Ancestral Components of Admixed Genomes in a Mexican Cohort

12 Pages·2011·0.48 MB·English

Ancestral Components of Admixed Genomes in a
Mexican Cohort
Nicholas A. Johnson1¤a, Marc A. Coram2, Mark D. Shriver3, Isabelle Romieu4¤b, Gregory S. Barsh5,6*,
Stephanie J. London7,8, Hua Tang5*
1DepartmentofStatistics,StanfordUniversity,Stanford,California,UnitedStatesofAmerica,2DepartmentofHealthResearchandPolicy,StanfordUniversitySchoolof
Medicine,Stanford,California,UnitedStatesofAmerica,3DepartmentofAnthropology,PennsylvaniaStateUniversity,UniversityPark,Pennsylvania,UnitedStatesof
America,4NationalInstituteofPublicHealth,Cuernavaca,Mexico,5DepartmentofGenetics,StanfordUniversitySchoolofMedicine,Stanford,California,UnitedStatesof
America,6HudsonAlphaInstituteforBiotechnology,Huntsville,Alabama,UnitedStatesofAmerica,7EpidemiologyBranch,NationalInstituteofEnvironmentalHealth
Sciences,NationalInstitutesofHealth,DepartmentofHealthandHumanServices,ResearchTrianglePark,NorthCarolina,UnitedStatesofAmerica,8Laboratoryof
RespiratoryBiology,NationalInstituteofEnvironmentalHealthSciences,NationalInstitutesofHealth,DepartmentofHealthandHumanServices,ResearchTrianglePark,
NorthCarolina,UnitedStatesofAmerica
Abstract
Formostoftheworld,humangenomestructureatapopulationlevelisshapedbyinterplaybetweenancientgeographic
isolation and more recent demographic shifts, factors that are captured by the concepts of biogeographic ancestry and
admixture,respectively.Theancestryofnon-admixedindividualscanoftenbetracedtoaspecificpopulationinaprecise
region, but current approaches for studying admixed individuals generally yield coarse information in which genome
ancestry proportions are identified according to continent of origin. Here we introduce a new analytic strategy for this
problem that allows fine-grained characterization of admixed individuals with respect to both geographic and genomic
coordinates.Ancestrysegmentsfromdifferentcontinents,identifiedwithaprobabilisticmodel,areusedtoconstructand
study ‘‘virtual genomes’’ of admixed individuals. We apply this approach to a cohort of 492 parent–offspring trios from
Mexico City. The relative contributions from the three continental-level ancestral populations—Africa, Europe, and
America—varysubstantiallybetweenindividuals,andthedistributionofhaplotypeblocklengthsuggestsanadmixingtime
of10–15generations.TheEuropeanandIndigenousAmericanvirtualgenomesofeachMexicanindividualcanbetracedto
precise regions within each continent, and they reveal a gradient of Amerindian ancestry between indigenous people of
southwestern Mexico and Mayans of the Yucatan Peninsula. This contrasts sharply with the African roots of African
Americans,whichhavebeencharacterizedbyauniformmixingofmultipleWestAfricanpopulations.Wealsousethevirtual
EuropeanandIndigenousAmericangenomestosearchforthesignaturesofselectionintheancestralpopulations,andwe
identifypreviouslyknowntargetsofselectioninotherpopulations,aswellasnewcandidateloci.Theabilitytoinferprecise
ancestralcomponentsofadmixedgenomeswillfacilitatestudiesofdisease-relatedphenotypesandwillallownewinsight
intothe adaptive anddemographic history ofindigenous people.
Citation: Johnson NA, Coram MA, Shriver MD, Romieu I, Barsh GS, et al. (2011) Ancestral Components of Admixed Genomes in a Mexican Cohort. PLoS
Genet7(12):e1002410.doi:10.1371/journal.pgen.1002410
Editor:GregoryP.Copenhaver,TheUniversityofNorthCarolinaatChapelHill,UnitedStatesofAmerica
ReceivedJuly4,2011;AcceptedOctober20,2011;PublishedDecember15,2011
Thisisanopen-accessarticle,freeofallcopyright,andmaybefreelyreproduced,distributed,transmitted,modified,builtupon,orotherwiseusedbyanyonefor
anylawfulpurpose.TheworkismadeavailableundertheCreativeCommonsCC0publicdomaindedication.
Funding:TheresearchwassupportedbyaSloanFoundationResearchFellowshipandNIGMSgrantGM073059toHTandbytheDivisionofIntramuralResearch,
NationalInstituteofEnvironmentalHealthSciences,NationalInstitutesofHealth,DHHS,toSJL.NAJissupportedbytheStanfordGenomeTrainingProgram(T32
HG000044).Thefundershadnoroleinstudydesign,datacollectionandanalysis,decisiontopublish,orpreparationofthemanuscript.
CompetingInterests:Theauthorshavedeclaredthatnocompetinginterestsexist.
*E-mail:[email protected](HT);[email protected](GB)
¤aCurrentaddress:Google,Mountainview,California,UnitedStatesofAmerica
¤bCurrentaddress:InternationalAgencyforResearchonCancer,Lyon,France
Introduction driving force in shaping the pattern of genetic variation that we
observe today [1–5]. In parallel, analyses based on European,
During the past decade, data generated by high-throughput African and East Asian populations have revealed that recent
genotyping technologies have enabled studies probing into two positive selection is a prevalent phenomenon throughout the
central questions in human evolutionary biology: the character- genome [6–8]. Using data from the Human Genome Diversity-
izationofhumanpopulationgeneticstructure,andthesearchfor CEPH Panel (HGDP), a recent and comprehensive survey
themolecularsignatureofnaturalselection.Insightsgleanedfrom suggeststhat,whileadaptationtolocalenvironmentisacommon
thesestudieshaveprovidedimportantcluesforunderstandingthe theme throughout human evolution, the genetic loci involved in
phenotypic diversity of our species, and variables representing adaptation show little overlap among non-contiguous geographic
population structure are routinely incorporated as covariates in regions [9].
genome-wideassociationstudiesofcomplextraitsanddiseases.At While geography poses a significant reproductive barrier,
a global level, as well as within a continent or even a sub- multiple waves of massive trans-continental migration have
continentalregion,geographyhasbeenshowntoactastheleading occurred during the past centuries, giving rise to admixed
PLoSGenetics | www.plosgenetics.org 1 December2011 | Volume 7 | Issue 12 | e1002410
AncestralComponentsofAdmixedMexicanGenomes
Wetackledthisproblembyemployingananalyticstrategythat
Author Summary
works backwards according to the temporal nature of demo-
Admixed individuals, such as African Americans and graphic events that underlie human admixture: genomes are first
Latinos, arise from mating between individuals from separatedintothemajorandmostrecentcomponentsthatreflect
different continents. Detailed knowledge about the inter-continental migration, then each of those components is
ancestral origin of an admixed population not only further investigated separately. As described below, we apply a
provides insight regarding the history of the population probabilisticmethodforinferringlocus-specificancestryalongthe
itself, but also affords opportunities to study the evolu- chromosome, followed by a variant of PCA tofurther investigate
tionary biology of the ancestral populations. Applying
eachoftheancestry-specificgenomiccomponents,whichweterm
novel statistical methods, we analyzed the high-density
‘‘virtual genomes’’. This hierarchical strategy yields a fine-scale
genotype data of nearly 1,500 Mexican individuals from
view of genetic structure in admixed populations, and provides
Mexico City, who are admixed among Indigenous Amer-
insight into the population history of nonextant ancestral
icans, Europeans, and Africans. The relative contributions
populations. As an example, we study a cohort of 492 parent-
fromthethreecontinental-levelancestralpopulationsvary
offspringtriosrecruitedfromMexicoCity.Ourresultsconfirmthe
substantiallybetweenindividuals.TheEuropeanancestors
a priori expectation that the most significant European contrib-
of these Mexican individuals genetically resemble South-
ern Europeans, such as the Spaniard and the Portuguese. utors tothe Mexican gene pool are populations from the Iberian
TheIndigenousAmericanancestry oftheMexicansinour Peninsula,butrevealthattheIndigenousAmericancomponentof
study is largely attributed to the indigenous groups theMexican genomesismore complex.
residing in the southwestern region of Mexico, although Studying the genetic structure of admixed genomes also offers
some individuals have inherited varying degrees of the unique opportunity to probe the adaptive landscape of the
ancestry from the Mayans of the Yucatan Peninsula and ancestralpopulations.Thisisparticularlypowerfulforstudyingthe
other indigenous American populations. A search for Indigenous American populations, for which limited genotype
signatures of selection, focusing on the parts of the data is available. As proof of principle, we report a novel
genomes derived from an ancestral population (e.g. applicationoftheextendedhaplotypehomozygositytestforrecent
IndigenousAmerican),identifiesregionsinwhichagenetic positive selection to the European and Indigenous American
variantmayhavebeenfavoredbynaturalselectioninthat ‘‘virtual genomes’’ evident in the Mexican cohort, and identify
ancestral population.
numerous loci aspotential targets of positiveselection.
populations.Theancestryofnon-admixedindividualscanoftenbe Results
traced to precise regions based solely on genetic data, but
characterizingthesub-continentalancestryoriginsofanadmixed Overview
individual has not been demonstrated to date. For example, the Our analytic strategy for studying population structure in
two largest minority groups in North America, Latinos and admixedpopulationsisshowninFigure1;detailsoftheapproach
African Americans, both arose as a result of mating among are described in what follows, and in the Materials and Methods
populationsthathadbeeninhistoricalreproductiveisolation.The section. This approach first applies a model-based clustering
‘‘Hispanic’’or‘‘Latino’’populationsincludetheethnicallydiverse method, frappe, to the intact genotype matrix, identifying
groups of Latin America; although significant genetic contribu- components that correspond to variation in continental-level
tionscanbetracedtoIndigenousAmerican,EuropeanandWest admixture proportions, and estimating the relative proportion of
Africanpopulations,ithasbeenchallengingtodeterminewhether those components for each individual. Locus-specific continental
one’s Indigenous American ancestors originate from North, ancestry along a genome is then inferred using SABER+, an
Central,orSouthAmerica.Solvingthisproblemhasimplications extension of a Markov-Hidden Markov Model method [12] that
for both a deeper understanding of human evolution and for partitions each genome into ancestral haplotype segments or
humandisease,sincegeneticdiversitybetweenLatinopopulations ‘‘virtual genomes’’. Finally, within-continent population structure
ischaracterizedbothbyvariationincontinent-levelancestry–e.g. is determined by applying PCA to the virtual genomes, treating
Mexicans on average have lower African ancestry than Puerto therestofthegenomeasmissing.Toaccountforthelargeamount
Ricans – and by the population structure among the ancestral of the missing data resulted from the continent-specific genomes,
Indigenous American populations [4,10]. weimplementavariationofthesubspacePCA(ssPCA)algorithm
The assessment of the precise ancestral origin and the [13].
quantification of genetic structure within an ancestry component Most of the results described here are from a panel of 492
are limited, in part, by analytic challenges. Principal Component Mexican parent-offspring trios recruited from Mexico City
Analysis(PCA)isaclassictechniqueformultivariatedataanalysis, (MEX1) as part of a previous genome-wide association study
which aims to project high-dimensional data to a much lower using genotype data from the Illumina 550K platform [14]. For
dimensionwhilecapturingthegreatestlevelofvariation[11].This comparison, we also examined data from 23 HapMap Phase3
approach has gained popularity in genetic analyses due to both Mexican trios recruited from Los Angeles, California (MEX2;
computationalefficiencyandinterpretability:whentheunderlying http://hapmap.org). Reference populations for inferring conti-
populationstructureisdrivenmainlybyreproductiveisolationand nental-levelancestryweretakenfromHapMap(CEU,YRI),and
subsequentgeneticdifferentiation,theprincipalcomponents(PCs) additional sources asdescribed belowandin TableS1.
mirrorthegeographicoriginsofindividuals[3].Byitself,however,
PCA is not well suited for studying admixed populations: while Continental-level ancestry: Global and local estimates
leading PCs usually represent the relative contributions of Among the 984 parents of the Mexico City trios (MEX1), we
continentally-divided ancestral populations, subsequent PCs may used frappe to estimate median ancestry proportions of 65%
be simultaneously influenced by structures withinone ormore of Indigenous American, 31% European, and 3% African; the
the ancestral populations, and are consequently difficult to corresponding statistics in the 46 HapMap Mexican individuals
interpret. from Los Angeles (MEX2) are 45%, 49%, and 5%, respectively
PLoSGenetics | www.plosgenetics.org 2 December2011 | Volume 7 | Issue 12 | e1002410
AncestralComponentsofAdmixedMexicanGenomes
Figure 1. Schematic describing the analytic framework for characterizing continental-level and within-continent populations
structureinanadmixedpopulation.Forvirtualgenomes,haplotypesfromallbutoneancestralpopulationare‘‘masked’’asmissingdata.
doi:10.1371/journal.pgen.1002410.g001
(Figure2A).ThedistributionofIndigenousAmericanancestryin clusteratavertexofthetriangle.Theseobservationssuggestthat
theMexicoCitypopulationisshiftedupwardcomparedtotheLos the ability of SABER+ to assign local ancestry to a specific
Angeles population (Figure 2B), which may reflect differences in continental origin is highly accurate, which is essential for
theextentofEuropeanadmixture.Africanancestryislowinboth subsequent analyses.
cohorts,althoughthedistributionisskewedtotheright,reaching
over40% forsomeindividuals. History of admixture
We next used SABER+toestimaterecombination breakpoints The distribution of the length of ancestry blocks is shaped by
between ancestral chromosomes and thus locus-specific ancestral population history since admixture. When two individuals from
origin— Indigenous American, European, or African—in indi- different parental populations mate, the first generation offspring
viduals from the MEX1 and MEX2 cohorts. For the work inherits exactly one chromosome from each parental population.
described here, the primary goal of SABER+ is to partition the In subsequent generations, recombination events in an admixed
Mexican genomes into haplotype segments according to conti- individual generate mosaic chromosomes of smaller ancestry
nentalancestrythatcanbeusedforsubsequentanalysis.However, segments. Intuitively, more recent admixing gives rise to longer
theoutputofSABER+canalsobeusedasanindependentmeans ancestry blocks than older admixture. Furthermore, conditioning
of assessing global ancestry, simply by averaging locus-specific onthetimesinceadmixingwithinanindividual’spedigree,block
ancestries across all markers, and yields estimates that are highly length distribution also depends on the individual level ancestry
correlated (r.0.99)with frappe (FigureS1). proportions:e.g.,anindividualwith90%Europeanancestrytends
To facilitate the analyses of sub-continental genetic structure, to have long European ancestral blocks because recombination
weconstructedvirtualgenomesbyretaininghaplotypesegmentsfrom events in the person’s genealogy are likely to have joined two
a single continental-ancestral population, while masking (i.e. European haplotypes, and therefore fewer ancestry changes are
setting to missing) segments from all other ancestral populations; expected.
for example, MEX1AMR and MEX1EUR denote the sets of A likelihood-based model has been proposed that can estimate
IndigenousAmericanandEuropeanhaplotypesegmentsfromthe severalaspectsofadmixturehistory[15].However,theadmixing
Mexico Cityindividuals, respectively. rates in Mexicans from the European, Indigenous American and
Inaprincipalcomponentanalysisofthisdatathatincludesthe Africanancestralpopulationsarelikelydependentanddifficultto
YRI and CEU HapMap populations, the Indigenous American, modelwiththislikelihood-basedmethod;therefore,weattempted
European,andAfricanvirtualgenomesmarkverticesofatriangle to estimate admixing time using a different approach. We first
(Figure2C)inwhichtheintactgenomesoftheMEX1andMEX2 computedthetheoreticalnumberofancestryblocksforindividuals
individualsaredistributedbroadlyalonganIndigenousAmerican according to their ancestral proportions, and carried out that
– European axis represented by PC1. The exact position of the computation assuming a series of different admixing times (5–25
intact MEX1 and MEX2 genomes depends on admixture generations, dotted lines in Figure 2D). The parabolic shape of
proportions;individualswiththegreatestlevelofAfricanancestry, thesecurvesconformstotheintuitiveideaoutlinedabovethatthe
which corresponds to PC2, mostly lie at intermediate positions number of blockpeaksat an intermediate ancestryproportion.
along the Indigenous American -European axis. Importantly, the Wethensuperimposedtheobservednumberofancestryblocks
MEXEUR and MEXAFR virtual genomes (red and blue points, ineachMEX1individualontothetheoreticalcurves;theseresults
respectively) form discrete clusters whose locations coincide with suggest an admixing time of 10–15 generations ago (Figure 2D).
those of the HapMap CEU and YRI, respectively, and, while The admixing time of the European component appears slightly
there is no reference population in this analysis for Indigenous longer than that for the Indigenous American component (15
American, the MEXAMR virtual genomes also form a discrete generationsvs.12);onepotentialexplanationisthatsomemixing
PLoSGenetics | www.plosgenetics.org 3 December2011 | Volume 7 | Issue 12 | e1002410
AncestralComponentsofAdmixedMexicanGenomes
Figure 2. Continental-level ancestry proportions and admixing time. (A) Individual ancestry proportions (red=European; yellow=-
IndigenousAmerican,blue=African).(B)HistogramcomparingtheIndigenousAmericanancestryintheMexicoCitycohort(Mex1)andLosAngeles
cohort(Mex2).(C)PrincipalcomponentanalysisoftheMexicanindividualsfromMexicoCityandLosAngeles,CA.Redandbluecirclesindicatethe
locationoftheHapMapCEUandYRIindividuals,respectively.Graypointsrepresentadmixedindividuals;virtualgenomes,MexAMR(yellow),MexEUR
(blue)andMexEUR(red)areprojectedtothePCplot.(D)Admixingtimesestimatedbythenumberofancestryblocks.ThenumberofEuropean(vs
non-European)ancestryblocksisplottedagainstEuropeanancestry(red);analogously,thenumbersofIndigenousAmerican(vsnon-Indigenous
American)blocksareplottedagainsttheIndigenousAmericanancestry(yellow).Eachcurverepresentstheexpectednumberofsuchblocksfora
specificadmixingtime(ingenerations).
doi:10.1371/journal.pgen.1002410.g002
occurred between the European and the African ancestral bewellseparatedinthepresenceofupto5%error,i.e.Indigenous
individuals prior to admixing with the Indigenous American American alleles mistakenly included in the European virtual
populations. genomes, which is well above the level of uncertainty (,2%)
associated with theSABER+approach.
Regional ancestry of virtual genomes InadditiontotheHapMapCEU,whoaremostlyofNorthern
WiththeMEXEURuncoupledfromtheMEXAMRgenomes,we European ancestry, we used individuals recruited from Dublin,
investigated structure within each of these virtual genomes (Ireland), Warsaw (Poland), Rome (Italy) and Porto (Portugal) to
separately. (We did not investigate the MEXAFR virtual genomes providereferencesfordifferentareaswithinEurope.Thefirsttwo
duetotheirsmallsamplesize).Becausethereisalargeamountof PCs provide good separation of these reference populations, and
missingdata,e.g.thevirtualgenomeofoneindividualmaycover correspond roughly to North-South and West-East gradients
verydifferentlocifromthevirtualgenomeofotherindividuals,we (Figure3A).BoththeMEX1EURandMEX2EURvirtualgenomes
usedthessPCAapproachasdescribedinMaterialsandMethods. are most closely related to intact genomes from Porto, which we
To help evaluate the robustness of our approach, we carried out interpret as a surrogate for populations from the Iberian
simulationexperiments,inwhichtheeffectsofrandomerrorinthe Peninsula, [3], consistent with the historical record that the first
inference of continental locus-specific ancestry were measured Europeanmigrants toMexico wereSpaniards.
with regard to their impact on accuracy of within-continent For analysis of the MEXAMR virtual genomes, we introduced
substructure estimates. Results summarized in Materials and 129 individuals representing 8 different Indigenous American
Methods and Figure S2 indicate that European substructure can populationsasreferencegenomes(TableS1)[16].Initially,wealso
PLoSGenetics | www.plosgenetics.org 4 December2011 | Volume 7 | Issue 12 | e1002410
AncestralComponentsofAdmixedMexicanGenomes
Figure 3. Population structure within the European and Indigenous American components of Mexican genomes. (A) Principal
componentanalysisoftheEuropeanchromosomalsegmentstracestheancestryoriginclosesttoPortuguese.(B)Principalcomponentanalysisof
IndigenousAmericansegments,HapMapCEUandvariousIndigenousAmericanpopulations.(C)Sameas(B),withCEUindividualsremoved.(D)Same
as(B),withCEU,Surui,KaritianaandPimaremoved.ThearrowhighlightsaMexicanindividualwhoseancestryistracedtotheSouthAmericangroup
ofAymara.
doi:10.1371/journal.pgen.1002410.g003
included the HapMap CEU based on previous results in which similar to those from Los Angeles (MEX2AMR); further, we
someIndigenousAmericanindividualsfromtheHumanGenome observe a gradient with varying contribution from Mayans, with
Diversity Panel (HGDP) were observed to have non-negligible some Mexicans deriving their Indigenous American ancestry
levelsofEuropeanancestry[2].Indeed,thefirsttwoPCsforthis predominantly from Mayans. One individual from Mexico City
analysis occur along European-Indigenous American and within- hasanIndigenousAmericanvirtualgenomethatislocalizedwith
America axes (Figure 3B), and reveal varying levels of European the Quechua (arrow, Figure 3C) and therefore is likely to have a
ancestryintheMayan,QuechuaandColombianpopulations.In source of Indigenous American ancestrythat isdistinct fromthat
this analysis and subsequent ones carried out in which certain of theother Mexicans.
reference populations were removed (CEU removed from
Figure 3C; CEU, Surui, Karitiana and Pima removed from Investigating natural selection in ancestors of admixed
Figure3D),theMEXAMRvirtualgenomesaremostcloselyrelated genomes
tointactgenomesofindividualsfromsouthwesternMexicanstate The ability to accurately construct ancestral virtual genomes
ofGuerrero(Guerr),whichincludesNahua,MixtecandTlapanec fromadmixedgenomesprovidesanumberofopportunitiesinthe
indigenous groups. Although the Guerrero individuals and the areas of human evolution and genetic anthropology. As an
PimaindividualsclustertogetherinFigure3C,theyareseparable example of how such data can be used more generally, we
on PC 3 (Figure S3), along which the Guerrero, but not Pima examined the Mexican ancestral components for regions of
individuals, cluster with MEXAMR. The Indigenous American extended haplotype homozygosity, which mark loci that have
virtual genomes of Mexicans from Mexico City (MEX1AMR) are undergone recent positive selection. We used the integrated
PLoSGenetics | www.plosgenetics.org 5 December2011 | Volume 7 | Issue 12 | e1002410
AncestralComponentsofAdmixedMexicanGenomes
haplotype score (iHS) statistic [8], with a modified normalization andat least10%of SNPswith|iHS|.2.5,andrankedwindows
procedure so astofita standard normal distribution. by the maximum |iHS| score. The top 10 regions within the
For the virtual genome SNPs that show the strongest evidence MEXEUR and MEXAMR components are shown in Table 1 and
ofpositiveselection,thedegreeofoverlapbetweentheEuropeans Table2.Theonlygenomiclocationthatfeaturesinbothlistsisthe
and Indigenous Americans is similar to that expected by chance HLAregiononchr6p,aregionknowntohaveexperiencedstrong
(Figure 4A). Specifically, we considered SNPs with |iHS|.2.5, selection [17]; however, the precise variants that show high iHS
which represent approximately the top 1% scores in either scores differ between the Europeans and Indigenous Americans.
components;3874and3931SNPsmeetthiscriterioninMEXAMR Outside the HLA region, the most prominent signal in the
and MEXEUR, respectively, with 57 SNPs overlap between the EuropeancomponentcoincideswithAPBA2onchr15q,whichis
two sets (expected overlap=40, p=0.094). Similarly, we found in close proximity to a known pigmentation gene, OCA2. In the
little overlap between the iHS scores in MEXAMR and those Indigenous Americans component, the strongest signal occurs in
computed based on the HapMap populations [8] (Figure 4B). In chr 6p12.3-2; this region harbors numerous genes, including
contrast, the correlation is much higher between the iHS in IL17A which is associated with chronic inflammatory diseases
MEXEURandthosefromHapMapCEU(r=0.79),whichreflects suchasrheumatoidarthritis,andPKHD1whichisassociatedwith
shared population and adaptive histories of Southern Europeans polycystic kidneydisease [18,19].
(the MEXEUR)andtheCEU(mostly fromNorthern andCentral
Europe).Specifically,of3257and3460SNPswith|iHS|.2.5in Discussion
MEXEUR and CEU, respectively, 655 are overlapping (expected
overlap=32,p,2.2216)(Figure4C).Thesefindingsareconsistent Previous approaches to analyzing the ancestry in admixed
with previous observations that intact genomes from the HGDP individuals have largely focused on estimating continental-level
collection exhibit histories of positive selection that differ admixtureproportions.Withincontinentalancestryanalyseshave
according tocontinent[9]. beenperformedatapopulationlevelbutnotatanindividuallevel.
We also asked what genes might underlie the strongest Our approach is distinct in several ways from a recent study,
signatures of positive selection. Towards this end, we grouped which reports the affinity, at a population level, of admixed
SNPs into 50kb windows, selected regions with at least 20 SNPs populationstovariousancestralgroups[20].Thislatterapproach
Figure4.Signaturesofrecentpositiveselection.(A)Overlapoftop1%SNPs(with|iHS|.2.5)inMexEURandMexAMR.(B)OverlapofSNPswith
|iHS|.2.5 in MexAMR, HapMap CEU and YRI [8]. (C) Overlap of SNPs with |iHS|.2.5 in MexEUR, HapMap CEU and YRI. Numbers in red denotes
significantenrichmentinoverlap.
doi:10.1371/journal.pgen.1002410.g004
PLoSGenetics | www.plosgenetics.org 6 December2011 | Volume 7 | Issue 12 | e1002410
AncestralComponentsofAdmixedMexicanGenomes
Table1. Regionsshowing strongest evidenceofrecent positiveselection inthe Europeancomponent.
CytologicalPosition Genes(Number) Size(kb) NumberofSNPswith|iHS|.2.5 Max|iHS|
6p21.33-32 TRIM31,HLA(88) 2000 113/581 5.71
15q11-q12 APBA2(1) 194 30/37 4.41
17q24 RGS9(1) 268 33/54 4.36
18p11.23 PTPRM(1) 192 24/34 4.31
15q26.1 none 154 20/50 4.02
5q22.1 TMEM232,SLC25A46(2) 309 19/26 4.00
9p22.3 SMARCA2(1) 87 29/47 3.95
3q22.1 COL6A5(1) 164 17/36 3.89
9q33.2 DENND1A(1) 480 34/61 3.86
3p14.1 none 82 13/23 3.84
22q12.2 SFI1,PISD(3) 267 17/31 3.83
Gene(Number)displaysthenumberofgenesintheregion;inthecasearegionencompassesmultiplegenes,wearbitrarilychoosetwo.Sizedenotesthelengthofthe
regionunderselection;consecutiveregionsaremerged.NumberofSNPswith|iHS|.2.5providesthenumberofSNPswith|iHS|.2.5/totalnumberofSNPs.Max|iHS|
isthemaximum|iHS|scoreachievedinaregion.
doi:10.1371/journal.pgen.1002410.t001
requiresapre-definednotionofsubpopulation,suchasMexicans and is more accurate for analyzing high-density genotype data.
versusPuertoRicans,andproducesapopulationlevelsummaryof The accuracy of the locus-specific ancestry is supported by two
genetic relationship. In contrast, our approach does not rely on observations. First, in the continental-level PCA analysis
suchpre-definedethnicgroups,andthushastheabilitytoidentify (Figure 1A), all ‘‘virtual genomes’’ that are attributed to a single
previously unrecognized substructure at an individual level, such ancestralpopulation,clustertightlywiththereferenceindividuals.
as thedetection of one individual withSouth Americanancestry. Had there been substantial error in the local ancestry inference,
Inwhatfollows,wefirstdiscussaspectsoftheapproachthatmay someofthesegenomeswouldappearadmixedandlieinbetween
be generally relevant, and then provide some insights in the thevertices.Second,weincludedtheHapMapCEUindividualsin
evolutionaryhistoryoftheMexicanpopulation.Inthecontextof the analysis of the Indigenous American components of the
genome-wide association studies of complex traits and diseases, genomesbecausesomeoftheMayanindividualshavebeenshown
variablesrepresentingbothcontinental-levelandwithin-continent to have European admixture [2]. Indeed, although Figure 3B
population structure need to be adjusted to provide a more clearlyrevealsEuropeanadmixtureinsomeMayanandQuechua
accurate correction forpopulation stratification[21,22]. individuals, little European admixture is detected in the putative
Twomethodologicalinnovationscontributedtothehierarchical Indigenous American genomes of the Mexicans, MexAMR. We
depictionofindividualancestryorigin:animprovedalgorithmfor note that, although many methods for estimating local ancestry,
locus-specific ancestry inference, which accommodates multiple including the method used in this study, are applicable to
ancestralpopulations,andasubspacePCAalgorithmthatpermits unphaseddata,theparent-offspringtriostructureoftheMexican
varyingdegreesofmissingdata.SABER+usesagraphicalmodel data (both the Mexico City cohort and the HapMap Mexican
toaccountforhaplotypestructurewithinanancestralpopulation, sample) allows accurate haplotype phasing for each individual,
Table2. Regionsshowing strongest evidenceofrecent positiveselection inthe IndigenousAmerican component.
CytologicalPosition Genes(Number) Size(kb) NumberofSNPswith|iHS|.2.5 Max|iHS|
6p21.33 TRIM40,TRIM31(4) 75 4/22 4.33
6p12.3-2 IL17,PKHD1(18) 3083 181/333 4.26
19q13.11 SLC7A9,GPATC1(6) 421 37/59 4.23
12p12.1-23 SSPN,ITPR2(2) 547 70/123 4.15
1q24.1 MAEL,GPA33(3) 164 24/45 4.14
10p12.32 PLXDC2(1) 123 11/40 3.94
14q12 STXBP6(1) 146 13/30 3.92
16q23.2 none 197 17/48 3.72
5q33.1 SLC36A3,GM2A(3) 133 14/29 3.54
2q24.2 LY75,PLA2R1(2) 244 18/53 3.53
Gene(Number)displaysthenumberofgenesintheregion;inthecasearegionencompassesmultiplegenes,wearbitrarilychoosetwo.Sizedenotesthelengthofthe
regionunderselection;consecutiveregionsaremerged.NumberofSNPswith|iHS|.2.5providesthenumberofSNPswith|iHS|.2.5/totalnumberofSNPs.Max|iHS|
isthemaximum|iHS|scoreachievedinaregion.
doi:10.1371/journal.pgen.1002410.t002
PLoSGenetics | www.plosgenetics.org 7 December2011 | Volume 7 | Issue 12 | e1002410
AncestralComponentsofAdmixedMexicanGenomes
which likely improves the accuracy of inference of local ancestry African American individual to multiple West/Central West
along each haplotype. As a result, both phasing and ancestry African groups, but the relative proportions are nearly constant
inference are likely more accurate than those estimated based on acrossallindividuals[24].Thisdifferencecanbereconciledbythe
unphased genotype data. distinct migratory histories: the African ancestry in African-
Typically, application of PCA for genetic structure analyses American populations is largely derived from the trans-Atlantic
makesuseoftheprogramEigenstrat,whichisbasedontheeigen- slave trade, which forcibly departed African individuals from
decompositionofthecovariancematrix,V~GG’,whereG9isthe various geographic regions of Western Africa, ranging from
transpose of the centered and scaled genotype matrix, G [21]. In Senegal to Nigeria to Angola [25]. In contrast, no evidence
computingthiscovariancematrix,missinggenotypesaresettothe suggests massive relocation of the Indigenous Americans during
column means; thus V is computed based on genotypes that are the colonization in North America, and hence reproductive
ij
non-missing in both individuals i and j. While this approach is isolation likely has been maintained between geographically
adequate for analyses based on high-density genotypes with very separated Indigenous American populations. One limitation of
lowlevelsofmissinggenotypes,itisnotappropriateforanalyzing the current study is the incomplete sampling of the Indigenous
thevirtual genomes, whichfeature large andvarying proportions American populations in our reference panel, which represents
ofmissingdata.Considertwoindividualseachwith30%ancestry two distinct regions in Mexico: the Southwest coastal State of
from the population of interest (e.g. Europe): within each GuerreroandtheYucatanPeninsula.Thus,whilemostMexicans
individual, 9% of the genome is expected to be homozygous in trace their Indigenous American ancestries to the indigenous
European ancestry, and therefore ,1% of the markers are groups from the State of Guerrero (Guerr), it is possible that the
expectedtobenon-missinginbothgenomesafterexcludingnon- true ancestors of the extant Mexicans are an un-sampled group
European genotypes. This leads to two problems: first, it has that is genetically similar to Guerr. With the coming of whole
reduced power for detecting population substructure because it genomesequencingdata,itispossiblethatindigenouspopulations
uses only a small fraction of informative genotypes for the fromneighboringstatescanbedistinguished,andthusitmayeven
continentofinterest;moreimportantly,thesamplingvariabilityof be possible to detect admixture from closely related Indigenous
the covariance estimates depends heavily on the proportion of American groups.
missinggenotypes,biasingthePCssuchthatindividualswithhigh
missing rate become outliers along each PC. The ssPCA we Selection
implement does not require the computation of the covariance The EHH analyses of the Southern European and the
matrix,andusesallinformativemarkersineachgenome;henceit Indigenous American components of the Mexican genomes
is less sensitive to the missing data. Since the algorithm can separatelyrevealednumerousintriguingputativetargetsofrecent
compute the first k PCs without computing all PCs, it also has positiveselection.Wenotethatmanyotherapproacheshavebeen
computational advantages over the current covariance-based developed to detect specific types of selective events, and are
implementation, especially when the number of individuals is equallyapplicable[26,27].WechosetousetheiHStestbecauseit
large. has been applied to both the HapMap dataset and the HGDP
dataset,thusfacilitatingcomparison.Thegoalofthispaperisnot
Pattern of ancestry origin to conduct a comprehensive survey of the selective landscape in
We find extensive variation with respect to continental-level theancestralpopulationsofthepresentdayMexicans,butrather
ancestryproportions,bothbetweengeographicregions–shownby to illustrate the potential benefits of such endeavors. Given the
the much higher Indigenous American ancestry in the Mexico difficulties in recruitinglarge samples ofnon-admixed indigenous
City cohort compared to the HapMap Mexican Americans from individuals from each well-defined Indigenous American group,
Los Angeles – and between individuals within each cohort. This wearguethatadmixedpopulationswillprovidevaluableinsightin
study benefits from the ability to divide the genome of a single futureendeavorsinunderstandingtheevolutionaryhistoriesofthe
Mexicanindividualintoitsconstituentancestralcomponents.The IndigenousAmericanpopulations,someofwhichmayhavebeen
abilitytotracechromosomalsegmentstotheirrespectiveancestral extinct.Forexample,individualswithfullTa´ınoancestryarerare,
populations allows us to scrutinize the ancestry origin of each butapproximately15%ofthecontemporarygenepoolofPuerto
individualwithinacontinent.WithintheEuropeancomponentof Ricans may have been derived from Ta´ınos. Hence, admixed
theMexicangenomes(MexEUR),nearlyallindividuals,bothfrom Puerto Rican genomes can be used to learn about those of the
Mexico City and from Los Angeles, trace their European ancestral Ta´ınos [28]. We note that this approach of assembling
ancestries to a Southern European population, as represented in an ancestral population from a mixed population has also
our study by the Portuguese. Within the Indigenous American provided important insights in the Aboriginal Australian popula-
component of the genomes (MexAMR), a majority of individuals tion ina recentstudy [29].
tracetheirancestriestogroupsfromthesouthwestcoastalregions Distinguishingbetweenselectiveeventsthatoccurredwithinthe
ofMexico,consistentwithapreviousstudy,whichfoundZapotec ancestral populations and those that occurred post-admixing
individuals from the State of Oaxaca to best approximate the requires careful consideration of the tests and associated
Indigenous American ancestral population for Mestizos [23]. assumptions. In the current setting, we reasoned that, since a
Importantly, we find evidence of varying levels of Mayan novel adaptive allele is unlikely to be swept to a substantial
admixture, as well as one individual with Indigenous American frequencywithinaperiodoflessthan500years(sincethearrival
ancestry from Bolivia/Peru. Of note, individuals with high levels oftheEuropeansinMexico),andsincetheEHHmethoddoesnot
of Mayan or South American ancestries do not stand out in the have appreciable power to detect low frequency adaptive alleles
continental-level PCA, as their continental-level ancestry propor- [9],mostofthesignalsdetectedbytheEHHhadoccurredpriorto
tionsare comparable totherestof theMexicans. admixing, and hence represent selection within the ancestral
ThefindingthatmostMexicanindividualstracetheirEuropean populations. On the other hand, the preservation of a long
and Indigenous American ancestry to well-defined geographic haplotype excludesthepossibilityofveryancientselectiveevents;
regions contrasts sharply the lack of structure in the African this belief is also supported by the observation that there is little
ancestry in the African Americans: not only did we trace each overlapbetweenthesignaturesdetectedintheSouthernEuropean
PLoSGenetics | www.plosgenetics.org 8 December2011 | Volume 7 | Issue 12 | e1002410
AncestralComponentsofAdmixedMexicanGenomes
andtheIndigenousAmericancomponents.Inpreviousstudiesof TableS1.WeusedBEAGLEtoconstructhaplotypesforMexican
Puerto Ricans and African Americans, numerous genomic trios[34].Aschildrenprovidenoadditionalinformationregarding
locations were found where locus-specific ancestry deviate from population structure or adaptation, they are not used in
thegenome-wideaverage,andcouldrepresenttargetsofselection subsequent analyses.
in the admixed populations [30,31]. In the current analyses, the
onlylocusshowingdeviationfromthegenome-wideaverageisthe Genome-wide and locus-specific ancestry inference
HLA region on chr 6, again supporting a population-specific Continental-level admixture proportions were estimated two
pattern of selection. Therefore, the adaptive history of the ways:(1)amodel-basedclusteringalgorithmimplementedinfrappe
Indigenous American groups may vary considerably, and should [35], and (2) average locus-specific ancestries across all markers.
bestudiedseparatelyandnotasawholegroup.Suchanalysescan Locus-specificancestrywasestimatedwithSABER+,anextension
beachieved,forexample,byexaminingtheIndigenousAmerican
ofapreviouslydescribedapproach,SABER,thatusesaMarkov-
components inMexicansversus that of Puerto Ricans.
Hidden Markov Model [12]. SABER+ differs from SABER in
Our results have important implications for the design of
implementation of a new algorithm, an Autoregressive Hidden
genome-wide association studies based on admixed populations.
Markov Model (ARHMM), in which haplotype structure within
Epidemiologicstudieshavefoundvaryingprevalenceofconditions
theancestral populations isadaptively constructed using a binary
such as asthma, diabetes and alcohol-related problems across
decisiontreebasedonasmanyas15markers,andwhichtherefore
Hispanic national groups [28,32,33]. Distinct population and
does not require a priori knowledge of genome-wide ancestry
adaptive history among Hispanics ethnic groups can give rise to
proportions(Johnsonetal.,inpreparation).Insimulationstudies,
heterogeneity in complex traits. Therefore, the importance of
theARHMMachievesaccuracycomparabletoHapMix[36]but
accounting for intra-continental genetic structure in disease
is more flexible in modeling the three-way admixture in the
mapping studies, in addition to adjusting inter-continental
Mexican population and does not require information about the
admixture proportions, needstobecarefully evaluated.
recombination rate.
HapMapCEUandYRIindividualswereusedasthereference
Materials and Methods
ancestral populations.Basedonfrappe andsupportedbyPCA, 50
individuals in MEX1 set have more than 95% Indigenous
Populations
American ancestry. These individuals were initially used to
The Mexican individuals analyzed in this project come from
approximate the Indigenous American ancestors in the locus-
two sources: a panel of 492 Mexican parent-offspring trios
specificancestryanalyses;aniterativeprocedureisusedtoidentify
recruited from Mexico City as part of a previous genome-wide
and correct for the non-Indigenous American segments in these
associationstudy(MEX1)[14],and23HapMapPhase3Mexican
individuals. Accuracy of the locus-specific ancestry is verified by
trios recruited from Los Angeles, California (MEX2; http://
performing a PC analysis, treating each individual as three non-
hapmap.org). For estimating locus-specific ancestry, we used the
admixed genomes, MexEUR, MexAMR, and MexAFR (see section
HapMap CEU (N=88) and YRI (N=100) individuals for the
‘‘subspace PCA’’ below).
ancestralpopulations.ToanalyzetheEuropeancomponentofthe
admixed genome, we augmented the Mexican datasets with
individuals recruited from Dublin, Ireland (N=43), Rome, Italy Subspace PCA (ssPCA)
(45), Warsaw, Poland (N=45) and Porto, Portugal (N=43). For We implemented this algorithm to accommodate the large
the Indigenous American component analyses, we combined the amount of missing genotype data in partially masked virtual
data generated in two previous studies [2,16]. Four Mayan genomes,andusedittoderiveallthePCAresultsreported here.
individuals with substantial European admixture are removed. The statistical theory of the algorithm in a general data mining
The combined set used for the subsequent analyses includes 14 context can be found in [13]; however, various modifications are
individualsfromGuerrero,Mexico(twoNahua,sevenMixtecand required for the current setting, as described below. Let Gh
fiveTlapanec),24MayanindividualsfromtheYucatanPeninsula, (h=1,2) be two N6M matrices, in which (cid:2)g1 ,g2 (cid:3) denote the
nm nm
24 Quechua collected in Cerro de Pasco, Peru, 25 individuals of unordered pair of alleles at SNP m (m=1,…,M) in individual n
largelyAymaraancestrycollectedinLaPaz,Bolivia,13Karitiana (n=1,…,N); the columns of Gh are standardized to have mean 0
and eight Surui from Brazil, seven Colombians, and 14 Pima. and variance 1. To compute the subspace spanned by the first k
Because the sample sizes for Nahua, Mixtec and Tlapnec are principal components (PC), we begin by finding a matrix
small, and all individuals were recruited from the same state, we decomposition, G(cid:2)&AST, which minimizes the reconstruction
considered these individuals as one group. Table S1 summarizes error, R, defined as:
theindividuals usedforeach analysis.
Genotyping QC and haplotype construction R&jjG{G(cid:2)jj2F~XXX(gnhm{Xankskm)2,
Genotypingandqualitycontrolprocedureshavebeendescribed h n m k
intheprimarypublicationsforeachdataset,exceptforthedataset
of 176 European individuals. Briefly, MEX1 and the HGDP subjecttotheconstraintsthatthecolumnvectorsofAareofunit
individuals were genotyped on Illumina 550K and on 650K norm and mutually orthogonal and the row vectors of S are also
Beadchip, respectively. The Indigenous American individuals mutuallyorthogonal.HereAisaN6dmatrix,SisaM6dmatrix,
fromBighametal.(2009)weregenotypedonAffymetrix1MSNP andd,N#MrepresentsthedesirednumberofleadingPC’s.The
arrays[16].Thesetof176Europeanindividualsweregenotyped algorithm we use is a generalized instance of the coordinate
using Illumina HumanHap300 arrays; this dataset originally descent approach [37], which iteratively optimizes matrix A for
included 180 individuals; four individuals were found with non- fixed Sandthenoptimizes Sfixing Aaccording totherules:
negligiblenon-Europeanancestryandwereexcluded.SNPswitha
call rate of less than 95% were excluded. The number of
individuals and markers used for each analysis is summarized in Ar~Ar{1zl½(G{Ar{1Sr{1)(Sr{1)0(cid:3) and
j j j
PLoSGenetics | www.plosgenetics.org 9 December2011 | Volume 7 | Issue 12 | e1002410
AncestralComponentsofAdmixedMexicanGenomes
Estimating time since admixing
Sr~Sr{1zl½(Ar{1)0(G{ArSr{1)(cid:3), We used the number of ancestry blocks in an individual as
j j j summary statistics. Tracing through a pedigree of T generations,
the expected number of recombination events in a haploid
where l is a learning rate, the superscripts, r, indicate iteration,
genomeis0.016TL,whereListhetotalgenomelength(takento
andthesubscripts,j,denotethej-thcolumnofamatrix.Itcanbe
be3435cM[38]).Underahybrid-isolationmodelandassuminga
shownthatthecolumnsofAandSspanthesubspaceofthefirstd
genome-wide ancestry proportion of z, a fraction of 26z(12z) of
PCs, and that the leading PCs can be computed by orthogonal-
the recombination events occurs between two haplotypes of
izingthecolumnsofAandS[13].Toevaluatetheaccuracyofour
opposite ancestry and thus leads to transitions in ancestry. When
modifiedssPCAapproach,weapplieditinparallelwithEigenstrat
wecountthenumberofancestryblocksintherealdata,wedonot
[21] to the intact Mexican genomes, and found the leading PCs
observerecombination eventsthat occur between twohaplotypes
produced by the two algorithms were virtually identical, up to a
of the same ancestry. Hence the expected number of ancestry
permutation of signs.
switchesinadiploidgenomeisB=(26260.01)6TL6z(12z),and
eachancestryswitchcreatesoneadditionalancestryblock.When
Simulation study with known substructure
there is no ancestry switch in a genome, the number of ancestry
We carried out two simulation experiments to evaluate the
blocks is defined to be the same as the number of chromosomes.
impactofstatisticaluncertaintiesassociatedwithestimatinglocus-
Therefore,foreachspecifictimeofadmixing,T,wecomputedthe
specificancestry,andtoinvestigatetheperformanceofthessPCA
expectednumberofancestryblocksasB+2622,withthegenome-
approach.
wide ancestry proportion, z, varying from 0 to 1 at 100 equally
In the first set of simulations, we created 10 datasets in which
spaced grid points. Each curve in Figure 2D shows the expected
400 admixed genomes were modeled to mimic a Latino
numberofancestryblocksasafunctionofadmixtureproportions
population: each individual draws chromosomal segments from
foraspecificadmixingtime.TheestimatednumbersofEuropean
EuropeanandIndigenousAmericanancestry,andtheproportion
and non-European ancestry blocks from the Mexican individuals
of Indigenous American ancestry in each individual matches
were tallied and compared to the expected values. To assess the
what we observed in MEX1. For 200 individuals, European-
impact of uncertainty associated with estimating the number of
derived segments were sampled from the HapMap CEU
ancestry blocks, we note that errors in estimating locus-specific
haplotypes, representing Northern and Western European
ancestry often create very short ancestry blocks. Hence, we
ancestry, while for the remaining 200 individuals, the Europe-
simulated admixed genomes according to the hybrid-isolation
an-derived segments were sampled from MexEUR inferred from
model, but removed extremely short blocks (segments with ,10
the actual Mexican genotype data, representing Southern
SNPs)frombothsimulatedgenomesandrealdata.Theestimated
European ancestry. The chromosomal segments from CEU and
admixing timeremainedthesameunderthisalternative analysis,
MexEUR in the admixed individuals were treated as the true
suggesting the estimated admixing time is relatively robust. The
European virtual genomes.
hybrid-isolation model was chosen because of the mathematical
To evaluate the potential impact of statistical uncertainty, we
simplicity;underamorerealisticcontinuousgene-flowmodel,the
introducedrandomerrorsinwhichthetrueidentitiesofEuropean
estimated times of admixing should be interpreted as an
vs.IndigenousAmericansegmentswereswitchedwithprobability
approximationofaverageadmixingtime,weightedbytherelative
e.ThetopPCforeachsetofsimulatedvirtualgenomes(ateachof
levelof gene-flow ineachgeneration.
8 error rates, e=0.01–0.20) was computed with ssPCA. We
evaluate the effect of these errors by calculating a confusion
Substructure within the European and Indigenous
fraction, j, that quantifies the accuracy with whichthe estimated
American component of the genome
first PC separates individuals with Northern vs. Southern
Europeanancestry,andisdefinedastheproportionofindividuals To assess the sub-continental population structure, each
thatlieonthe‘‘wrong’’sideofathresholdthatbestseparatesthe Mexican genome was partitioned into three non-admixed
twogroups.Thus,jcanrangefrom0(perfectseparation)tonearly genomes, by masking (i.e. setting to missing) alleles from all but
50% (complete confusion as would be observed for genetically one ancestral population. In other words, the European
homogenous groups). Finally, we analyze each of the 10 datasets component of a Mexican’s genome (MexEUR) was derived by
usingSABER+,exactlyaswasdoneforrealdata:applyssPCAto treatingasmissingallalleleswhoseoriginswereinferredasAfrican
estimate substructure, and calculate a confusion fraction. The or Indigenous American. For within European analysis, we
results for this simulation experiment are depicted in Figure S2, applied ssPCA on the dataset consisting of MexEUR (including
andshowthattheconfusionfractionincreasessubstantially,froma bothMexicoCityandHapMapsamples),88HapMapCEUand
mean of 2.14% to 17.5%, at error rates between 0.03 and 0.05. 176 European individuals from four cities: Dublin (Ireland),
UsingSABER+onthesesame10datasetsyieldsameanconfusion Warsaw (Poland), Rome (Italy) and Porto (Portugal). Because of
fraction of 1.58%, which corresponds to an error rate ,0.02 the limited number of informative haplotype segments, Mexican
(indicated bythearrowin Figure S2). individuals with less than 25% European ancestry were excluded
In a second set of simulations to investigate the ability of the from this analysis. In an analogous fashion, we analyzed the
ssPCAapproachtodealwithmissingdata,wecreatedfivedatasets Mexican component of the genome, MexAMR, along with 129
in which the proportion of genome-wide European ancestry in indigenous Indigenous American individuals representing 8
each of 400 admixed genomes was fixed at either 50% or 30%, populations (Table S1). Because the African ancestry is low in
respectively.ApplyingSABER+andssPCAtothesedatasetsyields both Mexican cohorts (3% and 5%, respectively), we did not
mean confusion fractions of 0 and 0.7%, respectively, indicating analyze thewithin-Africa population structure.
that our approach performs well for situations such as the one
described here, where mean genome-wide continental ancestry Detecting signature of selection
proportions are above 30% for both the European and the or all SNPs with frequencies between .05 and .95 in the
Indigenous American components. respectivepopulations,iHSwascalculatedfollowingVoightetal.
PLoSGenetics | www.plosgenetics.org 10 December2011 | Volume 7 | Issue 12 | e1002410