator subsp.

enterica serovar T hi 695 AAG00152 Homo SapiensGEST Human secreted protein,198 100 SEQ ID

NO: 4233.

695 g114022310Mesorhizobiuhypothetical protein 66 46 m loti 696 g14959568Homo Sapiensnuclear pore complex 1742 99 interacting protein NPIP (NPIP) mRNA, complete cds.

696 g12342743Homo SapiensHuman Chromosome 16 BAC 1724 98 clone CIT987SK-A-589H1, complete se uence.

696 AAY10915 Homo SapiensHUMA- Amino acid sequence865 98 of a human secreted a tide.

697 g14959568Homo Sapiensnuclear pore complex 1583 87 interacting protein NPIP (NPIP) mRNA, complete cds.

697 g12342743Homo SapiensHuman Chromosome 16 BAC 1565 87 clone CIT987SK-A-589H1, complete se uence.

697 g13337385Homo SapiensChromosome 16 BAC clone 886 63 CIT987SK-A-761H5, complete se uence.

698 g14959568Homo Sapiensnuclear pore complex 1586 92 interacting protein NPIP (NPIP) mRNA, complete cds.

698 g12342743Homo SapiensHuman Chromosome 16 BAC 1573 91 clone CIT987SK-A-589H1, complete se uence.

698 AAY10915 Homo SapiensHUMA- Amino acid sequence865 98 of a human secreted a tide.

699 g14959568Homo Sapiensnuclear pore complex 1503 88 interacting protein NPIP (NP1P) mRNA, complete cds.

699 12342743 Homo sa Human Chromosome 16 BAC 1485 87 iens clone Table 2 SEQ ID Accession Species Description Score NO: No.

Identit CIT987SK-A-589H1, complete se uence.

699 gi3337385 Homo SapiensChromosome 16 BAC clone 871 68 CIT987SK-A-761H5, complete se uence.

700 gi17389867Homo SapiensSimilar to protein phosphatase572 100 1, regulatory (inhibitor) subunit IA, clone MGC:24041 IMAGE:4288919, mRNA, com fete cds.

700 110198117 Mus musculusrotein hos hatase inhibitor-1226 49 700 g17271433 Rattus protein phosphatase inhibitor-1223 48 norve icus 701 g11710282 Homo SapiensHuman clone 23803 mRNA, 1899 100 partial cds.

701 g115215400Homo Sapienshypothetical protein 458 37 MGC4675, clone MGC:2450 IMAGE:2961135, mRNA, com fete cds.

701 g113278936Homo SapiensSimilar to RIKEN cDNA 458 37 5430432M24 gene, clone MGC:4675 IMAGE:3532660, mRNA, complete cds.

702 AAB93771 Homo SapiensHELI- Human protein sequence1107 100 SEQ

ID N0:13481.

702 g110432902Homo SapienscDNA FLJ11608 fis, clone1107 100 HEMBA 1003976.

702 g16599138 Homo SapiensmRNA; cDNA DKFZp434I036 86 23 (from clone DKFZ 434I036 ;
artial cds.

703 AAW89046 Homo SapiensHUMA- Polypeptide fragment196 100 encoded b ene 182.

703 g12313995 Helicobacterlipid A disaccharide 74 30 synthetase (IpxB) lori 26695 703 gi4I55351 HelicobacterLIPID-A-DISACCHARIDE 68 37 lori J99 SYNTHASE

704 g115930206Homo Sapienshypothetical protein 1583 99 FLJ12806, clone MGC:9516 IMAGE:3903579, mRNA, com lete cds.

704 AAB94314 Homo SapiensHELI- Human protein sequence1576 99 SEQ

ID N0:14787.

704 g110434510Homo SapienscDNA FLJ12806 fis, clone1576 99 NT2RP2002235.

705 AAY64818 Homo SapiensGEST Human 5' EST related429 97 of a tide SEQ ID N0:979.

705 g13913990 MycobacteriuATP-DEPENDENT PROTEASE 66 37 LA >

m sme coatis 705 g1122240 Rattus RT1 CLASS II 66 28 norvegicusHISTOCOMPATIBILITY ANTIGEN, A BETA CHAIN >

706 AAB95004 Homo SapiensHELI- Human protein sequence664 99 SEQ

ID N0:16665.

706 g110433328Homo SapienscDNA FLJ11952 fis, clone664 99 HEMBB1000831, weakly similar to Homo Sapiens breast cancer nuclear rece tor-bindin auxiliar rotein Table 2 SEQ ID Accession Species Description Score NO: No.

Identit (BItX) mRNA.

706 gi10803146Streptomycesputative regulatory protein88 42 coelicolor 707 AAG74480 Homo SapiensHUMA- Human colon cancer2371 99 antigen rotein SEQ ID N0:5244.

707 AAB53417 Homo SapiensHUMA- Human colon cancer2371 99 antigen rotein se uence SEQ ID
N0:957.

707 gi15489153Homo Sapienshypothetical protein 1729 100 FLJ11896, clone MGC:16887 IMAGE:3858181, mRNA, com lete cds.

708 gi12862476Homo sapiensSIMPLE mRNA for small 903 99 integral membrane protein of lysosome/late endosome, com lete cds.

708 i 17391332Mus musculusLPS-induced TNF-al ha 813 86 factor 708 16739573 Mus musculusTBX1 rotein 813 86 709 AAG03860 Homo SapiensGEST Human secreted protein,425 72 SEQ ID

NO: 7941.

709 g1337508 Homo SapiensHuman ribosomal protein 425 72 S25 mRNA, corn lete cds.

709 g113436422Homo Sapiensribosomal protein 525, 425 72 clone MGC:421 I IMAGE:2905996, mRNA, com lete cds.

710 AAB63957 Homo SapiensLUDW- Human prostate 696 100 cancer associated antigen protein sequence SEQ ID NO:1319.

710 g115082563Homo Sapiensclone MGC:20481 IMAGE:4644158,696 100 mRNA, com lete cds.

710 g112804525Homo Sapiensclone IMAGE:2823236, 696 100 mRNA, artial cds.

711 g1 13929452Homo SapiensHuman DNA sequence from 3655 100 clone ItP3-337018 on chromosome 20q12-13.1. Contains the PLPT
gene encoding Phospholipid Transfer Protein, the PPGB gene coding for Lysosomal Protective Protein precursor (EC

3.4.16.5, Cathepsin A, Carboxypeptidase C) and the gene encoding peroxisomal acyl-CoA

thioesterase (PTE1, thioesterase II), four novel genes, the gene for a novel protein similar to Drosophila Neuralized (Neu) and the 5' end of an isoform of the TNNC2 gene for fast troponin C2. Contains three CpG

islands, ESTs, STSs and GSSs, com lete se uence.

71 I g1 16552100Homo SapienscDNA FLJ32079 fis, clone3645 99 OCBBF2000013.

711 AAM70804 Homo SapiensMOLE- Human bone marrow 936 100 expressed probe encoded protein SEQ

ID NO: 31110.

712 AAY60350 Homo SapiensMETA- Human normal bladder247 90 tissue EST encoded rotein 22.

Table 2 SEQ ID Accession Species Description Score NO: No.

Identit 712 gi13883230Mycobacteriuhydrolase, Ama/HipO/I-IyuC65 44 family m tuberculosis 712 gi2894215 MycobacteriuamiB 65 44 m tuberculosis H37Rv '713 AAY94970 Homo SapiensGEMY Human secreted protein523 100 clone dm365_3 protein sequence SEQ ID

N0:146.

713 gi15161741AgrobacteriumAGR~AT_14p 70 41 tumefaciens str. C58 (Cereon) 713 gi17743430Agrobacteriumconserved hypothetical 70 41 protein tumefaciens str. C58 Du ont) 714 AAG93310 Homo sa NISC- Human rotein HP10561.1124 97 iens 714 112858071 Mus musculusutative 819 73 714 112751094 Homo sa PNAS-124 mRNA, com lete 667 99 iens cds.

715 AAM78541 Homo SapiensHYSE- Human protein SEQ 788 86 ID NO

1203.

715 g115080755Homo Sapiensribonuclease P subunit 788 86 (RPP21) mRNA, com lete cds.

715 110439106 Homo sa cDNA: FLJ22638 fis, clone788 86 iens HSI06727.

71b 112849817 Mus musculusutative 679 83 716 AAY57925 Homo SapiensINCY- Human transmembrane670 100 protein HTMPN-49.

716 g14926831 ArabidopsisT17H7.16 111 30 thaliana 717 g19885192 Homo SapiensHuman DNA sequence from 1939 100 clone RPS-881L22 on chromosome Contains ESTs, GSSs, STSs and CpG

islands. Contains a gene for a novel protein similar to a trypsin inhibitor and four other genes for novel proteins, com lete se uence.

717 1 14017764Mus musculusCG 10671-like 348 35 717 114017773 Mus musculusC 10671-like 348 35 718 g17959173 Homo SapiensmRNA for KIAA1456 protein,1942 99 partial cds.

718 g116741666Homo Sapiensclone MGC:16945 IMAGE:3867327,1942 99 mRNA, com fete cds.

718 g17301415 DrosophilaCG8968 gene product 270 59 melano aster 719 AAG75423 Homo SapiensHUMA- Human colon cancer994 98 antigen rotein SE ID N0:6187.

719 AAB53454 Homo SapiensHUMA- Human colon cancer994 98 antigen rotein se uence SEQ ID
N0:994.

719 1 12839939Mus musculusutative 801 92 720 g114582152Xenopus maxi-K potassium channel151 100 alpha laevis subunit Slo 720 15577974 Trachem calcium-activated otassium151 100 s channel Table 2 SEQ ID Accession Species Description Score NO: No.

Identit scri to isoform thc7 720 12072759 Gallus calcium-activated otassium151 100 allus channel 721 AAG03177 Homo SapiensGEST Human secreted protein,244 100 SEQ ID

NO: 7258.

722 AAG78876 Homo sa SHAN- Human zinc fin 1749 100 iens er rotein 36.

722 g112804829Homo Sapiensclone MGC:4707 IMAGE:3534541,1749 100 mRNA, com lete cds.

722 g110438507Homo SapienscDNA: FLJ22210 fis, clone1744 99 HRC01503.

723 AA003397 Homo SapiensHYSE- Human polypeptide 364 89 SEQ ID

NO 17289.

723 g110697002Homo SapiensHuman DNA sequence from 330 84 clone RP11-408E5 on chromosome 13q11-12.2 Contains an FSH
primary respone homolog 1 (FSHPRH1) pseudogene, two genes for novel proteins, a gene for an orthologue of mouse tubulin alpha 3 (TUBA3) or 7 (TUBA7) and a gene for a novel protein sinular to DMPK-like CDC42-binding protein kinase beta (CDC42BPB). Contains ESTs, STSs and GSSs, com lete se uence.

723 AAB42069 Homo SapiensCUBA- Human ORFX ORF1833282 75 polypeptide sequence SEQ ID

N0:3666.

724 g11045612 Human pol polyprotein 242 71 endogenous retrovirus 724 AA003158 Homo SapiensHYSE- Human polypeptide 138 41 SEQ ID

NO 17050.

724 AAM41750 Homo SapiensHYSE- Human polypeptide 134 37 SEQ ID

NO 6681.

725 AAW88411 Homo SapiensUYMA- Acute myeloid leukaemia103 100 nuclear matrix associated protein AML-1 B.

725 g1966999 Homo SapiensHuman AML1 mRNA for AMLIc103 100 protein (alternatively spliced product), com fete cds.

725 g13153104 Homo Sapiens959 kb contig between 103 100 AML1 and CBR1 on chromosome 21q22, segment 3/3.

726 g110437131Homo SapienscDNA: FLJ21106 fis, clone1268 99 CAS05176.

726 g17294550 DrosophilaCG10982 gene product 294 40 melano aster 726 g13875258 Caenorhabditiswaek similarly with bacillus201 46 elegans amyloliquefaciens permease IIBC

(Swiss Prot accession number P41029)~cDNA EST yk573h3.3 comes from this gene~cDNA EST
yk573h3.5 comes from this gene~cDNA
EST

EMBL:AU109975 comes from this ene~cDNA EST EMBL:AU110906 Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit comes from this gene-cDNA
EST

EMBL:AU112278 comes from this gene~cDNA EST EMBL:AU110642 comes from this gene--cDNA
EST

EMBL:AU114810 comes from this gene~cDNA EST EMBL:AU114566 comes from this gene~cDNA
EST

EMBL:AU116117 comes from this gene~cDNA EST EMBL:AUI

comes from this ene 727 AAB97828 Homo SapiensPFIZ Human G protein-coupled195 54 receptor PFI-014 protein sequence SEQ

ID N0:2.

727 AAE06763 Homo SapiensINCY- Human G-protein 174 45 coupled . rece tor-13 (GCREC-13) rotein.

727 gi13384175Homo so FKSG46 166 44 iens 728 AAG02577 Homo SapiensGEST Human secreted protein,263 98 SEQ ID

N0: 6658. ' 728 ABB 12137Homo SapiensHYSE- Human secreted 261 100 protein homolo ue, SEQ ID N0:2507.

728 gi14334860Arabidopsisputative ATP-dependent 78 39 Clp protease thaliana re ulatory subunit CLPX

729 AAG03340 Homo SapiensGEST Human secreted protein,230 97 SEQ ID

NO: 7421.

729 gi15075752SinorhizobiumPROBABLE ADENYLOSUCCINATE64 34 meliloti SYNTHETASE IMP--ASPARTATE

LIGASE PROTEIN

730 AAG02081 Homo SapiensGEST Human secreted protein,565 99 SEQ ID

NO: 6162.

730 AAB65702 Homo SapiensSUGE- Novel protein lcinase,80 26 SEQ ID

NO: 231.

730 115289906Or za sativah othetical rotein 72 29 731 g116549183Homo SapienscDNA FLJ30046 fis, clone1593 100 3NB692001719.

731 ABB 11357Homo SapiensHYSE- Human secreted 1470 93 protein homolo ue, SEQ ID N0:1727.

731 AAG00669 Homo SapiensGEST Human secreted protein,600 100 SEQ ID

NO: 4750.

732 g111611585Macaca hypohtetical protein 2151 90 fascicularis 732 g1 12698180Macaca hypothetical protein 2142 90 fascicularis 732 g113279047Homo Sapiensclone MGC:10761 IMAGE:3606108,1446 100 rnRNA, com lete cds.

733 AAG03184 Homo SapiensGEST Human secreted protein,254 84 SEQ ID

NO: 7265.

734 AAB36365 Homo SapiensASAH Human TRAF6 binding2317 99 protein (T6BP SEQ ID NO:1.

734 g113435951Mus musculusSimilar to TAK1-binding 610 32 protein 2;

KIAA0733 rotein 734 AAG64616 Homo SapiensMATS/ Human TAB2 amino 600 32 acid se uence. r 735 19988100 Homo so Human DNA se uence from 562 100 iens clone Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit RP3-467N11 on chromosome 6q16.1-16.3 Contains part of a gene for a novel protein. Contains GSSs, STSs, ESTs and a C G island, com lete se uence.

735 11322280 Mus musculusunconventional m osin 78 24 VI

735 g112321496Arabidopsishypothetical protein 75 25 thaliana 736 110437991Homo sa cDNA: FLJ21816 fis, clone2205 100 iens HEP01116.

736 g13253105CaenorhabditisHypothetical protein 88 22 B0041.7 ele ans 736 g15901659CaenorhabditisXNP-1 88 22 ele ans 737 AAB36671 Homo SapiensTAKE Human secretory 406 100 protein TGC-715 SEQ ID NO:11.

737 AAU12423 Homo SapiensGETH Human PR01273 polypeptide406 100 se uence.

737 AAM94192 Homo SapiensHUMA- Human reproductive406 100 system related anti en SEQ ID
NO: 2850.

738 112856120Mus musculusutative 781 91 738 g17292255DrosophilaCG16984 gene product 229 33 melano aster 738 1161290 Loligo kinesin heav chain 101 31 ealei 739 g110439252Homo SapienscDNA: FLJ22746 fis, clone1284 99 HUV01174.

739 g116549966Homo SapienscDNA FLJ30707 fis, clone562 41 FCBBF2001211.

739 113376148Homo sa h othetical rotein FLJ227461284 99 iens 740 AAY86331 Homo SapiensHUMA- Human secreted 179 100 protein HLDCE79, SEQ ID N0:246.

741 AAB70489 Homo SapiensSREN- Human hHAIERbs-iso1116 91 protein se uence SEQ ID N0:7.

741 AAM25809 Homo SapiensHYSE- Human protein sequence1116 91 SEQ

ID N0:1324.

741 ABB 11989Homo sapiensHYSE- Human secreted 1116 91 protein homolo ue, SEQ ID N0:2359.

742 AAB70489 Homo SapiensSREN- Human hHAIERbs-iso835 73 protein se uence SEQ ID N0:7.

742 AAM25809 Homo SapiensHYSE- Human protein sequence835 73 SEQ

ID N0:1324.

742 ABB 11989Homo SapiensHYSE- Human secreted 835 73 protein homolo ue, SEQ ID N0:2359.

743 AAG03428 Homo SapiensGEST Human secreted protein,389 98 SEQ ID

N0: 7509.

743 AAY59723 Homo sapiensGEST Secreted protein 389 98 FL1.

743 112852865Mus musculusutative 295 41 744 AAB95034 Homo SapiensHELI- Human protein sequence807 100 SEQ

ID N0:16786.

744 g1 10433444Homo SapienscDNA FLJ 12057 fis, clone807 100 HEMBB 1002068.

744 114715075Mus musculusmitotic arrest deficient85 27 1-like 1 745 AAY13128 Homo SapiensGEST Human secreted protein632 100 encoded by 5' EST SEQ ID NO:
142.

Table 2 SEQ ID Accession Species Description Score NO: No.

Identit 745 112844331 Mus musculusutative 509 91 745 AAM25781 Homo SapiensHYSE- Human protein 411 48 sequence SEQ

ID N0:1296.

746 AAB43357 Homo SapiensCURA- Human ORFX ORF3121652 54 polypeptide sequence SEQ ID

N0:6242.

746 112851679 Mus musculusutative 640 52 746 AAM38640 Homo SapiensHUMA- Human colorectal 615 62 cancer anti en SEQ ID NO: 155.

747 g116552467Homo SapienscDNA FLJ32372 fis, clone1067 100 SALGL 1000005.

747 g115278389Homo SapiensSimilar to hypothetical1067 100 protein, MGC:7036, clone MGC:4797 IMAGE:3544761, mRNA, complete cds.

747 113097090 Mus musculusUnknown ( rotein for 750 73 MGC:7036 748 AAB64418 Homo SapiensINCY- Amino acid sequence248 100 of human intracellular signalling molecule INTRA50.

748 AAM43637 Homo SapiensHUMA- Human polypeptide248 100 SEQ ID

NO 315.

748 AAM43562 Homo SapiensHUMA- Human polypeptide248 100 SEQ ID

NO 240.

749 g117512087Homo Sapiensclone IMAGE:4544931, 733 100 mRNA, artial cds.

749 115488867 Mus musculusRIKEN cDNA 2210010N10 596 77 ene 749 g113905220Mus musculusSimilar to RIKEN cDNA 591 77 ene 750 116553708 Homo sa cDNA FLJ25045 fis, clone580 76 iens CBL03591.

750 AAB65273 Homo SapiensGETH Human PR01287 (UNQ656)152 31 rotein se uence SEQ
ID N0:381.

750 AAB87561 Homo sa GETH Human PR01287. 152 31 iens 751 AAE02443 Homo SapiensCHIL- Human beta-glucuronidase290 77 (GUS).

751 AAW93828 Homo sa CAMB- Human GUS rotein 290 77 iens fra ment.

751 AAR50092 Homo SapiensBEHW Humanised anti-CEA290 77 sFv fragment-human beta-glucuronidase fusion rotein.

752 AAY54593 Homo SapiensINCY- Amino acid sequence2334 100 of a human transferase designated HUTRAN-3.

752 AAB43316 Homo SapiensCURA- Human ORFX ORF30802334 100 polypeptide sequence SEQ ID

N0:6160.

752 15257221 Mus musculusrotein ar mine meth 2289 98 ltransferase 753 AAB43316 Homo SapiensCURA- Human ORFX ORF30802400 100 polypeptide sequence SEQ ID

N0:6160.

753 15257221 Mus musculusrotein ar mine meth 2355 98 ltransferase 753 AAY54593 Homo SapiensINCY- Amino acid sequence2334 100 of a human transferase designated HUTRAN-3.

754 AAG00395 Homo sa GEST Human secreted 268 100 iens rotein, SE ID

Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit NO: 4476.

754 gi14574333CaenorhabditisHypothetical protein 66 30 Y41D4B.21 ele ans 755 AAY10869 Homo SapiensHUMA- Amino acid sequence129 68 of a human secreted rotein.

755 gi1170402Perameles SPERM PROTAMINE P1 > 63 32 unnii 756 AAB95812 Homo SapiensHELI- Human protein sequence1914 100 SEQ

ID N0:18806.

756 gi12652907Homo Sapiensclone MGC:2603 IMAGE:3350471,1914 100 mRNA, com fete cds.

756 gi10436683Homo SapienscDNA FLJ14264 fis, clone1914 100 PLACE 1002004.

757 gi11493710Homo Sapiensp10-binding protein BITE3022 99 (BITE) mRNA, com lete cds.

757 AAB95280 Homo SapiensHELI- Human protein sequence3014 99 SEQ

ID N0:17491.

757 gi10434862Homo sapienscDNA FLJ13036 fis, clone3014 99 NT2RP3001253, weakly similar to NUF 1 PROTEIN.

758 AAB41848 Homo SapiensCURA- Human ORFX ORF1612559 93 polypeptide sequence SEQ ID

N0:3224.

758 gi12861339Mus musculusutative 443 74 758 AAY36414 Homo SapiensHUMA- Fragment ofhuman 442 93 secreted rotein encoded b ene 7.

759 14128039 Homo sa mRNA for TL132. 994 99 iens 759 AAM38692 Homo SapiensHYSE- Human polypeptide 887 95 SEQ ID

NO 1837.

759 AAM38691 Homo SapiensHYSE- Human polypeptide 887 95 SEQ ID

NO 1836.

760 g112320889ArabidopsisATP-dependent DNA helicase69 35 RecQ, thaliana utative 760 g1 17426897Arabidopsishelicase 69 35 thaliana 760 AAM92379 Homo SapiensHUMA- Human digestive 68 43 system anti en SEQ ID NO: 1728.

761 AAB31473 Homo SapiensZYMO Amino acid sequence924 100 of a human helical cytokine designated Zal ha33.

761 AAG93271 Homo sa NISC- Human rotein HP10431.924 100 iens 761 g114198326Homo SapiensSimilar to RIKEN cDNA 924 100 gene, clone MGC:9890 IMAGE:3868437, mRNA, complete cds.

762 g19790624Homo Sapienstestis-specific kinase 3062 100 substrate (TSKS) ene, co lete cdS.

762 111068125Mus musculustestis s ecific serine 2084 81 kinase substrate 762 AAM95529 Homo SapiensHUMA- Human reproductive785 85 system related anti en SEQ ID
NO: 4187.

763 16502963 Mus musculusKX anti en 944 43 763 112841470Mus musculusutative 944_ 43 763 14883433 Homo sa mRNA for membrane traps 930 44 iens ort rotein Table 2 SEQ ID Accession Species Description Score NO: No.

Identit XK ene).

764 AAB95836 Homo SapiensHELI- Human protein sequence6026 99 SEQ

ID N0:18865.

764 g110436735Homo SapienscDNA FLJ14303 fis, clone6026 99 PLACE2000132.

764 114971110 Homo sa mucin 16 (MUC16) mRNA, 6023 99 iens artial cds.

765 g16807698 Homo SapiensmRNA; cDNA DKFZp434A1014308 48 (from clone DKFZp434A1014);
partial cds.

765 AAM77697 Homo SapiensMOLE- Human bone marrow 278 74 expressed probe encoded protein SEQ

ID NO: 38003.

765 AAM64969 Homo SapiensMOLE- Human brain expressed278 74 single exon probe encoded protein SEQ ID

NO: 37074.

766 AAB95310 Homo SapiensHELI- Human protein sequence551 100 SEQ

ID N0:17554.

766 114794914 Mus musculusca icua rotein 101 32 766 112836037 Mus musculusutative 101 32 767 g14309887 Homo SapiensPAC clone ltPS-1163J12 1047 99 from 7q21.2- s 31.1, com lete se uence.

767 AAM73703 Homo sapiensMOLE- Human bone marrow 136 100 expressed probe encoded protein SEQ

ID NO: 34009.

767 AAM61008 Homo sapiensMOLE- Human brain expressed136 100 single exon probe encoded protein SEQ ID

NO: 33113.

768 12664295 Homo sa H.sa iens MDR3 ene, exonl,141 100 iens exon2.

768 g1307181 Homo SapiensHuman membrane glycoprotein136 100 P

(mdr3 mRlVA, com lete cds.

768 g11006663 Homo SapiensH.sapiens mRNA for MDR3 136 100 P-1 co rotein.

769 112854186 Mus musculusutative 1703 88 769 g15596697 Homo SapiensNovel human gene mapping818 49 to chomosome 22.

769 g14493522 Homo SapiensHuman DNA sequence from 818 49 clone RP3-323M22 on chromosome Contains the 5' part of the PACSIN2 (protein kinase C and casein kinase substrate in neurons 2) gene and a novel gene coding for a protein similar to KIAA0173 and worm tubulin tyrosine ligase, genomic marker D22S418, CA repeat, ESTS, STSs, GSSs and putative CpG
islands, com fete se uence.

770 AAB94472 Homo SapiensHELI- Human protein sequence1284 100 SEQ

ID N0:15137.

770 g110434955Homo SapienscDNA FLJ13096 fis, clone1284 100 NT2RP3002166.

770 AAM66773 Homo SapiensMOLE- Human bone marrow 258 100 expressed probe encoded protein SEQ

ID NO: 27079.

Table 2 SEQ ID Accession Species Description Score NO: No.

Identit 771 AAB93902 Homo SapiensHELI- Human protein sequence892 95 SEQ

ID N0:13857.

771 gi10433555Homo SapienscDNA FLJI2147 fis, clone892 95 MAMMA 1000410.

771 AAG03840 Homo SapiensGEST Human secreted protein,89 56 SEQ ID

NO: 7921.

772 gi13325313Homo SapiensSimilar to RIKEN cDNA 678 100 gene, clone MGC:10325 IMAGE:3936182, mltNA, complete cds.

772 AAG74090 Homo SapiensHUMA- Human colon cancer500 97 antigen rotein SE ID N0:4854.

772 112837136 Mus musculusutative 487 75 773 AAB68986 Homo SapiensUYJO Human polyamine-modulated832 98 factor-I PMF-1.

773 g15737759 Homo Sapienspolyamine modulated factor-1832 98 (PMF1) mRNA, com lete cds.

773 g15737757 Homo Sapienspolyamine modulated factor-1832 98 (PMF1) gene, exons 2 through 5 and complete cds.

774 g110440444Homo SapiensmRNA for FLJ00058 protein,696 100 partial cds.

774 g1882260 Homo SapiensNuman chromatin assembly86 28 factor-I

60 subunit mRNA, com lete cds.

774 g17768767 Homo Sapiensgenomic DNA, chromosome 86 28 21q, section 69/105.

775 g110437174Homo SapienscDNA: FLJ21135 fis, clone1236 99 CAS07262.

775 AA001368 Homo SapiensHYSE- Human polypeptide 158 46 SEQ ID

NO 15260.

775 g110645308LeishmaniaL8453.1 101 27 ma'or 776 AAB87431 Homo SapiensHUMA- Human gene 14 encoded883 100 secreted protein fragment, SEQ ID

N0:172.

776 AAB87398 Homo SapiensHUMA- Human gene 14 encoded640 100 secreted protein HTEAM34, SEQ ID

N0:139.

776 AAB87355 Homo SapiensHUMA- Human gene 14 encoded640 100 secreted protein HTEAM34, SEQ ID

N0:96-777 g113374939Homo sapiensHuman DNA sequence from 371 100 clone RPI1-204H22 on chromosome 20.

Contains part of a novel gene, ESTs, STSs and GSSs, com lete se uence.

777 112843034 Mus musculusutative 362 85 777 AAG02702 Homo SapiensGEST Human secreted protein,278 98 SEQ ID

NO: 6783.

778 AAG02713 Horno GEST Human secreted protein,299 100 Sapiens SEQ ID

NO: 6794.

778 g16563166 QuiscalusNADH dehydrogenase subunit68 38 1u ubris 778 AAW57056 Homo sa CHIL- Class II trans 66 44 iens activator CIITA) Table 2 SEQ ID Accession Species Description Score NO: No.

Identity of a tide.

779 AAY13108 Homo SapiensGEST Human secreted 237 100 protein encoded b 5' EST SEQ ID NO:
122.

780 gi14124974Homo SapiensSimilar to CG12113 gene4048 100 product, clone IMAGE:3532726, mRNA, partial cds.

780 gi14602672Homo SapiensSinular to CG12113 gene2702 100 product, clone IMAGE:3928539, mRNA, partial cds.

780 gi14603034Homo Sapiensclone MGC:16733 IMAGE:4129693,2557 100 mRNA, co lete cds.

781 gi17223622Homo SapiensATP-binding cassette 721 100 A6 mRNA, com lete cds.

781 AAY57954 Homo SapiensINCY- Human transmembrane541 100 protein HTMPN-78.

781 AAM25936 Homo SapiensHYSE- Human protein 484 100 sequence SEQ

ID N0:1451.

782 gi8979818 Homo SapiensHuman DNA sequence from954 100 clone RP3-447E21 on chromosome 6p12.1-21.1 Contains the 5' end of gene similar to bovine chloride channel protein (p64), a fragment similar to X.laevis Xrel2 protein, a fragment similar to Myelin-associated oligodendrocytic basic protein (MOBP-81), a novel pseudogene, a CpG island, ESTs, STSs and GSSs, com lete se uence.

782 114031047 Homo sa CLICSB mRNA, com lete 954 100 iens cds.

782 14588530 Bos tauruschloride channel rotein398 46 783 AAY72161 Homo SapiensBAUG/ Human RNA metabolism829 100 rotein (RMEP-1 .

783 14680653 Homo sa CGI-07 rotein mRNA, 829 100 iens com lete cds.

783 g115426434Homo SapiensCGI-07 protein, clone 829 100 MGC:13335 IMAGE:4291797, mRNA, complete cds.

784 g17298468 DrosophilaCG15164 gene product 413 35 melano aster 784 g114026730Mesorhizobiuhomoserine kinase 359 28 m loti 784 g115075719SinorhizobiumPUTATIVE AMINOTRANSFERASE300 27 meliIoti PROTEIN

785 AAM65753 Homo SapiensMOLE- Human bone marrow661 100 expressed probe encoded protein SEQ

ID NO: 26059.

785 AAM53375 Homo SapiensMOLE- Human brain expressed661 100 single exon probe encoded protein SEQ ID

NO: 25480.

785 113879308 Mus musculuscentromere autoanti 368 30 en B

786 AAY11439 Homo SapiensGEST Human 5' EST secreted163 100 protein SEQ ID No 261.

787 g19967303 Macaca hypothetical protein 297 96 fascicularis 787 AAM55988 Homo sa MOLE- Human brain ex 184 100 iens ressed single Table 2 SEQ ID Accession ~ SpeciesDescription Score NO: No.

Identit exon probe encoded protein SEQ ID

NO: 28093.

787 gi7379384 Neisseriaputative pilus assembly 68 36 protein meningitidis 788 gi15080333Homo Sapiensclone MGC:20510 IMAGE:4542472,1380 100 mRNA, com fete cds.

788 AAB41490 Homo SapiensCURA- Human ORFX ORF 1267 81 polypeptide sequence SEQ ID

N0:2508.

788 gi12698051Homo SapiensmRNA for KIAA1753 protein,1227 73 partial cds.

789 AAY00277 Homo SapiensHUMA- Human secreted 165 100 protein encoded b ene 20.

789 AAB08450 Homo SapiensCOMP- A human kallikrein-275 30 (KLK-2) s lice variant of a tide.

789 gi14574289CaenorhabditisHypothetical protein 72 58 Y37E11C.1 ele ans 790 gi16550493Homo SapienscDNA FLJ31139 fis, clone1281 99 IMR322001185.

790 gi3876588 Caenorhabditispredicted using Genefinder~cDNA239 33 elegans EST yk185a11.3 comes from this gene~cDNA EST yk185a11.5 comes from this gene~cDNA EST
yk223d12.5 comes from this gene--cDNA
EST

yk266b2.5 comes from this gene--cDNA EST yk460f10.5 comes from this gene~cDNA EST
yk643b12.3 comes from this gene-cDNA
EST

yk504b3.5 comes from this gene--cDNA EST yk627c11.5 comes from this gene~cDNA EST
yk643b12.5 comes from this gene~cDNA
EST

k681b10.3 comes from this ene 790 gi3880607 CaenorhabditiscDNA EST yk443f7.5 comes109 37 from this ele ans ene 791 gi9837427 Lytechinusembryonic blastocoelar 271 44 extracellular varie matrix rotein recursor atus 791 gi17135842Nostoc ORF_ID:alr7304--similar 121 31 sp. to hlyA

791 gi4566524 Rattus Na+/Ca2+-exchanging protein120 32 norve recursor icus 792 gi14250766Homo Sapienshypothetical protein 2119 100 FLJ21959, clone MGC:14921 IMAGE:4100186, mRNA, com lete cds.

792 110438183 Homo sa cDNA: FLJ21959 fis, clone2119 100 iens HEP05511.

792 AAY36034 Homo SapiensGEST Extended human secreted1659 97 rotein se uence, SEQ
ID NO. 419.

793 AAB82316 Homo SapiensUYCO Human immunoglobulin491 100 rece for IRTA3 rotein.

793 g116033594Homo SapiensSH2 domain-containing 491 100 phosphatase anchor protein 2c mRNA, complete cds, alternativel s liced.

Table 2 SEQ ID Accession Species Description Score NO: No.

Identit 793 gi16033591Homo SapiensSH2 domain-containing 491 100 phosphatase anchor protein 2b mRNA, complete cds, altemativel s liced.

794 AAG66841 Homo sa SHAN- Human dih droorotase710 99 iens 40.

794 gi12052764Homo SapiensmRNA; cDNA DKFZp56400523703 98 (from clone DKFZp56400523);

com fete cds.

794 ABB 12204 Homo SapiensHYSE- Human HSPC304 homologue,698 98 SEQ ID N0:2574.

795 AAU12298 Homo SapiensGETH Human PR09820 polypeptide874 98 se uence.

795 AAH23959_asHomo SapiensKYOW Human Klotho cDNA, 460 52 SEQ ID

1 NO:S.

795 AAB73618 Homo SapiensKYOW Human Klotho protein460 52 encoded b SEQ ID N0:5.

796 AAU12298 Homo SapiensGETH Human PR09820 polypeptide169 100 se uence.

796 AAB29903 Homo SapiensHUMA- Human secreted 83 40 protein BLAST search protein SEQ ID NO:

161.

796 gi1777770 Cavia cytosolic beta-glucosidase83 40 orcellus 797 AAY13002 Homo SapiensGEST Human secreted protein222 100 encoded b 5' EST SEQ ID NO: 16.

798 AAB65161 Homo SapiensGETH Human PR0203 (UNQ177)1901 100 rotein se uence SEQ ID
N0:30.

798 AAY66638 Homo SapiensGETH Membrane-bound protein1901 100 PR0203.

798 AAB 19407 Homo SapiensCHIR Amino acid sequence1896 99 of a human secreted rotein.

799 gi16306705Homo Sapiensclone MGC:3298 IMAGE:3508400,962 100 mRNA, com lete cds.

799 AAY58614 Homo SapiensINCY- Protein regulating571 69 gene ex ression PRGE-7.

799 AAM42020 Homo SapiensHYSE- Human polypeptide 87 28 SEQ ID

NO 6951.

800 AAY48414 Homo SapiensMETA- Human prostate 191 100 cancer-associated rotein I 11.

800 gi7293155 DrosophilaCG8916 gene product 68 27 melano aster 801 AAG02085 Homo SapiensGEST Human secreted protein,271 100 SEQ ID

NO: 6166.

801 gi16421767SalmonellaDNA biosynthesis; DNA 67 34 primase typhimurium 801 gi16504287SalmonellaDNA primase 67 34 enterica subsp.

enterica serovar T hi 802 AAB93911 Homo SapiensHELI- Human protein sequence335 97 SEQ

ID N0:13877.

802 AAM91037 Homo sapiensHUMA- Human 335 97 immune/haemato oietic anti en SEQ

Table 2 SEQ ID Accession Species Description Score NO: No.

Identit ID N0:18630.

802 AAGO1S19 Homo SapiensGEST Human secreted protein,335 97 SEQ ID

NO: 5600.

803 110438284 Homo sa cDNA: FLJ22032 fis, clone1485 99 tens HEP08743.

803 g114017927Homo sapiensmRNA for KIAA1855 protein,1214 93 partial cds.

803 g14589614 Homo SapiensmRNA for KIAA0985 protein,140 31 com lete cds.

804 AAG00145 Homo SapiensGEST Human secreted protein,225 95 SEQ ID

NO: 4226.

804 AAY07867 Homo SapiensHUMA- Human secreted 225 95 protein fra ment encoded from ene 16.

804 AAW71684 Homo SapiensINCY- Amino acid sequence22S 95 of the human tumourigenesis associated rotein.

805 AAB41200 Homo SapiensCURA- Human ORFX ORF964 694 99 polypeptide sequence SEQ ID

N0:1928.

805 112855307 Mus musculusutative 377 91 805 AAG02108 Homo SapiensGEST Human secreted protein,333 57 SEQ ID

NO: 6189.

806 AAG02252 Homo SapiensGEST Human secreted protein,330 98 SEQ ID

NO: 6333.

806 g16730714 ArabidopsisUnknown protein 68 38 thaliana 806 g15729893 Homo Sapiens]A kinase (PRKA) anchor 63 47 protein 6; A-> [Homo kinase anchor protein sa tens 807 AAB93899 Homo SapiensHELI- Human protein sequence3873 99 SEQ

ID N0:13848.

807 g114042001Homo SapienscDNA FLJ14464 fis, clone3873 99 MAMMA 1000309.

807 g117512096Homo SapiensSimilar to hypothetical 2081 100 protein FLJ14464, clone IMAGE:4554168, mRNA, artial cds.

808 g112654201Homo Sapiensclone IMAGE:3449838, 621 100 mRNA, artial cds.

808 g117068388Homo SapiensSimilar to hypothetical 609 99 protein FLJ1477S, clone MGC:24018 IMAGE:4105917, mRNA, complete cds.

808 AAG01516 Homo SapiensGEST Human secreted protein,446 98 SEQ ID

NO: 5597.

809 AAB58340 Homo SapiensROSE/ Lung cancer associated942 100 of a tide se uence SE
ID 678.

809 ABB 11637 Homo SapiensHYSE- Human secreted 600 100 protein homolo ue, SEQ ID N0:2007.

809 g116878257Homo Sapiensclone MGC:29726 IMAGE:4547604,477 52 mRNA, com fete cds.

810 ABB 11722 Homo Sapienssegment homologue, 382 59 HYSE- Human V

_ SEQ ID N0:2092 810 g11199646 Homo SapiensHuman T cell receptor 330 57 ~ ~ beta chain ~ ~

(TCRB) mRNA, VDJ region, partial Table 2 SEQ ID Accession Species Description Score NO: No.

Identit cds.

810 gi1864067 CallithrixT-cell receptor beta 328 56 chain ~acchus 811 gi10437049Homo SapienscDNA: FLJ21047 fis, clone797 98 CAS00253.

811 gi13880570Mycobacteriuconserved hypothetical 79 35 protein m tuberculosis 811 gi3261634 Mycobacteriuhypothetical protein 79 35 Rv0976c m tuberculosis H37Rv 812 112838791 Mus musculusutative 566 76 812 AAG01260 Homo SapiensGEST Human secreted protein,338 65 SEQ ID

NO: 5341.

812 g17297946 DrosophilaCG5435 gene product 96 25 melano aster 813 AAB43507 Homo SapiensHUMA- Human cancer associated1378 98 rotein se uence SEQ ID
N0:952.

813 g14205084 Homo SapiensHuman WW domain binding 1378 98 protein-1 mRNA, com fete cds.

813 g114603081Homo SapiensSimilar to WW domain 1378 98 binding protein 1, clone MGC:15305 IMAGE:4309279, mRNA, complete cds.

814 g115020649Homo SapiensmRNA for hypothetical 1854 100 protein and STS SHGC-2390.

814 110439232 Homo sa cDNA: FLJ22729 fis, clone793 100 iens HSI15685.

814 g114290514Homo Sapienshypothetical protein 789 99 FLJ22729, clone MGC:16790 IMAGE:4184795, mRNA, com fete cds.

815 AAY41454 Homo SapiensHUMA- Fragment of human 232 93 secreted rotein encoded b ene 30.

815 g13758843 Plasmodiumhypothetical protein, 71 26 PFC0820w falci arum 815 g115025672ClostridiumCarbamoylphosphate synthase67 33 Large acetobutylicusubunit , m 816 AAG03514 Homo SapiensGEST Human secreted protein,189 97 SEQ ID

NO: 7595.

816 g1190508 Homo SapiensHuman PRB4 locus salivary80 30 proline-rich rotein mRNA, co lete cds.

816 g115196112human, PRB4 (PRB4M PO-)=~arotid'o'80 30 peripheralprotein {exon 3}

blood leukocytes, subject 'J.J.', Genomic Mutant, nt]. [Homo sa iens 817 AAY65007 Homo SapiensGEST Human 5' EST related300 100 of a tide SEQ ID NO:
I 168.

817 AAG03529 Homo SapiensGEST Human secreted protein,300 ~ 100 SEQ ID

Table 2 SEQ ID Accession Species Description Score NO: No.

Identit NO: 7610.

817 g11932727 Homo SapiensHuman armadillo repeat 64 59 protein mRNA, com fete cds.

818 AAG01406 Homo SapiensGEST Human secreted protein,397 100 SEQ ID

NO: 5487.

818 g112804657Homo sapiensclone IMAGE:3354845, 397 100 mRNA, artial cds.

818 112841742 Mus musculusutative 320 76 819 g110440259Homo SapienscDNA: FLJ23537 fis, clone1045 100 LNG07690.

819 g148491 Vibrio tryptophan synthase; 74 35 alpha suburut parahaemolyti cus 819 g115155988AgrobacteriumAGR_C_1792p 72 23 tumefaciens str. C58 (Cereon 820 g110439767Homo SapienscDNA: FLJ23168 fis, clone1679 99 LNG09905.

820 g13193250 CaenorhabditisHypothetical protein 122 23 ZK1055.1 ele ans 820 g115290033Oryza putative myosin heavy 121 23 sativa chain-like rotein 821 AAB95117 Homo SapiensHELI- Human protein sequence1515 100 SEQ

ID N0:17106.

821 g110434031Homo SapienscDNA FLJ12505 fis, clone1515 100 NT2RM2001699.

821 g16056365 Homo Sapienschromosome 14 clone 99E15857 57 containing gene for KIAA
1036, com lete CDS, com lete se uence.

822 ABB44606 Homo SapiensSWIT- Human wound healing989 100 related of a tide SEQ ID NO 89.

822 ABB44607 Homo SapiensSWIT- Human wound healing876 91 related of a tide SEQ ID NO 90, 822 ABB44596 Homo SapiensSWIT- Human wound healing747 100 related of a tide SEQ ID NO 55, 823 AAB94920 Homo SapiensHELI- Human protein sequence760 100 SEQ

ID N0:16368.

823 g110432815Homo sapienscDNA FLJ11539 fis, clone760 100 HEMBA1002748.

823 g111071808Leishmaniahypothetical protein 96 31 P214.45 ma'or 824 AAE03641 Homo SapiensINCY- Human extracellular1599 100 matrix and cell adhesion molecule-5 (XMAD-5 .

824 g115559374Homo Sapiensclone IMAGE:3628973, 1599 100 mRNA, artial cds.

824 AAW54090 Homo sa TEXA Homo sa iens BE123 1340 99 iens se uence.

825 AAB85771 Homo SapiensINCY- Human drug metabolizing1587 100 enz a ID No. 3861612CD1 .

825 g116877032Homo Sapiensclone MGC:24011 IMAGE:4091916,1573 98 mRNA, com lete cds.

825 AAB73512 Homo Sapiens1NCY- Human transferase 773 50 HTFS-19, SE ID N0:19.

Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit 826 AAY08477 Homo SapiensABBO Human BS274 protein181 100 epitope 3.

826 AAY08476 Homo SapiensABBO Human BS274 protein102 100 epitope 2.

826 AAY08478 Homo SapiensABBO Human BS274 protein97 100 epitope 4.

827 12231329 Ovis ariesbactinecin 1 I 89 37 827 g13044086Myxococcusunknown 89 35 xanthus 827 AAY41496 Homo SapiensHUMA- Fragment of human 88 37 secreted rotein encoded b ene 70.

828 g111093911Homo SapiensBcl-2 related proline-rich1158 100 protein (BCL2L12) gene, complete cds, alternativel s liced.

828 g114043469Homo SapiensSimilar to RIKEN cDNA 1150 99 5430429M05 gene, clone MGC:13155 IMAGE:4302950, mRNA, complete cds.

828 AAW38358 Homo SapiensAPOP- Apoptosis associated1141 99 protein Bbk.

829 g11054887Homo SapiensHuman HMGI-C chimeric 239 68 transcript mRNA, artial cds.

829 AAG02793 Homo SapiensGEST Human secreted protein,197 77 SEQ ID

NO: 6874.

829 AAG74844 Homo SapiensHUMA- Human colon cancer146 59 antigen rotein SEQ ID N0:5608.

830 g115341178Homo Sapienslymphocyte alpha-kinase 472 100 (LAK) mRNA, com lete cds.

830 AAB56768 Homo SapiensROSE/ Human prostate 465 98 cancer antigen rotein se uence SEQ ID
N0:1346.

830 112858085Mus musculusutative 412 85 831 g110436233Homo SapienscDNA FLJ13936 fis, clone2754 100 Y79AA1000802.

831 AAB95616 Homo SapiensHELI- Human protein sequence2747 100 SEQ

ID N0:18326.

831 AA005842 Homo SapiensHYSE- Human polypeptide 687 97 SEQ ID

NO 19734.

832 g115426492Homo Sapienshypothetical protein 1029 93 FLJ21657, clone MGC:14939 IMAGE:3621124, mRNA, com fete cds.

832 g110437800Homo sapienscDNA: FLJ21657 fis, clone1025 93 COL08663.

832 g17292406DrosophilaCG10866 gene product 263 35 melano aster 833 AAY66151 Homo sapiensMETA- Human bladder tumour412 98 EST

encoded rotein 9.

833 g16690682RhodobacterOrf173 84 36 s haeroides 833 g1 14023427Mesorhizobiumaltose-binding protein 78 35 component of m loti ABC su ar trans orter 834 AAM25486 Homo SapiensHYSE- Human protein sequence765 100 SEQ

ID NO:1001.

834 AAV43605 Homo sa CHIR Human secreted rotein352 39 as iens 5 Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit 1 encodin DNA.

834 AAY03241 Homo SapiensSAGA Clone HP10484 of 352 39 a human secreto s1 nal rotein (2).

835 AAB36599 Homo SapiensINCY- Human FLEXHT-21 1332 100 protein se uence SEQ ID N0:21.

835 14929699 Homo sa CGI-115 rotein mRNA, 1332 100 iens com fete cds.

835 112846260Mus musculusutative 1018 74 836 AAY10855 Homo SapiensHUMA- Amino acid sequence185 100 of a human secreted rotein.

837 g1975846 Bos taurusimmunoglobulin lambda 74 33 light chain variable re ion 837 g13411264Emericellahomeodomain DNA-binding 70 58 nidulans transcri tion factor 837 g17299135DrosophilaMst85C gene product 69 33 melano aster 838 g19948733Pseudomonasconserved hypothetical 75 40 protein aeru inosa 838 AAB34864 Homo SapiensHUMA- Human secreted 71 38 protein sequence encoded by gene N0:68.

838 g16562167Homo SapiensmRNA; cDNA DKFZp564M191671 33 (from clone DKFZp564M1916);
partial cds.

839 g110437026Homo SapienscDNA: FLJ21031 fis, clone663 98 CAE07336.

839 g17188828Gibberellahistone H3 75 39 circinata 839 g15106126Aeropyrum 172aa long hypothetical 75 40 protein ernix 840 g110439719Homo SapienscDNA: FLJ23132 fis, clone2269 100 LNG08559.

840 g114017917Homo SapiensmRNA for KIAA 1850 protein,2256 99 partial cds.

840 g113365945Macaca hypothetical protein 2093 93 fascicularis 841 AAY21589 Homo SapiensGEMY Human secreted protein470 100 (clone BV278-2 .

841 AAW52984 Homo SapiensGEMY Homo Sapiens clone 420 100 BV278~2 rotein.

841 AAG03462 Homo SapiensGEST Human secreted protein,383 98 SEQ ID

N0: 7543.

842 116588712Homo sa P33 mRNA, com fete cds. 1284 94 iens 842 g114334374Homo Sapiensleucine zipper protein 1284 94 AFSalpha mRNA, com fete cds.

842 g114250169Homo SapiensSimilar to leucine zipper1284 94 protein FKSG14, clone MGC:14847 IMAGE:3511065, mRNA, complete cds.

843 AAB95308 Homo SapiensHELI- Human protein sequence1366 99 SEQ

ID N0:17550.

843 g110434984Homo SapienscDNA FLJ13114 fis, clone1366 99 NT21tP3002603.

843 AAB40721 Homo SapiensCUBA- Human ORFX ORF485 ~ 1286~ 98 Table 2 SEQ ID Accession Species Description Score NO: No.

Identit of a tide se uence SEQ
ID N0:970.

844 112839493 Mus musculusutative 714 68 844 AAG01527 Homo SapiensGEST Human secreted protein,666 98 SEQ ID

NO: 5608.

844 g12950243 Hordeum extensin 77 31 vul are 845 g110798772Homo SapiensmRNA for p53AIPlgamma, 579 100 complete cds.

845 110798770 Homo sa mRNA for 53AIPlbeta, 257 100 iens com fete cds.

845 110798768 Homo sa mRNA for 53AIP1, com 257 100 iens lete cds.

846 AAB73675 Homo SapiensINCY- Human oxidoreductase620 100 protein ORP-8.

846 112841928 Mus musculusutative 536 84 846 g115421813Salmonellaputative protein 350 54 enteritidis 847 AAB95773 Homo SapiensHELI- Human protein sequence1180 83 SEQ

ID N0:18713.

847 g110436616Homo SapienscDNA FLJ14213 fis, clone1180 83 NT2RP3003572.

847 g1 14286252Homo SapiensSimilar to hypothetical 681 100 protein FLJ 14213, clone MGC:16218 IMAGE:3659247, mRNA, complete cds.

848 g116552616Homo SapienscDNA FLJ32480 fis, clone2291 99 SKNMC2001057.

848 g113278954. Homo clone IMAGE:3543931, 1246 100 sapiens mRNA, artial cds.

848 AAB94905 Homo SapiensHELI- Human protein sequenceI 155 99 SEQ

ID N0.16300.

849 AAB48789 Homo SapiensHOSP- Human prostate 73 42 cancer-redis osin rotein, CA7 CG04.

849 AAM40386 Homo SapiensHYSE- Human polypeptide 73 42 SEQ ID

NO 3531.

849 g110862762Homo SapiensHuman DNA sequence from 73 42 clone RP4-595C2 on chromosome 1q24.1-25.3 Contains ESTs, STSs and GSSs.

Contains the 3' part of the gene for two isoforms of the KIAA0351 protein and the gene for angiopoietin Yl, complete se uence.

850 g112248877Oryctolagusmitsugumin72/junctophilin2009 92 typel cuniculus 850 19927301 Mus musculus'uncto hilin t a 1 1971 91 850 _ g19886738 Homo SapiensJP3 mRNA for junctophilin1475 67 type3, com lete cds.

851 g110334802Homo Sapiensfanconi anemia protein 2735 100 E (FANCE) mRNA, com fete cds.

851 112850619 Mus musculusutative 339 50 851 g15929884 Rattus nucleolin-related protein103 24 NRP

norve icus 852 AAY59931 Homo SapiensMETA- Human myometrium 398 98 tumour EST encoded rotein 11.

852 AAY59934 Homo sa META- Human m ometrium 215 70 iens tumour Table 2 SE(~ ID Accession Species Description Score NO: No.

Identit EST encoded rotein 14.

852 AAY59933 Homo SapiensMETA- Human myometrium 193 94 tumour EST encoded rotein 13.

853 AAY66147 Homo SapiensMETA- Human bladder tumour365 98 EST

encoded rotein 5.

853 112833738 Mus musculusutative 71 52 853 g13293036 PseudomonasxcpY 64 24 utida 854 g110437476Homo SapienscDNA: FLJ21386 fis, clone1645 100 COL03414.

854 g117028379Homo SapiensSimilar to hypothetical 1537 98 protein FLJ22792, clone MGC:22933 IMAGE:4905554, mRNA, complete cds.

854 g1791119 Saccharomyceunknown 81 26 s cerevisiae 855 AAG62621 Homo sa BIOR- Human SNARE rotein1101 100 iens 25.

855 g19719422 Rattus SNARE Vtila-beta protein1062 96 norve icus 855 g19719420 Rattus SNARE Vtila protein 1012 93 norve icus 856 AAB39312 Homo sapiensHUMA- Human secreted 315 98 protein sequence encoded by gene N0:61.

856 AAW88596 Homo SapiensHUMA- Secreted protein 307 96 encoded by ene 63 clone HFEBA88.

857 AAU 14106 Homo SapiensTRIM- Peptide sequence 243 100 from human c-fos roto-onco rotein.

857 AAR53646 Homo sa VEDA c-fos gene roduct. 243 100 iens 857 g16518629 Homo Sapiensgene for cellular oncogene243 100 c-fos, partial cds.

858 110798770 Homo sa mRNA for 53AIPlbeta, 449 100 iens com fete cds.

858 110798768 Homo sa mRNA for 53AIP1, com 440 100 iens lete cds.

858 g110798772Homo SapiensmRNA for p53AIPlgamma, 257 100 complete cds.

859 g117511697Homo Sapienshypothetical protein 901 100 FLJ14950, clone MGC:31757 IMAGE:5013235, mRNA, com fete cds.

859 AAB95526 Homo SapiensHELI- Human protein sequence897 99 SEQ

ID N0:18113.

859 g114042838Homo SapienscDNA FLJ14950 fis, clone897 99 PLACE2000371, weakly similar to TENSIN.

860 AAG02557 Homo SapiensGEST Human secreted protein,297 100 SEQ ID

NO: 6638.

860 AAG89349 Homo SapiensGEST Human secreted protein,241 100 SEQ ID

NO: 469.

860 AAB42657 Homo sapiensCURA- Human ORFX ORF2421126 100 polypeptide sequence SEQ ID

N0:4842.

861 112855891 Mus musculusutative 173 68 861 g15360235 Oryctolaguslectin-like oxidized 77 40 LDL receptor cuniculus Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit 861 AAY24153 Chimeric NISB Bovine LOX-1 extracellular74 36 -Homo Sapiensregion/human IgGI Fc region chimeric rotein.

862 AAY42390 Homo SapiensGEMY Alternative reading615 100 frame amino acid se uence of 1v310 7.

863 gi15278033Homo Sapiensnuclear LIM interactor-interacting1356 99 factor, clone MGC:15065 . IMAGE:3687816, mRNA, complete cds.

863 gi10257410Homo Sapiensnatural resistance-associated1356 99 macrophage protein 1 (SLC11A1) gene, complete cds, alternatively spliced; and nuclear LIM interactor-interacting factor (NLI-IF) gene, com lete cds.

863 gi10257407Homo Sapiensnuclear LIM interactor-interacting1356 99 factor (NLI-IF mRNA, com fete cds.

864 AAG78191 Homo SapiensSHAN- Human mitochondrial512 98 ATPase cou lin factor 6-14.

864 AAG01252 Homo SapiensGEST Human secreted protein,332 98 SEQ ID

NO: 5333.

864 112861731Mus musculusutative 307 64 865 g12323287multiple polyprotein 304 53 sclerosis associated retrovirus 865 g138333 Homo SapiensHuman endogenous retrovirus260 60 pHE.l ERV9).

865 g1 17432485porcine pol 254 47 endogenous retrovirus 866 g116041690Homo Sapienshypothetical protein 2544 100 SP192, clone MGC:16819 IMAGE:3909296, mRNA, com lete cds.

866 1 10503966Homo sa clone SP 192 unknown 2544 100 iens mRNA.

866 g110437401Homo SapienscDNA: FLJ21319 fis,.clone2540 99 COL02312.

867 g113938183Homo Sapienshypothetical protein 1237 100 FLJ23584, clone MGC:14863 IMAGE:3344580, mRNA, com lete cds.

867 g110440321Homo SapienscDNA: FLJ23584 fis, clone1237 100 LNG 14307.

867 g13191978Streptomycesputative protein pII 84 27 uridylyltransferase coelicolor A3(2) 868 110438988Homo sa cDNA: FLJ22558 fis, clone841 100 iens HSI01557.

868 112852764Mus musculusutative 88 36 868 g1768821 Homo sapiensHuman DNA sequence from 85 35 S clone RP4-788L20 on chromosome Contains the HNF3B (hepatocyte nuclear factor 3, beta) gene, a novel gene, ESTs, STSs, GSSs and five CpG

islands, com lete se uence.

Table 2 SEQ ID Accession Species Description Score NO: No.

Identit 869 AAE02001 Homo SapiensUSSH Human viral IAP-associated1044 86 factor (VIAF).

869 AAB43903 Homo SapiensHUMA- Human cancer associated1044 86 rotein se uence SE ID
N0:1348.

869 gi12654393Homo Sapiensclone MGC:3062 IMAGE:3344703,1044 86 mRNA, com lete cds.

870 gi13384257Homo Sapiensapolipoprotein L5 mRNA, 2167 98 complete cds.

870 gi6572236 Homo SapiensHuman DNA sequence from 1614 97 clone RP1-41P2 on chromosome 22 Contains the 3' part of the RBM9 gene for RNA

binding motif protein 9 and the 3' part of the gene for a novel protein similar to part of APOL (apolipoprotein L) and TNF-inducible protein CG12-1.

Contains ESTs, STSs and GSSs, com fete se uence.

870 gi13384259Homo Sapiensapolipoprotein L6 mRNA, 478 39 complete cds.

871 110732650 Homo sa PP3111 mRNA, com lete 452 63 iens cds.

871 g15051823 Amycolatopsisputative peptide synthetase72 30 orientalis 871 g12894188 AmycolatopsisPCZA363.3 72 30 orientalis 872 110438351 Homo sa cDNA: FLJ22087 fis, clone3942 100 iens HEP15918.

872 g110438800Homo SapienscDNA: FLJ22417 fis, clone3937 99 HRC08579.

872 g113278208Mus musculusSimilar to hypothetical 3410 86 protein 873 AA010235 Homo sapiensHYSE- Human polypeptide 810 99 SEQ ID

NO 24127.

873 g1 11244871Homo Sapiensdioxin receptor repressor784 89 (AHRR) ene, exon 12 and com fete cds.

873 g16330736 Homo sapiensmRNA for KIAA1234 protein,776 88 partial cds.

874 AAB94957 Homo SapiensHELI- Human protein sequence732 100 SEQ

ID N0:16495.

874 g110433031Homo SapienscDNA FLJ11715 fis, clone732 100 HEMBA1005223.

874 g17620533 Bradyrhizobiuunknown 80 26 m ~a onicum 875 g112652943Homo Sapiensclone MGC:2488 IMAGE:3351245,1031 100 mRNA, com lete cds.

875 g112053307Homo SapiensmRNA; cDNA DKFZp434I209 1031 100 (from clone DKFZ 434I209 ;
co lete cds.

875 112846815 Mus musculusutative 805 78 876 AAG03976 Homo sapiensLEST Human secreted protein,457 92 SEQ ID

NO: 8057.

876 g15922723 Rattus KPL2 73 35 norve icus 876 g116604679Arabidopsisputative WD-repeat membrane67 31 protein thaliana 877 17959931 Homo sa PR02893 351 100 iens Table 2 SEQ ID Accession Species Description Score NO: No.

Identit 877 17544787 Sus scrofa1 co rotein ZP 1 68 33 877 1347421 Sus scrofazona ellucida 1 co rotein68 33 878 AAM41443 Homo SapiensHYSE- Human polypeptide 287 83 SEQ ID

NO 6374.

878 AAM39657 Homo sapiensHYSE- Human polypeptide 287 83 SEQ ID

NO 2802.

878 AAM82707 Homo SapiensHUMA- Human 287 83 immune/haematopoietic antigen SEQ

ID N0:10300.

879 AAB68986 Homo SapiensUYJO Human polyamine-modulated749 98 factor-1 PMF-1.

879 g15737759 Homo Sapienspolyamine modulated factor-1749 98 (PMF1) mRNA, com lete cds.

879 g15737757 Homo Sapienspolyamine modulated factor-1749 98 (PMF1) gene, exonS 2 through 5 and complete cds.

880 AAY14462 Homo SapiensHUMA- Human secreted 366 98 protein encoded b ene 52 clone HFIUR35.

880 g16729212 ClostridiumNTNHA 67 34 botulinum 880 g17240602 Clostridiumprogenitor toxin L nontoxic-65 34 botulinumnonhema lutinin com onent 881 AAB94110 Homo SapiensHELI- Human protein sequence3481 99 SEQ

ID N0:14346.

881 g110434088Homo SapienscDNA FLJ12542 fis, clone3481 99 NT2RM4000534.

881 AAG02676 Homo sapiensGEST Human secreted protein,210 97 SEQ ID

NO: 6757.

882 19956045 Homo sa clone CDABP0066 mRNA 894 94 iens se uence.

882 g13413800 Homo sapiensHomo sapien mRNA for 894 94 putative secreto rotein, hBET3.

882 12791804 Homo sa beta (BET3) mRNA, com 894 94 iens fete cds.

883 g1579068 BacteriophagecII gene (AA 1 - 132) 651 99 hi-80 883 g112516141Escherichiaunknown protein encoded 102 36 within coli 0157:H7prophage CP-933U

883 g113362232Escherichiahypothetical protein 102 36 coli 0157:H7 884 g17303583 DrosophilaCG9005 gene product 78 33 melano aster 884 112861859 Mus musculusutative 76 32 884 g110241798Streptomyceshypothetical protein 75 33 SCE41.24c coelicolor 885 g117059636Homo SapiensNovel human gene mapping2527 99 to chomosome 22.

885 114594694 Mus musculusadi onutrin 1419 67 885 AAY53641 Homo SapiensCHIR A bone marrow secreted880 45 protein desi nated BMS42.

886 AAY36025 ~ Homo GEST Extended human secreted198 94 Sapiens rotein se uence, SEQ
ID NO. 410.

886 AAY11423 Homo SapiensGEST Human 5' EST secreted137 100 protein SEQ ID No 245.

Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit 887 1687590 Homo so Human (AF1 mRNA, com 431 93 iens lete cds.

887 g116307092Homo SapiensALL1-fused gene from 431 93 chromosome 1q, clone MGC:17309 IMAGE:3878959, mRNA, complete cds:

887 g114250081Homo SapiensALLI-fused gene from 431 93 chromosome 1q, clone MGC:14664 IMAGE:4103485, mRNA, complete cds.

888 AAG74085 Homo SapiensHUMA- Human colon cancer286 94 antigen rotein SEQ ID N0:4849.

888 g114043788Homo Sapiensclone MGC:14288 IMAGE:4135996,286 94 mRNA, com fete cds.

888 AAY36036 Homo SapiensGEST Extended human secreted281 92 rotein se uence, SEQ
ID NO. 421.

889 g116550275Homo SapienscDNA FLJ30968 fis, clone1018 98 HEART2000411.

889 AAM75969 Homo SapiensMOLE- Human bone marrow 661 100 expressed probe encoded protein SEQ

ID NO: 36275.

889 AAM63155 Homo SapiensMOLE- Human brain expressed661 100 single exon probe encoded protein SEQ ID

NO: 35260.

890 g1 13559062Homo SapiensHuman DNA sequence from 667 100 clone RP11-552M11 on chromosome 1.

Contains the OVGP1 gene for oviductal glycoprotein 1 (mucin 9, oviductin), three novel genes, the ATPSF 1 gene for mitochondrial FO

complex H+ transporting ATP synthase b1, the ADORA3 gene for adenosine A3 receptor and an RPS29 (40S

ribosomal protein S29) pseudogene.

Contains ESTs, STSs, GSSs and two C G islands, com lete se uence.

890 AAY59703 Homo so GEST Secreted rotein 509 97 iens 47-2-3-G9-FL2.

890 AAY11473 Homo SapiensGEST Human 5' EST secreted472 94 protein SEQ ID No 295.

891 110439198Homo so cDNA: FLJ22704 fis, clone1336 100 iens HSI12602.

891 g116877288Homo SapiensSimilar to Hermansky-Pudlak1191 100 syndrome 3, clone MGC:21006 IMAGE:4415076, mRNA, complete cds.
.

891 g116552016Homo SapienscDNA FLJ32013 fis, clone1191 100 NTONG 1000033.

892 AAB27247 Homo SapiensINCY- Human EXMAD-25 2242 100 SEQ ID

NO: 25.

892 g113938404Homo Sapiensclone MGC:1526 IMAGE:2989807,1544 99 mRNA, com lete cds.

892 115011984Homo so b stin mRNA, com Iete 1532 99 iens cds.

893 AAG03168 Homo SapiensGEST Human secreted protein,415 97 SEQ ID

NO: 7249.

893 15911457 Pseudomonasochelin s thetase PchF 75 51 Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit aeru inosa 893 gi14286324Homo Sapienshigh-mobility group (nonhistone72 39 chromosomal) protein isoforms I and Y, clone MGC:4242 IMAGE:2962998, mRNA, com lete cds.

894 AAB56417 Homo SapiensROSE/ Human prostate 890 97 cancer antigen rotein se uence SEQ ID
N0:995.

894 AAB08450 Homo SapiensCOMP- A human kallikrein-2257 52 (KLK-2) s lice variant of a tide.

894 AAY95014 Homo SapiensALPH- Human secreted 228 67 protein vp3~l, SEQ ID N0:68.

895 111034809Homo sa leucine-zi er rotein 1914 99 tens FKSG13 895 g12674195Mus musculuspolymerase I-transcript 1779 92 release factor;

PTRF

895 1517089 Gallus leucine z1 er rotein 1311 72 allus 896 g112697951Homo SapiensmRNA for KIAA1703 protein,1130 98 partial cds.

896 AAB94772 Homo SapiensHELI- Human protein sequence1002 99 SEQ

ID N0:15858.

896 g110435978Homo SapienscDNA FLJ13839 fis, clone1002 99 THYRO 1000777.

897 AAY87322 Homo SapiensINCY- Human signal peptide888 100 containing protein HSPP-99 SEQ ID

N0:99.

897 AAB90648 Homo SapiensHUMA- Human secreted 871 98 protein, SEQ

ID NO: 191.

897 AAG03630 Homo SapiensGEST Human secreted protein,463 97 SEQ ID

NO: 7711.

898 AAY35953 Homo SapiensGEST Extended human secreted330 98 rotein se uence, SEQ
ID NO. 202.

898 AAY36105 Homo SapiensGEST Extended human secreted319 95 rotein se uence, SEQ
ID NO. 490.

898 AAG00625 Homo sapiensGEST Human secreted protein,269 98 SEQ ID

NO: 4706.

899 AAY64868 Homo sapiensGEST Human 5' EST related486 97 of a tide SEQ ID N0:1029.

900 AAG00723 Homo SapiensGEST Human secreted protein,304 100 SEQ ID

NO: 4804.

900 g1330019 Hepatitis structural viral protein69 54 E

virus 900 g1418310 Hepatitis STRUCTURAL PROTEIN 1 69 54 E >

virus 901 g115779204Homo Sapienshypothetical protein 1318 100 FLJ12448, clone MGC:22955 IMAGE:4860511, mRNA, com fete cds.

901 AAB94014 Homo SapiensHELI- Human protein sequence1302 99 SEQ

ID N0:14138.

901 g110433939Homo SapienscDNA FLJ12448 fis, clone1302 99 NT2RM 1000300.

902 AAB94507 Homo SapiensHELI- Human protein sequence1220 100 SEQ

ID N0:15214.

902 g110435098Homo SapienscDNA FLJ13188 fis, clone1220 100 NT2RP3004246.

Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identity 902 g110439526Homo SapienscDNA: FLJ22977 fis, clone1201 99 KAT11312.

903 g1 14517331Homo Sapienstestis-development related672 98 NYD-SP20D mRNA, com lete cds.

903 g1 14517329Homo Sapienstestis-development related672 98 NYD-SP20C mRNA, com lete cds.

903 g114039851Homo Sapienstestes development-related672 98 mRNA, com fete cds.

904 AAW88724 Homo SapiensHUMA- Secreted protein 373 98 encoded by ene 191 clone HJABZ65.

904 g113592178LeishmaniaSerine Threonine Protein68 36 Kinase like ma'or rotein 4 904 AA001200 Homo SapiensHYSE- Human polypeptide 66 62 SEQ ID

NO 15092.

905 110439085Homo sa cDNA: FLJ22624 fis, clone1749 100 iens HSI05951.

905 g113938004Homo SapiensSimilar to hypothetical 1290 99 protein FLJ22624, clone IMAGE:4104833, mRNA, artial cds.

905 AAM38631 Homo SapiensHUMA- Human colorectal 714 98 cancer anti en SEQ ID NO: 146.

906 AAW67838 Homo SapiensHUMA- Human secreted 448 95 protein encoded b ene 32 clone HLTCJ63.

906 g115029372Homo Sapienssorbinpolypeptide mRNA, 80 31 complete cds.

906 112860722Mus musculusutative 80 30 907 112854928Musmusculusutative 688 82 907 g116552651Homo SapienscDNA FLJ32509 fis, clone592 100 SMINT1000054.

907 AAB53906 Homo SapiensHUMA- Human colon cancer491 98 antigen rotein se uence SEQ ID
N0:1446.

908 AAG93309 Homo sa NISC- Human rotein HP 598 100 iens 10560.

908 g19954173Homo SapiensDNA polymerase delta 598 100 smallest subunit 12 (POLDS) mRNA, com fete cds.

908 1128 Mus musculusutative 492 83 909 _ Homo SapiensMETA- Human prostate 334 100 AAY48253 cancer-associated rotein 39.

909 g16458749Deinococcushypothetical protein 70 38 radiodurans 909 g11420437SaccharomyceORF YOR181w 66 55 s cerevisiae 910 AAY48598 Homo SapiensMETA- Human breast tumour-370 98 associated rotein 59.

910 g113424450Caulobacterhypothetical protein 68 32 crescentus 910 g115833006Escherichiahypothetical protein 66 39 coli 0157:H7]

> [Escherichia coli 0157:H7 911 116 Homo sa cDNA FLJ25219 fis, clone667 100 553936 iens STM00503.

911 _ Homo SapiensSimilar to RIKEN cDNA 667 100 g114250164 2310030606 gene, clone MGC:14839 IMAGE:4294167, mRNA, complete cds.

Table 2 SEQ ID Accession Species Description Score NO: No.

Identi 911 AAG00856 Homo sapiensGEST Human secreted protein,488 98 SEQ ID

NO: 4937.

912 AAG01735 Homo SapiensGEST Human secreted protein,349 98 SEQ ID

NO: 5816.

912 g13834380 Rattus intrinsic factor-B12 67 33 receptor precursor norve icus 912 g19968545 Narcissus beta-carotene hydroxylase65 33 pseudonarcissu s 913 g113279077Homo sapiensclone MGC:10820 IMAGE:3613742,373 100 mRNA, com fete cds.

913 AAM91638 Homo SapiensHUMA- Human 352 91 immune/haematopoietic antigen SEQ

ID N0:19231.

913 136424 Homo sa Human sec oncogene for 308 84 iens SEC rotein.

914 AAM79478 Homo SapiensHYSE- Human protein SEQ 386 54 ID NO

3124.

914 AAM78494 Homo SapiensHYSE- Human protein SEQ 386 54 ID NO

1156.

914 AAB28200 Homo sa CORI- Human xs99. 386 54 iens 915 g117391253Homo Sapiensclone MGC:98S0IMAGE:3865616,645 100 mRNA, com lete cds.

915 g115929794Homo SapiensSimilar to RNA polymerase645 100 1-3 (16 kDa subunit), clone MGC:21099 IMAGE:3847651, mRNA, complete cds.

915 g112805135Mus musculusUnknown (protein for 492 78 IMAGE:3591169) 916 g112698063Homo SapiensmRNA for KIAA1759 protein,3964 99 partial cds.

916 g112052965Homo sapiensmRNA; cDNA DKFZp566M10463929 97 (from clone DKFZp566M1046);

com lete cds.

916 110439143 Homo sa cDNA: FLJ22665 fis, clone3691 99 iens HSI08219.

917 g1 12052965Homo SapiensmRNA; cDNA DKFZp566M 4028 99 (from clone DKFZp566M1046);

com lete cds.

917 g112698063Homo SapiensmRNA for KIAA1759 protein,3939 98 partial cds.

917 110439143 Homo sa cDNA: FLJ22665 fis, clone3666 97 iens HSI08219.

918 19956045 Homo sa clone CDABP0066 mRNA 270 56 iens se uence.

918 g13413800 Homo SapiensHomo sapien mRNA for 270 S6 putative secreto rotein, hBET3.

918 12791804 Homo sa beta BET3 mRNA, com fete270 56 iens cds.

919 g113925848Homo Sapienskelch-like protein KLHL4c765 81 mRNA, com lete cds, alternativel s liced.

919 g113925845Homo Sapienskelch-like protein KLHL4765 81 mRNA, com lete cds, alternativel s liced.

919 g112697919Homo SapiensmRNA for KIAA1687 protein,765 81 partial cds.

920 113185301 Homo sa unnamed rotein roduct 871 100 iens 920 g1 14043484Homo sapiensSimilar to RIKEN cDNA 711 100 ene, clone MGC:13159 Table 2 SEQ ID Accession Species Description Score NO: No.

Identit IMAGE:4303698, mRNA, complete cds.

920 112850457 Mus musculusutative 702 81 921 g16649859 Pneumocystiskexin-like serine endoprotease71 75 carinii 921 AA005346 Homo sapiensHYSE- Human polypeptide 70 62 SEQ ID

NO 19238.

921 g11780925 human HCMVIRL4 = TRL4 70 61 he esvirus 922 AAB93760 Homo SapiensHELI- Human protein sequence1529 100 SEQ

ID N0:13446.

922 g110432860Homo SapienscDNA FLJ11577 fis, clone1529 100 HEMBA1003556.

922 1128 Mus musculusutative 1257 83 923 _ Homo Sapienshypothetical protein 1220 99 g113177760 FLJ21324, clone MGC:4744 IMAGE:3536686, mRNA, com lete cds.

923 g110437407Homo SapienscDNA: FLJ21324 fis, clone1217 99 COL02394.

923 AAB43543 Homo SapiensHUMA- Human cancer associated1216 99 rotein se uence SEQ ID
N0:988.

924 g110438571Homo SapienscDNA: FLJ22257 fis, clone902 100 HRC02873.

924 g114518442CaenorhabditisHypothetical protein 85 29 CO1G8.9 ele ans 924 AAB84577 Homo SapiensUYEM- Amino acid sequence77 37 of a mature human EP2 a tide.

925 AAB95224 Homo SapiensHELI- Human protein sequence837 99 SEQ

ID N0:17350.

925 g110434642Homo SapienscDNA FLJ12891 fis, clone837 99 NT2RP2004142.

925 gi1159561INeurosporarelated to U1 SMALL NUCLEAR83 50 crassa RIBONUCLEOPROTEIN C

926 AAE06150 Homo SapiensHUMA- Human gene 14 encoded837 100 secreted protein fragment, SEQ ID

N0:212.

926 AAY87173 Homo SapiensHUMA- Human secreted 837 100 protein se uence SEQ ID N0:212.

926 AAE06151 Homo SapiensHUMA- Human gene 14 encoded212 100 secreted protein fragment, SEQ ID

N0:213.

927 17959917 Homo sa PR02605 816 100 iens 927 g114603187Homo Sapienshypothetical protein 642 100 PR02605, clone MGC:19796 IMAGE:3845525, mRNA, com fete cds.

927 AAY66180 Homo SapiensMETA- Human bladder tumour370 84 EST

encoded rotein 38.

928 g1189989 Homo SapiensHuman protein kinase 301 72 C-L (PRKCL) mRNA, com lete cds.

928 g156916 Rattus protein kinase 286 67 norve icus 928 1220527 Mus musculusnPKC-eta 286 67 929 AAG03419 Homo SapiensGEST Human secreted protein~ 273 ~ 100 SEQ ID

Table 2 SEQ ID Accession Species Description Score NO: No.

Identit NO: 7500.

929 gi2746865 CaenorhabditisHypothetical protein 67 34 T05A8.4 ele ans 930 113879555 Mus musculusbinder ofRho GTPase 3 612 79 930 15731209 Mus musculusCRIB-containin BORG3 612 79 rotein 930 112842166 Mus musculusutative 6I2 79 931 g114017917Homo SapiensmRNA for KIAA1850 protein,3878 99 partial cds.

931 g113365945Maraca hypothetical protein 2320 94 fascicularis 931 g110439719Homo SapienscDNA: FLJ23132 fis, clone2256 99 LNG08559.

932 g110440377Homo SapiensmRNA for FLJ00024 protein,937 99 partial cds.

932 110440377 Homo sa FLJ00024 rotein 937 99 iens 933 g115207959Maraca hypothetical protein 632 88 fascicularis 933 g1552009 Streptococcuspeptidase 97 25 o enes 933 g1 13623022StreptococcusCSA peptidase precursor 95 24 pyogenes GAS

934 1 12860619Mus musculusutative 609 96 934 AAM74162 Homo SapiensMOLE- Human bone marrow 182 97 expressed probe encoded protein SEQ

ID NO: 34468.

934 AAG03513 Homo SapiensGEST Human secreted protein,136 96 SEQ ID

NO: ?594.

935 AAW88598 Homo SapiensHUMA- Secreted protein 400 100 encoded by ene 65 clone HFVHY45.

935 112862020 Mus musculusutative 269 92 935 AAW88821 Homo SapiensHUMA- PoIypeptide fragment148 100 encoded b ene 65.

936 AAY60495 Homo SapiensMETA- Human normal bladder326 98 tissue EST encoded rotein 167.

937 AAG81401 Homo SapiensZYMO Human AFP protein 551 100 sequence SEQ ID N0:320.

937 AAG93300 Homo sa NISC- Human rotein HP10417.551 100 iens 937 AAB43646 Homo SapiensHUMA- Human cancer associated551 100 rotein se uence SEQ ID
N0:1091.

938 AAY17388 Homo SapiensINCY- Human vesicle membrane950 90 rotein-like rotein I.

938 g19802048 Homo Sapienshypothetical protein 950 90 SBBI10 mItNA, com lete cds.

938 g18745394 Homo SapiensAlu co-repressor 1 (ACRl)950 90 mRNA, com lete cds.

939 AAG78658 Homo SapiensBODE- Human peroxidase 303 60 antioxidisin enz a 24.

939 AAG04043 Homo SapiensGEST Human secreted protein,303 60 SEQ ID

NO: 8124.

939 AAY17388 Homo SapiensINCY- Human vesicle membrane303 60 rotein-like rotein 1.

Table 2 SEQ ID Accession Species Description Score NO: No.

Identit 940 AAY17388 Homo SapiensINCY- Human vesicle membrane805 79 rotein-like rotein 1.

940 gi9802048 Homo Sapienshypothetical protein 805 79 SBBI10 mRNA, com lete cds, 940 gi8745394 Homo SapiensAlu co-repressor 1 (ACR1)805 79 mRNA, com fete cds.

941 gi17132972Nostoc ORF_ID:a113838~similar 100 25 Sp. to kinesin PCC 7120 1i ht chain 941 gi1335276 Homo SapiensHuman PRB3 gene (PRB3S) 94 24 for G1 rotein, exon 3.

941 gi1335274 Homo SapiensHuman prbl gene for salivary93 22 proline-rich rotein, exon 3.

942 AAY22155 Homo SapiensSAKA/ Human Nck associated3552 59 protein 1.

942 gi4760464 Homo SapiensmRNA for Nck-associated 3552 59 protein 1 a 1 , com lete cds.

942 gi15929137Homo SapiensNCK-associated protein 3552 59 1, clone MGC:8981 IMAGE:3907646, mRNA, com lete cds.

943 154004 Mus musculusut. RP2 rotein (aa 1-357)1210 63 943 g17298591 DrosophilaCG10194 gene product 472 34 melano aster 943 g17298588 DrosophilaCG1019S gene product 381 31 melano aster 944 g117389434Homo Sapienshypothetical protein 876 100 FLJ22639, clone MGC:22172 IMAGE:4700838, mRNA, co lete cds.

944 g110439108Homo sa cDNA: FLJ22639 fis, clone876 100 iens HSI06816.

944 AAG98701 Homo SapiensCOGE- Human cell death 72 28 protective cDNA clone CNI-00717 ORFS protein, SEQ:194.

945 AAB95692 Homo SapiensHELI- Human protein sequence1163 100 SEQ

ID N0:18510.

945 g110436474Homo SapienscDNA FLJ14100 fis, clone1163 100 MAMMA 1000855.

945 17020531 Homo sa cDNA FLJ20433 fis, clone75 25 iens KAT03767.

946 AAB15389 Homo SapiensTOYJ Human interleukin 86 26 6 receptor rotein.

946 g14699964 Homo SapiensPAC clone RPS-953A4 from85 2S
7q11.23-21.1, com lete se uence.

946 g1896310 Mamestra unknown protein 84 32 brassicae nucleopolyhed rovirus 947 AAY12607 Homo SapiensGEST Human 5' EST secreted395 98 protein SEQ ID NO: 272 from WO
9906553.

947 117223776 Mus musculusMLLT6 76 33 947 g17297961 Drosophilanub gene product 71 34 melano aster 948 g117046389Homo SapiensC21orf70 isoform B protein695 71 ~ (C21orf70) mRNA, complete cds, alternatively s liced.

948 1 17046387Homo sa C21 orf70 isoform A rotein670 66 iens (C21 orf70) Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit mRNA, complete cds, alternatively s liced.

948 gi14424633Homo Sapiensclone MGC:16722 IMAGE:4128732,670 66 mRNA, com fete cds.

949 gi15779053Homo SapiensSimilar to RIKEN cDNA 869 100 gene, clone MGC:26639 IMAGE:4826612, mRNA, complete cds.

949 112859857Mus musculusutative 777 88 949 AAG02322 Homo SapiensGEST Human secreted protein,630 99 SEQ ID

NO: 6403.

950 AAG89289 Homo SapiensGEST Human secreted protein,374 98 SEQ ID

NO: 409.

950 AAY45307 Homo sapiensHUMA- Human secreted 374 98 protein fra ment encoded from ene 15.

950 g16523815Homo sapiensphosphotidylethanolamine374 98 N-methyltransferase (PNMT) mRNA, com fete cds.

952 AAB94360 Homo SapiensHELI- Human protein sequence3208 99 SEQ

ID N0:14887.

952 g110434636Homo SapienscDNA FLJ12888 fis, clone3208 99 NT2RP2004081.

952 112855328Mus musculusutative 2247 72 953 g1476224 Homo SapiensHuman anion exchanger 399 100 3 cardiac isoform (cAE3) mRNA, artial cds.

953 53762 Mus musculusanion exchan er 3 cardiac383 64 1109 isoform 953 _ Rattus ORF-cardiac specific 233 63 g1202771 rattus 5' coding region;

utative 954 112850828Mus musculusutative 173 75 954 g1203519 Rattus cytochrome c oxidase 172 72 subunit VIc norve icus 954 AAM23875 Homo SapiensHYSE- Human EST encoded 161 70 protein SEQ ID NO: 1400.

955 AAY36057 Homo SapiensGEST Extended human secreted313 88 rotein se uence, SEQ
ID NO. 442.

955 AAY35931 Homo SapiensGEST Extended human secreted295 100 rotein se uence, SEQ
ID NO. 180.

955 AAY11851 Homo SapiensGEST Human 5' EST secreted171 77 protein SEQ ID No: 451.

956 g116549966Homo SapienscDNA FLJ30707 fis, clone2757 99 FCBBF2001211.

956 AAM77437 Homo SapiensMOLE- Human bone marrow 658 100 expressed probe encoded protein SEQ

ID NO: 37743.

956 AAM64659 Homo SapiensMOLE- Human brain expressed658 100 single exon probe encoded protein SEQ ID

NO: 36764.

957 g116551351Homo SapienscDNA FLJ31509 fis, clone1226 100 NT2RI1000016.

957 g114133227Homo SapiensmRNA for KIAA0970 protein,938 98 partial cds.

957 AAG02178 Homo SapiensGEST Human secreted protein,738 98 SEQ ID

NO: 6259.

Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit 958 gi3800830Rattus putative four repeat 711 83 ion channel norve icus 958 i 17901375Homo sa unnamed rotein roduct 71 83 iens I

958 gi7292976DrosophilaCG1517 gene product 382 44 melano aster 959 AAY60063 Homo SapiensMETA- Human endometrium 235 97 tumour EST encoded rotein 123.

959 AAY60064 Homo SapiensMETA- Human endometrium 231 97 tumour EST encoded rotein 124.

959 gi15081715ArabidopsisAt2g41840/T11A7.6 81 36 thaliana 960 gi13177691Homo SapiensSimilar to RIKEN cDNA 689 100 gene, clone MGC:2560 IMAGE:2989772, mRNA, complete cds.

960 112858411Mus musculusutative 585 86 960 AAG01650 Homo SapiensGEST Human secreted protein,270 98 SEQ ID

NO: 5731.

961 g17981304Homo SapiensHuman DNA sequence from 715 98 clone RP4-551D2 on chromosome 20q13.2-13.33 Contains the gene for a cadherin-like protein VR20, a novel gene, the PPP 1 R6 gene for protein phosphatase I

regulatory subunit 6, the 5' end of the SYCP2 gene for synaptonemal complex protein 2, ESTs, STSs, GSSs and two putative CpG
islands, complete se uence.

961 AAU18881 Homo SapiensHUMA- Novel prostate 652 100 gland antigen, Se ID No 180.

961 AAM96033 Homo SapiensHUMA- Human reproductive652 100 system related anti en SEQ ID
NO: 4691.

962 g19622236Homo sapienscadherin-like protein 1235 92 VR20 mRNA, artial cds.

962 g112743872Homo SapiensHuman DNA sequence from 1235 92 clone RP4-551D2 on chromosome 20q13.2-13.33 Contains the gene for a cadherin-like protein VR20, a novel gene, the PPP 1 R6 gene for protein phosphatase 1 regulatory subunit 6, the 5' end of the SYCP2 gene for synaptonemal complex protein 2, ESTs, STSs, GSSs and two putative CpG
islands, complete se uence.

962 AAB47329 Homo sa CURA- FCTR6. 1091 84 iens 963 g19622236Homo Sapienscadherin-like protein 1264 100 VR20 mRNA, artial cds.

963 g112743872Homo SapiensHuman DNA sequence from 1264 100 clone RP4-551D2 on chromosome 20q13.2-13.33 Contains the gene for a cadherin-like protein VR20, a novel gene, the PPP1R6 gene for protein phosphatase 1 re ulato subunit 6, the 5' end of the Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit SYCP2 gene for synaptonemal complex protein 2, ESTs, STSs, GSSs and two putative CpG
islands, complete se uence.

963 AAB47329 Homo sa CURA- FCTR6. 1085 84 iens 964 AAY60064 Homo SapiensMETH- Human endometrium 330 98 tumour EST encoded rotein 124.

965 114517637Homo sa mRNA for RGPR- 117, com 807 79 iens lete cds.

965 g114318616Homo Sapiensclone MGC:17455 IMAGE:3448742,807 79 mRNA, com lete cds.

965 AAG02383 Homo SapiensGEST Human secreted protein,505 96 SEQ ID

N0: 6464.

966 AAB94865 Homo SapiensHELI- Human protein sequence910 99 SEQ

ID N0:16066.

966 AAM94039 Homo SapiensHELI- Human stomach cancer910 99 expressed polypeptide SEQ ID NO

149.

966 g114718862Homo Sapienschronic myelogenous leukemia910 99 tumor antigen 66 mRNA, complete cds, alternativel s liced.

967 AAG02669 Homo SapiensGEST Human secreted protein,349 100 SEQ ID

NO: 6750.

968 g110438452Homo SapienscDNA: FLJ22170 fis, clone2870 100 HRC00652.

968 AAB41640 Homo SapiensCURA- Human ORFX ORF14042037 100 polypeptide sequence SEQ ID

N0:2808.

968 g1 15928410Mus musculusSimilar to hypothetical 1880 69 protein 970 g110440460Homo SapiensmRNA for FLJ00066 protein,655 99 partial cds.

970 g14512671ArabidopsisEn/Spm-like transposon 91 30 protein thaliana 970 g14929130Arabidopsisprotodermal factor 1 91 30 thaliana 971 g115930209Homo Sapienshypothetical protein 882 100 FLJ22477, clone MGC:9527 IMAGE:3917274, mRNA, com lete cds.

971 g110438882Homo SapienscDNA: FLJ22477 fis, clone882 100 HRC10815.

971 1I2838990Mus musculusutative 156 76 972 AAB94173 Homo sapiensHELI- Human protein sequence1542 100 SEQ

ID N0:14480.

972 g115215287Homo Sapienshypothetical protein 1542 100 FLJ12610, clone MGC:15029 IMAGE:4026495, mRNA, com fete cds.

972 g110434201Homo sapienScDNA FLJ12610 fis, clone1542 100 NT2RM4001565.

973 AAB94173 Homo SapiensHELI- Human protein sequence1419 93 SEQ

ID N0:14480.

973 g115215287Homo sapienshypothetical protein 1419 93 FLJ12610, clone MGC:15029 IMAGE:4026495, mRNA, com lete cds.

Table 2 SEQ ID Accession~ Species Description Score NO: No.

Identit 973 g110434201Homo SapienscDNA FLJ12610 fis, clone1419 93 NT2RM4001565.

974 AAY4I352 Homo SapiensHUMA- Human secreted 300 100 protein encoded b ene 45 clone HTXFH55.

974 g115029737Mus musculuscomplement component 67 58 2 (within H-ZS

974 1192435 Mus musculuscom lement com onent 67 58 975 AAB95342 Homo SapiensHELI- Human protein sequence721 100 SEQ

ID N0:17623.

975 g110435060Homo SapienscDNA FLJ13162 fis, clone721 100 NT2RP3003625.

975 g17302554DrosophilaCG15094 gene product 79 33 melano aster 976 AAY65192 Homo SapiensGEST Human 5' EST related206 100 of a tide SEQ ID N0:1353.

977 AAG00539 Homo SapiensGEST Human secreted protein,420 93 SEQ ID

NO: 4620.

977 g17243272Homo SapiensmRNA for KIAA1437 protein,199 55 partial cds.

977 g15824508Caenorhabditiscontains similarity to 68 33 Pfam domain:

elegans PF00018 (SH3 domain), Score=15.4, E-value=0.00062, N=l~cDNA
EST

yk300d7.3 comes from this gene-cDNA EST yk300d7.5 comes from this gene~cDNA EST
yk310d10.3 comes from this gene~cDNA
EST

yk310d10.5 comes from this gene--cDNA EST yk553a4.3 comes from this gene~cDNA EST
yk553a4.5 comes from this gene~cDNA
EST

yk622f8.3 comes from this gene~cDNA EST yk622f8.5 comes from this gene~cDNA EST
yk674e4.3 comes from this gene~cDNA
EST

k674e4.5 comes from this ene 978 AAM41583 Homo SapiensHYSE- Human polypeptide 620 100 SEQ ID

NO 6514.

978 AAM39797 Homo SapiensHYSE- Human polypeptide 620 100 SEQ ID

NO 2942.

978 AAG04036 Homo SapiensGEST Human secreted protein,607 99 SEQ ID

NO: 8117.

979 AAY65244 Homo SapiensGEST Human 5' EST related207 100 of a tide SEQ ID N0:1405.

979 AAG00117 Homo SapiensGEST Human secreted protein,77 55 SEQ ID

NO: 4198.

979 g1 16878268Homo sapiensSimilar to apolipoprotein77 55 L, clone MGC:29731 IMAGE:4661222, mRNA, com lete cds.

980 AAG02124 Homo SapiensGEST Human secreted protein,334 100 SEQ ID

NO: 6205.

980 14469399 Mus musculusa ithelial sodium channel69 37 al ha subunit 980 g12148928Rattus epithelial sodium channel69 37 alpha subunit norve icus Table 2 SEQ ID Accession Species Description Score NO: No.

Identit 981 gi7768773 Homo Sapiensgenomic DNA, chromosome 1065 99 21q, section 97/105.

981 gi1279678 Saccharomyceunknown 135 40 s cerevisiae 981 gi1431023 SaccharomyceORF YDL038c 135 40 s cerevisiae 982 AAG67395 Homo SapiensSUGE- Amino acid sequence1687 100 of human rotein kinase SGK258.

982 AAE00669 Homo SapiensHUMA- Human protein tyrosine1679 99 kinase rece for PTK from clone HDPSB68.

982 gi14017797Homo SapiensmRNA for KIAA1790 protein,1679 99 partial cds.

983 gi10440430Homo SapiensmRNA for FLJ00050 protein,1433 100 partial cds.

983 AAY84901 Homo SapiensINCY- A human proliferation258 40 and a o tosis related rotein.

983 gi12053225Homo SapiensmRNA; cDNA DKFZp434P2235257 40 (from clone DKFZ 434P2235 ;
com fete cds.

984 AAG03251 Homo SapiensGEST Human secreted protein,153 85 SEQ ID

N0: 7332.

984 112859308 Mus musculusutative 99 65 984 g17296664 DrosophilaCG10981 gene product 68 34 melano aster 985 AAY12780 Homo SapiensGEST Human 5' EST secreted203 100 protein SE ID N0:370.

985 g1 13879614MycobacteriuPE PGRS family protein 111 43 m tuberculosis 985 g19954108 TrypanosomeRNA binding protein RGGm104 38 cruzi 986 AAG67032 Homo SapiensSHAN- Human endothelial 2496 99 monocyte activatin of a tide II-62.

986 g110438461Homo SapienscDNA: FLJ22175 fis, clone1186 100 HRC00773.

986 g114250826Homo Sapienshypothetical protein 1171 99 FLJ22175, clone MGC:14955 IMAGE:4301828, mRNA, com fete cds.

987 AAB94225 Homo SapiensHELI- Human protein sequence1027 100 SEQ

ID N0:14591.

987 AAB56999 Homo SapiensROSEI Human prostate 1027 100 cancer antigen rotein se uence SEQ ID
N0:1577.

987 g110434297Homo SapienscDNA FLJ12666 fis, clone1027 100 NT2RM4002256.

988 AAG03612 Homo sapiensGEST Human secreted protein,302 100 SEQ ID

NO: 7693.

988 g115981929Yersinia putative iron ABC transporter,64 32 pestis ATP-bindin rotein 988 g116124148Yersinia putative iron ABC transporter,64 32 ATP-pesos] binding protein >

[Yersinia estis 989 AAG03478 Homo SapiensGEST Human secreted protein,190 83 SEQ ID

NO: 7559.

Table 2 SEQ ID Accession Species Description Score NO: No.

Identit 989 gil 1360118Homo Sapienshypothetical protein 63 36 DKFZp434M 1123.1 - human (fra ment >

990 AAG73521 Homo SapiensHUMA- Human colon cancer406 98 antigen rotein SEQ ID N0:4285.

990 AAY00280 Homo SapiensHUMA- Human secreted 359 98 protein encoded b gene 23.

991 AAG93309 Homo sa NISC- Human rotein HP 339 100 iens 10560.

991 gi9954173 Homo SapiensDNA polymerase delta 339 100 smallest subunit 12 POLDS mRNA, com fete cds.

991 i 12845953Mus musculusutative 288 84 992 AAW89035 Homo SapiensHUMA- Polypeptide fragment159 100 encoded b ene 171.

992 15852085 Or za sativazwh0008.1 93 27 992 AAB64815 Homo SapiensHUMA- Human secreted 87 30 protein sequence encoded by gene 43 SEQ ID

NO:101.

993 g114717079Homo SapiensHuman DNA sequence from1365 99 clone RP3-469A13 on chromosome Contains part of the gene for KIAA0889 and a novel protein similar to KIAA0802, a novel gene, the 5' end of the part of the gene for a novel protein similar to N-myc downstream regulated (NDRG1), ESTs, STSs, GSSs and four CpG islands, complete se uence.

993 AAB94598 Homo SapiensHELI- Human protein 1055 96 sequence SEQ

ID N0:15418.

993 g110435333Homo SapienscDNA FLJ13346 fis, clone1055 96 OVARC 1002107.

994 AAG02845 Homo sapiensLEST Human secreted 273 100 protein, SEQ ID

NO: 6926.

995 AAM93342 Homo SapiensHELI- Human polypeptide,283 60 SEQ ID

NO: 2883.

995 19279975 Homo sa mRNA for Re rimo, com 283 60 iens fete cds.

995 g112804111Homo Sapienscandidate mediator of 283 60 the p53-dependent G2 arrest, clone MGC:11260 IMAGE:3942270, mRNA, co lete cds.

996 g12633213 Bacillus yhzB 79 35 subtilis 996 g19802541 ArabidopsisF17L21.23 74 24 thaliana 996 g17303166 DrosophilaCG12864 gene product 74 33 melano aster 997 ABB 12196 Homo SapiensHYSE- Human secreted 424 98 protein homolo ue, SEQ ID N0:2566.

997 AAG03905 Homo SapiensGEST Human secreted 173 59 protein, SEQ ID

NO: 7986.

997 g114043862Homo Sapiensclone MGC:14138 IMAGE:3948518,173 59 mRNA, com lete cds.

998 AAM78349 Homo sa HYSE- Human protein 72 42 iens SEQ ID NO

Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit 1011.

998 AAM79333 Homo SapiensHYSE- Human protein SEQ 71 41 ID NO

2979.

998 gi15042611Homo SapiensSer/Thr protein kinase 71 41 PAR-lBalpha mRNA, com fete cds.

999 gi16550716Homo SapienscDNA FLJ31318 fis, clone2201 100 LIVER1000433, moderately similar to Homo Sapiens mRNA for neuropathy tar et esterase.

999 AAM25456 Homo SapiensHYSE- Human protein sequence1423 100 SEQ

ID N0:971.

999 AAY70474 Homo SapiensINCY- Human cyclic nucleotide-1422 65 associated rotein-2 (CNAP-2).

1000 gi7293162DrosophilaCG15603 gene product 71 46 melano aster 1000 gi4586294Rhodococcustransposase 71 47 s . CIR2 1000 gi7300412DrosophilaCG14304 gene product 69 41 melano aster 1001 AAY07759 Homo SapiensHUMA- Human secreted 793 88 protein fra ment encoded from ene 16.

1001 gi14603397Homo Sapiensmitochondrial ribosomal 787 86 protein 528, clone MGC:19500 IMAGE:4331173, mRNA, com lete cds.

1001 14454702 Homo sa HSPC007 787 86 iens 1002 g116549918Homo SapienscDNA FLJ30671 fis, clone1527 95 FCBBF1000687, moderately similar to Mus musculus Rap2 interacting protein 8 (RPIPB mRNA.

1002 AAB42726 Homo SapiensCURA- Human ORFX ORF24901314 98 polypeptide sequence SEQ ID

N0:4980.

1002 g12588624Homo SapiensBAC clone CTB-60N22 from1314 98 7q21, com lete se uence.

1003 110439134Homo sa cDNA: FLJ22659 fis, clone756 100 iens HSI07953.

1003 AAM70124 Homo SapiensMOLE- Human bone marrow 157 96 expressed probe encoded protein SEQ

ID NO: 30430.

1003 g114027542Mesorhizobiuhypothetical protein 72 32 m loti 1004 AAG62909 Homo SapiensKLEE/ Amino acid sequence3614 99 of a human x los 1 ansferase XT .

1004 g111322268Homo Sapienspartial mRNA for xylosyltransferase3614 99 I

(XT-I ene).

1004 115209651Homo sa human XT-I (not com letel3614 99 iens 1005 AAG02478 Homo SapiensGEST Human secreted protein,380 100 SEQ ID

NO: 6559.

1005 AAY86496 Homo SapiensHUMA- Human gene 61-encoded69 35 rotein fra ment, SEQ
ID N0:411.

1005 AAY86324 Homo SapiensHUMA- Human secreted 69 35 protein HSRGW 16, SEQ ID N0:239.

1006 AAB90708 Homo SapiensGEMY Human CJ397 241 100 1 protein _ se uence SEQ ID 109 Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit 1006 AAW48809 Homo SapiensGEMY Homo Sapiens clone 241 100 CJ397_1 rotein.

1006 gi671656 Sorghum gamma-kafirin preprotein83 32 bicolor 1007 AAY59661 Homo SapiensGEST Secreted protein 408 100 B7-FL.

1007 gi431033 Homo SapiensHuman beta-1,4 N- 65 45 acetylgalactosaminyltransferase mRNA, com fete cds.

1007 gi8250584Streptomycesputative integral membrane6S 45 protein coelicolor 1008 AAG73798 Homo SapiensHUMA- Human colon cancer653 98 antigen rotein SEQ ID N0:4562.

1008 AAG03987 Homo SapiensGEST Human secreted protein,653 98 SEQ ID

NO: 8068.

1008 AAB54311 Homo SapiensHUMA- Human pancreatic 653 98 cancer antigen protein sequence SEQ ID

N0:763.

1009 AAB24198 Homo SapiensHONJI Human activation-induced1086 100 c idine deaminase SEQ
ID N0:8.

1009 gi9988410Homo SapiensAID mRNA for activation-induced1086 100 c idine deaminase, com lete CDS.

1009 gi9988408Homo SapiensAID gene for activation-induced1086 100 c idine deaminase, com lete cds.

1010 gi 10439796Homo SapienscDNA: FLJ23189 fis, clone~ 1172100 LNG12061.

1010 AAM70456 Homo SapiensMOLE- Human bone marrow 467 100 expressed probe encoded protein SEQ

ID NO: 30762.

1010 12627231 Bos taurusNDP52 101 28 1011 110438050Homo sa cDNA: FLJ21858 fis, clone744 97 iens HEP02301.

1011 AAG66887 Homo sa SHAN- Human zinc fin 156 30 iens er rotein 17.

1011 g116553140Homo SapienscDNA FLJ32873 fis, clone146 38 TESTI2003998, weakly similar to T-CELL RECEPTOR BETA CHAIN

ANA 11.

1012 AAG03653 Homo SapiensGEST Human secreted protein,425 100 SEQ ID

NO: 7734.

1012 AAU19393 Homo sapiensPHAA Human G protein-coupled87 36 rece for nGPCR-2326.

1013 g16180179Homo Sapienstranscription factor 3632 99 IGHM enhancer 3, JM11 protein, JM4 protein, protein, TS4 protein, JM10 protein, A4 differentiation-dependent protein, triple LIM domain protein 6, and synaptophysin genes, complete cds;

and L-type calcium channel alpha-1 subunit gene, partial cds, complete se uence.

1013 g114250618Homo Sapiensclone MGC:2962 IMAGE:3139519,3077 94 mRNA, com fete cds.

1013 17242943 Homo sa mRNA for KIAA1294 rotein,297 32 iens artial Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit cds.

1014 AAY65004 Homo SapiensGEST Human 5' EST related194 79 of a tide SEQ ID N0:1165.

1014 g13875122CaenorhabditisC50F4.4 68 38 ele ans 1014 g17497774Caenorhabditishypothetical protein 68 38 C50F4.4 -ele ans Caenorhabditis ele ans >

1015 AAY60578 Homo SapiensMETA- Human normal bladder477 100 tissue EST encoded rotein 250.

1016 112849116Mus musculusutative 1072 76 1016 AAB50970 Homo sa GETH Human PR04302 rotein.306 35 iens 1016 AAU12446 Homo SapiensGETH Human PR04302 polypeptide306 35 se uence.

1017 g12313745HelicobacterH. pylori predicted coding73 35 region lori 26695HP0614 1017 g110038760Buchnera flagellar assembly protein72 32 Sp. flies APS

1017 g115149090lumpy skinLSDV079 mRNA capping 66 32 enzyme disease lar a subunit virus 1018 g19967289Macaca hypothetical protein 356 91 fascicularis 1019 AAG03026 Homo SapiensGEST Human secreted protein,243 100 SEQ ID

NO: 7107.

1019 g112853136Mus musculusutative 166 67 1019 AAB41285 Homo SapiensCURA- Human ORFX ORF104964 34 polypeptide sequence SEQ ID

N0:2098.

1020 AAY36512 Homo SapiensHUMA- Fragment of human 748 100 secreted rotein encoded b ene 32.

1020 g17243179Homo SapiensmRNA for KIAA1399 protein,82 41 partial cds.

1020 17243179 Homo sa KIAA1399 rotein 82 41 iens 1021 AAB95621 Homo SapiensHELI- Human protein sequence2058 99 SEQ

ID N0:18338.

1021 giI0436272Homo SapienscDNA FLJ13958 fis, clone2058 99 Y79AA1001216.

1021 g114165529Homo Sapienshypothetical protein 2056 99 FLJ12438, clone MGC:2473 IMAGE:3050071, mRNA, com lete cds.

1022 g1514268 Homo SapiensHuman proto-oncogene 248 100 tyrosine-protein kinase (ABL) gene, exon la and exons 2-10, com lete cds.

1022 1555876 Mus musculusc-abl rotein, a IV 242 95 1022 149841 Mus musculusc-abl rotein 242 95 1023 AAG66758 Homo SapiensBIOW- Human promoter 627 100 binding factor 13.

1023 19963908 Homo sa NPD009 mRNA, co lete 627 100 iens cds.

1023 g114290450Homo SapiensNPD009 protein, clone 624 99 MGC:16898 IMAGE:4156159, mRNA, complete cds.

1024 gil 1138042Homo SapiensmRNA, similar to rat 1227 99 myomegalin, com lete cds.

1024 AAY00346 Homo sa HUMA- Fragment of human 1206 97 iens secreted Table 2 SEQ ID Accession Species Description Score NO: No.

Identit rotein encoded b ene 2.

1024 AAM25852 Homo SapiensNYSE- Human protein sequence1199 96 SEQ

1D N0:1367.

1025 AAG00700 Homo SapiensGEST Human secreted protein,393 98 SEQ ID

NO: 4781.

1025 112858787 Mus musculusutative 313 93 1025 g116553210Homo SapienscDNA FLJ32921 fis, clone209 70 TESTI2006872.

1026 g116924223Homo Sapienshypothetical protein 682 100 FLJ12929, clone MGC:22200 IMAGE:4070101, mRNA, corn fete cds.

1026 AAB95241 Homo SapiensHELI- Human protein sequence673 99 SEQ

ID N0:17394. .

1026 g110434702Homo SapienscDNA FLJ12929 fis, clone673 99 NT2RP2004775.

1027 g114017897Homo SapiensmRNA for KIAA1840 protein,2216 100 partial cds.

1027 g110437539Homo SapienscDNA: FLJ21439 fis, clone2210 99 COL04352.

1027 AAG81395 Homo SapiensZYMO Human AFP protein 1308 100 sequence SEQ ID N0:308.

1028 g13127176 Homo Sapienssulfonylurea receptor 723 100 2B (SUR2) gene, alternatively spliced product, exon 38b and corn lete cds.

1028 g13127175 Homo Sapienssulfonylurea receptor 723 100 2A (SUR2) gene, alternatively spliced product, exon 38a and corn lete cds.

1028 g1 15778680Oryctolagussulphonylurea receptor 710 98 cuniculus 1029 g114333990Homo Sapiensenhancer of polycomb 3911 99 2 (EPC2) mRNA, corn lete cds.

1029 g1 11907923Homo Sapiensenhancer of polycomb 3879 97 mRNA, corn fete cds.

1029 13757892 Mus musculusenhancer of of comb 3613 92 1030 g19967305 Macaca hypothetical protein 313 94 fascicularis 1030 AAM80165 Homo SapiensHYSE- Human protein SEQ 76 43 ID NO

3811.

1030 AAM79181 Homo SapiensHYSE- Human protein SEQ 76 43 ID NO

1843.

1031 AAM93813 Homo SapiensHELI- Human polypeptide,346 95 SEQ ID

NO: 3861.

1031 AAG01877 Homo SapiensGEST Human secreted protein,341 100 SEQ ID

NO: 5958.

1031 15917666 Zea ma extensin-like rotein 67 53 s 1032 AAM93813 Homo SapiensHELI- Human polypeptide,341 100 SEQ ID

NO: 3861.

1032 AAGO 1877 Homo sapiensGEST Human secreted protein,341 100 SEQ ID

NO: 5958.

1032 g110799949Rattus ABC2 72 36 norve icus 1033 AAY 19473 Homo SapiensHUMA- Amino acid sequence264 100 of a human secreted rotein.

Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit 1034 gi17390437Homo Sapiensclone MGC:9829 IMAGE:3863118,879 99 mRNA, com lete cds.

1034 i 12850729Mus musculusutative 777 85 1034 110440154Homo sa cDNA: FLJ23459 fis, clone758 100 iens HSI07588.

1035 AAR97285 Homo SapiensKYOW Human 26S proteasome1331 100 constitutive rotein P31.

1035 g13702282Homo Sapienschromosome 19, cosmid 1331 100 F5960, co lete se uence.

1035 g112654653Homo Sapiensproteasome (prosome, 1331 100 macropain) 26S

subunit, non-ATPase, 8, clone MGC:1660 IMAGE:3528096, mRNA, com Iete cds.

1036 g112654125Homo Sapienshypothetical protein 766 99 PP5395, clone MGC:5610 IMAGE:3461724, mRNA, com lete cds.

1036 110441968Homo sa clone PP5395 unknown 766 99 iens mRNA.

1036 112843917Mus musculusutative 535 73 1037 AAG02764 Homo SapiensGEST Human secreted protein,281 100 SEQ ID

NO: 6845.

1037 g117221344Kluyveromycehypothetical protein 87 35 s lactis 1037 g116649041ArabidopsisUnknown protein 75 37 thaliana 1038 AA002417 Homo SapiensHYSE- Human polypeptide 445 96 SEQ ID

NO 16309.

1038 AAG03101 Homo SapiensGEST Human secreted protein,385 97 SEQ ID

NO: 7182.

1038 g12209200HelobdellaLOXS 73 34 robusta 1039 AAE09718 Homo SapiensMILL- Human ubiquitin 571 100 carboxy-terminal h drolase, 23436 rotein.

1039 116547646Homo sa unnamed rotein roduct 571 100 iens 1039 AAB74684 Homo SapiensINCY- Human protease 561 100 and protease inhibitor PPIM-17.

1040 AAM25866 Homo SapiensHYSE- Human protein sequence877 100 SEQ

ID N0:1381.

1040 110440168Homo sa cDNA: FLJ23468 fis, clone877 100 iens HSI11603.

1040 112839602Mus musculusutative ~ 573 65 1041 AAB60118 Homo SapiensINCY- Human transport 1250 100 protein TPPT-38.

1041 g116552638Homo SapienscDNA FLJ32499 fis, clone842 98 SKNSH2000347, weakly similar to EC 1.1.2.3 .

1041 g19801259Leishmaniapossible CG15429 protein449 44 major 1042 AAB94782 Homo SapiensHELI- Human protein sequence330 70 SEQ

ID N0:15884.

1042 AAU27665 Homo sa ZYMO Human rotein AFP 330 70 iens 162878.

1042 g115215279Homo Sapienshypothetical protein 330 70 MGC11349, clone MGC:14984 IMAGE:3635966, mRNA, com lete cds.

1043 110439613Homo sa cDNA: FLJ23047 fis, clone668 99 iens Table 2 SEQ ID AccessionSpecies Description Score NO: No.

Identit LNG02513.

1043 112850050Mus musculusutative 340 53 1043 g113622152Streptococcushypothetical protein 88 29 pyogenes GAS

1044 AAB94493 Homo SapiensHELI- Human protein sequence193 90 SEQ

ID N0:15184.

1044 116307381Mus musculusSimilar to d amin 2 191 88 1044 1 12853743Mus musculusutative 191 88 1045 AAM25873 Homo SapiensHYSE- Human protein sequence516 100 SEQ

ID N0:1388.

1045 AAY57878 Homo SapiensINCY- Human transmembrane516 100 protein HTMPN-2.

1045 AAU39009 Homo SapiensGEMY Human secreted protein80 30 am728 60.

1046 AAG03414 Homo SapiensGEST Human secreted protein,328 100 SEQ ID

NO: 7495.

1046 12301526 unidentifiedAMYLOID PROTEIN AA 100 29 1046 g1160229 Plasmodiumcircumsporozoite protein95 30 reichenowi 1047 g116550135Homo SapienscDNA FLJ30851 fis, clone840 100 FEBRA2002908.

1047 g19967240Macaca hypothetical protein 557 71 fascicularis 1047 112853386Mus musculusutative 210 46 1048 g13746069Arabidopsisputative non-LTR retroelement74 31 reverse thaliana transcri tase 1048 g17271069Candida hypothetical protein 71 36 albicans 1048 g113882111MycobacteriuPE family protein 70 34 m tuberculosis 1049 g19947823Pseudomonashypothetical protein 643 70 aeru inosa 1049 giI7429445Ralstonia CONSERVED HYPOTHETICAL 365 56 solanacearumPROTEIN

1049 g19950333Pseudomonashypothetical protein 321 47 aeru inosa 1050 AAY27754 Homo SapiensHUMA- Human secreted 555 100 protein encoded b ene No. 38.

1050 g12104464Schizosaccharhypothetical protein 71 29 om ces ombe 1050 g13287941SchizosaccharHYPOTHETICAL 44.3 KD 71 29 PROTEIN

om ces C25H2.15 IN CHROMOSOME
ombe II >

1051 AAB95246 Homo SapiensHELI- Human protein sequence757 100 SEQ

ID N0:17407.

1051 AAB95127 Homo SapiensHELI- Human protein sequence757 100 SEQ

ID N0:17129.

1051 g110434139Homo SapienscDNA FLJ12572 fis, clone757 100 NT2RM4000971.

1052 AAB53066 Homo SapiensGETH Human angiogenesis-associated71 64 rotein PR0178, SEQ ID
NO:11.

1052 AAB51330 Homo SapiensHERI- Human NEW angiopoietin-like71 64 Table 2 SEQ ID Accession Species Description Score NO: No.

Identit rotein SEQ ID N0:8.

1052 AAY72626 Homo sapiensHYSE- Human angiopoietin71 64 protein, CGO1 Salt2.

Table 3 SEQ DatabaseDescription *Results ID

NO: entr ID

588 BL01183 ubiE/COQS methyltransferaseBL01183B 21.31 3.317e-11 family 146-191 roteins.

629 BL00223 Annexins repeat proteinsBL00223A 15.59 4.414e-30 domain 20-54 BL00223C

roteins. 24.79 1.186e-11 7-62 629 PR00198 ANNEXIN TYPE II SIGNATUREPR00198B 8.71 4.767e-13 29-52 7.65 4.758e-12 24-46 PR00198D
7.65 3.298e-629 PR00202 ANNEXIN TYPE VI SIGNATUREPR00202B 11.44 8.986e-19 13.34 4.452e-16 69-86 PR00202D
5.58 5.182e-629 PR00199 ANNEXIN TYPE III SIGNATUREPR00199B 6.86 1.651e-16 29-52 5.65 7.039e-13 24-46 PR00199D
5.65 3.586e-10 96-118 PR00199C 13.84 7.152e-10 69-86 629 PR00197 ANNEXIN TYPE I SIGNATUREPR00197D 7.50 8.125e-15 24-46 7.56 9.143e-12 29-52 PR00197D
7.50 8.813e-629 PR00196 ANNEXIN FAMILY SIGNATUREPR00196A 11.16 3.700e-21 10.36 3.298e-17 96-118 PR00196B
10.68 7.750e-17 69-86 PR00196C
10.36 4.536e-14 24-46 PR00196E 9.19 1.563e-09 629 PR00200 ANNEXIN TYPE IV SIGNATUREPR00200B 7.39 5.919e-15 29-52 10.00 5.871e-13 24-46 PR00200E
10.00 8.941e-13 96-118 PR00200D
10.01 9.471e-12 69-86 PR00200G 9.43 6.067e-09 629 PR00201 ANNEXIN TYPE V SIGNATUREPR00201A 6.05 1.000e-28 29-52 10.49 3.250e-24 96-118 PR00201C
11.13 _ 1.474e-21 69-86 PR00201B
8.88 2.552e-11 53-62 PR00201D 10.49 7.198e-09 795 BL00572 Gl cos 1 h drolases familBL00572C 20.73 2.324e-25 1 roteins. 40-75 938 PD00210 PROTEIN ANTIOXIDANT PD00210 15.25 3.912e-09 88-104 PEROXIDASE RED.

940 PD00210 PROTEIN ANTIOXIDANT PD00210 15.25 5.500e-09 88-104 PEROXIDASE RED.

* Results include in order: Accession No., subtype, e-value, and amino acid position of the signature in the corresponding polypeptide Table 4 SEQ Pfam Model Description E-valueScore No: Position ID of of Pfam the Domain Domain s 527 ion trans Ion trans ort rotein8.3e-1872.6 1 438-672 527 ank Ankyrin repeat 1.9e-0634.8 2 77-108:163-527 Srg C.elegans Srg family8.1 -222.41 418-669 integral membrane rot 546 vwa von Willebrand factor0.77 -42.3 1 776-958 type A
domain 553 TPR TPR Domain 7.1 7.4 1 40-73 566 PTPS 6-pyruvoyl tetrahydropterin0.54 -52.2 1 52-149 s thase 575 Pol A of Pol A of erase famil1.3 -61.4 1 37-155 588 Ubie methyltranubiE/COQS methyltransferase0.6 -150.71 65-249 famil 591 ubi uitin Ubi uitin famil 0.15 11.5 1 106-197 593 zf C4 TopoisomTopoisomerase DNA 9.2 -5.6 1 96-130 C binding 4 zinc fin 594 zf C2H2 Zinc finger, C2H2 1.1 15.8 1 61-85 a 599 CBFD NFYB HMF Histone-like transcription3.8 -8.3 1 26-89 f actor 610 vwd von Willebrand factor7.7 -30.1 1 169-321 type D
domain 610 HRM Hormone rece for 7.8 -13.5 1 85-150 domain 612 Metallophos Calcineurin-like 7.9 -8.2 1 18-177 hos hoesterase 618 Pe tidase C54 Pe tidase famil 5.9e-207700.9 1 42-332 627 AT hook AT hook motif 8.5 7.9 1 97-109 629 annexin Annexin 7.6e-31115.9 1 17-84 631 ABC-3 ABC 3 trans ort 2.1 -182.91 152-349 famil 631 ion trans Ion trans ort rotein8.3 -13.4 1 187-389 653 LEA Late embryogenesis 8.2 -6.8 1 203-270 abundant rotein 655 PMP22_Claudin PMP-22/EMP/MP20/Claudin2.9 -60.0 1 8-159 famil 669 CBM 21 Putative phosphatase0.0056 5.1 1 280-418 re ulator subunit 67I V-ATPase C V-ATPase subunit 1.3e-54194.8 1 1-225 C

677 Timl7 Mitochondria) import4e-74 259.7 1 51-184 inner membrane transloc 678 Timl7 Mitochondria) import3.1e-57203.6 1 51-234 inner membrane transloc 681 PARP Poly(ADP-ribose) 5.2 -96.7 1 397-577 polymerase catal 'c domain 692 vATP-synt E ATP synthase (E/31 4.1 -92.4 1 276-459 kDa) subunit 693 vATP-synt E ATP synthase (E/31 4.1 -92.4 1 332-515 kDa) subunit 709 Ribosomal S25 S25 ribosomal rotein7.9e-44159.0 1 1-113 716 DUF6 Integral membrane 3.1 -16.3 1 I1-145 protein 717 PAP2 PAP2 superfamily 1.7 -22.6 1 174-355 Table 4 SEQ Pfam Model Description E-valueScore No: Position ID of of Pfam the Domain Domain s 718 IBR 1BR domain 6.2 -14.4 1 59-110 732 zf C2H2 Zinc fin er, C2H2 9.7 9.4 1 389-410 t a 745 DUF81 Domain of unknown 4.7 -44.7 1 3-150 function 751 Glyco hydro~2 Glycosyl hydrolases0.44 -75.0 1 37-144 N family 2, su ar b 761 M c-LZ M c Ieucine zi er 2.2 12.8 1 136-168 domain 762 Tro om osin Tro om osin 5.2 -116.0 1 318-529 762 LEM LEM domain 10 -4.0 1 461-504 764 SEA SEA domain 0.076 17.1 4 I 12-245:270-395:561-684:955-1085 769 TTL Tubulin-t osine 2.4e-93323.5 1 35-344 1i ase famil 780 HEAT PBS PBS lyase HEAT-like0.17 18.4 2 298-323:390-repeat 22 780 Ada tin N Ada tin N terminal 0.46 -162.5 1 65-643 re ion 780 Diox enase Diox enase 2.5 -106.2 1 807-937 785 CENP-B CENP-B rotein 1.4e-074.9 I 178-367 785 HTH 5 Bacterial regulatory0.48 5.3 1 9-93 protein, arsR famil 785 HTH 3 Helix-turn-helix 1.4 10.3 1 20-74 788 zf CCCH Zinc finger C-x8-C-x5-C-x3-1.4 9.4 2 76-103:116-H t a 144 791 Calx-beta Calx-beta domain 0.0011 16.7 1 82-160 795 Gl co h dro Gl cos t h drolase 7.4e-07-205.2 1 2-171 I famil 1 807 mn RNA reco nition 0.78 3.4 1 13-80 motif.

807 UIM Ubiquitin interaction3.4 13.2 2 650-667:673-motif 690 822 Keratin B2 Keratin, high sulfur0.15 -55.4 1 2-161 rotein 825 Acetyltransf Acetyltransferase 5.7 1.1 1 191-277 (GNAT) famil 846 Glyoxalase Glyoxalase/Bleomycin0.074 11.7 1 2-118 resistance rotein/Di 850 MORN MORN repeat 1.1e-28108.7 7 14-36:38-59:60-80:106-128:157-179:309-331:332-354 863 NIF NLI interactin factor1.6e-104360.6 1 82-256 869 Phosducin Phosducin 0.0067 -89.2 I 1-239 870 MotA_ExbB MotA/ToIQ/ExbB proton1.5 -49.3 1 89-204 channel fanul 872 Armadillo seg Armadillo/beta-catenin-like0.42 17.1 2 677-717:727-re eat 769 872 HEAT PBS PBS lyase HEAT-like6.1 13.2 3 410-436:704-repeat 45:756-798 872 Ada tin N Ada tin N terminal 9.5 -204.6 1 215-972 re ion 885 Patatin Patatin-like hos 9.2e-30112.3 1 10-179 holi ase 890 Gl co horin Gl co horin A 5.9 -44.6 1 2-91 A

Table 4 SEQ Pfam Model Description E-valueScore No: Position ID of of Pfam the Domain Domain s 901 deh drin Deh drin 6.6 -77.8 1 52-223 931 ubi uitin Ubi uitin famil 8.5 -6.5 1 405-478 938 Ah C-TSA Ah C1TSA famil Se-OS 3.6 1 58-189 940 Ah C-TSA Ah CITSA famil 0.28 -43.3 1 58-165 943 NUDIX MutT-like domain 8.6e-0736.0 1 12-264 949 V-ATPase_G Vacuolar (H+)-ATPase5.8 -48.6 1 10-120 G
subunit 954 COX6C Cytochrome c oxidase1.2e-1462.1 1 1-47 subunit VIc 956 M c N term M c amino-terminal8.1 -185.0 1 209-500 re ion 961 Cadherin C termCadherin c o lasmic7.8 -83.3 1 41-148 re ion 962 cadherin Cadherin domain 0.17 9.3 1 19-109 962 Cadherin C termCadherin c o lasmic0.89 -70.9 1 159-319 re ion 963 cadherin Cadherin domain 0.17 9.3 1 19-109 963 Cadherin C termCadherin c to lasmic0.21 -62.6 1 159-301 re ion 992 Keratin_B2 Keratin, high sulfur5.8 -80.3 1 28-166 B2 , rotein 999 Patatin Patatin-like hos 1.4e-54194.7 1 30-196 holi ase 1001 S1 S1 RNAbindin domain1.3 4.5 1 67-131 1004 Branch Core-2/I-Branching0.00014-64.7 1 3-317 enz a 1029 Mur-ligase_C Mur ligase family,7.9 -11.9 1 161-235 glutamate 1i ase doma 1040 Seryl tRNA4N Seryl-tRNA synthetase6 0.1 1 56-102 t N-erminal domain 1041 heme 1 Heme/Steroid binding0.0002422.9 1 19-98 domain ° ~ ~ W o ~ ~_ . _~ ._a ..:
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ao ~z Table 6 SEQ.ID NO: Position of SignalMaximum score Mean score Pe tide 530 23 0.923 0.602 569 23 0.923 0.602 961 23 0.923 0.602 Table 7 SEQ ID NO: Chromsomal location 2 13 21.1-21.3 3 21 22.3-ter 6 7 31.1-31.3 17 16 13.3 18 llcen- 12.1 22 9 34.13- 34.3 32 15 15- 21.1 34 l3cen-13 14.2 21 22.3 36 21 22.3 53 19 13.3 68 1 ter- 12 73 1p36.3-p36.2 Table 7 SEQ ID NO: Chromsomal location 79 22 13.1 g0 16 g2 2 13 g3 10 g7 16 24.3 92 X 22.1-22'.3 94 19 13.3- 12 9g 12 12.1 I00 6 21.3 101 4 13.3 105 6 21.3 112 7 21.3- 22.1 117 21 11.1 126 22 11.2 127 18 I I.2 128 1 12-1 21.2 131 5 ter- 13.3 132 21 22.3 135 xq23 Table 7 SEQ ID NO: Chromsomal location 137 17 21.2 142 14 24.3 143 X 1 I .23 151 X 11.23 152 X 11.23 154 1 21.3- 13.1 15S 5 ter- 15.1 161 5 14.3 164 7 31.1- 31.2 166 6 25.3-27 167 6 25.3-27 169 3 26.2 182 16 13.3- 12 183 11 23.3 185 20 12-13.1 189 6 21.3 193 6 21.3 196 19 13.1 198 X 21.1-X 21.3 205 3 13- 26.1 206 14 21.1- 24.2 Table 7 SE ID NO: Chromsomal location 209 6 16.1- 16.3 215 ' 11 11- 11 218 3 13- 26.1 219 19 13.2 225 22 11.23 230 1 35.1-36.11 235 X 27.3-28 236 19 13.3- 13.4 241 7 21.2- 31.1 243 20 11.2 244 2 23.3- 24.3 256 6 12.1-21.1 278 10 ter- 22.1 282 ~ 14 I

Table 7 SE ID (~O: Chromsomal location 2g7 2 12 293 10 25.1 296 21 22.1 300 1 36.11-36.2 316 5 15.2- 12.3 325 6 21.2-21.3 328 X 21.1-21.32 331 14 24.3 342 14 21.1- 21.3 344 22 13.1 345 22 11.23 348 ~ 5 I

Table 7 SE ID NO: Chromsomal location 355 18 11.2 359 22 13.1-13.32 366 6 21.1 376 lOcen- 26.11 377 17 13.3 380 22 11.2 381 17 11.2 389 l3cen-13 14.2 393 X 21.1-21.33 406 34.11-34.3 415 16 24.3 416 12 13.1 Table 7 SE ID h10: Chromsomal location 422 21 22.3 430 13 14.2-21.1 431 13 12.2- 13.3 435 20 13.2- 13.33 436 20 13.2- 13.33 437 20 13.2- 13.33 440 8 22.3 442 3 29- ter 446 2 23.3- 34 447 2 23.3- 34 455 21 22.3 457 17 11.2 463 20 11.2 475 8 21.1- 21.2 480 11 12.2 4g7 X 11.23 489 1 32.1 490 Xq2l. I

Table 7 SEQ ID NO: Chromsomal location 496 9 34.1 497 19 13.3 498 I 21.2- 22 502 12 12.1 516 3 13- 26.1 Table 8 SEQ ID NO of Full-lengthSEQ ID NO of Full-lengthSEQ ID NO in Priority Nucleotide Se Pe tide Se uence Application uence USSN 09/810,173 34 560 ' 34 36. 562 36 51 577 51 _ Table 8 SEQ ID NO of Full-lengthSEQ ID NO of Full-lengthSEQ ID NO in Priority Nucleotide Se uencePe tide Se uence Application USSN 09/810,173 Table 8 SEQ ID NO of Full-lengthSEQ ID NO of Full-lengthSEQ ID NO in Priority Nucleotide Se Pe tide Se uence Application uence USSN 09/810,173 105 631 t05 t19 645 119 Table 8 SEQ ID NO of Full-lengthSEQ ID NO of Full-lengthSEQ ID NO in Priority Nucleotide Se uencePe tide Se uence Application USSN 09/810,173 _1_85 711 185 _ 712 186 __ 722 196 1_97 723 197 _ 207 733 207 Table 8 SEQ ID NO of Full-lengthSEQ ID NO of Full-lengthSEQ ID NO in Priority Nucleotide Se Pe tide Se uence Application uence USSN 09/810,173 Table 8 SEQ ID NO of Full-lengthSEQ ID NO of Full-lengthSEQ ID NO in Priority Nucleotide Se Pe tide Se uence Application uence USSN 09!810,173 3_04 830 304 Table 8 SEQ ID NO of Futl-lengthSEQ ID NO of Fuli-lengthSEQ ID NO in Priority Nucleotide Se Pe tide Se uence Application uence USSN 09/810,173 341 . 867 341 364 ' 890 364 Table 8 SEQ ID NO of Full-lengthSEQ ID NO of Full-lengthSEQ ID NO in Priority Nucleotide Se uencePe tide Se uence Application USSN 09/810,173 Table 8 SEQ ID NO of Full-lengthSEQ ID NO of Full-lengthSEQ ID NO in Priority Nucleotide Se Pe tide Se uence Application uence USSN 09/810,173 467 993 467 _ Table 8 SEQ ID NO of Full-lengthSEQ ID NO of Full-lengthSEQ ID NO in Priority Nucleotide Se Pe tide Se uence Application uence USSN 09/810,173 Table 8 SEQ ID NO of Full-lengthSEQ ID NO of Full-lengthSEQ ID NO in Priority Nucleotide Se Pe tide Se uence Application uence USSN 09/810,173

Claims (27)

WHAT IS CLAIMED IS:

1. An isolated polynucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 - 526, a mature protein coding portion of SEQ
ID NO: 1 - 526, an active domain coding protein of SEQ ID NO: 1 - 526, and complementary sequences thereof.

2. An isolated polynucleotide encoding a polypeptide with biological activity, wherein said polynucleotide has greater than about 90% sequence identity with the polynucleotide of claim 1.

3. The polynucleotide of claim 1 wherein said polynucleotide is DNA.

4. An isolated polynucleotide of claim 1 wherein said polynucleotide comprises the complementary sequences.

5. A vector comprising the polynucleotide of claim 1.

6. An expression vector comprising the polynucleotide of claim 1.

7. A host cell genetically engineered to comprise the polynucleotide of claim 1.

8. A host cell genetically engineered to comprise the polynucleotide of claim operatively associated with a regulatory sequence that modulates expression of the polynucleotide in the host cell.

9. An isolated polypeptide, wherein the polypeptide is selected from the group consisting of a polypeptide encoded by any one of the polynucleotides of claim 1 i.e.
SEQ ID NO: 527 - 1052).

10. A composition comprising the polypeptide of claim 9 and a carrier.

11. An antibody directed against the polypeptide of claim 9.

12. A method for detecting the polynucleotide of claim 1 in a sample, comprising:
a) contacting the sample with a compound that binds to and forms a complex with the polynucleotide of claim 1 for a period sufficient to form the complex; and b) detecting the complex, so that if a complex is detected, the polynucleotide of claim 1 is detected.

13. A method for detecting the polynucleotide of claim 1 in a sample, comprising:
a) contacting the sample under stringent hybridization conditions with nucleic acid primers that anneal to the polynucleotide of claim 1 under such conditions;
b) amplifying a product comprising at least a portion of the polynucleotide of claim 1; and c) detecting said product and thereby the polynucleotide of claim 1 in the sample.

14. The method of claim 13, wherein the polynucleotide is an RNA molecule and the method further comprises reverse transcribing an annealed RNA molecule into a cDNA polynucleotide.

15. A method for detecting the polypeptide of claim 9 in a sample, comprising:
a) contacting the sample with a compound that binds to and forms a complex with the polypeptide under conditions and for a period sufficient to form the complex; and b) detecting formation of the complex, so that if a complex formation is detected, the polypeptide of claim 9 is detected.

16. A method for identifying a compound that binds to the polypeptide of claim 9, comprising:

a) contacting the compound with the polypeptide of claim 9 under conditions sufficient to form a polypeptide/compound complex; and b) detecting the complex, so that if the polypeptide/compound complex is detected, a compound that binds to the polypeptide of claim 9 is identified.

17. A method for identifying a compound that binds to the polypeptide of claim 9, comprising:
a) contacting the compound with the polypeptide of claim 9, in a cell, under conditions sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a reporter gene sequence in the cell; and b) detecting the complex by detecting reporter gene sequence expression, so that if the polypeptide/compound complex is detected, a compound that binds to the polypeptide of claim 9 is identified.

18. A method of producing the polypeptide of claim 9, comprising, a) culturing a host cell comprising a polynucleotide sequence selected from the group consisting of a polynucleotide sequence of SEQ ID NO:

526, a mature protein coding portion of SEQ ID NO: 1-526, an active domain coding portion of SEQ ID NO: 1-526, complementary sequences thereof, under conditions sufficient to express the polypeptide in said cell; and b) isolating the polypeptide from the cell culture or cells of step (a).

19. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of any one of the polypeptides from the Sequence Listing, the mature protein portion thereof, or the active domain thereof.

20. The polypeptide of claim 21 wherein the polypeptide is provided on a polypeptide array.

21. A collection of polynucleotides, wherein the collection comprising the sequence information of at least one of SEQ ID NO: 1 - 526.

22. The collection of claim 21, wherein the collection is provided on a nucleic acid array.

23. The collection of claim 22, wherein the array detects full-matches to any one of the polynucleotides in the collection.

24. The collection of claim 22, wherein the array detects mismatches to any one of the polynucleotides in the collection.

25. The collection of claim 21, wherein the collection is provided in a computer-readable format.

26. A method of treatment comprising administering to a mammalian subject in need thereof a therapeutic amount of a composition comprising a polypeptide of claim 9 or 19 and a pharmaceutically acceptable carrier.

27. A method of treatment comprising administering to a mammalian subject in need thereof a therapeutic amount of a composition comprising an antibody that specifically binds to a polypeptide of claim 9 or 19 and a pharmaceutically acceptable carrier.