Indian Journal of Biotechnology Vol 6 October 2007, pp 456-462

eno!ic analy"i" of #$%" in brea"t cancer by u"ing bioinfor!atic" databa"e"

& #i'a #an(ar , $ #ati"h )handra *eddy , &ai"er Ja!il , and Va!"y ) -ohana
+ 2

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enetic" .epart!ent, Bhag/an -aha'ir -edical and *e"earch )entre, 0yderabad 500 004, India *e"earch 1ing, Indo 2!erican )ancer In"titute and *e"earch )entre, 0yderabad 500 034, India Received 20 December 2005; revised 27 November 2006; accepted 5 February 2007

4he role of "ingle nucleotide poly!orph" 5#$%"6 in gene" that !odulate or pro!ote cancer proce"" ha" not been fully under"tood7 0ence, an atte!pt ha" been !ade to collect data fro! 8ntre9 eno!e Vie/, )ancer eno!e 2nato!y %ro:ect 5$)BI6 and Online -endelian Inheritance in -an 5O-I-6 databa"e" for enu!erating and locating the nu!ber of #$%" in the loci of 'ariou" chro!o"o!e" in'ol'ed in cancerou" and non-cancerou" brea"t ti""ue7 .$2 !ethylation and !utation" in the hot"pot" of the proto-oncogene" leading to for!ation of carcino!a" in the brea"t ti""ue ha'e been identified and di"cu""ed7 4ran"ition in the hot"pot" !ay reflect endogenou" !utation" and "poradic lo"" of .$2 repair factor"7 4hi" ha" been related to 'ariou" !olecular !echani"!" and gene e;pre""ion 'ariation"7 #$%" al"o play i!portant role" in confor!ational change" in protein", re"ulting in non-functional or truncated protein" at the po"t-tran"lational le'el"7 2lthough #$%" in intron" !ay not directly re"ult in a change in function of a gene, they !ay be ta(en a" bio!ar(er" to locate the "ite near gene"7 #$%" technology ha" enor!ou" potential in clinical re"earch and phar!acogeno!ic"7 0ence, effort ha" been to under"tand the ba"ic difference bet/een candidate and 'alidated #$%" and their "ignificance in carcinogene"i" or predi"po"ition7 Keywords: #$%", brea"t cancer gene", loci, .$2-repair, phar!acogeno!ic" IPC Code: Int7)l7 )+2$+5<00
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Introduction 4he !o"t funda!ental a"pect in genetic" of cancer i" to locate the da!age in the .$2 "e>uence of protooncogene" that lead to oncogene"i" through the production of a functional oncogene7 1ide range of +-3 carcinogen" i" re"pon"ible for oncogenecity 7 #tudie" on carcinogenic !echani"! ha'e "ho/n that ioni9ing radiation" produce a 'ariety of genetic le"ion", including chro!o"o!al aberration, .$2 "trand brea(, deletion, gene rearrange!ent and point 4 !utation 7 *adiation i" a /ell-docu!ented ri"( factor 5 for the production of brea"t cancer a" e;po"ure to it 6 can induce the for!ation of free radical" , /hich !ay da!age .$2 through !odification of guanine and 7,= other ba"e" 7 #$%" are "ingle ba"e pair 'ariation" in geno!ic .$27 4here ha" been a great deal of intere"t in the den"ity of #$%" re>uired to reliably detect a""ociation bet/een #$%" and co!ple; di"ea"e"7 #cienti"t" hope to e'entually u"e the"e #$%" to find out /hy one per"on de'elop" cancer and the other doe" not, and
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/hy "o!e /o!en ha'e a ri"( of brea"t cancer or /hy "o!e ha'e increa"ed "ide-effect" to certain drug"? )elera ha" reported about 400,000 uni>ue #$%", /hich !ean" 372 !illion #$%" are no/ (no/n7 Varied indi'idual re"pon"e to a particular di"ea"e or drug !ay be cau"ed by a co!bination of #$%-ba"ed a""ociation and it" analy"i" /ill help u" to under"tand the genetic ba"i" of co!ple; di"ea"e"7 It !ay ta(e ti!e to under"tand /hich #$%" !ean "o!ething and /hich are :u"t rando! difference"7 2" annotation of the geno!e continue", /e /ill be able to (no/ /hether #$%" are located in the protein-coding region" or regulatory region" and /hich one" ha'e a chance of being a""ociated /ith a function7 It i" al"o po""ible that genetic 'ariation" could occur in putati'e @ regulatory loci, /hich control gene e;pre""ion 7 4he abnor!al #$%" on the .$2 "e>uence that encode for the "tructural or functional do!ain" of the protein ha'e the capacity to alter the nor!al para!eter" of the protein"7 0ence, it i" po""ible that the"e #$%" !ay ha'e been induced by !i""en"e or any other !utation"7 $u!erou" #$%" a""ociated /ith cancer belong to abnor!al #$%" and in'ol'e A) 4B = to A 2B change 7 4he typical fre>uency /ith /hich one ob"er'e" "ingle ba"e difference in geno!ic .$2

#IV2 #2$&2* et alD #$%B" I$ B*82#4 )2$)8*

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bet/een e>ui'alent chro!o"o!e" i" in the order of @ + out of e'ery +,000 bp and the typical fre>uency of #$%" in a /hole population i" reported to about + in 300 bp"7 It i" rea"onable to thin( that genetic heterogeneity and epi"ta"i" /ill in'alidate !any po""ible e;ten"ion" of the !ethod" u"ed for identifying "ingle-locu" di"ea"e"7 #$%" al"o "er'e a" e""ential tool" on !edical and +0,++ hu!an e'olutionary re"earch 7 4o under"tand the co!ple; pheno!ena of their a""ociation /ith +2 di"ea"e , /e need to under"tand !ore about #$%" and their occurrence and di"tribution7 2naly"i" u"ing #$% !ar(er" di"tributed acro"" the lin(age region ha" the potential for refining the di"ea"e "u"ceptibility locu" to a region enco!pa""ing only one or a "!all nu!ber of gene"7 Interaction" bet/een #$%" confer +3 ri"( of brea"t cancer 7 1ith the de'elop!ent of #$% !ap", phar!acogenetic "tudie" can be perfor!ed to locate #$%" a""ociated /ith genetically undefined ad'er"e +4,+5 drug reaction" 7 #uch "tudy can define ho/ genetic difference" influence the 'ariability in patientB" +6 re"pon"e" to drug" 7 Gor under"tanding thi", ad'ance" ha'e to be !ade in t/o proble! area", i7e7 patient" /ho e;perience drug-induced threatening "ide effect" and tho"e patient" /ho do not re"pond to "tandard drug treat!ent7 enotype profiling of patient" before ad!ini"tering therapy !ay help tho"e indi'idual" /ho !ay not re"pond to a gi'en treat!ent or /ho !ay "uffer potentially "e'ere "ide-effect"7 4he candidate gene approach ha" not yet been e;hau"ti'ely e;plored due to the "till li!ited, but increa"ing, nu!ber of +7 #$%" di"co'ered in candidate gene" 7 2ccording to the 2!erican -edical 2""ociation, ad'er"e reaction to pre"cribed drug" cau"ed o'er +00,000 death" in H#2 and o'er 2 !illion people had "eriou" "ide effect"7 )linical trial" /ere being de"igned to detect gene" that /ere re"pon"ible for "uch ad'er"e reaction" to drug"7 2 nu!ber of %har!a co!panie" ha'e planned to in'e"tigate the ad'er"e effect" of drug" u"ed in the treat!ent of 0IV, leu(e!ia, a"th!a and li'er di"ea"e"7 #uch "tudie" /ill correlate certain #$% += haplotype" /ith patient re"pon"i'ene"" to the drug" 7 4he detection of #$%" in gene" that !odulate re"pon"e to drug" could lead to "afe che!otherapeutic reco!!endation" for the patient7 -edicine could be pre"cribed to patient", /hich /ould ha'e high efficacy and a reduced chance of "ide effect"7 $ot only /ould thi" pre'ent "uffering, but al"o "peed up the proce"" of reco'ery7

2t pre"ent there i" a concerted effort to detect #$%" in the hu!an geno!e in relation to di"ea"e "u"ceptibility7 4herefore, an atte!pt ha" been !ade to collect and analy9e the data pre"ented in public #$% databa"e" !aintained by the $ational )enter for +@ Biotechnology Infor!ation 5$)BI6 for pic(ing up the infor!ation<data related to brea"t cancer7 Gurther, effort" /ere !ade to identify the geno!e, /ide nu!ber of #$%" and their loci in brea"t cancer gene" u"ing bioinfor!atic tool" for defining appropriate bio!ar(er"7 Materials and Methods
Data Acquisition

#e'eral hot "pot" on a total of +7 chro!o"o!e", /hich !ay lead to brea"t cancer, /ere "elected after "earching the 8ntre9 eno!e Vie/7 4he #$%" at the"e loci, including proto-oncogene", /ere collected fro! the databa"e of )ancer eno!e 2nato!y %ro:ect 5) 2%6 for analy"i" of clinical, "cientific and phar!acogeno!ic" i!portance in brea"t cancer7 4he !ultiple #$% re"ource" a'ailable on the %ub-ed re"ource" and chro!o"o!e bro/"er" !a(e it ea"y for "earching the re>uired data on #$%"7 4he /eb"ite" u"ed for thi" "tudy /ereD httpD<<ncbi7nl!7nih7go'<!ap'ie/<!apC"earch7 cgi5build306EhttpD<<cgap7nci7nih7go'EhttpD<<cgap7nci7 nih7go'<4ool"E and httpD<<gai7nci7nih7go'<ht!l#$%<i!age!ap"7ht!l7 2naly"i" /a" carried out ba"ed on build-30 of 8ntre9 eno!e Vie/, /hich i" being ti!ely updated a" ne/ #$%" are identified7 4he #$% hyperlin( gi'e" infor!ation about the chro!o"o!e, ti""ue and hi"tology7 4he di"tribution of #$%", genetic and phy"ical !ap", reference !ar(er" and chro!o"o!e ideogra! /ere identified7 Gro! thi" the total nu!ber of confir!ed, 'alidated and candidate #$%" /ere counted and tabulated7 In the pre"ent "tudy #$%" at particular loci on chro!o"o!e" are focu"ed7
Types of SNPs

#$%" are ba"ically of t/o type"Inor!al and abnor!al #$%"7 $or!al #$%" are the poly!orphi"!" on the .$2 "e>uence that ha'e no capacity of altering the nor!al protein "tructure7 4hi" type of #$%" !ay ha'e originated a" a re"ult of e'olutionary proce"" and becau"e of "e'eral geographical 9one"7 2bnor!al #$%" on the .$2 "e>uence encode for the "tructural or functional do!ain" of the protein, /hich ha'e the capacity to alter the nor!al para!eter" of the protein7 2bnor!al #$%" leading to brea"t cancer !ay

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ari"e fro! !i""en"e or fra!e "hift !utation"7 %rotooncogene" !ay be con'erted to functional oncogene" through the occurrence of #$%"7 Gurther, depending on the "tage" of their identificationE #$%" can be broadly cla""ified a"D)andidate #$%"Iare tho"e /hich can be predicted fro! the "e>uence data u"ing co!puter tool", "uch gene loci can be u"ed to detect a""ociation of #$%" to a di"ea"e trait7 Validated #$%"Iare tho"e /hich are ob"er'ed in an e;peri!ent, u"ing the enetic 2nnotation Initiati'e 5 2I6, a !ini!u! of eight or fe/er indi'idual" "hould be te"ted for reporting the #$%"7 )onfir!ed #$%"Iare tho"e /hich follo/ a -endelian pattern of tran"!i""ion in a !ini!u! of 5 fa!ilie"7
Data Analysis and Interpretation

#$% data generated fro! enBan(" /ere analy9ed and pre"ented "y"te!atically in the for!at, /hich could be u"eful in brea"t cancer diagno"i" and further re"earch7 4hi" i" an e""ential "tep to/ard" !o'ing #$% technology and application" into clinical re"earch, phar!acology and drug !ar(et"7 #$% di"co'erie", "coring and "creening !ethod" focu" on #$% !ar(er" on 'ariou" loci on certain chro!o"o!e" and ha'e !ade an i!pact for phar!acogeno!ic" profiling of the data7 4o reduce the candidate region", lin(age di"e>uilibriu! !apping approach /a" applied through bioinfor!atic" u"ing a large body of public "e>uence", #$% data and #$% detection analy"i"7 Results and Discussion
Data Analysis

4he data of hot"pot" on the entire geno!e, /hich !ay lead to brea"t cancer, /ere collected 54able +6 and the nor!al and brea"t cancer ti""ue #$%" dra/n fro! ) 2% /ere tabulated 54able 267 2uthor"B "earch ha" yielded 45+= #$%" 54able 26 at =00 loci 54able 36 in'ol'ed in nor!al and cancerou" brea"t ti""ue", re"pecti'ely7 #$% i" the !o"t co!!on for! of genetic poly!orphi"!" in hu!an geno!e occurring on an a'erage in e'ery +000 bp"7 In the pre"ent "tudy, author" could deter!ine 7@2 nor!al #$%" and 3726 cancerou" #$%"7 It i" belie'ed that nor!al #$%" do not po""e"" the capacity of altering the nor!al protein "tructure in a gi'en ti!e period7 4he"e #$%" !ay ha'e originated a" re"ult of e'olutionary proce"" becau"e of 'ariation in geographical 9one"7 In "earch for gene" in'ol'ed in brea"t cancer, author" /ere able

to pic( up "e'eral candidate region" fro! the geno!e /ide "can" through the Internet7 4he nu!ber of aberration "ite" on each chro!o"o!e in brea"t cancer ca"e" i" pre"ented in 4able +7 It ha" been ob"er'ed that chro!o"o!e" +35=6, +7566, ++556 and +546 ha'e the large"t nu!ber of hit" co!pared to the re"t of the chro!o"o!e"7 Out of the total 46 aberration" "ite", about 50K of aberration" occur on the"e four chro!o"o!e"7 4he candidate, 'alidated and confir!ed #$%", /hich are naturally pre"ent in the nor!al and cancerou" brea"t ti""ue", are indi'idually li"ted in 4able 27 It i" e'ident fro! the data that cancerou" brea"t ti""ue "ho/" 5 ti!e" !ore candidate, confir!ed and 'alidated #$%" a" co!pared to nor!al nd brea"t ti""ue 5Gig" +-367 In brea"t cancer ca"e", 22 chro!o"o!e ha" 452 candidate, +5+ 'alidated and +2 confir!ed #$%"7 4hi" re"ult i" une;pected and, hence, ha" to be ta(en note of7 0o/e'er, in the nor!al brea"t ti""ue for the "a!e chro!o"o!e, there are only ++ candidate", @ 'alidated and 0 confir!ed #$%"7 4hi" ob"er'ation i" 'ery intere"ting, "ince the nor!al brea"t ti""ue ha" 4 candidate, 5 'alidated and 0 confir!ed #$% loci7 0o/e'er, in the cancerou" brea"t ti""ue, there are 7 candidate", 7 'alidated and 6 confir!ed #$% loci 54able 367 2l"o, the da!age "ite" nd are only 2 on the 22 chro!o"o!e, /hile the !a;i!u! = on chro!o"o!e +3 54able +6, /hich i" re"pon"ible for B*)22 related fa!ilial brea"t cancer7 B*)2+, located on chro!o"o!e +7, ha" "ho/n only nd 6 da!age prone "ite" 54able+67 )0&+ region at 22 chro!o"o!e pro'ide" u" the infor!ation that #$%" at )0&+ affect the (ina"e acti'ity differentially and, thu", !a(ing the "ub:ect" differentially "u"ceptible to +3-+5 brea"t cancer 7 4he peru"al of data related to #$% loci on chro!o"o!e" in'ol'ed in brea"t cancer proce"" 54able 36, a" per the reference dra/n fro! the aberration prone "ite" a" !entioned in 4able +, "urpri"ingly "ho/" that the loci are !a;i!u! in nu!ber on the chro!o"o!e + and 2, /hile chro!o"o!e +7 that ha" a lin( /ith brea"t cancer, a" indicated, ha" co!parati'ely le"" than half loci7 In total, +65 candidate, +36 'alidated and = confir!ed loci /ere detected on the chro!o"o!e" in nor!al ti""ue" in co!pari"on to 236 candidate", 2+@ 'alidated and 36 confir!ed loci in cancerou" ti""ue" 54able 36, ha'ing a ratio of c +D+7257 By co!paring and correlating the abo'e obtained data, it can be concluded that the nu!ber of #$%" of

#IV2 #2$&2* et alD #$%B" I$ B*82#4 )2$)8* 4able +I$u!ber of da!age" on entire geno!e relating to brea"t cancer )hro!o"o!e" Damages + 4 2 + 5 + 6 3 7 + @ + +0 4 ++ 5 +3 = +5 3 +6 2 +7 6 += + 20 + 2+ 2 22 2

45@

L +

4able 2I%attern of #$%" di"tribution in each chro!o"o!e in nor!al and cancerou" brea"t ti""ue" )hro!o"o!e" $o7 of candidate #$%" + 2 5 6 7 @ +0 ++ +3 +5 +6 +7 += 20 2+ 22 L 4otal 74 52 33 42 30 46 2@ 66 = 20 25 23 +6 += = ++ 20 522 $or!al brea"t ti""ue $o7 of 'alidated #$%" 42 23 +7 +2 24 +6 7 2= 6 +5 @ +@ +3 = 4 @ +0 262 4otal nor!al #$%" M 7@2 4otal #$%" M 45+= 4able 3I%attern of #$%" loci di"tribution in each chro!o"o!e in nor!al and cancerou" brea"t ti""ue" )hro!o"o!e" $o7 of candidate #$%" locu" + 2 5 6 7 @ +0 ++ +3 +5 +6 +7 += 20 2+ 22 L 4otal 20 +@ +0 +4 +2 ++ ++ +3 5 = 7 7 6 +0 2 4 6 +65 $or!al brea"t ti""ue $o7 of 'alidated #$%" locu" 2+ +4 +2 @ @ 7 7 +3 4 6 3 = 6 6 2 5 4 +36 4otal nor!al #$%" locu" M 30@ 4otal #$%" locu" M =00 $o7 of confir!ed #$%" locu" + + 0 0 0 0 + 2 0 0 0 3 0 0 0 0 0 = )ancerou" brea"t ti""ue $o7 of candidate #$%" locu" 27 25 2+ += +5 +4 +4 +7 @ @ +0 +2 +2 ++ 4 7 ++ 236 $o7 of 'alidated #$%" locu" 26 23 +6 +5 +6 +4 +2 +6 7 +0 ++ +4 = +0 4 7 +0 2+@ 4otal cancerou" #$%" locu" M 4@+ $o7 of confir!ed #$%" locu" 5 3 2 + 2 2 2 3 0 + 2 5 0 0 + 6 + 36 $o7 of confir!ed #$%" + + 0 0 0 0 + 2 0 0 0 3 0 0 0 0 0 = )ancerou" brea"t ti""ue $o7 of candidate #$%" 274 +== +2= +6= +=2 +3= +25 +70 50 +57 +5+ +4= 45 == 2= 452 74 2566 $o7 of 'alidated #$%" +3= +02 60 74 72 5= 53 67 += 54 76 @+ +4 34 24 +5+ 2@ +++5 4otal cancerou" #$%" M 3726 $o7 of confir!ed #$%" 6 3 2 + 2 2 2 3 0 + 2 6 0 + + +2 + 45

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Gig7 +I)hro!o"o!e" vs nor!al<cancerou" candidate #$%"

Gig7 2I)hro!o"o!e" vs nor!al<cancerou" 'alidated #$%"

Gig7 3I)hro!o"o!e" vs nor!al<cancerou" confir!ed #$%"

cancerou" ti""ue are !ore than 4-ti!e" /hen co!pared /ith nor!al brea"t ti""ue #$%"7 2lthough the effect of an indi'idual #$% i" generally "!all, the genetic effect of co!bination" of functionally rele'ant #$%" !ay additi'ely or "ynergi"tically contribute to increa"ed brea"t cancer ri"(7 It i" reported that epi"ta"i" or gene-gene interaction" are li(ely to be a ubi>uitou" co!ponent of the genetic architecture of +3 co!!on di"ea"e", "uch a" brea"t cancer 7 4here are

t/o !a:or !echani"!" by /hich #$%" can confer the di"ea"e "u"ceptibility7 One i" by the !odification of .$2 regulation and another by !odification of protein function through induction of !i""en"e !utation"7 4he later proce"" cau"e" "e'eral inherited di"ea"e", 4hu", /here'er the protein "tructure i" in'ol'ed, the #$% data pro'ide a /ealth of infor!ation on the po""ible !echani"! of action at !olecular le'el"7

#IV2 #2$&2* et alD #$%B" I$ B*82#4 )2$)8* SNPs in Phar aco!enetics

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4he #$%" at the geno!ic le'el that encode" for "ub"trate binding do!ain, i7e7 drug binding do!ain !ay then alter the a!ino acid /hich affect" &I7 &I, the inhibitor con"tant, /hich in turn affect" & ! and thu" V o of the reactionE therefore, the 'aried rate" of re"pon"e7 #o /e can i!agine that the drug en9y!e affinitie" ha'e a role in rate of reaction 5drug target 20 en9y!e6 7 -o"t of the pre'iou" data on #$%" ha" co!e fro! 2+-25 analytical technologie" li(e -2J.I-4OG-# 7 2nother approach to analy9e #$%" i" by u"ing the Ain'ader a""ayB, /ell "uited for the high throughout analy"e" on a geno!e /ide "cale7 Variou" other #$%" data are pro'ided in the #$% )on"ortiu! Ji!ited 54#)67 2t pre"ent, the databa"e of #$%" contain" 2,42,+26+ confir!ed uni>ue #$%"7 4he #$% databa"e" can be "earched u"ing a 'ariety of !ethod", e7g7 "earch by gene na!e or "earching on certain chro!o"o!e"7 It i" e'ident fro! the pre"ent "tudy that e'en a "ingle nucleotide change in the .$2 "e>uence need" to be !onitored carefully7 4he"e alteration" in .$2 "e>uence !ay not al/ay" alter the functional a"pect" but !ay change "o!e of the !inute para!eter" of a protein7 #o there i" a chance of 'ariable protein function" bet/een t/o per"on" /ith "ingle nucleotide change in particular gene "e>uence"7
SNPs and Disease Suscepti"ility

4he gene" /hich are not "elected naturally /ith nucleotide "e>uence 'ariation" beco!e e;tinct and in thi" /indo/ period of e;tinction they !ay generate a nu!ber of di"ea"e" or abnor!alitie"7 4he e;i"tence of "uch gene "e>uence" !ay cau"e di"turbance in cellular, bio-che!ical and phy"iological ho!eo"ta"i", /hich could be fatal to the indi'idual or organi"!7 In thi" /indo/ period of e;tinction the"e unfa'orable gene "e>uence" !ay be inherited and influence the progeny, for e;a!ple fa!ilial brea"t cancer gene" /ith /ell characteri9ed change" in nucleotide "e>uence 5B*)2 + and 2-!utation are inheritable67 )ellular ho!eo"ta"i" lin(ed to bioche!ical ho!eo"ta"i" i" a re"ult of gene e;pre""ion product7 8'en though it i" not ea"ily altered by "o!e unfa'ourable gene !utation", but could be fatal if a""ociated /ith a co!bination of !utation" at tho"e different gene" that !ay "a'e the cell fro! the effect" of unfa'ourable gene induced di"turbance" of cellular ho!eo"ta"i"7 Gor e;a!ple"D +7 2ccording to pre"ent day "tati"tic", nearly 5-+0K of the /o!an /ith deleteriou" B*)2 + and 2 !utation" /ill ne'er de'elop the brea"t cancer in their life ti!e7 4hi" i" becau"e of "e'eral other factor" that control the cellular ho!eo"ta"i" for e;a!ple the fa!ily of tu!or "uppre""or gene product" 27 8'en the cell" /ith !utated p53 "tatu" "ho/" the ele'ated p2+ gene product /hich arre"t" cell cycle in re"pon"e to .$2 da!age thi" i" becau"e p2+ al"o get" induced by V.* 5'ita!in . receptor67 4he co!bined !utation of both p53 N V.* /ill be fatal to the indi'idual7 By thi" approach /e can hypothe"i9e that cancer cau"ing gene !utation" !ay co!e under "uch di"cu""ion7 2ny of "uch /ell-characteri9ed gene !utation" !ay al"o ari"e due to abnor!al #$%" and the chance" of nucleotide change, "uch a" #$%" in the due cour"e of e'olution !ay lead to ne/ functional change or #$%" !ay get accu!ulated and lead to higher gene !utation"7 %olygenic !odel" ha'e been propo"ed to e;plain :oint effect of !any "u"ceptibility allele" on brea"t cancer7 #$% !icroarray analy"i" for geno!e /ide detection of cro""o'er region" ha'e al"o been reported 27 by 1irtenberger et al 7 4hu", by adopting "y"te!atic approache", genetici"t" are hoping to gain 'aluable in"ight" into the relation"hip" bet/een gene", gene 'ariant" and phenotype" that /ould ne'er ha'e been

#tudie" ha'e been conducted /here candidate gene loci /ere found to be a""ociated /ith di"ea"e identification, e7g7 2l9hei!erB" di"ea"e, non-in"ulin dependent diabete" !ellitu" 5type II- $I..-6 and chronic li'er di"ea"e7 In the"e ca"e" atte!pt" /ere !ade to deter!ine the e;act location of di"ea"e cau"ing allele" by "aturating a geno!ic region /ith 26 #$% !ar(er" 7 4he propo"ed hypothe"i" of the a""ociation of #$%" of a particular gene lin(ed to a di"ea"e i" depicted belo/D
$ucleotide "e>uence of a particular gene 8'olution #election by gene poly!orphi"!

#elected gene" by nature

Hn"elected gene" 1indo/ period

ene" /ith ne/ function"

Beco!e e;tinct e'entually

cro""o'er region", Hum Genet, ++7 520056 3=@-3@7

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predicted ba"ed on pre'iou" biological (no/ledge7 4he re"ult" of thi" "tudy ha'e been u"eful in predicting bio!ar(er" for brea"t cancer7 Ac#nowled!e ent 2uthor" ac(no/ledge public data ba"e" li(e 8ntre9 eno!e Vie/ for pro'iding /onderful acce"" to hu!an geno!e and )ancer eno!e 2nato!y %ro:ect for pro'iding u"er-friendly acce"" to infor!ation on brea"t cancer7 2uthor" are than(ful to B--*), 0yderabad for pro'iding the facilitie", the .epart!ent of Biotechnology 5.B46, $e/ .elhi for a/ard of fello/"hip" to ## and #)* and )ouncil of #cientific N Indu"trial *e"earch 5)#I*6 $e/ .elhi for a/ard of 8!eritu" #cienti"t to .r &ai"er Ja!il7 References
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