Gene encoding for a L5/3 growth factor and its CDNA

A growth factor protein similar in structure and function to hepatocyte growth factor has been discovered along with the DNA and cDNA coding for this in both the mouse and human. The DNA includes 18 exons and is homologous to DNA at the D3F15S2 locus on human chromosome 3; a region predicted to code for one or more tumor suppressor genes.

BACKGROUND 
Growth factors are important for normal developmental processes, as well as 
for healing of wounds. Their abnormal expression has been implicated in 
neoplasia and other proliferative disorders. The kringle-containing 
protein hepatocyte growth factor (HGF) was originally identified as a 
potent growth factor involved in liver regeneration after liver injury or 
partial hepatectomy. It is now known that HGF functions as a growth factor 
for a broad spectrum of tissues and cell types. In addition, it has been 
recently discovered that HGF is identical to scatter factor (SF) a 
cytokine secreted from certain fibroblasts that enhances movement and 
causes the dissociation and scattering of epithelial cells (Gheradi & 
Stoker, 1990). The proto-oncogene c--met, a tyrosine kinase, has been 
found to be the cell surface receptor for HGF (Rubin et al., 1991; Bottaro 
et al., 1991). These properties may be important for metastasis of tumor 
cells. 
In 1973 it was recognized that serum from partially hepatectomized rats 
stimulated hepatocyte proliferation in vitro (Morley et al., 1973). One of 
the agents responsible for this phenomenon was identified and isolated 
from such serum and from serum of patients with fulminant liver failure 
(Morley et al., 1973; Michalopoulous et al., 1984; Nakamura et al., 1984; 
Gohda et al., 1988). This agent was named hepatopoietin A or hepatocyte 
growth factor (HGF). HGF stimulates hepatocyte DNA synthesis and 
proliferation. Its serum concentration increases dramatically after rats 
undergo partial hepatectomy and decreases when the liver regenerates. HGF 
is produced by non-parenchymal liver cells (Schirmacher et al., 1992) and 
acts directly on hepatocytes in a paracrine fashion to stimulate cell 
multiplication. Although HGF stimulates growth of normal hepatocytes, it 
also has antiproliferative effects on hepatocarcinoma cells in culture 
(Tajima et al., 1991; Shiota et al., 1992). 
HGF is a heterodimer of 82 kD composed of a .alpha.- and .beta.-subunit 
with 51 kD and 26 kD molecular weight, respectively. The cDNAs for human 
and rat HGF have been cloned and characterized by several groups (Miyazawa 
et al., 1989; Nakamura et al., 1989; Okajima et al., 1990; Seki et al., 
1990; Tashiro et al., 1990; Rubin et al., 1991). 
HGF has no obvious homology with other known growth factors but is 38% 
homologous to plasminogen. It contains four kringle domains followed by a 
serine protease-like domain where the active site His and Ser have been 
changed to Gln and Tyr, respectively. HGF has no detectable protease 
activity. At present the function of the kringle domains in HGF is 
unknown. 
Kringle domains were first identified in bovine prothrombin as an internal 
duplication of a triple-disulfide--bonded structure containing 
approximately 80 amino acids (Magnusson et al., 1975). Kringle domains 
were until recently only characterized in plasma proteins that functioned 
in blood coagulation or fibrinolysis (Davie et al., 1986) which includes 
prothrombin, Factor XII, urokinase-type plasminogen activator, tissue-type 
plasminogen activator and plasminogen. Recently, apolipoprotein(a) and HGF 
have also been shown to contain kringle domains. Apolipoprotein(a) is 
thought to be involved in atherosclerosis (McLean et al., 1987). Kringle 
structures are thought to function autonomously (Trexler & Patthy, 1983; 
van Zonneveld et al., 1986) and fold independently (Tulinsky et al., 
1988). 
Kringles appear to be protein-binding domains and have been shown to be 
essential for the function of prothrombin, plasminogen and tissue 
plasminogen activator. The functions of all other kringle structures has 
not been determined, but since these structures are over 50% identical 
with each other, it is reasonable to assume that they are involved in 
binding interactions with other proteins essential for their regulation. 
Two functional variants of HGF have been identified and have been found to 
be expressed at variable levels depending on the cell line or tissue being 
analyzed. A form of HGF containing the aminoterminal end of the protein 
including the first two kringle domains appears to result from alternative 
processing of the gene coding for HGF (Chan et al., 1991; Miyazawa et al., 
1991). This variant binds to the c-met receptor although not as 
effectively aS the full-length protein. Another variant has a five amino 
acid deletion in the first kringle domain that appears to have no effect 
on its activity (Seki et al., 1990; Rubin et al., 1991). Specific domains 
in HGF have been deleted by using techniques in molecular biology and the 
resultant proteins have been studied in various assays where native HGF 
can be measured. Matsumoto et al. (1991) concluded that the amino-terminal 
portion of the protein including the first and second kringle domains are 
essential for biological activity of HGF and possibly binding to the 
receptor. 
Chromosomal abnormalities in a number of neoplastic diseases are sometimes 
associated with the activation of a proto-oncogene or the loss of a gene 
that suppresses tumor growth. Growth factors are important for normal 
developmental processes, as well as healing of wounds. Their abnormal 
expression has been implicated in neoplasia and other proliferative 
disorders (Aaronson, 1991). Growth factors are involved in signaling 
pathways that influence normal cellular differentiation. These proteins 
cause cells in the resting phase (Go) to enter and progress through the 
cell cycle. Oncogenic mutations in several growth factors result in 
unregulated cell growth. Tumor suppressor genes are genes expressed in 
normal cells that play regulatory roles in cell proliferation, 
differentiation and other cellular events. Loss or inactivation of these 
genes is oncogenic. Tumor suppressor genes that have been extensively 
characterized include the genes for colon carcinoma, retinoblastoma, type 
2 neurofibromatosis, the genes involved in Wilms tumor and the p53 gene 
(reviewed in Weinberg, 1991). Tumor suppressor genes are involved in cell 
cycle control, signal transduction, anglogenesis, and development (Sager, 
1989; Weinberg, 1991). 
The concept that the loss of genetic material or the inactivation of a gene 
plays an important role in human cancer is based on the original 
observation that somatic cell hybrids between tumor cells and normal cells 
were no longer tumorigenic. This indicated that normal cells contain genes 
coding for tumor suppressors whose function was absent in cancer cells. In 
addition, cytogenic and restriction fragment length polymorphism (RFLP) 
analyses have established an association between the loss of genetic 
material on specific chromosomes and the development of various human 
malignancies. 
Deletion of the short arm of human chromosome 3 has been implicated in 
small cell lung carcinoma (SCLC; Whang-Peng et al., 1982; Naylor et al., 
1987), other lung cancers (Kok et al., 1987; Brauch et al., 1987), renal 
cell carcinoma (Zbar et al., 1987; Kovacs et al., 1988) and yon 
Hippel-Lindau syndrome (Seizinger et al., 1988) which suggests that one or 
more tumor suppressor genes reside on chromosome 3p which manifest their 
transformed phenotype upon their inactivation. The chromosomal locus 
DNF15S2 (also called D3F15S2) is a RFLP probe that most consistently is 
associated with loss of heterozygosity in SCLC, being detected in 
virtually 100% of SCLC. 
Lung cancer is a common human malignancy with 150,000 new cases reported 
each year in the United States. Unfortunately, 90% of affected persons 
will die within 5 years of diagnosis. Mortality due to lung cancer has 
increased more than 15% since 1973. Increases in cigarette smoking from 
1900 until the early 1960s has transformed lung cancer from a rare disease 
at the turn of the century to the current leading cause of cancer death. 
In women, lung cancer surpassed breast cancer as the leading cause of 
cancer death in 1986 with rates expected to continue to increase for at 
least another ten years (Henderson et al., 1991). 
Lung cancer is divided into small cell and non-small cell varieties. The 
non-small cell lung cancers include adenocarcinoma, squamous and 
epidermoid lung cancer and large-cell lung cancer. Chromosome 3p(14-23) 
changes have been found in nearly all small cell lung cancers and in a 
large fraction of non-small cell lung cancers. 
Cancer of the kidney accounts for 1-2% of all malignancies (excluding skin 
cancer) with renal cell carcinoma comprising 85% of these. Renal cell 
carcinoma (RCC) occurs in sporadic and familial forms and are commonly 
seen in the age group between 50 to 70 years. Cigarette smoking is a known 
risk factor for this form of cancer (Walter et al., 1989). Deletion of the 
short arm of chromosome 3 is the most commonly involved region of the 
genome in RCC and therefore appears to play a role in the development 
and/or progression of this form of cancer. 
Several genes have been localized near or at the D3F15S2 locus. The 
ER.beta.AB locus coding for a DNA-binding thyroid hormone receptor is 
localized to human chromosome 3p21-25, and overlaps deletions found in 
SCLC. Leduc et al. (1989) determined that many non-SCLC tumors retained 
both ERBAB alleles while the D3F15S2 locus was reduced to homozygosity, 
ruling out a role for the thyroid hormone receptor in this form of cancer. 
The gene encoding aminoacylase-1 at 3p21 is inactivated in a large 
fraction of SCLC (Naylor et al., 1982, 1989). A similar allelic loss is 
observed in sporadic renal cancers and there are cytogenetic abnormalities 
of this region in familial renal cell cancer. The gene coding for 
protein-tyrosine phosphatase7 (PTP.gamma.) maps to 3p21 (LaForgia et al., 
1991). This protein and homologous family members reverse the effect of 
protein tyrosine kinases, of which, some have been identified as oncogenes 
(ie., met, fms, kit, ERBB). In one study, one PTP.gamma. allele was 
deleted in 3 of 5 renal carcinoma cell lines and in 5 of 10 lung carcinoma 
samples tested (LaForgia et al., 1991). In summary, the key gene(s) 
responsible for tumor suppressor activity at this locus is unknown, 
although there are some candidate genes. 
SUMMARY OF THE INVENTION 
The present invention is based on the isolation and characterization of the 
human gene located at the D3F1552 locus on human chromosome 3 referred to 
as L5/3. The protein coded for by this gene is referred to as the L5/3 
protein. The translated amino acid sequence indicates that L5/3 protein is 
composed of four kringle structures followed by a serine protease-like 
domain. This is identical in composition to hepatocyte growth factor (HGF) 
although L5/3 protein and HGF are only 50% identical to each other when 
their amino acid sequences are compared. The corresponding human cDNA has 
also been isolated, as well as the mouse gene and cDNA. 
The L5/3 protein can be employed to alter cell growth (as a growth factor 
or tumor suppressor). The L5/3 protein has properties similar to HGF that 
is actively involved in liver regeneration. 
In addition, the L5/3 gene is identical to the gene at a locus on human 
chromosome 3 (3p21) that is deleted in DNA from all small cell lung 
carcinomas and has been hypothesized to contain one or more tumor 
suppressor genes. Thus this isolated gene L5/3 can be used as a probe to 
provide an indication of a predisposition for certain cancers. Further, 
identification of the coded L5/3 protein can also be utilized to evaluate 
a predisposition to cancer.

DETAILED DESCRIPTION OF THE INVENTION 
The methods discussed below to obtain DNA sequences encoding L5/3 are 
merely for purposes of illustration and are typical of those that might be 
used. However, other procedures may also be employed. 
The human L5/3 gene was isolated using a multistep process employing 
various DNA and cDNA probes which were both of human and mouse origin. 
Further, the initial probe is a bovine prothrombin cDNA. 
A human liver genomic DNA library cloned into bacteriophage Charon 28 (Lawn 
et al., 1978) was obtained from Dr. Tom Maniatis, Harvard University (this 
library is presently available from the ATCC). This library is an Alu/Hae 
III fetal human genomic DNA library. The library containing approximately 
2.times.10.sup.6 recombinant phage was plated out on E. coli strain LE392 
and grown overnight at 37.degree. C. and was screened by the in situ 
plaque hybridization technique of Benton & Davis (1977) as modified by Woo 
(1979). 
Approximately 1.times.108.sup.8 cpm of nick-translated bovine prothrombin 
cDNA probe (obtained by Ava I and Bam HI digestion of pBII102; this probe 
is 1200 bp in length coding for amino acids 109-500; MacGillivray & Davie, 
1984) was hybridized to nitrocellulose filters containing the recombinant 
phage under conditions of reduced stringency. These conditions included 
hybridization at 60.degree. overnight in 2.times.Denhardt's solution 
(0.04% polyvinylpyrrolidone, 0.04% Ficoll and 0.04% bovine serum albumin) 
containing 6.times.SSC [1.times.SSC: 0.15M sodium chloride and 0,015M 
trisodium citrate (pH 7.0)], 1 mM EDTA and 0.5% sodium dodecyl sulfate 
(SDS). The filters were washed three times at 60.degree. C. in 6.times.SSC 
with 0.5% SDS. Twelve positive phage were identified. Two of these phage 
have been identified to code for the human L5 gene. 
This human L5 gene and its method of selection is also disclosed in the 
doctoral thesis of Sandra J. Friezner Degen entitled Isolation and 
Characterization of the Human Prothrombin Gene And Related Genes published 
in 1982. As discussed below this gene characterized as L5 is an incomplete 
gene but is useful in isolation and characterization of the gene of the 
present invention. Until now its function was also unknown. 
The obtained L5 gene was then used to obtain the corresponding human L5 
cDNA. The human cDNA corresponding to the L5 gene was used to obtain the 
mouse cDNA. This mouse cDNA was in turn used to obtain the mouse L5/3 
gene. The mouse L5/3 gene was used to obtain the human L5/3 gene. 
A .lambda.gtll cDNA library prepared from human fetal liver mRNA (provided 
by Dr. Vincent Kidd, University of Alabama, Birmingham; Kwok et al., 1985) 
was screened for the human cDNA coding for L5 by using a probe isolated 
from the human L5 gene (680 bp Bam HI and Hind III fragment isolated from 
a 1850 bp subclone (obtained by digestion of L5 with Hind III and cloning 
into pBR322) and coding for part of the second kringle and all of the 
third; nucleotides 2190-2868 of Sequence ID No. 6). Approximately 
1.times.105 phage were screened at high stringency using standard 
techniques (Degen & Davie, 1987). These conditions include hybridization 
with the same solution used for isolation of the human L5 gene discussed 
above but at 68.degree. C. and washing at 68.degree. C. in 1.times.SSC 
containing 0.5% SDS. Six positives were identified. The longest (#46) was 
1.9 kb in length. A 5'-end fragment from this cDNA (340 bp Eco RI and Nco 
I fragment coding for part of kringles 1 and 2; nucleotides 388-733 in 
sequence ID No. 1) was used to rescreen the library to obtain clones with 
longer 5' ends. Two clones (#33 and #19) were identified and characterized 
(Sequence ID No. 1,2,3). The longest clone (#33) is 2200 bp in length 
excluding the poly(A) tail and is not full-length since its 5' end starts 
16 bp downstream from the putative initiator methionine codon in the first 
exon of the gene (starting at nucleotide 290 in Sequence ID No. 6). 
A .lambda.gt10 mouse liver cDNA library (Stratagene, La Jolla, Calif.; from 
mouse strain C57BL/6) was then screened using a fragment from the human 
cDNA #33. Approximately 1.times.10.sup.6 phage were screened with a probe 
isolated from the 5' end of the human cDNA (the 340 bp fragment was 
isolated from human cDNA-33 after digestion with Eco RI and Kpn I and 
coded for the amino-terminal portion of the protein including eight amino 
acids of the first kringle; nucleotides 1 to 334 in Sequence ID No. 1) 
using the conditions of reduced stringency discussed above for the 
isolation of the human L5 gene. These conditions were used to allow for 
cross species hybridization. Ten positives were identified and eight were 
characterized after cloning the cDNAs into pBR322. 
The longest cDNA (pML5-2) was 2188 bp in length and was not full-length 
since the open reading frame was present at the 5' end of the sequence 
with no codon for the initiator methionine in-frame with the coding 
sequence (Sequence ID No. 4). After determination of the sequence of the 
mouse gene it was determined that the cDNA lacked 44 bp of coding and 94 
bp of 5' noncoding sequence at its 5' end. 
A mouse liver genomic DNA library cloned into the Bam HI site of EMBL-3 
SP6/T7 (Clontech; mouse strain Balb/c; catalog #M 1030 J) was screened for 
the gene coding for mouse L5/3. Approximately 1.times.10.sup.6 phage from 
the library were screened with a probe isolated from the previously 
isolated mouse cDNA (the 1450 bp insert was isolated from pML5-2 after 
digestion with Eco RI and coded for eight amino acids of the second 
kringle, all of the third and fourth kringles and the serine protease-like 
domain; nucleotides 738 to 2188 in sequence ID No. 4) using the identical 
high stringency conditions discussed above for the isolation of the human 
L5 cDNA. On the initial screen, 65 positives were identified; 9 were 
characterized. Restriction fragments of phage DNA were subcloned into 
pBR322. 
A second human genomic DNA library prepared from placental DNA using EMBL-3 
SP6/T7 as the cloning vector (Clontech; catalog #HL 1067 J) was screened 
for the 5' end of the gene coding for L5/3 with a mouse genomic fragment 
containing the first exon of the gene for mouse L5/3. This fragment was 
400 bp in length and was isolated by digestion of a genomic subclone from 
the mouse gene (a 3.3 kb Bgl II fragment cloned into the Bam HI site of 
pBR322) with Bam HI and Eco RI (nucleotides 1086-1486 in Sequence ID No. 
5). Approximately, 500,000 recombinant phage were screened under identical 
reduced stringency conditions discussed above for the original isolation 
of the L5 gene. Thirteen positives were identified; three were 
characterized and found to code for the 5' end of the human L5/3 gene 
(referred to as L3). 
Fragments from two overlapping phage (L5 and L3) were subcloned into pBR322 
and the DNA sequence of the inserts were determined. The entire sequence 
of the gene present in L5 and L3 is shown in Sequence ID No. 6. This gene 
is the complete gene L5/3 of the present invention. The gene is 4690 bp in 
length (from the codon for the putative initiator methionine to the 
polyadenylation site; nucleotides 274-4963 in Sequence ID No. 6). The gene 
is composed of 18 exons separated by 17 intervening sequences. In 
addition, sequence has been determined both upstream and downstream of the 
gene. 
The 3' end of the acyl-peptide hydrolase gene is 444 base pairs downstream 
of L5/3 gene on the complementary strand (nucleotides 5408 to 6100 in 
Sequence ID No. 6). 
Several isolated cDNA fragments were characterized. One cDNA (#19) had two 
parts of the coding region deleted when compared to cDNA (#33) which 
included nucleotides 1366-1486 and 1565-1613 in Sequence ID No. 1. The 
cDNA for #19 is Sequence ID No. 3. In the L5/3 gene the region deleted 
included exon 13 (nucleotides 3532-3652 in Sequence ID No. 6) and the 5' 
end of exon 18 (nucleotides 4033-4081 in Sequence ID No. 6). If this cDNA 
represents a translated mRNA, it would code for the four kringle domains 
followed by only 22 amino acids since there are two in-frame stop codons 
at that point. 
Comparison of all cDNA sequences indicates that at least five polymorphisms 
occur; only one of which results in an amino acid substitution. This 
substitution is a Cys (Sequence ID No. 1) to Phe (Sequence ID No. 2) at 
amino acid residue 212. When the sequence of the exons in the L5/3 gene 
are compared to the cDNA sequences, one additional polymorphic site is 
identified that results in a Tyr (in the cDNAs; Sequence ID No.1 and 
Sequence ID No. 2) to Cys (in the gene; Sequence ID No. 6) substitution at 
residue 13. All of these polymorphisms should occur in the population and 
all would represent functional L5/3 protein. 
The gene and cDNA coding for L5/3 codes for a protein with similar domain 
structure as HGF with four kringles followed by a serine protease-like 
domain. The translated amino acid sequences of the gene (shown in the 
Figure) and cDNA for human L5/3 predict a protein with 80,325 molecular 
weight containing 711 amino acids (excluding additional post-translational 
processing). The figure is a schematic diagram of the amino acid sequence 
of human L5/3. The amino acid sequence of human L5/3 is shown starting 
with residue 1 at the amino-terminal end and ending with residue 711 at 
the carboxy-terminal end. Placement of disulfide bonds was determined 
solely on the basis of homology with this protein sequence to plasminogen, 
where placement of disulfides has been determined. The four kringle 
domains are indicated by K1, K2, K3, and K4. The region homologous to the 
preactivation peptide of plasminogen is indicated by PAP. The three 
potential N-linked cleavage sites are indicated by open arrows. The 
sequence following the second open arrow is homologous to other serine 
proteases. The active site amino acids His, Asp and Ser have been changed 
to Gln, Gln and Tyr, respectively and are indicated in boxes. Amino acids 
are represented in the one letter code where A-Ala, C=Cys, D=Asp, E=Glu, 
F=Phe, G=Gly, H=His, I=Ile, K=Lys, L=Leu, M=Met, N=Asn, P=Pro, Q=Gln, 
R=Arg, S=Ser, T=Thr, V=Val, W=Trp and Y=Tyr. There are three potential 
carbohydrate additions sites at asparagines in the sequence Asn-X--Thr/Ser 
at positions 72, 296 and 615 (in the Figure). The sequence at the 
amino-terminal end of the putative protein is hydrophobic and therefore 
may be part of a signal sequence required for secretion of the protein 
from the cell. Comparison of the amino-terminal sequence to a consensus 
sequence compiled for known signal peptidase cleavage sites (Von Heijne, 
1983; Watson, 1984) predicts that the cleavage site could be between 
residues Gly-31 and Thr-32 (in the Figure). The active protein coded by 
the L5/3 gene refers to the protein as modified during expression and 
passage through the cell wall. Thus the active protein would exclude the 
signal sequence which may include residues 1-31. 
Based on homology to plasminogen and other serine proteases, two additional 
proteolytic cleavage sites are predicted. Between the kringle domain 
region and the serine protease-like domain is an amino acid sequence that 
is typically found at the activation sites of other coagulation and 
fibrinolytic proteins with serine protease activity. Residue 483 is an Arg 
followed by the sequence Val-Val-Gly--Gly that is typically found at the 
amino-terminal end of serine proteases (in the Figure). On the basis of 
this sequence, it is anticipated that active L5/3 protein is 
proteolytically cleaved to yield a two-chain molecule held together by 
disulfide bonds or cleaved into two separate polypeptide chains. Amino 
acid residues 56-103 in human L5/3 are homologous to the preactivation 
peptide (PAP) in plasminogen and HGF (in the Figure). The PAP region in 
plasminogen is between the amino-terminal end of the mature protein and 
the plasmin activation site between Lys-77 and Lys--78. Both lysines are 
conserved in L5/3 (residues 103 and 104 in the Figure). Cleavage at this 
site would remove a peptide of 103 amino acids from the protein (including 
the putative signal peptide) if it is not disulfide-bonded to the 
remainder of the protein (there is one additional cysteine in this 
region). 
The amino acids found in the active site of serine proteases have been 
changed from His to Gln, Asp to Gln, and Set to Tyr at positions 522, 568, 
and 661, respectively (in the Figure). Therefore, we anticipate that this 
protein has no proteolytic activity. 
Only a portion of the entire primary structure may be required for 
function. Also included within the definition the active proteins coded 
for by the L5/3 gene are fragments of the entire sequence which retain 
activity particularly those which result from post-translational 
processing such as glycosylation. It is further understood that minor 
modifications of primary amino acid sequence may result in proteins which 
have substantially equivalent or enhanced activity as compared to any 
particular illustrated sequence. These modifications may be deliberate, as 
through site-directed mutagenesis, or may be accidental, such as mutations 
of hosts which are L5/3 producing organisms. All of these modifications 
are included as long as the activity of the L5/3 protein is retained. 
The complete mouse L5/3 DNA sequence and the amino acid coding regions of 
the gene are shown in Sequence I.D. No. 5. The mouse L5/3 gene is composed 
of 18 exons separated by 17 intervening sequences. The gene is 4613 bp in 
length from the site of initiation of transcription to the polyadenylation 
site. (Nucleotides 1192 to 5804 in Sequence ID No. 5.) The gene coding for 
acyl-peptide hydrolase is 410 base pairs downstream of the L5/3 gene, but 
is transcribed from the complementary strand (nucleotides 6215-6751 in 
Sequence ID No. 5). 
The mouse cDNA (Sequence ID No. 4) codes for a putative protein with the 
same domain structure as its human homolog with four kringle domains 
followed by a serine protease-like domain. Translated sequence from the 
gene and cDNA coding for mouse L5/3 indicate that a protein of 716 amino 
acids with a molecular weight of 80,593 would be synthesized (excluding 
any additional post-translational processing). There are four potential 
N-linked carbohydrate attachment sites at asparagines in the sequence 
Asn-X--Thr/Ser at positions 72, 173, 305 and 624. The sequence at the 
amino-terminal end of the putative protein is hydrophobic and therefore 
may be part of a signal sequence required for secretion of the protein 
from the cell. Based on homology with the human cDNA the signal peptidase 
cleavage site is between amino acid residues Gly-31 and Thr--32 Sequence 
ID No. 4. 
There is only one difference found when the sequences of the cDNA and gene 
coding for mouse L5/3 are compared which results in the substitution of a 
Gln in the gene (Sequence ID No. 5) to a Pro in the cDNA (Sequence ID No. 
4) at residue 19. It is anticipated that this site is polymorphic in the 
population and that both are representatives of functional L5/3 protein. 
The primary site of synthesis of mRNA for L5/3 is in the liver as 
determined by analysis of rat tissue RNA by Northern analysis. Lesser 
amounts of L5/3 mRNA were found in the lung, adrenal, and placenta. 
A fusion protein was produced as well as polyclonal antibodies. A 968 bp 
fragment from the human L5/3 cDNA (#33) was obtained after digestion with 
Bam HI and Bgl II and cloned into the prokaryotic expression vector pUR278 
(Ruther & Muller-Hill, 1983). This fragment represents nucleotides 
746-1714 in Sequence ID No. 1 and codes for part of kringle 2, all of 
kringles 3 and 4 and part of the serine protease-like domain of L5/3. In 
pUR278, the L5/3 cDNA fragment was cloned into the Bam HI site near the 
3'end of the lac Z gene to allow for expression of an active 
.beta.-galactosidase fused with the peptide encoded by the L5/3 cDNA 
fragment in E. coli. The correct reading frame was maintained in the 
construct as determined by DNA sequence analysis. The 968 bp insert codes 
for 321 amino acids (residues 255-576 in Sequence ID No. 1) with a 
calculated molecular weight of approximately 35,000 daltons. The predicted 
size for the fusion protein is approximately 151,000 daltons which 
contains the human L5/3 protein peptide fused to .beta.-galactosidase 
(116,000 MW). 
The fusion protein was isolated and electroeluted after SDS-polyacrylamide 
gel electrophoresis of isopropyl thiogalactoside (IPTG) induced E.coli 
cell extract from cells that had been transformed with the fusion 
construct. 
Fusion protein (.beta.-galactosidase/L5/3) was injected into New Zealand 
rabbits in order to obtain polyclonal antibodies against the fusion 
protein by standard techniques. 
Tissue lysate from human liver and human plasma were electrophoresed on 
SDS-polyacrylamide gels under reducing condition, transferred to an 
Immobilon-P membrane (Amersham, Inc.) and reacted with rabbit 
anti-.beta.-galactosidase/human L5/3 fusion protein serum. The antibody 
reacted primarily with a polypeptide of approximately 84,000 molecular 
weight in plasma and to a lesser extent with a polypeptide of 60,000 
molecular weight. Non-immune serum did not react with polypeptides of 
these sizes on either reducing or non-reducing gels. The antibody did not 
react with any detectable protein in the liver extract. The antibody did 
not cross react with purified human prothrombin. On nonreducing gels the 
antibody detected a protein of approximately 90,000 molecular weight. 
These results are consistent with the presence of a signal peptide at the 
amino-terminal of L5/3 that is required for secretion from the cell since 
the antibody reacted only with a polypeptide present in plasma and not in 
liver extract. The signal peptide of approximately 3500 daltons would be 
removed before secretion from the cell. In addition, these results are 
consistent with proteolysis at possibly both of the putative proteolytic 
sites present in L5/3 (in the Figure). Based on the translated cDNA 
sequence, the full-length protein would be approximately 80,000 daltons. 
Carbohydrate addition to some or all of the three possible N-linked 
glycosylation sites might increase the molecular weight to the 
approximately 90,000 dalton size seen in plasma on non-reducing gels. On 
reducing gels where the disulfide bonds have been removed, the 84,000 
molecular weight protein could be the result of proteolytic cleavage 
between amino acid residues 103 and 104 (Sequence ID No. 1 in the Figure). 
The predicted size of the protein with the amino-terminal 103 residues 
removed is approximately 70,000 daltons. The 84,000 molecular weight 
protein may be this fragment of L5/3 after glycosylation. On non-reducing 
gels this fragment could possibly be disulfide-bonded to the remainder of 
the protein (there is one additional cysteine in this part of the protein 
that could be involved in disulfide formation) and may be the reason why a 
larger protein was observed on the non-reduced gel compared to the reduced 
one. The 60,000 dalton polypeptide also seen in plasma on reducing gels 
could be the result of additional proteolytic cleavage of the protein 
between residues 483 and 484 (Sequence ID No. 1 in the Figure) which is a 
typical serine protease activation site. The resultant fragments would 
have molecular weights of 50,000 and 25,000 daltons (excluding any 
post-translational modifications such as glycosylation). If the two 
potential N-linked carbohydrate additions sites in the 50,000 dalton 
fragment are glycosylated the fragment could be 60,000 daltons in size. 
The smaller fragment may not have been resolved on this gel or the 
antibody may not react with it. 
These results are analogous to the form of HGF seen in plasma which is a 
heterodimeric protein of 82,000 daltons composed of .alpha. and .beta. 
subunits of 51,000 and 26,000 daltons, respectively. 
A full-length human L5/3 cDNA was then constructed. Since the longest human 
L5/3 cDNA was not full-length and was missing 16 bp from the 5' end 
(Sequence ID No. 1), a full-length L5/3 cDNA was constructed by addition 
of adaptors. The following complementary oligonucleotides were 
synthesized: coding: 5' GCGAATTCCACCATGGGGTGGCTCCCA 3' complementary 3' 
CGCTTAAGGTGGTACCCCACCGAGGGTTTAA 5 ' 
When hybridized to each other this adaptor has the following features: 1) 
the presence of an Eco RI restriction site (5' GAATTC 3') at the 5' end 
for cloning into the Eco RI sites in expression vectors; 2) a Kozak 
consensus sequence surrounding the ATG coding for the initiator methionine 
(5' CCACCATGG 3'; Kozak, 1986) to optimize translation from this 
methionine; 3) an overhanging-end at the 3' end of the adaptor that is 
compatible with the EcoRI site present at the 5' end of the L5/3cDNA-(33) 
for ligation together; and 4) after ligation of the adaptor to the cDNA 
insert the Eco RI sites at the ends of the original cDNA will not be 
reconstituted and therefore the only Eco RI sites will be due to the 
adaptor. 
The 2200 bp cDNA insert from the human L5/3cDNA-(33) was isolated after 
digestion with Eco RI (nucleotides 1-2219 in Sequence ID No. 1) and 
ligated to the hybridized oligonucleotides (adaptor). The resulting 
mixture was digested with Eco RI and electrophoresed on low melting point 
agarose. The band representing the cDNA with ligated adaptors was excised 
and the DNA isolated. This DNA was then ligated to the vector Bluescript 
SK +/- (Stratagene, La Jolla, Calif.), and used to transform E. coli. E. 
Coli transformed with the anticipated full-length L5/3cDNA containing 
plasmid were initially identified by restriction enzyme digestion of 
plasmid isolated from white colonies on agar plates containing IPTG, X-Gal 
and ampicillin (E. coli containing the recombinant vector will give white 
colonies while Bluescript without an insert will give blue colonies). 
Final confirmation of the full-length construct was determined by DNA 
sequence analysis. 
After adaptor ligation to the human L5/3 cDNA insert there are eight 
nucleotide differences when the sequence is compared to the exons in the 
gene for human L5/3 (nucleotides 1301-1312 in Sequence ID No. 6). These 
are due to the original Eco RI site present at the 5' end of the L5/3cDNA 
insert that is the result of linker addition during the construction of 
the cDNA library and is not naturally present in the cDNA (as determined 
from the sequence of the gene for this region). These differences result 
in three amino acid substitutions that we do not anticipate will affect 
the function of recombinant full-length L5/3 protein since they are 
present in the proposed signal peptide. The sequence of the full-length 
construct is shown in Sequence ID No. 7. Residues 6-8 are Leu-Leu-Leu in 
the gene coding for human L5/3 (Sequence ID No. 6) and Asn-Ser-Val in the 
full length L5/3 cDNA (Sequence ID No. 7). Adaptor(s) are also present at 
the 3' end of the cDNA but should not affect the expression of L5/3 since 
they are present in the 3' noncoding region of the cDNA. 
Mammalian expression vectors were also constructed. The full-length L5/3 
insert was isolated from the Bluescript vector after digestion with Eco 
RI. The insert was then cloned into the Eco RI site of the expression 
vector pDX. This expression vector was obtained from Dr. Kathy Berkner of 
Zymogenetics. pDX contains an origin of replication, a SV-40 enhancer, a 
adenovirus promoter, splice sequences and a polyadenylation signal for 
appropriate replication and transcription of the inserted cDNA and the 
accurate synthesis and secretion of the expressed protein. The cDNA 
provides the signal sequence for secretion. This expression vector has 
been used to transfect the eukaryotic cell line--Hela which does not 
normally express L5/3 protein. 
Expression in general may be achieved in a variety of host systems 
including, in particular, mammalian and bacterial systems, as well as 
yeast based systems. In addition, other cell systems have become available 
such as the baculovirus vectors used to express protein encoding genes in 
insect cells. The expression system discussed here is illustrative, and it 
is understood by those in the art that a variety of expression systems can 
be used. 
Additional factors necessary or helpful in effecting expression may 
subsequently be identified. 
As the nucleotide sequences encoding the human and mouse L5/3 proteins are 
now available, these may be expressed in a variety of systems. If 
procaryotic systems are used, an intronless coding sequence should be 
used, along with suitable control sequences. The cDNA clones for any of 
the above L5/3 proteins may be excised with suitable restriction enzymes 
and ligated into procaryotic vectors for such expression. For procaryotic 
expression of L5/3 genomic DNA, the DNA should be modified to remove the 
introns, either by site-directed mutagenesis, or by retrieving 
corresponding portions of cDNA and substituting them for the 
intron-containing genomic sequences. The intronless coding DNA is then 
ligated into expression vectors for procaryotic expression. 
As discussed above, L5/3 encoding sequences may also be used directly in an 
expression system capable of processing the introns, usually a mammalian 
host cell culture. To effect such expression, the genomic sequences can be 
ligated downstream from a controllable mammalian promoter which regulates 
the expression of these sequences in suitable mammalian cells. 
E. coli RRI cells carrying the plasmid containing L5/3cDNA (#33) exhibited 
in Sequence ID No. 1 has been deposited with the American Type Cell 
Culture in Rockville, Md. and is designated ATCC No. 68976 (deposited on 
May 6, 1992). 
The gene sequence No. 1 submitted below is useful of course when labeled by 
for example Nick translation as a probe for the D3F15S2 locus on human 
chromosome 3. This is significant with respect to detection of mutations 
which provide an indication of one's predisposition to lung carcinoma, 
renal cell carcionoma and Von Hipple-Lindau syndrome. Further, the protein 
coded by the DNA and associated cDNA is useful as an in vitro growth 
promoter particularly for hepatocytes. This can be used to alter growth 
characteristics of hepatocytes by combining minor amounts (0.1 to 100 
nanograms) of the protein per milliliter of growth serum with hepatocytes. 
Further the antibody to the L5/3 protein is useful for detection of the 
L5/3 protein in human serum. This again is useful for the purpose of again 
detecting any alteration of the chromosome 3 locus D3F15S2 and again an 
indication of the predisposition towards cancer. 
Further, cited below are the DNA sequences for both the human and the mouse 
along with the cDNA sequences for the human and mouse and the protein 
associated with the human DNA. 
Sequence ID No. 1: cDNA for Human L5/3 clone #33 and associated protein. 
Sequence ID No. 2: cDNA for Human L5/3 clone #33 with polymorphism relative 
to Sequence ID No. 1 and associated protein. 
Sequence ID No. 3: cDNA for Human L5/3 clone #19 and associated protein. 
Sequence ID No. 4: cDNA for Mouse L5/3 and associated protein. 
Sequence ID No. 5: DNA for Mouse L5/3 and associated protein. 
Sequence ID No. 6: DNA Sequence of Human L5/3 and associated protein. 
Sequence ID No. 7: cDNA Sequence of Human L5/3 with 5' and 3' adaptors 
added to make a full length cDNA. 
__________________________________________________________________________ 
SEQUENCE LISTING 
(1) GENERAL INFORMATION: 
(iii) NUMBER OF SEQUENCES: 7 
(2) INFORMATION FOR SEQ ID NO:1: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 2219 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA to mRNA 
(iv) ANTI-SENSE: no 
(vi) ORIGINAL SOURCE: 
(A) ORGANISM: human 
(D) DEVELOPMENTAL STAGE: fetal 
(F) TISSUE TYPE: liver 
(vii) IMMEDIATE SOURCE: 
(A) LIBRARY: cDNA 
(B) CLONE: #icrosoft Corp 
(viii) POSITION IN GENOME: 
(A) CHROMOSOME/SEGMENT: human 3p21/D3F15S2 
(ix) FEATURE: 
(C) IDENTIFICATION METHOD: experimental 
(D) OTHER INFORMATION: Includes five polymorphisms at the 
nucleotide level; one of which results in an amino acid 
substitution (nucleotide 619). Sequence ID NO:2: 
contains the identical sequence with the other 
polymorphic amino acid. 
(x) PUBLICATION INFORMATION: 
(K) RELEVANT RESIDUES IN SEQ ID NO: 1: FROM 1 TO 2219 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: 
TCCTGCTGCTTCTGACTCAATACTTAGGGGTCCCTGGGCAGCGCTCG 47 
LeuLeuLeuLeuThrGlnTyrLeuGlyValProGlyGlnArgSer 
101520 
CCATTGAATGACTTCCAAGTGCTCCGGGGCACAGAGCTACAGCACCTG95 
ProLeuAsnA spPheGlnValLeuArgGlyThrGluLeuGlnHisLeu 
253035 
CTACATGCGGTGGTGCCCGGGCCTTGGCAGGAGGATGTGGCAGATGCT143 
LeuHisAlaValValProGlyPr oTrpGlnGluAspValAlaAspAla 
404550 
GAAGAGTGTGCTGGTCGCTGTGGGCCCTTAATGGACTGCCGGGCCTTC191 
GluGluCysAlaGlyArgCysGlyProLeuMetAsp CysArgAlaPhe 
556065 
CACTACAACGTGAGCAGCCATGGTTGCCAACTGCTGCCATGGACTCAA239 
HisTyrAsnValSerSerHisGlyCysGlnLeuLeuProTrpThrGln 
70758085 
CACTCGCCCCACACGAGGCTGCGGCGTTCTGGGCGCTGTGACCTCTTC287 
HisSerProHisThrArgLeuArgArgSerGlyArgCysAspLeuP he 
9095100 
CAGAAGAAAGACTACGTACGGACCTGCATCATGAACAATGGGGTTGGG335 
GlnLysLysAspTyrValArgThrCysIleMetAsnAsnGlyValGly 
105 110115 
TACCGGGGCACCATGGCCACGACCGTGGGTGGCCTGCCCTGCCAGGCT383 
TyrArgGlyThrMetAlaThrThrValGlyGlyLeuProCysGlnAla 
120125 130 
TGGAGCCACAAGTTCCCGAATGATCACAAGTACACGCCCACTCTCCGG431 
TrpSerHisLysPheProAsnAspHisLysTyrThrProThrLeuArg 
135140145 
AATGGCCTGGAAGAGAACTTCTGCCGTAACCCTGATGGCGACCCCGGA479 
AsnGlyLeuGluGluAsnPheCysArgAsnProAspGlyAspProGly 
1501551601 65 
GGTCCTTGGTGCTACACAACAGACCCTGCTGTGCGCTTCCAGAGCTGC527 
GlyProTrpCysTyrThrThrAspProAlaValArgPheGlnSerCys 
170175180 
GGCATCAAA TCCTGCCGGGAGGCCGCGTGTGTCTGGTGCAATGGCGAG575 
GlyIleLysSerCysArgGluAlaAlaCysValTrpCysAsnGlyGlu 
185190195 
GAATACCGCGGCGCGGTAGAC CGCACGGAGTCAGGGCGCGAGTGCCAG623 
GluTyrArgGlyAlaValAspArgThrGluSerGlyArgGluCysGln 
200205210 
CGCTGGGATCTTCAGCACCCGCACCAGCACCCC TTCGAGCCGGGCAAG671 
ArgTrpAspLeuGlnHisProHisGlnHisProPheGluProGlyLys 
215220225 
TTCCTCGACCAAGGTCTGGACGACAACTATTGCCGGAATCCTGAC GGC719 
PheLeuAspGlnGlyLeuAspAspAsnTyrCysArgAsnProAspGly 
230235240245 
TCCGAGCGGCCATGGTGCTACACTACGGATCCGCAGATCGAG CGAGAG767 
SerGluArgProTrpCysTyrThrThrAspProGlnIleGluArgGlu 
250255260 
TTCTGTGACCTCCCCCGCTGCGGGTCCGAGGCACAGCCCCGCCAAGAG815 
PheCysAspLeuProArgCysGlySerGluAlaGlnProArgGlnGlu 
265270275 
GCCACAACTGTCAGCTGCTTCCGCGGGAAGGGTGAGGGCTACCGGGGC863 
AlaThrThrVa lSerCysPheArgGlyLysGlyGluGlyTyrArgGly 
280285290 
ACAGCCAATACCACCACTGCGGGCGTACCTTGCCAGCGTTGGGACGCG911 
ThrAlaAsnThrThrThrAlaGl yValProCysGlnArgTrpAspAla 
295300305 
CAAATCCCTCATCAGCACCGATTTACGCCAGAAAAATACGCGTGCAAA959 
GlnIleProHisGlnHisArgPheThrProGluLy sTyrAlaCysLys 
310315320325 
GACCTTCGGGAGAACTTCTGCCGGAACCCCGACGGCTCAGAGGCGCCC1007 
AspLeuArgGluAsnPheCysArgAsnProAs pGlySerGluAlaPro 
330335340 
TGGTGCTTCACACTGCGGCCCGGCATGCGCGCGGCCTTTTGCTACCAG1055 
TrpCysPheThrLeuArgProGlyMetArgAlaAlaPheCysTy rGln 
345350355 
ATCCGGCGTTGTACAGACGACGTGCGGCCCCAGGACTGCTACCACGGC1103 
IleArgArgCysThrAspAspValArgProGlnAspCysTyrHisGly 
360 365370 
GCAGGGGAGCAGTACCGCGGCACGGTCAGCAAGACCCGCAAGGGTGTC1151 
AlaGlyGluGlnTyrArgGlyThrValSerLysThrArgLysGlyVal 
375380 385 
CAGTGCCAGCGCTGGTCCGCTGAGACGCCGCACAAGCCGCAGTTCACG1199 
GlnCysGlnArgTrpSerAlaGluThrProHisLysProGlnPheThr 
3903954 00405 
TTTACCTCCGARCCGCATGCACAACTGGAGGAGAACTTCTGCCGGAAC1247 
PheThrSerGluProHisAlaGlnLeuGluGluAsnPheCysArgAsn 
410415 420 
CCAGATGGGGATAGCCATGGGCCCTGGTGCTACACGATGGACCCAAGG1295 
ProAspGlyAspSerHisGlyProTrpCysTyrThrMetAspProArg 
425430435 
ACCCCA TTCGACTACTGTGCCCTGCGACGCTGCGCTGATGACCAGCCG1343 
ThrProPheAspTyrCysAlaLeuArgArgCysAlaAspAspGlnPro 
440445450 
CCATCAATCCTGGACCCC CCAGACCAGGTGCAGTTTGAGAAGTGTGGC1391 
ProSerIleLeuAspProProAspGlnValGlnPheGluLysCysGly 
455460465 
AAGAGGGTGGATCGGCTGGATCAGCGGCGT TCCAAGCTGCGCGTGGTT1439 
LysArgValAspArgLeuAspGlnArgArgSerLysLeuArgValVal 
470475480485 
GGGGGCCATCCGGGCAACTCACCCTGG ACAGTCAGCTTGCGGAATCGG1487 
GlyGlyHisProGlyAsnSerProTrpThrValSerLeuArgAsnArg 
490495500 
CAGGGCCAGCATTTCTGCGGGGGGTCTCTAGTGAAGGAG CAGTGGATA1535 
GlnGlyGlnHisPheCysGlyGlySerLeuValLysGluGlnTrpIle 
505510515 
CTGACTGCCCGGCAGTGCTTCTCCTCCTGCCATATGCCTCTCACGGGC1 583 
LeuThrAlaArgGlnCysPheSerSerCysHisMetProLeuThrGly 
520525530 
TATGAGGTATGGTTGGGCACCCTGTTCCAGAACCCACAGCATGGAGAG1631 
TyrGluVal TrpLeuGlyThrLeuPheGlnAsnProGlnHisGlyGlu 
535540545 
CCAAGCCTACAGCGGGTCCCAGTAGCCAAGATGGTGTGTGGGCCCTCA1679 
ProSerLeuGlnArgValPro ValAlaLysMetValCysGlyProSer 
550555560565 
GGCTCCCAGCTTGTCCTGCTCAAGCTGGAGAGATCTGTGACCCTGAAC1727 
GlySerGlnLeuValLeu LeuLysLeuGluArgSerValThrLeuAsn 
570575580 
CAGCGYGTGGCCCTGATCTGCCTGCCCCCTGAATGGTATGTGGTGCCT1775 
GlnArgValAlaLeuIleCysLeuProPro GluTrpTyrValValPro 
585590595 
CCAGGGACCAAGTGTGAGATTGCAGGCTGGGGTGAGACCAAAGGTACG1823 
ProGlyThrLysCysGluIleAlaGlyTrpGlyGluThrLys GlyThr 
600605610 
GGTAATGACACAGTCCTAAATGTGGCCTTGCTGAATGTCATCTCCAAC1871 
GlyAsnAspThrValLeuAsnValAlaLeuLeuAsnValIleSerAsn 
615 620625 
CAGGAGTGTAACATCAARCACCGAGGACGTGTGCGKGAGAGTGAGATG1919 
GlnGluCysAsnIleLysHisArgGlyArgValArgGluSerGluMet 
63063 5640645 
TGCACTGAGGGACTGTTGGCCCCTGTGGGGGCCTGTGAGGGTGACTAC1967 
CysThrGluGlyLeuLeuAlaProValGlyAlaCysGluGlyAspTyr 
650 655660 
GGGGGCCCACTTGCCTGCTTTACCCACAACTGCTGGGTCCTGGAAGGA2015 
GlyGlyProLeuAlaCysPheThrHisAsnCysTrpValLeuGluGly 
665670 675 
ATTATAATCCCCAACCGAGTATGCGCAAGGTCCCGCTGGCCAGCTGTC2063 
IleIleIleProAsnArgValCysAlaArgSerArgTrpProAlaVal 
680685690 
TTC ACGCGTGTCTCTGTGTTTGTGGACTGGATTCACAAGGTCATGAGA2111 
PheThrArgValSerValPheValAspTrpIleHisLysValMetArg 
695700705 
CTGGGTTAGGCCCAGCC TTGATGCCATATGCCTTGGGGAGGACAAAACTTCTTGTC2167 
LeuGly 
710 
AGACATAAAGCCATGTTTCCTCTTTATGCCTGTAAAAAAAAAAAAAAAAAAA2219 
(2) INFORMATION FOR SEQ ID NO:2: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 2219 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA to mRNA 
(iv) ANTI-SENSE: no 
(vi) ORIGINAL SOURCE: 
(A) ORGANISM: human 
(D) DEVELOPMENTAL STAGE: fetal 
(F) TISSUE TYPE: liver 
(vii) IMMEDIATE SOURCE: 
(A) LIBRARY: cDNA 
(B) CLONE: #icrosoft Corp 
(viii) POSITION IN GENOME: 
(A) CHROMOSOME/SEGMENT: human 3p21/D3F15S2 
(ix) FEATURE: 
(C) IDENTIFICATION METHOD: experimental 
(D) OTHER INFORMATION: Includes five polymorphisms at the 
nucleotide level; one of which results in an amino acid 
substitution (nucleotide 619). Sequence ID NO:1: 
contains the identical sequence with the other 
polymorphic amino acid. 
(x) PUBLICATION INFORMATION: 
(K) RELEVANT RESIDUES IN SEQ ID NO: 2: FROM 1 TO 2219 
( xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: 
TCCTGCTGCTTCTGACTCAATACTTAGGGGTCCCTGGGCAGCGCTCG47 
LeuLeuLeuLeuThrGlnTyrLeuGlyValProGlyGlnArgSer 
101520 
CCATTGAA TGACTTCCAAGTGCTCCGGGGCACAGAGCTACAGCACCTG95 
ProLeuAsnAspPheGlnValLeuArgGlyThrGluLeuGlnHisLeu 
253035 
CTACATGCGGTGGTGCCCGGG CCTTGGCAGGAGGATGTGGCAGATGCT143 
LeuHisAlaValValProGlyProTrpGlnGluAspValAlaAspAla 
404550 
GAAGAGTGTGCTGGTCGCTGTGGGCCCTTAATG GACTGCCGGGCCTTC191 
GluGluCysAlaGlyArgCysGlyProLeuMetAspCysArgAlaPhe 
556065 
CACTACAACGTGAGCAGCCATGGTTGCCAACTGCTGCCATGGACTC AA239 
HisTyrAsnValSerSerHisGlyCysGlnLeuLeuProTrpThrGln 
70758085 
CACTCGCCCCACACGAGGCTGCGGCGTTCTGGGCGCTGTGACCT CTTC287 
HisSerProHisThrArgLeuArgArgSerGlyArgCysAspLeuPhe 
9095100 
CAGAAGAAAGACTACGTACGGACCTGCATCATGAACAATGGGGTTGGG335 
Gl nLysLysAspTyrValArgThrCysIleMetAsnAsnGlyValGly 
105110115 
TACCGGGGCACCATGGCCACGACCGTGGGTGGCCTGCCCTGCCAGGCT383 
TyrArgGlyThrMe tAlaThrThrValGlyGlyLeuProCysGlnAla 
120125130 
TGGAGCCACAAGTTCCCGAATGATCACAAGTACACGCCCACTCTCCGG431 
TrpSerHisLysPheProAsnAspHi sLysTyrThrProThrLeuArg 
135140145 
AATGGCCTGGAAGAGAACTTCTGCCGTAACCCTGATGGCGACCCCGGA479 
AsnGlyLeuGluGluAsnPheCysArgAsnProAspGl yAspProGly 
150155160165 
GGTCCTTGGTGCTACACAACAGACCCTGCTGTGCGCTTCCAGAGCTGC527 
GlyProTrpCysTyrThrThrAspProAlaValAr gPheGlnSerCys 
170175180 
GGCATCAAATCCTGCCGGGAGGCCGCGTGTGTCTGGTGCAATGGCGAG575 
GlyIleLysSerCysArgGluAlaAlaCysValTrpCysAsnGlyGl u 
185190195 
GAATACCGCGGCGCGGTAGACCGCACGGAGTCAGGGCGCGAGTTCCAG623 
GluTyrArgGlyAlaValAspArgThrGluSerGlyArgGluPheGln 
200 205210 
CGCTGGGATCTTCAGCACCCGCACCAGCACCCCTTCGAGCCGGGCAAG671 
ArgTrpAspLeuGlnHisProHisGlnHisProPheGluProGlyLys 
215220 225 
TTCCTCGACCAAGGTCTGGACGACAACTATTGCCGGAATCCTGACGGC719 
PheLeuAspGlnGlyLeuAspAspAsnTyrCysArgAsnProAspGly 
230235240 245 
TCCGAGCGGCCATGGTGCTACACTACGGATCCGCAGATCGAGCGAGAG767 
SerGluArgProTrpCysTyrThrThrAspProGlnIleGluArgGlu 
2502552 60 
TTCTGTGACCTCCCCCGCTGCGGGTCCGAGGCACAGCCCCGCCAAGAG815 
PheCysAspLeuProArgCysGlySerGluAlaGlnProArgGlnGlu 
265270275 
GCCACAACT GTCAGCTGCTTCCGCGGGAAGGGTGAGGGCTACCGGGGC863 
AlaThrThrValSerCysPheArgGlyLysGlyGluGlyTyrArgGly 
280285290 
ACAGCCAATACCACCACTGCG GGCGTACCTTGCCAGCGTTGGGACGCG911 
ThrAlaAsnThrThrThrAlaGlyValProCysGlnArgTrpAspAla 
295300305 
CAAATCCCTCATCAGCACCGATTTACGCCAGAA AAATACGCGTGCAAA959 
GlnIleProHisGlnHisArgPheThrProGluLysTyrAlaCysLys 
310315320325 
GACCTTCGGGAGAACTTCTGCCGGAACCCC GACGGCTCAGAGGCGCCC1007 
AspLeuArgGluAsnPheCysArgAsnProAspGlySerGluAlaPro 
330335340 
TGGTGCTTCACACTGCGGCCCGGCATGCGCGCGGCCTTTTGC TACCAG1055 
TrpCysPheThrLeuArgProGlyMetArgAlaAlaPheCysTyrGln 
345350355 
ATCCGGCGTTGTACAGACGACGTGCGGCCCCAGGACTGCTACCACGGC1103 
IleArgArgCysThrAspAspValArgProGlnAspCysTyrHisGly 
360365370 
GCAGGGGAGCAGTACCGCGGCACGGTCAGCAAGACCCGCAAGGGTGTC1151 
AlaGlyGluGl nTyrArgGlyThrValSerLysThrArgLysGlyVal 
375380385 
CAGTGCCAGCGCTGGTCCGCTGAGACGCCGCACAAGCCGCAGTTCACG1199 
GlnCysGlnArgTrpSerAlaGl uThrProHisLysProGlnPheThr 
390395400405 
TTTACCTCCGARCCGCATGCACAACTGGAGGAGAACTTCTGCCGGAAC1247 
PheThrSerGluProHisAl aGlnLeuGluGluAsnPheCysArgAsn 
410415420 
CCAGATGGGGATAGCCATGGGCCCTGGTGCTACACGATGGACCCAAGG1295 
ProAspGlyAspSerHisGlyProTrpCysTy rThrMetAspProArg 
425430435 
ACCCCATTCGACTACTGTGCCCTGCGACGCTGCGCTGATGACCAGCCG1343 
ThrProPheAspTyrCysAlaLeuArgArgCysAlaAspAspGln Pro 
440445450 
CCATCAATCCTGGACCCCCCAGACCAGGTGCAGTTTGAGAAGTGTGGC1391 
ProSerIleLeuAspProProAspGlnValGlnPheGluLysCysGly 
455 460465 
AAGAGGGTGGATCGGCTGGATCAGCGGCGTTCCAAGCTGCGCGTGGTT1439 
LysArgValAspArgLeuAspGlnArgArgSerLysLeuArgValVal 
470475 480485 
GGGGGCCATCCGGGCAACTCACCCTGGACAGTCAGCTTGCGGAATCGG1487 
GlyGlyHisProGlyAsnSerProTrpThrValSerLeuArgAsnArg 
49049 5500 
CAGGGCCAGCATTTCTGCGGGGGGTCTCTAGTGAAGGAGCAGTGGATA1535 
GlnGlyGlnHisPheCysGlyGlySerLeuValLysGluGlnTrpIle 
505510 515 
CTGACTGCCCGGCAGTGCTTCTCCTCCTGCCATATGCCTCTCACGGGC1583 
LeuThrAlaArgGlnCysPheSerSerCysHisMetProLeuThrGly 
520525530 
TATGAG GTATGGTTGGGCACCCTGTTCCAGAACCCACAGCATGGAGAG1631 
TyrGluValTrpLeuGlyThrLeuPheGlnAsnProGlnHisGlyGlu 
535540545 
CCAAGCCTACAGCGGGTC CCAGTAGCCAAGATGGTGTGTGGGCCCTCA1679 
ProSerLeuGlnArgValProValAlaLysMetValCysGlyProSer 
550555560565 
GGCTCCCAGCTTGTC CTGCTCAAGCTGGAGAGATCTGTGACCCTGAAC1727 
GlySerGlnLeuValLeuLeuLysLeuGluArgSerValThrLeuAsn 
570575580 
CAGCGYGTGGCCCTGATCTGCCTGCCC CCTGAATGGTATGTGGTGCCT1775 
GlnArgValAlaLeuIleCysLeuProProGluTrpTyrValValPro 
585590595 
CCAGGGACCAAGTGTGAGATTGCAGGCTGGGGTGAGACC AAAGGTACG1823 
ProGlyThrLysCysGluIleAlaGlyTrpGlyGluThrLysGlyThr 
600605610 
GGTAATGACACAGTCCTAAATGTGGCCTTGCTGAATGTCATCTCCAAC1 871 
GlyAsnAspThrValLeuAsnValAlaLeuLeuAsnValIleSerAsn 
615620625 
CAGGAGTGTAACATCAARCACCGAGGACGTGTGCGKGAGAGTGAGATG1919 
GlnGluCys AsnIleLysHisArgGlyArgValArgGluSerGluMet 
630635640645 
TGCACTGAGGGACTGTTGGCCCCTGTGGGGGCCTGTGAGGGTGACTAC1967 
CysThr GluGlyLeuLeuAlaProValGlyAlaCysGluGlyAspTyr 
650655660 
GGGGGCCCACTTGCCTGCTTTACCCACAACTGCTGGGTCCTGGAAGGA2015 
GlyGlyProLeuAlaCys PheThrHisAsnCysTrpValLeuGluGly 
665670675 
ATTATAATCCCCAACCGAGTATGCGCAAGGTCCCGCTGGCCAGCTGTC2063 
IleIleIleProAsnArgValCysAlaArg SerArgTrpProAlaVal 
680685690 
TTCACGCGTGTCTCTGTGTTTGTGGACTGGATTCACAAGGTCATGAGA2111 
PheThrArgValSerValPheValAspTrpIleHisLysVal MetArg 
695700705 
CTGGGTTAGGCCCAGCCTTGATGCCATATGCCTTGGGGAGGACAAAACTTCTTGTC2167 
LeuGly 
710 
AGACATAAAGCCATGTTTCCTCTTTATGCCTGTAAAAAAAAAAAAAAAAAA A2219 
(2) INFORMATION FOR SEQ ID NO:3: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 2021 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA to mRNA 
(iv) ANTI-SENSE: no 
(vi) ORIGINAL SOURCE: 
(A) ORGANISM: human 
(D) DEVELOPMENTAL STAGE: fetal 
(F) TISSUE TYPE: liver 
(vii) IMMEDIATE SOURCE: 
(A) LIBRARY: cDNA 
(B) CLONE: #Microsoft Corp 
(viii) POSITION IN GENOME: 
(A) CHROMOSOME/SEGMENT: human 3p21/D3F15S2 
(ix) FEATURE: 
(C) IDENTIFICATION METHOD: experimental 
(D) OTHER INFORMATION: This sequence is a variant where two 
regions were found to be deleted when compared to 
SEQ ID NO:1. 
(x) PUBLICATION INFORMATION: 
(K) RELEVANT RESIDUES IN SEQ ID NO:3: FROM 1 TO 2021 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: 
ATGCTTAGGGGTCCCTGGGCAGCGCTCGCCATTGAATGACTTCCAA46 
CysLeuGlyValProGlyGlnArgSerProLeuAsnAspPheGln 
1520 25 
GTGCTCCGGGGCACAGAGCTACAGCACCTGCTACATGCGGTGGTGCCC94 
ValLeuArgGlyThrGluLeuGlnHisLeuLeuHisAlaValValPro 
30354 0 
GGGCCTTGGCAGGAGGATGTGGCAGATGCTGAAGAGTGTGCTGGTCGC142 
GlyProTrpGlnGluAspValAlaAspAlaGluGluCysAlaGlyArg 
455055 
TGTGGGCCCT TAATGGACTGCCGGGCCTTCCACTACAACGTGAGCAGC190 
CysGlyProLeuMetAspCysArgAlaPheHisTyrAsnValSerSer 
60657075 
CATGGTTG CCAACTGCTGCCATGGACTCAACACTCGCCCCACACGAGG238 
HisGlyCysGlnLeuLeuProTrpThrGlnHisSerProHisThrArg 
808590 
CTGCGGCGTTCTGGGCGCTGT GACCTCTTCCAGAAGAAAGACTACGTA286 
LeuArgArgSerGlyArgCysAspLeuPheGlnLysLysAspTyrVal 
95100105 
CGGACCTGCATCATGAACAATGGGGTTGGGTAC CGGGGCACCATGGCC334 
ArgThrCysIleMetAsnAsnGlyValGlyTyrArgGlyThrMetAla 
110115120 
ACGACCGTGGGTGGCCTGCCCTGCCAGGCTTGGAGCCACAAGTTC CCG382 
ThrThrValGlyGlyLeuProCysGlnAlaTrpSerHisLysPhePro 
125130135 
AATGATCACAAGTACACGCCCACTCTCCGGAATGGCCTGGAAGAGAAC430 
Asn AspHisLysTyrThrProThrLeuArgAsnGlyLeuGluGluAsn 
140145150155 
TTCTGCCGTAACCCTGATGGCGACCCCGGAGGTCCTTGGTGCTACACA478 
PheCysArgAsnProAspGlyAspProGlyGlyProTrpCysTyrThr 
160165170 
ACAGACCCTGCTGTGCGCTTCCAGAGCTGCGGCATCAAATCCTGCCGG526 
ThrAspProAla ValArgPheGlnSerCysGlyIleLysSerCysArg 
175180185 
GAGGCCGCGTGTGTCTGGTGCAATGGCGAGGAATACCGCGGCGCGGTA574 
GluAlaAlaCysValTrpCysAsn GlyGluGluTyrArgGlyAlaVal 
190195200 
GACCGCACGGAGTCAGGGCGCGAGTGCCAGCGCTGGGATCTTCAGCAC622 
AspArgThrGluSerGlyArgGluCysGlnArgTrp AspLeuGlnHis 
205210215 
CCGCACCAGCACCCCTTCGAGCCGGGCAAGTTCCTCGACCAAGGTCTG670 
ProHisGlnHisProPheGluProGlyLysPheLeuAspGlnGlyLeu 
220225230235 
GACGACAACTATTGCCGGAATCCTGACGGCTCCGAGCGGCCATGGTGC718 
AspAspAsnTyrCysArgAsnProAspGlySerGluArgProTrp Cys 
240245250 
TACACTACGGATCCGCAGATCGAGCGAGAGTTCTGTGACCTCCCCCGC766 
TyrThrThrAspProGlnIleGluArgGluPheCysAspLeuProArg 
255 260265 
TGCGGGTCCGAGGCACAGCCCCGCCAAGAGGCCACAACTGTCAGCTGC814 
CysGlySerGluAlaGlnProArgGlnGluAlaThrThrValSerCys 
270275 280 
TTCCGCGGGAAGGGTGAGGGCTACCGGGGCACAGCCAATACCACCACT862 
PheArgGlyLysGlyGluGlyTyrArgGlyThrAlaAsnThrThrThr 
28529029 5 
GCGGGCGTACCTTGCCAGCGTTGGGACGCGCAAATCCCTCATCAGCAC910 
AlaGlyValProCysGlnArgTrpAspAlaGlnIleProHisGlnHis 
300305310 315 
CGATTTACGCCAGAAAAATACGCGTGCAAAGACCTTCGGGAGAACTTC958 
ArgPheThrProGluLysTyrAlaCysLysAspLeuArgGluAsnPhe 
320325330 
TGCCGG AACCCCGACGGCTCAGAGGCGCCCTGGTGCTTCACACTGCGG1006 
CysArgAsnProAspGlySerGluAlaProTrpCysPheThrLeuArg 
335340345 
CCCGGCATGCGCGCGGCC TTTTGCTACCAGATCCGGCGTTGTACAGAC1054 
ProGlyMetArgAlaAlaPheCysTyrGlnIleArgArgCysThrAsp 
350355360 
GACGTGCGGCCCCAGGACTGCTACCACGGC GCAGGGGAGCAGTACCGC1102 
AspValArgProGlnAspCysTyrHisGlyAlaGlyGluGlnTyrArg 
365370375 
GGCACGGTCAGCAAGACCCGCAAGGGTGTCCAGTGCCAGCGC TGGTCC1150 
GlyThrValSerLysThrArgLysGlyValGlnCysGlnArgTrpSer 
380385390395 
GCTGAGACGCCGCACAAGCCGCAGTTCACGTTTACCTCC GAACCGCAT1198 
AlaGluThrProHisLysProGlnPheThrPheThrSerGluProHis 
400405410 
GCACAACTGGAGGAGAACTTCTGCCGGAACCCAGATGGGGATAGCCAT1 246 
AlaGlnLeuGluGluAsnPheCysArgAsnProAspGlyAspSerHis 
415420425 
GGGCCCTGGTGCTACACGATGGACCCAAGGACCCCATTCGACTACTGT1294 
GlyProTrp CysTyrThrMetAspProArgThrProPheAspTyrCys 
430435440 
GCCCTGCGACGCTGCGCTGATGACCAGCCGCCATCAATCCTGGACCCC1342 
AlaLeuArgArgCysAlaAsp AspGlnProProSerIleLeuAspPro 
445450455 
CCAGGCAGGGCCAGCATTTCTGCGGGGGGTCTCTAGTGAAGGAGCAGTGGATA1395 
ProGlyArgAlaSerIleSerAlaGlyGlyLeu 
460465470 
CTGACTGCCCGGCAGTGCTTCTCCTCCTGAACCCACAGCATGGAGAGCCAAGCCTACAGC1455 
GGGTCCCAGTAGCCAAGATGGTGTGTGGGCCCTCAGGCTCCCAGCTTGTCCTGCTCAAGC1515 
TGGA GAGATCTGTGACCCTGAACCAGCGCGTGGCCCTGATCTGCCTGCCCCCTGAATGGT1575 
ATGTGGTGCCTCCAGGGACCAAGTGTGAGATTGCAGGCTGGGGTGAGACCAAAGGTACGG1635 
GTAATGACACAGTCCTAAATGTGGCCTTGCTGAATGTCATCTCCAACCAGG AGTGTAACA1695 
TCAAGCACCGAGGACGTGTGCGTGAGAGTGAGATGTGCACTGAGGGACTGTTGGCCCCTG1755 
TGGGGGCCTGTGAGGGTGACTACGGGGGCCCACTTGCCTGCTTTACCCACAACTGCTGGG1815 
TCCTGGAAGGAATTATAATCCCCAACCGAGT ATGCGCAAGGTCCCGCTGGCCAGCTGTCT1875 
TCACGCGTGTCTCTGTGTTTGTGGACTGGATTCACAAGGTCATGAGACTGGGTTAGGCCC1935 
AGCCTTGATGCCATATGCCTTGGGGAGGACAAAACTTCTTGTCAGACATAAAGCCATGTT1995 
TCCTCTTTAAA AAAAAAAAAAAAAAA2021 
(2) INFORMATION FOR SEQ ID NO:4: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 2188 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA to mRNA 
(iv) ANTI-SENSE: no 
(vi) ORIGINAL SOURCE: 
(A) ORGANISM: mouse 
(B) STRAIN: C57BL/6 
(D) DEVELOPMENTAL STAGE: adult 
(F) TISSUE TYPE: liver 
(vii) IMMEDIATE SOURCE: 
(A) LIBRARY: cDNA 
(B) CLONE: ML5-2 
(viii) POSITION IN GENOME: 
(A) CHROMOSOME/SEGMENT: mouse 9, Hgfl locus 
(B) MAP POSITION: Trf-Gnai-2-Hgfl- Cck 
(ix) FEATURE: 
(C) IDENTIFICATION METHOD: experimental 
(x) PUBLICATION INFORMATION: 
(K) RELEVANT RESIDUES IN SEQ ID NO: 4: 1 TO 2188 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: 
GGCTCTTGGGCCGCGCTCACCACTGAATGACTTCCAGCTGTTCCGG46 
AlaLeuGlyProArgSerProLeuAsnAspPheGlnLeuPheArg 
20 2530 
GGCACAGAGTTAAGGAACCTGTTACACACAGCGGTGCCGGGGCCATGG94 
GlyThrGluLeuArgAsnLeuLeuHisThrAlaValProGlyProTrp 
3540 45 
CAGGAGGATGTGGCAGATGCTGAGGAGTGTGCTAGGCGCTGTGGGCCC142 
GlnGluAspValAlaAspAlaGluGluCysAlaArgArgCysGlyPro 
505560 
CTTCT GGACTGTCGGGCCTTCCACTACAACATGAGCAGCCATGGTTGC190 
LeuLeuAspCysArgAlaPheHisTyrAsnMetSerSerHisGlyCys 
657075 
CAGCTGCTGCCGTGGACC CAGCACTCGCTGCACACACAGCTATACCAC238 
GlnLeuLeuProTrpThrGlnHisSerLeuHisThrGlnLeuTyrHis 
808590 
TCGAGTCTGTGCCATCTCTTCCAGAAGAAAGA TTATGTGCGGACCTGC286 
SerSerLeuCysHisLeuPheGlnLysLysAspTyrValArgThrCys 
95100105110 
ATTATGGACAATGGGGTCAGCTACCGGGGC ACTGTGGCCAGGACAGCT334 
IleMetAspAsnGlyValSerTyrArgGlyThrValAlaArgThrAla 
115120125 
GGTGGCCTGCCCTGCCAAGCCTGGAGTCGCAGGTTCCCCAATG ACCAC382 
GlyGlyLeuProCysGlnAlaTrpSerArgArgPheProAsnAspHis 
130135140 
AAGTATACGCCCACGCCAAAGAATGGCCTGGAAGAGAACTTCTGTAGG430 
Ly sTyrThrProThrProLysAsnGlyLeuGluGluAsnPheCysArg 
145150155 
AACCCTGATGGGGATCCCAGAGGTCCCTGGTGCTACACAACAAACCGC478 
AsnProAspGlyAsp ProArgGlyProTrpCysTyrThrThrAsnArg 
160165170 
AGTGTGCGTTTCCAGAGCTGTGGCATCAAAACCTGCAGGGAGGCTGTT526 
SerValArgPheGlnSerCysGlyIle LysThrCysArgGluAlaVal 
175180185190 
TGTGTTCTGTGCAACGGTGAGGATTACCGTGGCGAGGTAGACGTTACA574 
CysValLeuCysAsnGlyGluAspT yrArgGlyGluValAspValThr 
195200205 
GAGTCAGGGCGGGAGTGTCAACGCTGGGACCTGCAGCACCCCCACTCG622 
GluSerGlyArgGluCysGlnArgTrpAspLeuGlnHi sProHisSer 
210215220 
CACCCTTTCCAGCCTGAAAAGTTCCTAGACAAAGATCTGAAAGACAAC670 
HisProPheGlnProGluLysPheLeuAspLysAspLeuLysAspAsn 
22 5230235 
TATTGTCGTAATCCGGACGGATCTGAGCGGCCCTGGTGCTACACCACA718 
TyrCysArgAsnProAspGlySerGluArgProTrpCysTyrThrThr 
240 245250 
GACCCGAATGTTGAGCGAGAATTCTGCGACCTGCCCAGTTGCGGGCCT766 
AspProAsnValGluArgGluPheCysAspLeuProSerCysGlyPro 
255260 265270 
AACCTGCCTCCGACCGTCAAAGGATCCAAGTCACAGCGGCGCAACAAG814 
AsnLeuProProThrValLysGlySerLysSerGlnArgArgAsnLys 
275280 285 
GGCAAGGCTCTTAACTGCTTCCGCGGAAAAGGTGAAGACTATCGAGGC862 
GlyLysAlaLeuAsnCysPheArgGlyLysGlyGluAspTyrArgGly 
290295300 
ACA ACCAATACCACCTCTGCGGGCGTGCCCTGCCAGCGGTGGGATGCG910 
ThrThrAsnThrThrSerAlaGlyValProCysGlnArgTrpAspAla 
305310315 
CAGAGTCCACACCAGC ACCGCTTTGTGCCAGAGAAATATGCTTGCAAG958 
GlnSerProHisGlnHisArgPheValProGluLysTyrAlaCysLys 
320325330 
GACCTTCGTGAGAATTTCTGCCGGAATCC TGATGGCTCCGAGGCGCCT1006 
AspLeuArgGluAsnPheCysArgAsnProAspGlySerGluAlaPro 
335340345350 
TGGTGCTTCACATCTCGACCTGGTTTG CGCATGGCCTTCTGCCACCAG1054 
TrpCysPheThrSerArgProGlyLeuArgMetAlaPheCysHisGln 
355360365 
ATCCCACGCTGCACTGAAGAACTGGTGCCAGAGGGATGC TACCACGGC1102 
IleProArgCysThrGluGluLeuValProGluGlyCysTyrHisGly 
370375380 
TCAGGTGAACAGTATCGTGGCTCAGTCAGCAAGACGCGCAAGGGCGTT115 0 
SerGlyGluGlnTyrArgGlySerValSerLysThrArgLysGlyVal 
385390395 
CAGTGCCAGCACTGGTCCTCTGAGACACCGCACAAGCCACAATTTACA1198 
GlnCysGlnHi sTrpSerSerGluThrProHisLysProGlnPheThr 
400405410 
CCCACCTCGGCACCGCAGGCGGGACTGGAGGCCAACTTCTGCAGGAAT1246 
ProThrSerAlaProGlnAlaGly LeuGluAlaAsnPheCysArgAsn 
415420425430 
CCTGATGGGGATAGCCATGGGCCCTGGTGCTATACCTTGGACCCGGAT1294 
ProAspGlyAspSerHisGly ProTrpCysTyrThrLeuAspProAsp 
435440445 
ATCCTGTTTGACTACTGTGCCCTACAGCGCTGTGATGATGACCAGCCA1342 
IleLeuPheAspTyrCysAlaLeuGlnArgCysA spAspAspGlnPro 
450455460 
CCATCCATTCTGGACCCCCCAGACCAGGTGGTGTTTGAAAAGTGTGGC1390 
ProSerIleLeuAspProProAspGlnValValPheGluLysCysGl y 
465470475 
AAGAGAGTTGACAAGAGTAATAAACTTCGTGTGGTGGGAGGCCATCCT1438 
LysArgValAspLysSerAsnLysLeuArgValValGlyGlyHisPro 
480 485490 
GGGAACTCCCCATGGACGGTCAGCTTGCGGAATCGACAGGGCCAGCAT1486 
GlyAsnSerProTrpThrValSerLeuArgAsnArgGlnGlyGlnHis 
495500 505510 
TTCTGTGGGGGCTCCCTAGTGAAGGAGCAGTGGGTACTGACTGCCCGG1534 
PheCysGlyGlySerLeuValLysGluGlnTrpValLeuThrAlaArg 
515520 525 
CAATGCATCTGGTCATGCCACGAACCTCTCACAGGATACGAGGTATGG1582 
GlnCysIleTrpSerCysHisGluProLeuThrGlyTyrGluValTrp 
530535540 
TTGGGTACAATTAACCAGAACCCACAGCCTGGAGAGGCAAACCTGCAG1630 
LeuGlyThrIleAsnGlnAsnProGlnProGlyGluAlaAsnLeuGln 
545550555 
AGGGTCCCAGTG GCCAAGGCAGTGTGCGGCCCTGCAGGCTCCCAGCTT1678 
ArgValProValAlaLysAlaValCysGlyProAlaGlySerGlnLeu 
560565570 
GTTCTGCTCAAGCTGGAGAGACCTG TGATCCTGAACCATCACGTGGCC1726 
ValLeuLeuLysLeuGluArgProValIleLeuAsnHisHisValAla 
575580585590 
CTGATTTGCCTGCCTCCTGAACA GTATGTGGTACCTCCAGGGACCAAG1774 
LeuIleCysLeuProProGluGlnTyrValValProProGlyThrLys 
595600605 
TGTGAGATCGCAGGCTGGGGTGAATCCATCGGTACA AGCAATAACACA1822 
CysGluIleAlaGlyTrpGlyGluSerIleGlyThrSerAsnAsnThr 
610615620 
GTCCTTCATGTGGCCTCGATGAATGTCATCTCCAACCAGGAATGTAAC 1870 
ValLeuHisValAlaSerMetAsnValIleSerAsnGlnGluCysAsn 
625630635 
ACGAAGTACCGAGGACACATACAAGAGAGTGAGATATGCACCCAGGGA1918 
ThrLysT yrArgGlyHisIleGlnGluSerGluIleCysThrGlnGly 
640645650 
CTGGTGGTCCCTGTGGGGGCTTGTGAGGGTGACTACGGGGGCCCACTT1966 
LeuValValProValGlyAl aCysGluGlyAspTyrGlyGlyProLeu 
655660665670 
GCCTGCTATACCCATGACTGCTGGGTCCTACAGGGACTTATCATCCCG2014 
AlaCysTyrThrHisAsp CysTrpValLeuGlnGlyLeuIleIlePro 
675680685 
AACAGAGTGTGTGCACGGCCCCGCTGGCCAGCTATCTTCACACGGGTG2062 
AsnArgValCysAlaArgProArgTrpPro AlaIlePheThrArgVal 
690695700 
TCTGTGTTCGTGGACTGGATTAACAAGGTCATGCAGCTGGAG2104 
SerValPheValAspTrpIleAsnLysValMetGlnLeuGlu 
705710715 
TAGGCCTGCTTTTGAGCCCTTAGAGATGTCAAGACTTCTCAAACATAAAGCGGCCTTTTC2164 
TCTCTGTCAAAAAAAAAAAAAAAA2188 
(2) INFORMATION FOR SEQ ID NO:5: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 6751 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: genomic DNA 
(iv) ANTI-SENSE: no 
(vi) ORIGINAL SOURCE: 
(A) ORGANISM: mouse 
(B) STRAIN: Balb/c 
(D) DEVELOPMENTAL STAGE: adult 
(F) TISSUE TYPE: liver 
(vii) IMMEDIATE SOURCE: 
(A) LIBRARY: genomic 
(B) CLONE: MGL5-12 
(viii) POSITION IN GENOME: 
(A) CHROMOSOME/SEGMENT: mouse 9, Hgfl locus 
(B) MAP POSITION: Trf-Gnai-2-Hgfl- Cck 
(ix) FEATURE: 
(C) IDENTIFICATION METHOD: experimental 
(x) PUBLICATION INFORMATION: 
(K) RELEVANT RESIDUES IN SEQ ID NO: 5: 1 TO 6751 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: 
AGATCTGATCGGCCAG GGGCTCGAGGGGAGTCACCGAACCCGCCCGGCTCATAGCCAGGC60 
CGCCTCTCACTCACCCCCGGCCTCAGCCTCCGCGACCGGCTCACAACATCCGCCCAGCTT120 
TTCGGCTACGGCACCCGTCCAGGCCAAACCGCGTGCTCGCTCGAGCGCTGCTCCAGCCGC1 80 
GCACGCGCATATGCACAGACCGCAACAGGCTGGCAGAAAACCCTCCTCCGTCTCCTACCA240 
AGGTGTTTACCCGTTTTGCCTGATGGTCCACCTGTTTCGCCCCCACCTTTCCTAGCCCAG300 
CCGTAGCAGGGACTATGTTCTAATCGGTCCCTAGGTCCACCTG TCTTAACTCCTACCTTG360 
CCTGGAGGAGGCCTGACCCACATGCAGCCTGAAAGACCACTTCTGACAGCAGATTTGCTA420 
CCTGTCACAGCCGCGCACGCCCCCTCCAGATGGTCATTGACACCAGATCCAATGGGCAGG480 
GTTGCTTAGCTTACCCTGGTTTG ACACTTCTGAGGGGCGATGGGATGGATGCTCCTCGGA540 
TGTGCTGCTAGGGGTGTAGGCTGACTGCCCTACAGCTGGGACTCAGCTGATAAGGCAGCT600 
TGAACAGGGAGAGGCAGCATTGGGACTGGGGAAATTGCAGTCCTCACTTTACAAGAAGAA660 
ACT GAGGCCCAGAAAAGTATAATCCAGGGGTCTGGGAAATCTTGGCAACTCCTGTATAGC720 
AGAGTCTTTTGGCATAGAAGTGTCAGTGGTGATGGCAGCCACTGTGGTCACTAGACTCTT780 
GACATGTGACCCGTGTAACTGAAAATTTCAGTTTTTCACTTTGTAAATCG TAATCACATA840 
GAGTCTGACTACTGTGATGGGTACCACACCTCTACAGTAAAGCAGGCACCAGGGACTCCA900 
TGCAACTTCTGGAGCGCGTGTAGCAACAGCATGCGACCTCAGGGATAGATGGTGGCAGGA960 
AGACAGTGGAGTGATCTTGGCAAGTCTGGG GATTGCATAGAGTAGACGGGCTCTGCCTCA1020 
GGGACACCTAACGTTTCCACACAGAACCCTCCTAAGTCCTGCCTACCACACAGAGAGGCC1080 
TCTCAGGATCCAGCTGCAATGAGACAGCACTCGAGGGCCTCAAACCTAGGCTCCACCTAG1140 
CAACTGTCAC CCTATGTGTCAGTCAAGTCCAGGCAGGTTCAGAGAGGGGGTGTGGAGCCA1200 
GAGTCACCCAATCCTGAAGGGACAGATTTCACCATTTCCGGGATGGGGCTGTGGTGGGTC1260 
ACCGTGCAGCCTCCAGCTTAGGAGAATGGGGTGGCTCCCACTTCTGCTGCTT 1312 
MetGlyTrpLeuProLeuLeuLeuLeu 
CTGGTACAGTGTTCAAGGGCTCTTGGTGAGTGTCACCCACCCTGATCCCAGTCTG1367 
LeuValGlnCysSerArgAlaLeuG 
1015 
CCTTCACGAGGGAG TTCACCCCTGGTCTACATAGCTATTCTCATTGAGAGTTTACTTTTC1427 
TTTGGGTCCGGGATCAGTGACCTTGGCCTGTTGAGCAGAGCTGAGAAGGCCTGGGAATTC1487 
AAATACACACAGTCTGATCAGGACTACATTAGAGCATACTGTAGCCCAGAGGCAGTCTTT 1547 
CAACCAGAGAAACTATCCAACCCAGAAGGCAGGGCTCCTAAGCCCGATGCACCACTGTAA1607 
CTTATGCCTTTATTCTGGTGAGAGGCCAGACTTGGGGCCTTCCCCAGGAAGTGTCCAAGC1667 
ATTCTCATCTGAGGGGTGAGAAGGGGCAAGTGTCACAAGGC CAACACACTGTCACCCAAA1727 
TTCTCATGGAGTGGATGTGGTAGACCAGAGCCCAGTGCCAGGTCTCCTAGCAGATGGGCA1787 
ATAATCACTGTATCTGGGCCTCCCCAGCTCACTGGCATGAAGGGACTTGCTGGGCCCTTG1847 
AAAATATACATAAGGCCTGCC CCAAAGACCTTGTATTAGATTCCCTAAATGAACAAAAGA1907 
TAGGGTGTGTTAAAGTACTAATGCGCTCATGCTCACCACGCAGGGCAGCGCTCA1961 
lyGlnArgSer 
20 
CCACTGAATGACTTCCAGCTGTTCCGGGGCACAGAGTTAAG GAACCTG2009 
ProLeuAsnAspPheGlnLeuPheArgGlyThrGluLeuArgAsnLeu 
253035 
TTACACACAGCGGTGCCGGGGCCATGGCAGGAGGATGTGGCAGATGCT2057 
LeuHisThrAlaValProGlyProTrpGlnGluAspValAlaAspAla 
404550 
GAGGAGTGTGCTAGGCGCTGTGGGCCCCTTCTGGACTGTCGGTGAGTGGCT2108 
GluGluCysAla ArgArgCysGlyProLeuLeuAspCysAr 
556065 
AAGTAGCCTAGATATGGCTGAGGGCATGAGAATCTGGGTTGCCAGTTAACTTTGTGTCTG2168 
CCACCCCCCCCCCCTTCTCCAGGGCCTTCCACT ACAACATGAGCAGCCAT2218 
gAlaPheHisTyrAsnMetSerSerHis 
7075 
GGTTGCCAGCTGCTGCCGTGGACCCAGCACTCGCTGCACACACAGCTA2266 
GlyCysGlnLeuLeuProTrpTh rGlnHisSerLeuHisThrGlnLeu 
808590 
TACCACTCGAGTCTGTGCCATCTCTTCCAGAAGAAAGGCAAGTGGTG2313 
TyrHisSerSerLeuCysHisLeuPheGlnLysLysA 
95100 
GTGAGGAGGGGAAACAGGCTGAGTAACAGGGGCCACGAGGCTCAGGCCTGTTGACCTTCC2373 
TCCATTGCTTCCAGATTATGTGCGGACCTGCATTATGGACAATGGGGTC2422 
spTyrValArgThrCysIleM etAspAsnGlyVal 
110115 
AGCTACCGGGGCACTGTGGCCAGGACAGCTGGTGGCCTGCCCTGCCAA2470 
SerTyrArgGlyThrValAlaArgThrAlaGlyGlyLeuProCysGln 
120 125130 
GCCTGGAGTCGCAGGTTCCCCAATGACCACAAGTGAGTCAGACACTTCAGGT2522 
AlaTrpSerArgArgPheProAsnAspHisLy 
135140 
CAGACCGTTAGGCCTGAAGCAGTAT TCCCCCAGTGTGCACTGTAGTAAGAATCTTTGTCT2582 
ACAGGTATACGCCCACGCCAAAGAATGGCCTGGAAGAGAACTTCTGT2629 
sTyrThrProThrProLysAsnGlyLeuGluGluAsnPheCys 
1451 50155 
AGGAACCCTGATGGGGATCCCAGAGGTCCCTGGTGCTACACAACAAAC2677 
ArgAsnProAspGlyAspProArgGlyProTrpCysTyrThrThrAsn 
160165 170 
CGCAGTGTGCGTTTCCAGAGCTGTGGCATCAAAACCTGCAGGGAGG2723 
ArgSerValArgPheGlnSerCysGlyIleLysThrCysArgGluA 
175180185 
GTAAGCGGC TGGGGTCAATCAAGCCTAAGGAGGGAGTGATAGGCCTGCCCCCACTTAGAA2783 
GTGCATTGGCCCTGTTTCCAGCTGTTTGTGTTCTGTGCAACGGTGAGGAT2833 
laValCysValLeuCysAsnGlyGluAsp 
19019 5 
TACCGTGGCGAGGTAGACGTTACAGAGTCAGGGCGGGAGTGTCAACGC2881 
TyrArgGlyGluValAspValThrGluSerGlyArgGluCysGlnArg 
200205210 
TGGGACCTG CAGCACCCCCACTCGCACCCTTTCCAGCCTGAAAA2925 
TrpAspLeuGlnHisProHisSerHisProPheGlnProGluLy 
215220225 
GTATGTAGGCAGAATCCTTATTTTGAGGGT GGGGCTCAGCTCTACTGGGACTGAGTCCCA2985 
GAGTCTTGTTACTGCTTTCAGGTTCCTAGACAAAGATCTGAAAGACAACTAT3037 
sPheLeuAspLysAspLeuLysAspAsnTyr 
230235 
TGTCGTAATCCGG ACGGATCTGAGCGGCCCTGGTGCTACACCACAGAC3085 
CysArgAsnProAspGlySerGluArgProTrpCysTyrThrThrAsp 
240245250255 
CCGAATGTTG AGCGAGAATTCTGCGACCTGCCCAGTTGCGGTAGGCTGCA3135 
ProAsnValGluArgGluPheCysAspLeuProSerCysG 
260265 
GGGTCAGGGTCTAGGAAGGAGCTTGGAAAAAACTGGCGGGCACGGTTCAACTGG GAGAGG3195 
TACTAGGGAAGTTAGGCGTGGGTAGAGAGCAAAGCCTGCTGAGTACCAGAGACCAATTCC3255 
AGTTTTCGGTCAGGGCCTAACCTGCCTCCGACCGTCAAAGGATCCAAGTCA3306 
lyProAsnLeuProProThrValLysGly SerLysSer 
270275280 
CAGCGGCGCAACAAGGGCAAGGCTCTTAACTGCTTCCGCGGAAAAGGT3354 
GlnArgArgAsnLysGlyLysAlaLeuAsnCysPheArgGlyLysGly 
28 5290295 
GAAGACTATCGAGGCACAACCAATACCACCTCTGCGGGCGTGCCCTGC3402 
GluAspTyrArgGlyThrThrAsnThrThrSerAlaGlyValProCys 
300 305310 
CAGCGGTGGGATGCGCAGAGTCCACACCAGCACCGCTTTGTGCCAGAG3450 
GlnArgTrpAspAlaGlnSerProHisGlnHisArgPheValProGlu 
315320 325 
AAATATGCTTGCAAGTGAGGTGACAGGCCGGAGCAGGGAGAGTGCACCTGTGGG3504 
LysTyrAlaCysLy 
330 
TGGAGGCAGAGCGTATGCGAAGGTGGGACCTGGGGGCGGAGTCAGAGGTTCCAGCCTACT3564 
GCGGGTTGGCTGGT GGGCTAGGTGGGACCCCACTCTCGATAAGGGAAGTGACTACTCAG3623 
GGACCTTCGTGAGAATTTCTGCCGGAATCCTGATGGCTCCGAGGCG3669 
sAspLeuArgGluAsnPheCysArgAsnProAspGlySerGluAla 
335 340345 
CCTTGGTGCTTCACATCTCGACCTGGTTTGCGCATGGCCTTCTGCCAC3717 
ProTrpCysPheThrSerArgProGlyLeuArgMetAlaPheCysHis 
35035 5360365 
CAGATCCCACGCTGCACTGAAGAACTGGTGCCAGAGGGTGAGGCTGG3764 
GlnIleProArgCysThrGluGluLeuValProGluG 
370375 
AGCGGG GGTACAGAATCTGGGCAGGAATCAACCCAGGGCTGACCACCGCTCTTGCCTGCC3824 
CACCACAGGATGCTACCACGGCTCAGGTGAACAGTATCGTGGCTCAGTC3873 
lyCysTyrHisGlySerGlyGluGlnTyrArgGlySerVal 
380 385390 
AGCAAGACGCGCAAGGGCGTTCAGTGCCAGCACTGGTCCTCTGAGACA3921 
SerLysThrArgLysGlyValGlnCysGlnHisTrpSerSerGluThr 
395 400405 
CCGCACAAGCCACAGTGAGTGTGTGCTATGTGCAGATAGGGCCTTAACTCTAGG3975 
ProHisLysProGl 
410 
GCAGAATACCTTAAGTTCTTGTGAGCCTAAAGAGGGTCTAAGTGGCCTGATGTGTCCCCC4035 
TACCTCCTGCCCCTACATCTAGATTTACACCCACCTCGGCACCGCAGGCG4085 
nPheThrProThrSerAlaProGlnAla 
415420 
GGACTGGAGGCCAACTTCTGCAGGAATCCTGATGGGGATAGCCATGG G4133 
GlyLeuGluAlaAsnPheCysArgAsnProAspGlyAspSerHisGly 
425430435 
CCCTGGTGCTATACCTTGGACCCGGATATCCTGTTTGACTACTGTGCC4181 
ProT rpCysTyrThrLeuAspProAspIleLeuPheAspTyrCysAla 
440445450 
CTACAGCGCTGTGGTTAGTGCTTAAGACTTCCCCTTGTCTGGGTTTCAAACCT4234 
LeuGlnArgCysA 
45 5 
CACCTCCATAGACTGGCTCCCTTAACCTGAGTGAACTTGATCTTGCAGATGATGAC4290 
spAspAsp 
460 
CAGCCACCATCCATTCTGGACCCCCCAGGTATGGGGTTGGGCCAATTG4338 
GlnProProSerIleLeuAspPro ProA 
465 
TGGGTACACAGTCTTTGACCCTGACCCTCACTGAAGGTTTCATCCTGCCCCATCCCCAG4397 
ACCAGGTGGTGTTTGAAAAGTGTGGCAAGAGAGTTGACAAGAGTAAT4444 
spGlnValValPheGluLysCysGlyLysA rgValAspLysSerAsn 
475480485 
AAACTTCGTGTGGTGGGAGGCCATCCTGGGAACTCCCCATGGACGGTC4492 
LysLeuArgValValGlyGlyHisProGlyAsnSerProTrpT hrVal 
490495500 
AGCTTGCGGAATCGGTGAGGCCTAAGCGCTTATCTCAAGGAGTGGAGGCTGGAA4546 
SerLeuArgAsnAr 
505 
ACTCTGTGGCTTTATCAGTAGAAGATGGATGCCTGGCCTTGTA CCAAAAGGTCCTTGTCA4606 
GAAATGACAGTCTAGCATGTGTCCCAGGACTCAGTGTGGCTTCTCATCTTTACTCCTCTA4666 
GACAGGGCCAGCATTTCTGTGGGGGCTCCCTAGTGAAGGAGCAGTGG4713 
gGlnGlyGlnHisPheCys GlyGlySerLeuValLysGluGlnTrp 
510515520 
GTACTGACTGCCCGGCAATGCATCTGGTCATGGTGAGCAGACTGGGGACTCC4765 
ValLeuThrAlaArgGlnCysIleTrpSerCy 
525530 
TAGCCTACCTCTCCCTGCCATTGTCTGTCCCACAAGCAAACTAAATTGTGACAGCTGATT4825 
GGGAGTCAAGCATGAACTAGCAGAGTCTCTTTCTCCCAGCCACGAACCTCTCACA4880 
sHisGluProLeuThr 
535 
GGATACGAGGTATGGTTGGGTACAATTAACCAGAACCCACAGCCTGGA4928 
GlyTyrGluValTrpLeuGlyThrIleAsnGlnAsnProGlnProGly 
540545550 
GAGGCAAACCT GCAGAGGGTCCCAGTGGCCAAGGCAGTGTGCGGCCCT4976 
GluAlaAsnLeuGlnArgValProValAlaLysAlaValCysGlyPro 
555560565 
GCAGGCTCCCAGCTTGTTCTGCT CAAGCTGGAGAGGTATGTGGAT5021 
AlaGlySerGlnLeuValLeuLeuLysLeuGluAr 
570575580 
GTGTTGAGAGGGTGTGAGGCAGGGCTAGCCTCATGGTCATAGGTCCTGAAAACCCTCA TT5081 
CCCACTAAAGACCTGTGATCCTGAACCATCACGTGGCCCTGATTTGCCTG5131 
gProValIleLeuAsnHisHisValAlaLeuIleCysLeu 
585590 
CCTCCTGAACAGTATGTGGTACCTCCA GGGACCAAGTGTGAGATCGCA5179 
ProProGluGlnTyrValValProProGlyThrLysCysGluIleAla 
595600605610 
GGCTGGGGTGAATCCATCGGTAAGA GCACAGTGCATAGACATGGACTGC5228 
GlyTrpGlyGluSerIleG 
615 
TATGGGCCGGGAGGTCCAGCACTGGTTTTGGCTCAAGGGTCCCCTCCTTATCATTGTCTG5288 
TACTTCAGGTACAAGCAATAACACAGTCCTTCATGTGGCC TCGATGAAT5337 
lyThrSerAsnAsnThrValLeuHisValAlaSerMetAsn 
620625630 
GTCATCTCCAACCAGGAATGTAACACGAAGTACCGAGGACACATACAA5385 
Val IleSerAsnGlnGluCysAsnThrLysTyrArgGlyHisIleGln 
635640645 
GAGAGTGAGATATGCACCCAGGGACTGGTGGTCCCTGTGGGGGCTTGT5433 
GluSerGluIleCys ThrGlnGlyLeuValValProValGlyAlaCys 
650655660 
GAGGTCAGTGGGAGAGCCCCTGGGCCAGCCTGGGAAGGGCTTGGGAGCTGAAA5486 
Glu 
TTATAGTACTTGATTGCCAAGGGGGTGG GATGTCAGGAGAGGGTAGTCACTGCCGAGGTC5546 
CAGAGCCTTCACCCGTTTTTCTACCTGCCAGGGTGACTACGGGGGCCCACTT5598 
GlyAspTyrGlyGlyProLeu 
665670 
GCCTGCTATACCCATGACTGC TGGGTCCTACAGGGACTTATCATCCCG5646 
AlaCysTyrThrHisAspCysTrpValLeuGlnGlyLeuIleIlePro 
675680685 
AACAGAGTGTGTGCACGGCCCCGCTGGCCAGCT ATCTTCACACGGGTG5694 
AsnArgValCysAlaArgProArgTrpProAlaIlePheThrArgVal 
690695700 
TCTGTGTTCGTGGACTGGATTAACAAGGTCATGCAGCTGGAG 5736 
SerValPheValAspTrpIleAsnLysValMetGlnLeuGlu 
705710715 
TAGGCCTGCTTTTGAGCCCTTAGAGATGTCAAGACTTCTCAAACATAAAGCGGCCTTTTC5796 
TCTCTGTCTG TATAGAGTGCTTCTTAGTTTCTGTCTCTAGGGAAGGTGTTGACTCCTTGC5856 
AAGAGGCTGTGTGGCTTAAGACCAGCACACTCTAGGCTAAGTGCTCTGATCCCAGAACAA5916 
CTTCAAAAGGTATGTACTGTGTGTGGGCAGGGTGCACCATCTTCCAGAGGCACTCCT GGG5976 
AATGCAAGGACAGTGCAGAAGTTCCCAGCCCATGGACCAGAGCAGAAAGAGTGATGTAGG6036 
TCTACACCAGTCCCGTTTGGCTAGGACAGGCAGGGGTTGAGTCTCTCATGGCTTCTCTCT6096 
GTCACATGACAGGGATGAATACACTGTGGATATCAAA CCAAGGACCTAGGGTTTCTGAAC6156 
CCCAAGGTAGAGGCTGGGGCTGGGGATGGCTTGTACAAAGTACCAGCACAGACCAGGCTC6216 
TGTGTCCTCCTTTATTATGATTAGAGTCCATAGTCCTCTGCCCACTCATTCGGAGTCCAG6276 
AGCCCAGGAAACCTCTA GGCAGTTCTGCCAGATCCTGGGGCTTACCGAAGAGCAAAGTTC6336 
GAGACGGACTGCCCAGCTCACAAAGAGCAACAGGGCTTCAGCTGCCCAAGTGTGTGTGTA6396 
GCCAAAGCACAGTGTTCATGAAGCTGTCTGATTCCACCTCCACCTCTGACAGCGCATGGG645 6 
TGCTCTTGGGATACAGCAGGAGCCTGTATGAGCAGCAACACATGACATTGGAGGGTCCTG6516 
TCCTGTTTACCTGCCACCAGCTGCCCAACTATCCTGTACACTCACCGGACAGGCACATTC6576 
CGGGCCTTGAGGGCATGGTAATACTCCAGACCCTGCTTGAAGGG TACACGCCGGTCCTCC6636 
TGGCCCAGCATCAGTAACACTGGTGTCTTTACCTAGGTGTATGGGAGGCAAGGAGCTGTG6696 
GCGAGCTGAGCTCTGGACTCTGGAGGAATGGGTGGCACAAGGATACCTGGGTACC6751 
(2) INFORMATION FOR SEQ ID NO:6: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 6100 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: genomic DNA 
(iv) ANTI-SENSE: no 
(vi) ORIGINAL SOURCE: 
(A) ORGANISM: human 
(D) DEVELOPMENTAL STAGE: fetal 
(F) TISSUE TYPE: liver 
(vii) IMMEDIATE SOURCE: 
(A) LIBRARY: genomic 
(B) CLONE: L5/3 
(viii) POSITION IN GENOME: 
(A) CHROMOSOME/SEGMENT: human 3p21/D3F15S2 
(ix) FEATURE: 
(C) IDENTIFICATION METHOD: experimental 
(D) OTHER INFORMATION: This is the combined sequence of the e 
from two different recombinant phage isolates (L5 & L5/3) 
(x) PUBLICATION INFORMATION: 
(K) RELEVANT RESIDUES IN SEQ ID NO:6: FROM 1 TO 6100 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: 
CTGCAGAGGGGTTTCACCCC AACCCCAGGGCACCTCAAGTGTCCCCACCAAACCTTCCTA60 
ACACCTGTCCACTAAGCTGTACTAGGCCCTTGCAACTGACCTATGGGACCCTGAGGCCTG120 
GCCCCTCATGGCTCCTGTCACCAGGTCTCAGGTCAGGGTCCAGCAGGGCCCTGAGCTGAC180 
GTGTGGAGCCAGAGCCACCCAATCCCGTAGACAGGTTTCACAACTTCCCGGATGGGGCTG240 
TGGTGGGTCACAGTGCAGCCTCCAGCCAGAAGGATGGGGTGGCTCCCACTCCTG294 
MetGlyTrpLeuProLeuLeu 
5 
CTGCTTCTGACTCAA TGCTTAGGGGTCCCTGGTAAGTGCCCCCAACCCTGA345 
LeuLeuLeuThrGlnCysLeuGlyValProG 
1015 
TCCCCATCTGCCTTCAGGAGGGGGTTGGCCCCATTCTCCTATTCTAGGATGAGAAAAAAG405 
TCGGG AGCAGAGGCTCAGTGGGCATGGGGCAGTGACCTTGCCCTCTTGAGCACAGCTGGG465 
AAGCCCTAGGAACACATAGACATTGCCCACTTAGGCCTCTATTAGCACGTCTGCTCTAGC525 
ACTGAAGCAGTGTCAGGACCACACAGATGCACGCACACAGCAGGCAGTGACC CCTCCTGA585 
GCCTGATCTACCCCTCTAACCTAGCATATGCCTTTGTGCAGGTGAGAGCCCAGATTTGGA645 
GTCTGAATGCCTAGCCAGGGCCCTTGGCTGGGTAATGTGATGGCTCTGAGCCTTAGCATT705 
CTCATTTGAGAGATGAGGTGGGGCAAGCTTCA TCACCCACTGCTCTCACAGAGCGTATGT765 
GTTAGATCTGAGCCCGGTGCCTGGGCCACTAAACAGAGGCACCGGTGATAACTACCAAGT825 
CTGGGCCTGCTTCCCAGGGGAAATTTTTTTCACAAGTATCTGTGCAGGGGGCTAGACTGG885 
CCCTTGAAAGTG CATACAGGGTCCATCCCAGAAGCTTGTAGCTTTGATCCCCTGAATGAA945 
CAAAGTGTGGACATGCCAATACACATTACTGACATGTATGCCCACCTGACCTGCACCCAC1005 
TCATGCCTACTCTGCAGGGCAGCGCTCGCCATTGAATGACTTCCAAGTGCTC 1057 
lyGlnArgSerProLeuAsnAspPheGlnValLeu 
2025 
CGGGGCACAGAGCTACAGCACCTGCTACATGCGGTGGTGCCCGGGCCT1105 
ArgGlyThrGluLeuGlnHisLeu LeuHisAlaValValProGlyPro 
30354045 
TGGCAGGAGGATGTGGCAGATGCTGAAGAGTGTGCTGGTCGCTGTGGG1153 
TrpGlnGluAspValAlaAsp AlaGluGluCysAlaGlyArgCysGly 
505560 
CCCTTAATGGACTGCCGGTGAGTGGCCACTGGGCTAGATAAGACTGG1200 
ProLeuMetAspCysAr 
65 
GGGCAGGGAAGCCTG GGCTGTGGCGTTACCCTGTGCCTTCTTCTCTCCAGGGCCTTC1257 
gAlaPhe 
CACTACAACGTGAGCAGCCATGGTTGCCAACTGCTGCCATGGACTCAA1305 
HisTyrAsnValSerSerHisGlyCysGlnLeuLeuProTrpTh rGln 
70758085 
CACTCGCCCCACACGAGGCTGCGGCGTTCTGGGCGCTGTGACCTCTTC1353 
HisSerProHisThrArgLeuArgArgSerGlyArgCysAsp LeuPhe 
9095100 
CAGAAGAAAGGCAAGTGGGGGTGGAGAGGGGCAGGGTGGGAGACAGGGGA1403 
GlnLysLysA 
CCTCAGCCCAAGTTGATCTTCTGTCTCTTGCTCCCAGACTACGTACGG ACCTGC1457 
spTyrValArgThrCys 
110 
ATCATGAACAATGGGGTTGGGTACCGGGGCACCATGGCCACGACCGTG1505 
IleMetAsnAsnGlyValGlyTyrArgGlyThrMetAlaThrThrVal 
115 120125 
GGTGGCCTGCCCTGCCAGGCTTGGAGCCACAAGTTCCCGAATGATCAC1553 
GlyGlyLeuProCysGlnAlaTrpSerHisLysPheProAsnAspHis 
130135 140 
AAGTGAGACAAACACCTTCCCTCCGTCCCGGCCTGGGGCTTCCCCCAGCACA1605 
Ly 
CACTATAGTGATGCTCTGGGCCCTCAGGTACACGCCCACTCTCCGGAATGGC1657 
sTyrThrProThrLeuArgAsnGly 
145150 
CTGGAAGAGAACTTCTGCCGTAACCCTGATGGCGACCCCGGAGGTCCT1705 
LeuGluGluAsnPheCysArgAsnProAspGlyAspProGlyGlyPro 
155160 165 
TGGTGCTACACAACAGACCCTGCTGTGCGCTTCCAGAGCTGCGGCATC1753 
TrpCysTyrThrThrAspProAlaValArgPheGlnSerCysGlyIle 
170175180 
AAAT CCTGCCGGGAGGGTAAGCGGCGCCGGGTCAAGCTGGGAGAGTGGAGACAAGC1809 
LysSerCysArgGluA 
185 
CCACGTCCATCCACGAACCCACTGGCTCTTTGTCTCCAGCCGCGTGTGTCTGGTGC1865 
laAlaCysValTrpCys 
190 
AATGGCGAGGAATACCGCGGCGCGGTAGACCGCACGGAGTCAGGGCGC1913 
AsnGlyGluGluTyrArgGlyAlaValAspArgThrGluSerGlyArg 
19520020521 0 
GAGTGCCAGCGCTGGGATCTTCAGCACCCGCACCAGCACCCCTTCGAG1961 
GluCysGlnArgTrpAspLeuGlnHisProHisGlnHisProPheGlu 
215220225 
CCGGGCAAG TACGCGTAGGCGGTATCGGCGTCCTGGGGGCCGGGCTAGGGAAGGTCCA2019 
ProGlyLy 
GGACTCCAGGGGCAGGGCTCCGTGTAGGGCAATTGGGCGGGGCCAGATAAGCCAGAGTCC2079 
CAGGGTCTTGTTCACGCCCCATTACCGCCCCCAGGTTCCTCGAC CAAGGTCTG2132 
sPheLeuAspGlnGlyLeu 
230235 
GACGACAACTATTGCCGGAATCCTGACGGCTCCGAGCGGCCATGGTGC2180 
AspAspAsnTyrCysArgAsnProAspGlySerGluArgP roTrpCys 
240245250 
TACACTACGGATCCGCAGATCGAGCGAGAGTTCTGTGACCTCCCCCGC2228 
TyrThrThrAspProGlnIleGluArgGluPheCysAspLeuProArg 
255 260265 
TGCGGTAGGCGGCGGGGACCAGGCCTGGGAGGGTACCTGGGAACCTTGGGGAGG2282 
CysG 
GGCGTGGCTTGGCCGGGGAGGTAAGAGGGGCTGGGCGTGACCTGAGAGCATACCCCGTGG2342 
AGT ACCGTACACCTGGGAAAGGCGGGTTTGGTCCCAGCCCCAGAGGGATCTCAGCTCTCG2402 
CTCGGGGCCCGACCTATCTCGGTCCATCTAAGGGTCCGAGGCACAGCCCCGC2454 
lySerGluAlaGlnProArg 
270275 
CA AGAGGCCACAACTGTCAGCTGCTTCCGCGGGAAGGGTGAGGGCTAC2502 
GlnGluAlaThrThrValSerCysPheArgGlyLysGlyGluGlyTyr 
280285290 
CGGGGCACAGCCAA TACCACCACTGCGGGCGTACCTTGCCAGCGTTGG2550 
ArgGlyThrAlaAsnThrThrThrAlaGlyValProCysGlnArgTrp 
295300305 
GACGCGCAAATCCCTCATCAGCACCG ATTTACGCCAGAAAAATACGCG2598 
AspAlaGlnIleProHisGlnHisArgPheThrProGluLysTyrAla 
310315320 
TGCAAGTGAGGTGGGGGGGGGGGGCGGGCGTTGGGACGTGCTGCT GCGGGTGAGA2653 
CysLy 
CGGGAGGAAGGTAGTCACGGGCTCAAGGCTGGAGGCTGGCGGGCTAGGGCTGAGTGGAGC2713 
GCCTGCTTAGAGACCTTCGGGAGAACTTCTGCCGGAACCCCGACGGCTCA2763 
sAspLeuArgGluAsn PheCysArgAsnProAspGlySer 
330335 
GAGGCGCCCTGGTGCTTCACACTGCGGCCCGGCATGCGCGCGGCCTTT2811 
GluAlaProTrpCysPheThrLeuArgProGlyMetArgAlaAlaPhe 
34 0345350 
TGCTACCAGATCCGGCGTTGTACAGACGACGTGCGGCCCCAGG2854 
CysTyrGlnIleArgArgCysThrAspAspValArgProGlnA 
355360 365 
GTGAGGCCCAAGCTTGGGGGCTACAGAGCCGGGCTGGAAGCTGGAACCGGAGGCCGGGGC2914 
GAGGTCTCGGCCTGATGGCTGCCCGCACCCGCCACAGACTGCTACCACGGCGCA2968 
spCysTyrHisGlyAla 
370 
G GGGAGCAGTACCGCGGCACGGTCAGCAAGACCCGCAAGGGTGTCCAG3016 
GlyGluGlnTyrArgGlyThrValSerLysThrArgLysGlyValGln 
375380385390 
TGCCAGCGCTGGTCCGCTGAGACGCCGCACAAGCCGCAGTGAGTCCCT3064 
CysGlnArgTrpSerAlaGluThrProHisLysProGl 
395400 
GGTGCTCCCGGCCCCGCCAGGGCCCTAACCCTGGGGCGGCAT GCTTTGGTGTCTGGGACC3124 
AGAGCCTGGAAATGGTTGAGACTACCCTGCCACGATTTTGCTCCCGCTTCCGCCTAGG3182 
n 
TTCACGTTTACCTCCGAACCGCATGCACAACTGGAGGAGAACTTCTGC3230 
PheThrPheThrSerGl uProHisAlaGlnLeuGluGluAsnPheCys 
405410415 
CGGAACCCAGATGGGGATAGCCATGGGCCCTGGTGCTACACGATGGAC3278 
ArgAsnProAspGlyAspSerHisGlyPr oTrpCysTyrThrMetAsp 
420425430435 
CCAAGGACCCCATTCGACTACTGTGCCCTGCGACGCTGCGGTGAGCACTA3328 
ProArgThrProPheAspTyrCysAl aLeuArgArgCysA 
440445 
GTGACGCTTCCCCCATGACCCTGCCTCAGCCCCCACCCAAAGGCTGGCTCCCTTAACCCC3388 
AGTGAACTTTGTCTTTCAGCTGATGACCAGCCGCCATCAATCCTGGACCCC3439 
laAsp AspGlnProProSerIleLeuAspPro 
450455 
CCAGGTTAGGAGTTGGGCCAGTTATGGGTCAGGCCCTTTAGCCCACGACATCCA3493 
ProA 
CACAGTCTGGGTTTCATCCAGCCCACCCCATCCTACAGACCAGGTGCA GTTTGAG3548 
spGlnValGlnPheGlu 
465 
AAGTGTGGCAAGAGGGTGGATCGGCTGGATCAGCGGCGTTCCAAGCTG3596 
LysCysGlyLysArgValAspArgLeuAspGlnArgArgSerLysLeu 
470 475480 
CGCGTGGTTGGGGGCCATCCGGGCAACTCACCCTGGACAGTCAGCTTG3644 
ArgValValGlyGlyHisProGlyAsnSerProTrpThrValSerLeu 
485490 495 
CGGAATCGGTGAGGCACAACTGCCTGTCTCCCACAGAGAGGAGCTGAGGTTGTGTCCT3702 
ArgAsnAr 
500 
CTGTGGTTATCCACTGGGGCTGGGAATCTATCCGTGCCCCTTGAGAGGTCCTAGCCAAGA3762 
AGATGGCAGGTCTTACGA ATCTGTCCCAGGAGTCTGTTACCTGTCCTAATTCCCCACTCC3822 
TCTAGGCAGGGCCAGCATTTCTGCGGGGGGTCTCTAGTGAAGGAGCAG3870 
gGlnGlyGlnHisPheCysGlyGlySerLeuValLysGluGln 
505 510515 
TGGATACTGACTGCCCGGCAGTGCTTCTCCTCCTGGTGAGCCTCC3915 
TrpIleLeuThrAlaArgGlnCysPheSerSerCy 
520525 
CTTGTGTTTGGGGACCCAG TCTCATCCCACCTTCCCCCTTCCCCAGGCAAGCTAACAAGT3975 
GAGCCTTGGGGCAATGGACTGAGAGTCACAAATGACCTAGCAGAGCTTCTCTCCCAGC4033 
s 
CATATGCCTCTCACGGGCTATGAGGTATGGTTGGGCACCCTGTTCCAG40 81 
HisMetProLeuThrGlyTyrGluValTrpLeuGlyThrLeuPheGln 
530535540 
AACCCACAGCATGGAGAGCCAAGCCTACAGCGGGTCCCAGTAGCCAAG4129 
AsnProGln HisGlyGluProSerLeuGlnArgValProValAlaLys 
545550555 
ATGGTGTGTGGGCCCTCAGGCTCCCAGCTTGTCCTGCTCAAGCTGGAG4177 
MetValCysGlyProSerGly SerGlnLeuValLeuLeuLysLeuGlu 
560565570575 
AGGTATGTGGACAACCTGGGAGGGTGTGAGGTGGGGCTGGGCCTTGTGGCCT4229 
Ar 
CAGACCCTGAGTGCCCCC ATTCTTGCTAAAGATCTGTGACCCTGAACCAGCGT4282 
gSerValThrLeuAsnGlnArg 
580 
GTGGCCCTGATCTGCCTGCCCCCTGAATGGTATGTGGTGCCTCCAGGG4330 
ValAlaLeuIleCysLeuProProGlu TrpTyrValValProProGly 
585590595 
ACCAAGTGTGAGATTGCAGGCTGGGGTGAGACCAAAGGTAAGAGCAC4377 
ThrLysCysGluIleAlaGlyTrpGlyGluThrLysG 
6 00605610 
AGTGCACAGGACTGCTGGTGGCCAGGAGGCCAGCCCTGGATCTTCCTGCAGGACCCTCTC4437 
CCTCTCCCCATTCCCCTCACTGCAGGTACGGGTAATGACACAGTCCTAAAT4488 
lyThrG lyAsnAspThrValLeuAsn 
615620 
GTGGCCTTGCTGAATGTCATCTCCAACCAGGAGTGTAACATCAAGCAC4536 
ValAlaLeuLeuAsnValIleSerAsnGlnGluCysAsnIleLysHis 
625 630635 
CGAGGACGTGTGCGGGAGAGTGAGATGTGCACTGAGGGACTGTTGGCC4584 
ArgGlyArgValArgGluSerGluMetCysThrGluGlyLeuLeuAla 
640645 650 
CCTGTGGGGGCCTGTGAGGTTGGTGGCAGGGCCTGGGCAGCCCTGGAA4632 
ProValGlyAlaCysGlu 
655 
GTATGGGGGGCTAGAAATGAACTATTTTATCATGAAGCAGGCTAGTCATTGCTGTGGCCC4692 
GGGGCCTCATCAGTTCTCCTACCTGCCAGGGTGACTACGGGGGCCCACTTGCC4745 
GlyAspTyrGlyGlyProLeuAla 
660665 
TGCTTTACCCACAACTGCTGGGTCCTGGAAGGAATTATAATCCCCAAC4 793 
CysPheThrHisAsnCysTrpValLeuGluGlyIleIleIleProAsn 
670675680 
CGAGTATGCGCAAGGTCCCGCTGGCCAGCTGTCTTCACGCGTGTCTCT4841 
ArgValCys AlaArgSerArgTrpProAlaValPheThrArgValSer 
685690695 
GTGTTTGTGGACTGGATTCACAAGGTCATGAGACTGGGTTAGGCCCAGC4890 
ValPheValAspTrpIleHis LysValMetArgLeuGly 
700705710 
CTTGATGCCATATGCCTTGGGGAGGACAAAACTTCTTGTCAGACATAAAGCCATGTTTCC4950 
TCTTTATGCCTGTACAGATGCTTCTTAGCCTTTGCTTCCAGGAAATGTGT CAGTGACTCC5010 
TTGCTAGGGCTCGGGTGGCTTGAGCCCAGCACACCCTGGGCTAGGTGATCTGTCCAGCCT5070 
AGGGGCTTCCCCAACCAAGGCAATGTCCCTGGGACTACTTTTGCCCATGGGTGCCGTGGA5130 
AAGACAGGGCCTCACACTAGTCCTCCAGAC ATACTCTTGGGAAGGGTGGTACAGAGTAGT5190 
TGCTAATGGAAGGGGCTGCAGCAGGGAAGCTAGGCTGGTACAGAGTCCTGGTTGCCAGGA5250 
CAGGCAGAGGCTAAGCCTCTCACTGTTCCCTCCCTTCTCACACTGGAGGCAGATGAAGCC5310 
CTTGTGGCTG CCACACCCAGAACCTAGGGTCTCTGCACCCCAGAGTGGGAGGTGGGGTTG5370 
GGGATGGTTTGGTACAAAGTACCAGCAGGAACCAGGCTCTGTGTCCTAATTTATTATGAC5430 
TACATAGCCCACATTCCTCTGCCCATGCATCCGTGGAGTCCAGAGCCCAGAAAGCCT CCT5490 
GCTGCCCTGCCAGACCGTTGAGCTCCTCAAGAGGAAGTGTGGCACAGGCTGATCAGCTCA5550 
TGCAGAATGGCAGGGCTTCAGCTGCCCAAGTGTGTGCGTAGCCAGAGCACAGCATTCATG5610 
AAGCTGTCTGACTCCACCTCCACCTCTGATAATGCGT GGGTGCTTTTGGGATAGAGCAGG5670 
AGCCTGTAGGGATTAGTCAGCAACATTTAAGGTTGGAGGGTCCTCCTGTGCTCACCTGCC5730 
CACCAGCTGCCAGGGCCTTCATGCTGCACTCACCGAACAGGCACATTCCGGGTCTTGAGG5790 
GCACGGTAATACTCCAT GCCCTGCTTGAAGGGCACACGCCGGTCCTCCTGGCCCAACATC5850 
AGTAACAGTGGTGTCTTCACCTGGGTGTTTGGGGAAGAGTGGGGAGCTGTGTTGAGCTGG5910 
GCCCTGGATTCTGGATGGATGGGCAGCACACAGGGCAAGCAGGGGGCTGCATACCTGAGG597 0 
GATGTATCTGATGGGCGATTTGTCCAGCATCTCAGCCCACACGCTGAGGTCTGGCAGGCA6030 
GTCACTGCTGAAAGGAAAGCCAGCCTCCACCACGCACCTGCAAGACACCGAGCTGTTGCA6090 
GCCCCAGGAA 6100 
(2) INFORMATION FOR SEQ ID NO:7: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 2262 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA to mRNA 
(A) DESCRIPTION: Identical to sequence ID NO: 1: with 5'and 
adaptors added to make a full-length cDNA 
(iv) ANTI-SENSE: no 
(vi) ORIGINAL SOURCE: 
(A) ORGANISM: human 
(D) DEVELOPMENTAL STAGE: fetal 
(F) TISSUE TYPE: liver 
(vii) IMMEDIATE SOURCE: 
(A) LIBRARY: cDNA 
(B) CLONE: #icrosoft Corp 
(x) PUBLICATION INFORMATION: 
(K) RELEVANT RESIDUES IN SEQ ID NO: 7: FROM 1 TO 2262 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: 
AATTCCACCATGGGGTGGCTCCCA AATTCCGTCCTGCTGCTTCTGACT48 
MetGlyTrpLeuProAsnSerValLeuLeuLeuLeuThr 
510 
CAATACTTAGGGGTCCCTGGGCAGCGCTCGCCATTGAATGACTTCCAA96 
Gln TyrLeuGlyValProGlyGlnArgSerProLeuAsnAspPheGln 
152025 
GTGCTCCGGGGCACAGAGCTACAGCACCTGCTACATGCGGTGGTGCCC144 
ValLeuArgGlyThr GluLeuGlnHisLeuLeuHisAlaValValPro 
30354045 
GGGCCTTGGCAGGAGGATGTGGCAGATGCTGAAGAGTGTGCTGGTCGC192 
GlyProTrpGln GluAspValAlaAspAlaGluGluCysAlaGlyArg 
505560 
TGTGGGCCCTTAATGGACTGCCGGGCCTTCCACTACAACGTGAGCAGC240 
CysGlyProLeuMetAspCysArg AlaPheHisTyrAsnValSerSer 
657075 
CATGGTTGCCAACTGCTGCCATGGACTCAACACTCGCCCCACACGAGG288 
HisGlyCysGlnLeuLeuProTrpThrGlnHisSer ProHisThrArg 
808590 
CTGCGGCGTTCTGGGCGCTGTGACCTCTTCCAGAAGAAAGACTACGTA336 
LeuArgArgSerGlyArgCysAspLeuPheGlnLysLysAspTyrVal 
95100105 
CGGACCTGCATCATGAACAATGGGGTTGGGTACCGGGGCACCATGGCC384 
ArgThrCysIleMetAsnAsnGlyValGlyTyrArgGlyThrMetAla 
110 115120125 
ACGACCGTGGGTGGCCTGCCCTGCCAGGCTTGGAGCCACAAGTTCCCG432 
ThrThrValGlyGlyLeuProCysGlnAlaTrpSerHisLysPhePro 
130 135140 
AATGATCACAAGTACACGCCCACTCTCCGGAATGGCCTGGAAGAGAAC480 
AsnAspHisLysTyrThrProThrLeuArgAsnGlyLeuGluGluAsn 
145150 155 
TTCTGCCGTAACCCTGATGGCGACCCCGGAGGTCCTTGGTGCTACACA528 
PheCysArgAsnProAspGlyAspProGlyGlyProTrpCysTyrThr 
160165 170 
ACAGACCCTGCTGTGCGCTTCCAGAGCTGCGGCATCAAATCCTGCCGG576 
ThrAspProAlaValArgPheGlnSerCysGlyIleLysSerCysArg 
175180185 
GAGGCCG CGTGTGTCTGGTGCAATGGCGAGGAATACCGCGGCGCGGTA624 
GluAlaAlaCysValTrpCysAsnGlyGluGluTyrArgGlyAlaVal 
190195200205 
GAC CGCACGGAGTCAGGGCGCGAGTGCCAGCGCTGGGATCTTCAGCAC672 
AspArgThrGluSerGlyArgGluCysGlnArgTrpAspLeuGlnHis 
210215220 
CCGCACCAGCACCCC TTCGAGCCGGGCAAGTTCCTCGACCAAGGTCTG720 
ProHisGlnHisProPheGluProGlyLysPheLeuAspGlnGlyLeu 
225230235 
GACGACAACTATTGCCGGAATCCTGA CGGCTCCGAGCGGCCATGGTGC768 
AspAspAsnTyrCysArgAsnProAspGlySerGluArgProTrpCys 
240245250 
TACACTACGGATCCGCAGATCGAGCGAGAGTTCTGTG ACCTCCCCCGC816 
TyrThrThrAspProGlnIleGluArgGluPheCysAspLeuProArg 
255260265 
TGCGGGTCCGAGGCACAGCCCCGCCAAGAGGCCACAACTGTCAGCTGC 864 
CysGlySerGluAlaGlnProArgGlnGluAlaThrThrValSerCys 
270275280285 
TTCCGCGGGAAGGGTGAGGGCTACCGGGGCACAGCCAATACCACC ACT912 
PheArgGlyLysGlyGluGlyTyrArgGlyThrAlaAsnThrThrThr 
290295300 
GCGGGCGTACCTTGCCAGCGTTGGGACGCGCAAATCCCTCATCAG CAC960 
AlaGlyValProCysGlnArgTrpAspAlaGlnIleProHisGlnHis 
305310315 
CGATTTACGCCAGAAAAATACGCGTGCAAAGACCTTCGGGAGAACTTC1008 
ArgPheThrProGluLysTyrAlaCysLysAspLeuArgGluAsnPhe 
320325330 
TGCCGGAACCCCGACGGCTCAGAGGCGCCCTGGTGCTTCACACTGCGG1056 
CysArgAsnPro AspGlySerGluAlaProTrpCysPheThrLeuArg 
335340345 
CCCGGCATGCGCGCGGCCTTTTGCTACCAGATCCGGCGTTGTACAGAC1104 
ProGlyMetArgAlaAlaPheCy sTyrGlnIleArgArgCysThrAsp 
350355360365 
GACGTGCGGCCCCAGGACTGCTACCACGGCGCAGGGGAGCAGTACCGC1152 
AspValArgProGlnAspC ysTyrHisGlyAlaGlyGluGlnTyrArg 
370375380 
GGCACGGTCAGCAAGACCCGCAAGGGTGTCCAGTGCCAGCGCTGGTCC1200 
GlyThrValSerLysThrArgLysGlyVal GlnCysGlnArgTrpSer 
385390395 
GCTGAGACGCCGCACAAGCCGCAGTTCACGTTTACCTCCGAACCGCAT1248 
AlaGluThrProHisLysProGlnPheThrPheThrSerGlu ProHis 
400405410 
GCACAACTGGAGGAGAACTTCTGCCGGAACCCAGATGGGGATAGCCAT1296 
AlaGlnLeuGluGluAsnPheCysArgAsnProAspGlyAspSerHis 
415 420425 
GGGCCCTGGTGCTACACGATGGACCCAAGGACCCCATTCGACTACTGT1344 
GlyProTrpCysTyrThrMetAspProArgThrProPheAspTyrCys 
430 435440445 
GCCCTGCGACGCTGCGCTGATGACCAGCCGCCATCAATCCTGGACCCC1392 
AlaLeuArgArgCysAlaAspAspGlnProProSerIleLeuAspPro 
450 455460 
CCAGACCAGGTGCAGTTTGAGAAGTGTGGCAAGAGGGTGGATCGGCTG1440 
ProAspGlnValGlnPheGluLysCysGlyLysArgValAspArgLeu 
465470 475 
GATCAGCGGCGTTCCAAGCTGCGCGTGGTTGGGGGCCATCCGGGCAAC1488 
AspGlnArgArgSerLysLeuArgValValGlyGlyHisProGlyAsn 
480485490 
TCACCCTGGACAGTCAGCTTGCGGAATCGGCAGGGCCAGCATTTCTGC1536 
SerProTrpThrValSerLeuArgAsnArgGlnGlyGlnHisPheCys 
495500505 
GGGGGGTCTCT AGTGAAGGAGCAGTGGATACTGACTGCCCGGCAGTGC1584 
GlyGlySerLeuValLysGluGlnTrpIleLeuThrAlaArgGlnCys 
510515520525 
TTCTCCT CCTGCCATATGCCTCTCACGGGCTATGAGGTATGGTTGGGC1632 
PheSerSerCysHisMetProLeuThrGlyTyrGluValTrpLeuGly 
530535540 
ACCCTGTTCCAGAACCCA CAGCATGGAGAGCCAAGCCTACAGCGGGTC1680 
ThrLeuPheGlnAsnProGlnHisGlyGluProSerLeuGlnArgVal 
545550555 
CCAGTAGCCAAGATGGTGTGTGGGCCCTCA GGCTCCCAGCTTGTCCTG1728 
ProValAlaLysMetValCysGlyProSerGlySerGlnLeuValLeu 
560565570 
CTCAAGCTGGAGAGATCTGTGACCCTGAACCAGCGCGTGGC CCTGATC1776 
LeuLysLeuGluArgSerValThrLeuAsnGlnArgValAlaLeuIle 
575580585 
TGCCTGCCCCCTGAATGGTATGTGGTGCCTCCAGGGACCAAGTGTGAG1 824 
CysLeuProProGluTrpTyrValValProProGlyThrLysCysGlu 
590595600605 
ATTGCAGGCTGGGGTGAGACCAAAGGTACGGGTAATGACACAGTCCTA 1872 
IleAlaGlyTrpGlyGluThrLysGlyThrGlyAsnAspThrValLeu 
610615620 
AATGTGGCCTTGCTGAATGTCATCTCCAACCAGGAGTGTAACATCAAG1920 
AsnV alAlaLeuLeuAsnValIleSerAsnGlnGluCysAsnIleLys 
625630635 
CACCGAGGACGTGTGCGTGAGAGTGAGATGTGCACTGAGGGACTGTTG1968 
HisArgGlyArgVal ArgGluSerGluMetCysThrGluGlyLeuLeu 
640645650 
GCCCCTGTGGGGGCCTGTGAGGGTGACTACGGGGGCCCACTTGCCTGC2016 
AlaProValGlyAlaCysGluGlyAsp TyrGlyGlyProLeuAlaCys 
655660665 
TTTACCCACAACTGCTGGGTCCTGGAAGGAATTATAATCCCCAACCGA2064 
PheThrHisAsnCysTrpValLeuGluGlyIleIleIl eProAsnArg 
670675680685 
GTATGCGCAAGGTCCCGCTGGCCAGCTGTCTTCACGCGTGTCTCTGTG2112 
ValCysAlaArgSerArgTrpProAlaValPheT hrArgValSerVal 
690695700 
TTTGTGGACTGGATTCACAAGGTCATGAGACTGGGTTAGGCCCAGC2158 
PheValAspTrpIleHisLysValMetArgLeuGly 
705 710 
CTTGATGCCATATGCCTTGGGGAGGACAAAACTTCTTGTCAGACATAAAGCCATGTTTCC2218 
TCTTTATGCCTGTAAAAAAAAAAAAAAAGAACGCCCCATGGTGG2262