AU2002337671A8 - Polymorphisms associated with multiple sclerosis - Google Patents

Description

WO 03/014319 PCT/US02/25268 1 POLYMORPHISMS ASSOCIATED WITH MULTIPLE SCLEROSIS FIELD OF THE INVENTION The present invention resides in the field of polymorphisms in genes associated 5 with multiple sclerosis. BACKGROUND OF THE INVENTION Multiple sclerosis is an inflammatory, autoimmune, demyelinating disorder of the central nervous system. It has a relatively late age of onset, usually arising in the second 10 to fourth decade of life. It is approximately twice as common in women as in men. The first detailed description of the disease was given by Charcot in the 1860s and many other reports quickly followed. Multiple sclerosis has a widely variable phenotype with symptoms including weakness of the limbs, temporary blindness, lack of co-ordination and many others. Currently there is no satisfactory test for multiple sclerosis and 15 diagnosis is based on clinical criteria. This results in early cases often being misdiagnosed due to the lack of sufficiently characteristic clinical features. Additionally, individuals with unrelated conditions that have a similar clinical appearance have been misdiagnosed with multiple sclerosis. Furthermore, different clinicians still use different criteria in evaluating and diagnosing patients. Thus, there exits a need for a more definitive method 20 of diagnosis of multiple sclerosis based on something other than observed symptomatology. The population prevalence of multiple sclerosis in Western countries is approximately 0.1% and the lifetime incidence of multiple sclerosis is 0.2-0.3%. However, the lifetime risk of the disease in the siblings of affected individuals is much 25 higher at 3-5%. Notably, the recurrence risk in niono-zygotic (identical) twins is between 20% and 30% whereas in di-zygotic (non-identical) twins it is only 3-4%, comparable to the recurrence risk for pairs of siblings. It has also been observed that the risk to offspring when both parents have the disease is considerably higher (10-12%) than when only one parent is affected (2%). Finally, there is no increase in the incidence of disease in non 30 biological relatives of affected individuals adopted at an age before their affection status WO 03/014319 PCT/US02/25268 2 was known. This incidence data indicates that genetic, rather than environmental, factors are important in transmission of multiple sclerosis, and suggests that it may be possible to identify genetic mutations useful in diagnosing and developing treatments for multiple sclerosis. 5 SUMMARY OF THE INVENTION The invention provides isolated polynucleotides comprising a nucleic acid having at least 15 contiguous nucleotides of the variant nucleic acid sequences shown in Table 4. Additionally, the invention provides a nucleic acid sequence that is fully complementary 10 to the variant nucleic acid sequences shown in Table 4. These polynucleotides may be nucleic acid probes for the detection of loci associated with multiple sclerosis. These probes may be conjugated to a detectable marker. Another embodiment of the invention provides an array of polynucleotides having two or more isolated polynucleotides, at least one of which is variant nucleic acid 15 sequences shown in Table 4. The invention also provides a method for detecting in an individual a polynucleotide containing a variant sequence associated with multiple sclerosis in which a nucleic acid sample from an individual is contacted with a polynucleotide probe that contains a nucleic acid sequence from one of the variant sequences of Table 4 or the 20 complement thereof and detecting the specific hybridization between said polynucleotide probe and said nucleic acid sample. The detection of such hybridization is indicative of the presence of a multiple sclerosis polynucleotide in the nucleic acid sample. The method of the present invention may be conducted with an array of polynucleotides having at least one polynucleotide probe from the variant sequences of 25 Table 4. The invention also provides a computer-readable storage medium for storing data for access by an application program being executed on a data processing system, having a data structure stored in the computer-readable storage medium, the data structure including information resident in a database used by the application program including a WO 03/014319 PCT/US02/25268 3 plurality of records, each record of the plurality comprising information identifying a variant sequence shown in Table 4. Another embodiment of the invention provides a signal carrying data for access by an application program being executed on a data processing system having a data 5 structure encoded in the signal. The data structure includes information resident in a database used by the application program including a plurality of records, each record of the plurality comprising information identifying a polymorphism shown in Table 4. DETAILED DESCRIPTION OF THE INVENTION 10 The invention provides a collection of novel polymorphisms in genes encoding products known or suspected to affect the susceptibility to, course or outcome of multiple sclerosis. Detection of polymorphisms in such genes is useful in designing and performing diagnostic assays for evaluation of genetic risks for multiple sclerosis and other related conditions. Analysis of polymorphisms is also useful in designing 15 prophylactic and therapeutic regimes customized to underlying abnormalities. Detection of polymorphisms is also useful for conducting clinical trials of drugs for treatment of these diseases and the underlying biological abnormalities. A drug or pharmaceutical agent means any substance used in the prevention, diagnosis, alleviation, treatment or cure of a disease. These terms include a vaccine, for example. The present invention also 20 includes nucleic acid molecules that are oligonucleotides capable of hybridizing, under stringent hybridization conditions, with complementary regions of a gene associated with multiple sclerosis containing a polymorphism of the present invention. A nucleic acid can be DNA or RNA, and single- or double-stranded. Oligonucleotides can be naturally occurring or synthetic, but are typically prepared by synthetic means. Preferred 25 oligonucleotides of the invention include segments of DNA, or their complements including any one of the polymorphic sites shown in Table 4. The segments are usually between 5 and 100 contiguous bases, and often range from 5, 10, 12, 15, 20, or 25 nucleotides to 10, 15, 30, 25, 20, 50 or 100 nucleotides. Nucleic acids between 5-10, 5 20, 10-20, 12-30, 15-30, 10-50, 20-50 or 20-100 bases are common. The polymorphic 30 site can occur within any position of the segment. The segments can be from any of the WO 03/014319 PCT/US02/25268 4 allelic forms of DNA shown in Table 4. For brevity in Table 4, the symbol T is used to represent both thymidine in DNA and uracil in RNA. Thus, in RNA oligonucleotides, the symbol T should be construed to indicate a uracil residue. Oligonucleotides of the present invention can be RNA, DNA, or derivatives of either. The minimum size of such 5 oligonucleotides is the size required for formation of a stable hybrid between an oligonucleotide and a complementary sequence on a nucleic acid molecule of the present invention. The present invention includes oligonucleotides that can be used as, for example, probes to identify nucleic acid molecules or primers to produce nucleic acid molecules. Also provided are oligonucleotides that can be used as primers to amplify 10 DNA. Preferred oligonucleotide probes or primers include a single base change of a polymorphism of the present invention or the wildtype nucleotide that is located at the same position. Preferably the nucleotide of interest occupies a central position of a probe. Preferably the nucleotide of interest occupies a 3' position of a primer. In another embodiment of the present invention, an array of oligonucleotides are provided, where 15 discrete positions on the array are complementary to one or more of the provided polymorphic sequences, e.g. oligonucleotides of at least 12 nucleotides, frequently 20 nucleotides or larger and including the sequence flanking the polymorphic position. Such an array may comprise a series of oligonucleotides, each of which can specifically hybridize to a different polymorphism. For examples of arrays, see Hacia et al., 1996, 20 Nat. Genet., vol. 14, pages 441-447 and DeRisi et al., 1996, Nat. Genet., vol. 14, pages 457-460. Arrays of interest may further comprise sequences, including polymorphisms, of other genetic sequences, particularly other sequences of interest for pharmacogenetic screening. As with other human polymorphisms, the polymorphisms of the invention also have more general applications, such as forensics, paternity testing, linkage analysis and 25 positional cloning. Polymorphism refers to the occurrence of two or more genetically determined alternative sequences or alleles in a population. A polymorphic marker or site is the locus at which divergence occurs. Preferred markers have at least two alleles, each occurring at a frequency of greater than 1%, and more preferably greater than 10% or 20% of a 30 selected population. A polymorphic locus may be as small as one base pair.

WO 03/014319 PCT/US02/25268 5 Polymorphic markers include restriction fragment length polymorphisms, variable number of tandem repeats (VNTR's), hypervariable regions, minisatellites, dinucleotide repeats, trinucleotide repeats, tetranucleotide repeats, simple sequence repeats, and insertion elements such as Alu. The first identified allelic form is arbitrarily designated 5 as the reference form and other allelic forms are designated as alternative or variant alleles. The allelic form occurring most frequently in a selected population is sometimes referred to as the wildtype form. Diploid organisms may be homozygous or heterozygous for allelic forms. A diallelic polymorphism has two forms. A triallelic polymorphism has three forms. 10 A single nucleotide polymorphism (SNP) occurs at a polymorphic site occupied by a single nucleotide, which is the site of variation between allelic sequences. The site is usually preceded by and followed by highly conserved sequences of the allele (e.g., sequences that vary in less than 1/100 or 1/1000 members of the population). A single nucleotide polymorphism usually arises due to substitution of one 15 nucleotide for another at the polymorphic site. A transition is the replacement of one purine by another purine or one pyrimidine by another pyrimidine. A transversion is the replacement of a purine by a pyrimidine or vice versa. Single nucleotide polymorphisms can also arise from a deletion of a nucleotide or an insertion of a nucleotide relative to a reference allele. A set of polymorphisms means at least 2, and sometimes 5, or more of 20 the polymorphisms shown in Table 4. The present application provides 100 polymorphisms in 15 genes that may play a significant role in the incidence, detection or treatment of multiple sclerosis. Table 1 lists these genes, their chromosomal location, and related GenBank accession numbers. The estrogen receptor gene, referred to as ESRI, has been localized to 25 chromosome 6q25. 1. This gene has a suspected link to multiple sclerosis as the disease state occurs predominately in females of reproductive age. The interleukin-12p35 gene, referred to as IL12A, has been localized to chromosome 3p12-ql3.2. This gene has a suspected link to multiple sclerosis because it is necessary for Th1 responses.

WO 03/014319 PCT/US02/25268 6 The interleukin-12p40 gene, referred to as IL12B, has been localized to chromosome 5q33. This gene has a suspected link to multiple sclerosis because IL-12 treatment exacerbates disease in EAE while anti-IL-12 blocks disease development and progression in EAE. Additionally IFN-3 treatment decreases IL-12 production by human 5 dendritic cells and monocytes. Further, an increase in 11-12 p40 expression correlates with acute formation of MS plaques. The monocyte chemoattractant protein 1 gene, referred to as MCP1, has been localized to chromosome 17q11-12. This gene has a suspected link to multiple sclerosis because knockout mice failed to mount a Th2 response indicating that monocyte 10 chemoattractant protein is involved in T cell polarization. Additionally, the protein stimulates production of IL-4 and IL-10, and the protein is found in brain lesions in astrocytes and glia cells. The homo sapiens small inducible cytokine subfamily B (Cys-X-Cys), member 10 gene, referred to as IP-10, has been localized to chromosome 4q21. This gene has a 15 suspected link to multiple sclerosis because it is expressed in brain lesions caused by astrocytes and macrophages while the IP-10 receptor (CXCR3) is expressed within the plaques by T cells and astrocytes. Additionally, the expression of the gene is stimulated by IFN-gamma while antisense molecules directed against the RNA protects animals from EAE. Further, the protein stimulates migration of T cells, monocytes and NK cells 20 while modulating adhesion molecule expression. The interleukin-6 gene, referred to as IL6, has been localized to chromosome 7p14-p21. This gene has a suspected link to multiple sclerosis because it is a mediator of inflammatory responses and shows increased expression in the CNS of MS patients. The interferon receptor 1 gene, referred to as IFNAR1, has been localized to 25 chromosome 21. This gene has a suspected link to multiple sclerosis because it is a receptor for type I interferons including INF alpha, beta and omega, inducing a signal through Jak/STAT and the IRS pathways. The interferon receptor 2 gene, referred to as IFNAR2, has been localized to chromosome 21q22.1-q22.2. This gene has a suspected link to multiple sclerosis because WO 03/014319 PCT/US02/25268 7 it too is a receptor for type I interferons including INF alpha, beta and omega, inducing a signal through Jak/STAT and the IRS pathway. The chemokine receptor type 3 gene, referred to as CXCR3, has been localized to the X chromosome at q13. This gene has a suspected link to multiple sclerosis because 5 the protein is involved in leukocyte trafficking including integrin activation, cytoskeleton changes and chemotactic migration and forms the receptor for IP10, MIG and I-TAC. Additionally, the protein is preferentially expressed on Th1 cells with CCR5 and by T cells and astrocytes in MS plaques. The interferon gamma receptor 1 gene, referred to as INFGR1, has been localized 10 to chromosome 6q23-24. This gene has a suspected link to multiple sclerosis because it participates in the receptor complex for type 2 interferon and is involved in ligand binding. The interferon gamma receptor 2 gene, referred to as INFGR2, has been localized to chromosome 21q22.1-22.2. This gene has a suspected link to multiple sclerosis 15 because it participates in the receptor for type 2 interferon and is involved in signal transduction. The tumor necrosis factor alpha gene, referred to as TNFa, has been localized to chromosome 6q21.3. This gene has a suspected link to multiple sclerosis because it is mostly produced by macrophages and monocytes and has a dual role in EAE including 20 inflammation and immunosuppression. Additionally, an innate low IL-10 level with a high innate TNFa level has been linked to increased risk for developing MS. The myelin-associated glycoprotein gene, referred to as MAG, has been localized to chromosome 19ql 3.1. This gene has a suspected link to multiple sclerosis because the protein may play a role in myelination and it is a putative autoantigen in MS as both T 25 cells and antibodies specific for MAG have been detected in the CSF of MS patients. The myeloperoxidase gene, referred to as MPO, has been localized to chromosome 17q23.1. This gene has a suspected link to multiple sclerosis because the protein is a major component of neutrophile azurophilic granules and is present in invading macrophages in the CNS of MS patients. Additionally, knockout mice show 30 increased susceptibility to EAE. Further, the protein plays a role in processing of light WO 03/014319 PCT/US02/25268 8 and heavy chain proteins and produces hypohalous acids central to the anti-microbial activity of neutrophiles. The interleukin 3 gene, referred to as IL3, has been localized to chromosome 5q31.1. This gene has a suspected link to multiple sclerosis because transgenic mice 5 expressing IL-3 in the brain develop a MS-like disease. Additionally, the protein activates macrophages and microglia and shows decreased production by PBMC in MS patients. The nucleotide-binding oligomerization domain 2 gene, referred to as NOD2, has been localized to chromosome 16q12. This gene has a suspected link to multiple 10 sclerosis because it is associated with inflammatory bowel disease. Three tables describe these new polymorphisms and how they were identified; Table 1 summarizes information about the 15 genes analyzed. Table 2 shows the manner in which each gene was divided into sub-regions for analysis, including information about the primers for PCR amplification. Table 3 shows the base occupying the polymorphic 15 sites, the observed frequency of the alleles in the study population, data on whether the polymorphism is in the coding region of the gene or not and the number of observation in the study population of each genotype. Table 4 describes the polymorphisms that were detected. A study population can consist of any number of individuals, subjects or biological samples that may come from human or non-human organisms. The study 20 population in which the polymorphisms described below were identified consisted of 176 multiple sclerosis patients from the USA. The demographics of this population were typical of a cohort of multiple sclerosis patients (e.g. >90% Caucasian, 2:1 female to male ratio). Table 4 shows the reference or variant base occupying the polymorphic sites and the nucleotides observed on either side of the polymorphic site. Column 5 of Table 4 25 shows the two bases that can occupy each polymorphic site. The first base was observed more frequently in the study population and is therefore designated as being a wildtype or reference base. The second base is designated as an alternative or variant base. These polymorphisms were identified by direct-sequencing of PCR products amplified from genomic DNA from the study population.

WO 03/014319 PCT/USO2/25268 9 zz < C. 0 o E Il 0 XL 0 - <C M C.0 m r- 0 0) CNO M <~ = oJe ECO co ~O coC 0 -' 0 It - "0 OC' co (N ~ ~ C:E -o C N-0 0 co -J C'-. 0j C 0 CY) CD C,) C >~ 0 :O 0 - : 2 ) u ) z. _o CEN 01 04~C~' C) - ' no0I> x o Lo Z ~~0N-< ~L- C - L~N OZ 0 0 00 (zC oc )a <c Ce- -X C C'mz4 C -e Z < cc) ~ ~ ~ ~ ~ 0 0)<XL NE;50 0 0~ ~ ~ 0 "I -0 ZE *o -i z o D X CDEL Cr C C'C E 0O -) m5 - c 0 L C~o C, C i 00) 10 ~ -)C)c Y)0 O' LO m 0 0) D < 140' L 1 C5 x~ - 1 wwL -- I 04D N c (ci 040D LOd C) LL >-04 04 C 0) 0U) 0- L 0 CEE z 0CD -Ci a) :) 0.x0 -0 . M 0 W( E E 0 C: 0)cCC . C wcnC '-4 Z 04 04 C)(D 0 D E (9 () zIw 2

L

WO 03/014319 PCT/US02/25268 10 o Co Co -t t J- - 0 Co Co tO CO t (0 W O V) C 0) 0) CO CO ,I- LO Mo LO LO (-CoCo CO CO CD 0) 2 1 t t -, 4 )a) C") c) co o C') c) co w O CO co C) Cm co cq r r, W W1 oo oo Lo Lo -, t Co Co co a- C Co L o Lo C Lo Lo Lo Lo Lo Co Lo Lo Lo Co Lo Lo Lo Lo Lo Lo Co Lo Lo Co C Lo Lo Lo Lo Lo Lo Lo Lo E O O~JNNN N N N N N N N N N N N N N N N N N N N N N4 N N1 N4 N4 N4 N~ N4 N N 0) o 9 C90~ (-< L)< < Lo)~ ooD < g Q o <oDo F-ooooDo <~~~~~«. I- I-D(DC )L <~~~ 0 o os <o Hoo o<go~& 0D -- Loo <)e s - o- o < < D < (oD (o < o ( oD L < ooo (D 0 F < 0<(l 0000- < 0H0 0<0D( ooo ooOOo <oooc(< o0oo< ooooooO o(D L) < C< o o- F-< o - o

[-

(D L o o. < C < < o(DwCD o< o u soDF ( s o L) ( a) o (oo ooD L)< I C) < o Q0 oD CC)o Lo W< s~~C <<ossso (o Dooooso a) < 0 < N N oN < o< HO (D< o o(De s F o o< 0 c 0 0 -< D< 0 0 (D (D < s.. o o< <<< N<N 0 0 00 . E NNNNNNo'<oo o oo<T o *M o ko -2 sO < o oOO wO< O-r< 0 o 0 0 0 022 EDIn1 1 o [ 0 Lo 10 <<FX XLo E D r o < o LD 10 zo L FxD bD (L L . 1- - -L - - a a a a.a.a. - -CL - M CL CL C 0. B- 0 CL a- CL a. 0-..

E ) E E ) E ) E E E E0 E ) E E ) E ) E E ) E 2 E D E 0 E ) E p E ) E 0 E 7e ) E 2 E ) E 0 E ) E E aEE) o ' I E 2 E - 2 2 " e w 2 " e m 2 "M W" o 2 w e " 2 " 2 M 2,C) 2'C m"2)C'2c2 L U) W LL W~ LL 0 LL r- LL W- LL W- LL W- -L W LL - LL - - LL w rL t- W~ LL w~ LL W in a 0 000 00DlD 0fr ~ ~ ~ < < 0g g S o o N N N N N N N > E 040 40 404_ N; I I I 1 0 0 I z XWXXXX>XXXXXXXXXXXoXXXXXXoXoXXXXXXm r 00 C) o o C D O O , w w w w f w w w P w I I,- - o(<o~~ ~ ~ W5 E o < <<o O -- ,~ < 8-s~~~~)~ a aw re OtOOco < C)EC0C00001 0 owwwwwwcwwwwwwwwwwwwwwwwwwwwwwwwwwwU-L < W XXXXXXooooooo< < U)ooooooo oy [- 0UOO000UWWWWWWWWWWWWWWWWWW............ w - -------------------------------- WO 03/014319 PCT/USO2/25268 -M ITI CDCDo 0) 00 00m LO ) c co CO co I-- r-N '- 0) 0) N- [I M' CMC CO CD C 0 LO ) LO LO 00 00 LO CD )C 2~~~~~ N0 CY) CO 00 00r U)U t C) 0) a) - CD C') Nl 1- 0) 0) 00 C0 (0 CO It 't CO CD CO) MM 0) 0 CD0C 0 C/) cD ' t C ) CD CD C04 C C D 04 C l CD CD C D C D C C O CD0 CD -D -D C D C 0)4-a 0) - NCO~- i NC' N D C < -N~-- C "J -l C-) < -0~ -C 0 0~ E <(DCJ< (D<OCH- <O (DOOOEI CD0O 0<0000000000000000000000 -. - - -. - -. - - - - - - - - - - - ~ - 5 - ~ I - 5 - 5 - 5 - 5 - 5 0e) o ie) Zv 0e) Vo 0o) 0) Vo 0) Vo 0) vo 0) Q Z,) v ) V0)V 0 0)v )V 0)V )V 0) ) oo b- M N 10 b< m N x 0b t o1 n1 b1 r .~ .N N N N NND1N2NN N 40 No 40 2mmo2 2I 2 t RI 2 IR o 2 R j R E~~~ ~N ENN EEEEEEEEEEEE 0- ~ ~ ~ ~ ~ ~ m a-. ILN NL0 -0 -0 -0 LI La -a _MMMMa CO M C N 0000 C -20E ) - ))R C < <<<C000C0C 0 0 2 0 a)202aE D-2-2) m coZ2ZZZZZaZZZ MZZC M E2 C62 M M CM COCOC"<M << <<<UO E<m >m >< mm > > > > > r )0 C )000a )0C ) D0a w)0 [If LL Iy LL 0 LL w U- W LL 0 LL W LL W LL Of LL al LL cl LL i W Ir LL X~~~~~~~c XXX )<XXXXXXX Xc rlf~xx xx x x (DD~WWWWWWWWWWWWWWQ0~WWNWWWWWWW cyNN0 N co n NgaC N- -- , , >1 0 c c C-4 << 2, OOJCC 9OO41-f-1-1C C'4 C7OO0OO r ItC cCE C ZZZZ ZZZ ZZZ ZZC C) N a' cDC CO OC < << << -- -- - -- - I I-- - - - - - - - - - - - - -0 WO 03/014319 PCT/USO2/25268 12 a) c coC~ N N t CD C,4 (N 0) 0) co D a0)) C 00 Noc N q Nq cD co N Nq 0) 0) ,t- 't 0) o 0 co 0) 3 C2 CN 0) N0oo ) 00 o ) co c co oo * *0q) q) ,t 4 Co Co q) o) a) a) m) co - ' m) 0) 00 o ) co co a. U) V) LO It 1; LO M) It- m LO LO U-) LO U) L) Lo ) V) 'ti 't V) m) M) Io U) U U.) M) M) O CD wD U) U") UO 0 00 M m NN mN C 0...~JN NN N N NN -N NN N N NN N N N N N N N 14 N N N NN 00 <<0< < < < <D Q 00< ~00 00 H00 0 O~r( < 0) 0 ~00 -00 o ~ ~ ~ ~ ~ C <HH 00 00L 0Lfr 0~ 1-<H ~ )C 0000 00C( <OHOO (D 0 0 oood - -( 00<0nH <0< U) < 0 CD 0 o 0 I~0 000C)C- 0 1~OOH 0HCD <H (D O00000 CD 0 (D - 0HHH<HH0M 36 <0 00 0 0 E -o 0o~Foo~I- 00O ~0F~ <0< :3 00 CD CD <00 < I- 0f-<0 -I-- - O .4- -- -- - -- - P - ---- C 4 F- 44-4 -4-4 -44- 4- 4- 4- 4- - - I'< c- I- 4 D I- 4- 4- - 1- 0- F- 4- 4-4 4 0.20..)000 0.20.000000000.200 00000000000 M~ M- (L C- M - M.. m- - 0 - 0- a- l- 0.. - - - . a. a. n - a. a. a.5- U.- 0- - a) 0) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0o 0 0 0 0 0 0o 0 -o 0 0 0 0o 0 -o E0 a- mIE-mc Lc -c Lmmmmmn -mmmmmc 'e CD- )- )' )" )- )7 )-2 )- )-2 a 0 1)- )- ) )- u)' D- ) a)0w2..2 u2" 2(uW ~ 2 c " a)ao) a ) a ) D Q ) a ) a 0) < <NN> 00 JCD000000 ) - I l Io o o o a a . Q. 22C < << < ' 0OO OO0OO0o 0011100 0 U01 U - -U-! LU-' - 000COCNNNNNNO z00 M M CL M M M .0.0- 0 M ..LZZZ Z Z Z -- 0 o'<<<< Im O< < 00 <<momc *cY l) 0 0NNcy) N 0 0 0 0OO OIT WWA wo A Ax AX XX) X w 0< w< x xx xxx xx OCYzwwom.wwwwWWWWW....0.0.0.0.0.0.WWWW WWW 0 - -ommmmm <<<<<<N C C=0- - ILa_ 000 U L L - LUoo L 000 )NNcN 8N 0 00 00 ..0..0.0....0.0....zzzzzzz 0 ~ H HH H -HH-------------------z WO 03/014319 PCT/USO2/25268 13 ( _ 4~- 4 0 ,-LOL~ 0~ c co co 00 -cq~ N LO LO CO 00 0w C'4 N NN a- CFO co Co 0t T LO U) 0 0' Cm mO U') Ct It Ct Ct Wc 0 0 (D 0 _~J 0N N N N IN N IN N NC N -N N N~ IN0 N 0IN N N4 04 a- a Cd 0 CD(D0 <00 1- c~ 0k < (D CD (D << H 0 Q (D~ <~ (D t (D (D F_ < < )<~ 0D u 0 0 E~~ <<~ =0- H 0000< SF-0H~0~-0-<<= F--40w - ------- - F -- 0 00 O O O O 0O O O O 0. <) (Da< 000 0 0 0 0 0 0 0 0 0 0 -D ()(() U- U M C 4- -4- 4-4- 4- 4- - 4- - - - 4- 4- 4- - 4- 4- 4-4- Zo L. Zo 1o L.) Ze Ze 3o L.) j,) Zo I... Ze Z-) L, Z. L) &- Zo m m. 0 0 0 x t 0 ~ 0. 0 ~ 0. 0 . 0 . 0 . 0 0 . . 0 . U. 0 . 0 . 0 . 0 . 0 . 10 D o r 4 zoLDb b4)b 4 bb bLD4) bto -0!_ . .O O O O O O O O O ) W 0 .a) ........ CL m CL M M Lfl II a) (N -o a)- )- )- D )- 3 0 a 2 D )) ) C/)~~a NN NCDNN NN N N N N N Q) a (D a) E > > >' >' ? > > 9 > > O~ zi QOOOOOOOOOOOOOOOOOOOOOO0 0 0 0 E) < N < < 0W WU-LL IN C~ C I< o < . I I . - F- p 0C)Z ZZ ZZ Z ZZ ZZ ZZ Z Z (N 04 C410 < OM00000000000 WO 03/014319 PCT/USO2/25268 14 N 0 ) M )M tr- N -O )M It0 MO ) C1 I . -0 ) CO 0)rI'0) COU)mNL1L) ( 0 C n 0 C) 0 mO CDrOOO t CDtCO. C OCOO CD OOO0CotOC OO ' Nt 6666 000 666 6666 60N000z0000U0co-0000t '1 100t0 00 0 Mr O 0 0m; OL )L)M0 )c )0 rj co trO)Cm0 rrWCa) O fltWU N t- -CW) m )0 m1 o it 6Loooooooooo66661o-olcoO oOooor-OOOOO70o0oooooo C, 2:1 0 C: (D oo oCneOO OO r O CO mOO ONco NIN orOOOOON r a) C3. En0 CL ) 0 M N WO * , W) MOO0 0 r-N M' "t O M r- M0M 0 '-N MO 4t 0 CD t- CO M) 0 ,- N -eN N N O~cm m "~~ 000000 0 00 0 0 00000000000 00 OO WW 00000ODs, cxx000000000000X* 00000 0'j QQC fLro to Cooo O ozoo 0 Q o 00 QUO) 0 00 C()C))()Z () 0 0 J Cj .IL IL WO 03/014319 PCT/USO2/25268 15 c'J CD 10O r'0)M t (D U.0)C0oNt- o OC00W 1 t O -- CO co r- 0 0 mZ U)M D Lo0 t tot ) It 0 o O rO "1. nO NCfwrON) 0 000000C)cl 0 rN-rcor &- 666666DCooooC:o666666666660000000000000000000000C CD tJ , c -,I-Oc) COCOmz;oomc r-l flr 0C') t N0tlCO0-L NMM-tCdOCItJTC'fJ t- mNt0C0N 0tLoC 0r c co CCN ItLOC N-c )1 mL 1 oC O 0)m U 0 c D N -0 ~UUCOW C o c D0 qmS mmI )C 0))U rn W N - N - U ) N-r*- N- qr l qqqqC Cq qr-qO iC -: C) 0 W) m Dr ONr-0 Urm--C1L) t CC , C9o4 0 I o . l OCONOO mO M a)-N-0LA 0 0 .04r -tM tN -- roooo O 00N 0c)rIOoNIDI 0 O 0I O) 0 300 ON- LA ND N- LoN CNLA N -U )C N to C)i < 1OLACON CO 010(5CL 6A N C & ( F:0 N

C)

0a a a ay cc a ar aY cr cc uo ",. 00000000000 0 0 0 0 0 0 0 0 0 C~o o coo m~ << <Ll< ggCO << Q0~ 0~mw ww w 0w W WWW W WW WW W WW W ID W WWiW WW W WW WWJ W W W WWW WW w W Co Co Co CO) Co 000000~00 ""0~oD O mc U I LILLI 0 0 a0000000 0E INNNNNNI C a) z z z z z z < < ' < O O Cx 0 0 0 0 -HH H - O O O~ - - -Z-ZZZZ WO 03/014319 PCT/USO2/25268 Cd) S3 Cd) 63 C U - C ') 0CDC cL LC0 Ccc 0 C.) I0 00 U)0 0a)No 00 U- 0 C'0 0,0C0 0 C) 0 0 6.) 63V3 LL0 00 0 0 0 0 0 6 - 0 0 0C:)C> 0 ~0 0 CD 'Co3 c 2U 00 0 0 0 0 0 0046 63 C.) co I-~ CO M) c It co~ 6O3 0D 10010)1 00 00 0 0C 0 000O IO Or -- Cdd 6 Cd -U 0 ,0 0~ 6) 63 Q Q D Da 5 IL tfccL C ) 0 - r- 0 - N -l It O -D 1 - - - 4 . 6) 0:) ) o C Cd) 0o6 0 00 '0 C) 0 *z Q 0 0C oo U6 En 63 -o 'o -0 b~ En6 03 4 0 4S b C" CI 63 63 0. r 000000000000000 -. ! ZZ ZZ Z Z '-i C;) WO 03/014319 PCT/US02/25268 17 00

-

(D (D85 Z 0 0 < < < f- < < 888[k 00-000000-800000 <<00000000O<_ co<<6<66 <656-8 < <#< < 089 0 8880 0 #-0?0 00U 88< oof 88 8 <~0 0 (D (9 0D00 00 01-0 0 -<1 ~i~00 o ~0-00 0(D 0 1 < 1 1 8 88 88886880668888SO$ 86 88S6oo0 0008 (1) 000~( -HO( 00C L1 001 Uo (DCD- 00I 00C Uo9 0« C CD) U Q) 0) 1 0 0 0 0 0) << 00) r = 6) 6<0 ) ) ) ) 0 0) (3) a) C) a) ( D a ) ( a a) a) a) C) a) a) a) a) a) e u e ).( ( e a cu 5 A a ba Q)r (L a) o o o o C OcC(.Cocc N C CCO C C C CVCCC ~ C . a0) 0 ow0 m0)0)0 a000))) )) w0)0(a0 a)i ) a0 0 m a m )00))0 0)0) m 0 z 0 CO - < - < < < < < o O O < SE o o < - - o CO 06 000000 z. 0 z z z z .. z z z 0 0 z z z z z 000 o 0 0 a 0 0 0 0 0 0 a a--0000 00a Z a 0 0 0 w 0 0 0 w w w w w w .. .. ~ ~.- 0 0 0 0 0 0 w. . . o 0 0 0 ~~ N 00 000 0 0 CO 0 0' 0 D C1 No CD r- Lo CD C , 6 6 0 o U o ) C C C m C l r- CD r- I'd I- W m C . m n m C C . ) Co U) 0o of oL o o o o o oD 'I o r- o (At CA A ) AoA () () ) (A) 000) CA) mA A CA) ) (A) * (A () (A) It o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 .0 0 -J 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 F- <1 < <0< <1 <0 0 <1-0 0. a. o0 0 (D0 0< 0 - 010 - <0 - 0 -1- WO 03/014319 PCT/USO2/25268 18 00~~ C)~000 HO 0H 0 0H000< 0 0 OI DD<0 <0Q C0C9 < C < 0<< 0 0 q ~0F OOM88<< <0 oflo («000--0I C) C) U C .) (D) ( . ) _. . U C) ) ) - F- (D C) U U . C C . ~ C C C CD C 4 . CD ( C. C C C . 66C<)C DI 4 -. 4 - C - C )~ - r 4 C 4 - C 4 L - 4 C 4 - C ) 4 - 3 4 4 - 4 - 0 4 L . 4 - - . 4 . C 4 C)(D( C) a)CCC C) C)C))o)o)oCCC C)CC D(DC)CaW )C )C )C )C )C aCO CU CC 0 r 0 D88o.8 CD ~ ~ ~ ~ ~ ~ C C)C ' ) CC ' C) 00 C) 0)5 0)) 0 0 0 ND (D cC) C'9 (D ) C') - F- ( D C D ot r 00 00 0 00 0D 00 00 0 0 0 00 0 0 0) 0 0 0 0 D 0 (0 0 0 0(- (0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 CO~~~ <O <l (D) 0l (D (D) UOC) C O C l) C) C) C C Cl) C) PCF) a) D (D a D 0) ) (I (_, 0 C') a- (D ( (D 0D ) (D 0)( D ) CD a 0 CD a: . 0_ U' C) CD L- C ) - 0 D C ) C D C D C) ~ C) C' 4Ca cu a) M C' ' (C)1 ) ( D m D a ' a' ') ) a) a') CD D C ) C C C C C) C) c Cat C) C- C C C C C Cu C >) >C >_ o() o t 0o 0J - o 0 0C 0Im r 0m 0 0 0 0t 0o 0 - 0 0 0 0t 0 . 0 o 0 0J 0. 0. . 0. 0 0~ 0 o . o . o . o o o o o 0 0 0 0 0 0 0 0 0 0< o I - a o- o- o- o- 0< ' It It I-- 't I) I-4 It (1- N- I- I- It LO N- N- I- I- C0 m- (0 00 a-j ( n ( C ( ( c 0 0 0< I0<0 0 < < H 0 0 0 0 0 WO 03/014319 PCT/USO2/25268 19 ou 8 0000c. 0000) 000 << o-- 0 (Doo 00 0 0 000000o 000 00o 00«gb0030 000000 0OW 00 OO -ooo «00000oooo000 0 88C~~OO0 « 0 00I~t000r OPi 00 0060 <000 «00000 oo«00 0 0 0 0. () C.) (. ( .) . 0. 0. C) (DC C C9) 1.D if C.) C D CD ) C . 4- < 4P- F ~ C 4 - C ) CD 1-. 0 0 - F- C (- -C - Q - 4- < 4- 4 4 - 8 U) 0CD D( UCOCC)CCUCOOC)C )CCC) CCCC)CCUCU)C<UCC) 0 C ) ) C) 0 ) M * -t C)~~~CC C ~ r - U 0) 0 CC CC) CC CC CC CC ( . t ')()I < 0 00D 0D 0 0 0 0 0 0 0 0) 0D 0 0 0- 0- 0D 0- 0- 0 0% 00(D0000000000000000000 -wF- wD o w D o 0 w w( w- < < l)< < C.) 0 (D C) od al ol Cl 8l 8 l o l a l (D ) <l <l l9 0CQ) Q ) l C) C Q.~ C) CC 0 I (D 886 F-) C)) QC C) (D) (9 0) (D 0- N ) 8) 6 9 D) - 0 N 0 .) C) F- F- <C < C <) < ND (D N 0 C N) (1) ) LI) ) CD N) Ca) a) CC C) (1) W a ) N aN o 0 0 0 0 0 0 0) 0) 0U 0 0 0 0 0 0 0 0 0 ... i~~~ 0.) a. 2. C . 0 . 0 . 0 . 0 . 0 . 0 . T. . 0. m 0. (-.J 2 _ C ucu ( 2-1 ID ca (a W- (-I 0= a)0-1 < 0 0 CL D ( . ? r 2 S Q - ! = 4 . ? _ _ E o(Q i 00 0r000000 000r0000 a) ) ( W- I- 1) a) I- (1) (a 1- I- a) 1-1 a) 1b ca a) co L) m- Iu IUa )m2 ma)> )m C.EO m 000< OMMO CO oo100 ----- << WO 03/014319 PCT/USO2/25268 20 00I C0 000c 00-1 (9(01-

-

1-0P< 01-- «0 0(9 0088000 < 8«0 ~~(oo ci) OO<~(D ,erm( (D009C o0 u~ C C9 c~ ~ 00 r00<999 ci) ~ ~ 0 0D 0 f92000(99(99(99( (D~~cg< 0 <(9(9(90C9 < 9 (D < C9( <C 0 <( <1-1-1001- 006 ED C.C C9 < 0)~( 0)~ 00 F )0 4- C 4- Q (-. 0 (- 0- 0- (D (C (DL 4 . C) 0 - 4- (9 4 < - < . (9 c!) 49 (9 <- <. <- 4D4 C (. 0~D >DC DC )<0 q( D( -0C L0 C C) C.) 00 (9 0Nu u (D (D F (. < <'C)C)' <000000)C' 0 (DOC<C<CCCON-N< ND N

C.

a) 0) (D a) a)0 0 ) (1 C C D a ) 0 a) 0) a) (D N) a) a) 0) 0 0 U 0. 0 0 0 0) 0 0 - 0 0 0 - 0 0 W 0 N m WT Wo Wr G 0W Nr Wa Wl NM *M lW C) Wq WIr WJr cl) l L L ) Col Cl) Cl) Cl) l) ) Cl) ZC-t Tr LO) CLO )t O)U O) C O) Cl) Cl) (0( ( CC) to- Clz Cl) f r- 0D 4-4-4 4-C- -4-4D4- 0 4- 0 m 0) m0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Z. 0 0 0 0 z U)~ aD C) 0 ) 0 U) 0 N N- U) N - 0C N- N- 0 .2 0< 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 ) 0 0 0 w 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 1-1 -< 9 <0(00 (91--1-C 1- - Z5 -01 1- 1- ' 16- 16 1- - 11 1-1 1- 1- 11-t V)1 aC 0 0t (9 (9 (9 ( 0 (9 (9 1- 0 -It 1- * (9 r- (9 T 0 0 WO 03/014319 PCT/US02/25268 21 ANALYSIS OF POLYMORPHISMS Polymorphisms are detected in a target nucleic acid from an individual being analyzed. For assay of genomic DNA, virtually any biological sample (other than pure red blood cells) is suitable. Tissue means any sample taken from any subject, preferably 5 a human. For example, convenient tissue samples include whole blood, semen, saliva, tears, urine, fecal material, sweat, buccal epithelium, skin and hair. For assay of cDNA or mRNA, the tissue sample must be obtained from an organ in which the target nucleic acid is expressed. Many of the methods described below require amplification of DNA from target 10 samples. This can be accomplished by e.g., PCR. See generally PCR Technology: Principles and Applications for DNA Amplification (ed. H.A. Erlich, Freeman Press, NY, NY, 1992); PCR Protocols: A Guide to Methods and Applications (eds. Innis, et al., Academic Press, San Diego, CA, 1990); Mattila et al., Nucleic Acids Res. 19, 4967 (1991); Eckert et al., PCR Methods and Applications 1, 17 (1991); PCR (eds. McPherson 15 et al., IRL Press, Oxford); and U.S. Patent 4,683,202 (each of which is incorporated herein in its entirety by this reference for all purposes). Other suitable amplification methods include the ligase chain reaction (LCR) (see Wu and Wallace, Genomics 4, 560 (1989), Landegren et al., Science 241, 1077 (1988), transcription amplification (Kwoh et al., Proc. Natl. Acad. Sci. USA 86, 1173 (1989)), 20 self-sustained sequence replication (Guatelli et al., Proc. Nat. Acad. Sci. USA, 87, 1874 (1990)) and nucleic acid based sequence amplification (NASBA). The latter two amplification methods involve isothermal reactions based on isothermal transcription, which produce both single stranded RNA (ssRNA) and double stranded DNA (dsDNA) as the amplification products in a ratio of about 30 or 100 to 1, respectively. 25 The term "patient" refers to both human and veterinary subjects. The term "subject" or "individual" typically refers to humans, but also to mammals and other animals, multicellular organisms such as plants, and single-celled organisms or viruses. The identity of bases occupying the polymorphic sites shown in Table 4 can be determined in an individual (e.g., a patient being analyzed) by several methods, which are 30 described as follows: WO 03/014319 PCT/US02/25268 22 1. Single Base Extension Methods Single base extension methods are described by e.g., US 5,846,710, US 6,004,744, US 5,888,819 and US 5,856,092. In brief, the methods work by hybridizing a primer that is complementary to a target sequence such that the 3' end of the primer is immediately 5 adjacent to, but does not span a site of, potential variation in the target sequence. That is, the primer comprises a subsequence from the complement of a target polynucleotide terminating at the base that is immediately adjacent and 5' to the polymorphic site. The term primer refers to a single-stranded oligonucleotide capable of acting as a point of initiation of template-directed DNA synthesis under appropriate conditions (i.e., in the 10 presence of four different nucleoside triphosphates and an agent for polymerization, such as DNA or RNA polymerase or reverse transcriptase) in an appropriate buffer and at a suitable temperature. The appropriate length of a primer depends on the intended use of the primer but typically ranges from 15 to 40 nucleotides. Short primer molecules generally require cooler temperatures to form sufficiently stable hybrid complexes with 15 the template. A primer need not reflect the exact sequence of the template but must be sufficiently complementary to hybridize with a template. The term primer site refers to the area of the target DNA to which a primer hybridizes. The term primer pair means a set of primers including a 5' upstream primer that hybridizes with the 5' end of the DNA sequence to be amplified and a 3', downstream primer that hybridizes with the 20 complement of the 3' end of the sequence to be amplified. Hybridization probes are capable of binding in a base-specific manner to a complementary strand of nucleic acid. Such probes include nucleic acids and peptide nucleic acids as described in Nielsen et al., Science 254, 1497-1500 (1991). A probe primer can be labeled, if desired, by incorporating a label detectable by spectroscopic, photochemical, biochemical, 25 immunochemical, or chemical means. For example, useful labels include 32P, fluorescent dyes, electron dense reagents, enzymes (as commonly used in an ELISA), biotin, or haptens and proteins for which antisera or monoclonal antibodies are available. A label can also be used to "capture" the primer, so as to facilitate the immobilization of either the primer or a primer extension product, such as amplified DNA, on a solid support. The 30 hybridization is performed in the presence of one or more labeled nucleotides WO 03/014319 PCT/US02/25268 23 complementary to base(s) that may occupy the site of potential variation. For example, for biallelic polymorphisms, two differentially labeled nucleotides can be used. For tetraallelic polymorphisms, four differentially-labeled nucleotides can be used. In some methods, particularly methods employing multiple differentially labeled nucleotides, the nucleotides are dideoxynucleotides. Hybridization is performed under conditions permitting primer extension if a nucleotide complementary to a base occupying the site of variation if the target sequence is present. Extension incorporates a labeled nucleotide thereby generating a labeled extended primer. If multiple differentially-labeled nucleotides are used and the target is heterozygous then multiple differentially-labeled 10 extended primers can be obtained. Extended primers are detected providing an indication of which base(s) occupy the site of variation in the target polynucleotide. 2. Allele-Specific Probes The design and use of allele-specific probes for analyzing polymorphisms is described by e.g., Saiki et al., Nature 324, 163-166 (1986); Dattagupta, EP 235,726, 15 Saiki, WO 89/11548. Allele-specific probes can be designed that hybridize to a segment of target DNA from one individual but do not hybridize to the corresponding segment from another individual due to the presence of different polymorphic forms in the respective segments from the two individuals. Hybridization conditions should be sufficiently stringent such that there is a significant difference in hybridization intensity 20 between alleles, and preferably an essentially binary response, whereby a probe hybridizes to only one of the alleles. Hybridizations are usually performed under stringent conditions that allow for specific binding between an oligonucleotide and a target DNA containing one of the polymorphic sites shown in Table 4. Stringent conditions are defined as any suitable buffer concentrations and temperatures that allow 25 specific hybridization of the oligonucleotide to highly homologous sequences spanning at least one of the polymorphic sites shown in Table 4 and any washing conditions that remove non-specific binding of the oligonucleotide. For example, conditions of 5X SSPE (750 mM NaCl, 50 mM Na Phosphate, 5 mM EDTA, pH 7.4) and a temperature of 25 30'C are suitable for allele-specific probe hybridizations. The washing conditions usually 30 range from room temperature to 60 0 C. Some probes are designed to hybridize to a WO 03/014319 PCT/US02/25268 24 segment of target DNA such that the polymorphic site aligns with a central position (e.g., in a 15 mer at the 7 position; in a 16 mer, at either the 8 or 9 position) of the probe. This probe design achieves good discrimination in hybridization between different allelic forms. 5 Allele-specific probes are often used in pairs, one member of a pair showing a perfect match to a reference form of a target sequence and the other member showing a perfect match to a variant form. Several pairs of probes can then be immobilized on the same support for simultaneous analysis of multiple polymorphisms within the same target sequence. The polymorphisms can also be identified by hybridization to nucleic acid 10 arrays, some examples of which are described by WO 95/11995 (incorporated by this reference in its entirety for all purposes). 3. Allele-Specific Amplification Methods An allele-specific primer hybridizes to a site on target DNA overlapping a polymorphism and only primes amplification of an allelic form to which the primer 15 exhibits perfect complementarily. See Gibbs, Nucleic Acid Res. 17, 2427-2448 (1989). This primer is used in conjunction with a second primer that hybridizes at a distal site. Amplification proceeds from the two primers leading to a detectable product signifying that the particular allelic form is present. A control is usually performed with a second pair of primers, one of which shows a single base mismatch at the polymorphic site and 20 the other of which exhibits perfect complementarity to a distal site. The single-base mismatch prevents amplification and no detectable product is formed. In some methods, the mismatch is included in the 3'-most position of the oligonucleotide aligned with the polymorphism because this position is most destabilizing to elongation from the primer. See, e.g., WO 93/22456. In other methods, a double-base mismatch is used in which the 25 first mismatch is included in the Y-most position of the oligonucleotide aligned with the polymorphism and a second mismatch is positioned at the immediately adjacent base (the pen-ultimate 3' position). This double mismatch further prevents amplification in instances in which there is no match between the 3' position of the primer and the polymorphism. 30 4. Direct-Sequencing WO 03/014319 PCT/US02/25268 25 The direct analysis of the sequence of polymorphisms of the present invention can be accomplished using either the dideoxy-chain termination method or the Maxam Gilbert method (see Sambrook et al., Molecular Cloning, A Laboratory Manual (2nd Ed., CSHP, New York 1989); Zyskind et al., Recombinant DNA Laboratory Manual, (Acad. 5 Press, 1988)). 5. Denaturing Gradient Gel Electrophoresis Amplification products generated using the polymerase chain reaction can be analyzed by the use of denaturing gradient gel electrophoresis. Different alleles can be identified based on the different sequence-dependent melting properties and 10 electrophoretic migration of DNA in solution. Erlich, ed., PCR Technology, Principles and Applications for DNA Amplification, (W.H. Freeman and Co, New York, 1992), Chapter 7. 6. Single-Strand Conformation Polymorphism Analysis Alleles of target sequences can be differentiated using single-strand conformation 15 polymorphism analysis, which identifies base differences by alteration in electrophoretic migration of single stranded PCR products, as described in Orita et al., Proc. Nat. Acad. Sci. 86, 2766-2770 (1989). Amplified PCR products can be generated as described above, and heated or otherwise denatured, to form single stranded amplification products. Single-stranded nucleic acids may refold or form secondary structures that are partially 20 dependent upon the base sequence. The different electrophoretic mobilities of single stranded amplification products can be related to base-sequence differences between alleles of target sequences. METHODS OF USE After determining polymorphic form(s) present in an individual at one or more 25 polymorphic sites, this information can be used in a number of methods. The polymorphisms of the invention may contribute to the phenotype of an organism in different ways. Some polymorphisms occur within a protein coding sequence and contribute to phenotype by affecting protein structure. The effect may be neutral, beneficial or detrimental, or both beneficial and detrimental, depending on the 30 circumstances. By analogy, a heterozygous sickle cell mutation confers resistance to WO 03/014319 PCT/US02/25268 26 malaria, but a homozygous sickle cell mutation is usually lethal. Other polymorphisms occur in noncoding regions but may exert phenotypic effects indirectly via influence on replication, transcription, and translation. A single polymorphism may affect more than one phenotypic trait. Likewise, a single phenotypic trait may be affected by 5 polymorphisms in different genes. Further, some polymorphisms predispose an individual to a distinct mutation that is causally related to a certain phenotype. The polymorphisms shown in Table 4 can be analyzed for a correlation with multiple sclerosis or specific sub-phenotypes associated with multiple sclerosis including, but not limited to, relapsing remitting, primary progressive, secondary progressive and 10 progressive relapsing multiple sclerosis as well as with response to drugs used to treat these diseases. Correlation is performed for a population of individuals who have been tested for the presence or absence of multiple sclerosis or an intermediate phenotype and for one or more polymorphic markers. To perform such analysis, the presence or absence of a set of 15 polymorphic forms (i.e. a polymorphic set) is determined for a set of the individuals, some of whom exhibit a particular trait, and some of which exhibit lack of the trait. The alleles of each polymorphism of the set are then reviewed to determine whether the presence or absence of a particular allele is associated with the trait of interest. Correlation can be performed by standard statistical methods including, but not limited to, 20 chi-squared test, Analysis of Variance, parametric linkage analysis, non-parametric linkage analysis, etc. and statistically significant correlations between polymorphic form(s) and phenotypic characteristics are noted. For example, it might be found that the presence of allele Al at polymorphism A correlates with multiple sclerosis or a sub phenotype including relapsing remitting, primary progressive, secondary progressive and 25 progressive relapsing multiple sclerosis , measured either as a dichotomous or continuous trait. As a further example, it might be found that the combined presence of allele Al at polymorphism A and allele B1 at polymorphism B correlates with multiple sclerosis or a sub-phenotype. Polymorphic forms that correlate with multiple sclerosis or sub-phenotypes are 30 also useful in diagnosing multiple sclerosis or susceptibility thereto. Combined detection WO 03/014319 PCT/US02/25268 27 of several such polymorphic forms typically increases the probability of an accurate diagnosis. For example, the presence of a single polymorphic form known to correlate with multiple sclerosis might indicate a probability of 20% that an individual has or is susceptible to multiple sclerosis, whereas detection of five polymorphic forms, each of 5 which correlates with less than 20% probability, might indicate a probability up to 80% that an individual has or is susceptible to multiple sclerosis. Analysis of the polymorphisms of the invention can be combined with that of other polymorphisms or other risk factors of multiple sclerosis, such as family history. Polymorphisms can be used to diagnose multiple sclerosis or sub-phenotypes of multiple sclerosis at the pre 10 symptomatic stage, as a method of post-symptomatic diagnosis, as a method of confirmation of diagnosis or as a post-mortem diagnosis. Patients diagnosed with multiple sclerosis can be treated with conventional therapies and/or can be counseled to avoid environmental factors that exacerbate the condition or trigger episodes. Conventional therapies for multiple sclerosis include, but 15 are not limited to, the use of steroids, beta-interferon, physiotherapy and immune suppressor therapies. Patients diagnosed with multiple sclerosis may also be counseled about the risk of genetically transmitting the disease to offspring, or counseled about the risk of family members sharing genetic variation(s) relevant to multiple sclerosis. The polymorphism(s) showing the strongest correlation with multiple sclerosis 20 within a given gene are likely either to have a causative role in the manifestation of the phenotype or to be in linkage disequilibrium with the causative variants. Such a role can be confirmed by in vitro gene expression of the variant gene or by producing a transgenic animal expressing a human gene bearing such a polymorphism and determining whether the animal develops insulin resistance. Polymorphisms in coding regions that result in 25 amino acid changes usually cause multiple sclerosis by decreasing, increasing or otherwise altering the activity of the protein encoded by the gene in which the polymorphism occurs. Polymorphisms in coding regions that introduce stop codons usually cause multiple sclerosis by reducing (heterozygote) or eliminating (homozygote) functional protein produced by the gene. Occasionally, stop codons result in production 30 of a truncated peptide with aberrant activities relative to the full-length protein.

WO 03/014319 PCT/US02/25268 28 Polymorphisms in regulatory regions typically cause multiple sclerosis by causing increased or decreased expression of the protein encoded by the gene in which the polymorphism occurs. Polymorphisms in intronic or untranslated sequences can cause multiple sclerosis either through the same mechanism as polymorphisms in regulatory 5 sequences or by causing altered splicing patterns resulting in an altered protein. The precise role of polymorphisms in the genes shown in Table 4 can be elucidated by several means. Alterations in expression levels of a protein can be determined by measuring protein levels in sample groups of persons characterized as having or not having multiple sclerosis (or intermediate phenotypes). Alterations in 10 enzyme activity can similarly be detected by assaying for enzyme activity in samples from the above groups of persons. Alterations in receptor-transducing activity can be detected by comparing receptor ligand binding, either in vitro or in a cellular expression system. Having identified certain polymorphisms as having causative roles in multiple 15 sclerosis, and having elucidated, at least in general tenns, whether such polymorphisms increase or decrease the activity or expression level of associated proteins, customized therapies can be devised for classes of patients with different genetic subtypes of metabolic diseases. For example, if a polymorphism in a given protein causes multiple sclerosis by increasing the expression level or activity of the protein, the diseases 20 associated with the polymorphism can be treated by administering an antagonist of the protein. If a polymorphism in a given protein causes insulin resistance by decreasing the expression level or activity of a protein, the form of multiple sclerosis associated with the polymorphism can be treated by administering the protein itself, a nucleic acid encoding the protein that can be expressed in a patient, or an analog or agonist of the protein. 25 Agonists can be obtained by producing and screening large combinatorial libraries. Combinatorial libraries can be produced for many types of compounds that can be synthesized in a step by step fashion. Such compounds include polypeptides, beta-turn mimetics, polysaccharides, phospholipids, hormones, prostaglandins, steroids, aromatic compounds, heterocyclic compounds, benzodiazepines, oligomeric N-substituted glycines 30 and oligocarbamates. Large combinatorial libraries of the compounds can be constructed WO 03/014319 PCT/US02/25268 29 by the encoded synthetic libraries (ESL) method described in Affymax, WO 95/12608, Affymax, WO 93/06121, Columbia University, WO 94/08051, Pharmacopeia, WO 95/35503 and Scripps, WO 95/30642 (each of which is incorporated herein by this reference for all purposes). Peptide libraries can also be generated by phage display 5 methods. See, e.g., Devlin, WO 91/18980. The libraries of compounds can be initially screened for specific binding to the protein for which agonists or antagonists are to be identified, or to its natural binding ligand. Preferred agents bind with a Kd < 1 M. For example, for receptor ligand combinations, the assay can be performed using a cloned receptor immobilized to a support such as a microtiter well and binding of compounds 10 can be measured in competition with ligand to the receptor. Agonist or antagonist activity can then be assayed using a cellular reporter system or a transgenic animal model. The polymorphisms of the invention are also useful for conducting clinical trials of drug candidates for multiple sclerosis. Such trials are performed on treated or control populations having similar or identical polymorphic profiles at a defined collection of 15 polymorphic sites. Use of genetically matched populations eliminates or reduces variation in treatment outcome due to genetic factors, leading to a more accurate assessment of the efficacy of a potential drug. Furthermore, the polymorphisms of the invention may be used after the completion of a clinical trial to elucidate differences in response to a given treatment. For 20 example, the set of polymorphisms may be used to stratify the enrolled patients into disease sub-types or classes. It may further be possible to use the polymorphisms to identify subsets of patients with similar polymorphic profiles who have unusual (high or low) response to treatment or who do not respond at all (non-responders). In this way, information about the underlying genetic factors influencing response to treatment can be 25 used in many aspects of the development of treatments (these range from the identification of new targets, through the design of new trials to product labeling and patient targeting). Additionally, the polymorphisms may be used to identify the genetic factors involved in adverse response to treatment (adverse events). For example, patients who show adverse response may have more similar polymorphic profiles than would be 30 expected by chance. This would allow the early identification and exclusion of such WO 03/014319 PCT/US02/25268 30 individuals from treatment. It would also provide information that might be used to understand the biological causes of adverse events and to modify the treatment to avoid such outcomes. In addition to multiple sclerosis, the polymorphisms in Table 4 can also be tested 5 for association with other diseases in which auto immunity or demyelination are a common feature but the underlying genetic defects are poorly understood. These include: systemic lupus erythematosus, type I diabetes (IDDM), rheumatoid arthritis, inflammatory bowel disease, scleroderma, thyroid diseases, Graves disease, psoriasis and other conditions. 10 The polymorphic DNA sequences of the present invention listed in Table 4 can also be used to prepare probes or as primers for detection of the presence of the genes listed in Table 2. In this manner, the presence of these genes can be detected from biological samples isolated from an individual of interest. This allows the presence of these genes to be assayed in selected patients. Additionally, the sequences listed in 15 Tables 3 and 4 that have been found to reside within the coding regions of these genes can be used to assay a biological sample from an individual for the presence of gene expression by detection of the corresponding mRNA transcript. Using detection means known to those of skill in the art, these sequences of the present invention can also be used to evaluate quantitative expression of these genes as it may differ between 20 individuals or within different tissues in the same individual. The reported polymorphisms may also be in linkage disequilibrium with nearby genes (within 30 kb or greater) that are not related to multiple sclerosis, but contribute to phenotypes such as autoimmune diseases, inflammation, cancer, diseases of the nervous system, and infection by pathogenic microorganisms. Some examples of cancers include 25 cancers of the bladder, brain, breast, colon, esophagus, kidney, leukemia, liver, lung, oral cavity, ovary, pancreas, prostate, skin, stomach and uterus. Phenotypic traits also include characteristics such as longevity, appearance (e.g., baldness, obesity), strength, speed, endurance, fertility, and susceptibility or receptivity to particular drugs or therapeutic treatments.

WO 03/014319 PCT/US02/25268 31 Such correlations can be exploited in several ways. In the case of a strong correlation between a set of one or more polymorphic forms and a disease for which treatment is available, detection of the polymorphic form set in a human or animal patient may justify immediate administration of treatment, or at least the institution of regular 5 monitoring of the patient. Detection of a polymorphic form correlated with serious disease in a couple contemplating a family may also be valuable to the couple in their reproductive decisions. For example, the female partner might elect to undergo in vitro fertilization to avoid the possibility of transmitting such a polymorphism from her husband to her offspring. In the case of a weaker, but still statistically significant 10 correlation between a polymorphic set and human disease, immediate therapeutic intervention or monitoring may not be justified. Nevertheless, the patient can be motivated to begin simple life-style changes (e.g., diet, exercise) that can be accomplished at little cost to the patient but confer potential benefits in reducing the risk of conditions to which the patient may have increased susceptibility by virtue of variant 15 alleles. Identification of a polymorphic set in a patient correlated with enhanced receptiveness to one of several treatment regimes for a disease indicates that -this treatment regime should be followed. Determination of which polymorphic forms occupy a set of polymorphic sites in an individual identifies a set of polymorphic forms that distinguishes the individual. See 20 generally National Research Council, The Evaluation of Forensic DNA Evidence (Eds. Pollard et al., National Academy Press, DC, 1996). The more sites that are analyzed the lower the probability that the set of polymorphic forms in one individual is the same as that in an unrelated individual. Preferably, if multiple sites are analyzed, the sites are unlinked. Thus, polymorphisms of the invention are often used in conjunction with 25 polymorphisms in distal genes. Preferred polymorphisms for use in forensics are diallelic because the population frequencies of two polymorphic forms can usually be determined with greater accuracy than those of multiple polymorphic forms at multi-allelic loci. The capacity to identify a distinguishing or unique set of forensic markers in an individual is useful for forensic analysis. For example, one can determine whether a 30 blood sample from a suspect matches a blood or other tissue sample from a crime scene WO 03/014319 PCT/US02/25268 32 by determining whether the set of polymorphic forms occupying selected polymorphic sites is the same in the suspect and the sample. If the set of polymorphic markers does not match between a suspect and a sample, it can be concluded (barring experimental error) that the suspect was not the source of the sample. If the set of markers does match, 5 one can conclude that the DNA from the suspect is consistent with that found at the crime scene. If frequencies of the polymorphic forms at the loci tested have been determined (e.g., by analysis of a suitable population of individuals), one can perform a statistical analysis to determine the probability that a match of suspect and crime scene sample would occur by chance. 10 p(ID) is the probability that two random individuals have the same polymorphic or allelic form at a given polymorphic site. The term genotype as used herein broadly refers to the genetic composition of an organism, including, for example, whether a diploid organism is heterozygous or homozygous for one or more alleles of interest. In diallelic loci, four genotypes are possible: AA, AB, BA, and BB. If alleles A and B occur in a haploid 15 genome of the organism with frequencies x and y, the probability of each genotype in a diploid organism can be calculated as described in International Publication WO 95/12607 which is incorporated herein by this reference in its entirety. These calculations can be extended for any number of polymorphic forms at a given locus. For example, in a locus of n alleles, the appropriate binomial expansion is used to calculate p(ID) and 20 p(exc). If several polymorphic loci are tested, the cumulative probability of non-identity for random individuals becomes very high (e.g., one billion to one). Such probabilities can be taken into account together with other evidence in determining the guilt or innocence of the suspect. 25 The object of paternity testing is usually to determine whether a male is the father of a child. In most cases, the mother of the child is known and thus, the mother's contribution to the child's genotype can be traced. Paternity testing investigates whether the part of the child's genotype not attributable to the mother is consistent with that of the putative father. Paternity testing can be performed by analyzing sets of polymorphisms in 30 the putative father and the child.

WO 03/014319 PCT/US02/25268 33 If the set of polymorphisms in the child attributable to the father does not match the putative father, it can be concluded, barring experimental error, that the putative father is not the real father. If the set of polymorphisms in the child attributable to the father does match the set of polymorphisms of the putative father, a statistical calculation can be 5 performed to determine the probability of a coincidental match. The probability of parentage exclusion (representing the probability that a random male will have a polymorphic form at a given polymorphic site that makes him incompatible as the father) can be calculated as described in International Publication WO 95/12607 which is incorporated herein by this reference in its entirety. 10 If several polymorphic loci are included in the analysis, the cumulative probability of exclusion of a random male is very high. This probability can be taken into account in assessing the liability of a putative father whose polymorphic marker set matches the child's polymorphic marker set attributable to his/her father. Linkage describes the tendency of genes, alleles, loci or genetic markers to be 15 inherited together as a result of their location on the same chromosome, and can be measured by percent recombination between the two genes, alleles, loci or genetic markers that are physically-linked on the same chromosome. Loci occurring within 50 centimorgan of each other are linked. Some linked markers occur within the same gene or gene cluster. 20 Linkage disequilibrium (LD) or allelic association means the preferential association of a particular allele or genetic marker with a specific allele, or genetic marker at a nearby chromosomal location more frequently than expected by chance for any particular allele frequency in the population. For example, if locus X has alleles a and b, which occur with equal frequency, and linked locus Y has alleles c and d, which occur 25 with equal frequency, one would expect the haplotype ac to occur with a frequency of 0.25 in a population of individuals. If ac occurs more frequently, then alleles a and c are considered in linkage disequilibrium. Linkage disequilibrium may result from natural selection of a certain combination of alleles or because an allele has been introduced into a population too recently to have reached equilibrium (random association) between 30 linked alleles.

WO 03/014319 PCT/US02/25268 34 A marker in linkage disequilibrium with disease predisposing variants can be particularly useful in detecting susceptibility to disease (or association with sub-clinical phenotypes) notwithstanding that the marker does not cause the disease. For example, a marker (X) that is not itself a causative element of a disease, but which is in linkage 5 disequilibrium with a gene (including regulatory sequences) (Y) that is a causative element of a phenotype, can be used to indicate susceptibility to the disease in circumstances in which the gene Y may not have been identified or may not be readily detectable. Younger alleles (i.e., those arising from mutation relatively late in evolution) are expected to have a larger genomic segment in linkage disequilibrium. The age of an 10 allele can be determined from whether the allele is shared among different human ethnic groups and/or between humans and related species. The polymorphisms shown in Table 4 can also be used to establish physical linkage between a genetic locus associated with a trait of interest and polymorphic markers that are not associated with the trait, but are in physical proximity with the 15 genetic locus responsible for the trait and co-segregate with it. Such analysis is useful for mapping a genetic locus associated with a phenotypic trait to a chromosomal position, and thereby cloning gene(s) responsible for the trait. See Landau et al., Proc. Natl. Acad. Sci. (USA) 83, 7353--7357 (1986); Landau et al., Proc. Natl. Acad. Sci. (USA) 84, 2363 2367 (1987); Donis-Keller et al., Cell 51, 319-337 (1987); Landau et al., Genetics 121, 20 185-199 (1989)). Genes localized by linkage can be cloned by a process known as directional cloning. See Wainwright, Med. J. Australia 159, 170-174 (1993); Collins, Nature Genetics 1, 3-6 (1992) (each of which is incorporated herein by this reference in its entirety for all purposes). Linkage studies are typically performed on members of a family. Available 25 members of the family are characterized for the presence or absence of a phenotypic trait and for a set of polymorphic markers. The distribution of polymorphic markers in an informative meiosis is then analyzed to determine which polymorphic markers co segregate with a phenotypic trait. See, e.g., Kerem et al., Science 245, 1073-1080 (1989); Monaco et al., Nature 316, 842 (1985); Yamoka et al., Neurology 40, 222-226 (1990); 30 Rossiter et al., FASEB Journal 5, 21-27 (1991).

WO 03/014319 PCT/US02/25268 35 Linkage is analyzed by calculation of lod (log of the odds) values. A lod value is the relative likelihood of obtaining observed segregation data for a marker and a genetic locus when the two are located at a recombination fraction 0, versus the situation in which the two are not linked, and thus segregating independently (Thompson & Thompson, 5 Genetics in Medicine (5th ed, W.B. Saunders Company, Philadelphia, 1991); Strachan, "Mapping the human genome" in The Human Genome (BIOS Scientific Publishers Ltd, Oxford), Chapter 4). A series of likelihood ratios are calculated at various recombination fractions (0), ranging from 0 = 0.0 (coincident loci) to 0 = 0.50 (unlinked). Thus, the likelihood at a given value of 0 is: probability of data if loci linked at 0 to probability of 10 data if loci unlinked. The computed likelihoods are usually expressed as the log10 of this ratio (i.e., a lod score). For example, a lod score of 3 indicates 1000:1 odds against an apparent observed linkage being a coincidence. The use of logarithms allows data collected from different families to be combined by simple addition. Computer programs are available for the calculation of lod scores for differing values of 0 (e.g., LIPED, 15 MLINK (Lathrop, Proc. Nat. Acad. Sci. (USA) 81, 3443-3446 (1984)). For any particular lod score, a recombination fraction may be determined from mathematical tables. See Smith et al., Mathematical tables for research workers in human genetics (Churchill, London, 1961); Smith, Ann. Hum. Genet. 32, 127-150 (1968). The value of 0 at which the lod score is the highest is considered to be the best estimate of the recombination 20 fraction. Positive lod score values suggest that the two loci are linked, whereas negative values suggest that linkage is less likely (at that value of 0) than the possibility that the two loci are unlinked. By convention, a combined lod score of +3 or greater (equivalent to greater than 1000:1 odds in favor of linkage) is considered definitive evidence that two loci are linked. Similarly, by convention, a negative lod score of -2 or less is taken as 25 definitive evidence against linkage of the two loci being compared. Negative linkage data are useful in excluding a chromosome or a segment thereof from consideration. The search focuses on the remaining non-excluded chromosomal locations. MODIFIED POLYPEPTIDES AND GENE SEQUENCES The invention further provides variant forms of nucleic acids and corresponding 30 proteins. The nucleic acids comprise one of the sequences described in Table 4 in which WO 03/014319 PCT/US02/25268 36 the polymorphic position is occupied by an alternative base for that position. Some nucleic acids encode full-length variant forms of proteins. Similarly, variant proteins have the prototypical amino acid sequences encoded by a nucleic acid sequence shown in Table 4 (read so as to be in-frame with the full-length coding sequence of which it is a 5 component) except at an amino acid encoded by a codon including one of the polymorphic positions shown in the Table. That position is occupied by the amino acid coded by the corresponding codon in the alternative forms shown in Table 4. Variant genes can be expressed in an expression vector in which a variant gene is operably linked to a native or other promoter. Usually, the promoter is a eukaryotic 10 promoter for expression in a mammalian cell. The transcription regulation sequences typically include a heterologous promoter and optionally an enhancer that is recognized by the host. The selection of an appropriate promoter, for example trp, lac, phage promoters, glycolytic enzyme promoters and tRNA promoters, depends on the host selected. Commercially available expression vectors can be used. Vectors can include 15 host-recognized replication systems, amplifiable genes, selectable markers, host sequences useful for insertion into the host genome, and the like. The means of introducing the expression construct into a host cell varies depending upon the particular construction and the target host. Suitable means include fusion, conjugation, transfection, transduction, electroporation or injection, as described 20 in Sambrook, supra. A wide variety of host cells can be employed for expression of the variant gene, both prokaryotic and eukaryotic. Suitable host cells include bacteria such as E. coli, yeast, filamentous fungi, insect cells, mammalian cells, typically immortalized, e.g., mouse, CHO, human and monkey cell lines and derivatives thereof. Preferred host cells are able to process the variant gene product to produce an appropriate mature 25 polypeptide. Processing includes glycosylation, ubiquitination, disulfide bond formation, general post-translational modification, and the like. The protein may be isolated by conventional means of protein biochemistry and purification to obtain a substantially pure product, i.e., 80, 95 or 99% free of cell component contaminants, as described in Jacoby, Methods in Enzymology Volume 104, 30 Academic Press, New York (1984); Scopes, Protein Purification, Principles and Practice, WO 03/014319 PCT/US02/25268 37 2nd Edition, Springer-Verlag, New York (1987); and Deutscher (ed), Guide to Protein Purification, Methods in Enzymology, Vol. 182 (1990). If the protein is secreted, it can be isolated from the supernatant in which the host cell is grown. If not secreted, the protein can be isolated from a lysate of the host cells. 5 The invention further provides transgenic nonhuman animals capable of expressing an exogenous variant gene and/or having one or both alleles of an endogenous variant gene inactivated. Expression of an exogenous variant gene is usually achieved by operably linking the gene to a promoter and optionally an enhancer, and microinjecting the construct into a zygote. See Hogan et al., "Manipulating the Mouse Embryo, A 10 Laboratory Manual," Cold Spring Harbor Laboratory. Inactivation of endogenous variant genes can be achieved by forming a transgene in which a cloned variant gene is inactivated by insertion of a positive selection marker. See Capecchi, Science 244, 1288 1292 (1989). The transgene is then introduced into an embryonic stem cell, where it undergoes homologous recombination with an endogenous variant gene. Mice and other 15 rodents are preferred animals. Such animals provide useful drug screening systems. In addition to substantially full-length polypeptides expressed by variant genes, the present invention includes biologically active fragments of the polypeptides, or analogs thereof, including organic molecules that simulate the interactions of the peptides. Biologically active fragments include any portion of the full-length polypeptide 20 that confers a biological function on the variant gene product, including ligand binding and antibody binding. Ligand binding includes binding by nucleic acids, proteins or polypeptides, small biologically active molecules or large cellular structures. Polyclonal and/or monoclonal antibodies that specifically bind to variant gene products but not to corresponding prototypical gene products are also provided. 25 Antibodies can be made by injecting mice or other animals with the variant gene product or synthetic peptide fragments thereof. Monoclonal antibodies are screened as are described, for example, in Harlow & Lane, Antibodies, A Laboratory Manual, Cold Spring Harbor Press, New York (1988); Goding, Monoclonal antibodies, Principles and Practice (2d ed.) Academic Press, New York (1986). Monoclonal antibodies are tested 30 for specific immunoreactivity with a variant gene product and lack of immunoreactivity WO 03/014319 PCT/US02/25268 38 to the corresponding prototypical gene product. These antibodies are useful in diagnostic assays for detection of the variant form, or as an active ingredient in a pharmaceutical composition. KITS 5 The invention further provides kits comprising at least one allele-specific oligonucleotide as described above. Often, the kits contain one or more pairs of allele specific oligonucleotides hybridizing to different forms of a polymorphism. In some kits, the allele-specific oligonucleotides are provided immobilized to a substrate. For example, the same substrate can comprise allele-specific oligonucleotide probes for detecting any 10 or all of the polymorphisms shown in Table 4. Optional additional components of the kit include, for example, restriction enzymes, reverse-transcriptase or polymerase, the substrate nucleoside triphosphates, means used to label (for example, an avidin-enzyme conjugate and enzyme substrate and chromogen if the label is biotin), and the appropriate buffers for reverse transcription, PCR, or hybridization reactions. Usually, the kit also 15 contains instructions for carrying out the methods. COMPUTER SYSTEMS FOR STORING POLYMORPHISM DATA Fig. 1A depicts a block diagram of a computer system 10 suitable for implementing the present invention. Computer system 10 includes a bus 12 which interconnects major subsystems such as a central processor 14, a system memory 16 20 (typically RAM), an input/output (1/0) controller 18, an external device such as a display screen 24 via a display adapter 26, serial ports 28 and 30, a keyboard 32, a fixed disk drive 34 via a storage interface 35 and a floppy disk drive 36 operative to receive a floppy disk 38, and a CD-ROM (or DVD-ROM) device 40 operative to receive a CD-ROM 42. Many other devices can be connected such as a user pointing device, e.g., a mouse 44 25 connected via serial port 28 and a network interface 46 connected via serial port 30. Many other devices or subsystems (not shown) may be connected in a similar manner. Also, it is not necessary for all of the devices shown in Fig. 1A to be present to practice the present invention, as discussed below. The devices and subsystems may be interconnected in different ways from that shown in Fig. 1A. The operation of a 30 computer system such as that shown in Fig. 1A is well known. Databases storing WO 03/014319 PCT/US02/25268 39 polymorphism information according to the present invention can be stored, e.g., in system memory 16 or on storage media such as fixed disk 34, floppy disk 38, or CD ROM 42. An application program to access such databases can be operably disposed in system memory 16 or sorted on storage media such as fixed disk 34, floppy disk 38, or 5 CD-ROM 42. Fig. 1B depicts the interconnection of computer system 10 to remote computers 48, 50, and 52. Fig. 1B depicts a network 54 interconnecting remote servers 48, 50, and 52. Network interface 46 provides the connection from client computer system 10 to network 54. Network 54 can be, e.g., the Internet. Protocols for exchanging data via the 10 Internet and other networks are well known. Information identifying the polymorphisms described herein can be transmitted across network 54 embedded in signals capable of traversing the physical media employed by network 54. Information identifying polymorphisms shown in Table 4 is represented in records, which optionally, are subdivided into fields. Each record stores information 15 relating to a different polymorphisms in Table 4. Collectively, the records can store information relating to all of the polymorphisms in Table 4, or any subset thereof, such as 5, 10, 50, or 100 polymorphisms from Table 4. In some databases, the information identifies a base occupying a polymorphic position and the location of the polymorphic position. The base can be represented as a single letter code (i.e., A, C, G or T/U) present 20 in a polymorphic form other than that in the reference allele. Alternatively, the base occupying a polymorphic site can be represented in IJPAC ambiguity code as shown in Table 4. The location of a polymorphic site can be identified as its position within one of the sequences shown in Table 4. For example, in the first sequence shown in Table 4, the polymorphic site occupies the A or C base. The position can also be identified by 25 reference to, for example, a chromosome, and distance from known markers within the chromosome. In other databases, information identifying a polymorphism contains sequences of 10-100 bases shown in Table 4 or the complements thereof, including a polymorphic site. Preferably, such information records at least 10, 15, 20, or 30 contiguous bases of sequences including a polymorphic site.

WO 03/014319 PCT/US02/25268 40 From the foregoing, it is apparent that the invention includes a number of general uses that can be expressed concisely as follows. The invention provides for the use of any of the nucleic acid segments described above in the diagnosis or monitoring of diseases, particularly insulin resistance and related metabolic syndrome. The invention 5 further provides for the use of any of the nucleic acid segments in the manufacture of a medicament for the treatment or prophylaxis of such diseases. The invention further provides for the use of any of the DNA segments as a pharmaceutical. All publications and patent applications cited above are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication or 10 patent application were specifically and individually indicated to be so incorporated by reference. Although the present invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims. 15 WO 03/014319 PCT/US02/25268 41 1. Appendix A. Location of the polymorphisms in the gene sequences 2. In Table 3 of Section I, the genomic sequence flanking all of the polymorphisms is given. Complete genomic sequence for all the exons and promoter regions are given below with the polymorphisms described in Tables 3 indicated as [X/Y] 5 where X is the nucleotide in the consensus genomic sequence and Y is the novel nucleotide. Intronic sequence flanking the exons is also given and some the primers given in Table 2 lie in these intronic segments. The beginning of each exon or promoter is marked by "[" and the end of each exon or promoter is marked by "]". 3. >ESR1_01 10 CCAGGGTCATCCTATGTACACACTACGTATTTCTAGCCAACGAGGAGGGGGAATCAAACAGA AAGAGAGACAAACAGAGATATATCGGAGTCTGGCACGGGGCACATAAGGCAGCACATTAGA GAAAGCCGGCCCCTGGATCCGTCTTTCGCGTTTATTTTAAGCCCAGTCTTCCCTGGGCCACC TTTAGCAGATCCTCGTGCGCCCCCGCCCCCTGGCCGTGAAACTCAGCCTCTATCCAGCAGC GACGACAAGTAAAGTAAAGTTCAGGGAAGCTGCTCTTTGGGATCGCTCCAAATC[GAGTTGT 15 GCCTGGAGTGATGTTTAAGCCAATGTCAGGGCAAGGCAACAGTCCCTGGCCGTCCTCCAGC ACCTTTGTAATGCATATGAGCTCGGGAGACCAGTACTTAAAGTTGGAGGCCCGGGAGCCCA GGAGCTGGCGGAGGGCGTTCGTCCTGGGACTGCACTTGCTCCCGTCGGGTCGCCCGGCTT CAC[C/T]GGACCCGCAGGCTCCCGGGGCAGGGCCGGGGCCAGAGCTCGCGTGTCGGCGGG ACATGCGCTGCGTCGCCTCTAACCTCGGGCTGTGCTCTTTTTCCAGGTGGCCCGCCGGTTT 20 CTGAGCCTTCTGCCCTGCGGGGACACGGTCTGCACCCTGCCCGCGGCCACGGACCATGAC CATGACCCTCCACACCAAAGCATCTGGGATGGCCCTACTGCATCAGATCCAAGGGAACGAG CTGGAGCCCCTGAACCGTCCGCAGCTCAAGATCCCCCTGGAGCGGCCCCTGGGCGAGGTG TACCTGGACAGCAGCAAGCCCGCCGTGTACAACTACCCCGAGGGCGCCGCCTACGAGTTCA ACGCCGCGGCCGCCGCCAACGCGCAGGTCTACGGTCAGACCGGCCTCCCCTACGGCCCCG 25 GGTCTGAGGCTGCGGCGTTCGGCTCCAACGGCCTGGGGGGTTTCCCCCCACTCAACAGCG TGTCTCCGAGCCCGCTGATGCTACTGCACCCGCCGCCGCAGCTGTCGCCTTTCCTGCAGCC CCACGGCCAGCAGGTGCCCTACTACCTGGAGAACGAGCCCAGCGGCTACACGGTGCGCGA GGCCGGCCCGCCGGCATTCTACAGGTACCCGCGC]CCGCGCCGCCCGTCGGGGTGGCCGC CGCGCCCGGCAGGAGGGAGGGAGGGAGGGAGGGAGAAGGGAGAGCCTAGGGAGCTGCG 30 GGAGCCGCGGGACGCGCGACCCGAGGGTGCGCGCAGGGAGCCCGGGGCGCGCGGCCCA GCCCGGGGGTTCTGCGTGCAGCCCGCGCTGCGTTCAGAGTCAAGTTCTCTCGCCGGGCAG CTGAAAAAAACGTACTCTCCACCCACTTACCGTCCGTGCGAGAGGCAGACCCGAAAGCCCG GGCTTCCTAACAAA 4. >ESR1_02 35 CATTGGTCTCTAATGGTTCTGAAATAATTGTATATTCCTGCAAAAACATTAAGTCTATTAGAAA

CCAGCTAATTTCATTTTGTCATTTTTATAGGTAACATATTCTGGTGCAGGTAGTATGTTTTTAA

WO 03/014319 PCT/US02/25268 42 AACAAGTTTGCAATAAACAATTTCCCCTCAAGGTTAATATAATAGGCAACACCTTTTGCTGCAA CAGACGGCAAGAGGTAATGAAAGATTAGCTTACATTATGATTCATTATTTCAAAATGTCAGGA TAAAGTGGATCTGCTGCATCTCCCAGAGAGTGCATGTTTTGCTTT[TCTAATGTTAATGGATTT ACTGTTTTTTTCCCCCCAGGCCAAATTCAGATAATCGACGCCAGGGTGGCAGAGAAAGATTG 5 GCCAGTACCAATGACAAGGGAAGTATGGCTATGGAATCTGCCAAGGAGACTCGCTACTGTG CAGTGTGCAATGACTATGCTTCAGGCTACCATTATGGAGTCTGGTCCTGTGAGGGCTGCAAG GCCTTCTTCAAGAGAAGTATTCAAGGTAATAGTGTGTTGAAAACGACTTCTATTTTTGATCCTA TGAGCAGATCCTA]AGAGCCAAAGCGACTGAGGAAGGAAGACATAGAATCAGCCATTTGTAC AAAACATGAATCCCTAGTAGGTCCACTAGTATCTTTGGTAGAAACATGGAGAAGAGACAGGA 10 TCTCAGGAGAAGGAGTTGACACATGGCAGGGCAGCTGAGGCTGAGTAATTCCGCTTCCTTC CTTTGGCAAGACTCAATCAGTCTTGAGCAACTCTACAGAAGAATTCCACTAGCTGGATCTCTG AGGAAAAAAGAAATGTTGTCTGTGCCCTGACTGGGG 5. >ESR1_03 GGATTACAGGTGTACACCACCATACCCAGGTTTTTTTTGTATTTTTAGTAGAGACGGGGTTTC 15 ACCATGTTGGTCAGGCTGGTCTTGAACTCCTGACGTCGTGATCCACCTGCCTCGGCCTCCCA AAGTTCTGGGATTACAGGCATGAGCCACCGTGCCCGGCCCATGAGAGGTTTTGTTTGCACTT CAAGAAGGACAGAAAAAGGCAGGCAGGCTGGGAGCAACATAGTAAGGCTGAGGAAGTGATA GGAAAACAGCCTCCAAAAGGTTTCCCTGTAGA[TTCTGACTGGCTAAGTTTCCTGAAATAATAT TAATTCTGTCCTCTTGCTTTTAATAGGACATAACGACTATATGTGTCCAGCCACCAACCAGTG 20 CACCATTGATAAAAACAGGAGGAAGAGCTGCCAGGCCTGCCGGCTCCGTAAATGCTACGAA GTGGGAATGATGAAAGGTGGTAGGTACATCTCTCCCAGGGGCCCTTGGGGGATGGCCCTG GCCACCGCCCAGTGCITGGCTCTACCCATTGGAATAACACCATGGGAATTTTGTGTTTTTTTC TTTTAATTGTTTTTTTTCTATTCTTATTTTTCTTTGCAACAAAAGTATTTTCATAATCCATTTTATT TTAAAAAGGTGGAAGTGTCTGGAACTGGAAATTCTAACATGGCATTTTGTGTTTTGGATTTTC 25 AATGTAAATAATTATATTTTAAATCAAAGGTGTGTGGGAGGCGGTGATGGAAGGAAACGAAG AGTGCTTAGTAAATTATTCTAGAAATATTTTTCAGTTACTGTTTATGTTGC 6. >ESR1_04 CACAGGTTACTATTATAGCTGTCTAAGTAGAAGGCACACAAGTTTTCACACTGAGTATAACAC TTTATAGAAAGCTAAGTGTGTTGCTCAAGTTGGTACATTTCTGTAGATGTGACACTATGGCAC 30 TAAGAAACTTAATGCCACATTGAAATTCATTGAGATAGCTAGACTTTAAAAATAATTACTTGAC TTCACTATAAAGTATGTTCGTATTGCATTTACTCCATCTAGTAGAAAATAGACCTTGTCAGTTC AAATCCCTGTTGCATT[AATTTCACCAGTAATGAGTCTTTTTCATTTGAGTCAGCAGGGTTTTT CTTGCTTGTTTTCAGGCTTTGTGGATTTGACCCTCCATGATCAGGTCCACCTTCTAGAATGTG CCTGGCTAGAGATCCTGATGATTGGTCTCGTCTGGCGCTCCATGGAGCACCCAGGGAAGCT 35 ACTGTTTGCTCCTAACTTGCTCTTGGACAGGTAAGTGACCTGGCTGTAGCTTAGGAGTAGCA TGTTCTTTACGATCATAGTTCATTCAT]GAAACTATTTTATTCATCTCTCGGTGAAGCTTCAGAG AACTTTATTAGGTATGTTTACTTAACAAAAGAGTGCATTGGGGGTGATGAAGCCTAGTCAAAT

TCACAGAAAGCTAAGGATAACTTTCTGCTAGACATTACCTCAGAAGAATTCTATTATTTCTAAT

WO 03/014319 PCT/US02/25268 43 ACACACACACACACACACACACACACACACTCACACTCTCTCTCTCTCTCTCTCTGTCATTAT GAATGGTAATTTTCTAACTCCATCTTCAACTTGTATCATATAA 7. >ESR1_05 ACCCAGATCTTGATCATTTTCAATTACCCATAGGTTGAAGAACTCCATATTTAACATGGCAGA 5 CTTGAGGACTGAACTACCTACCTCTTCTAAGAAGTTGAAATGAGAATGTTTTATTGATGGGAA ATTATTTTTTTGTTTTGCCTTCTAGAATTCAAATGAATGTTCATATTCCATGAAGACAATGGCT GATAGTTTTTTGTTAAAGATTTAGAACCAGTGGATTTTTATGAATGTGAACCCTTTCATGTCTT GTGGAA[GATTTTCTGTTTTTTAATCTTTTTATTTATTTATTTATTTTTGCTATGTTTTCATAGGAA CCAGGGAAAATGTGTAGAGGGCATGGTGGAGATCTTCGACATGCTGCTGGCTACATCATCTC 10 GGTTCCGCATGATGAATCTGCAGGGAGAGGAGTTTGTGTGCCTCAAATCTATTATTTTGCTTA ATTCTGGTGAGTTGATAACACAAGATAACTCAATGCTGGATGAAATGTTTATTTGTA[G/T]TTTT CAA]CCAGATACGATCTACCCACTCCAAAGGCATAATGTCATAAATAGAAAGAAACTACTGAC ACACGTTTTAAAATAACCTACCAACATTGCAGATTCCTTATAAAGGTAGAACCATGCTAGCCA AATAGACACATGAAAAATTGTAATTTGGCATTGAATCAAATGGCCTTTGAGCTAAAATTTTTGT 15 ATGCTTTCACAGATAGGATGTTTTTATTCAAATGGTACATGTATATAGACATATGTTAGTTGAT AGTTATATTATGTCTGAAAATAAGTAGACCAAGTAATTCT 8. >ESR1_06 ATGATGGTGTCAGACCTGTCTGAGAAAAGGTGGCCCATGTTACCATGACAGGCCCCAAGGC TAACAGCCCCTTTCTGGGTCATGGCTCATACAAAGGAGCCCTCCTTGGTTTGCTGGTGCTCT 20 GAGACTTGCAAATGCATTAGGAATTTTACACTGTAACCCGGTTTTAAATGGGTCCAGAGCATC CCCATTGCTAGACTACTGTGCTGAGGAAGGGCACTGGCTCATTGTTACATCCCATGAACACT CTGGGTCTCCTAGACCTCATCCTCTTTGAGCTTCTCTCTCTC[ACTCTCTCTCTGCGCATTCAG GAGTGTACACATTTCTGTCCAGCACCCTGAAGTCTCTGGAAGAGAAGGACCATATCCACCGA GTCCTGGACAAGATCACAGACACTTTGATCCACCTGATGGCCAAGGCAGGCCTGACCCTGC 25 AGCAGCAGCACCAGCGGCTGGCCCAGCTCCTCCTCATCCTCTCCCACATCAGGCACATGAG GTGAGGCATCTGTGGGCTTCCTACA]GGAGAGACATAAAGAAAACATGCCCCCAAACCTATG TGACAGCTGGCCGGGAAGGACTGGTGCCTGCATATGGAGAGTGCACTTGTGACAGTTCCTG GCATAGAATAAGCATAAATGCTATAGGAGGACAGAAGAGAGAGGTTTTAAATCTGCGAGGGT CACAGGGCAAGTGTCAGAGAAGGCATAGAGGAAGCGATACTTACGCTTGGTTTAAAGCATGT 30 GCTTTGGGGCAGTGGTTTAGAGATTGGGTGCAGTGTGCAAATAGGAGGAGGGGGCCAAT 9. >ESR1_07 GCCACGGAGGTCCATGGAAGTCACCTGCATAGCAAATACCCTGAAAGTGGCTGCAGGGAGA GTGTGAGGGTGGGACCGCCCTGGTAGGAGGTGGAAAATGAAAAACACACGGCCATGAGTTC CAGATTAGGGCTTCTGAAAGCCCTCAGCTTTCCCAGCTCCCATCCTAAAGTGGGTCTTTAAA 35 CAGGAAGAAAGAAAGATTGCTAAGTGTCTTTGGAGTTCCTCTTCCTTCCCCTTCTAGGGATTT CAGCACTCCTGGGGCTCGGGTTGGCTCTAAAGTAGTCCTTTCTGTGTCTTC[CCACCTACAGT

AACAAAGGCATGGAGCATCTGTACAGCATGAAGTGCAAGAACGTGGTGCCCCTCTATGACCT

WO 03/014319 PCT/US02/25268 44 GCTGCTGGAGATGCTGGACGCCCACCGCCTACATGCGCCCACTAGCCGTGGAGGGGCATC CGTGGAGGAGACGGACCAAAGCCACTTGGCCACTGCGGGCTCTACTTCATCGCATTCCTTG CAAAAGTATTACATCACGGGGGAGGCAGAGGGTTTCCCTGCCACGGTCTGAGAGCTCCCTG GCTCCCACACGGTTCAGATAATCCCTGCTGCATTTTACCCTCATCATGCACCACTTTAGCCAA 5 ATTCTGTCTCCTGCATACACTC[C/T]GGCATGCATCCAACACCAATGGCTTTCTAGATGAGTG GCCATTCATTTGCTTGCTCAGTTCTTAGTGGCACATCTTCTGTCTTCTGTTGGGAACAGCCAA AGGGATTCCAAGGCTAAATCTTTGTAACAGCTCTCTTTCCCCCTTGCTATGTTACTAAGCGTG AGGATTCCC[G/A]TAGCTCTTCACAGCTGAACTCAGTCT[A/G]TGGGTTGGGGCTCAGATAACT CTGTGCATTTAAGCTACTTGTAGAGACCCAGGCCTGGAGAGTAGACATTTTGCCTCTGATAA 10 GCACTTTTTAAATGGCTCTAAGAATAAGCCACAGCAAAGAATTTAAAGTGGCTCCTTTAATTG GTGACTTGGAGAAAGCTAGGTCAAGGGTTTATTATAGCACCCTCTTGTATTCCTATGGCAATG CATCCTTTTATGAAAGTGGTACACCTTAAAGCTTTTATATGACTGTAGCAGAGTATCTGGTGA TTGTCAATTCATTCCCCCTATAGGAATACAAGGGGCACACAGGGAAGGCAGATCCCCTAGTT GGCAAGACTATTTTAACTTGATACACTGCAGATTCAGATGTGCTGAAAGCTCTGCCTCTGGCT 15 TTCCGGTCATGGGTTCCAGTTAATTCATGCCTCCCATGGACCTATGGAGAGCAGCAAGTTGA TCTTAGTTAAGTCTCCCTATATGAGGGATAAGTTCCTGATTTTTGTTTTTATTTTTGTGTTACAA AAGAAAGCCCTCCCTCCCTGAACTTGCAGTAAGGTCAGCTTCAGGACCTGTTCCAGTGGGCA CTGTACTTGGATCTTCCCGGCGTGTGTGTGCCTTACACAGGGGTGAACTGTTCACTGTGGTG ATGCATGATGAGGGTAAATGGTAGTTGAAAGGAGCAGGGGCCCTGGTGTTGCATTTAGCCC 20 TGGGGCATGGAGCTGAACAGTACTTGTGCAGGATTGTTGTGGCTACTAGAGAACAAGAGGG AAAGTAGGGCAGAAACTGGATACAGTTCTGAGGCACAGCCAGACTTGCTCAGGGTGGCCCT GCCACAGGCTGCAGCTACCTAGGAACATTCCTTGCAGACCCCGCATTGCCCTTTGGGGGTG CCCTGGGATCCCTGGGGTAGTCCAGCTCTTCTTCATTTCCCAGCGTGGCCCTGGTTGGAAG AAGCAGCTGTCACAGCTGCTGTAGACAGCTGTGTTCCTACAATTGGCCCAGCACCCTGGGG 25 CACGGGAGAAGGGTGGGGACC[G/A]TTGCTGTCACTACTCAGGCTGACTGGGGCCTGGTCA GATTACGTATGCCCTTGGTGGTTTAGAGATAATCCAAAATCAGGGTTTGGTTTGGGAAGAA AATCCTCCCCCTTCCTCCCCCGCCCCGTTCCCTACCGCCTCCACTCCTGCCAGCTCATTTCC TTCAATTTCCTTTGACCTATAGGCTAAAAAAGAAAGGCTCATTCCAGCCACAGGGCAGCCTTC CCTGGGCCTTTGCTTCTCTAGCACAATTATGGGTTACTTCCTTTCTTAACAAAAAAGAATGT 30 TTGATTTCCTCTGGGTGACCTTATTGTCTGTAATTGAAACCCTATTGAGAGGTGATGTCTGTG TTAGCCAATGACCCAGGTGAGCTGCTCGGGCTTCTCTTGGTATGTCTTGTTTGGAAAAGTGG ATTTCATTCATTTCTGATTGTCCAGTTAAGTGATCACCAAAGGACTGAGAATCTGGGAGGGCA AAAAAAAAAAAAAAGTTTTTATGTGCACTTAAATTTGGGGACAATTTTATGTATCTGTGTTAAG GATATGTTTAAGAACATAATTCTTTTGTTGCTGTTTGTTTAAGAAGCACCTTAGTTTGTTTAAG 35 AAGCACCTTATATAGTATAATATATATTTTTTTGAAATTACATTGCTTGTTTATCAGACAATTGA ATGTAGTAATTCTGTTCTGGATTTAATTTGACTGGGTTAACATGCAAAAACCAAGGAAAAATAT TTAGTTTTTTTTTTTTTTTTTGTATACTTTTCAAGCTACCTTGTCATGTATACAGTCATTTATGCC

TAAAGCCTGGTGATTATTCATTTAAATGAAGATCACATTTCATATCAACTTTTGTATCCACAGT

WO 03/014319 PCT/US02/25268 45 AGACAAAATAGCACTAATCCAGATGCCTATTGTTGGATACTGAATGACAGACAATCTTATGTA GCAAAGATTATGCCTGAAAAGGAAAATTATTCAGGGCAGCTAATTTTGCTTTTACCAAAATAT CAGTAGTAATATTTTTGGACAGTAGCTAATGGGTCAGTGGGTTCTTTTTAATGTTTATACTTAG ATTTTCTTTTAAAAAAATTAAAATAAAACAAAAAAAAA[T/A]TTCTAGGACTAGACGATGTAATAC 5 CAGCTAAAGCCAAACAATTATACAGTGGAAGGTTTTACATTATTCATCCAATGTGTTTCTATTC ATGTTAAGATACTACTACATTTGAAGTGGGCAGAGAACATCAGATGATTGAAATGTTCGCCCA GGGGTCTCCAGCAACTTTGGAAATCTCTTTGTATTTTTACTTGAAGTGCCACTAATGGAC/TIA GCAGATATTTTCTGGCTGATGTTGGTATTGGGTGTAGGAACATGATTTAAAAAAAAACTCTTG CCTCTGCTTTCCCCCACTCTGAGGCAAGTTAAAATGTAAAAGATGTGATTTATCTGGGGGGC 10 TCAGGTATGGTGGGGAAGTGGATTCAGGAATCTGGGGAATG[G/A]CAAATATATTAAGAAGA GTATTGAAAGTATTTGGAGGAAAATGGTTAATTCTGGGTGTGCACCAGGGTTCAGTAGAGTC CACTTCTGCCCTGGAGACCACAAATCAACTAGCTCCATTTACAGCCATTTCTAAAATGGCAGC TTCAGTTCTAGAGAAGAAAGAACAACATCAGCAGTAAAGTCCATGGAATAGCTAGTGGTCTG TGTTTCTTTTCGCCATTGCC[T/C]AGCTTGCCGTAATGATTCTATAATGCCATCATGCAGCAAT 15 TATGAGAGGCTAGGTCATCCAAAGAGAAGACCCTATCAATGTAGGTTGCAAAATCTAACCCC TAAGGAAGTGCAGTCTTTGATTTGATTTCCCTAGTAACCTTGCAGATATGTTTAACCAAGCCA TAGCCCATGCCTTTTGAGGGCTGAACAAATAAGGGACTTACTGATAATTTACTTTTGATCACA TTAAGGTGTTCTCACCTTGAAATCTTATACACTGAAATGGCCATTGATTTAGGCCACTGGCTT AGAGTACTCCTTCCCCTGCATGACACTGATTACAAATACTTTCCTATTCATACTTTCCAATTAT 20 GAGATGGACTGTGGGTACTGGGAGTGATCACTAACACCATAGTAATGTCTAATATTCACAGG CAGATCTGCTTGGGGAAGCTAGTTATGTGAAAGGCAAATAGAGTCATACAGTAGCTCAAAAG GCAACCATAATTCTCTTTGGTGCAGGTCTTGGGAGCGTGATCTAGATTACACTGCACCATTC CCAAGTTAATCCCCTGAAAACTTACTCTCAACTGGAGCAAATGAACTTTGGTCCCAAATATCC ATCTTTTCAGTAGCGTTAATTATGCTCTGTTTCCAACTGCATTTCCTTTCCAATTGAATTAAAG 25 TGTGGCCTCGTTTTTAGTCATTTAAAATTGTTTTCTAAGTAATTGCTGCCTCTATTATGGCACT TCAATTTTGCACTGTCTTTTGAGATTCAAGAAAAATTTCTATTCTTTTTTTTGCATCCAATTGTG CCTGAACTTTTAAAATATGTAAATGCTGCCATGTTCCAAACCCATCGTCAGTGTGTGTGTTTA GAGCTGTGCACCCTAGAAACAACATATTGTCCCATGAGCAGGTGCCTGAGACACAGACCCCT TTGCATTCACAGAGAGGTCATTGGTTATAGAGACTTGAATTAATAAGTGACATTATGCCAGTT 30 TCTGTTCTCTCACAGGTGATAAAC[A/G]ATGCTTTTTGTGCACTACATACTCTTCAGTGTAGAG CTCTTGTTTTATGGGAAAAGGCTCAAATGCCAAATTGTGTTTGATGGATTAATATGCCCTTTTG CCGATGCATACTATTACTGATGTGACTCGGTTTTGTCGCAGCTTTGCTTTGTTTAATGAAACA CACTTGTAAACCTCTTTTGCACTTTGAAAAAGAATCCAGCGGGATGCTCGAGCACCTGTAAAC AATTTTCTCAACCTATTTGATGTTCAAATAAAGAATTAAACTAAAGACAACG]AGTTTGTTTTTT 35 GTAAGCTCCACTTCTTGCTAGCAGTTCACCACTGATCCTCTAAAATCAAAGTGGTTAAACGAT CTGTCACACACAGTGAGTCTGAATGCTAAAGCCTCTCCTCACCTCACTCCCTCTGCCCAACA

CCCCCAGGTGTATCAGGAAGTGTGTGGACACTGTGGTCAGGCAGAACTGGCCTCAATTCTT

WO 03/014319 PCT/US02/25268 46 GGCTTCACCACTTACAAATTTTATGATCATTGGCAGTTGATTTTTCAGAGTTTCGGCTTCCTTA TCAACAATATGATGATAAGTAATAACAC 10. >IFNAR1_01 CTCCCAACGCCACTGTCCAAGACTCTAGGGTCAGCAAGCGCCCCGGGCGGAGAAGGGCGA 5 GGACGAAGAGCGCCGGGCCGCGACCAGGAGCCCACCCGCGCCCTCCGACTGCAGACATG GGGAAGAGACGCGGGAACTCCAAAGTCGCTGGGTCTGCGCAGGTGTGTGCCGCGATCCTG TGAAGGTCAAGGCCTCCTGTGAGGGGGAGTCGTCCTGGAATGCGATGGTGAAGTGCTCCAG ACCGGCCATAGGCCGGAAAGAGTGAGGAAGAAGAGAATGCAGGAGGCCTGCGATTTCTAAG GCGCGCGCGCACAGGGGTGCTGCAATTAGGATGGGGCAATGGGAGCTTG[GAGAAGGGGT 10 GCTAGCTAGGAGGAAAGGCGCGTGCGTGGAGGAACGGCGCGTGCGCGGAGGGGCGGTGT GTGTGTCAGAAGAGGCGGCGCGTGCGTAGAGGGGCGGTGAGAGCTAAGAGGGGCAGCGC GTGTGCAGAGGGGCGGTGTGACTTAGGACGGGGCGATGGCGGCTGAGAGGAGCTGCGCG TGCGCGAACATGTAACTGGTGGGATCTGCGGCGGCTCCCAGATGATGGTCGTCCTCCTGGG CGCGACGACCCTAGTGCTCGTCGCCGTGGCGCCATGGGTGTTGTCCGCAGCCGCAGGTGA 15 GAGGCGGGGAGGAGAGTCTTGGCGCAGGGCGGGAGGTAGGGC]ACGCAGCTGGGCTACG GGGGCGGCGATGCTGTTGGGGGCGACAGACGCCCAGTCTGGGAAACCTTCGGTCCACTTT GCCGCGCCAAAGATTAAACCCGACCTGGGCTCGCAAATCAACCAGGAGAAAGTGGTGTTCT GGGTCCTCTCTTGCCGCTTGCCTGTGGCCGTGTACGGGTCCTCGGGAGCGCCCGGGTCCC ACC 20 11. >IFNAR1_02 AGGCCATAAAACAGTTGAACCTCATCATAAGAGTGACTCATCGGTGTCACTTCTAAGACCAA GAAAAATTCTATTTTTATGCAGAGACCATTTGTTTTTTAATTAAAAGACAACTCTATTTCAAAGA GGAAAAAAAATCAACTCTTTTTTCAGCTCTCTCAGATGCAGAAATGTAATTATCAGCATCCCT GTGCTGGGAG[CAATCATTAGTTTTTTTAGATTTTTAAAATATACTTCATTATGTTTCACTGTAT 25 TCATTCTTTAATCAGGGATGTGAGGGATAGAATAACATTTAGAATATCTGTACAGTTTGTATAT AATGTTCTTATTTCTTGTTGCTTTTATAGGTGGAAAAAATCTAAAATCTCCTCAAAAAGTAGAG GTCGACATCATAGATGACAACTTTATCCTGAGGTGGAACAGGAGCGATGAGTCTGTCGGGAA TGTGACTTTTTCATTCGATTATCAAAAGTATGTGACTCTACTTACTGATTTGTCAG]AATGACCT GAATAATTTTTACAAGTTTAACAACACCATAATTTTTAGATTTGGAAAGTGTTTGGTTTTTCTAT 30 TTTTTAGAAATGTTACGCCTATTTTACATAATATTTTTAACTTTGTTTCTGTAGAGACTTAGTCA AATACATCTTTGGGTGTTGAAGCAAAAAATTGGGGATGAGGGTGGTAGACAGCGTCTCTAAC 12. >IFNAR1_03 TTTTACCTTATGGGTCATTTATTTCTCTGCTTCCTGAAGCAACCACCCACAAAATTATATAAAG AACTGTATTTTAAAATTCAGTTTCATAAGTAATAACTTGGCTTATATGCATTGAAAAAGAGTGG 35 AAGGGTGTATGCTAAAATGTTAATAGGACATTAGCTCAAGTAGAAGAAATAACTCTTAAACCA AAAATAGAAATAACTCTTAAACAAGAGTTATTAAGAGTTAAGAAATAACTCTTATACCA[GTAAA

TAGAAAGTATTTGACACTTACATTTATACATTTGCTCACTCATTCATTTGTTTTTTTTACTTTAAA

WO 03/014319 PCT/US02/25268 47 GAACTGGGATGGATAATTGGATAAAATTGTCTGGGTGTCAGAATATTACTAGTACCAAATGCA ACTTTTCTTCACTCAAGCTGAATGTTTATGAAGAAATTAAATTGCGTATAAGAGCAGAAAAAGA AAACACTTCTTCATGGTATGAGGTTGACTCATTTACACCATTTCGCAAAGGTAAGAAAAAGTT GCTAGCTGAATTATATTCTTTAGTAAATATTACCAGAGCAGTTCACTTTCC]AAGCCATTCATTT 5 GCATGATGCAAAATCTAACATCTTTTAAAAAGAACAAAAATTCCCTTAAACCTATATCTTCTTC CTGCTATGGCTCCATTTGTCCTACTTTCCCTGTAGTAGTGGTTCTCAAAGAGTGATCCTCAAG GCCCTTTCAGGGGGCTGTAAAGACAAAGCTATATTTATGACAAATCTAAGACTTAGTTGCCTT TTTAATTTTTGTTCTTTCTTGTATTCACAGTGGAG 13. >IFNAR1_4 10 TGCTCATTGATCGCTTCATCTTCCCAACTTTTCAGTGTTAGACTGCTGCTGGGCTCAGTCATT GAACCTCTTCTCTTTCTGTATCACTCCACTGGTGATCTTACAGCTTTCTATCCTATCTGTATGC TCTTAACTCCCAGAAGTGGCAGGCACATATTAAGTGCTCAGAATTATTTGTTGAATGAAGGTT TTGGCATTGTATTAATAAAGTTCCATAGTAATTGTTTTGATTTTTTTGCAG[CTCAGATTGGTCC TCCAGAAGTACATTTAGAAGCTGAAGATAAGGCAATAGTGATACACATCTCTCCTGGAACAAA 15 AGATAGTGTTATGTGGGCTTTGGATGGTTTAAGCTTTACATATAGCTTA[G/CTTATCTGGAAA AACTCTTCAGGTGTAGAAGTAAGCATTATTTTTACCTCTGTTTAATCGATGTGAGAGAAAAATT AGGCGAATTAATCCTAAAATTTGACTTTATACTTTTTTAAAGAACCAACTTATATTTGTGTTATA GGAAAGGATTGAAAATATTTATTCCAGACATAAAATTTATAAACTCTCACCAGAGACTACTTAT TGTCTAAAAGTTAAAGCAGCACTACTTACGTCATGGAAAATTGGTGTCTATAGTCCAGTACAT 20 TGTATAAAGACCACAGIGTAAGGAAGATGTTTTGTTTTAGATTCAATAAATATATAAACAGATT GTCAATTTTGGCATCTTCCCCATATTGCTGAAGTTTACATGATAGGTCAATATATGTTAAAAAC ATTGTAACATTTACATAAGCAAAATAAATGTTACTTGGGATTTTTGTCTCAAATAGTAATGAAA ATTAATTCTACTTAAAAGTTCAGGC 14. >IFNAR1_06 25 GGGGTTTCACCATGTTGGCCAGGCGCGTCTCGAACTCCTGACCTCAGGTGATCCATCCACC TCAGCCTCCCAAAGTTCTGGGATTACAGGTGTGAGCCACTGCGCCCGGCCTGTAGTCTTTCA AATGGCTGCATAGTATTACATAGTGTGAATACAAACCATATTTAACTATTACCTTATAATGATA AAATGCGAGCCTT[TATCTTCTTGCCAGTTATCTCACTTGAGTAAAAATGTGTGCTTTTTTT[T/A] ATCTGTTCTTTGGCTTCTAGTTGAAAATGAACTACCTCCACCAGAAAATATAGAAGTCAGTGT 30 CCAAAATCAGAACTATGTTCTTAAAGTGGGATAAAACATATGCAAACATGACCTTTCAAGTTC AGTGGCTCCAGTAAGTTCCATTCCATAAATTTCCTTTTGCCCAGTTTGTTTTGATTATGCTTCT TTTCG[C/T]TCTGC]ATCAGTCACCAGGTCCTTGCACACAGAATGACCGACTGGGAGGTGGGT ACGATATATTGGAAACGTGAGAAATCTCATTTCTAACCCCAGTTCTGCCAGTAACTAACTGGA TGACATTGAGCTAATCGCTTAACCTCCATGGGCCTCAATTTCTTCACTTGTAAAATAGATGGA 35 TTCTAATATCTGGGGTTCTTACTGGC 15. >IFNAR1_7 WO 03/014319 PCT/US02/25268 48 ACCAGCTTGCAGCATTCCTGGAAATTCTAACTAACAGATGTTCTTGCATATTGATATGAGCCA CCTCCAGCAGAGCACAACATGACCACAGTCTGGAACAGTCTTTGGTTTTCTTTTATGTTAGAT GCATATCTCTTCCATTGTTTGTGAGTTTCCTGAGTGTGGATACTATTTATTTCTGTAACCTTAG CCCCTAACATAGTGTCTGGCAATTGTAAATACTTAATAAATATCTAATGAATTTAAAAAATATTT 5 GTCTTAAAAG[CGCCTTTTTAAAAAGGAATCCTGGAAACCATTTGTATAAATGGAAACAAATAC CTGACTGTGAAAATGTCAAAACTACCCAGTGTGTCTTTCCTCAAAACGTTTTCCAAAAAGGAA TTTACCTTCTCCGCGTACAAGCATCTGATGGAAATAACACATCTTTTTGGTCTGAAGAGATAA AGTTTGATACTGAAATACAAGGTAAGGCAGTAGTTTTTACTGGAGATTGTAATTCTCTGGTGC AAGTTTTTAAAATTGTTTTTCTAATTGAACATTATTTCTTTACAAATTTTTTCTAGCTTTCCTACT 10 TCCTCCAGTCTTTAACATTAGATCCCTTAGTGATTCATTCCATATCTATATCGGTGCTCCAAAA CAGTCTGGAAACACGCCTGTGATCCAGGATTATCCACTGATTTATGAAATTATTTTTTGGGAA AACACTTCAAATGCTGAG]GTAAAAAGACTGTATAGTATAATTTTGTAACTTAGAGTTATAATTA TGATTTGGGTAAATAAAGCTTGAATGTAAAATTTGGGGGAAATTTTTAAACTTTATGTGGGCT GGATGCAGTGGCCTGTAATCCCAGCACTTCAGGAGGCCAAGGCGAGAGGATCACTTGAGCC 15 TAAGGGTTTGAGACCAGCCTGGGCAACATAGGGAGACCCTGTCTCAATAAAAATTTTAAAAA 16. >IFNAR1_09 ATCTGTAATCCCAACTACTCAGGAGGGTGAGGCAGGAGAATCGCTTGAACCCAGGAGGCAG AGATTGCAGTGAGCCCAGATTGCACCACTGCACTCTAGCCTGGGTGACAGAGCGAGACTGT CTCACAAAAAAAACAAAACAAAACAAAACAAAACAAAAAATACATACCAACTACGTGGGAGAG 20 GCCAATGTTAGACTG[AACATAAAAAATTGAGAAAGCACATATTCCCTGATTTCTTGAGGTGAC TAAATTTTATCAGTGATTTAATTATATTTTCTAGAGAAAAATTATCGAGAAAAAAACTGA[T/C]GT TACAGTTCCTAATTTGAAACCACTGACTGTATATTGTGTGAAAGCCAGAGCACACACCA[T/G] GGATGAAAAGCTGAATAAAAGCAGTGTTTTTAGTGACGCTGTATGTGAGAAAACAAAACCAG GTCAGAATCTTTTATTGTCTTTTTTAAAAATGTAGCTAGACATAATAAAAGTAATTCTATACTGT 25 AC]ATTGAAAATTGTAAAACATTTTCTCTTTACTGCAAAAAATATATAGAAAGAATGTTTTCTTC ATGAACTACATGAATCAAAAGTAGACTTTTTAGAAAATATTTGTAACGCTTAACTCTCAAGTCG GTGTTGTTGGATGCTTTATATTTCATCCAGTATCCCTATAATTAATTTCCTTAATGTATTTCTCT TTAACATTT 17. >IFNAR1 10 30 AGGATACTTGCATGTTTGGCCTGTATGTCAATATTGTATTTCTCCCTGAGGATCTCTTACTTCA GTTCCCACGCCAATCTTTAAATGTAAATGTCATTGCCTATGGTTGCTGTGGACTCAGTGCTGC CAGAAATATTTTTAAGAGTATTATTTAATAGATTTTATATTTCCTTTCATATGGCTAGTCTTTCA CACAGCTG[TCAGCACTGTTAAGGCATTTGTATGTCAAAATATATGCTAAATATCACGTATATC TTTTTAGGAAATACCTCTAAAATTTGGCTTATAGTTGGAATTTGTATTGCATTATTTGCTCTCC 35 CGTTTGTCATTTATGCTGCGAAAGTCTTCTTGAGATGCATCAATTATGTCTTCTTTCCATCACT TAAACCTTCTTCCAGTATAGATGAGGTATGTTACTTTTTTTATTTTTTTGTCAACAGCTAGGTAA TGAACAGAAAATGTGTTTGATTTCAACAGGATATATGTAGGTTTTCTTGATA]TCCAGAAAATA

ATAGAGACTGATTTGGGTATCTTCTTCAAAGCTTTAGTCAATTAACTTTAAAAACAGTAATTTC

WO 03/014319 PCT/US02/25268 49 ATGTAATAACATAGCATGAGATAGTAATGATTGTCCTTAATTTCATATTTTTCTGGCAATTCCT AGATTCACTGTGGCATTTGTTTTACCGTTTAAAGCCTGTGATTCTTGGCCAAGCGTGGTGG 18. >IFNAR1_11 CTTTCTTAGGTACTCTTCAAAGACTCACCACAGAAGGTACTAAGATATGAGTGACCTCACTAA 5 TGATGCTTTTAAACATTATAAGGCAATTAGTATGTTCTTAGGCGACTTTTTAATATGCATGCCA GAAGATAGGTTTTCTCAGTAATGGATGTAAGAAACTAAAGCTATTACAACTAGAAAAGGAATT TTTATTATTTTAAATAATTGATTTCTACTCTTTCCCTTTTTTTAAATTAG[TATTTCTCTGAACAGC CATTGAAGAATCTTCTGCTTTCAACTTCTGAGGAACAAATCGAAAAATGTTTCATAATTGAAAA TATAAGCACAATTGCTACAGTAGAAGAAACTAATCAAACTGATGAAGATCATAAAAAATACAG 10 TTCCCAAACTAGCCAAGATTCAGGAAATTATTCTAATGAAGATGAAAGCGAAAGTAAAACAAG TGAAGAACTACAGCAGGACTTTGTATGACCAGAAATGAACTGTGTCAAGTATAAGGTTTTTCA GCAGGAGTTACACTGGGAGCCTGAGGTCCTCACCTTCCTCTCAGTAACTACAGAGAGGACG TTTCCCTGTTTAGGGAAAGAAAAAACATCTTCAGATCATAGGTCCTAAAAATACGGGCAAGCT CTTAACTATTTAAAAATGAAATTACAGGCCCGGGCACGGTGGCTCACACCTGTAATCCCAGC 15 ACTTTGGGAGGCTGAGGCAGGCAGATCATGAGGTCAAGAGATCGAGACCAGCCTGGCCAAC GTGGTGAAACCCCATCTCTACTAAAAATACAAAAATTAGCCGGGTGTGGTGGCGCGCGCCTG TTGTCTTAGCTACTCAGGAGGCTGAGGCAGGAGAATCGCTTGAAAACAGGAGGTGGAGGTT GCAGTGAGCCGAGATCACGCCACTGCACTCCAGCCTGGTGACAGCGTGAGACTCTTTAAAA AAAGAAATTAAAAGAGTTGAGACAAACGTTTCCTACATTCTTTTCCATGTGTAAAATCATGAAA 20 AAGCCTGTCACCGGACTTGCATTGGATGAGATGAGTCAGACCAAAACAGTGGCCACCCGTC TTCCTCCTGTGAGCCTAAGTGCAGCCGTGCTAGCTGCGCACCGTGGCTAAGGATGACGTCT GTGTTCCTGTCCATCACTGATGCTGCTGGCTACTGCATGTGCCACACCTGTCTGTTCGCCAT TCCTAACATTCTGTTTCATTCTTCCTCGGGAGATATTTCAAACATTTGGTCTTTTCTTTTAACAC TGAGGGTAGGCCCTTAGGAAATTTATTTAGGAAAGTCTGAACACGTTATCACTTGGTTTTCTG 25 GAAAGTAGCTTACCCTAGAAAACAGCTGCAAATGCCAGAAAGATGATCCCTAAAAATGTTGA GGGACTTCTGTTCATTCATCCCGAGAACATTGGCTTCCACATCACAGTATCTACCCTTACATG GTTTAGGATTAAAGCCAGGCAATCTTTTACTATG]CATTAAGACCTCTGATTCAAAACTTATTA GAACAGTAGCTTCTGCTGGAATTTGCAATCACTGAAGTCATAGAAAATAGGTAACTATCTAAT TAGAGAAATAATTGTTGTATTTTAAGATCTGAGAGTGTGTACAAGTTTTAGTATACATGCCATG 30 CCAGAAGATAGTGTATGCAAGAAGTCTTGGGACCAGAAAATGGCAATGATAGGAGACTGACA TAGAAGAAGAATGCTTCCCTAGGAAAAAGGTCGCTGGCTTTGGTGCAAGAGGAAGAAGAATG TTCCACTGGAAGCCTGAGCACCTAATCAGCTCTCAGTGATCAACCCACTCTTGTTATGGGTG GTCTCTGTCACTTTGAATGCCAGGCTGGCTTCTCGTCTAGCAGTATTCAGATACCCCTTCTGC TCAGCCTGCTTGGCGTTAAAATACAAATCATTGAACTGAGGGGGAAAAATGTAACTAGGAAG 35 AAAAACCCAATTTAAGAAATTACATAATGCTTT 19. >IFNAR2_01 AGCTTTCTCGGCGAAGGCGGGATTGGTTAGGAGCTGACAATCGGCAGCAGACGATTGTAAA

TGACCGGACCTTTTTTCTATTCTCCTGCCCAGCCCCCGGCCCGGCCTCCGCCTCCGGCCCT

WO 03/014319 PCT/US02/25268 50 GCTCCAGCCCCGCCAGCGGCCCAGGACCCGCCCCTGGCTCCGGCCCCGCCCCTGGCTCC GCCCCCGCCCCCGCGCCGGCGGCGGCGCG[GCGCCCGCGCTTCCGTATCGCTCCTCGTAG GCCGGGGCTCGGCGCGCGCACCCGCACTAAAGACGCTTCTTCCCGGCGGGTAGGAATCCC GCCGGCGAGCCGAACAGTTCCCCGAGCGCAGCCCGCGGACCACCACCCGGCCGCACGGG 5 CCGCTTTTGTCCCCCGCCCGCCGCTTCTGTCCGAGAGGCCGCCCGCGAGGCGCATCCTGA CCGCGAGCGTCGGGTCCCAGAGCCGGGCGCGGCTGGGGCCCGAGGCTAGCATCTCTCGG GAGCCGCAAGGCGAGAGCTGCAAAGGTAACGCAGCGTGGCGGGGTCGCGGGAGCGGAGC GCGTGGCCAGCTGACTGGAGGGA]AAACGCCGCCTCCCTGCAGCGGTTCCCGGAATCCCCT CCGGTTCCCTCTCGCTCTCCCCGACTCCTCCTCCTCCTCCTGCCCTCCCTCTGCGTCTTGAG 10 TATGCGGCTAGTGCGCCCTTCCTCTCTCCCGGGGCCGCACCTGCGACCCCAGGACCCCTCC CGGGCCCTGTCCTGCGCCCTCCACGCGTCGCCCCTGCTGG 20. >IFNAR2_02 GATGGGGAAATTAGGAATATGTATTTGTTTTTGCTTATGCATGAAGATACTCTGAAGGATTCA CAAAAGAAAAAAAAGTTTTCTAAAGGGAGCAAGACTTTTCACAATTTTTTTTTTGAATGCTTAA 15 AATTGTTGAACCCAACGACTGTTGCCTGTTCAAAAGTTAAATTTAAAATTCCTCCCAGACTAG GTAGGGGATTGGGCCCAGAAGCTGAGACCAGGCTCACTTGAATAAATGGGGTAAATGACT[A GGAATTTTACTATTCCTTACAGGTCTCTCATTATCTTGTCTTTGCTCCCATTTTTATATTTGCAG TTTAATTAGACACTTCAGAATTTTGATCACCTAATGTTGATTTCAGATGTAAAAGTCAAGAGAA GACTCTAAAAATAGCAAAGATGCTTTTGAGCCAGAATGCCT[T/AICATCT[T/GICAGATCACTTA 20 ATTTGGTTCTCATGGGTAAGTGCTGCTTTTTATCTTAGCTCTTATAGAAGCAAGCTGTGATGC CATCCTCA]CTGAGAGCACTGGCAGGAAGTCGCAAACTCATTTCCCTGACTAGAGGACCCAG TACCACCCTGCCTAGTGTCAGGAGTTAAGTGGAAAGCAAATAGGAAACCTACACTAGTAGTT TAGATTCAATGTAGATTCCTGTCCTGTTGTTAATTTTAGGAAAACAAATGAGTGACTTAAGGCA ATAATAATCAGGACTATCCTCGCCATAATTTGAAGAGTAATTTCTCCTAACACGCTTTCTT 25 21. >IFNAR2_03 CCACCCACCTCGGCCTCCCAAAGTGCTGGGATTACAGACGTGAGCCACGACGCCCGGCCC CAGATATATTTTTAAGTGGAAAAAGCAGGGCAGAACAGGGACCGTACATATTGTTGTTAGTGT CAGCTCCCAAATGGATCTTATTTTATCTCAGATCACAGTCCTTGCACCATGTGCTGCTGGCAC CAATGTAGAGTAAAAACCATCTATGTGGGCATTTTTTTGGCACAAGAAAAATCTCAATCTGAT 30 A[CCAATAAATGTGTGTTAAAGAATGTCAGACTTAGAGTAATCATTGCAAGTTGAGCCCAGATA AAACTATTGCCTCTCTAATGTGTTTTCTTCCTTCTAGTGTATATCAGCCTCGTGTTTGGTATTT CATATGATTCGCCTGGTAAGAGATGTTTTTT[G/C]GCTTCACTAAATTTTGTATAAGAGTGAAA GTGTTGGGGCAACCATTCAGAGGTATAAAATGTGGGAGATTTGATTTCTGATTGTACATCTGT ]TGCCTGTTTTATTGGGATTCTTTCTCTG[T/CAAAAGGAGCTAAAATGAGCTAACTCTGGTTTT 35 TTGAGAGATACAAAACTAGTCTAAGAAATGAACACTAGAGATCATTTTTAAACTTCTTTAAAGA ATATTCAAACTCTTAATAATCTCACTAATAAAAGAATGAGGAGACACAGACTGTGCCAAATAAA AAATGGCCCAGAAATATTTACTCTTTAATTTACATTCTTCCACCCTGATGATTCCAGACAA 22. >IFNAR2_04 WO 03/014319 PCT/US02/25268 51 GGCTGGGATGGCCTGGGTTATTTTGGTCCAGTGAACCATGGAGGGACAGTCCAAGGGCATC GGAGAAGCCCTTCTGTCCAGACTCTCCTTACACAGTGCACAGTCCCTGTTTCCCATGCTTGC CTGCCCTGACAATATGTTGCTCGTTAATTGACTTACTAATTTATTTCCCATGTCCTGTAGACTT CCTGTTTTCAAGACACCAGGGCTCTCTGGAGAGGTTATCTGCCAGAGGTGTGGGTTCTAGAT 5 C[CCAAGAAATGACTGAACAGTGGCCAGAATACAACTGTGGGTTCCAAATTTCAATGCCCTTT TTCTTCTTCTCTTTAGATTACACAGATGAATCTTGCACTTTCAAGATATCATTGCGAAATTTCC GGTCCATCTTATCATGGGAATTAAAAAACCACTCCATTGTACCAACTCACTATACATTGCTGT ATACAATCATGAGGTTGGTTTGATATTTCATTTTCTCTTGGTAAACATATTATTGTTCTGTTATA TGGGGAGAGGTGATCTTTTCTCTCTCTCTGTCTCTCCCTCTCCCTTTTCCTATCTACCTCTCC 10 TTCTCTCTGCGTTTCTTATTCAGAGCCTTAAAAAGCCAAAGACAAAACACCATCACACATCCA TTTTTAATTCAGTTGAATACTTTAATAATCCAAATCTATTTTGACAAAGCTTGTATGTGTCATCA AAGCCA 23. >IFNAR2_05 CCAAAGTCCCTGCCCTCCTGGAGCAGACATTATGTAAATGGAGACATCAGTAAACAAAGGTA 15 TAATGTGACAGGTGTGGGTAAATGCTACAATCAAGAAAAGAGAGGGATTGAAAGTGCAGGG GTGGGGAGGGCATAAGATGTTCCATTTTCAATAAGATGGTTGGGGAAGATCACTTAATACAA TGATATTTGGGCAGAGCCCTAAAGGAAACAATGAAGTAAGGCGCC[CAAAAATAGACTCTCAT TACATCAATGCTAACAATTTCCTTTTTCCATTTTTTTCTTTCCAAAGTAAACCAGAAGATTTGAA GGTGGTTAAGAACTGTGCAAATACCACAAGATCATTTTGTGACCTCACAGATGAGTGGAGAA 20 GCACACACGAGGCCTATGTCACCGTCCTAGAAGGATTCAGCGGGAACACAACGTTGTTCAG TTGCTCACACAATTTCTGGCTGGCCATAGACAGTGAGTTTTATCTCTGTTTCTCCACTTCGTC CCCATCATCAAGATCTTTATTATTTGCTATTC]CATGAAATAGGAGGTCTACAAAGGTGTTTTA GACCTGGGGCTGGGCTCACCTCTTGGCCCTGCCACTTCCTAGCTCTGTAACCGTGGACTGC TTTGCTTCTCTGAGCCTTGGTTTTCTAAATCTGAAAAGTGGAATGATAATTTGTACTTTGCAGA 25 TTTGCCCCGTGCCTGTATAAGGCAGTAGGAACTGCTGTTTTCGGTTTTGCAGCCTGACAGGA AG 24. >IFNAR2_06 AAAGAAAGAAATTATTAAGGACAAATGCAAAAATTTAGTTCCAAGAATATCCCATGATACATTA AGTCTTTAATAAAAATCAGAGACAATTTAAATGTTCAAAACAGTGAATCAGTTAAATCATGATA 30 CAGTCACTTAGTGGAATAGCATTAGCAATGAAAAATTATGATGTAAATCAGGACTTGGCAGAT TTTCTATACAGGGCCAGAG[AAGAACCACTTTAGACTTTGTGGGCCACATATGGTCTCTGTGA CATATTCCTGTCTGTTTTTGTTTTTTGCACAGTGTCTTTTGAACCACCAGAGTTTGAGATTGTT GGTTTTACCAACCACATTAATGTGATGGTGAAATTTCCATCTATTGTTGAGGAAGAATTACAG TTTGATTTATCTCTCGTCATTGAAGAACAGTCAGAGGGAATTGTTAAGAAGGTAAGTGGCTTC 35 TCCTGTTAGGATCAAAACAGTTCTGAGTGGGCAATCAATGCACTTGACTGTCTCTTTTGAAAG GAAATTTGCAGTTGAACAATTAAAGCTAAAACGTCAGGCTTCAGTATGGTCCGA]CTTAGGGA

AGAAGTCACTATGGTTCATTCACTATTGATCTAAACCTGCAGCACAGTGTTCTTTAAAAGAATA

WO 03/014319 PCT/US02/25268 52 AGCCACGGCTGGGCCTGGTGGCTCACGCCTATAATCCCAGCACTTTGGGAGGCCGAGGCG GGCAGATC 25. >IFNAR2_07 AGAGACTTTTATTCCTCTTTGAAGACTTTTATCTCATTTGTAAAATGAAGGCGCTAGACTAGAT 5 GTCATGGTTATAAAATATGTGTGTGTGCAGGTGTATATTAAAAGTGCATGTAGGTGTAGTTTT CTGATAAATTACTTGCTCCAGATGACTTATAAATCCTTTTTCTTACCAAGCCTGTGATAAATCT AACCCTGTTTGAGATTTGAAGACAAATCCCAAAAGAGAT[TAAGGCCTACCTCTAAATGAAATT CTCAGTCTTACTGATTTTTTGCTTATGTTTACAGCATAAACCCGAAATAAAAGGAAACATGAGT GGAAATTTCACCTATATCATTGACAAGTTAATTCCAAACACGAACTACTGTGTATCTGTTTATT 10 TAGAGCACAGTGATGAGCAAGCAGTAATAAAGTCTCCCTTAAAATGCACCCTCCTTCCACCT GGCCAGGAATCAGGTATGTTCATTTTTTTAAATTCATGTTTTGAGTATTCATGCTTTTACTCTG AGIGGCAAGCCTATTTAAAGAAAAGAATCTGAAAAGAATTCATGGAGCACTAAAGGTCTTTCTT CCAGTAAACACCTCACAGAGATGTTTTCTGTTGGTTCGTGTGTATGATCTGGTAGAGTCACTT TTATATTGTCATACCAAAAAACAATCAGATACTACTCGATGAGATCAGAAATCTTGAAATGGAA 15 ACGCTTTTGTTTCAGGGAGTCAGGATTAAATTCAGCACTGTGTGCCCTTTGT 26. >IFNAR2_08 GCCAGCTGCAGCCAGTGGCTACTCCACTGTACAGTGCAGTTATAGAACATAAACTGAAGGAA ATTTTACTTTTAAAAGCTAAGTCTATTTTATTGTTTAAAAAATGCACACTTAGATAATTCTCCAG TCTCTGGTATTTCTCAATATAAAACTGTTTTTTCAAACCTTTGGTTTCTTGATCATCTTGTAACA 20 CCAGGCCAATGTACATTTATTTCCATCT[GCAATTGTTTATTGCATTTTTTGAAATAAAGTCATT TAATTTTTCATCAACAGAATCAGCAGAATCTGCCAAAATAGGAGGAATAATTACTGTGTTTTTG ATAGCATTGGTCTTGACAAGCACCATAGTGACACTGAAATGGATTGGTTATATATGCTTAAGA AATAGCCTCCCCAAAGTCTTGGTAGGTAGTTTTTTTGTTTTGTTTTGTTTTTTCTATCTTTGTTT TTTATTTTAACT]TAAGAATTTGTATTTATATAAATATTTTCACAGAAGAAAATCTCATTTTCTATA 25 AACACCAAAATGCTTTCTCACTCTGAGTTCTTTTCCATATCTATAAATGTATATTTTGCAGGGT TTTTGTTTTGTTTTTGTTTTTATTATACTTTTAAGTTTTAGGGTACATGTGCACAGTGTGCAGGT TAGTTACATATATATACATGTGCAGTTGTAAGTGTATCTGTGCATCTGTGCATTTTA 27. >IFNAR2_09 GCATAGTGGCGGGCGCCTGTAATCCCAGCTACTCAGGAGGCTGAGGCAGAGAATTGCTTGA 30 ACCTGGGAGGTGGAGGTTGCAGTGAGCCAAGACCGCACTACTGCACTCCAGCCTGGGCAA CAGAGCGAGACTCCCGTCTCAAAAAAAAAAAAAAAAAAAAATAGTAAGCATACCTCATAGAGC AGTTGCAAGGGAAAGGTAAATTATATATAAAGCACCAAGAGTCATGCCCAGCATATAGTAAG CATGGTGTAACTGTTAGCTGTTATTATTGCTGTCATCATCATCAACTGCATCATCATTCAATCT[ CATTAAGTTTATTTTTTATTTTTTTAGAGGCAAGGTCTCGCTAAGGGCTGGAATGCAGTGGCT 35 ATTCACAGGTGCAGTCATAATGCACTACAGTCTGAAACTCCTGAGCTCAAACAGTCGTCCTG CCTAAGCTTCCCCAGTAGCTGGGATTACAAGCGTGCATCCCTGTGCCCCAGTGATTAAGTTT

TATTATGTAGAAAATAAAGAGCAAACAGTACAGCTGATACGGACTCTCTCTCTCTTTTTTTTTT

WO 03/014319 PCT/US02/25268 53 TTTTTAAGAATTTTCATAACTTTTTAGCCTGGCCATTTCCTAACCTGCCACCGTTGGAAGCCAT GGATATGGTGGAGGTCATTTACATCAACAGAAAGAAGAAAGTGTGGGATTATAATTATGATGA TGAAAGTGATAGCGATACTGAGGCAGCGCCCAGGACAAGTGGCGGTGGCTATACCATGCAT GGACTGACTGTCAGGCCTCTGGGTCAGGCCTCTGCCACCTCTACAGAATCCCAGTTGATAG 5 ACCCGGAGTCCGAGGAGGAGCCTGACCTGCCTGAGGTTGATGTGGAGCTCCCCACGATGC CAAAGGACAGCCCTCAGCAGTTGGAACTCTTGAGTGGGCCCTGTGAGAGGAGAAAGAGTCC ACTCCAGGACCCTTTTCCCGAAGAGGACTACAGCTCCACGGAGGGGTCTGGGGGCAGAATT ACCTTCAATGTGGACTTAAACTCTGTGTTTTTGAGAGTTCTTGATGACGAGGACAGTGACGAC TTAGAAGCCCCTCTGATGCTATCGTCTCATCTGGAAGAGATGGTTGACCCAGAGGATCCTGA 10 TAATGTGCAATCAAACCATTTGCTGGCCAGCGGGGAAGGGACACAGCCAACCTTTCCCAGC CCCTCTTCAGAGGGCCTGTGGTCCGAAGATGCTCCATCTGATCAAAGTGACACTTCTGAGTC AGATGTTGACCTTGGGGATGGTTATATAATGAGATGACTCCAAAACTATTGAATGAACTTGGA CAGACAAGCACCTACAGGGTTCTTTGTCTCTGCATCCTAACTTGCTGCCTTATCGTCTGCAAG TGTTCTCCAAGGGAAGGAGGAGGAAACTGTGGTGTTCCTTTCTTCCAGGTGACATCACCTAT 15 GCACATTCCCAGTATGGGGACCATAGTATCATTCAGTGCATTGTTTACATATTCAAAGTGGTG CACTTTGAAGGAAGCACATGTGCACCTTTCCTTTACACTAATGCACTTAGGATGTTTCTGCAT CATGTCTACCAGGGAGCAGGGTTCCCCACAGTTTCAGAGGTGGTCCAGGACCCTATGATATT TCTCTTCTTTCGTTCTTTTTTTTTTTTTTTTTTGAGACAGAGTCTCGTTCTGTCGCCCAAGCTG GAGCGCAATGGTGTGATCTTGGCTCACTGCAACATCCGCCTCCCAGGTTCAAGTGATTCTCC 20 TGCCTCAGCCTCCCTCGCAAGTAGCTGGGATTACAGGCGCCTGCCACCATGCCTAGCAAAT TTTTGTATTTTTAGTAGAGACAGGATTTTACCATGTTGGCCAGGCTGGTCTCAAACTCCTGAC CTCAAGTGATCTGCCCTCCTCAGCCTCGTAAAGTGCTGGGATTACAGGGGTGAGCCGCTGT GCCTGGCTGGCCCTGTGATATTTCTGTGAAATAAATTGGGCCAGGGTGGGAGCAGGGAAAG AAAAGGAAAATAGTAGCAAGAGCTGCAAAGCAGGCAGGAAGGGAGGAGGAGAGCCAGGTG 25 AGCAGTGGAGAGAAGGGGGGCCCTGCACAAGGAAACAGGGAAGAGCCATCGAAGTTTCAG TCGGTGAGCCTTGGGCACCTCACCCATGTCACATCCTGTCTCCTGCAATTGGAATTCCACCT TGTCCAGCCCTCCCCAGTTAAAGTGGGGAAGACAGACTTTAGGATCACGTGTGTGACTAATA CAGAAAGGAAACATGGCGTCGGGGAGAGGGATAAAACCTGAATGCCATATTTTAAGTTAAAA AAAAAAAA]AGCAAACACAAAGATGCTTCAAGATCTTCAGGAGAAGTATGGTATACAAGTTTCA 30 GGGACCCTATTTGACAATTTTCAGAGTGCTCTCTATGCTGATTCCGAGTCGAGTGTGTCAGC TGTGATTACAGTGCCTGTGGATCTAGGCCGGGTTGGGGGGGTGTGGGCGGGGGAAGGGGAA GTCTGGCCCGGAGCAATTGCTCCTGCCGGTAACCCCAGCACTTTGGGATGCCTAAACAGGC GTATCGCTTGAGGCCAGTAATTCGAGACCAGCCTGGGCAACATGGCAAATCTGTCTCTACAA AACAAAATTAGAAAAATTAACTGGGCGTAGTGGCATGTGCCTGTTGTCC 35 28. >IFNGR1_01 AATGGCTTTTGAAGTCTCATTCTCTTCTAAAAATGTCAGGCTCCAAGACAACCAGGTGAAGTC CAAGAGTTAGTAAAATAAGGATTGTGGCTCGGCTGTGGCCTAATGCAAACTTGCACAACCCC

AGGAAACCGAAAAAAACTGGAAGAAGAATTGCAGAATGGGGTGCCAGGTTGAAAGACCTTAA

WO 03/014319 PCT/US02/25268 54 CCTTTGCACTCAAATTCCTCCCACACCCAGAAGTCCAGGTCCCGACCGCACGACGCCGTGC TC[ACTGCTGGGTGCTGCGCCTGAGTCCGCCTCCTGCGGCTTCCCGGACTTGACCCCGCCC ACGCCCTGGTCCCGCCTCCTGCCGACGCCGGCACAGACCCCGGTGACGGAAGTGACGTAA GGCCGGGGCTGGAGGGCAGTGCTGGGCTGGTCCCGCAGGCGCTCGGGGTTGGAGCCAGC 5 GACCGTCGGTAGCAGCATGGCTCTCCTCTTTCTCCTACCCCTTGTCATGCAGGGTGTGAGCA GGGCTGAGATGGGCACCGCGGATCTGGGGCCGTCCTCAGGTACCGTCGTTCGCGGCAGG GCTGCGGCCGGGTCGGGACGAGAGGGAGGGAGGGATCCGCCCCAGCCGGGAAGCCCCGC CCCGCTTCTCCGAGGTCGCCCTAGCCCGGGACCCCTGCGTCGGGCCCTGAGCGGGCGACG GGGACGCGAGGTGGGGTCGCGAGACTGGGGCTCCGTGGTTTGAACTCGTCGGTTGCCTTT 10 CTCCTGCCTCTTCCCTGGTTGCCGCCACAACAAATCACGCCGCTTGTTTTTCCGACTCTTGTA ATCCACTTTT 29. >IFNGR1_02 AATTCTAGTGATGAAATGAGGATTATTAATTCAATAATCAGTGCATTTGATTATAAAACTTCTAT CATATTAAGGGAATTTATTGCTTCATGCTGTATTTGTGTTTCCTTTATATTGCAATGATGTTTCC 15 ATAATTTAAAACGAATCAGAACTCTTCTATAGATTTTTCAATAAAATTAATTTCTAGATGTCTAC TCTTCATTTAAATAATTTTGGTATCCTGGTGAATTCTACTTTTCTTCAAATATACATATCTGGGC AATGTGGCATCTTACAATAAGGCTTTCCAATAT[TAATGTTAGTTTCTTACAATTGTCCCTTTTA CTTTTTTATTTTCTTACAGTGCCTACACCAACTAATGTTACAATTGAATCCTATAACATGAACC CTATCGTATATTGGGAGTACCAGATCATGCCACAGGTCCCTGTTTTTACC[G/A]TAGAGGTAA 20 AGAACTATGGGTGAGTGTCACTCTTTTATTTATCCTTTTTATTCCATTTTTGTTTAGGTC]CTTG GAAATTCCACAACTGTGTTCTTTCATCAGCCTTCCCACGTGGCAAAACATTCTAAACTGCTTA TAGAGGTCCAAAAGTACTAAAGATGCAAATTCTTTGCCAAATATTTCTTGCCTCTTATTTCCTC TTCCTTATCAGTATTGAAATAGAGAAGTATCACTAAACTTCTGAGATTAGCATGACAAATAAAG CTAATAGTTACTATGTCATCTTCCTGTAGTGTATTTTTAGTAGAACA 25 30. >IFNGR1_03 ACAGATTTTTAAAAAATTGAATGTGGAATGTGGCTTGCATAGGTCTTACATTTTGAATTGAGCC TCTTTACTGTAACAGAGTTTGTAGTTCTTCTAACTAAAGAGTAAGGGTTTCCTACTTTCTCTGG CGTCTCCATCCTATTCTTAGCTCTGCTCTTTCTACCGCTTTGTGCTGTGAATAAAAAGCAAAG CACAGACAGAAATGGTTTGAGTTTATTTAATAACAATAAAAGTT[ATCTTCGCATTTTTTTATTC 30 TTTTTAGTGTTAAGAATTCAGAATGGATTGATGCCTGCATCAATATTTCTCATCATTATTGTAAT ATTTCTGATCATGTTGGTGATCCATCAAATTCTCTTTGGGTCAGAGTTAAAGCCAGGGTTGGA CAAAAAGAATCTGCCTATGCAAAGTCAGAAGAATTTGCTGTATGCCGAGATGGTGAGTAGAA TGTGTACACATGTAAAT]TTTAAATTGGAAAATATTTATACATGTCTTCTGTATGTTTGCTTTTAT TAGCAGTTGCTGAAAATTATCACAATGCTTAAGAAACACTTGGAGGAATTTAGAGTCAGTACA 35 GGTTGAGCATCCCAAGTCTAGAAACCCAGAATGCTCCAAAATCTGAAACTTTTTGAGCGCCA GCATGGCACTCAAAGGAAATACTCATTGGAGCATTTTGGATGTTCAGATTTAGAATGTTCAAC TG 31. >IFNGR1_04 WO 03/014319 PCT/US02/25268 55 ATTTACAACTAGAAATGAAATTAAACTGCTAAATAGGCATTCAGATTAAATAAGAGTACTTCTT GCCTGAGATTTATGAAACATTTGTTTATTAAGGACCCCGAGACTATCTTCTAGATATTTGTGG AGTGGTTTAAATGTGGTCCTGCTTTAGAACAACCAGAACAAAAACAATAGGTTGATTGATAGA TTCTGGTAATTTTATGAAATGTACCATTTAGTTCCAAGGCCAGTATTTATTATACT[TCCTCCTC 5 CTCCTTCCCCAGGAAAAATTGGACCACCTAAACTGGATATCAGAAAGGAGGAGAAGCAAATC ATGATTGACATATTTCACCCTTCAGTTTTTGTAAATGGAGACGAGCAGGAAGTCGATTATGAT CC[C/T]GAAACTACCTGTTACATTAGGGTGTACAATGTGTATGTGAGAATGAACGGAAGTGAG GTATGTGTTTCACATTTTTC]ATAATGGAAATTCTTGTGTAGCTAGCAAAAGTTGTTCCTTTCTG TAGTGTAATGAAAATAGGATGCTTATAAATATTCAAGCAAGACTCACAGATCATAGATTTGATA 10 AGAAAAATATGTGAATGCTATTAAAGCAAAAATGATACAGAGTTAGTCACTAACACTGACCAT GTGAATACATTTAGTTTTTATTTGCTTCATTTAGCAGAATGGCTCTAATCTAGGATTTTTCCCA GTACAC 32. >IFNGR1_05 AATGAATAGGACAAATGAACATTTGTTAGTTTAACAACTAACAATAAACATTCCTGCAATTTGA 15 GTTTTTAAATTTACCATTTTTATAAGGAATATAACAGATGCATAGTATCGTGCTGTGTTGAAGT AACAAATTGACTTATTGATAGTAAAGCTATTTTTAGACATGTTCAAGTCAATCATATATATTTCT TCAGTTGTTTGACCAGGACTAATATGGTGATTTTTTTTTTTTTTCAGATTAAAAGAAGCTGTGC ATTTT[CACTGTTTTCTTTTTTCATCTAGATCCAGTATAAAATACTCACGCAGAAGGAAGATGAT TGTGACGAGATTCAGTGCCAGTTAGCGATTCCAGTATCCTCACTGAATTCTCAGTACTGTGTT 20 TCAGCAGAAGGAGTCTTACATGTGTGGGGTGTTACAACTGAAAAGTCAAAAGAAGTTTGTATT ACCATTTTCAATAGCAGTATAAAAGGTAAGTTCTTGCCATTTTTTTTCTA]AATATAGAGGGAG CAGTAACTAAAATAGGATCATGTGAGGAAAGCAAACTCATTTGCAGTTTCAAAAGATCTGTTT TAACAATATTCATTTGCATTAGTTCCATTCCTTAGAGAAGTTCAAAATTAAAAATAAAGCAGTTT CTCACACATTTAAAGATATAGAACAACTAATTTGGAAAGCCATGTGATGGCCCCTTGACCCAG 25 GAAAGAAAAAATATATAATAAGTACATAAAACTACACAAATGTTTGCAT 33. >IFNGR1_06 ACCCTGGAAACACACTGTATGTAGGGCTGTAAGGAAATTATTGTAGAAAAGCTATTTTAACTA TGTTGTGTCATAGTAGAATAGTCCCAGAAAGTTCTAGAATTGCAGAGCTGGGAAGAACCATAT TGCTATCTAAGACAGATACCTAATTTTTTACTCAGATTTCCTAACTTCTGCTTCCTTCAGTGTT 30 CTTTAAAACTCTGGCCCTATTCACTAATTTGTAAATCTATTCAAGAATGGCACTAAGACTTTTT GATAGAT[AATAGCAGTATTCCATCTTAATTGTAACTTGTGATTTCTGCCTTTTTTAAGGTTCTC TTTGGATTCCAGTTGTTGCTGCTTTACTACTCTTTCTAGTGCTTAGCCTGGTATTCATCTGTTT TTATATTAAGAAAATTAATCCATTGAAGGAAAAAAGCATAATATTACCCAAGTCCTTGGTAATG TATTTAATTTTTTTATATACACTAAAAAGTTAACTTGAACCTTT]TTTGATAGTTTCTTAAATTATG 35 TTTTTAAAGTAGAATGATATTCAACAAGATGTCACCTGCCATCAATCAGTCAGTCTACCACAC ATGCAAAATCACATACTGTGTCTTTTGCTGTGCAGCAAGTATTTTGTTTTTTTTTTTATTCTCAG GGAAAAACACGGTGAGACAATTCTGTTAAAGATCTTAAAGTCTAGGGAAGAAAAGATAAA

TATACATTGGCTATATAACGTGTGATAGATTCAAAGATTTATACCTGA

WO 03/014319 PCT/US02/25268 56 34. >IFNGR1_07 ATCCTTCAGTCCAATCAAGTTGACACTCAGTATTAACCATCACAGTAACGTACAAAAAGCAAC ATATATTAGTAAGATATCTGATGGCTTTTTAAAAATTCTAAAACTTTGTTTTTAATATTACTATG GGACCTTTCATTAAAAAGAAATGGCAACATCTGATTCACCCATTATCCTAAATGTGCCATTTG 5 GTGGTCCATTACTTCAGACCTTTGTTTTTTTTGAGGGTAGGCACTTAAGCTTAACAATTTTTTA TCTTTAATCAATTTTT[CTCCCC[AIG]TAGATCTCTGTGGTAAGAAGTGCTACTTTAGAGACAAA ACCTGAATCAAAATATGTATCACTCATCACGTCATACCAGCCATTTTCCTTAGAAAAGGAGGT GGTCTGTGAAGAGCCGTTGTCTCCAGCAACAGTTCCAGGCATGCATACCGAAGACAATCCA GGAAAAGTGGAACATACAGAAGAACTTTC[T/G]AGTATAACAGAAGTGGTGACTACTGAAGAA 10 AATATTCCTGACGTGGTCCCGGGCAGCCATCTGACTCCAATAGAGAGAGAGAGTTCTTCACC TTTAAGTAGTAACCAGTCTGAACCTGGCAGCATCGCTTTAAACTCGTATCACTCCAGAAATTG TTCTGAGAGTGATCACTCCAGAAATGGTTTTGATACTGATTCCAGCTGTCTGGAATCACATAG CTCCTTATCTGACTCAGAATTTCCCCCAAATAATAAAGGTGAAATAAAAACAGAAGGACAAGA GCTCATAACCGTAATAAAAGCCCCCACCTCCTTTGGTTATGATAAACCACATGTGCTAGTGGA 15 TCTACTTGTGGATGATAGCGGTAAAGAGTCCTTGATTGGTTATAGACCAACAGAAGATTCCAA AGAATTTTCATGAGATCAGCTAAGTTGCACCAACTTTGAAGTCTGATTTTCCTGGACAGTTTT CTGCTTTAATTTCATGAAAAGATTATGATCTCAGAAATTGTATCTTAGTTGGTATCAACCAAAT GGAGTGACTTAGTGTACATGAAAGCGTAAAGAGGATGTGTGGCATTTTCACTTTTGGCTTGTA AAGTACAGACTTTTTTTTTTTTTTAAACAAAAAAAGCATTGTAACTTATGAACCTTTACATCCAG 20 ATAGGTTACCAGTAACGGAACAGTATCCAGTACTCCTGGTTCCTAGGTGAGCAGGTGATGCC CCAGGGACCTTTGTAGCCACTTCACTTTTTTTCTTTTCTCTGCCTTGGTATAGCATATGTTTTT GTAAGTTTATGCATACAGTAATTTTAAGTAATTTCAGAAGAAATTCTGCAAGCTTTTCAAAATT GGACTTAAAATCTAATTCAAACTAATAGAATTAATGGAATATGTAAATAGAAACGTGTATATTT TTTATGAAACATTACAGTTAGAGATTTTTAAATAAAGAATTTTAAAACTCGTTTTTGTAT]TCATT 25 TATTCAAGCACTTAGGCAGTCTTTCATAGTTAAGCAGAATATTTTTATATCCACTGCTTGTTTC CATGCATTAATGCTATAGGATTATTTGCTAATTGTTCATATTTAATATTTAAAACAACCCTAAAA ATAATATTTTTAAATGGTCCTTATAGGTCTATATTTCAGTGCTTAACACCCAGTGTGCAGAACA CTGTTCTAAGTGGTTTGAGAAGAAAAGATTTAGCTGTAGAGCATGTGGATTGAGGA 35. >IFNGR2_01 30 AACAGGCGTCAAACGACATGGTGCAGGCTCGGGCTGGGGAGCGGGCCTGCGGCTGCCCAG CTGCTAAAGGACTTCCTACTCGTGCACCGCCGCCGGCTCCAGGGCAAACCCCACGCCATTT AGAAATGCTGGAAGTTTCTGTCTCTCCCTCCCCCTGCTCGGAGGCCATTCCCCCCACCCCCA GAGCCCCACCTCCTCCTTCACTGGGCCCTTTCTAACTCCTTCCCCTTAAAACCCTTT[TCAAAA TGGGGTTGACTGGAGGCGGAGGTTGCAGTGAGCCGAGATCGCCCCACTGCACTCCAGCCT 35 GGTGACTCCGTCTCAAAAAAAAGGGGAGGGGGGCGGGGGAGAGTTGAAAGCTTAATATGTA CTTTGGGGGCTATTAAAGCAAACATTTCGACTAAAGGGGCGAATCCTCGAATTGTGCGATCA AGCACCCGAGAGGAGAGTTGGGGGGGGTCAGGAGGGGTGGGGGCTCCAGGGAAAGCCCG

GGGGTCTGGGCCGGGGTCTCGCGGGGCCCTTCCGGAAGGATCGCGGCCCCCGAAGGTGG

WO 03/014319 PCT/US02/25268 57 GCGTCCCGCGGGGCTCCAGTCTCCAGGACGTTCCGGGAGGCTCCGCGCTCTGGGAGGCC GGCTGCGTGGGGTCCCCGCGCTGCAGCCGCAGAGGCCCCCCAGGGCCGCGGTTCCCGGA GCGGGAAAGTCCCGCGCGGGGGCGGTGGCCTCGGGGGCGGGACGGGGCGGGGGCGGG GGCGCGGGCGGCCGAGCCGAATCCCCTCCACCGGGACGCCCCGCTGCTGCTCGGGAAGA 5 GGCGGGCCCTGCGCGCCCTGCGCTCGCCATGGCGGTTTGGGCGGCGACGTGAGCGGCTC CGCGGACCCCGAGCGGGGCCCCGGCCGCGACCTGAGCCGCCGCCGAGCGCCCGGGGCC ATGCGACCGACGCTGCTGTGGTCGCTGCTGCTGCTGCTCGGAGTCTTCGCCGCCGCCGCC GCGGCCCCGCCAGGTGAGCCGGG]CCTGGGCCTCCGCGGCGGGACGCGGGCGCAGCCGC AGCATGTGGGGGCTGGGGGACTCCCGGATCGTGGGGTGGGGGGAATCTGCCGGGTGCTC 10 AGAGTGGGTGGGAATCTGCGGGGTGCTCCTGGTGGGTGGGATATGCGGAGTGCTCAGATC AGGTGGGAACCTGCGGGTGCCCCAGGTGGGGGTCTTGCGGGGTGCCCAGGGCTAGAGGG GCCCGCTGGGAGCCCGCAGCGGGGCTGGGATGGGCGGCCAGGAGTTCCAGACAGGA 36. >IFNGR2_02 CCGGCCAGACTCCAGGGCCCAGGACCTGTTCGTAACAACTGGGACCTGCAGGTGGAAAGG 15 CTGCCCCAGGCGCCTCTTTTCTTTTTGTGCTGCCTGTACCAGTAGGGCCATCTTTGTAGCCA AAAGTCGGGGGTGTGGGGCCATGCCCAGGGGGACCTGGTAATGCCATTTCTGCACTTTGAC AAAAACTGAGTTGTATGAATGACTTAGATAATGGACATTGAAACATTTTTGTAATTATTT[CCCT CTCTCTCCTCCCTTCCTCCCTCTTCTTTTTCTCTGTCCCCCTCAAGACCCTCTTTCCCAGCTG CCCGCTCCTCAGCACCCGAAGATTCGCCTGTACAACGCAGAGCAGGTCCTGAGTTGGGAGC 20 CAGTGGCCCTGAGCAATAGCA[C/G]GAGGCCTGTTGTCTACC[A/G]AGTGCAGTTTAAATAGT AAGCCGGTATTTCTGTTGGATCCTTGCTGGGAGCTGTGGGGGCATCGT]GCGGAACCCTGG GGCCACATACTAGTCCCTGCCTCTGTGCAGGGTTTGTTATCAAACCCGTGGGAAACACATCG TTCTTGGAGCTTGTAAAATCTCTGAGGACAGAGGTTTCACAGCCTCCCACTCATCTGAAGGC TTAAACTACACTGGCAGTCAGGACTCCGCTGTCTAACCACACGGGTTCTTGCTTTGGTGGAA 25 AGTTCATTCTTTCGCTGGTTTCAGGA 37. >IFNGR2_03 GGTGGCTCACACCTGTAGTTCCAGCTACTCGGGAGGCTGAGGCACAAGAATCACTTGAACC CAGGAGGTGGAGGTTGCTGTGAGCCAAGATTGCGCTACTGCACTCCAGCCTGGGTGACAGA GCAAAACTCCATCTCAAAAAAAAAAAAAAAAAAAGCGGGGGGGAACTGTATGGTACATATAAA 30 TTGTATCTCAATAAACCTGCGTTTTGAACAAAAGCTCTGGGGAAACTATTACACATGAAACAG AGAATTCTGTGAATTGAAATCCTTTTTT[CCTTCCCAGCACCGACAGTAAATGGTTCACGGCC GACATCATGTCCATAGGGGTGAATTGTACACAGATCACAGCAACAGAGTGTGACTTCACTGC CGCCAGTCCCTCAGCAGGCTTCCCAATGGATTTCAATGTCACTCTACGCCTTCGAGCTGAGC TGGGAGCACTCCATTCTGCCTGGGTGACAATGCCTTGGTTTCAACACTATCGGAATGGTAAG 35 AGAACITTGAGTATAGAACTTCCTTTATACTTTCCAGGTTTTCTTCACTTGCGGTATCGACTCC ACACACCTCTGTCCTGCCTGTCACCCTAAATGACCAGCAGACAAATGGGTAGGACAGTCAAA

CCCACACTCTGACCTTGGAGGCTGATGCTAAGGGAGTGTGATTTGCTAAACCAGGGGTTGG

WO 03/014319 PCT/US02/25268 58 CCAACTACAGCCTGCAGGCCAAATCGGGCCCACCACTTGTTTTTGTAAATAAAGTTTTATTGG AACAC 38. >IFNGR2_04 TTGTAATCCCAGCTACTTGAGAGGCTGATGCAAGAGAATTGCTTGAGCCCGGGAGGTGGAG 5 GTTGCAGTGAGCCGAGATCGCACAACTGCACTCTAGCCTGGGCGACAGAGCAAAACTGTCT CGAAAAAATAATAATAAATAAAGAGATAGATAAAAACGTGTGTGTATATATCTACACCCACTAT ATATATATATATACATATATATATAGCATTATATAATACATTGTATTATATCT[ATAATACATATGT GTATGTGTGTGGTTTTCTCTTTGTAATTCTTTTTCAGTGACTGTCGGGCCTCCAGAAAACATT GAGGTGACCCCAGGAGAAGGCTCCCTCATCATCAGGTTCTCCTCTCCCTTTGACATCGCTGA 10 TACCTCCACGGCCTTTTTTTGTTATTATGTCCATTACTGGGAAAAAGGAGGAATCCAACAGGC AAGAGCATCTTTCTTTTTTGTTTGGATTTTCTTTTCTTTGCAGTTTCT]GGCTTAGCAAAAGAAA GAAACCTTTAACATGGGCAAGAACAGGGTGTCTCCATGTCCCCGTGTCCCCATAGAGGCTGA GCCCTGAGCCTGTTTTCATTGTCCTCTTCAAGACCTGTTTTTCCACTCGGTTTGCTGAGACCT CCCTCCGCCAGGCTGATCTGAAGGGCCAGCCATCCTTTGATGTCACTCTGTGTCCCTTGTGT 15 GGGGTTGAG 39. >IFNGR2_05 TTATCCTAGAAATTGGGATTTACTGAAGTCTAGTTACTACAATGGGCACTCTGAGACCTCACA GCCAGAAACACAGTTCTAAAGCTATCAGCCTCTTTGGCCACACAACACACCAATTTTCACACA TAAAATGTGTCCACTGCCAGCCAGTGACCCACTAAAAATGGCATCTTGTTCTTCTTTGGTTGT 20 CGTGTTCACAGTGAATTTGAGGAAACATCAGAAAAGATGTAGGCAGCTTGGCCATGTTCATTT ACATGTGTGC[TTGTGATGTTTTTAAAACAGGTCAAAGGCCCTTTCAGAAGCAACTCCATTTCA TTGGATAACTTAAAACCCTCCAGAGTGTACTGTTTACAAGTCCAGGCACAACTGCTTTGGAAC AAAAGTAACATCTTTAGAGTCGGGCATTTAAGCAACATATCTTGCTACGAAACAATGGCAGAT GGTAAAATATACCTTCTTATGTCCTTTCTGAACTGGGAAAAGAATACTCCTCCAATAGTGAAA 25 TCGGGGAATGCTTATGAGGTCATGGGTGGTGGGAGTGGGGAGACCCAGTGAGAAGAGTGC TGAACTGCAGGAATAATGAGCTTGTGCTGAGATTTGCAGTAGTGGAGGCTACCAGACAGCTA CCACTTGCTTTATTTCATTACAGGATTGACTTTAGCTATTAATGTAAGCATACCAGGTGAGGG TGGGGGGTAGA 40. >IFNGR2_06 30 AGTGAGAAGAGTGCTGAACTGCAGGAATAATGAGCTTGTGCTGAGATTTGCAGTAGTGGAG GCTACCAGACAGCTACCACTTGCTTTATTTCATTACAGGATTGACTTTAGCTATTAATGTAAGC ATACCAGGTGAGGGTGGGGGGTAGAGGGACTTGCCCATTTTACTAGGACAGGAATGCTCTT TAAGCAGCATGGATGGAACATTAACTGATGTTTGTGTTGTGCGTAGGAAGATCATTCTGTTCA [CTTTCGTGTCCTCTTTTTAGCCTCCACTGAGCTTCAGCAAGTCATCCTGATCTCCGTGGGAA 35 CATTTTCGTTGCTGTCGGTGCTGGCAGGAGCCTGTTTCTTCCTGGTCCTGAAATATAGAGGC CTGATTAAATACTGGTTTCACACTCCACCAAGCATCCCATTACAGATAGAAGAGGTACGTGTG

CACACATCTCT]TTTTTTTTTTTTGAGACAGGGTCTTGCTCTGTTGCCCAGGCGGGAGTGTCAT

WO 03/014319 PCT/US02/25268 59 GGTACAATCTCTGCTCACTGCAGCCTCCATCTCCCAGGTTCAAGCGATTCTCCTGCCTCAGC CTCCTGAGTAGCTGGTATTACAAGTGCTCACCACCATGGCCTGCTAATTTTTGTATTTTTGGT AGAAACAGGGTTTTGCTATGTTGGCCAGACTGGTCTCAAACTCCTGACCTCAAGTGATCCAC CCACCTCAGCCTCC 5 41. >IFNGR2_07 AAACCCTGTCTCTACTAAAAATACAAAATTAGCCAGGCAAGGTGGTGGGCACCTGTAGTCCC AGCTACTTGGAGGATTGAGGCAGGAGAATCGCTTGAACCTGGGAAGCAGAGGTTGCAGTGA GCTGAGATCACACCACTATACTCCAGCCTAGGCAAGAGTAAGACTCCATCTCAAAAAAAAAAT AAAAATAAAAATAAAATAAAAACAAAAACTAAAGTTAAAAGGTCTGGTATACTGAACTGGTAAA 10 CTAATTACAATTTTGCTTTCCAA[CCTCCTCAAGTATTTAAAAGACCCAACTCAGCCCATCTTA GAGGCCTTGGACAAGGACAGCTCACCAAAGGATGACGTCTGGGACTCTGTGTCCATTATCTC GTTTCCGGAAAAGGAGCAAGAAGATGTTCTCCAAACGCTTTGAACCAAAGCATGGGCCTAGC CCACTGGCTCCCTGGAAGAGATCAAGCCATCGGAGCTGCTAGAGTTCTGTCTGGACTTTCCA GAGACCAGTATTCCCTTTTGCTGCCTCTAAAAGGCCTGTCCCTGCAGACATGAGAGACAGCA 15 GGTCTCATGGGGGTGACAAGCTTTTTTTTTTTTTCTTAAAGAATTTCAAAATCAAATTCCAGA ATGATTTTACGGAGATATCCCAGGAAAATTAAGGCTTCTCTTAAACACTAAAAAGGCATGTAA TTGCTTGTTAGCAAAATGGATATGACACATCTCTGATACTTTTTTCATTATTGGTTGGGCTGAG CAGTCAGAAGACCTGGTCGTCGTCTTGACTTTGGCAAATGAGCCGGAGCCCCTTGGGCAGG TCACACAACCTGTCCCAGCGAGGGACACCGAGTGGCCCTTCATGTACATCCATGGTGTGCT 20 GGCTTAAAATGTAATTAATCTTGTAAATATACTCCTAGTAATTTAAGATTTTGTTTTTAAACTGG AAATAAAAGATTGTATAGTGCATGTTTTTTAAAGTCTATGITGAAGTGTTTTCTTTATTGTAGCC TATTTTCTGCAGAGTTTCAGCTTTCTAAAATTACTCAATCTAAACTTGTTTTTTCTTAAATAACA CCTGCTAGAGCTACTGAGGCCTCATGGGAACTCAGCAAACACTTCCTATGGATGTCACTTGA TCCTCCAAAGGTTATAAAGAAGGCCAGGGCCTAGTGCAGTGGCCCACGCCTATAATCCCAG 25 CACTTTGGGAGGCTGAGGTGGGTGGATCACTTGAGGCCAGGAGTTCTAGACCCACCTGG 42. >IL3pro AGCGGCACCAAGAGATGTGCTTCTCAGAGCCTGAGGCTGAACGTGGATGTTTAGCAGCGTG ACCGGCTACCAGACAAACTCTCATCTGTTCCAGTGGCCTCCTGGCCACCCACCAGGACCAA GCAGGGCGGGCAGCAGAGGGCCAGGGTAGTCCAGGTGATGGCAGATGAGATCCCACTGGG 30 CAGGAGGCCTCAGTGAGC[TGAGTCAGGCTTCCCCTTCCTGCCACAGGGGTCCTCTCACCTG CTGCCATGCTTCCCATCTCTCATCCTCCTTGACAAGATGAAGTGATAACGTTTAAGTAATCTT TTTTCTTGTTTCACTGATCTTGAGTACTAGAAAGTCATGGATGAATAATTACGTCTGTGGTTTT CTATGGAGGTTCCATGTCAGATAAAGATCCTTCCGACGCCTGCCCCACACCACCACCTCCCC CCGCCTTGCCCGGGGTTGTGGGCACCTTGCTGCTGCACATATAAGGCGGGAGGTTGTTGCC 35 AACTCTT]CAGAGCCCCACGAAGGACCAGAACAAGACAGAGTGCCTCCTGCCGATCCAAACA TGAGCCGCCTGCCCGTCCTGCTCCTGCTCCAACTCCTGGTCCGCCCCGGACTCCAAGCTCC

CATGACCCAGACAACGCCCTTGAAGACAAGCTGGGTTAACTGCTCTAACATGATCGATGAAA

WO 03/014319 PCT/US02/25268 60 TTATAACACACTTAAAGCAGCCACCTTTGCCTTTGCTGGTGAGTAGCTTGGATAAGACTGGC CTGCAGCAGTG 43. >IL3_01 GGCCAGGGTAGTCCAGGTGATGGCAGATGAGATCCCACTGGGCAGGAGGCCTCAGTGAGC 5 TGAGTCAGGCTTCCCCTTCCTGCCACAGGGGTCCTCTCACCTGCTGCCATGCTTCCCATCTC TCATCCTCCTTGACAAGATGAAGTGATAACGTTTAAGTAATCTTTTTTCTTGTTTCACTGATCT TGAGTACTAGAAAGTCATGGATGAATAATTACGTCTGTGGTTTTCTATGGAGGTTCCATGTCA GATAAAGATCCTTCCGACGCCTGCCCCACACCACCACCTCCCCCCGCCTTGCCCGGGGTTG TGGGCACCTTGCTGCTGCACATATAAGGCGGGAGGTTGTTGCCAACTCTTCAGAGCCCCAC 10 GAAGGACCAGAACAAGACAGAGTGCCTCCTGCCGATCCAAACATGAGCCGCCTGCCCGTCC TGCTCCTGCTCCAACTCCTGGTCCGCCCCGGACTCCAAGCTCCCATGACCCAGACAACGCC CTTGAAGACAAGCTGGGTTAACTGCTCTAACATGATCGATGAAATTATAACACACTTAAAGCA GCCACCTTTGCCTTTGCTGGTGAGTAGCTTGGATAAGACTGGCCTGCAGCAGTGAGGGGTG GTGGCTGCCTAAGGCCAAAAGGCCTCATGGGCCTTTCTCTCCCTTCACCCCCACAGGACTTC 15 AACAACCTCA[A/G]TGGGGAAGACCAAGACATTCTGATGGTAAGAGCTC]AGCCCGTGGATCC CGATCCACTTCCTGCCTGGGTGACTTCAGCCATGTCATTCCATCTTACCTAGCCTTGCTTTCT TCATCTGTAAAATAGGGTTAATAGCACCTATCTCAGTGGGATTGTTATGACAATCAAATGGCA CAATGTGCATGTTCTGGCCCAGCATCTGGCACTTAAGAGTTCAATACATGGCCACAGCCATG GCTATAATAATGAAAATGACTTTTAAATTAGAAA 20 44. >IL3_03 TGCCTGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCTTGAGCCACTGCGCCCAGCCCAC CTAGGCCCTTTATGTAGCTCAAATGGAGCCAGAGACTGGGGGCTTGAGGAAACCAGGTCCT GCCTGCCACTCACTTCTAGGCCTGTGCCCTTGGGCAGGGACCCACCTGAGGCAAGAACGG GACTAGGAGGGAACCCGAGGATGTTCCCAACAGTGGGCTTGGGAAACTGTGGGGGTGACTT 25 CCACCTGCTTGTGGGAGGGATACTCTGTAACCTTTCCCCCTTAAGTG{TATTCTCTGCCCCGT TAGGAAAATAACCTTCGAAGGCCAAACCTGGAGGCATTCAACAGGGCTGTCAAGAGTTTACA GAACGCATCAGCAATTGAGAGCATTCTTAAAGTATGTGAAGCTGTTGAGGGTTTGGGATCCC TGTGTTGGCCCTGCCCTGCCTCTGGGGAGGAGAGCAGGGCCCACTCCCTTTCCAAGGGAAT CTCTGACCATCTGCTTTGGTCTCTTTCCACAGAATCTCCTGCCATGTCTGCCCCTGGCCA[C/T 30 ]GGCCGCACCCACGGTAAGCTGTCCCCCAA]GATGCCCGTCATGGCTTGCTCCTCAGCTGGT CATCACCATTACAGCCTGGACTCACCTAATGCCACCTTCTTGGTTTCTTTATAGCGACATCCA ATCCATATCAAGGACGGTGACTGGAATGAATTCCGGAGGAAACTGACGTTCTATCTGAAAAC CCTTGAGAATGCGCAGGCTCAACAGACGACTTTGAGCCTCGCGATCTTTTGAGTCCAACGTC CAGCTCGTTCTCTGGGCCTTCTCACCACAGAGCCTCGGGACATCAAAAACAG 35 45. >IL3_05 ATGTGAAGCTGTTGAGGGTTTGGGATCCCTGTGTTGGCCCTGCCCTGCCTCTGGGGAGGAG

AGCAGGGCCCACTCCCTTTCCAAGGGAATCTCTGACCATCTGCTTTGGTCTCTTTCCACAGA

WO 03/014319 PCT/US02/25268 61 ATCTCCTGCCATGTCTGCCCCTGGCCA[C/T]GGCCGCACCCACGGTAAGCTGTCCCCCAAGA TGCCCGTCATGGCTTGCTCCTCAGCTGGTCATCACCATTACAGCCTGGACTCACCTAATGCC ACCTTC[TTGGTTTCTTTATAGCGACATCCAATCCATATCAAGGACGGTGACTGGAATGAATTC CGGAGGAAACTGACGTTCTATCTGAAAACCCTTGAGAATGCGCAGGCTCAACAGACGACTTT 5 GAGCCTCGCGATCTTTTGAGTCCAACGTCCAGCTCGTTCTCTGGGCCTTCTCACCACAGAGC CTCGGGACATCAAAAACAGCAGAACTTCTGAAACCTCTGGGTCATCTCTCACACATTCCAGG ACCAGAAGCATTTCACCTTTTCCTGCGGCATCAGATGAATTGTTAATTATCTAATTTCTGAAAT GTGCAGCTCCCATTTGGCCTTGTGCGGTTGTGTTCTCATTTTTATCCCATTGAGACTATTTATT TATGTATGTATGTATTTATTTATTTATTGCCTGGAGTGTGAACTGTATTTATTTTAGCAGAGGA 10 GCCATGTCCTGCTGCTTCTGCAAAAAACTACAGAGTGGGGTGGGGAGCATGTTCATTTGTAC CTCGAGTTTTAAACTGGTTCCTAGGGATGTGTGAGAATAAACTAGACTCTGAACAACTGCTTT G]TTACCAGTGTCTCAATTTGACTTGGGACTTAGTGACCATTTTAAGGGAGACTGGTGTGCCA CAAATCCTGGGTGGCTTGATCCTGCCACGTGGATGCTGTCTGGGTGAGCTTGTTCTCACACT GCCCTCCTGCCACCCCCATTTCCAGAAAGGTGATGATAACCCTAGCAATCTTGAAAATCCAC 15 AGAACTGCTACCAGGTACCAGGAGCCGTTCTGAGCATTTTACCTATGCTATCTAACTTATTCC TCACCCCAACCAAGAGTATGTT 46. >IL6_pro ATAAACACAAACTCTGCAAGATGCCACAAGGTCCTCCTTTGACATCCCAACAAAGAGGTGA GTAGTATTCTCCCCCTTTCTGCCCTGAACCAAGTGGGCTTCAGTAATTTCAGGGCTCCAGGA 20 GACCTGGGGCCCATGCAGGTGCCCCAGTGAAACAGTGGTGAAGAGACTCAGTGGCAATGG GGAGAGCACTGGCAGCACAAGGCAAACCTCTGGCACAGAGAGCAAAGTCCTCACTGGGAG GATTCCCAAGGGGTCACTTGGGAGAGGGCAGGGCAGCAGCCAACCTCCTCTAAGTG[GGCT GAAGCAGGTGAAGAAAGTGGCAGAAGCCACGCGGTGGCAAAAAGGAGTCACACACTCCACC TGGAGACGCCTTGAAGTAACTGCACGAAATTTGAGGATGGCCAGGCAGTTCTACAACAGCC 25 GCTCACAGGGAGAGCCAGAACACAGAAGAACTCAGATGACTGGTAGTATTACCTTCTTCATA ATCCCAGGCTTGGGGGGCTGCGATGGAGTCAGAGGAAACTCAGTTCAGAACATCTTTGGTTT TTACAAATACAAATTAACTGGAACGCTAAATTCTAGCCTGTTAATCTGGTCACTGAAAAAAAAT TTTTTTTTTTTCAAAAAACATAGCTTTAGCTTATTTTTTTTCTCTTTGTAAAACTTCGTGCATGAC TTCAGCTTTACTCTTTGTCAAGACATGCCAAAGTGCTGAGTCACTAATAAAAGAAAAAAAGAA 30 AGTAAAGGAAGAGTGGTTCTGCTTCTTAGCGCTAGCCTCAATGACGACCTAAGCTGCACTTT TCCCCCTAGTTGTGTCTTGCCATGCTAAAGGACGTCACATTGCACAATCTTAATAAGGTTTCC AATCAGCCCCACCCGCTCTGGCCCCACCCTCACCCTCCAACAAAGATTTATCAAATGTGGGA TTTTCCCATGAGTCTCAATATTAGAGTCTCAACCCCCAATAAATATAGGACTGGAGATGTCTG AGGCTCA]TTCTGCCCTCGAGCCCACCGGGAACGAAAGAGAAGCTCTATCTCCCCTCCAGGA 35 GCCCAGCTATGAACTCCTTCTCCACAAGTAAGTGCAGGAAATCCTTAGCCCTGGAACTGCCA GCGCGGTCGAGCCCTGTGTGAGGGAGGGGTGTGTGGCCCAGGGAGGGCTGGCGGGCGGC CACGAGCAGAGGCAGGCTCCCAGCTGTGCTGTCAGCTCACCCCTGCGCTCGCTCCCCTCC

GGCACAGGCGCCTTC

WO 03/014319 PCT/US02/25268 62 47. >IL6_01 GAAGAGTGGTTCTGCTTCTTAGCGCTAGCCTCAATGACGACCTAAGCTGCACTTTTCCCCCT AGTTGTGTCTTGCCATGCTAAAGGACGTCACATTGCACAATCTTAATAAGGTTTCCAATCAGC CCCACCCGCTCTGGCCCCACCCTCACCCTCCAACAAAGATTTATCAAATGTGGGATTTTCCC 5 ATGAGTCTCAATATTAGAGTCTCAACCCCCAATAAATATAGGACTGGAGATGTCTGAGGCTCA [TTCTGCCCTCGAGCCCACCGGGAACGAAAGAGAAGCTCTATCTCCCCTCCAGGAGCCCAGC TATGAACTCCTTCTCCACAAGTAAGTGCAGGAAATCCTTAGCCCTGGAACTGCCAGCGCGGT CGAGCCCTGTGTGAGGGAGGGGTGTGTGGCCCAGGGAGGGCTGGCGGGCGGCCACGAGC AGAGGCAGGCTCCCAGCTGTGCTGTCAGCTCACCCCTGCGCTCGCTCCCCTCCGGCACAG 10 GCGCCTTCGGTCCAGTTGCCTTCTCCCTGGGGCTGCTCCTGGTGTTGCCTGCTGCCTTCCC TGCCCCAGTACCCCCAGGAGAAGATTCCAAAGATGTAGCCGCCCCACACAGACAGCCACTC ACCTCTTCAGAACGAATTGACAAACAAATTCGGTACATCCTCGACGGCATCTCAGCCCTGAG AAAGGAGGTGGGTAGGCTTGGCGATGGGGTTGAAGGGCCCGGTGCGCATGCGTTCCCCTT GCCCCTGCGTGTGG 15 48. >IL6_02 TTCTGCCCTCGAGCCCACCGGGAACGAAAGAGAAGCTCTATCTCCCCTCCAGGAGCCCAGC TATGAACTCCTTCTCCACAAGTAAGTGCAGGAAATCCTTAGCCCTGGAACTGCCAGCGCGGT CGAGCCCTGTGTGAGGGAGGGGTGTGTGGCCCAGGGAGGGCTGGCGGGCGGCCACGAGC AGAGGCAGGCTCCCAGCTGTGCTGTCAGCTCACCCCTGCGCTCGCTCCCCTCCGGCACAG[ 20 GCGCCTTCGGTCCAGTTGCCTTCTCCCTGGGGCTGCTCCTGGTGTTGCCTGCTGCCTTCCC TGCCCCAGTACCCCCAGGAGAAGATTCCAAAGATGTAGCCGCCCCACACAGACAGCCACTC ACCTCTTCAGAACGAATTGACAAACAAATTCGGTACATCCTCGACGGCATCTCAGCCCTGAG AAAGGAGGTGGGTAGGCTTGGCGA]TGGGGTTGAAGGGCCCGGTGCGCATGCGTTCCCCTT GCCCCTGCGTGTGGCCGGGGGTGCCTGCATTAGGAGGTCTTTGCTGGGTTCTAGAGCACTG 25 TAGATTTGAGGCCAACGGGGCGAACTAGACTGACTTCTGTATTTATCCTTTGCTGGTGTCAG GAAGTTCCTTTCCTTTCTGGAAAATGCAGAATGGGTCTGAA 49. >IL6_03 TAATTATTGTCAAAATTGCTGTTATTAAGTATCTACTGTGTGCCAGGCACTTTAAATAAATATT GTGTCTAATCTTCAAAACAAATTTGCAAGGAAGGTTTTTGGAGATAAGGAAACTGAGACTCAG 30 GATTAAGTAACACACCTAAAGTCACAGGTGAGCTTGGAACTGAACCCAAGTGTGCCCCCACT CCACTGGAATTTGCTTGCCAGGATGCCAATGAGTTGTAGCTTCATTTTTCTTAGAGACTTTCC TGGCTGTGGTTGAACAATGAAAAG[G/T]CCCTCTAGTGGTGTTTGTTTTAG[GGACACTTAGGT GATAACAATTCTGGTATTCTTTCCCAGACATGTAACAAGAGTAACATGTGTGAAAGCAGCAAA GAGGCACTGGCAGAAAACAACCTGAACCTTCCAAAGATGGCTGAAAAAGATGGATGCTTCCA 35 ATCTGGATTCAATGAGGTACCAACTTGTCGCACTCACTTTTCACTATTCCTTAGGCAAAACTT] CTCCCTCTTGCATGCAGTGCCTGTATACATATAGATCCAGGCAGCAACAAAAAGTGGGTAAA

TGTAAAGAATGTTATGTAAATTTCATGAGGAGGCCAACTTCAAGCTTTTTTAAAGGCAGTTTAT

WO 03/014319 PCT/US02/25268 63 TCTTGGACAGGTATGGCCAGAGATGGTGCCACTGTGGTGAGATTTTAACAACTGTCAAATGT TTAAAACTCCCACAGGTTTAATTAGTTCATCCTGGGAAAGGTACTCTCAGGGCCTTTTCCCTC TCTGGCTGCCCCTGGCAGGGTCCAGGTCTGCCCTCCCTCCCTGCCCAGCTCATTCTCCACA GTGAGATAACCTGCACTGTCTTCTGATTATTTTATAAA 5 50. >IL6_04 AGGAGGTTCCAGCCCAGCATTAACAAGGGCAAGAGTGCAGGAAGAACATCAAGGGGGACAA TTCAGAGAAGGATCCCCATTGCCACATTCTAGCATCTGTTGGGCTTTGGGATAAAACTAATTA CATGGGGCCTCTGATTGTCCAGTTATTTAAAATGGTGCTGTCCAATGTCCCAAAACATGCTGC CTAAGAGGTACTTGAAGTTCTCTAGAGGAGCAGAGGGAAAAGATGTCGAACTGTGGCAATTT 10 T[AACTTTTCAAATTGATTCTATCTCCTGGCGATAACCAATTTTCCCACCATCTTTCCTCTTAGG AGACTTGCCTGGTGAAAATCATCACTGGTCTTTTGGAGTTTGAGGTATACCTAGAGTACCTCC AGAACAGATTTGAGAGTAGTGAGGAACAAGCCAGAGCTGTGCAGATGAGTACAAAAGTCCTG ATCCAGTTCCTGCAGAAAAAGGTGGGTGTGTCCTCATTCCCTCAACTTGGTGTGGGGGAAGA CAGGCTCAA]AGACAGTGTCCTGGACAACTCAGGGATGCAATGCCACTTCCAAAAGAGAAGG 15 CTACACGTAAACAAAAGAGTCTGAGAAATAGTTTCTGATTGTTATTGTTAAATCTTTTTTTGTTT GTTTGGTTGGTTGGCTCTCTTCTGCAAAGGACATCAATAACTGTATTTTAAACTATATATTAAC TGAGGTGGATTTTAACATCAATTTTTAATAGTGCAAGAGATTTAAAACCAAAGGCGGGGGGG CGGGCAGAAAAAAGTGCATCCAACTCCAGCCAGTGATCCACAGAAACA 51. >IL6_05 20 CACTTGAACCCAGGAGGCAGAGGTTGCTGTGCACCACTGCACTCCAGCCTGGGTGACAGAA CGAGACCTTGACTCAAAAAAAAAAAAAAGAAGTTTGTTGCTATGGAAGGGTCCTACTCAGAG CAGGCACCCCAGTTAATCTCATTCACCCCACATTTCACATTTGAACATCATCCCATAGCCCAG AGCATCCCTCCACTGCAAAGGATTTATTCAACATTTAAACAATCCTTTTTACTTTCAT[TTTCCT TCAGGCAAAGAATCTAG[A/T][T/AGCAATAACCACCCCTGACCCAACCACAAATGCCAGCCTG 25 CTGACGAAGCTGCAGGCACAGAACCAGTGGCTGCAGGACATGACAACTCATCTCATTCTGC GCAGCTTTAAGGAGTT[C/T]CTGCAGTCCAGCCTGAGGGCTCTTCGGCAAATGTAGCATGGG CACCTCAGATTGTTGTTGTTAATGGGCATTCCTTCTTCTGGTCAGAAACCTGTCCACTGGGCA CAGAACTTATGTTGTTCTCTATGGAGAACTAAAAGTATGAGCGTTAGGACACTATTTTAATTAT TTTTAATTTATTAATATTTAAATATGTGAAGCTGAGTTAATTTATGTAAGTCATATTTATATTTTT 30 AAGAAGTACCACTTGAAACATTTTATGTATTAGTTTTGAAATAATAATGGAAAGTGGCTATGCA GTTTGAATATCCTTTGTTTCAGAGCCAGATCATTTCTTGGAAAGTGTAGGCTTACCTCAAATAA ATGGCTAACTTATACATATTTTTAAAGAAATATTTATATTGTATTTATATAATGTATAAATGGTTT TTATACCAATAAATGGCATTTTAAAAAATTC]AGCAACTTTGAGTGTGTCACGTGAAGCTTAAT ATAAACAAGTTTCTTGTCACTGCCACCACCACGACCAAAAAAAGCTAATCAATCACTATATATA 35 ATACATATATATACTATATATAATAAATATATATACTATATATAATACATATATACACTATATATA ATACATATATACTATATATACACATATATACTATATATACACATATATATTATGAATGTATATATA TAGTATATATAGTATATATACTATGTATGTATATATATAGTATATATAGTATATATACTATGTATG

TGTATA

WO 03/014319 PCT/US02/25268 64 52. >TNF-pro ACTTCCCAGTCTATCTAAGGAATGGAGGGAGGGACAGAGGGCTCAAAGGGAGCAAGAGCTG TGGGGAGAACAAAAGGATAAGGGCTCAGAGAGCTTCAGGGATATGTGATGGACTCACCAGG TGAGGCCGCCAGACTGCTGCAGGGGAAGCAAAGGAGAAGCTGAGAAGATGAAGGAAAAGT 5 CAGGGTCTGGAGGGGCGG[GGGTCAGGGAGCTCCTGGGAGATATGGCCACATGTAGCGGC TCTGAGGAATGGGTTACAGGAGACCTCTGGGGAGATGTGACCACAGCAATGGGTAGGAGAA TGTCCAGGGCTATGGAAGTCGAGTATGGGGACCCCC[C/A]CTTAA[C/T]GAAGACAGGGCCAT GTAGAGGGCCCCAGGGAGTGAAAGAGCCTCCAGGACCTCCAGGTATGGAATACAGGGGAC GTTTAAGAAGATATGGCCACACACTGGGGCCCTGAGAAGTGAGAGCTTCATGAAAAAAATCA 10 GGGACCCCAGAGTTCCTTGGAAGCCAAGACTGAAACCAGCATTATGAGTCTCCGGGTCAGA ATGAAAGAAGAAGGCCTGCCCCAGTGGGGTCTGTGAATTCCCGGGGGTGATTTCACTCCCC GGGGCTGTCCCAGGCTTGTCCCTGCT[A/C]CCCCCACCCAGCCTTTCCTGAGGCCTCAAGCC TGCCACCAAGCCCCCAGCTCCTTCTCCCCGCAGGGACCCAAACACAGGCCTCAGGACTCAA CACAGCTTTTCCCTCCAACCCCGTTTTCTCTCCCTCAAGGACTCAGCTTTCTGAAGCCCCTCC 15 CAGTTCTAGTTCTATCTTTTTCCTGCATCCTGTCTGGAA[G/A]TTAGAAGGAAACAGACCACAG ACCTGGTCCCCAAAAGAAATGGAGGCAATAGGTTTTGAGGGGCATG[G/AGGACGGGGTTCA GCCTCCAGGGTCCTACACACAAATCAGTCAGTGGCCCAGAAGACCCCCCTCGGAATC[G/A]G AGCAGGGAGGATGGGGAGTGTGAGGGGTATCCTTGATGCTTGTGTGTCCCCAACTTTCCAA ATCCCCGCCCCCGCGATGGAGAAGAAACCGAGACAGAAGGTGCAGGGCCCACTACCGCTT 20 CCTCCAGATGAGCTCATGGGTTTCTCCACCAAGGAAGTTTTCCGCTGGTTGAATGATTCTTTC CCCGCCCTCCTCTCGCCCCAGGGACATATAAAGGCAGTTGTTGGCACACCCAGCCAGCAGA CGCTCCCTCAGCAAGGACAGCAGAGGACCAGCTAAGAGGGAGAGAAGCAACTACAGACCC CCCCTGAAAACAACCCTCAGACGCCACATC]CCCTGACAAGCTGCCAGGCAGGTTCTCTTCC TCTCACATACTGACCCACGGCTCCACCCTCTCTCCCCTGGAAAGGACACCATGAGCACTGAA 25 AGCATGATCCGGGACGTGGAGCTGGCCGAGGAGGCGCTCCCCAAGAAGACAGGGGGGCC CCAGGGCTCCAGGCGGTGCTTGTTCCTCAGCCTCTTCTCCTTCCTGAT 53. >TNF_01 CATGGGTTTCTCCACCAAGGAAGTTTTCCGCTGGTTGAATGATTCTTTCCCCGCCCTCCTCTC GCCCCAGGGACATATAAAGGCAGTTGTTGGCACACCCAGCCAGCAGACGCTCCCTCAGCAA 30 GGACAGCAGAGGACCAGCTAAGAGGGAGAGAAGCAACTACAGACCCCCCCTGAAAACAACC CTCAGACGCCACATC[CCCTGACAAGCTGCCAGGCAGGTTCTCTTCCTCTCACATACTGACC CACGGCTCCACCCTCTCTCCCCTGGAAAGGACACCATGAGCACTGAAAGCATGATCCGGGA CGTGGAGCTGGCCGAGGAGGCGCTCCCCAAGAAGACAGGGGGGCCCCAGGGCTCCAGGC GGTGCTTGTTCCTCAGCCTCTTCTCCTTCCTGATCGTGGCAGGCGCCACCAC[G/AICTCTTCT 35 GCCTGCTGCACTTTGGAGTGATCGGCCCCCAGAGGGAAGAG]GTGAGTGCCTGGCCAGCCT TCATCCACTCTCCCACCCAAGGGGAAATGGAGACGCAAGAGAGGGAGAGAGATGGGATGG

GTGAAAGATGTGCGCTGATAGGGAGGGATGGAGAGAAAAAAACGTGGAGAAAGACGGGGAT

WO 03/014319 PCT/US02/25268 65 GCAGAAAGAGATGTGGCAAGAGATGGGGAAGAGAGAGAGAGAAAGATGGAGAGACAGGAT GTCTGGCACATGGAAGGTGCTCACTAAGTGTGT 54. >TNF_02 AGGAGAGAGATGGGGGAGATAAGGAGAGAAGAAGATAGGGTGTCTGGCACACAGAAGACA 5 CTCAGGGAAAGAGCTGTTGAATGCCTGGAAGGTGAATACACAGATGAATGGAGAGAGAAAA CCAGACACCTCAGGGCTAAGAGCGCAGGCCAGACAGGCAGCCAGCTGTTCCTCCTTTAAGG GTGACTCCCTCGATGTTAACCATTCTCCTTCTCCCCAACAG[TTCCCCAGGGACCTCTCTCTA ATCAGCCCTCTGGCCCAGGCAGTCAGTAAGTGTCTCCAAACCTCTTTCCTAATTCTGGGTTT GGGTTTGGGGGTAGGGTTAGTACCGGTATGGAAGCAGTGGGGGAAATTTAAAGTTTTGGTC 10 TTGGGGGAGGATGGATGGAGGTGAAAGTAGGGGGGTATTTTCTAGGAAGTTTAAGGGTCTC AGCTTTTTCTTTTCTCTCTCCTCTTCAGGATCATCTTCTCGAACCCCGAGTGACAAGCCTGTA GCCCATGTTGTAG]GTAAGAGCTCTGAGGATGTGTCTTGGAACTTGGAGGGCTAGGATTTGG GGATTGAAGCCCGGCTGATGGTAGGCAGAACTTGGAGACAATGTGAGAAGGACTCGCTGAG CTCAAGGGAAGGGTGGAGGAACAGCACAGGCCTTAGTGGGATACTCAGAACGTCATGGCCA 15 GGTGGGATGTGGGATGACAGACAGAGAGGACAGGAACCGGATGTGGGGTGGGCAGAGCTC GAGGGCCAGGATGTGG 55. >TNF_04 AGGACTCGCTGAGCTCAAGGGAAGGGTGGAGGAACAGCACAGGCCTTAGTGGGATACTCA GAACGTCATGGCCAGGTGGGATGTGGGATGACAGACAGAGAGGACAGGAACCGGATGTGG 20 GGTGGGCAGAGCTCGAGGGCCAGGATGTGGAGAGTGAACCGACATGGCCACACTGACTCT CCTCTCCCTCTCTCCCTCCCTCCAG[CAAACCCTCAAGCTGAGGGGCAGCTCCAGTGGCTGA ACCGCCGGGCCAATGCCCTCCTGGCCAATGGCGTGGAGCTGAGAGATAACCAGCTGGTGG TGCCATCAGAGGGCCTGTACCTCATCTACTCCCAGGTCCTCTTCAAGGGCCAAGGCTGCCC CTCCACCCATGTGCTCCTCACCCACACCATCAGCCGCATCGCCGTCTCCTACCAGACCAAG 25 GTCAACCTCCTCTCTGCCATCAAGAGCCCCTGCCAGAGGGAGACCCCAGAGGGGGCTGAG GCCAAGCCCTGGTATGAGCCCATCTATCTGGGAGGGGTCTTCCAGCTGGAGAAGGGTGACC GACTCAGCGCTGAGATCAATCGGCCCGACTATCTCGACTTTGCCGAGTCTGGGCAGGTCTA CTTTGGGATCATTGCCCTGTGAGGAGGACGAAC/T]ATCCAACCTTCCCAAACGCCTCCCCTG CCCCAATCCCTTTATTACCCCCTCCTTCAGACACCCTCA/C]ACCTCTTCTGGCTCAAAAAGA 30 GAATTGGGGGCTTAGGGTCGGAACCCAAGCTTAGAACTTTAAGCAACAAGACCACCACTTCG AAACCTGGGATTCAGGAATGTGTGGCCTGCACAGTGAAGTGCTGGCAACCACTAAGAATTCA AACTGGGGCCTCCAGAACTCACTGGGGCCTACAGCTTTGATCCCTGACATCTGGAATCTGGA GACCAGGGAGCCTTTGGTTCTGGCCAGAATGCTGCAGGACTTGAGAAGACCTCACCTAGAA ATTGACACAAGTGGACCTTAGGCCTTCCTCTCTCCAGATGTTTCCAGACTTCCTTGAGACAC 35 GGAGCCCAGCCCTCCCCATGGAGCCAGCTCCCTCTATTTATGTTTGCACTTGTGATTATTTAT TATTTATTTATTATTTATTTATTTACAGATGAATGTATTTATTTGGGAGACCGGGGTATCCTGG GGGACCCAATGTAGGAGCTGCCTTGGCTCAGACATGTTTTCCGTGAAAACGGAGCTGAACA

ATAGGCTGTTCCCATGTAGCCCCCTGGCCTCTGTGCCTTCTTTTGATTATGTTTTTTAAAATAT

WO 03/014319 PCT/US02/25268 66 TTATCTGATTAAGTTGTCTAAACAATGCTGATTTGGTGACCAACTGTCACTCATTGCTGAGCC TCTGCTCCCCAGGGGAGTTGTGTCTGTAATCGCCCTACTATTCAGTGGCGAGAAATAAAGTT TGCTTAGAAAAGAA]ACATGGTCTCCTTCTTGGAATTAATTCTGCATCTGCCTCTTCTTGTGGG TGGGAAGAAGCTCCCTAAGTCCTCTCTCCACAGGCTTTAAGATCCCTCGGACCCAGTCCCAT 5 CCTTAGACTCCTAGGGCCCTGGAGACCCTACATAAACAAAGCCCAACAGAATATTCCCCATC CCCCAGGAAACAAGAGCCTGAACCTAATTACCTCTCCCTCAGGGCATGGGAA 56. >MAG_01 TGGGGTGGGAGAGGGCGGCAGGAATTCACGCGGCATGTCGGGAATGCTGATACTGTGAAA CCCAGTCATTGATGGCTCTGGGTCCCTGCCCGCCACCCCCAGGCCCCGGCCGTGGGACAT 10 CTGCTCCCTCACTCCACTCGCCACACCCCTCAGTCTCACCCCCGTACCCCGATGCGGTCGT TCCCCCTTCCCTCCCCACA[GTTCTCTGACACCCCAGCTTGGAGGGAGTTGTTGCCAGAGAG TGGCTTCGAGGCTGTGTGGGAGGGTCCCAGGCACAATGGGAGGGCCACATGGGCAGCCTG ACAACAGGTCACAACCCATGCAGGAGATACTGAAGCGGGGGTGGGTTGGGTGCCTCAATCC CGCCCCCTTGCACCTGAGTGACTCTTGTTGCATGCAGGTTGTCTGGCGGCTTCAGGTGGAC 15 CCAGAAGACGTCCCCAACTCAGGGAGATTCAGGTGAGGGGCAGGGTACCAACTCTCTTCCC TTGCTTCAGCTTTGC]AATGCTGGCCCTGCCTTGGCTCTCTGGTTCTTACTTTCTGGAGATCT CCAGGGGCATCACGGTGACAAAGATAATGATCAGCACATCATCACTGCATAGAGACAGGACA TGCAGCAAAGACTGCAGACCAACTGTGTGGCCTTGGGCGAGTCACTTAACCTCTCTGGACCT CAGCTATAAAATGAGGATAATGCATCTTC 20 57. >MAG_02 ACAACCATTTCCACAAAAAAGAAGAAAAATTAACTGGGTGTGGGGTGGCGCATACCAGAAGC TGAGACAAGAGGATAACACGAGCTCAGGATTTTGAGGCTATAGTGAGCTGTTATTGTGTCAC TGCATTCCAGCCCGGGCAATGAAACAAGACCCTGTCTCAGAAAAATAAGTAAATAAATGCATA AATAAATAATAAT[AGCAGCAGCAGCTAACATATGAATGGGCCCCTTCCTGAAGCCCAGATGG 25 AACACCCCCTTTCACTTCCCCCAGCCTTTAACCCTCTCCTCTCCCTTTCCAGCGATCACTCAC TCGCTGTACAGAATGATATTCCTCACGGCACTGCCTCTGTTCTGGATTATGATTTCAGGTAA[ C/T]GGCTGACAGGTGCTGGGGACCTAAAGGCTTTGGCCCCTGAGCAGGTTGGAGGTGGGTC CCCGCAGCCCCCCGGCA]TGTGGTTGGGGATGGGAGCCGGAGGGGGTGATCGGGTAGGAC GTGTCCCTGAGCCTCAGCTCTCCTGCTTGCCCGCAGCCTCCCGAGGGGGTCACTGGGGTG 30 CCTGGATGCCCTCGTCCATCTCGGCCTTCGAAGGCACGTGCGTCTCCATCCCCTGCCGCTT TGACTTCCCGGATGAGCTGCGGCCCGCTGTGGTGCAT 58. >MAG_03 GCGATCACTCACTCGCTGTACAGAATGATATTCCTCACGGCACTGCCTCTGTTCTGGATTAT GATTTCAGGTAACGGCTGACAGGTGCTGGGGACCTAAAGGCTTTGGCCCCTGAGCAGGTTG 35 GAGGTGGGTCCCCGCAGCCCCCCGGCATGTGGTTGGGGATGGGAGCCGGAGGGGGTGAT CGGGTAGGACGTGTCCCTGAGCCTCAGCTCTCCTGCTTGCCCGCAG[CCTCCCGAGGGGGT

CACTGGGGTGCCTGGATGCCCTCGTCCATCTCGGCCTTCGAAGGCACGTGCGTCTCCATCC

WO 03/014319 PCT/US02/25268 67 CCTGCCGCTTTGACTTCCCGGATGAGCTGCGGCCCGCTGTGGTGCATGGTGTCTGGTACTT CAATAGCCCCTACCCCAAGAACTACCCCCCGGTGGTCTTCAAGTCGCGCACCCAAGTAGTC CACGAGAGCTTCCAGGGCCGCAGCCGCCTCCTGGGGGACCTGGGCCTGCGAAACTGCACC CTCCTGCTCAGCAACGTCAGCCCCGAGCTGGGCGGGAAGTACTACTTCCGTGGGGACCTG 5 GGCGGCTACAACCAGTACACCTTCTCAGAGCACAGCGTCCTGGATATCGTCAGTGAGTCCC CAGCGGTTGTGCAGGCACCGGGAGCTGGGGCAGCGGGGCGGGAAGGAGTGTGGCCGGAA GGCCTCCCCGCACCTTCCCCAGCAGGCCTGGATGGCAGATCTGGGAGGTGCTGATTTGGCT GGGGGTGCAAACCTCAAGGCCCACGCAGACCATGCAGATGACAGACATGAACAAAGCAGG GCCCCAAAATAGTCTTGCTGCCCTCAGGGGGAAACAGGTGCTGCTACTCTTTTGGAAACACC 10 TG 59. >MAG_04 TTACGATGGCGCTCTGGTGGCTCCGTGGAGGGCTCCGGGGTGACCAAGAGGAGGAAGGGT AAAGGGAATTCTGAATCTGGAGGCAGGGAGCGGAGGCGATACCGTTGAGGAGTACCATTGC CAGCAATGGAGGTGGACAAGGAGGAGGGTGGGTGGGGTGGGACCGGGACCGTAGCCCAG 15 TGCTGCTTTCTCAGCCCTCC[CTTTCCCCGCCTCGTATAGACACCCCCAACATCGTGGTGCC CCCAGAGGTGGTGGCAGGCACGGAGGTGGAGGTCAGCTGCATGGTGCCGGACAACTGCCC AGAGCTGCGCCCTGAGCTGAGCTGGCTGGGCCACGAGGGGCTGGGGGAGCCCGCTGTGC TGGGCCGGCTGCGGGAGGACGAGGGCACCTGGGTGCAGGTGTCACTGCTGCACTTCGTGC CCACGAGGGAGGCCAACGGCCACAGGCTGGGCTGCCAGGCCTCCTTCCCCAACACCACCC 20 TGCAGTTCGAGGGCTACGCCAGCATGGACGTCAAGTGTGAGCCTGGGT]GCGGGCGGGGC GGGGTGGGGCGGGGTGGGGCGGGGTCCGGGGAGGGGGTGGACCTGGGGATGCGGCCGG AGGCGGGGCCGGGCCGTGATGGGGGCGGGGCCATGCCCAGGGCCAGGCAGGGATTGGG GGGTTGGGTGGGACGGGGGCGGAACCAGGCAGTCCTGGGGCGGGGCCAAGGCTGAGGGC GGGGCCGGACAGTGTTGGGGGCGGGGCCGGGCTGGG 25 60. >MAG_05 CGGGGCCGGGCCGTGATGGGGGCGGGGCCATGCCCAGGGCCAGGCAGGGATTGGGGGG TTGGGTGGGACGGGGGCGGAACCAGGCAGTCCTGdGGCGGGGCCAAGGCTGAGGGCGGG GCCGGACAGTGTTGGGGGCGGGGCCGGGCTGGGAGAGGGCACTGGGCCGGTTCCCCAGC ACCTGCTCACTAACCTCGCTGTGT[CGCGGGCCTTAGACCCCCCGGTGATTGTGGAGATGAA 30 CTCCTCGGTGGAGGCCATCGAGGGCTCCCACGTGAGCCTGCTCTGTGGGGCTGACAGCAA CCCCCCGCCGCTGCTGACCTGGATGCGGGACGGGACAGTCCTCCGGGAGGCGGTGGCCG AGAGCCTGCTCCTGGAGCTGGAGGAGGTGACCCCCGCCGAAGACGGCGTCTATGCCTGCC TGGCCGAGAATGCCTATGGCCAGGACAACCGCACCGTGGGGCTCAGTGTCATGTGTGAGTG GCCCACTCTGTGCGTCCACACGC]CCACCTGCAGCCGAGAGATAAAGGGAAAGGGGCCTCA 35 TCCAGGGCGAGCATGGGCTGGGTCCCGAGGGGACCGGCCATAAACAGTCGAGGCCAAGGT AGACAGGGGGGTTGCAAGTCAAGGTGTACCTTCATTCTTTCCACAAGAATCTGGGGAACACC TGCTCTGCCTCATCCTCCTTCCAGGACAAGACCCAGGCCTG 61. >MAG_06 WO 03/014319 PCT/US02/25268 68 ATGAGAAAAATGAGGCCCAGAGAGGTTAAGATGTGGGTCCACACACAACTGGACAGGGGTA GAGTAGGGATCTGAAGACAAGCATGCTGGCTACCAAGCTGCTGTTCTTGGAAATGAGATAGC CAGGACTGGGGTCACCTGAGCCTTCCTGAACCGGTGTGCTAGGTTTGGGGTGGGATCTGGG GTCATATCTGGGGATGGTAGTTGGCTGGCAGAAGAAGCACCTCCTGGGTTCTGACCATCAG 5 TCCCG[TCCTACCCCGCAGATGCACCCTGGAAGCCAACAGTGAACGGGACAATGGTGGCCG TAGAGGGGGAGACGGTCTCTATCTTGTGCTCCACACAGAGCAACCCGGACCCTATTCTCAC CATCTTCAAGGAGAAGCAGATCCTGTCCACGGTCATCTACGAGAGCGAGCTGCAGCTGGAG CTGCCGGCCGTGTCACCCGAGGATGATGGAGAGTACTGGTGTGTGGCTGAGAACCAGTATG GCCAGAGGGCCAC[C/T]GCCTTCAACCTGTCTGTGGAGTGTGAGTACCTTCCGCTCCCCTAT 10 GCT]GGGGATGGACGGTTCCGTGGGGGACACCAGGGTTACTGTGGGTGCCCACGCATCCCA ATCAGTATTGGCTTTGCCTGTCCTCCGCAGAGACAAGGAAGGGAGGGCAGGGAAGCTGAAT TCACAGCAGGAAAATAAAATCCCATCTGAGAATATTGTGTTCCCACATCCGGGAGTGGGCTT TTTTTTTTTTTTTTTTTTTTGAGACAGAGTATTGAGTCTTGCTCTGTCACCTAGGCTGGAGTGC AGTGGC 15 62. >MAG_07 CAAGGCCCCAGGCGTGGGTTAGTGAAGCTTGCAGTGAAAACAGGCAGCCGGCGGGGTCGT AGTGAGGTCAAGGCGCTCTCAGTCAGGACAGAGAAAAAAGGAGGGGAAATTGGAGGGCCCT ACAGGAAGCTACCGCCCCCATCCTTGGCCACACTGGCCTTGCCTTGAGCCAAGGAGTCTCC[ G/C]GGGCCGGGCCTCGCGTT[GGCTCCGGGCCACCCTCAGACCTGATTTTGCCCCTGCAGT 20 CGCCCCTGTGCTCCTCCTGGAGTCCCACTGCGCGGCAGCCCGAGACACGGTGCAGTGCCT GTGCGTGGTGAAGTCCAACCCGGAGCCGTCCGTGGCCTTTGAGCTGCCATCGCGCAATGTG ACCGTGAACGAGAGCGAGCGGGAGTTCGTGTACTCGGAGCGCAGCGGCCTCGTGCTCACC AGCATCCTCACGCTGCGGGGGCAGGCCCAGGCCCCGCCCCGCGTCATCTGCACCGCGAGG AACCTCTATGGCGCCAAGAGCCTGGAGCTGCCCTTCCAGGGAGCCCGTGAGTGGCGTGGA 25 CTTGGGGTG]GGAGCCACAGGAGGGAGCGGGCACGTCTTAGATCCAAGCTCCCAAGGCTGA CCAACAGCCACAGAGCATGGGCTATGCAGATTGACAGAAAGGTCAAATTCTCCCTTTCCGGT TGGAGAGGAGAAGCCGCCCTGAGTTTGCCCCGAGTTTGCTAGGACCTTTGAGGCATGAGCC CCTCCCCAGGGCCCTCTAGCATGAAA 63. >MAG_08 30 ACCAACAGCCACAGAGCATGGGCTATGCAGATTGACAGAAAGGTCAAATTCTCCCTTTCCGG TTGGAGAGGAGAAGCCGCCCTGAGTTTGCCCCGAGTTTGCTAGGACCTTTGAGGCATGAGC CCCTCCCCAGGGCCCTCTAGCATGAAAGGGATTGCCCTGGCACGAGGAGGCTCCGTGCCA ATCAGTCAGTGCAAGGA[TGCCCCGGCTGTGTGACTACATTGACTGTCATCCCAGCATGTCT CCAAAGTTCTCAGGTGTCGTCACCACCACCCATAGCCCTAAGGGCGCCTGGGTCTTTTCTGT 35 CCTCAGATCGACTGATGTGGGCCAAGATCGGGCCTGTGGGCGCCGTGGTCGCCTTTGCCAT CCTGATTGCCATCGTCTGCTACATTACCCAGACACGCAGGAAGTGAGTGCCAGCTGGGGCT GATCTGGGGATGGGAGTCTCCAAAAAGGGGACCTGGTGGGAGATGGAGGCCCAGAGTGGG

TGGGGGAAGGCA]GCACCATAAGTGTAGAGAAGGCAGATTCTGTTCTGGGAATGTTCAGCTG

WO 03/014319 PCT/US02/25268 69 GACAGAGGAGAGAGGGTTCCTGTTAATTCCAGCCCCTGCTGGTCAGGGGCACACCAGGGC CTGGGCTGAGCCCTTTACACACATCATTTGAGACCTGTTTGCCCACATTCTATTTTGACAGCC TCCCTATCTCTAGGAACTCTCCCCTACACACTCCAGTGTGGTGGGGAAAGCCCAGGTACCCC ACTGCAGCCACAGCAG 5 64. >MAG_09 AGAAAGACCCAGAGCCTATGAGGGGAACCTGGAGAATCCAGGTGGGGGTCCTGAAAAACG GCAGAGCTCAGGGGCCAGGTGGCTCGTCCCCAGCCGGGCAGGGGCCACAGAGGTGGGAA GGATGGGCTGTGTGGGTAGGAGAGGCTGGTGGTTCTGAAAGGGCTGCTTGCCACATCTTAG AGATGGGTGGGAGAACTCTG[AGGTCCCCTGAGCCAAACTCCTAAAACACGTGGGGGTGCA 10 GAAAGGGAGGGCAGAGAGAGGTCTGACGAGTCCTGCCCTGCAGAAAGAACGTGACAGAGA GCCCCAGCTTCTCGGCAGGGGACAACCCTCCCGTCCTGTTCAGCAGCGACTTCCGCATCTC TGGGGCACCAGAGAAGTACGAGGTAAGGACCAGGCTCCAGGCTGGCCTGGGAACCTGGAT GCCAGGGACACTGAAGGCCTGGGAAAGGCCTGTGAGGCCAAGGGGCAGGGGAGTGGGAG CGGCCTCTCACAGGAGGAGA]GGAAGGACATTCCAGGGCTGGGTTGGACCTGGAGGCTGG 15 GGAGGAGGTGCCCAGGCCGAAGCTGTGTAGGGGGCGATGGGACGTGGGGCCTAAGGGCC CCCTCCCCTCCCTGCCTGTGTCTGTGACTGCATTTCCTTCTCCAATAGTCCAAAGAGGTTTCT ACCCTGGAATCTCACTGAGTGCCCCAGGAGGTAGGTTCC 65. >MAG_10 AGAAGAAGCAGCTTCCTGGAGAAACTGAATTTGTAGGCAAATTTCAAGTTCAGCAATGATTAA 20 CACTGGCAGAAGCTCCAGAGTGGGACCTGGTGACCGCAGGGCTCGCTGGGCCTGCGGTCC TTGAGAAAGGAGGTTCTCGCAGGGATTTATTTGGGACTGAACTCAGGAGCTCTGAGGGTGC AAACGCTCTGTCCTCTGCATTGGGAAAAGGCAGGGAGCAGGACCCTGCTAATGGGCGGTTT[ CCCCTCTTAGAGCGAGAGGCGCCTGGGATCTGAGAGGAGGCTGCTGGGCCTTCGGGGTGA GCCCCCAGAGCTGGACCTGAGCTATTCTCACTCGGACCTGGGGAAACGGCCCACCAAGGAC 25 AGCTACACGCTGACGGAGGAGCTAGCTGAGTATGCTGAAATCCGGGTCAAGTGAAGGAGCT GGGGGCAGCCTGCGTGGCTGACCCCCCTCAGGACCCTCGCTGGCCCCCACTGGCTGTGGG CTCCCTTCCTCCCAAAAGTATCGGG[G/T]GCTGGGGCAGGAGGGGAGTGAGGCAGGTGACA GTGAGGTCCTGGGGGCCTGACCTCCCCCTCCTTCCCAGCTGCCCCTCCCTGCCAGCACCCC CACGCCCTCATTACGGCTCCTCTCTAACCTCCTTTACCCTCATCTGTCTGGAGGGGAGCTCT 30 GTCTGTC[C/G]GTGTTATTTATTGCTACTTCCTGCCTGGTCTCCTGCCCCCACACCTGGCCCT GGGGCCTGTACAAAAGGGACATGAAATAAATGCCCCAAAGCC]AAATGCCAGTCTAGATC[C/T ]TGATGCTTTCTGACCCGCCTTTGGGCAGCCTGCCATCCCACCGTCTACAGAACGATGACAG AATTTCTCCTTGCCCTCGGCTGAGCCTGGTATGCAGGCAAGGGCCCAGGGATTTTAGCCTTG AACCCAGGGCCAGTGGCCACTAAGTTGCTCCCACTCTGAGCTGGTAGCTGCGAGCTGGGTC 35 TGGTTTGACTTATGGATGATTTCACATAAAAATCCTCATGCTGGTTTTTGCCGCAGTCAGATC AGCTGACAGCACCAG 66. >MPO_01 WO 03/014319 PCT/US02/25268 70 AAAAAAAAAAAAAAAGGCTGGGGACAATGCTGGCCCCTCCTTTCCTGCCCCTTCCCCCCATT TCAGGGGCCCCTCTGTGTGTACCTTCCAACCCCAGTGGGGGAGGAGAAAGAGTTCAGTCTC CAGGATCAGACCTTCCTCTACCTCACCCCACCCCCAGCTTAGAGGACATAAAAGCGCAGATT GAGCTAAGAGGAGCT[GACAATATCAGGTGAGCTGTGGAGGTGGGGTCCTTGGAAGCTGGA 5 TGACAGCAGCTGGCAAGGGGATAAGAGAGCAGTGAGCCCCTCCCTCAAGGAGGTCTGGCTT TATCCA[T/C]AGACAGGGCCCTCTGAGGTGGGGCTGAGGTACAAAGGGGGATTGAGCAGCC CAGGAGAAGAGAGATGGGGGTTCCCTTCTTCTCTTCTCTCAGATGCATGGTGGACTTAGGAC CTTGCTGGGCTGGGGGTCTCACTGCAGAGATGAAGCTGCTTCTGGCCCTAGCAGGGCTCCT GGCCATTCTGGCCACGCCCCAGCCCTCTGAAGGTGCTGCTCCAG]GTAACAGTTCCCAAGGT 10 GGGAGAAGATGGTGTGTTGGGGTGGTTGTGTTCCAGAGACCCCTTTTCTCAGAGCAGGCCT TCCTAGCTCTGGGGCCTGATAGGGGGTTGGGGCCCATTCCTGACTTTGTGATCC[C/T]TGCT CTGGGCAGCT[G/T]TCCTGGGGGAGGTGGACACCTCGTTGGTGCTGAGCTCCATGGAGGAG GCCAAGCAGCTGGTGGACAAGGCC 67. >MPO_02 15 CAGAGATGAAGCTGCTTCTGGCCCTAGCAGGGCTCCTGGCCATTCTGGCCACGCCCCAGCC CTCTGAAGGTGCTGCTCCAGGTAACAGTTCCCAAGGTGGGAGAAGATGGTGTGTTGGGGTG GTTGTGTTCCAGAGACCCCTTTTCTCAGAGCAGGCCTTCCTAGCTCTGGGGCCTGATAGGG GGTTGGGGCCCATTCCTGACTTTGTGATCC[C/T]TGCTCTGGGCAG[CT[G/T]CCTGGGGGAG GTGGACACCTCGTTGGTGCTGAGCTCCATGGAGGAGGCCAAGCAGCTGGTGGACAAGGCC 20 TACAAGGAGCGGCGGGAAAG]GTGGGGCACGAGGCACTGCCCAGCTCTGGGCAAGGATGT CCCAGGCCTTTCAGAGAAGCAGCAGGCAGCAGGGAGCTTGAAGGTGGGAGAGGGGGACTA TGGGGACCCATGTGGACTCCCTTTCTGTCTGTCTGTCCCTGTGTTTCTGGATGGGAGAACAG CTTAAAAGCCATCCTTCCCAAAGCCTTGCCTCTGTCTGGACACCCAGGTCCATATCCTTTTTA TAAAAG 25 68. >MPO_03 TCTGTCCCTGTGTTTCTGGATGGGAGAACAGCTTAAAAGCCATCCTTCCCAAAGCCTTGCCT CTGTCTGGACACCCAGGTCCATATCCTTTTTATAAAAGGAAGCCTTCCTCCCACCCGTGGGC CTGCCTGCATGGTCCTGCATGTCTGCCCCTGGGCTGGGGCTCTGCTGGGTGGGTCTGTATC CCTTCTCTGGCCCTCACTCCTCCTTTCTCCAAGCAG[CATCAAGCAGCGGCTTCGCAGCGGC 30 TCAGCCAGCCCCATGGAACTCCTATCCTACTTCAAGCAGCC[G/A]GTGGCAGCCACCAGGAC GGCGGTGAGGGCCGCTGACTACCTGCACGTGGCTCTAGACCTGCTGGAGAGGAAGCTGCG GTCCCTGTGGCGAAGGCCATTCAATGTCACTG]GTACTGTTGCCCATCACACCCCAGGTCCC TGCTCCACTAGTGACTCCTCCTAGGGACCCCAGCCGTCTCTCAGTGATCCCCTCAACTTCTT CCTCCAGGGAGTCTCAGGAGTCTCCAGGGCTCCTCAGCCTCAGGTTGCCTGGGATAGGAAG 35 TGAGGCGGCTCAGCTCCCCCATTGTTCTTTCCCCCGGCAGATGTGCTGACG 69. >MPO_4 WO 03/014319 PCT/US02/25268 71 GGAGAGGAAGCTGCGGTCCCTGTGGCGAAGGCCATTCAATGTCACTGGTACTGTTGCCCAT CACACCCCAGGTCCCTGCTCCACTAGTGACTCCTCCTAGGGACCCCAGCCGTCTCTCAGTG ATCCCCTCAACTTCTTCCTCCAGGGAGTCTCAGGAGTCTCCAGGGCTCCTCAGCCTCAGGTT GCCTGGGATAGGAAGTGAGGCGGCTCAGCTCCCCCATTGTTCTTTCCCCCGGCAG[ATGTGC 5 TGACGCCCGCCCAGCTGAATGTGTTGTCCAAGTCAAGCGGCTGCGCCTACCAGGACGTGGG GGTGACTTGCCCGGAGCAGGACAAATACCGCACCATCACCGGGATGTGCAACAACAGGTGC GGCTGGCTGGGGGTGGCTGCAGGAACCGGGCTCAGAGAGGCGTCCCGGACGCCACAAGC CTCCCGGTGTCAGCGCCCTGTCCTCCCCTGCAGACGCAGCCCCACGCTGGGGGCCTCCAA CCGTGCCTTTGTGCGCTGGCTGCCGGCGGAGTATGAGGACGGCTTCTCTCTTCCCTACGGC 10 TGGACGCCCGGGGTCAAGCGCAACGGCTTCCCGGTGGCTCTG]GTGAGCGCCGGCGGGCA GAGGGGGCGAGGCCCGGCCACGCGGTGCGCGGACCCAGGCGCCAGCTGATCTCCGTGTC CCGCAGGCTCGCGCGGTCTCCAACGAGATCGTGCGCTTCCCCACTGATCAGCTGACTCCGG ACCAGGAGCGCTCACTCATGTTCATGCAATGGGGCCAGCTGTTGGACCACGACCTCGACTT CACCCCTGAGCCG 15 70. >MPO_06 CCCCTGCAGACGCAGCCCCACGCTGGGGGCCTCCAACCGTGCCTTTGTGCGCTGGCTGCC GGCGGAGTATGAGGACGGCTTCTCTCTTCCCTACGGCTGGACGCCCGGGGTCAAGCGCAA CGGCTTCCCGGTGGCTCTGGTGAGCGCCGGCGGGCAGAGGGGGCGAGGCCCGGCCACGC GGTGCGCGGACCCAGGCGCCAGCTGATCTCCGTGTCCCGCAG[GCTCGCGCGGTCTCCAAC 20 GAGATCGTGCGCTTCCCCACTGATCAGCTGACTCCGGACCAGGAGCGCTCACTCATGTTCA TGCAATGGGGCCAGCTGTTGGACCACGACCTCGACTTCACCCCTGAGCCGGCCGCCCGGG CCTCCTTCGTCACTGGCGTCAACTGCGAGACCAGCTGCGTTCAGCAGCCGCCCTGCTTCCC GCTCAAG]GTGGCCCTGCTTCCCGCCCACTGCCTGGGTTGGGAGAGGGGAGATTGTTTCTG GAAGGGGCCATCTCCCTTCTGTGCCCAGGTTTCCTTTCCCAGACGCTGAGGAAGGCTGGCC 25 CTGCCTCCCTTGTGTCCACAGCACTGGCTGCTCAGCTATGACCTGTCTCCTTCCTGCGCCTG GGCTCAGCCAGCTGGCAGCCAGGGCCGTCCATTTGCTCACTGCCTC 71. >MPO_07 AGGCCTGGCGGTGCCCAGACCCAGGGGTTGCCCAGGTTCCCAGTTCAGTGTTCTGCTCATT AACCCTGCACCTCAGAGGCTGTTGCTGATGGCGCCCTAGGCAGCGATCCCTTTCGGGCCTC 30 CGGAGGCCTCTCTGCAGGTTGAGGGTACCAGAGGTCCTGAGGGCAGGGGGAGATCCAGTT CTGCCTGGGCACCTTCCTTGCCCTCGGTGAGCCAGTCTAGCCTCTCTCTGTGCCTCAG[ATC CCGCCCAATGACCCCCGCATCAAGAACCAAGCCGACTGCATCCCGTTCTTCCGCTCCTGCC CGGCTTGCCCCGGGAGCAACATCACCATCCGCAACCAGATCAACG[C/T]GCTCACTTCCTTC GTGGACGCCAGCATGGTGTACGGCAGCGAGGAGCCCCTGGCCAGGAACCTGCGCAACATG 35 TCCAACCAGCTGGGGCTGCTGGCCGTCAACCAGCGCTTCCAAGACAACGGCCGGGCCCTG CTGCCCTTTGACAACCTGCACGATGACCCCTGTCTCCTCACCAACCGCTCAGCGCGCATCC CCTGCTTCCTGGCAG]GTCAGCTTTGGGGTGGGGACCAGAGGTGGCATAGGAGATGTTCCC

TGTTGGAGCCACAGTGAGTCTGTTTGTGAGCAGCTTGTGGGTTTGTACTTAGAGAGACTGTC

WO 03/014319 PCT/US02/25268 72 CTCACCAGCCATTACTATCAACTTCATGATATTAATCCAGTTGCCTTGGTAACAAGTCAGATG GAGCCAGAAAAGCAGAAAAGCAAACAACCTCTCCAACCCTAAGATGGAGACCCAGGCATGG CTGAGGAGCC 72. >MPO_08 5 GAGCATCCCCAACCAGCAGCGGCCCTGAGCTGAGGCAGAAGCTATCATTGTGGACTGGGG CATCAGGGAAGGCCTCCTAGAGGAGTGTAAATTGGGGATAGTTTGAAAAGATGGATGGGGA GGAGGGGTGAGTAGGAGGCATTTCAGGCCTTGGCTGGGGAGGGGGTTTCAGTGGAGCAAA TCTTTTCTGGGATGGAGGCCTTAAGAATGACAGTGGCTTTTGCCTCCCCAAG[GGGACACCC GTTCCAGTGAGATGCCCGAGCTCACCTCCATGCACACCCTCTTACTTCGGGAGCACAACCG 10 GCTGGCCACAGAGCTCAAGAGCCTGAACCCTAGGTGGGATGGGGAGAGGCTCTACCAGGA AGCCCGGAAGATCGTGGGGGCCATGGTCCAG]GTAGGCCGTCTTGAACACCGGGCACACGG GATCCAGATGTGTCCCTGCAACATCCTAGCTGTGTGACCTTGGGCAAGTTCCTAACGCTCCT GAGCCTTGCCTTCTTCATCCATGAGGCTGTAAGGATTATAATACATATATGAAAACACCTTTC AGATAGTAAGTGCTTGACAAAGCCTCCTTCCCTTCCCTCTCCTTCTTCGCAG 15 73. >MPO_09 ACCCAGCCAGCAAGCAGTAGAACTCTATTTATGCCTCTCAGTGCCACTCTGTTAGGCCCAGG TCCGGTATTGTGGGAGGCTATTCCCTGACCATAGAGGGATGGAAGGGGTCCCCGAAGCCAA GAGCAGGCAGAGACTCTGGCCCTCCTGTGCTGCCAGGCGGCATTTGCTGTGGAGGAGTGG GTGGAGAGGCCATTCCAAATGACTTGTCTTTAG[ATCATCACTTACCGGGACTACCTGCCCCT 20 GGTGCTGGGGCCAACGGCCATGAGGAAGTACCTGCCCACGTACCGTTCCTACAATGACTCA GTGGACCCACGCATCGCCAACGTCTTCACCAATGCCTTCCGCTACGGCCACACCCTCATCC AACCCTTCATGTTCCGCCTGGACAATCGGTACCAGCCCATGGAACCCAACCCCCGTGTCCC CCTCAGCAGGGTCTTTTTTGCCTCCTGGAGGGTCGTGCTGGAAGIGTAAGCAGGACCTAGGC CAGGAGCGAGTGGGCTGACAGCTAAAGGTGGGGTAGGGATCACCTTGGCTCTAGGGAGCT 25 AGGGTGGGGAGCAGTCTGCTTTCCTCCCATCTTGGAGATCTGGTCTGACTCTCTAGCCTCAG TTCCTCTGACTCTGCTTCCATATCTGATAATAAACAGTGGGGTGGGGATGGCCCTCAGAGGG AACTGGCTACTTCCTATGTGTTGTGGC 74. >MPO_10 CTGAATGGCATAATCTCCTGAGACCTATATGTCCCTGGGGTCATGTAGTGACCGGTGAGGAC 30 CTGCTCACTGGGGCCACCACCTTGGCACCAGGCACTGCTTGTGCCCAGCCCTCTTCTCGAA TCCTCCTGACCCTACCTGGACTTGTCCCTGACTCCAATCTGAGCTCTGATACTGAGCCAGAT ACTTCCCCTGACCTGGCTCCTCTGGTCCCCAG[GTGGCATTGACCCCATCCTCCGGGGCCTC ATGGCCACCCCTGCCAAGCTGAATCGTCAGAACCAAATTGCAGTGGATGAGATCCGGGAGC GATTGTTTGAGCAGGTCATGAGGATTGGGCTGGACCTGCCTGCTCTGAACATGCAGCGCAG 35 CAGGGACCACGGCCTCCCAG]GTGAGGGGCTGCAGGAGTCTCCCCTGATGCTCACCTCCCC

TGAGCTGCCTCCTAGGTAGCCCATCACCCCCCTTCCCACTCTAGGGTCCCTGCCCTCTCCAA

WO 03/014319 PCT/US02/25268 73 AGCATATTAGAGGCACTTTGCTCTCAGGAAGTAGCCTGAGGCCAGGCCCCTGCCTTTTCCCG GACCCACCTGATAAATTTCCAGCTCCTCTCAACCTCCTTTGCATGCTG 75. >MPO_11 TAGGAGGGCAAGAGAAAGACAGAGAGGGTCCCAGAGAGGCCCAGTTGTGCCCCTTGGTCTA 5 AGCCAAAGGTACAGGGTTCCTTGAGGTGAGGTCCTTCCCTCCCTCTATGACCTTGGTTGTGT TGGGAAGGTGGGTTTTCTGGGCTGCTGGCGATATGTGAATCTTCCCTGCTGTCTCCAGTGAC CTCCCCACCTTGAAGCAGAGAGACCTGCCCATAGCCACCTGTCCCCTCCCCCATGCAG[GAT ACAATGCCTGGAGGCGCTTCTGTGGGCTCCCGCAGCCTGAAACTGTGGGCCAGCTGGGCA CGGTGCTGAG[G/A]AACCTGAAATTGGCGAGGAAACTGATGGAGCAGTATGGCACGCCCAAC 10 AACATCGACATCTGGATGGGCGGCGTGTCCGAGCCTCTGAAGCGCAAAGGCCGCGTGGGC CCACTCCTCGCCTGCATCATCGGTACCCAGTTCAGGAAGCTCCGGGATGGTGATCG]GTGAG GAGGGGCAGGCGTCGTGGGCCGCTGGGTGGCTGTGGGCCCATCCTTGACTCTCTTGGAGC CCAAATTTCCTCCTGTCAGTTGAAGGACTGGAGGGAGTCAGTAATTTTCCAGTGTGTTCCAG GAATCCTCCAGATGCCCTGGAGTGCCCCTAATGTGCCCTGAACCTGTTGGGGGTGCAGCAA 15 GGAAAGACCTGGACCCCTGGTTGTAAAGGGT 76. >MPO_12 GGTAAGGGAAAGGCCACTGGGCAGCTGTGCTTTACTCTGCACGATGAGTGGAGCATCACTT GTGTGAAAGCCCCTGGGCTGCCCAAGGGCCTGGGGCCCTCCTGTGCTTCCAGGTGGCATTT GTTGTGGCTTTGTTATATCCTGGGAGCAGCACAAGCCCATCGATGCCCTGCCAGCCCAGAAT 20 ATCCTTGGGCACAGTGTCCATGGGTGTTCCCC[A/C]TGC[A/C]G[GTTTTGGTGGGAGAACGA GGGTGTGTTCAGCATGCAGCAGCGACAGGCCCTGGCCCAGATCTCATTGCCCCGGATCATC TGCGACAACACAGGCATCACCACCGTGTCTAAGAACAAC[A/G]TCTTCATGTCCAACTCATAT CCCCGGGACTTTGTCAACTGCAGTACACTTCCTGCATTGAACCTGGCTTCCTGGAGGGAAGC CTCCTAGAGGCCAGGTAAGGGGGTGCAGCAGTGAGGGGTATATCTGGGCTGGCCAGTTGG 25 AACCACGGAGATCTCCTTGCCCTAGATGAGCCCAGCCCTGTTCTGGGTGCAGCTGAGAAAA TGAGTGACTAGACGTTCATTTGTGTGCTCATGTATGTGCGAAGTATATAAATTGGCTTTTCAT GCGTGTGTGTTGTCTGAACATGGGGAGTGTTTCATGGGTTATGTGTATGTGCCATTTATGTG AGTGTGTGTTTGTGCTGATGAGAATACTGAGTATGTGGAAGGCAGCAGAGCGGACTGGTGA GGAGCACAGCTCAGGAACTAGACTGCCTGGGTTCCAATCCTGGCTCTGTGGCTTGCTAGCT 30 ATGTGACCTTGAGCAAATTACCCTCCTTAAACAAGAGTTTTCTTCCTTGTAAATTACATCTGTC ATGGTTTCTTGGAGGGCCCACTTGTATCCTCTGGTTCTTCATTTATTGAGCACCTACTACATG CAAGGCACTGTACTAGGCGTGAGAAGCATATAGAGGCAAGAAAGAGATACCAAGATGCCAT CTGTGTCCTGGTTAGCAGAGCTGGACCAGTGGTGCCTTGGAGGGATAAGCCAGCTGCAGCT GGGCTGTGTGGTTGACTTATGGGCCCAGCCAGCCAGGCTCAGGCCATGGCTCCCCTTTTTC 35 TTCCTCACCCTGATTTCTTGCTTATTCACTGAAGTTCTCCTGAAGAGGAACTGGGCCTGTTGC CCTTTCTGTACCATTTATTTGCTCCCAATGTTTATGATAATAAAGGCACCGCTGATGGGGACC TCC]ACTCTGTCTGTGTCTGAGGAGGAACTGGCGCTTTTGCAGAGGCTTACTCTGGGCTCTG

AGCTTGAACCAGTGTGGTCTGTGCTCAGGGCCCTGTGTTTCTGAACCGAGGGTGAGGATGT

WO 03/014319 PCT/US02/25268 74 TGGGGAGTTTTCCTTTGAGATCCGTACGTGGAGGGCAGCCATCTCTTGGAAGCCTGGGGGC CGGGGCATGCGGTGCAGACCCTCCTCCCTCACCTTCCACC 77. >MCP1_pro AGCGAGAGTCCAACCCAGGTTTGTGCCAGAGCCTAACCCAGGCTTGTGCCGAGATGTTCCC 5 AGCACAGCCCCATGTGAGAGCTCCCTGGCTCCGGGCCCAGTATCTGGAATGCAGGCTCCAG CCAAATGCATTCTCTTCTACGGGATCTGGGAACTTCCAAAGCTGCCTCCTCAGAGTGGGAAT TTCCACTCACTTCTCT[CACGCCAGCACTGACCTCCCAGCGGGGGAGGGCATCTTTTCTTGA CAGAGCAGAAGTGGGAGGCAGACAGCT[A/G]TCACTTTCCAGAAGACTTTCTTTTCTGATTCA TACCCTTCACCTTCCCTGTGTTTACTGTCTGATATATGCAAAGGC]CAAGTCACTTTCCAGAGA 10 TGACAACTCCTTCCTGAAGTAGAGACATGCTTCCAACACTCAGAAGCCTATGTGAACACTCA GCCAGCAAAGCTGGGAAGTTTTTCTCTGTGACCATGGGCTAATTGGTCTCCTTCTCTGGATT GTGGCTTTATCAGATAAAAACAAGTGGTCATGCCACAGGATGTCTATAAGCCCATTGATTCTG GGATTCTATGAGTGATGCTGATATGACTAAGCCAGGAGAGACTTA 78. >MCP1_01 15 TAGTTTCCTCGCTTCCTTCCTTTTCTGCAGTTTTCGCTTCAGAGAAAGCAGAATCCTTAAAAAT AACCCTCTTAGTTCACATCTGTGGTCAGTCTGGGCTTAATGGCACCCCATCCTCCCCATTTG CTCATTTGGTCTCAGCAGTGAATGGAAAAAGTGTCTCGTCCTGACCCCCTGCTTCCCTTTCCT ACTTCCTGGAAATCCACAGGATGCTGCATTTGCTCAGCAGATTTAACAGCCCACTTATCAC[T CATGGAAGATCCCTCCTCCTGCTTGACTCCGCCCTCTCTCCCTCTGCCCGCTTTCAATAAGA 20 GGCAGAGACAGCAGCCAGAGGAACCGAGAGGCTGAGACTAACCCAGAAACATCCAATTCTC AAACTGAAGCTCGCACTCTCGCCTCCAGCATGAAAGTCTCTGCCGCCCTTCTGTGCCTGCTG CTCATAGCAGCCACCTTCATTCCCCAAGGGCTCGCTCAGCCAGGTAAGGCCCCCTCTTCTTC TCCTTGAACCACATTGTCTTCTCTCTGAGTTATCATGGACCATCCAAGCAGA]CGTGGTACCC ACAGTCTTGCTTTAACGCTACTTTTCCAAGATAAGGTGACTCAGAAAAGGACAAGGGGTGAG 25 CCCAACCACACAGCTGCTGCTCGGCAGAGCCTGAACTAGAATTCCAGCTGTGAACCCCAAAT CCAGCTCCTTCCAGGATTCCAGCTCTGGGAACACACTCAGCGCAGTTACTCCCCCAGCTGCT TCCAGCAGAGTTTGGGGATCAGGGTAATCAAAGAGAGGGTGGGTGTGTAGGCTG 79. >MCP1_02 TCCCCAGCTGATCTTCCCTGGTGCTGATCATCTGGATTATTGGTCCGTCTTAATGACACTTGT 30 AGGCATTATCTAGCTTTAACAGCTCCTCCTTCTCTCTGTCCATTATCAATGTTATATACCCATT TTACAGCATAGGAAACTGAGTCATTGGGTCAAAGATCACATTCTAGCTCTGAGGTATAGGCA GAAGCACTGGGATTTAATGAGCTCTTT[G/CITCTTCTCCTGCCTGCCTTTTGCTTTTTCCTCAT[ GACTCTTTTCTGCTCTTAAGATCAGAATAATCCAGTTCATCCTAAAATGCTTTTTCTTTGTGGT TTATTTTCCAGATGCAATCAATGCCCCAGTCACCTGCTG[T/C]TATAACTTCACCAATAGGAAG 35 ATCTCAGTGCAGAGGCTCGCGAGCTATAGAAGAATCACCAGCAGCAAGTGTCCCAAAGAAG CTGTGATGTGAGTTCAGCACACCAACCTTCCCTGGCCTGAAGTTCTTCCTTGTGGAGCAAGG

GA]CAAGCCTCATAAACCTAGAGTCAGAGAGTGCACTATTTAACTTAATGTACAAAGGTTCCC

WO 03/014319 PCT/US02/25268 75 AATGGGAAAACTGAGGCACCAAGGGAAAAAGTGAACCCCAACATCACTCTCCACCTGGGTG CCTATTCAGAACACCCCAATTTCTTTAGCTTGAAGTCAGGATGGCTCCACCTGGACACCTATA GGAGCAGTTTGCCCTGGGTTCCCTCCTTCCACCTGCGTTCCTCCTCTAGCTCCCATGGCAGC CCTT 5 80. >MCP1_03 ACATCACTCTCCACCTGGGTGCCTATTCAGAACACCCCAATTTCTTTAGCTTGAAGTCAGGAT GGCTCCACCTGGACACCTATAGGAGCAGTTTGCCCTGGGTTCCCTCCTTCCACCTGCGTTCC TCCTCTAGCTCCCATGGCAGCCCTTTGGTGCAGAATGGGCTGCACTTCTAGACCAAAACTGC AAAGGAACTTCATCTAACTCTGTCCTCCCTCCCCACAG[CTTCAAGACCATTGTGGCCAAGGA 10 GATCTGTGCTGACCCCAAGCAGAAGTGGGTTCAGGATTCCATGGACCACCTGGACAAGCAA ACCCAAACTCCGAAGACTTGAACACTCACTCCACAACCCAAGAATCTGCAGCTAACTTATTTT CCCCTAGCTTTCCCCAGACACC[C/T]TGTTTTATTTTATTATAATGAATTTTGTTTGTTGATGTG AAACATTATGCCTTAAGTAATGTTAATTCTTATTTAAGTTATTGATGTTTTAAGTTTATCTTTCAT GGTACTAGTGTTTTTTAGATACAGAGACTTGGGGAAATTGCTTTTCCTCTTGAACCACAGTTC 15 TACCCCTGGGATGTTTTGAGGGTCTTTGCAAGAATCATTAATACAAAGAATTTTTTTTAACATT CCAATGCATTGCTAAAATATTATTGTGGAAATGAATATTTTGTAACTATTACACCAAATAAATAT ATTTTTGTACAAAA]CCTGACTTCCAGTGTTTTCTTGAAGGAAATTACAAAGCTGAGAGTATGA GCTTGGTGGTGACAAAGGAACATGATTTCAGAGGGTGGGGCTTACATTTTGAAGGAATGGGA AAGTGGATTGGCCCCGGTCTTCTCCACTGGGTGGTCTCCTCTGAGTCTCCGTAGAAGAATCT 20 TTATGGCAGGCCAGTTAGGCATTAAAGCACCACCCTTCCAGTCTTCAACATAAGCAGCCCAG AGTCCAAT 81. >CXCR3_01 CTGTCTCAGGCTTCCAAGTAGTTAGGACTACAGGCACATGCCACCATGCCCGGCTGGCTTTT TTTATTTTTGGTAGAGATGGAGCCTCGCTATGCTGCCCAGGCTGGTCTCAAACTCTTGGCCT 25 TAAGTGATCCTCTTGCCTCAGCCTCCCCAGTAGCTGGGATTACAGGAATGAGCCACTGCACC TAGCTGAAATTTTTAAGAAGGTGGATCTCCTCTGCAGACTTATTTCTCTACCCAGCCTTTACA ATCATGCAAAGATCAACTCAAGGCCAGGACAGATGAGTTCCAATCTATGGA[GCACTGACCCT ACCAGTGCAGGCAGTAGGGTTGCCCTTCACTTCTCAGCTGCATTGCTTCCTCTTCAGACCTC TCTTCTCAAAGGACCTGCCCCCAGCCAGTCATCCTCTGCCCAGCTTTTCTGGTCCCAAGCTT 30 GTAGCCAGCTCCTCCAGAGAGGTTTCACCCAGTCACGGAAACTCTGTGGCCTGAGGTTTAG GGAGGTCTGGTAGAGGTAACTCCCTGGAAGAGGCTGCTGCTGAGAACTGCCTGAAACTCCC ACTTCCTCTGTGACTGCAGGTTTCCAACCACAAGCACCAAAGCAGAGGGGCAGGCAGCACA CCACCCAGCAGCCAGAGCACCAGCCCAGCCATGGTCCTTGAGGTAAGTGCTGICTGCCCAG CCAGGCCAGGCCAGAATTCGAAGTGGAAAACCCGGGGCATCAGGGGAATGCCAGGGCTGG 35 CCCACAGCCCAGGGTCACCACAGGGTTGGGTGAGTAGCTGGAGGCCGCATGGGTTGTGGC AGAAACAGCACTGGGGAATTGGGAACCCAGCTTGGCCACTGACCCTGGGTGCCTCTCCTCT CCTCTCTGGCTTCGGTGTCTCGTCTGCAAAATGGGGGGGGCGGGGGGCAAGTAGACTCGA

AGGCTCCCTTCAGGAGACTTGGAACTTTGACTCTTGGCGTG

WO 03/014319 PCT/US02/25268 76 82. >CXCR3_02 GGAGAGCAGGGAGAGAGAGGACAGTGGGCAGAGAGGGCTCTGGGCACTGGAGGGACGCT CTTCTTCCTGCCCAGGGGTCCCTGGGCCGATGGGATCACGCAGAAGAATGCGAGAGAAGCA GCCTTTGAGAAGGGAAGTCACTATCCCAGAGCCCAGGCTGAGCGGATGGAGTTGAGGAAGT 5 ACGGCCCTGGAAGACTGGCGGGGACAGTTATAGGAGGAGCTGCTCAGAGTAAATCACAGAC TAAATCAGACTCAATCACAAAAGAGTTCCTGCCAGGCCTTTACACAGCCCCTTCCTCCCCGTT CCC[GCCCTCACAGGTGAGTGACCACCAAGTGCTAAATGA[C/TIGCCGAGGTTGCC[G/A]CCC TCCTGGAGAACTTCAGCTCTTCCTATGACTATGGAGAAAACGAGAGTGACTCGTGCTGTACC TCCCCGCCCTGCCCACAGGACTTCAGCCTGAACTTCGACCGGGCCTTCCTGCCAGCCCTCT 10 ACAGCCTCCTCTTTCTGCTGGGGCTGCTGGGCAACGGC[G/AICGGTGGCAGCCGTGCTGCT GAGCCGGCGGACAGCCCTGAGCAGCACCGACACCTTCCTGCTCCACCTAGCTGTAGCAGAC ACGCTGCTGGTGCTGACACTGCCGCTCTGGGCAGTGGACGCTGCCGTCCAGTGGGTCTTTG GCTCTGGCCTCTGCAAAGTGGCAGGTGCCCTCTTCAACATCAACTTCTACGCAGGAGCCCTC CTGCTGGCCTGCATCAGCTTTGACCGCTACCTGAACATAGTTCATGCCACCCAGCTCTACCG 15 CCGGGGGCCCCC[G/A]GCCCGCGTGACCCTCACCTGCCTGGCTGTCTGGGGGCTCTGCCTG CTTTTCGCCCTCCCAGACTTCATCTTCCTGTCGGCCCACCACGACGAGCGCCTCAACGCCAC CCACTGCCAATACAACTTCCCACAGGTGGGCCGCACGGCTCT[G/A]CGGGTGCTGCAGCTG GTGGCTGGCTTTCTGCTGCCCCTGCTGGTCATGGCCTACTGCTATGCCCACATCCTGGCCG TGCTGCTGGTTTCCAGGGGCCAGCGGCGCCTGCGGGCCATGCGGCTGGTGGTGGTGGTCG 20 TGGTGGCCTTTGCCCTCTGCTGGACCCCCTATCACCTGGTGGTGCTGGTGGACATCCTCAT GGACCTGGGCGCTTTGGCCCGCAACTGTGGCCGAGAAAGCAGGGTAGACGTGGCCAAGTC GGTCACCTCAGGCCTGGGCTACATGCACTGCTGCCTCAACCCGCTGCTCTATGCCTTTGTAG GGGTCAAGTTCCGGGAGCGGATGTGGATGCTGCTCTTGCGCCTGGGCTGCCCCAACCAGA GAGGGCTCCAGAGGCAGCCATCGTCTTCCCGCCGGGATTCATCCTGGTCTGAGACCTCAGA 25 GGCCTCCTACTCGGGCTTGTGAGGCCGGAATCCGGGCTCCCCTTTCGCCCACAGTCTGACT TCCCCGCATTCCAGGCTCCTCCCTCCCTCTGCCGGCTCTGGCTCTCCCCAATATCCTCGCTC CCGGGACTCACTGGCAGCCCCAGCACCACCAGGTCTCCCGGGAAGCCACCCTCCCAGCTC TGAGGACTGCACCATTGCTGCTCCTTAGCTGCCAAGCCCCATCCTGCCGCCCGAGGTGGCT GCCTGGAGCCCCACTGCCCTTCTCATTTGGAAACTAAAACTTCATCTTCCCCAAGTGCGGGG 30 AGTACAAGGCATGGCGTAGAGGGTGCTGCCCCATGAAGCCACAGCCCAGGCCTCCAGCTCA GCAGTGACTGTGGCCATGGTCCCCAAGACCTCTATATTTGCTCTTTTATTTTTATGTCTAAAAT CCTGCTTAAAACTTTTCAATAAACAAGATCGTCAGGACCAGGGCATGTTCGTGCATCA]TTAC AGTCAGCCCAGCCCACCTGGGCTCCAGGGGCACTTCCTGGTTCTCCCTGCCTGGCCCTGG GTCTGTGCCAGCCCATCCTGCCTTCATCAATGTCTGTCTGCAGCTTTGTCTCTGCCCTCGTG 35 GGCACTCCTGTTCTACTCACAGGGAAACACCCAAGTACATGGGTGCAGAGTGAGCAGTTAG GCAGCTGGTTGGCATAATTGGGGAAGGGGCCATCAGACATGAACACGAGAGCCCTGCACTC CAGCAGCTCAGGACAGGAGGCAAGATGTGTGTGAAACTAGCGAAACCCAGCAGCCTGGGC

CATGGGGCACATAAGTGGCACAGTGAACCCAG

WO 03/014319 PCT/US02/25268 77 83. >IL12A_01 TGATGAGTGAATGATTTGCCTACCCCTTCCAGTACTAGGCTGGAGGTCGTGGTTAGGGCCCA TCCCTACGCAGGACATGCAAAGTGGGAGGCACTCCTCTCTCTACGTCGGCAGGGGGCGCTG CACAGCTGCGGGGCGGGGTAGCTTAGACACGGGGCGTCCGGCTAAGGCCGGGGACCCAG 5 GGTGGTGGGCGGGGTGTCCCGCCCGCCTGTGGACCCCGCGCAGTAACTGCGAACATTTCG CTTTCATTTTGGGCCGAGCTGGAGGCGGCGGGGCCGTCCCGGAACGGCTGCGGCCGGGCA CCC[C/G]GG[GAGTTAATCCGAAAGCGCCGCAAGCCCCGCGGGCCGGCCGCACCGCACGTG TCACCGAGAAGCTGATGTAGAGAGAGACACAGAAGGAGACAGAAAGCAAGAGACCAGAGTC CCGGGAAAGTCCTGCCGCGCCTCGGGACAATTATAAAAATGTGGCCCCCTGGGTCAGCCTC 10 CCAGCCACCGCCCTCACCTGCCGCGGCCACAGGTCTGCATCCAGCGGCTCGCCCTGTGTC CCTGCAGTGCCGGCTCAGCATGTGTCCAGCGCGCAGTGAGTACTCAGCCCGCCAGGTCTTT GGCTCGCTCGGGTGCGGAGGGGCGGC]TGCTTGGGAAGAGTGGGTAGAAACTCAAGTCTGC CTAAGGAGAGACTGGAACAGCAGCAGCCGTCTCCTGCAAAGAGGAATAAGAATAGGGGTCT CACCGTGTGCTAAATAGGGCATGTCTCTTTTCATCTCGAAACAGCCTGATGAGCTATCATTAT 15 GCCCACTTCGTAGAGGAGAAACTGAGGCCCAGCGTGGGAGATTTCCTGCTTTCCTGCCTAG GGTCCCTCAGCTACAAACAGAAGGCAGATCCTAGCCAGTTCTAAAGTCAGGCTTGGCCGGG 84. >IL12A_02 TTCACCACCTGGTCTGGGTTTCCCTGATCAAAAACATGTAGGCTTTCTCTGGGTGAGTGTTG GGTTCAACACCCTTGTCCAAGCTCATCTCTAGACCCTCACAGGGAGCTGGCTTCTAGCCCTA 20 GAATAGAGTGGCGCTTTGTAATAACTCGAGTCATCTCTCAGGTGTTGAAGGAAAAGTGTTGG AAATGGGTTGAGGGAGGTGGGTGCCAAGCATGAATGGATGGGTG[AAGGTGGCCAGAATGG AGGGAAGGTGGTGCAGGCAGGCCATCCAGGCTGAAGCTCCTCCACCTGCTCCTCTTCCTTC CAGGCCTCCTCCTTGTGGCTACCCTGGTCCTCCTGGACCACCTCAGTTTGGCCAGAAACCTC CCCGTGGCCACTCCAGACCCAGGAATGTTCCCATGCCTTCACCACTCCCAAAACCTGCTGA 25 GGGCCGTCAGCAACATGCTCCAGAAGGTGAGCCTTTCCTGTCCTCTCCACTGTGGACCTGC ACCCTCCCTGAGGAAGGGGCCTCTGATCCTCCCCTCTGGITACCTGATGGAACTGCAGAGAA ATTGTGGAAGTTCATTAGCAGCTGTCAACAGCAGGAGAGGGAACTTTACAAATGGCCCAAGT GTTAAAGAGTCCTAGTGAAATTGTGTCTCCAGAGAAAGCAAGAGTAGTAATAAATTATAATGA TGTTGGTTTTGGCTATGTCTACACTGAGTAAAGTGGATATTTGCAGTGTTCCTGTAGCCTGCC 30 AACAGAGATA 85. >IL12A_03 GTGTCACAGTGAGGTGTGGAGGCTGGTTAGCACAGGCTGTTGACATGATTTATTGTGTTTAC ATAATGAAAAAATATGTAATCCAGAGAAACATGCCCCAAGCTTAGGGAGAGGAGGGTGAGAG ACAGAATGTAAGGAATCTATTTTCTTTTGTATTATGAAGAACCAGAATTTCCTGCAAGTCAAAG 35 TGACAGAGGTCAAGGGCAGCCAGCCGGAGCCT[TCCTGGCACCCTGGCTTACCAGCCTTGT GGGGTGCCAGGTGCATTATCAATGTTATAAACTGAGTTTCTCCTTCATTTTTTATAGGCCAGA

CAAACTCTAGAATTTTACCCTTGCACTTCTGAAGAGATTGATCATGAAGATATCACAAAAGATA

WO 03/014319 PCT/US02/25268 78 AAACCAGCACAGTGGAGGCCTGTTTACCATTGGAATTAACCAAGGTATAAAGGATTTCCTCC CAGAGCATGCAGTGTGGTTAAAAACTGTGCATCAAATCTCACCTGCTTCTAAAAATTCACGTT] TCTGTATCCATCATTATGGATTTTAACTGTCCTACTTCAGAAGTTAGATTTGGGAGAAAAATTA TTTTTAAAAAATGGTTTTTTTTGCAACAATGTGAATACACTTAACACTTAAAAATAGTTCAGATG 5 CTAAATATTATGATATGTGTTTTTACCATAATAAAAAAAATTTGAGACCTGAAGAGTCAGAG ATTTATA 86. >IL12A_4,5 GTGGTTAAAAACTGTGCATCAAATCTCACCTGCTTCTAAAAATTCACGTTTCTGTATCCATCAT TATGGATTTTAACTGTCCTACTTCAGAAGTTAGATTTGGGAGAAAAATTATTTTTAAAAAATGG 10 TTTTTTTTGCAACAATGTGAATACACTTAACACTTAAAAATAGTTCAGATGCTAAATATTATGAT ATGTGTTTTTACCATAATAAAAAAAATTTGAGACCTGAAGAGTCAGA[AAGATTTATACTAAGAA TTAATACTTTGATATATGATTTTTTCCCTCTAGAATGAGAGTTGCCTAAATTCCAGAGAGACCT CTTTCATAACTGTAAGTCAAAAAATGAAAAGTTTCAGCCTGTATGATGAATTCATATCACTGAT GTCTGATTATTTTTTCCTCTAGAATGGGAGTTGCCTGGCCTCCAGAAAGACCTCTTTTATGAT 15 GGTAAGACACACAGCTCTTTCCTCAAATGCAATGGGGGAAATGTTTTTAGCC]CATCTCAATG GATACTTCCCCATCTTGTCATGTCACCCAGGCCCTGTGCCTTAGTAGTATTTATGAAGACTTG AAGATGTACCAGGTGGAGTTCAAGACCATGAATGCAAAGCTTCTGATGGATCCTAAGAGGCA GATCTTTCTAGATCAAAACATGCTGGCAGTTATTGATGAGCTGATGCAGGTAAGACTTCATTC TA 20 87. >IL12A_06 GCCTAAATTCCAGAGAGACCTCTTTCATAACTGTAAGTCAAAAAATGAAAAGTTTCAGCCTGT ATGATGAATTCATATCACTGATGTCTGATTATTTTTTCCTCTAGAATGGGAGTTGCCTGGCCT CCAGAAAGACCTCTTTTATGATGGTAAGACACACAGCTCTTTCCTCAAATGCAATGGGGGAA ATGTTTTTAGCC[CATCTCAATGGATACTTCCCCATCTTGTCATGTCACCCAGGCCCTGTGCC 25 TTAGTAGTATTTATGAAGACTTGAAGATGTACCAGGTGGAGTTCAAGACCATGAATGCAAAGC TTCTGATGGATCCTAAGAGGCAGATCTTTCTAGATCAAAACATGCTGG.CAGTTATTGATGAGC TGATGCAGGTAAGACTTCATTCTATCAGTGAGAGCACCTTTTTCATGCTAAAGATAACCAGCC AGGGTCTTTGATAAAGAGATATAAAAAGAGGTCTGGAGGCCTTTTAAAGGCCTGACAGACCT ACATTTTCAAGAAGACAGCCTTGAGGGTGCCGTCTATAGGGAGCACAAATGTGAGCAGATCA 30 CATTATGAAAAGCAGACTCCAAAGTATTCACTCTGTGGTATCCCCCACACTCGGCAAATGTTT TTGTGCATTTTCTTATGTCAGCCTCAAAACAACCATATGGGATCTGCACAGGAGGGAACCA AACCTTAGGAG 88. >IL12A_07 AGATGTCATTTTAAAGGAACTGTTTCTTTCTAAGACACAACTCCCACTGATGATTTTTTCTAAA 35 TAGTTTTAAGGGTCTTTTCAGAGCTCATTGAAGATGGATGTGCTTGGAAAATGAGTATTTCTTT TCTCATTCTGCCTGGTGATCTGGCTGAGAGTAGATTTGGATTGGGTTTAGGAGTGGCATAAG

GGACTGAGTTGCAGGCTCTGAGACATGTACTGGCTTCACTCATTTTTATGAATGAATATTTGA

WO 03/014319 PCT/US02/25268 79 ATTTTGGAATACCATGTAAGTCATGC[TTACTGTTCATTCTCCTAGGCCCTGAATTTCAACAGT GAGACT[G/A]TGCCACAAAAATCCTCCCTTGAAGAACCGGATTTATAAAACTAAAATCAAGC TCTGCATACTTCTTCATGCTTTCAGAATTCGGGCAGTGACTATTGATAGAGTGATGAGCTATC TGAATGCTTCCTAAAAAGCGAGGTCCCTCCAACCGTTGTCATTTTTATAAAACTTTGAAATGA 5 GGAAACTTTGATAGGATGTGGATTAAGAACTAGGGAGGGGGAAAGAAGGATGGGACTATTA CATCCACAT[A/G]ATACCTCTGATCAAGTATTTTTGACATTCACTGTGGTTANATTGGTTTTAAG CCCTCATGAATGAATTGCTAAGAAGGTATTATATCCATCCTGAAGGTGTTTTTCATTCACTTTA ATAGAAGGGCAAATATTTATAAGCTATTTCTGTACCAAAGTGTTTGTGGAAACAAACATGTAA GCATAACTTATTTTAAAATATTTATTTATATAACTTGGTAATCATGAAAGCATCTGAGCTAACTT 10 ATATTTATTTATGTTATATTTATTAAATCATTTATCAAGTGTATTCTGAAAAATATTTTTAAGTGT TCTAAAAATAAAAGTATTGAATTAAAGAGATTCTGCAATTTTT]CTAATGTACTTTTAAGTGTTAA AATA[C/T]ACATTGTGGGAAAATTGAAAACTCTGATGAGACTTAACAAAATTACTCTGGAAAGA ATGCCACAATATTCTTATTCCTTTCCTAGTCCCTTTCATCTCATTTTAAAGGGACCCTAGTAAG ACAAGATATGCTTTACTACTAAGGCAGCCAAGTGAGTCATGGTTTTTGAGGGTTTATTATTTTT 15 GTTCAACATAAGACTAAAAGTATGCTGTGCATTAGAAAAATACTTCATAGTATTCTTCAACC 89. >IP1001 AACTGTAAAAGTTTAAGTGTTGAGAAAAAGCATTATAGTTAGAATGGATTGCAACCTTTGTTTT TTTCTATATGCAATGAAGTTCTTTTTTTCAAGAAACAGTTCATGTTTTGGAAAGTGAAACCTAA TTCACTATTACCAAAAAAAGAGGAGCAGAGGGAAATTCCGTAACTTGGAGGCTACAATAAATA 20 ATACCCTTCGAGTGCCAACATGGGACTTCCCCAGGAACAGCCAGCAGGT[TTTGCTAAGTCG ACTGTAATGCCCTTATCCAATCAGAATTAGGGAGGGAAAATGGCTTTGCAGATAAATATGGCA CACTAGCCCCACGTTTTCTGAGACATTCCTCAATTGCTTAGACATATTCTGAGCCTACAGCAG AGGAACCTCCAGTCTCAGCACCATGAATCAAACTGCCATTCTGATTTGCTGCCTTATCTTTCT GACTCTAAGTGGCATTCAAGGTAAGGAACATCAAAGGATACTTAATTTGTAAAATGAGAAATA 25 GGAATAGGTATAAATTCTAAAAATACAGAAATAATG]TATTTGTAAAAGTTTCACTGCATGCTTA TAAATAAGAGGGAAATAAATAGAGATTCCCTCAGATCATAAAACTTATATGAATTGAAGTGAG AGAAACAAATAGAATAAGAGAAAGAGAAGGAAAAAGGGAAGGAGGACAGAAGAGATGGGGA AGAGGGAGGATAGAGAGAGAAAATGTGAGGGAATGCGGACAGAGATGAGATACAGATACTT CCTTACCTAACTAAGCTCAATGAACCACATGAACTGTGCTTAAGGGTTTGACTTTATAATCAA 30 CAAGCTGCAATTCTTTTCTTCCAG 90. >IP1O_02 GAAAAAGGGAAGGAGGACAGAAGAGATGGGGAAGAGGGAGGATAGAGAGAGAAAATGTGA GGGAATGCGGACAGAGATGAGATACAGATACTTCCTTACCTAACTAAGCTCAATGAACCACA TGAACTGTGCTTAAGGGTTTGACTTTATAATCAACAAGCTGCAATTCTTTTCTTCCAGATAATC 35 AACTCTTTAATCATTTACAGTTGTGTTATGATGTGATCCATTCCTCCTCAGATTAAGTGACTAT TTGCTGATATGGGGATATAGGTTCTGCTAAATACCACCAGTCTACATTAA[ATGCCTAAAATGA ACACTGTGCTAACCTTCTCTGCTGTTCCTCTTTTCCTACAGGAGTACCTCTCTCTAGAACTGT

ACGCTGTACCTGCATCAGCATTAGTAATCAACCTGTTAATCCAAGGTCTTTAGAAAAACTTGA

WO 03/014319 PCT/US02/25268 80 AATTATTCCTGCAAGCCAATTTTGTCCACGTGTTGAGATCATGTGAGTGAAATCCCATCTGAT TATCACTTCCCTGGTTGTAATTATATACTGTATTAAAT]ATGTAATGATAATAAAAAAAGATCAG TAAAGGGTTTGTGATGATTCTAAAACTAATGTACAGCAAACAAAAACATGCAGAGTGAAACTT AAATGTCTGACTTCAGAACTGCGTATGCCATCTGTTTTATTGACCCAACACAGTTTTAAATATT 5 TTCATCCCTATTTATTTCTACAGTGCTACAATGAAAAAGAAGGGTGAGAAGAGATGTCTGAAT CCAGAATCGAAGGCCATCAAGAATTTACTGAAAGCAGTTAGCAAGGAAAGGTAGGTTTGCTG TTGCCTGCAGCCGAATTGCTCT 91. >IP1003 CTCTCTCTAGAACTGTACGCTGTACCTGCATCAGCATTAGTAATCAACCTGTTAATCCAAGGT 10 CTTTAGAAAAACTTGAAATTATTCCTGCAAGCCAATTTTGTCCACGTGTTGAGATCATGTGAG TGAAATCCCATCTGATTATCACTTCCCTGGTTGTAATTATATACTGTATTAAATATGTAATGATA ATAAAAAAAGATCAGTAAAGGGTTTGTGATGATTCTAAAACTAATGTAC[AGCAAACAAAAACA TGCAGAGTGAAACTTAAATGTCTGACTTCAGAACTGCGTATGCCATCTGTTTTATTGACCCAA CACAGTTTTAAATATTTTCATCCCTATTTATTTCTACAGTGCTACAATGAAAAAGAAGGGTGAG 15 AAGAGATGTCTGAATCCAGAATCGAAGGCCATCAAGAATTTACTGAAAGCAGTTAGCAAGGA AAGGTAGGTTTGCTGTTGCCTGCAGCCGAATTGCTCTTTAGGAAACGGCAATCTTGGGAGTC AGAA]ATACTTGCATTGTGGTTTGTGCTGCAATCGCTGGTTTAAAAGTATGTTACCACCACGC CCTCCCCTACCTCCATTTATTTAAATGCTGAGGCACCATCTTGTGTGATAAGTATCAGAAGTT ACCCTGATTACCAGTCAACCTTGAAGTACAGCTATAACTATCTAAGCAAAACTGACAACATTT 20 TCCCCAAGTCTTTCATGGTTGAAAAAAGCAACCCCTATAATCCATAATGAATGCATAGCAGCA GGAAAGCTCAGTTATCTATTCTATGAACTCGGTACTTTCCAAACACAACCCAATCTGAAGCCA GAGTCAGA[C/G]TATCACACTTTT 92. >IP1O_04 TTAGGAAACGGCAATCTTGGGAGTCAGAAATACTTGCATTGTGGTTTGTGCTGCAATCGCTG 25 GTTTAAAAGTATGTTACCACCACGCCCTCCCCTACCTCCATTTATTTAAATGCTGAGGCACCA TCTTGTGTGATAAGTATCAGAAGTTACCCTGATTACCAGTCAACCTTGAAGTACAGCTATAAC TATCTAAGCAAAACTGACAACATTTTCCCCAAGTCTTTCATGGTTGAAAAAAGCAACCCCTAT AATCCATAATGAATGCATAGCAGCAGGAAAGCTCAGTTATCTATTCTATGAACTCGGTACTTT CCAAAC[ACAACCCAATCTGAAGCCAGAGTCAGA[C/G]TATCACACTTTTATATCCCCTTTCTC 30 TTCTTACAGGTCTAAAAGATCTCCTTAAAACCAGAGGGGAGCAAAATCGATGCAGTGCTTCC AAGGATGGACCACACAGAGGCTGCCTCTCCCATCACTTCCCTACATGGAGTATATGTCAAGC CATAATTGTTCTTAGTTTGCAGTTACACTAAAAGGTGACCAAT[G/CATGGTCACCAAATCAGC TGCTACTACTCCTGTAGGAAGGTTAATGTTCATCATCCTAAGCTATTCAGTAATAACTCTACC CTGGCACTATAATGTAAGCTCTACTGAGGTGCTATGTTCTTAGTGGATGTTCTGACCCTGCTT 35 CAAATATTTCCTCACCTTTCCCATCTTCCAAGGGTACTAAGGAATCTTTCTGCTTTGGGGTTTA TCAGAATTCTCAGAATCTCAAATAACTAAAAGGTATGCAATCAAATCTGCTTTTTAAAGAATGC TCTTTACTTCATGGACTTCCACTGCCATCCTCCCAAGGGGCCCAAATTCTTTCAGTGGCTACC

TACATACAATTCCAAACACATACAGGAAGGTAGAAATATCTGAAAATGTATGTGTAAGTATTCT

WO 03/014319 PCT/US02/25268 81 TATTTAATGAAAGACTGTACAAAGTAGAAGTCTTAGATATTGTTTTCAGTGTACATGGAATAAC AATGTATATATTTCCTTGTAATTAAGTACTATGTATCAATGAGTAACAGGAAAATTTTAAAAATA CAGATAGATATATGCTCGCATGTTACATAAGATAAATGTGCTGAATGGTTTCAAAAATAAAAA TGAGGTACTCTCCTGGAAATATTAAGAAAGACTATCTAAATGTTGAAAGA[T/C]CAAAAGGTTA 5 ATAAAGTAATTATAACTAAGATGAAGTGCCTTGTGTGITCACTTGGTTGGGATATTTATTTCATA AGAAACTTAGATTGGAGAAATCTATGGCCTGGAGAAGAAGGTGGCATGGGCAGAAGACAAAT GAGTTAGAGAATTACCACTCTCTCTCCTTCCAACTGTAATCTCCTGAAAGGCCCATCATATAA GATCCTACAGAACTAATGTAGCATAACAGAGCTTGGCCTAATCTCCAAATCCCTATAGCCAAA TTTCTTTTTTTTTTAATCTCTTATTTTTTTAGACACAGGGTCTTCCTCTGTCACCCAAGCCGGA 10 GTGCAATGGTGCAATCATAGCTCACTGCAGCCTCGAAACTCCTGGGCTCA 93. >NOD2_EXON1 TTAGTGAGAACAGCACTAAGGCCAGGTTCTCCTCCCCAGATGTTTAAGATGAGACAGGACAA TGCCTGCTCAGAGACAGGGCCTGGCTGAATTGGCCCTCAGGATTCTCTCTGCTCTGAGGTTT CTGGAAGAAGGCCAGGGCAGAGGTGTGGTGATGTAGCTGCTGGGAGGACAGAGCTCCGAG 15 TCACGTGGCTTGGGCGGGCCTCCCCTTCCTGGTGTCCACAGAAGCCCAACGTCACTAGCTG GGGTGTGTATGGCTCACACGTAGGCCAGGCTGCCCTAGGCTTGGTGTGCAAGGGAggggcccc tacttacttgtggcctgtcccctogtgaatgtgtctcatgtccccagtggggtttttcagtgagggtcatggtctccaggatgcacaaggctTT GTGCCAGAATTGCTTGGAATTGCCTAGTTCTGGAAGGCTGGTTGGCCAACTCTGGCCTCCG GCTTTTCCTTTGGGAATTTCCCTTGAAGGTGGGGTTG[GTAGACAGATCCAGGCTCACCAGTC 20 CTGTGCCACTGGGCTTTTGGC[G/A]TTCTGCACAAGGCCTACCCGCAGATGCCATGCCTGCT CCCCCAGCCTAATGGGCTTTGATGGGGGAAGAGGGTGGTTCAGCCTCTCACGATGAGGAGG AAAGAGCAAGTGTCCTCCTCGGACATTCTCCGG]GTAAGAGGAGCAGGCATTGTCCCGTCCC AGCTTGATCCTCAGCCTTCTTTCATCCTTGGCCGCGACATGCTCCCAGGCCTGGGGTCAGAT GGGGAGTGCTGACTCTGTTTCTGGGCTGTTTTCTGGGGAGAATGGGTCGGCGGGTTTTTTTC 25 CCCAGGACCTGGGCAGGGTCAATGGTGGGGGCCGCTGTCGCATCCTTGGCTGGTGTTTCC ACAGCTGAGAACCACTCCAGGGCCAAGCCCAGAGCTTATTCTACCCTTTTTTGTCCTCTCTTC CCCTGTCCTCGGCCACCCCACCCTCTTGGCTCCTCTGCTTAGATGTGGGCACAAGGAGGAG AACTCCTTGGCCTGAGAGAACTACCTTAGATCCTGGCTTCCAGTGGCCTCTGCAGGGGGGT ACACCCTCTCTCCCAAGCAGCCAGACACACAAGTAACCTCATTGCCTCAGTTTCCCCATCTG 30 ACCAGCACAGGGC 94. >NOD2_EXON2 GGCTAATTTTTGTATTTTTAGTAGAGACAGCGTTTCACCGTGTTGGCCGGGCTGGTCTAGCG CTCCTGATCTCAAGTGACCTTGGGAGATCTCTTGCTCCTAATATTACCTCAAGCCTTTTTAAA CGTTTTAAGCCGGAGACCAAGCATGGATATGGGAGTTAGGGGTCTTGATTTAATTCTTGGTT 35 GCTTCAAACTCTGTGGAACCTTGAGGTGTTTCTTGCCTTCTCTGGGTCTCAATTTTCACATCT ATATGGTGGGGAGCTTGGATTGGGTAATGTCTGAGGCTAGAACCATGGCCAACTCGGGTTC

TGCTGGGGCTGACTTGCCCTGGCCTTCCCTGACCACCCTGCATCTGGCTTCTGGAGAAG[T/

WO 03/014319 PCT/US02/25268 82 G]CCC[G/TICACTGACCTTGTTCTCCTCCCCAG[GTTGTGAAATGTGCTCGCAGGAGGCTTTTC AGGCACAGAGGAGCCAGCTGGTCGAGCTGCTGGTCTCAGGGTCCCTGGAAGGCTTCGAGA GTGTCCTGGACTGGCTGCTGTCCTGGGAGGTCCTCTCCTGGGAGGACTACGAGGGCTTCCA CCTCCTGGGCCAGCCTCTCTCCCACTTGGCCAGGCGCCTTCTGGACACCGTCTGGAATAAG 5 GGTACTTGGGCCTGTCAGAAGCTCATCGCGGCTGCCCAAGAAGCCCAGGCCGACAGCCAG TCCCCCAAGCTGCATGGCTGCTGGGACCCCCACTCGCTCCACCCAGCCCGAGACCTGCAGA GTCACCGGCCAGCCATTGTCAGGAGGCTCCACAGCCATGTGGAGAACATGCTGGACCTGGC ATGGGAGCGGGGTTTCGTCAGCCAGTATGAATGTGATGAAATCAGGTTGCCGATCTTCACAC CGTCCCAGAGG]GTGAGGCACTCCTGGTGTGCATCACAGAGTTCTCAGGAAAGGGGTGCTTA 10 GTCACCAAGACTGATTTGTCCTCATGAAGTCAGCCTGTGGGGTAACTTGGTCCATGGGATTT CCCCTAAAAAGGTAGCCAGGCAGGTAAAATTTGCTCTTGACTCTTGGCAGGAAACGTACAAC TCTTTCTTTCTTCTTTTCTTTTCTTTTTCTCACTCTGTTACCCTGGCTAGAATGCAGTGGCACA ATCATAGCTCACTGTAGCCTTGAATTCCTGCGCTCAAGTGATCTTCTGGCCTTAGAGTAGCTG GGACTACGGCTGCTGTACCACCATGAACAGCTAATTTTTTTTTTTTCTTTTAGAGATGGGGTG 15 TTGCTATGTTGCCCAGGCTGGTCTCCAGCTCCTGGCTTTAAGCAATCCTCCCGCCTTGGCCT CCCAAACTGTTGGGATTGCAGGCATGAGCCACTTTGCCTGGCCAACAGAACACTTCTG 95. >NOD2-EXON3 CAGGTGCATGGGCAGGTTAGGAGTTTAGTTTTGAATATGTTGGAGGTGTTTATGAAACTTTTA AGTGGAGATGGAAAATAGGCAGTTGGATGTGCAAGTCCAGGGTTCAGGGAGACAGTTCAGG 20 CTGGAGATGAAGATGTGGGAGTCTGAGGAGAGATTGTATTCAAATATTCAATCCATGAGACT TGATGAAATCACTTCTCTTCCAAATGATTTACAGCCTGCAGAATCATTTTCCCTATCTTTGTAG GTTTATGTCTTCATTTTGTTTCATTTATTTTTCAGTTATTCACTGTTTTAGTGAGTTTTGAGTAG GAGCCAGATTGGATGCATGCGTTCAATTCACCATCCAACACTGTATTAACTACTTGAAACTCA TGTGGTTGTTCGGTTGTTTTTTTGACCTTTTATTCTGGATGGAAGAGAGATGCTTATGAAGTT 25 GCAGTAATCAGTAAGCCTTCCCACATTGCTCCATCAGCCTTCCTGGAAGAATAATGTCTTCTG CCTTTCCTGTAG[GCAAGAAGGCTGCTTGATCTTGCCA[C/T]GGTGAAAGCGAATGGATTGGC TGCCTTCCTTCTACAACATGTTCAGGAATTACCAGTCCCATTGGCCCTGCCTTTGGAAG1GTA GGTGTATGTTCTCAGTTAATCAGAAAGGGAAGGGCAGTCAGTGCAGATCCATGGTTAAGAGC AGAACACACCTCGGTTAACATCCCATATGCTGGCAGTATAGCCTCCCTATGACTCAATTTCCT 30 TGTTTTAAGGCTAGCACCACCCCGTCTCATTGGGATTTTGGGAGCATTAAAAGGACAAAAGC GTGTAATGTTAGCTATTAGCTTTCATTATCTCCCACACAGTATACTGACAATTGGGCTACCATA TATTGAGGGCTAACTAAAGGTGTTACTTACCATCCAAACTCTCATTATCTGTACCGAAAAGAT ATGGACACATGTTTTGAGTTAGGGCTGGTATCTCTTGATCTCTGAAATTTAGCAGCTCACAAT GGGAAACTCAAGAACCAAGTGGATCTAGAGACTCTGGTATCCCTCAGTGCCCAGGGTCACC 35 ACCCAAACTCAGGAACAGGAGGGGCTTGGACCGCACC 96. >NOD2_EXON4 WO 03/014319 PCT/US02/25268 83 ACCCCGAGGCCTTCCCTTGCTAGGTCCACCCAGATCAATCAGGATCATCTCCCCATCTCGAA GTTTAACTTTATCACATCTCAGAGTTCCTTTTGCCACGTAAGGTAACATATTCACAGGTTCTGA GAATCCGGACATGGACATCTTTGAGGGTCTATTGTTGTGCCTACTATATCCATGAATAATAAT GATAATAAGCACCATTTTTTGAGAGTTTGCCATGTCAGATATTCTTTTAAACTGTATTTTATCTC 5 GCTGCCTCCTGAAAAAATCCTTCCAGGTGTATATTGTCCCCATTTTTACAGATGAGAGAACTG AGGCCCAGAAAGGCTAAATGGCTTGCCCAAGTGTATGGTGGACCCAGGTTTTCAAACTCAG GTGTGTCTGGCTTCAGAGACTGGGCTCCTGAGCCCTTAAGCCCTTTGTTCCCCTTTAGAAAA AGTCACCTGAGGCTGAGTGGTGAAGGGATTTATCCAAAGCCACCCGGCCACTATGGCAGGA CAGATATCAGAATACAGGTCTTCCGATCCCAGCCCAGAGCCCCTTCCCGTCATCTAGAACTC 10 CTCCTGGTGTCAGTAATGATAACGGCAGTCACTGATGTCTTTTGAGCACTTACTTTGTGTTGA GCACTTACACTGTGCTAAGCACTTGACATAGGTCATCTTAGTTGATCCGTGTAAAACTCTGTG AGGTAGTGACCAACATTTCTCCCACCTTACAGAGGTGGAAACTGAGGGTTAGGAAGTTTCCT TGACTGTCCTCAAAGTGCACAGCTTGTGAATGGAGGAGCCAGGATGGGCGCCCGCTGGCTC TCCTATCCCTTCAGTTATGTCAGCGTCCCCCGCAGCAGCCCATTGTCTGGTTAGGTCCCGTC 15 TTCACCATGGTGCCACCTTCATCTGCCTCTTCTTCTGCCTTCCAG[CTGCCACATGCAAGAAG TATATGGCCAAGCTGAGGACCACGGTGTCTGCTCAGTCTCGCTTCCTCAGTACCTATGATGG AGCAGAGACGCTCTGCCTGGAGGACATATACACAGAGAATGTCCTGGAGGTCTGGGCAGAT GTGGGCATGGCTGGA[C/T]CCCCGCAGAAGAGCCCAGCCACCCTGGGCCTGGAGGAGCTCT TCAGCACCCCTGGCCACCTCA[A/G]TGACGATGCGGACACTGTGCTGGTGGTGGGTGAGGC 20 GGGCAGTGGCAAGAGCACGCTCCTGCAG[C/T]GGCTGCACTTGCTGTGGGCTGCAGGGCAA GACTTCCAGGAATTTCTCTTTGTCTTCCCATTCAGCTGCCGGCAGCTGCAGTGCATGGCCAA ACCACTCTCTGTGCGGACTCTACTCTTTGAGCACTGCTGTTGGCCTGATGTTGGTCAAGAAG ACATCTTCCAGTTACTCCTTGACCACCCTGACCGTGTCCTGTTAACCTTTGATGGCTTTGACG AGTTCAAGTTCAGGTTCACGGATCGTGAACGCCACTGCTCCCCGACCGACCCCACCTCTGT 25 CCAGACCCTGCTCTTCAACCTTCTGCAGGGCAACCTGCTGAAGAATGCCCGCAAGGTGGTG ACCAGCCGTCCGGCCGCTGTGTCGGCGTTCCTCAGGAAGTACATCCGCACCGAGTTCAACC TCAAGGGCTTCTCTGAACAGGGCATCGAGCTGTACCTGAGGAAGCG[C/T]CATCATGAGCCC GGGGTGGCGGACCGCCTCATCCGCCTGCTCCAAGAGACCTCAGCCCTGCACGGTTTGTGC CACCTGCCTGTCTTCTCATGGATGGTGTCCAAATGCCACCAGGAACTGTTGCTGCAGGAGG 30 GGGGGTCCCCAAAGACCACTACAGATATGTACCTGCTGATTCTGCAGCATTTTCTGCTGCAT GCCACCCCCCCAGACTCAGCTTCCCAAGGTCTGGGACCCAGTCTTCTTCGGGGCCGCCTCC CCACCCTCCTGCACCTGGGCAGACTGGCTCTGTGGGGCCTGGGCATGTGCTGCTACGTGTT CTCAGCCCAGCAGCTCCAGGCAGCACAGGTCAGCCCTGATGACATTTCTCTTGGCTTCCTG GTGCGTGCCAAAGGTGTCGTGCCAGGGAGTACGGCGCCCCTGGAATTCCTTCACATCACTT 35 TCCAGTGCTTCTTTGC[C/T]GCGTTCTACCTGGCACTCAGTGCTGATGTGCCACCAGCTTTGC TCAGACACCTCTTCAATTGTGGCAGGCCAGGCAACTCACCAATGGCCAGGCTCCTGCCCAC GATGTGCATCCAGGCCT[C/T]GGAGGGAAAGGACAGCAGCGTGGCAGCTTTGCTGCAGAAG

GCCGAGCCGCACAACCTTCAGATCACAGCAGCCTTCCTGGCAGGGCTGTTGTCCCGGGAGC

WO 03/014319 PCT/US02/25268 84 ACTGGGGCCTGCTGGCTGAGTGCCAGACATCTGAGAAGGCCCTGCTC[C/T]GG[C/T]GCCAG GCCTGTGCCCGCTGGTGTCTGGCCCGCAGCCTCCGCAAGCACTTCCACTCCATCCCGCCAG CTGCACCGGGTGAGGCCAAGAGCGTGCATGCCATGCCCGGGTTCATCTGGCTCATCCGGA GCCTGTACGAGATGCAGGAGGAGCGGCTGGCTCGGAAGGCTGCACGTGGCCTGAATGTTG 5 GGCACCTCAAGTTGACATTTTGCAGTGTGGGCCCCACTGAGTGTGCTGCCCTGGCCTTTGT GCTGCAGCACCTCCGGC[G/AIGCCCGTGGCCCTGCAGCTGGACTACAACTCTGTGGGTGAC ATTGGCGTGGAGCAGCTGCTGCCTTGCCTTGGTGTCTGCAAGGCTCTGTA]GTGAGTGTT[Al C]CTGGGCATTGCTGTTCAGGTATGGGGGAGCACCATCAAGGCTAAGTGTGGGAGCACCGA GCTGGGCTCTAGAAGTCTGGGCCCAGCTTCGCCTCTGCCACCCTGCTTTGCAACACTGCCC 10 AGATCCCTTCCCTTCTGGGCCTTAATTTCAATATGTGATGATGACAGCCACACTTTATTGACT GGCCTATGTGCTGGGTCTGGTGCTATGCTTTCCGGAATGACCTCATCTAATCTCTACAACCA CCCTGGCGGGTAGGCAGGAATGTTATTATCTCCATTATCCTTGACTTGAGGCTCAGAGAAGT GAAGTAACTTGTCCAGGAAATGGCAGAGCTGGGGTTCACAAATTGCATCATTCTGATTACAG GTTTTCTGCCTCCCACCAGTCTATGGATACACTTCAGAGGCTCCCTGAAAACCTTGAGGTCA 15 CTTGCAGAAAGTTTTGTGTAGTATGTGTCCGTATCAGGAACAACACCAAATCAGAGGTGACTT GTGCCCCATCAGAGACTTTAACACCCCAACCAGATGGGAATTTCAGGACCCAAGAAATAGAA AGTGGCTGCAGGGTTACAACTACTGTTGGATTCCTGAGGTAGCACAGTGTCCAAACAGGATT TCAGCACTACCCGTATTGCTTAGAGCCCCAGCCAAAGATGTGAGGTTTTGCCCTTTGGAGAA TCTGTGCCCCTGAACTCGGGGGCCTCTTTCCACATCTTGGGGGCAGGCAAGGGCAGAGGGT 20 GTGCCTAGGCCTGCGGATCAGCATGCGACAGATTCCCCAACATCCTTCCAGCTTGAAAGGG GAT 97. >NOD2_EXON5 TCATCCAGCTGGTCTACTGTCTGCTGACCTAGATGATGGTAAATTGTCCCCAGGGGTAGCCT GTCTAGTTCAGGCTGCACCTTTCGCATATATCAGCTCCTTTCCACCATCATCCCCTTTGTGAG 25 GCTGCTGTGATTATCATGTTCCTTTTGCAGAGATGGAAACATTGCCTCAAATTAGCTCTGTCA TTTCCTAAGGATTCCAGGGTTCTTTAGTAGGGGGTCTGGATCCTACGTCCTGGGCCATCCCC ATCATAGTGCACCACGTCACCTCCCTGGCCAGGGACCGTGGGGTCTCCACTTTTTTGGGGT GCTCCATCTATGCAGGGTTTCCTGGAAGCACAGATGCTGGCACTTCAGGGATGAATGAAAGT CTTTTTGGGGGATTTGTAGATTTTTTTCTTGTCTTACTAGCTCCATTTTCAAATGTATTTATTTT 30 GTCTCTTTAG[TTTGCGCGATAACAATATCTCAGACCGAGGCATCTGCAAGCTCATTGAATGT GCTCTTCACTGCGAGCAATTGCAGAAGTTAG]GTAAGTCAGCCTGGGCTGTGGACAATGGG CTCCAAGTGCCCTGGTCTCACCCCAGGTCGTGCAGCCTGGGAAGCTGTGAGTGATGGGCTG GGGCAGGGGCTGTTTGCATGATGGGGGGTGCAGGTGATTCCTGCCCAGAGGGGAAGGGCA ACCCTGGGATTTGGTGCTCACTGTCCAATGTGCTTTGCTTCTGTGTCTCCTCTCTTCTGGAAC 35 TGAACAGTCTATTCAACAACAAATTGACTGACGGCTGT[G/A]CACACTCCATGGCTAAGCTCC TTGCATGCAGGCAGAACTTCTTGGCATTGAGGTGAGCCCAGGTTTTCCTTATTCCCTGGAAA

CTATTTTTTGCCCCATTCCTGAGTCAGTCTGATCTGGTCTTGGCCTGGCACTGCCCACACTG

WO 03/014319 PCT/US02/25268 85 GCTCCTGACCTCCTGATTGAATGCAGGGACAGTGTCTCATTTTAAGCAGGGGTTCTCTAATG CTGTGATCTCCCCAGTAAACTCTGGACTAGCTCTGCTGAGGACTTCCTGTCTTTTGACCTTTA GCCCGTAGGGCAAGAAAGCTTTTCTAGGCCCCTTTCCTTTTCTGTGTCTAAGAGTGTCACAG CTTTCTGGGTTTACTGAGTTCCACGATGCATGTTGAGCTCGTCCTGGTGGGGGAGGCATACA 5 CAGTTACTTGCCACCCCAGCTGTGGCAGCGAGTTGCTGCAACACTCCCAGGAGGTCCTTTC ACCACTCAGAGCATGCAAGGTTTGCAGTCCATCTGGTTCTGCATTTCTGCTACTCCAGTGTCT CCCAGTTTCAACAGGAGTCTCTCTCTCTCCTACCTGATGCCTTTAAATTGCCCCTCTAGCTGG CCGCTGGGTTGGCCTGGCTTCTCTCTCCTTCTCTC 98. >NOD2_EXON6 10 TCATCCAGCTGGTCTACTGTCTGCTGACCTAGATGATGGTAAATTGTCCCCAGGGGTAGCCT GTCTAGTTCAGGCTGCACCTTTCGCATATATCAGCTCCTTTCCACCATCATCCCCTTTGTGAG GCTGCTGTGATTATCATGTTCCTTTTGCAGAGATGGAAACATTGCCTCAAATTAGCTCTGTCA TTTCCTAAGGATTCCAGGGTTCTTTAGTAGGGGGTCTGGATCCTACGTCCTGGGCCATCCCC ATCATAGTGCACCACGTCACCTCCCTGGCCAGGGACCGTGGGGTCTCCACTTTTTTGGGGT 15 GCTCCATCTATGCAGGGTTTCCTGGAAGCACAGATGCTGGCACTTCAGGGATGAATGAAAGT CTTTTTGGGGGATTTGTAGATTTTTTTCTTGTCTTACTAGCTCCATTTTCAAATGTATTTATTTT GTCTCTTTAGTTTGCGCGATAACAATATCTCAGACCGAGGCATCTGCAAGCTCATTGAATGTG CTCTTCACTGCGAGCAATTGCAGAAGTTAGCGTAAGTCAGCCTGGGCTGTGGACAATGGGC TCCAAGTGCCCTGGTCTCACCCCAGGTCGTGCAGCCTGGGAAGCTGTGAGTGATGGGCTGG 20 GGCAGGGGCTGTTTGCATGATGGGGGGTGCAGGTGATTCCTGCCCAGAGGGGAAGGGCAA CCCTGGGATTTGGTGCTCACTGTCCAATGTGCTTTGCTTCTGTGTCTCCTCTCTTCTGGAACT GAACAG[TCTATTCAACAACAAATTGACTGACGGCTGT[G/A]CACACTCCATGGCTAAGCTCCT TGCATGCAGGCAGAACTTCTTGGCATTGAG]GTGAGCCCAGGTTTTCCTTATTCCCTGGAAAC TATTTTTTGCCCCATTCCTGAGTCAGTCTGATCTGGTCTTGGCCTGGCACTGCCCACACTGG 25 CTCCTGACCTCCTGATTGAATGCAGGGACAGTGTCTCATTTTAAGCAGGGGTTCTCTAATGC TGTGATCTCCCCAGTAAACTCTGGACTAGCTCTGCTGAGGACTTCCTGTCTTTTGACCTTTAG CCCGTAGGGCAAGAAAGCTTTTCTAGGCCCCTTTCCTTTTCTGTGTCTAAGAGTGTCACAGC TTTCTGGGTTTACTGAGTTCCACGATGCATGTTGAGCTCGTCCTGGTGGGGGAGGCATACAC AGTTACTTGCCACCCCAGCTGTGGCAGCGAGTTGCTGCAACACTCCCAGGAGGTCCTTTCA 30 CCACTCAGAGCATGCAAGGTTTGCAGTCCATCTGGTTCTGCATTTCTGCTACTCCAGTGTCT CCCAGTTTCAACAGGAGTCTCTCTCTCTCCTACCTGATGCCTTTAAATTGCCCCTCTAGCTGG CCGCTGGGTTGGCCTGGCTTCTCTCTCCTTCTCTC 99. >NOD2_EXON7 TCTGGGGCTTCTCCGAAGCTCTCCGAGGTGTCTGGATTCAGTTGCAGCAGGAGCCTTCCTT 35 GCTGGGATCTTCCCCCACCCCTAGCCTTGGCCCTCCCTCTCTCCTTCCTTTCTGGAAGGCTC

AGTGGGCCCCACCCCTCCCTCCAGCCACCTGGACCTGCCCAGCGCTCTTGTGCAACAGGTA

WO 03/014319 PCT/US02/25268 86 AAGCCTACCTGTAGCAACAACAGATCTGGGAAGGCTGCAGAGGGCACGATGGGGTCTGGAT CGAGGGCGGCTGAGACCAGAGGGAAAGGTGTGACCCTGAGTCACCCTCGCTGTCCCGGGG AAACCACCTCCCAGGACAGCTGCCTACTGTGGCTCCTGCCTGGAATTGTCACACTGCTGTGC AAACAGCGTCCCGCTGCCCCTTTCCCTTTGCTGGGGGAAAATGAAGTTGTGGGAGCCGCTG 5 AGTAAACTAGACCTAGCAGCGAGGGCACCTGATGTGGCTGCTGCCTCCCGGGCAGGTCTTC AATGCTTTCTTCCTGTGTTTCCCTGGCCAGGGCACAGACGGCCCTCCTTTTCTGCCTGCCGC TGTGTTCTCTCAGCCTCCTCTGTCTTCCCTTCCAG[GCTGGGGAATAACTACATCACTGCCGC GGGAGCCCAAGTGCTGGCCGAGGGGCTCCGAGGCAACACCTCCTTGCAGTTCCTGGGIGTA GGTTGGATTCCAGGAAGAGGGACCTGCATGGAGGGGCTTGGGACTTTTGAGGATTTAGGGG 10 CAGGTGAAACTCTTCAGCCAGGAGGCCCCAGAGGCAGCCCAGCTCCAGTGGGGAGGACAA GCCAGGGAGAGAGTGGGCGGCCCTTGACTGCCACCTTCATACTTGGTCTATGCCTGACAAA CAGGAAGTTTGGGATGTTGGGGCTAGGGGAGGACAGTGCCCACGAGCTGGTGACAGGAAG CCCTCTGATCCTCAGGGGGCGCTAGGGCTGTACTTTAGCTGCATATTAAAACCACCTGGAAG CTTCTAAACACTATTGCCAGGCCTCCCACCCCAGACTGATGAAATGCAAATATCTAGGTGCA 15 AGGCCCAGGTATCAGGAGTTTTAAAAAGCTTCCCAGGGGATGTACAGCCAGGGGTGAGGAC CCCTGACCTAAGAAAGAGAAGGAAATGGGGAAGGATAGGAAGGCACCCAGGATAAGAGGG GCTGTGCTAGGTCCCTCGGAGCTCTTGCTCCCTGTAGGACCATGCTAGGGCCTGCCAGGGA GGGGAGTACCCCAACCTGCAGCCCCAGGGTGGGCTTCCTCTGTTTGCTAGGCACCCAGGCT TGCACCTGTGCTGTTTCC 20 100. >NOD2_EXON8 TTTTGGAAAGGGATGTTTTCAAACTACAGTGAGTCAGAGGAGGATGGCCCAGAAGCTGGGG GAGTTGAAGCTGATGGCGTGAAGGAATTAGGGGTGTTAGGAAGAAGCAGGAGATAAAGAGC TAGCTTGCAGAAGAAGTGTTAGACTTGTTATGGGCAGGTACTGGAGGGTAGCTAAGGACTTG TGGGTGGCAGTTACCAGGAAGCGTATCTGAACTAAGTGTCAGAAAAAGTGTCACAACTGTAA 25 ATTACTCTTGTCAGTGAGTTCCTGTCCTTAAGGGTTAGGGCTGGGTAGCCCTCTACTATTCTC TAAGTCTGTAATGTAAAGCCACTGAAAACTCTTGGGTTAAGTTTGGCCATCCCACCCAAAAGA TGGAGGCAGGTCCACTTTGCTGGGACCAGGAGCCCCAGTGAGGCCACTCTGGGATTGAGT GGTCCTGCCCCTCTGGCTGGGACTGCAGAGGGAGGAGGACTGTTAGTTCATGTCTAGAACA CATATCAGGTACTCACTGACACTGTCTGTTGACTCTTTTGGCCTTTTCAG[ATTCTGG[G/C]GC 30 AACAGAGTGGGTGACGAGGGGGCCCAGGCCCTGGCTGAAGCCTTGGGTGATCACCAGAGC TTGAGGTGGCTCAG]GTAAGCTTCAGAGTCTATCCTGCAGTTTTCTTGGGGAGATCAGGTGAA GAGGGAGGAGCTGGGGCCAGTTCTGAAGGTCTTTGAACTTTATTTCTACCCCACAATGTTAG GCAATGGAGTAAGGAAAAAAGACCATTGGATTTCAAGAGAGGACACTCGAGTCTTTCTGGGT GACTTGGAAATGTCCCTTGTCCTCTCAGGGTTTTGATACAGTATCTGTAAATTGAAGATATTG 35 GGCTGGATCAGGTACATTTTATCTTAAGGACCAATTCCAATCCATTGGTAGTGGGTGCCCAG TGCACCACATTAAAAAGAATTCTAAGGCTGCACCTGGGCTTAAAGAAGAGCACTATAATCAAT

TAGTGATGTCTAAAAAAGCTAAAAAAAAAAAAAAAAGAGCACTGCATTCAATTAGTGATGTCTA

WO 03/014319 PCT/US02/25268 87 AAAAGGGTAGAAAAAAAAAAAAAAAGAAAAAAGAAAGAGCACCGCAATCAATTAGTGATGTCT GAAATGGAGCAGACCAGGAGAGCACCACGAATTTTGCCCTCCATAGGTTAGCTCATCTCTGA GGTCTTTCCCTGCTCTGACATACTTTTGTTCCAT 101. >NOD2_EXON9 5 AGCTTGAGGTGGCTCAGGTAAGCTTCAGAGTCTATCCTGCAGTTTTCTTGGGGAGATCAGGT GAAGAGGGAGGAGCTGGGGCCAGTTCTGAAGGTCTTTGAACTTTATTTCTACCCCACAATGT TAGGCAATGGAGTAAGGAAAAAAGACCATTGGATTTCAAGAGAGGACACTCGAGTCTTTCTG GGTGACTTGGAAATGTCCCTTGTCCTCTCAGGGTTTTGATACAGTATCTGTAAATTGAAGATA TTGGGCTGGATCAGGTACATTTTATCTTAAGGACCAATTCCAATCCATTGGTAGTGGGTGCC 10 CAGTGCACCACATTAAAAAGAATTCTAAGGCTGCACCTGGGCTTAAAGAAGAGCACTATAAT CAATTAGTGATGTCTAAAAAAGCTAAAAAAAAAAAAAAAAGAGCACTGCATTCAATTAGTGAT GTCTAAAAAGGGTAGAAAAAAAAAAAAAAAGAAAAAAGAAAGAGCACCGCAATCAATTAGTGA TGTCTGAAATGGAGCAGACCAGGAGAGCACCACGAATTTTGCCCTCCATAGGTTAGCTCATC TCTGAGGTCTTTCCCTGCTCTGACATACTTTTGTTCCATGATTACCTCCAG[CCTGGTGGGGA 15 ACAACATTGGCAGTGTGGGTGCCCAAGCCTTGGCACTGATGCTGGCAAAGAAC[G/A]TCATG CTAGAAGAACTCTG]GTGAGTTTGGGGGATTCTCTGCTCTGGGGAAGTGGATCACAATCTCT GTTGATCCCCTGGCCTCATCCATAGGAGCGGTTGTGTGGACAGACAAAGGTGGATGATTGA GTGATTGACTGATTGATTGATTGTGTTTGTCTTTATATGTACTGAGTGGTATGAAGCTTATAGA GCCTGGTATGTACATGCTAATTTTTTTATTTAATAAAATATATGGGTTTGCTGGTTTGGTGACT 20 GCCTCCACATGGCATAAGTGTTAAGAGCACAGACTCTGTAATCAAGCAGGCCGTGATCTTAG GCAAGTTAAATAACAATTTCAGAATCTCAAGTTTCATGTCTGTAAAATGAGGGTAAGAATACTT CCAACCATAAAGGATTTTTGCAAGAATTAGATAAAGTAGTGCCTGTGAAGACCTTAATATAGT GCCTGGCATATTTGTAAGTGCTCCATAAATGTTAAATTAGAATAATGGCAGGGTTACTACTAC TATTACTGCTGCTGCTGCTGCTGCTGCTGCTACAACTACTATAGTACTGTGACTACTACTACT 25 AATAAAGTTTTGTTATTTTAAAGTGATTTTGAGTTCCTAGGAGCACTGGGTAT 102. >NOD2_EXON10 CTATAGAGGTTTAAACAAGGAAAGGGTTTATTTTTTCCTGTATAGGCAGCTGGATGTAGGCAG TGTAGGGTTTGTACAGTGGCTACAAGAGGCCAGGAGGGGTCTCAGCTCTGTCTCATTCTCTT CCTGTTCCATCATTCTTAGCCTGTGACTTCATTCACATGGTTGGTTGTCTCATGATCACAGGA 30 TGGCTGCTCCAGGTGCAGCACTACTTCTGTATTCCCGGATTCGATCTATATACCCAGGAAAG CCATCTGGGTTCTCTCCTTTAAAAAGCATTCCTGGAAGCCCCACCTGTCGACTTCCCCTTATG TATCAACCATGTGTATGTCACTTGACCAACCCACTTGTATGTTGTTTGACCAGCCCTGGCTGC AATGGAGAGTGGGAAATACAGTTTTTTCACCAAGTGCATGGCTGTCCAAATGAAATGAGACTT CCATTAATAAGGAAGAAAGGAAAGATGGAGATCAGGAAGCTGGGGGATCAGGGAACTTATTA 35 CATTGAGAGCCCTTGGAGTGAATTCTCTTGCAAATATGTCCCTGGAATTGAGAATCCCCACAA

CGTACTTTATCTGTTCTTTCTTTATCCATGAGTTTGGGTTTTCAGATGTTGGATTTCCTATATG

WO 03/014319 PCT/US02/25268 88 GGGGGCATGTGAGTTCATCATCTTCCATAATCAATGTTGTATCAACTGGATTTTCTCTCTTCTT CTCACCAGlCCTGGAGGAGAACCATCTCCAGGATGAAGGTGTATGTTCTCTCGCAGAAGGAC TGAAGAAAAATTCAAGTTTGAAAATCCTGAAJGTAAGGAACCCATAAGCAGGAAACAGGACAA TAATTGCTGGCCTTTGGAAGGGGCATTTCTGAATAAGATCTGGGCCGCTCTCCGCTGGGCTA 5 ACTCATGTGAGGTGGCCTGGTAGAACAGCTTGCCTTGGTCTAGGTGGACAAGGATTCCAGT GCAAGTTGTTTATCTGGGAGGTGGTCCCAGTAAATGCTGATAGGAGAGTGGTGAAGTGAGAT GGGGAAGTGAAGGTAACCAATAAAGGGGAGTTATCAAGCCAGTTATCAATGAGGGAAATTGG AGCTCAGTACTCTGGGGCACTCCTGGAGCCAGTGCAGAACACACATGGTCACCTACCCAAC CAATGGGCAAGAAAGCCATGGCATTTATCCACCAACCCTCTGTCCTTCCTATGTTGATGTGC 10 GCTCATGGGGCACTGATTCTCCAGCACTTCCAGCTCACCCTCACCCAGCTGAACATGCTTCT GGGGTCAGGAGAATGGCCTCAGGCAGAGAGTGGAAGGTCTTCTCTGCAAGCAGTGGCTGG GGAGGTGATGTGATGGGGAGTACTGTGGCCTCCTCCAGTGGCTGACTCAGTGGCTTGGGAC TTGTGCCACAAAGAGATGGACAGCTCAGGTGAACATGAACCCACCTAGTGACCATCATGGGT TTGTCAGGGTGCTCTCTGAGGCTGATGCCAAAATTCTTATTTCAAGTAGACCTCAGGAACCC 15 CATCAGAT 103. >NOD2_EXON11 CCGTTTTCATGCTGATGATAAAGATATACCCAAGACTGGGCACTTTATGAAAGAAAGAGTTTT ATTGAACTTACAGTTCCACGTGGCTGGGGAGGTCTCACAATCATGGCTGAAGGTGAAAGGCA CATCTCACATGGCAGCAGACAGGAGAAGAGGGCTTGTTCAGGGAAACTCCCCTTTTTAAAAC 20 CATCAGATATCATGAAACTTATTTACTGTAATGAGAACAGGATGGGATTCAATTACCTTCCACT GGGTCGCTCCCACAACACGTGGGAATTCAAGAGATTTGGGTGGGGACACAGCCAAACCATA TCAAGTACTGTGCAAGTGTTTTAGGCATGCAGAGAGTGGTGGGTCTTCCCAGCAAGCAGAGT GTGGGGAGGTAATGGGGGACTGGTGGCTGACTTAATGGCCCAGGACCCATGCCACAAGGA GATGGATGGTGGATGTGAATAGGAGCCTGCTTACACCCATCACAATTTAGATTCTTATGCTC 25 GATGGCACGGGTACTCTTTTAGGCCCATTTTACCAATGAGGAGATTGGGACTAATTTGCTCG AGATCAAAAAAGAAGTGGTGTAGGTGGGATTTAAACCCAGGATGTCTAGCACTAAAATGCAG GTACTTAACCACTATCCTAAGGGAGTGGCTACTTAATTTGATAAACTCATCTAGTGAATGGAA GAGAGACGGTTACATTTCACTGATGGTACTGAGCCTTTGTTGATGAGCTCATTGGGAATCTC AGACATGAGCAGGATGTGTCTAAGGGACAGGTGGGCTTCAGTAGACTGGCTAACTCCTGCA 30 GTCTCTTTAACTGGACAGTTTCAAGAGGAAAACCAAGAATCCTTGAAGCTCACCATTGTATCT TCTTTTCCAG[GTTGTCCAATAACTGCATCACCTACCTAGGGGCAGAAGCCCTCCTGCAGGC CC[C]TTGAAAGGAATGACACCATCCTGGAAGTCTG]GTAAGGCCCCTGGGCAGGCCTGTTTT AGCTCTCCGAACCTCAGTTTTTCTATCTGTAAAATGGGGTGACGGGAGAGAGGAATGGCAGA ATTTTGAGGATCCCTTCTGATTCTGACATTCAGTGAGAATGATTCTGCATGTGAAGGATCTGA 35 TTCTCTGTCTAAGAAAGAAGTCTTTACCTCTTTAAGTAGGGAGCAATGATTTCATTTTTAAACC TTGACTATTTATTCAGCAACTTCTCTGCTCTATGAGATAGTGTAGGAATGGGGATGTGGTTGA

AGAATGAAAAGAAAAGTCAGCTCCCGCCCTCCTAGAAATTGCATCTGCCTTCACAGGTCAAG

WO 03/014319 PCT/US02/25268 89 GATATTGGATCAGACCTTCTGCGGTTCTGAATGGAGATTACACAGGTTAGGAGCAGGTTGCA CAGTGTTTCCAATTCTCTATAATTAAAGCCATAGACTTTCATGTATTGAAAAAAGCAAGAATTG CATTCTTGACAGATTCTTTCATTGCCTTAAAAAGAATGACTAGCCTTGGGAGTCTGGGCAGCT GGGTCCAGTGTTGTAGACTTTCTCTCTGCTGAGCCACAGCTTCAAAGATTTGTCCTTCTTGTT 5 TCCAGGGATCTATTTCTCAGACAATAAGTAAAGGCTTTCCCTGGCCTAATGTGCTGTAAGTGA ATGCTACTATATATGTTCCAGGCACTGGGCTAGAGACTAATATTTAAAAGCCAGGAAATTTCC TATAGAAAATCTATATCTCAGGGTTTTCTCAAAAGAGCTGGGAACTCTGGATGCCCATTCATG ATTCCAGTAGTTAACCAGAGTACAAGAAGGGCTGAGTCTTCTCAGATGGGCAMCC 104. >NOD2_EXON12_UTR 10 AGAGGTTCAACACCATACCTTGTCTCTCAAAAAATAAAAAATTCAGCTGGGT GCGGTGTAGTTCCTAGCCACTTGGGAGGCTGGGATGGAAGGATCCCTTGAA CCCAGGAGTTCAAGGCTGCAGTGGGCCATGATTGCATCACTGCACAGGCGA CAGAATTAGATCCCATCTCTTAAAAAAATAAAAAATTTAAAAGTGACTTCAAAA ATCTATGCTGTGATGGAGAGATTTTTCCTTCTGTATGATTGTGATAGCTCTGT 15 GGCCTATGACGTCATCAGGTTCTGGGCAAAGTGTAGGTTTTCTGTTTCTTTG TTTTTGAAACCATTGCACAGTCCTAAGAAACATCACATTCTGGGTCCTGGGC ACCAGCCAACATGAGGTTGATATTTTAAGGGGTCTGATGTTATTTGCTGCCT GTTGATGGAACTTGGGAGGGCACCAGGGTTTGCTCATTGCATTCTTGACAG ATTCTCTTATTGCCTTAAAAAGAATCACTGGCCTTGGGGAGTCTGTGGCTGG 20 CTGGGTGCAGTGTTGTGGACTCTCTCTGCAGAGTCATGGAGCCTTGTTCAG AATGCTTCCTGAGCTGCCCTGGTTGGCCAAGGGTAAAAACAGCCCTGACTT CCCTGCAAGAAACACTGCAGCTGGGCCAGAGAGTCAGCCCATCCCAGGCAT GGGTTTAAAAAGTGGAGGCTTTTGTTTGAAAGCCCTGCTCTAATTTTGTCCT CACTCAAACCTCTGTTCACTTGATCTGCTTTAG[GCTCCGAGGGAACACTTTC 25 TCTCTAGAGGAGGTTGACAAGCTCGGCTGCAGGGACACCAGACTCTTGCTT TGAAGTCTCCGGGAGGATGTTCGTCTCAGTTTGTTTGTGAGCAGGCTGTGA GTTTGGGCCCCAGAGGCTGGGTGACATGTGTTGGCAGCCTCTTCAAAATGA GCCCTGTCCTGCCTAAGGCTGAACTTGTTTTCTGGGAACACCATAGGTCACC TTTATTCTGGCAGAGGAGGGAGCATCAGTGCCCTCCAGGATAGACTTTTCC 30 CAAGCCTACTTTTGCCATTGACTTCTTCCCAAGATTCAATCCCAGGATGTACA

AGGACAGCCCCTCCTCCATAGTATGGGACTGGCCTCTGCTGATCCTCCCAG

WO 03/014319 PCT/US02/25268 90 GCTTCCGTGTGGGTCAGTGGGGCCCATGGATGTGCTTGTTAACTGAGTGCC TTTTGGTGGAGAGGCCCGGCCTCTCACAAAAGACCCCTT[A/C]CCACTGCTC TGATGAAGAGGAGTACACAGAACACATAATTCAGGAAGCAGCTTTCCCCATG TCTCGACTCAT[C/T]CATCCAGGCCATTCCCCGTCTCTGGTTCCTCCCCTCCT 5 CCTGGACTCCTGCACACGCTCCTTCCTCTGAGGCTGAAATTCAGAATATTAG TGACCTCAGCTTTGATATTTCACTTACAGCACCCCCAACCCTGGCACCCAGG GTGGGAAGGGCTACACCTTAGCCTGCCCTCCTTTCCGGTGTTTAAGACATTT TTGGAAGGGGACACGTGACAGCCGTTTGTTCCCCAAGACATTCTAGGTTTG CAAGAAAAATATGACCACACTCCAGCTGGGATCACATGTGGACTTTTATTTC 10 CAGTGAAATCAGTTACTCTTCAGTTAAGCCTTTGGAAACAGCTCGACTTTAAA AAGCTCCAAATGCAGCTTTAAAAAATTAATCTGGGCCAGAATTTCAAACGGC CTCACTAGGCTTCTGGTTGATGCCTGTGAACTGAACTCTGACAACAGACTTC TGAAATAGACCCACAAGAGGCAGTTCCATTTCATTTGTGCCAGAATGCTTTA GGATGTACAGTTATGGATTGAAAGTTTACAGGAAAAAAAATTAGGCCGTTCC 15 TTCAAAGCAAATGTCTTCCTGGATTATTCAAAATGATGTATGTTGAAGCCTTT GTAAATTGTCAGATGCTGTGCAAATGTTATTATTTTAAACATTATGATGTGTG AAAACTGGTTAATATTTATAGGTCACTTTGTTTTACTGTCTTAAGTTTATACTC TTATAGACAACATGGCCGTGAACTTTATGCTGTAAATAATCAGAGGGGAATA AACTGTTGAGTCAAAAC]IAGCCATCTTCCTTGTGACCAAACATTTAAAAATATT 20 CTGGCTGGGCACAGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCC GAGGTGGGCAGATCACCTGAGGTTGGGGGTTTGAGACCAACCTGACCAACA TGGAGAAACCCTGTCTCTACTAAAAATAGTGGAGGTTGCAGTGAGCCAAGAT

CACACCGTTGT

Claims (12)

1. An isolated polynucleotide comprising a nucleic acid sequence selected from the group consisting of: (a) a nucleic acid sequence comprising at least 15 contiguous nucleotides of a nucleic acid sequence selected from the group consisting of the variant 5 sequences of Table 4, and (b) a nucleic acid sequence that is fully complementary to a nucleic acid sequence of (a).

2. An isolated polynucleotide according to Claim 1, wherein the polynucleotide is a nucleic acid probe for the detection of loci associated with multiple sclerosis.

3. An isolated polynucleotide according to Claim 2, wherein said polynucleotide 10 is conjugated to a detectable marker.

4. An array of polynucleotides comprising: two or more isolated polynucleotides comprising at least one polynucleotide of Claim 1.

5. A method for detecting in an individual a polynucleotide, the method 15 comprising: (a) contacting a nucleic acid sample from an individual with a polynucleotide probe, wherein said polynucleotide probe comprises a nucleic acid sequence selected from the group consisting of: (i) a nucleic acid sequence comprising at least 15 contiguous nucleotides 20 of a nucleic acid sequence selected from the group consisting of the variant sequences of Table 4; and, (ii) a nucleic acid sequence that is fully complementary to a nucleic acid sequence of (i); and, (b) detecting specific hybridization between said polynucleotide probe and said 25 nucleic acid sample as indicative of the presence of a multiple sclerosis polynucleotide in said nucleic acid sample.

6. A method according to Claim 5, wherein said detecting step comprises detecting hybridization between said nucleic acid sample with an array of polynucleotides comprising: WO 03/014319 PCT/US02/25268 92 two or more isolated polynucleotides comprising at least one polynucleotide probe of Claim 5.

7. The method of Claim 5, wherein said nucleic acid sample is a genomic DNA sample. 5

8. The method of Claim 5, wherein said nucleic acid sample is a RNA sample.

9. A computer-readable storage medium for storing data for access by an application program being executed on a data processing system, comprising: a data structure stored in the computer-readable storage medium, the data structure including information resident in a database used by the application 10 program and including: a plurality of records, each record of the plurality comprising information identifying a polymorphisms shown in Table 4.

10. The computer-readable storage medium of claim 9, wherein each record has a field identifying a base occupying a polymorphic site and a location of the 15 polymorphic site.

11. The computer-readable storage medium of claim 10, comprising at least 10 records, each record comprising information identifying a different polymorphism shown in Table 4.

12. A signal carrying data for access by an application program being 20 executed on a data processing system, comprising: a data structure encoded in the signal, said data structure including information resident in a database used by the application program and including: a plurality of records, each record of the plurality comprising information identifying a polymorphism shown in Table 4. 25