Báo cáo y học: "Migration events play significant role in genetic differentiation: A microsatellite-based study on Sikkim settlers" ppt

Genome Biology 2005, 6:P9 Deposited research article Migration events play significant role in genetic differentiation: A microsatellite-based study on Sikkim settlers Saurav Guha a , R.Trivedi a and V.K.Kashyap a, b* Addresses: a Central Forensic Science Laboratory, Kolkata, India. b National Institute of Biologicals, Noida, India. Correspondence: V.K. Kashyap. E-mail: vkk2k@hotmail.com and sauravguhain@yahoo.com comment reviews reports deposited research interactions information refereed research .deposited research AS A SERVICE TO THE RESEARCH COMMUNITY, GENOME BIOLOGY PROVIDES A 'PREPRINT' DEPOSITORY TO WHICH ANY ORIGINAL RESEARCH CAN BE SUBMITTED AND WHICH ALL INDIVIDUALS CAN ACCESS FREE OF CHARGE. ANY ARTICLE CAN BE SUBMITTED BY AUTHORS, WHO HAVE SOLE RESPONSIBILITY FOR THE ARTICLE'S CONTENT. THE ONLY SCREENING IS TO ENSURE RELEVANCE OF THE PREPRINT TO GENOME BIOLOGY'S SCOPE AND TO AVOID ABUSIVE, LIBELLOUS OR INDECENT ARTICLES. ARTICLES IN THIS SECTION OF THE JOURNAL HAVE NOT BEEN PEER-REVIEWED. EACH PREPRINT HAS A PERMANENT URL, BY WHICH IT CAN BE CITED. RESEARCH SUBMITTED TO THE PREPRINT DEPOSITORY MAY BE SIMULTANEOUSLY OR SUBSEQUENTLY SUBMITTED TO GENOME BIOLOGY OR ANY OTHER PUBLICATION FOR PEER REVIEW; THE ONLY REQUIREMENT IS AN EXPLICIT CITATION OF, AND LINK TO, THE PREPRINT IN ANY VERSION OF THE ARTICLE THAT IS EVENTUALLY PUBLISHED. IF POSSIBLE, GENOME BIOLOGY WILL PROVIDE A RECIPROCAL LINK FROM THE PREPRINT TO THE PUBLISHED ARTICLE. Posted: 3 June 2005 Genome Biology 2005, 6:P9 The electronic version of this article is the complete one and can be found online at http://genomebiology.com/2005/6/7/P9 © 2005 BioMed Central Ltd Received: 31 May 2005 This is the first version of this article to be made available publicly and no other version is available at present. This information has not been peer-reviewed. Responsibility for the findings rests solely with the author(s).   Migration events play significant role in genetic differentiation: A microsatellite-basedstudyonSikkimsettlers.    SauravGuha a ,R.Trivedi a andV.K.Kashyap a,b * a CentralForensicScienceLaboratory,Kolkata b NationalInstituteofBiologicals,Noida     Key Words : Microsatellite, Migration, Sikkim, Mongoloids, Genetic Diversity, Genetic Distance.     Runningtitle:MicrosatellitePolymorphismofSikkimSettelers.        *Correspondingauthor:- National  InstituteofBiologicals, A32,Sector62(InstitutionalArea) Noida-201307,India TEL:-+91-120-2400027,FAX:-+91-120-2400027, E-MAIL:vkk2k@hotmail.com andsauravguhain@yahoo.com    Abstract  Background: AwidespectrumofgeneticdiversityinmongoloidsofIndiaiswelldocumented.Thoughall mongoloidsofIndiaareknowntohaveoriginatedfromtheMongolregionofChinabutthe periodandrouteofmigrationfromtheirnativelandtodifferentHimalayanregionsislittle known.ThusthestudiesongenomicdiversityofpeopleofSikkim,acentralHimalayanstate ofIndiawithdifferentmigrantmongoloidgroups,assumegreatsignificanceinunderstanding theimpactofmigratoryeventsinthegeneticdifferentiationofpopulations.Wetherefore studiedthegeneticdiversityonthebasisof13-tetranucleotideand2pentanucleotide microsatellitelociforatotalof208allelefrequenciesinthreemajorpopulationsofSikkim, withdifferentethnohistoryandtimeofsettlement. Result: Thestudyonmicrosatelliteallelefrequencydatasuggeststhatallthethreepopulationsof SikkimaregeneticallymoreakintothemongoloidsofChinaanddistinctlyapartfromthe mongoloidsofNortheastIndia.HoweverSikkimpopulationsarealsogeneticallycloseto non-mongoloidsofsurroundingareas.Theaverageheterozygosityandcoefficientofgene differentiationamongSikkimpopulationsaremoderate.Numberofsharedallelesandtheir frequencies,timeofdivergenceandbottleneckeffectrevealadistinctivenessofthe mongoloidssettledinSikkimfromthemainIndianmongoloidstockasalsodifferentrouteof migrationthanthemongoloidpopulationofNortheastIndia . Conclusion: OurstudyclearlydemonstratesthatthepresentdaymongoloidsofSikkimaregenetically distinctfrommongoloidsofNortheastIndiaduetotheirdifferentrouteofmigration,timeof settlement,andadmixturewithothernon-mongoloidpopulationsofadjoiningareas.This substantiatesthatmigratoryeventshaveplayedasignificantroleinthedifferentiationof mongoloidsofIndia.          Background Theorigin,dispersalandantiquityofHomosapiensintheAsianpeninsulahave attainedhighsignificanceafterthediscoveryofnewarchaeologicalandanthropological evidencesfromEastAsia.Theextensivegeneticinformationpresentonmongoloids,amajor humanethnicgroupofeasternandsoutheasternAsia,alsoprovidesadeepinsightintothe originofmodernhumanandthetimeoftheirdispersalindifferentcontinents. Mongoloidsconstituteaboutone-fourthoftheworldpopulationandexhibitahigh levelofdiversity.InIndia,mongoloidscontributeapproximately3%ofthetotalpopulation, mainlyinhabitingthehillsandadjoiningplainsofNortheastandCentralHimalayas. MongoloidsinIndiaareoriginallythemigrantgroupsandtheirsettlementsindifferent regionsofthecountrywerenotasasingleinflux;rather,aprocessoflargerorsmallerwaves ofmigration.Thesemigrantpopulationsinteractedwiththenon-mongoloidpopulationsdue togeographicalproximity.Becauseofdifferentperiodsoforiginfromvariousregions, migrationandsettlement,mongoloidsofIndiadifferentiatedindifferentsocio-linguistic culturalgroupswhichhaveimpactedtheirgeneticstructure.  AmongthedifferentareasofmongoloidethnicityinIndia,Sikkim–anIndianstate whichisgeographicallyabufferzonebetweenmongoloidandnon-mongoloidpopulationsof SouthAsia isuniqueinitspopulationstructure.GeographicallySikkimissurroundedby theRoyalKingdomofNepalinthewest,theRoyalKingdomofBhutanintheeast,Chinain thenorthwithmongoloidpopulationsandtheIndianstateofWestBengalinthesouthwith bothmongoloidnon-mongoloidpopulations.Moreover,thegeneticstructureofSikkim populationwiththeirbiologicalaffinities,originsanddispersalisimportantinunderstanding theimpactofmigrationonthegeneticstructureofMongoloidsinIndia.TheNepali,Bhutia andLepcha thethreemajorpopulationsinthisHimalayanland representtheIndo-   mongoloidethnicgroup,albeittheLepchaaresaidtobetheforerunneramongthesettlersin thestate,followedbyBhutiaandNepalimigrationinthestate[1].TheBhutiacommunityis basicallythepeopleofTibetan(Chinese)origin,andtheirmigrationtoSikkimhadoccurred atleast800yearsago.TheNepalesearrivedinSikkimabout200yearsago[1].Thoughthe migrationofLepchatoSikkimisacontentiousissue,therearetwomajortheoriesaboutthe LepchaoriginandperiodofmigrationtoSikkim:(i)AsmallpopulationofNagastockfrom theGarohillsofAssammigratedtoSikkimabout2000yearsago,and(ii)agroupfromeast AsiamainlandmigratedthroughTibet(China)duringanearlierphaseofhumanmigrationto theHimalayasatleast3000yearsago[1]. ThecomplexmigrationandsettlementhistoryofdifferentgroupsinSikkimwith respecttotheirgenetichistoryisstilllittleknown .AutosomalandYchromosomeSTR markers[2-4],aswellasMitochondrialDNA[5]studiesillustratemigrationandgenetic diversityofmongoloidsinEastandSouth-EastAsia.Thesestudies,however,donotprovide anyinformationaboutmongoloidmigrationandsettlementindifferentregionsofIndia. Although,severalstudieshavebeencarriedoutongeneticdiversity,phylogenetic relationship,andthepatternofgeneflowamongIndianmongoloidpopulationsbasedon classicalgeneticmarkers,e.g.Tf,Ge,PGM1loci[6,7],serumproteinsandredcellenzymes [8],andacombinedstudybyRoychoudhuryandNei.[9],theyfailtoprovideanyinsightinto thehistoryofmigrationandsettlementofMongoloidsinIndia.Similarlythestudywith17 polymorphicsystemofthebloodbyBhasinetal.1986providesinformationaboutthegenetic structureofpeopleofSikkimtosomeextent. InthisstudyweusedmicrosatelliteDNAmarkerstoaddresstheconsequenceof migratoryeventsongeneticstructureofSikkimpopulationsas,theyaremoreabundantinthe   genomevis-à-visclassicalgeneticmarkers[10],havehighheterozygosity[11]and polymorphismisubiquitousevenininbredpopulatiosnorspecies[12].Microsatellitesare easilyamenabletoautomatedprocedureoftyping[13]andtostatisticaltoolsusedforother markers[14,15].Theanalyticaltechniquesofquantitativegeneticsarebeingappliedto microsatellitealleles,astheyarecharacterizedquantitativelybytheirsize,i.e.numberof repeatofDNAmotif.Measuresofpopulationsubdivision[16]anddistancebetweenthe populations[17,18]aswellashigherstatistics[19,20]havebeenextensivelyemployedfor thestudyofmicrosatellitepolymorphisms.  Theaboveadvantageshavemademicrosatellitemarkersextremelyinformativein understandingthegeneticstructure,migratoryhistoryandevolutionofhumanpopulations[21 -23]andourmarkerofchoicetoexaminetheimpactofmigratoryeventsonthegenetic differentiationofSikkimsettlersandtheirgeneticrelationshipwithothermongoloidsof NortheastIndia,andCaucasoid-affiliatedpopulationsofadjoiningarea.  Results Geneticdifferentiation&heterozygosity:- LocusandpopulationwiseheterozygosityandGst(coefficientofgenedifferentiation) valuesreflectingtheextentofdifferentiationamongthepopulationsofSikkimareshownin Table1.TheaverageGstvalue(0.0237)suggestsmoderatedegreeofgenedifferentiation amongthestudiedpopulations.Thevalueshowevervastlydifferfromlocitoloci;itisonly 0.004atlociD3S1358,andD16S539,while0.088atlociFGA.Similarlymoderate differentiation(0.0206to0.0365)wasobservedatlociPentaD,CSF1PO,TPOX,D8S1179, VWA,D5S818andD7S820.Averageheterozygosityobservedatdifferentlocidepictsthe   extentofvariationamongtheSikkimpopulations(Table1).Theaverageheterozygositiesof threepopulationswere0.786(Nepali),0.747(Bhutia)and0.684(Lepcha).Amongthe15loci, highestheterozygositywasobservedatlocusPentaE(0.841-0.902)andlowestatlocus TPOX(0.546-0.634). Alleledistribution&Variance:- Ingeneral,thenumberofsharedallelesandtheirfrequenciesamong12populations vastlydifferfromlocitoloci,(Table2)(noallelefrequenciesaregiven).Ofthetwelve microsatelliteloci(excludedPentaD,PentaEandD16S539),thenumberofallelespresentat lociD21S11(V=2.239),vWA(V=2.78),D8S1179(V=3.77)D18S51(V=6.38)andFGA (V=3.98)arequitevariedamongthepopulationswhereasotherlocidemonstrateanarrow rangeofvariation(V<2.000).InD21S11andFGAthenumberofsharedallelesrangesfrom (6-16)to(7-18)respectivelyindifferentpopulations.TheGaroexhibitonly6alleles(V= 0.892)whiletheLepchahave16alleles(V=2.93)atD21S11.TheLepchasshowonly7 alleles(V=1.123)atFGAlocusatwhichtheNepaliexhibit18alleles(V=5.096).AtD18S51 theNagaexhibit10alleles(V=5.892)whereasNepaleseexhibitamaximumof15 alleles,(V=8.736).Thevariationsofnumbersofsharedallelesarerelativelystablefor differentlociinnon-mongoloidsandChinesecomparedtoIndo-mongoloids.Thefrequencies ofsharedallelesfluctuatefrompopulationtopopulation.Atthetetranucleotiderepeatlocus THO1,theallelefrequencydistributionisquitevariedamongpopulations.Repeat9isthe predominantalleleineveryAsianmongoloidpopulationwithfrequencyof0.40to0.52[24], whichisalsoobservedinallthethreepopulationsofSikkimviz.theNepali(0.492),Bhutia (0.343)andLepcha(0.500).Butrepeat9.3not9showsanoticeablefrequency(≥0.300) amongthemongoloidpopulationofNortheastIndia,whichisobservedinmuchlower   frequency(<0.15)inSikkimpopulationslikeotherAsianmongoloidpopulations[24].At locusD13S317theallele18isalsopresentwithmoderatefrequency(>0.200)inmongoloid populationsofNortheastIndiacomparedtootherpopulations. Bottlenecktest:- WeperformedSIGNtestforthreeSikkimpopulationstofindouttheextentof bottleneckeffectthatthesepopulationsmighthaveexperienced.Inarecentlybottlenecked populationtheobservedgenediversity(He)ishigherthanexpectedequilibriumgene diversity(Heq)ifthelociareevolvingundertheIAM[25].IfthelocievolveundertheSMM, thentherecanbeasituationwhenheterozygosityexcess(He>Heq)isnotbeingobserved [26].TheSIGNtestresultsunderIAMandSMMassumptionsarepresentedinTable3.In NepalipopulationunderIAM14locishowedheterozygosityexcess(He>Heq)with(P= 0.00484)andunderSMM,8locishowed(He>Heq)with(P=0.41469).Bhutiapopulation exhibited13lociwith(He>Heq)(P=0.02380)underIAMandinSMM5lociwith(He>Heq), (P=0.04238).UnderIAMLepchashowed9lociwith(He>Heq)(P=0.57428)andinSMM2 lociwith(He>Heq)(P=0.00037).Thesevaluesindicateasignificantlevelofbottleneck withinthesepopulationsduringtheirperiodofmigrationtodifferentregions. GeneticDistance&Phylogeny:- Thegeneticdistancesamongthepopulationswerecomputedbyemployingdifferent geneticdistancemeasuresviz.D A, Ds , Dc,Dsw,Fstand(δµ) 2  forallelefrequenciesof12STR loci.TheNJ,(Figure1)andUPGMA(notshown)phylogeneticconstructionwiththese distanceswerequitesimilarinwhichNaga,Kuki,GaroandHmarformadifferentcluster with96-97%bootstrapvalueseparatedfromthemaincluster.InNJtreewithdistancesD A, Ds , Dc,Dsw,andFst,theNepali,BhutiaandLepchaformaclusterwithChineseand   Caucasoid affiliatedBrahminsofIndia,whereaswith(δµ) 2 Garopopulationformacluster withCaucasoid.InthisstudywepresentNJtreeforDcandDasincetheyaremoreprecisefor obtainingthecorrecttreetopology[27]. TimeofDivergence:- ThetimeofdivergenceofLepchafromNagawascalculatedbyusingDs , Dswand (δµ) 2 distancesasthesedistancesarelineartoevolutionarytime[27]andaverage microsatellitemutationratei.e.5.6x10 -4 pergeneration[28].Theseparationtimeforthese populationsisvariedfordifferentdistancecalculations,itis1718yearsforDsw,3730years forDsand8303yearsfor(δµ) 2 .ForourstudywefindDstobemoresuitablefordivergence timecalculationsince(δµ) 2 andDswarenotpreciseifthepopulationsizeisnotconstant throughoutevolutionandhasexperiencedbottleneck.Italsoexhibitshighheterozygosity level(nearly0.800)withsmalldivergencelevelamongthepopulationsthatareconnectedby weakgeneflow[27,29].    Discussion Themigrationofmongoloidsfromtheirnativelandisknowntooccurindifferent phases,periodsanddirections.Reportedly,atleast6.5Kybpyearsagoasmallgroupof populationfromtheSino-TibetanlinguisticfamilymovedfromthevalleyofYellowriver towardswest,andthenturnedtosouthtosouthwesterndirection[30].Tibeto-Burman speakers,asub-familyofSino-Tibetanlinguisticfamily,followedtwomainroutesof dispersal:(i)towardswestinTibet(China)andthendowntoNepal,Sikkim,Bhutanand NorthernIndia,and(ii)towardssouthwestdowntherivervalleysalongtheeasternedgeof theTibetanplateauthroughthe'EthnicCorridor'.Duringmigrationtherehavebeenseveral   contactsbetweennorthernandcentralAsianlanguageswithTibeto-Burmanlanguages[31]. TheselanguagecontactswereresponsibleforgeneticaffinityofTibeto-Burmanlinguistic familieswithnonTibeto-Burmanlinguisticfamiliesofadjoiningareas.  MongoloidsofCentralHimalayasandNortheastIndiabelongtotwodifferent linguisticsubfamiliesunderTibeto-Burmansublinguisticfamily.Sikkimpopulationsbelong toHimalayishlinguisticgroup(Indo-sphere)whilethenortheasternIndianMongoloid populationsbelongtoJingpho-konyak-bodoandkuku-chin-nagagroup(Sino-sphere)under Tibeto-Burmanlinguisticsubfamily[32].Thesesub-languagegroupshavebeendevelopedas theresultofaclosecontactofmongoloidswithsurroundingnon-mongoloids.TheIndo- spheregrouphasastronginfluencefromIndicandDravidianlanguagesofIndia[32]. Phylogenetictreesbasedupon12microsatellitemarkersclearlydepictapatternofco- evolutionofgenesandlanguagesinthestudiedpopulation.TheclusteringpatternofNJtree withDa,Ds,Dc,DswandFstdistancesexplicitlydemonstrated,Sikkimpopulations’genetic affinitytoCaucasoid affiliatedBrahminsofIndiaratherthanmongoloidsofNortheastIndia  TheSikkimpopulationsexhibitaclearclusteringpatternwithChinesepopulationasboth SikkimandChinesepopulationshaveexperiencedgeneflowfromCaucasianpopulation duringtheirmigrationfromthemainlandofeastAsiathroughdifferentroutes.Mongoloidsof NortheastIndia(Naga,Kuki,HmarandGaro)constituteaseparateclusterwith96-97% bootstrapvalueandarephylogeneticallydistantfromMongoloidsofSikkim,andChinaas wellasfromCaucasoidaffiliatedBrahminpopulationofIndia. Thenumbersofsharedallelesdistributionandtheirvariancewithinlocifluctuate frompopulationtopopulation,whichishighlynoticeableatlociD21S11,D18S51,D8S1179, VWAandFGA.Thisdistributionpatternclearlydepictsalargenumberofvariationspresent [...]... 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Princeton University Press, Princeton, NJ 1994 34 Singh KS: India's Communities, National Series People of India Oxford University Press, 1998 35 Kashyap VK, Guha S, Trivedi R: Concordance study on 15 STR loci in Three Major Population of Himalayan State Sikkim J Forensic Sci 2002, 47:1163-1167 36 Sambrook J, Fritsch EF, Maniatis T: Molecular Cloning A Laboratory Manual 2nd ed Cold Spring Harbor Laboratory... Laboratory Press, Cold Spring Harbor, NY, 1989 37 Dutta R, Kashyap VK: Genetic variation observed at three tetrameric short tandem repeat loci HUMTHO1, TPOX, and CSF1PO in five ethnic population groups of Northeastern India Am J Hum Biol 2001, 13: 23-29 38 Chattopadhyay P, Dutta R, Kashyap VK: Genetic variation observed at Nine Fluorescent labeled STR loci among Four Tribal population group of the Indian . SahaN,BhattacaryyaSP,MukhopadhyayB,BhattacharyyaSK,GuptaR,Basu A: A genetic study amongtheLepchasoftheDarjeelingareaofeasternIndia,Human Heredity198 7a, 37:113-121. 7. SahaN,MukhopadhyayB,BhattacharyyaSK,GuptaR,Basu A: Thedistributionof transferring,. KK, Wallace DC: Southeast Asia mitochondrial DNA analysis reveals genetic continuityofancientmongoloidmigrations.Genetics1992,130:139-152 6. SahaN,BhattacaryyaSP,MukhopadhyayB,BhattacharyyaSK,GuptaR,Basu A: A genetic study amongtheLepchasoftheDarjeelingareaofeasternIndia,Human Heredity198 7a, 37:113-121. 7.. representtheIndo-   mongoloidethnicgroup,albeittheLepchaaresaidtobetheforerunneramongthesettlers in thestate,followedbyBhutiaandNepalimigration in thestate[1].TheBhutiacommunityis basicallythepeopleofTibetan(Chinese)origin,andtheirmigrationto Sikkim hadoccurred atleast800yearsago.TheNepalesearrived in Sikkim about200yearsago[1].Thoughthe migrationofLepchato Sikkim is a contentiousissue,therearetwomajortheoriesaboutthe Lepchaoriginandperiodofmigrationto Sikkim: (i) A smallpopulationofNagastockfrom theGarohillsofAssammigratedto Sikkim about2000yearsago,and(ii) a groupfromeast AsiamainlandmigratedthroughTibet(China)duringanearlierphaseofhumanmigrationto theHimalayasatleast3000yearsago[1]. Thecomplexmigrationandsettlementhistoryofdifferentgroups in Sikkim with respecttotheir genetic historyisstilllittleknown .Autosomaland Y chromosomeSTR markers[2-4],aswellasMitochondrialDNA[5]studiesillustratemigrationand genetic diversityofmongoloids in EastandSouth-EastAsia.Thesestudies,however,donotprovide anyinformationaboutmongoloidmigrationandsettlement in differentregionsofIndia. Although,severalstudieshavebeencarriedout on genetic diversity,phylogenetic relationship,andthepatternofgeneflowamongIndianmongoloidpopulationsbased on classical genetic markers,e.g.Tf,Ge,PGM1loci[6,7],serumproteinsandredcellenzymes [8],and a combined study byRoychoudhuryandNei.[9],theyfailtoprovideanyinsightinto thehistoryofmigrationandsettlementofMongoloids in India.Similarlythe study with17 polymorphicsystemofthebloodbyBhasinetal.1986providesinformationaboutthe genetic structureofpeopleof Sikkim tosomeextent. In this study weusedmicrosatelliteDNAmarkerstoaddresstheconsequenceof migratory events on genetic structureof Sikkim populationsas,theyaremoreabundant in the   genomevis-à-visclassical genetic markers[10],havehighheterozygosity[11]and polymorphismisubiquitouseven in inbredpopulatiosnorspecies[12].Microsatellitesare easilyamenabletoautomatedprocedureoftyping[13]andtostatisticaltoolsusedforother markers[14,15].Theanalyticaltechniquesofquantitativegeneticsarebeingappliedto microsatellitealleles,astheyarecharacterizedquantitativelybytheirsize,i.e.numberof repeatofDNAmotif.Measuresofpopulationsubdivision[16]anddistancebetweenthe populations[17,18]aswellashigherstatistics[19,20]havebeenextensivelyemployedfor the study ofmicrosatellitepolymorphisms. 