The Genetics of Bene Israel from India Reveals Both Substantial Jewish and Indian Ancestry

28 Pages·2016·3.31 MB·English

RESEARCHARTICLE
The Genetics of Bene Israel from India
Reveals Both Substantial Jewish and Indian
Ancestry
YedaelY.Waldman1,2☯,ArjunBiddanda1☯,NatalieR.Davidson1¤,PaulBilling-Ross1,
MayaDubrovsky3,4,ChristopherL.Campbell5,CaroleOddoux5,EitanFriedman3,4,
GilAtzmon6,7,EranHalperin2,8,9,HarryOstrer5,10,AlonKeinan1*
1 DepartmentofBiologicalStatisticsandComputationalBiology,CornellUniversity,Ithaca,NY,United
StatesofAmerica,2 DepartmentofMolecularMicrobiologyandBiotechnology,TelAvivUniversity,Ramat
Aviv,TelAviv,Israel,3 DanekGertnerInstituteofHumanGenetics,ChaimShebaMedicalCenter,Tel-
Hashomer,Israel,4 SacklerSchoolofMedicine,TelAvivUniversity,RamatAviv,TelAviv,Israel,
5 DepartmentofPathology,AlbertEinsteinCollegeofMedicine,Bronx,NY,UnitedStatesofAmerica,
6 DepartmentsofMedicineandGenetics,AlbertEinsteinCollegeofMedicine,Bronx,NY,UnitedStatesof
America,7 DepartmentofHumanBiology,FacultyofNaturalSciences,UniversityofHaifa,Haifa,Israel,
8 TheBlavatnikSchoolofComputerScience,TelAvivUniversity,RamatAviv,TelAviv,Israel,
9 InternationalComputerScienceInstitute,Berkeley,California,UnitedStatesofAmerica,10 Departmentof
Pediatrics,AlbertEinsteinCollegeofMedicine,Bronx,NY,UnitedStatesofAmerica
OPENACCESS
☯Theseauthorscontributedequallytothiswork.
Citation:WaldmanYY,BiddandaA,DavidsonNR, ¤ Currentaddress:ComputationalBiologyCenter,MemorialSloanKetteringCancerCenter,NewYork,NY,
Billing-RossP,DubrovskyM,CampbellCL,etal. UnitedStatesofAmerica
(2016)TheGeneticsofBeneIsraelfromIndia *[email protected]
RevealsBothSubstantialJewishandIndian
Ancestry.PLoSONE11(3):e0152056.doi:10.1371/
journal.pone.0152056 Abstract
Editor:ManfredKayser,ErasmusUniversityMedical
Center,NETHERLANDS TheBeneIsraelJewishcommunityfromWestIndiaisauniquepopulationwhosehistory
Received:September7,2015 beforethe18thcenturyremainslargelyunknown.BeneIsraelmembersconsiderthem-
selvesasdescendantsofJews,yettheidentityofJewishancestorsandtheirarrivaltimeto
Accepted:March8,2016
Indiaareunknown,withspeculationsonarrivaltimevaryingbetweenthe8thcenturyBCE
Published:March24,2016
andthe6thcenturyCE.Here,wecharacterizethegenetichistoryofBeneIsraelbycollect-
Copyright:©2016Waldmanetal.Thisisanopen
ingandgenotyping18BeneIsraelindividuals.Combiningwith486individualsfrom41
accessarticledistributedunderthetermsofthe
otherJewish,IndianandPakistanipopulations,andadditionalindividualsfromworldwide
CreativeCommonsAttributionLicense,whichpermits
unrestricteduse,distribution,andreproductioninany populations,weconductedcomprehensivegenome-wideanalysesbasedonF ,principal
ST
medium,providedtheoriginalauthorandsourceare componentanalysis,ADMIXTURE,identity-by-descentsharing,admixturelinkagedisequi-
credited.
libriumdecay,haplotypesharingandallelesharingautocorrelationdecay,aswellascon-
DataAvailabilityStatement:Dataareavailablefrom trastedpatternsbetweentheXchromosomeandtheautosomes.ThegeneticsofBene
theDataAccessCommitteefortheJewishHapMap
IsraelindividualsresemblelocalIndianpopulations,whileatthesametimeconstitutinga
Project(EdwardBurns,GilAtzmonandHarryOstrer;
contacte-mail:[email protected]), clearlyseparatedanduniquepopulationinIndia.TheyareuniqueamongIndianandPaki-
followingthestudyprotocolapprovedbytheNYU stanipopulationsweanalyzedinsharingconsiderablegeneticancestrywithotherJewish
SchoolofMedicineInstitutionalReviewBoardin
populations.PuttingtogethertheresultsfromallanalysespointtoBeneIsraelbeingan
2008.
admixedpopulationwithbothJewishandIndianancestry,withthegeneticcontributionof
Funding:AKandYYWweresupportedinpartby
eachoftheseancestralpopulationsbeingsubstantial.Theadmixturetookplaceinthelast
NationalInstitutesofHealth(NIH)Grant
millennium,about19–33generationsago.ItinvolvedMiddle-EasternJewsandwassex-
R01HG006849.AKwasalsosupportedinpartby
NIHGrantR01GM108805andbyTheEllison biased,withmoremaleJewishandlocalfemalecontribution.Itwasfollowedbyapopulation
MedicalFoundationandtheEdwardMallinckrodt,Jr.
PLOSONE|DOI:10.1371/journal.pone.0152056 March24,2016 1/28
IndianBeneIsraelGeneticsRevealsBothJewishandIndianAncestry
Foundation.EHisafacultyfellowoftheEdmondJ. bottleneckandhighendogamy,whichcanleadtoincreasedprevalenceofrecessivedis-
SafraCenterforBioinformaticsatTelAvivUniversity. easesinthispopulation.Thisstudyprovidesanexampleofhowgeneticanalysisadvances
EHandYYWwerepartiallysupportedbytheIsraeli
ourknowledgeofhumanhistoryincaseswhereotherdisciplineslacktherelevantdatato
ScienceFoundation(grant1425/13),bytheUnited
States-IsraelBinationalScienceFoundation(Grant doso.
2012304)andbytheGerman-IsraeliFoundation
(Grant1094-33.2/2010).YYWwasalsopartially
supportedbytheLenBlavatnikandtheBlavatnik
FamilyFoundation.NRDwassupportedbytheTri-
InstitutionalTrainingPrograminComputational Introduction
BiologyandMedicine(viaNIHtraininggrant
Howwelldoestheoralhistoryofagroupreflectitsorigins?TheBeneIsraelcommunityin
1T32GM083937).PBRwassupportedbythe
NationalScienceFoundationGraduateResearch WestIndiaisauniquecommunitywhosehistoricalbackgroundbeforethe18thcenturyother
Fellowship(grantNo.2013172342). thantheiroralhistoryremainslargelyunknown[1–3].TheJewishphilosopher,Maimonides,
inaletterwritten800yearsago(circa1200CE),brieflymentionedaJewishcommunityliving
CompetingInterests:Theauthorshavedeclared
thatnocompetinginterestsexist. inIndiaandmayhavereferredtothem[4].Inthe18thcenturyBeneIsraelmemberslivedin
villagesalongtheIndianKonkancoastandwerecalledShanivarTeli(Marathifor'Saturdayoil
pressers'),astheywereoilpresserswhodidnotworkonSaturdays.After1948,mostofthe
communityimmigratedtoIsrael.Atthebeginningofthe21stcentury,approximately50,000
memberslivedinIsrael,whereasabout5,000remainedinIndia,mainlyinMumbai[2].Oral
historyamongBeneIsraelholdsthattheyaredescendantsofJewswhoseshipwreckedonthe
Konkanshore,withonlysevenmenandsevenwomensurviving[2,3,5].Theexacttimingof
thisevent,aswellastheoriginandidentityofthesurvivors,arenotpartofthisoralhistory.
Somedateitaroundtwomillenniaago[2],whereasotherssuggestaspecificdateandorigin:
around175BCE,wherethesurvivorswereJewslivinginthenorthernpartsofthelandofIsrael
thatlefttheirhomesduringthepersecutionsofAntiochusEpiphanes[5].Addingtothevague-
nessofBeneIsraeloriginisthefactthatasimilarstoryofsevensurvivingcouplesisfoundin
theoralhistoriesofotherIndianpopulations[2,3].OtherssuggestthattheancestorsofBene
IsraelarrivedtoIndiaearlier–asearlyasthe8thcenturyBCE–orlater–fromYemen,duringthe
firstmillenniumCEorfromSouthernArabiaorPersiainthe5thor6thcenturyCE[4].How-
ever,beyondvagueoralhistoryandspeculations,therehasbeennoindependentsupportfor
anyoftheseclaims,andBeneIsraeloriginandwhethertheyarerelatedatalltootherJewish
populationsandremain"shroudedinlegend"[4].
Inthelastdecades,geneticinformationhasbecomeanimportantsourceforthestudyof
humanhistoryandhasbeenappliednumeroustimesforvariousJewishpopulations,first
basedonuniparentalYchromosomalandmitochondrialDNA(mtDNA)markers[6–11]and
laterbyusinggenome-widemarkers[12–15].ThesestudiesfoundthatmostJewishDiasporas
shareancestrythatcanbetracedbacktotheMiddle-East,inaccordancewithhistoricalrecords
[12–15].SomeofthesestudiesincludedBeneIsraelmembers,thoughwithinconclusiveresults
[15].BeneIsrael’smtDNApoolwasshowntoconsistofmostlylocalIndianorigin[8,11,13]
althoughafewhaplogroupsfoundinBeneIsraelsampleswerenotpresentinlocalIndianpop-
ulations,butwerepresentinseveralJewishpopulations[11].AYchromosomeanalysishinted
atpaternallinkbetweenBeneIsraelandtheLevant,butthestudywasbasedononlyfourBene
Israelmales[13].AnotherYchromosomeanalysisshowedthatacommonIndianhaplogroup
wasalmostabsentinBeneIsraelmales,whereastheCohenModalHaplotype(CMH)[16]was
commoninBeneIsrael(andotherJewish)malesthoughalsopresentatlowerfrequenciesin
otherIndianpopulations[3].Theseresultssuggestthatthefoundingmalesofthispopulation
mighthavehadMiddleEastern,possiblyJewish,origins.Onthecontrary,analysisoftheauto-
somesortheXchromosomedidnotfindanyevidenceofJewishoriginofBeneIsrael,andit
hasbeenconcludedthattheyresembledotherIndianpopulations[13,15].Thus,geneticstudies
todateleftthegenetichistoryofBeneIsraellargelyunknown.
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IndianBeneIsraelGeneticsRevealsBothJewishandIndianAncestry
ThecomplexgeneticstructureofIndianpopulationsimposesagreatchallengeforgenetic
analysisofBeneIsrael.PreviousstudiesshowedthatmostcontemporaryIndianpopulations
arearesultofancientadmixture(64–144generationsago)oftwogeneticallydivergentpopula-
tions:AncestralNorthIndians(ANI),whoarerelatedtowestEurasians,andAncestralSouth
Indians(ASI),whoarenotcloselyrelatedtopopulationsoutsideIndiaandrelatedtoindige-
nousAndamanIslandpeople[17,18].DifferentIndianpopulationsvaryintheproportionof
admixturebetweenthesetwoancestralpopulations[18].AstheANIcomponentisrelatedto
westEurasia,whichincludestheMiddleEastandEurope,astudyanalyzingtheconnection
betweenBeneIsraelandotherJewishorMiddleEasternpopulationsneedstoexaminewhether
suchaconnectionreflectsauniqueancestrycomponent,ratherthansimplybeingaresultof
thelargeANIcomponent.
TostudythegenetichistoryofBeneIsrael,whileaddressingthischallenge,wepresenthere
thelargestcollectionofBeneIsraelindividualsthathasbeenassayedgenome-widetodate(18
individuals),andweusethecollectioninconjunctionwithgenotypedataof486individuals
from41otherJewish,IndianandPakistanipopulations,aswellassamplesfromvariousworld-
widepopulations.Weapplyanarrayofgenome-widepopulationgeneticstoolstocharacterize
theoriginsofBeneIsraelandtheirrelationstobothIndianandJewishpopulations,uncovering
thegenetichistoryofthisuniquepopulation.
Results
BeneIsraelclusterwithIndianpopulationsbutasadistinctgroup
WegenotypedBeneIsraelindividualsandcombinedthedatawith14otherJewishpopulations
fromworldwideDiasporapreviouslygenotypedusingthesamearray[12,14].Weappliedvari-
ousqualitycontrol(QC)stepsonthesesamples,resultingwith18individualsoftheBeneIsrael
communitytogetherwith347samplesfromtheother14Jewishpopulations.Wealsoapplied
thesameQCstepstoadifferentdatasetwithsamplesfrom18differentIndianpopulations(96
individuals)[17],aswellasHapMap3populations,thatweregenotypedpreviouslyonthe
samearray[17]andmergedthetwodatasets.Wealsomergedthedatawithadditionalpopula-
tionsfromtheHGDPpanel[19]:threenon-JewishMiddleEasternpopulations(Druze,Bed-
ouinandPalestinians),andninePakistanipopulations(S1Table).TheMiddle-Eastern
populationswereusedtodistinguishbetweenMiddle-EasternandJewishspecificancestry
whilethePakistanipopulationswereusedtorepresentpopulationsthataregeographically
locatedbetweenIndiaandtheMiddle-East.Inaddition,somePakistanipopulationsarealso
partoftheANI-ASIadmixture,witharelativelylargeANIcomponentascomparedtothe
Indianpopulations[17,18]andthereforealsorepresentthisancientadmixture.Asthemerging
withHGDPresultedinconsiderablereductioninnumberofSNPsavailableforanalysis,we
onlyconsideredthismergeddatasetforsomeanalyses.
PCA(PrincipalComponentAnalysis)ofthemergeddataset,includingfourHapMappopu-
lations(YRI,CEU,CHBandJPT;total873individuals)showedthatJewishpopulationscluster
togetherwithEuropeansandMiddle-Easternpopulations,whileIndianandPakistanipopula-
tionsformtheirowncluster,betweenEast-AsiansandJews/Europeans(Fig1A).TheBene
IsraelpopulationclusteredwiththeIndianandPakistanipopulations,similartotheresultsofa
previousstudy[13].BeneIsraelwastheclosesttotheJewish/Middle-Eastern/Europeancluster
ascomparedtoallotherIndianpopulations,whileseveralPakistanipopulationswereeven
closertothatclusterthanBeneIsrael(Fig1A).WhenfocusingonlyonJewish,Middle-Eastern,
PakistaniandIndiansamples(Fig1B),thefirstPCseparatedbetweenIndian/Pakistaniand
Jewish/Middle-EasternpopulationswhilethesecondPCspannedtheJewishpopulations.
Membersofnon-JewishMiddle-EasternpopulationswerelocatedwithintheJewishcluster,
PLOSONE|DOI:10.1371/journal.pone.0152056 March24,2016 3/28
IndianBeneIsraelGeneticsRevealsBothJewishandIndianAncestry
Fig1.PrincipalComponentAnalysisofJewish,Indianandworldwidepopulations.Eachpanelpresentsthetoptwoprincipalcomponentsforasetof
populationsthatincludeBeneIsraeltogetherwith:(A)Jewish,Indian,Pakistani,MiddleEasternandfourworldwideHapMappopulations(CEU,CHB,JPT
andYRI);(B)Jewish,Middle-Eastern,PakistaniandIndianpopulations;(C)IndianandPakistanipopulations;(D)Jewish,Middle-EasternandPakistani
populations.AbbreviationsofJewishpopulations:BeneIsrael(Bene),AlgerianJews(ALGJ),AshkenaziJews(ASHJ),DjerbanJews(DJEJ),GeorgianJews
(GEOJ),GreekJews(GRKJ),IranianJews(IRNJ),IraqiJews(IRQJ),ItalianJews(ITAJ),LibyanJews(LIBJ),MoroccanJews(MORJ),SyrianJews(SYRJ),
TunisianJews(TUNJ),YemeniteJews(YMNJ).
doi:10.1371/journal.pone.0152056.g001
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IndianBeneIsraelGeneticsRevealsBothJewishandIndianAncestry
nearMiddle-EasternJewishpopulations.Indianpopulationswereorderedbasedontheir
ANI-ASIadmixture[17,18]suchthatpopulationswithhigherANIproportionwerecloserto
Jewsingeneral,asexpectedfromtheMiddle-Easternoriginsofthelatter[12–15].BeneIsrael
memberswerelocatedcloselytomembersofotherIndianpopulationsbutwerealsotheclosest
tosamplesfromJewishpopulationsamongallIndiansamples,whilesomePakistanipopula-
tionsweremoresimilartoJewishandMiddle-Easternpopulations(Fig1B).PCAwithonly
BeneIsrael,IndianandPakistanipopulationshowedtheANI-ASIinclinespanningboth
IndianandPakistanipopulations,whileBeneIsraelwerenearpopulationswithhighANIcom-
ponent,butslightlyofftheincline,perhapssuggestingadifferentorigin.(Fig1C).PCAofonly
BeneIsrael,Pakistani,Middle-EasternandJewishpopulationsshowedtheseparationofBene
IsraelmembersfromotherJewishpopulationsandthefactthatsomePakistanipopulations
werecloserthanBeneIsraeltoJewishpopulations(Fig1D).ToavoidbiasinPCAduetodiffer-
encesinnumberofsamplesbetweenpopulations[20],werepeatedtheanalysiswhilelimiting
thenumberofsamplesfromeachpopulationto4,andobtainedsimilarresults(S1Fig).
WealsoexaminedtherelationbetweenBeneIsraelandotherIndianandJewishpopulations
usingtheF statistic,whichmeasuresgeneticdriftbetweenpopulationsbasedondifferences
ST
inallelefrequencies[17,21](S2FigandS2Table).Thisanalysisrevealedtheisolationand
geneticdriftofBeneIsraelfrombothIndianandJewishpopulations:WhiletheaverageF
ST
betweenpairsofJewishpopulationswas0.011,theaverageF betweenBeneIsraelandother
ST
Jewishpopulationswassignificantlyhigher(0.04,WilcoxonranksumP-value=1.97e-9).Simi-
larly,whiletheaverageF betweendifferentIndianpopulationswas0.011,themeanF
ST ST
betweenBeneIsraelandotherIndianpopulationswassignificantlyhigher(0.033,P-
value=8.63e-12,Wilcoxonranksumtest).
ADMIXTUREanalysissuggestsBeneIsraelmembershaveMiddle-
Easternancestry
ADMIXTURE[22]assignsforeachindividualitsproportioninanyofasetofhypothetical
ancestralpopulationsandhencecanrevealrelationsbetweendifferentpopulations.Weused
thistoolonourdatasetforvaryingvaluesofK(thenumberofhypotheticalancestralpopula-
tions)onthesamesetof873individualsfromthefirstPCA(Fig2andS3Fig).ForK=3,we
observedthreeclusters:EastAsian,Sub-SaharanAfricanandMiddleEastern/European.Indian
andPakistanipopulationsweremainlycomposedfromMiddle-Eastern/EuropeanandEast-
Asiancomponents.TheproportionoftheMiddle-Eastern/EuropeancomponentintheIndian
andPakistanipopulationswashighlycorrelatedtotheirANIcomponentintheANI-ASI
admixture[17](R=0.98,P-value<e-16,Spearmancorrelation).AmongtheIndianpopula-
tions,BeneIsraelhadthehighestproportionofMiddle-Eastern/Europeancomponent,butit
wascomparabletothatofsomeotherPakistanipopulations.AtK=4anIndiancluster
emergedwhichreflectstheASIcomponentinthesepopulationsandmostIndianandPakistani
populationswerecomposedfromthiscomponentandtheMiddle-Eastern/Europeancompo-
nent,whilesomeofthemalsohadanEast-Asiancomponent.Again,BeneIsraelandthree
Pakistanipopulations(Balochi,BrahuiandMakrani)hadthehighestproportionsofMiddle-
Eastern/EuropeancomponentamongIndianandPakistanipopulations.AtK=5,theEuro-
pean/Middle-Easternclusterwasdividedintotwoclusters:European(reflectedbytheEuro-
peanpopulationCEU)andMiddle-Eastern(reflectedbyJewishandMiddle-Eastern
populations).Importantly,BeneIsraelpopulationexhibitedadifferenttrendascomparedto
otherIndianpopulations:WhiletheANIcomponentofIndianpopulationswasnowmainly
reflectedintheEuropeancomponent,BeneIsraelshowedasignificantlyhigherproportionofa
Middle-Easterncomponent(mean29.5%ascomparedtolessthan14%inallmembersof
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IndianBeneIsraelGeneticsRevealsBothJewishandIndianAncestry
Fig2.ADMIXTUREanalysisforJewish,Indian,Pakistani,MiddleEastern(Druze,BedouinandPalestinians)andrepresentativeHapMap(CEU,
YRI,JPTandCHB)populations.K,thenumberofclusters,variesfromK=3toK=8.Wecoloredsomeofthepopulationsnamesbasedonthefollowing
groups:BeneIsrael(purple),Jews(red),Indian(blue)andMiddle-Eastern(green).SeealsoS3Fig.
doi:10.1371/journal.pone.0152056.g002
otherIndianpopulations,WilcoxonranksumP-value=1.75e-12).Nevertheless,somePaki-
stanipopulationsshowedsimilarorevenhigherproportionsoftheMiddle-Easterncomponent
(e.g.,meanof33%forMakrani).AtK=6,whichprovidedthebestfitbasedoncross-valida-
tion,anewclusteremergedwhichwasmainlyfoundinNorth-AfricanJews(Djerban,Libyan
andTunisianJews).AtK=7anewclusterrepresentedIranianJews,butwasalsopresentin
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IndianBeneIsraelGeneticsRevealsBothJewishandIndianAncestry
largerfractionsinotherMiddle-EasternandAsianpopulations,includingBeneIsrael.Interest-
ingly,atK=8BeneIsraelformedtheirownhypotheticalancestralcomponent,markingagain
theuniquenessofthispopulationanditsdeviationfromotherpopulations.Thisancestral
componentwaspresent,inminuteproportions,inmanyIndianandPakistanipopulationsbut
alsoinsomeMiddle-Easternpopulations(Jewishandnon-Jewish).
Identity-by-descentanalysissuggestBeneIsraelmembersarerelatedto
Jewishpopulations
TheresultsbasedonPCAandADMIXTURE,showthatBeneIsraelismoreclosely-relatedto
Middle-EasternandJewishpopulationsascomparedtoallotherIndianpopulationsexamined
here.However,thesameclaimcannotbemadewhencomparedtosomePakistanipopulations.
Therefore,thequestionremains:DoesBeneIsraelhaveJewishorMiddle-Easternancestrythat
isnotsharedbyotherAsianpopulations?Next,weanalyzedtherelationsbetweenpopulations
basedonIdentity-by-descent(IBD)sharingoftheirindividuals.IBDsegmentssharedbytwo
individualsrepresentasegmentinheritedfromacommonancestor.HigherIBDsharing,and
specificallyoflongsegments,suggestsamorerecentcommonancestorwithoutintervening
recombination[23].FollowingasimilarpreviousanalysisoftheJewishpopulationsexamined
here(exceptBeneIsrael)[12,14],weusedGERMLINE[24]todetectIBDsegmentsbetween
individualsanddefinedtheIBDsharingbetweenindividualstobethetotallength(incM
units)ofIBDsegmentssharedbetweenthetwoindividuals.IBDsharingbetweenpopulations
wasdefinedastheaverageIBDsharingofunrelatedindividualsfromthesepopulations.As
expectedfrompreviousresults,eachJewishpopulationexhibitedsignificanthigherIBDshar-
ingwithotherJewishpopulationsthanwithIndianpopulationsandeachIndianpopulation
exhibitedhigherIBDsharingwithotherIndianpopulationsthanwithJewishpopulations
(WilcoxonP-value<0.05forallpopulations;Fig3A).HavingthesetwoIBDclustersofIndian
andJewishpopulations,weobservedthatcomparedtoallJewishpopulations,BeneIsraelhad
thehighestIBDsharingwithallIndianpopulations,andcomparedtoallIndianpopulations,
BeneIsraelhadthehighestIBDsharingwithallJewishpopulations(S4AFig).Furthermore,
theonlypopulationwithnosignificantIBDsharingbetweenthetwoclustersofJewishand
IndianpopulationswasBeneIsrael:(meanIBDsharing=18.24cMvs.18.19cMwithIndian
andJewishpopulations,respectively.P-value=0.61;Wilcoxonranksumtest;Fig3B).Middle-
EasternJews(specificallyGeorgian,Iraqi,SyrianandIranianJews)showedsignificantlyhigher
averageIBDsharingascomparedtoallotherJewishpopulationsexamined(WilcoxontestP-
value<e-10forallpairs).Interestingly,theclosestIndianpopulationstoBeneIsrael(Velama,
LodiandBhil)werenotthosewiththehighestANIcomponent.
Next,weusedthemergeddatasetwithMiddle-EasternandPakistanipopulationsfora
lower-resolutionIBDanalysis.Still,BeneIsraelshowedhigherIBDsharingwithMiddle-
EasternJewishpopulationsinthisdatasetaswell(Fig3C).Importantly,whilethePCA,and
ADMIXTUREshowedthatsomePakistanipopulationsweremoresimilartoMiddle-Eastern
andJewishpopulationsthanBeneIsrael,noPakistanipopulationshowedashighIBDshar-
ingwithJewishpopulationsascomparedtoBeneIsrael(Fig3C).Inaddition,weusedthis
mergeddatasettoexaminewhethertherelativelyhighIBDsharingofBeneIsraelwithJewish
populationsandmainlyMiddle-EasternJewsisJewishspecificorMiddle-Easterningeneral.
TheIBDsharingofBeneIsraelandnon-JewishMiddle-Easternpopulationswaslowerthan
theirsharingwithallotherJewishpopulations(Fig3C;S4BFig),implyingthatthelink
betweenBeneIsraelandJewishpopulationsisatleastinpartJewish-specificandnotonly
Middle-Eastern.AlthoughthereweredifferencesbetweentheIBDsharinginthetwodatasets
duetothedifferentsetofSNPs,therewasoverallsignificantcorrelationbetweentheranking
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IndianBeneIsraelGeneticsRevealsBothJewishandIndianAncestry
Fig3.IBDsharingbetweenandwithinJewish,Indian,PakistaniandMiddle-Easternpopulations.(A)AverageIBDsharingbetweendifferent
populations.ForeachpopulationwemeasureditsaverageIBDwithBeneIsrael(purple)andallotherJewish(red)andIndian(blue)populations.(B)IBD
sharingofBeneIsraelwithotherJewishandIndianpopulations.(C)AverageIBDsharingbetweendifferentpopulations.ForeachpopulationfrompanelA,
withtheadditionofPakistaniandMiddle-Easternpopulations,wemeasureditsaverageIBDwithBeneIsrael(purple)andallotherJewish(red)andIndian
(blue)populations.(D)IBDsharingofBeneIsraelwithotherJewish,Indian,Pakistaniandnon-JewishMiddle-Easternpopulations.AnalysesinpanelsC-D
wereperformedonthedatasetmergedwithHGDPdatasetthatcontainedsmallernumberofSNPs,andthereforethedifferencesinIBDsharingvalues.(E)
IBDsharingwithinpopulations.
doi:10.1371/journal.pone.0152056.g003
ofIBDsharingofJewish(R=0.85,P-value=1.36e-4;Spearmancorrelation)andIndian
(R=0.52,P-value=0.03,Spearmancorrelation)populationsinthetwodatasets.Higher
sharingwithMiddle-EasternJewishpopulationswasalsoobservedwhenwerestrictedthe
analysistolongersegmentsofIBDthatreflectamorerecentancestor(S5Fig).Whilewedid
notseeacleartrendforIndianpopulationsshowinghigherIBDwithBeneIsrael,thehigher-
resolutionanalysisshowedVelamatohavethehighestIBDsharingalsoinrespecttolonger
IBDsegments(S5Fig).
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IndianBeneIsraelGeneticsRevealsBothJewishandIndianAncestry
BeneIsraelasanadmixedpopulationofJewishandIndianancestral
populations
Motivatedbytheaboveresults,wenextexaminedwhethertheBeneIsraelcommunitywasan
admixtureofIndianandJewishancestralpopulations,usingtwodifferentapproachesasimple-
mentedintheALDER[25]andGLOBETROTTER[26]tools.Givenaputativeadmixedpopu-
lationandtwopopulationsthataretakenassurrogatesforthetrueancestralpopulations,
ALDERcomputesanadmixturelinkagedisequilibrium(LD)statisticintheadmixedpopula-
tionandusesittoexaminewhetherthepopulationisindeedanadmixtureoftheancestralpop-
ulations[25].InmostcasesofoneJewishandoneIndianpopulationtakenassurrogate
ancestralpopulations,therewasaconsistentandsignificantevidenceforBeneIsraelbeing
admixturebetweenthesetwopopulations(147outof252possiblepairs.S3TableandS6Fig;
theonlypopulationthatdidnotshowasignificantevidenceforbeinganancestralpopulation
forBeneIsraelwastheIndianKashmiriPandit).Repeatingthesameanalysisbutwithpairsof
IndianpopulationsorpairsofJewishpopulations,aswellasreplacingBeneIsraelwithany
otherIndianorJewishpopulationdidnotfindanypairwithsignificantandconsistentevi-
denceforadmixture,suggestingthattheobservedadmixtureforBeneIsraelwasnotreflecting
ANI-ASIadmixturebutauniqueadmixturebetweenJewishandIndianpopulations.ALDER
admixtureestimatedtimevariedacrossthe147significantpairsofpopulations,from~19
(IraqiJewsandSatnami)to~33(GeorgianJewsandMala)generationsago(650–1050years
ago,assuming29yearspergeneration[18,27])withanaverageof~25generations(~820
years)ago(S2Table).TheseestimationsplacetheadmixturebetweenaJewishandIndianpop-
ulationwellaftertheestimatedtimefortheANI-ASIadmixturesofIndianpopulations(64–
144generationsago[18])andaftertheestablishmentofmanyJewishDiasporas[15](Fig4A).
TurningtoadmixtureproportionsestimationsbasedonALDER,thoseestimatedforIndian
populations,varyingbetween44%(Vaish)and20.2%(Kharia)weregenerallyhigherthanthat
ofJewishpopulations,varyingbetween23%(GeorgianJews)and15.5%(LibyanJews;Fig4B).
WhenrepeatingALDERanalysisusingthemergeddatasetwithnon-JewishMiddle-Eastern
populations,theresultswerelesssignificant,asexpectedbythesmallernumberofmarkers,
butstillmanypairsofoneJewish/Middle-EasternpopulationandoneIndianpopulationwere
significant.Importantly,theresultsweremoresignificantforJewishpopulationsascompared
tonon-JewishMiddle-Easternpopulations:While3ofthe17(17.6%)Jewish/Middle-Eastern
populationsexaminedwerenon-Jewish,only8ofthe113(7.1%)significantpairscontained
non-Jewishpopulation,andallotherpairscontainedaJewishpopulation(S4TableandS7
Fig).Furthermore,whenwereplacedBeneIsraelwithPakistanipopulations,therewasnoevi-
denceforanyPakistanipopulationbeinganadmixedpopulationwithbothJewishandIndian
ancestry.ThisresultfurtheremphasizesthattheadmixturedetectedbyALDERisnotthe
ANI-ASIadmixture.
Inaddition,weperformedf4-basedanalysis[17]totestwhetherBeneIsraelarecloserto
Jewsthantonon-JewishMiddle-Easternpopulations(MaterialsandMethods).Wefoundthat
Middle-EasternJewishpopulationswereclosertoBeneIsraelascomparedtootherMiddle-
Easternpopulationsexamined(Druze,BedouinandPalestinians).Non-Middle-EasternJewish
populationswerestillclosertoBeneIsraelascomparedtoBedouinandPalestinians,butnotas
comparedtoDruze(S8Fig).Theseresultsfurthersupportthehypothesisthatthenon-Indian
ancestryofBeneIsraelisJewishspecific,likelyfromaMiddle-EasternJewishpopulation.
Inaddition,wealsoappliedGLOBETROTTERonourdataset.GLOBETROTTERassigns
haplotypesegmentsoftheadmixedpopulationstodifferentpopulationsandusestheco-distri-
butionofsuchsegmentsfromdifferentpopulationstodetectandinferadmixture.Incompari-
sontoALDER,whichfocusesonapairofputativeancestralpopulations,itconsidersall
PLOSONE|DOI:10.1371/journal.pone.0152056 March24,2016 9/28
IndianBeneIsraelGeneticsRevealsBothJewishandIndianAncestry
PLOSONE|DOI:10.1371/journal.pone.0152056 March24,2016 10/28