Admixture
in
Latin
America
Kaustubh
Adhikari,
Javier
Mendoza-Revilla,
Juan
Camilo
Chaco´n-Duque,
Macarena
Fuentes-Guajardo
and
Andre´s
Ruiz-Linares
LatinAmericansarguablyrepresentthelargestrecently admixedpopulationsintheworld.Thisreflectsahistoryof massivesettlementbyimmigrants(mostlyEuropeansand Africans)andtheirvariableadmixturewithNatives,startingin 1492.ThisprocessresultedinthepopulationofLatinAmerica showinganextensivegeneticandphenotypicdiversity.Here wereviewhowgeneticanalysesarebeingappliedtoexamine thedemographichistoryofthispopulation,includingpatterns ofmating,populationstructureandancestry.Theadmixture historyofLatinAmerica,andtheresultingextensivediversityof theregion,representsanaturalexperimentofferingan advantageoussettingforgeneticassociationstudies.We reviewhowrecentanalysesinLatinAmericansarecontributing toelucidatingthegeneticarchitectureofhumancomplextraits.
Address
DepartmentofGenetics,EvolutionandEnvironment,UniversityCollege
London,LondonWC1E6BT,UK
Correspondingauthor:Ruiz-Linares,Andre´s(a.ruizlin@ucl.ac.uk)
CurrentOpinioninGenetics&Development2016,41:106–114
ThisreviewcomesfromathemedissueonGeneticsofhumanorigin
EditedbyJoshuaMAkeyandAnnaDiRienzo
ForacompleteoverviewseetheIssue andtheEditorial
Availableonline28thSeptember2016
http://dx.doi.org/10.1016/j.gde.2016.09.003
0959-437/#2016ElsevierLtd.Allrightsreserved.
Introduction
The population of Latin America and the Caribbean
currentlyaccountsforabout9%oftheworldpopulation
[1].Thehistoryofthisregionhasbeencharacterizedby
theextensiveadmixtureofNativeAmericansand
immi-grantsfromaroundtheworld,aprocesssetinmotionby
theSpanishcolonialexpansiontotheAmericasstartingin
1492.Historicalrecordsprovideanoutline ofthemajor
demographic events accompanyingthisprocess,
includ-ingthecollapseoftheNativeAmericanpopulationanda
massimmigrationofEuropeansandAfricans[2–5].
How-ever,historical accountsdonotenable aprecise
assess-ment of the impact of these events on the ancestry of
thecurrentpopulationofLatinAmerica.Geneticstudies
areenablingabetterdelineationofthebiological
corre-lates of this history, including detailed descriptions of
populationstructureandindividualancestry.Inaddition
torepresentingarichsettinginwhichtoexplorearange
of evolutionary questions, Latin America embodies a
natural experiment involving the admixture of
popula-tions with a relatively large phenotypic differentiation.
The resulting high diversity of Latin Americans can
benefittheanalysisofthegeneticarchitectureofcomplex
humantraits, including disease, as illustrated byrecent
genome-wideassociationstudies.Inthisshortreviewwe
put into perspective some major findings from genetic
analysesofthedemographichistoryofLatinAmerica,the
bearing of this history on phenotypic diversity in the
regionandhowtheseare beingexploitedtodissectthe
geneticarchitecturecomplexhumantraits.
Genetic
history
of
Latin
America
AprominentfindingemanatingfromearlymtDNA and
Y-chromosomestudiesisthatLatinAmericanscommonly
trace their paternal ancestry to Europeans and their
maternal ancestry to Native Americans [6–9,10,11]
(Figure 1). Thisobservation points to astrong sexbias
during admixture, which must have involved mainly
immigrant men and Native women. These results are
consistentwith historical recordsdocumenting that
mi-grationtotheNewWorld,particularlyintheinitialstages
of the colonial expansion was overwhelmingly by men
[12]and thatadmixturebetweenthese menand native
women was extensive at the foundation of the early
colonialsettlements[13].Theuniparentalmarkerstudies
havesubsequentlybeen extendedbycomparative
anal-yses of X-chromosome and autosomal marker data
(Figure 1). These studies have documented that
esti-matesofEuropeanancestrybasedonX-chromosomedata
are lower than the autosomal estimates, as expected
underthescenarioofsex-biasedadmixtureinferredfrom
mtDNA/Y-chromosome data (since women contribute
two X-chromosomesto the next generation,while men
onlycontributeone)[14,15,16,17,18,19].Thissexbias
inadmixturehasbeenfoundtobeacommon
phenome-noninmanyrecentlyadmixedpopulations[20–22,23].
Studies of autosomal markers have in the last decade
increased dramatically in density, allowing population
andindividualancestryanalysesatincreasingresolution.
Asalientobservationemanatingfromthesestudiesisthat
LatinAmericansshowgreatvariationin
African/Europe-an/Native ancestry betweenindividuals and geographic
beinggeneticallyhomogeneouspresentsextensive
pop-ulation structure, individual admixture estimates often
extending widely across the range of the three major
continental ancestries [14,15,16,17,18,24–29]. A
posi-tive correlation exists between variation in individual
ancestry and population census size, suggesting that
recent demographic events(such as urbanization) have
hadanoticeableimpactonthegeneticmakeupofLatin
Americans[14,27].Thus,althoughindividualsfromthe
parentalpopulationsadmixedextensivelyatthe
founda-tion of the early colonial settlements, this admixture
subsequently hadacomplexdynamicinvolving
popula-tion subdivision and further input from the parental
populations, in certain cases up to the present [30].
Interestingly, estimates for the time since the start of
admixtureobtainedfromgeneticdata(andrepresentinga
kindofhistoricaverage)havebeenfoundtobeconsistent
withthedatesrecordedformajorsettlementeventsinthe
areas examined. For instance, estimates for Caribbean
islands(16generations)[16],areinlinewithhistorical
information (about 500 years, for a generation time of
around30years)andolderthanthoseobtainedfor
popu-lationsfrom thecontinentalmainland (about9–14
gen-erations),whichweresettledbyimmigrantssubsequently
[16,18,31].Othergeneticanalysesareconsistentwitha
significant flow of immigrants over an extended time
period[9]orwithmultiplemajorpulsesofpastadmixture,
bothscenarioshavingsomehistoricalsupportfortheareas
examined[16,17,18].Theseresultsillustratethe
com-plex and variable dynamics of admixture across Latin
America underlying the great variation in continental
ancestry seenthroughouttheregion.
In addition to examining the proportion of European,
African and Native American ancestry in Latin
Ameri-cans,geneticstudieshaveallowedtheexplorationof
sub-continentalancestry.EarlyeffortsbasedonmtDNAdata
indicatedthatadmixedLatinAmericanscarryhaplotypes
characteristic of Native American populationscurrently
living in the vicinity [32]. This was interpreted as
European Native American Africa
mtDNA
Y-Chromosome
X-Chromosome
Autosomes
Br
azil:
R
GS
Catamarca
T
ucuman
Salta
Quetalmahue
P
aposo
P
asto
Cundinamarca
Medellin
P
eque
CVCR
Or
iente
Me
xico City
Argentina:
Chile:
Colombia:
Costa Rica:
Guatemala:
Me
xico:
Current Opinion in Genetics & Development
ProportionofAfrican,EuropeanandNativeAmericanancestryestimatedwithmtDNA,Y-chromosome,X-chromosomeandautosomalmarkersin
thirteenLatinAmericanpopulationsamples.TheproportionofEuropeanancestryestimatedfromtheY-chromosomeisconsistentlylargerthan
estimatedfrommtDNAmarkers.Conversely,NativeAmerican(andAfricanancestryislargeronthemtDNAthantheY-chromosome).Thispattern
pointstoasex-biasduringadmixture(mainlyEuropeanmenandNative/Africanwomen).Consistentwiththispattern,Europeanancestryinthe
autosomesislargerthanestimatedwithX-chromosomemarkers(sincemenandwomencontributeequalnumberofautosomesbutmenonlyone
X-chromosomeandwomentwo).Thispatternisseeninthedifferentsitessampledacrosscountries(thegeographiclocationofthesitessampled
isindicatedinthemapofFigure 3).
suggestive of a ‘genetic continuity’ between local
pre-Columbian populations and admixed Latin Americans
currently livingin thoseareas, thelocal Native
popula-tions effectively becoming incorporated into the
post-Columbianadmixedpopulation [32,33].Autosomaldata
have extended this inference at increasing resolution
fromgenome-widemicrosatellitesurveystohigh-density
SNP scans [14,16,18,26,28,34,35,36]. For instance,
thesedatahaveshownthattheNativeAmerican
compo-nentofMexicansismostcloselyrelatedtoNative
Meso-Americans,whilethatinPeruvians andChileansrelates
mostcloselyto Andeannatives,andin Colombiansthis
componentis closest totheChibchan-Paezan groups of
NorthWestSouthAmerica(Figure3).Analysesbasedon
high-densitySNPdatahavealsorevealed
subcontinental-structurewithinLatinAmericancountries.For instance
inMexico,theNativeAmericancomponentin
individu-alsfromthesoutheast of thecountryis predominantly
related to the Maya, while in individuals from central
Mexicoitrelatesmostcloselyto theNahua [37].The
detectablesub-continental ancestry seen in the Native
Americancomponent of LatinAmericansindicatesthat
recentmigrationhasnotbeenextensiveenoughtoerase
thesignalofNativeAmericanpopulationstructureacross
theregion,particularlyinruralsettlements[14].Similar
analysesoftheEuropeancomponenthaveconfirmedthat
ancestryinLatinAmericanstracesmostlytotheIberian
Peninsula, although some individuals have detectable
Italianand NorthernEuropean ancestry (particularly in
SouthernSouthAmerica)[18].TheAfricancomponent
in Latin Americans also shows substructure, it being
mostly West African in the Caribbean but with some
Mexico
Peru Chile
Colombia Brazil
America 57.5%
America 29.2%
America 12.1%
Africa 4.8%
Africa 9.6%
Africa 9.3% Europe
37.7%
America 64.8%
Africa 4.6%
Europe 30.6%
America 49.3%
Africa 4.6%
Europe 46.2% Europe
61.2%
Europe 78.6%
Current Opinion in Genetics & Development
ProportionofindividualAfrican,EuropeanandNativeAmericanancestryestimatedfrom93328SNPstypedin6357LatinAmericansfromfive
countries(Brazil,Chile,Colombia,MexicoandPeru).Themeanadmixtureestimatesaregivenattheedgesofthetriangleplots.Thelocationof
thecountriessampledisindicatedonthemapofFigure 3.
East African ancestry, particularly in Brazil [17]. The
high-densitySNPanalyseshavealsoallowedthe
detec-tion of low levels of East Asian ancestry in individuals
from Peru´ [18], consistent with historical information
documentingasubstantialimmigrationofChinese
work-ers to this country in the 19th century [3]. Altogether
these results emphasize the high level of population
structure present across Latin America. Other than its
evolutionary interest it is essential to account for this
structureingeneticassociationstudiesfocusedonLatin
Americansamples(andUSLatinos)[19].
Genetic
admixture
and
phenotypic
diversity
in
Latin
America
The relatively high geneticandphenotypic
differentia-tion of Africans, Europeans and Native Americans and
theirvariable admixtureinLatinAmerica underliesnot
onlyanextensivegeneticheterogeneityacrosstheregion
but also its high phenotypic diversity. This is most
apparentin thegreatvariation inphysicalfeaturesseen
in the general population of Latin America [27]. Of
medical relevance, this diversity also impinges on
pat-terns of disease susceptibility in the region. Genetic
studies have shown that for a number of disorders the
riskofdiseaseinLatinAmericansvarieswithcontinental
ancestry[38,39].Forinstance,LatinAmericahasavery
highprevalenceofType2diabetes[40]andriskforthis
diseasehaslongbeenknowntocorrelatepositivelywith
NativeAmericanancestry[41,42].Barringthepossibility
thatthecorrelationofdiseaseriskwithancestryrelatesto
environmentalcovariates[43,44],suchacorrelation
sug-gests the existence of underlying susceptibility alleles
withavariablefrequencyacrossAfricans,Europeansand
NativeAmericans[45,46].Interestinidentifyingtraitloci
withdifferentiatedallelefrequenciesbetweenthe
popu-lationsthatcontributedtorecentlyadmixedpopulations
prompted the development of ‘Admixture mapping’
[47–49].Thisapproach seekstoexploit thevariationin
ancestry alongthegenomeseenin admixedindividuals
andidentifygenomicregionsinwhichvariationin
ances-trycorrelateswithphenotypicvariation[50–52].A
grow-ingnumberofadmixturemappingandstandard
genome-wideassociationstudies(GWAS)inLatinAmerican(and
US Latino) samples have been conducted for disease
phenotypesthatcorrelatewithNativeancestry,including
Type2 diabetes[53,54],breast cancer[55,56],asthma [57,58] and autoimmunity [59,60]. Other than disease
traits, recentgenome-wide analyses havealso soughtto
identifylocifornon-diseasephenotypes,including
plate-let count[61], IgE levels [62] and physical appearance
[63,64,65].
The analyses carried out on physical appearance traits
illustrate well some of the advantages of conducting
genetic association studies in Latin Americans.
Many of these traits are highly heritable and show a
Mestizos Quetalmahue Catamarca Tucuman RGS Salta Paposo Pasto Inga Quechua Aymara Colla Mapuche Hulliche Hulliche Mapuche Colla Quechua Aymara Inga Hulliche Mapuche Colla Inga Aymara Quechua Wichi Toba Toba Wichi Wichi Toba Cundinamarca Medellin Peque CVCR Oriente Mexico City Linguistic groups: Central Amerind EuropeAfrica Northern Amerind Chibchan-Paezan Equatorial-Tucanoan Ge-Pano-Carib Andean Central Amerind Northern Amerind Chibchan-Paezan Equatirial-Tucanoan Ge-Pano-Carib Andean Pima Mixtec Pima PimaMixtec Zapotec Mixtec Zapotec Xapotec Mixe Mayan Mixe Mixe Mayan Kaqchikel Mayan Kaqchikel Kaqchikel Kogi Cabecar Cabecar Guaymi Kogi Embera Waunana Guaymi Embera Waunana Kogi Wayuu Piapoco Ticuna Wayuu Wayuu Ticuna Piapoco SuruiKaritiana ChaneGuarani Piapoco Ticuna Karitiana Surui Guarani Chane Karitiana Surui Chane Guarani Cabecar GuaymiEberga Waunana
0.03 Mexico Colombia Peru Chile Brazil
0.02 0.01 0 –0.01 –0.02 –0.03
–0.02 –0.015 –0.01 –0.005 0 0.005 0.01 0.015 0.02 0.025 0.03 PC4
PC5
Current Opinion in Genetics & Development
Populationstructureandsub-continentalancestryinLatinAmerica.APrincipalComponent(PC)analysiswascarriedoutonthedataofFigure2
(thisanalysiswasconductedtoaccountforpopulationstructureingenome-wideassociationstudiesperformedinthissample[63,64,65]).On
therightweshowtheplotforPC4andPC5.Tosimplify,thespreadofindividualsonthisplotispresentedasacolouredrange.DataforNative
Americanpopulations[90]werealsoincludedintheanalysis(withpopulationnamescolour-codedbasedonthelinguisticclassificationofRuhlen
[91],aslistedinthemiddleofthefigure).Themapontheleftshowsthegeographiclocationofcountriesandpopulationssampled.Thismapalso
displaysthelocationofthesamplingsitesexaminedinFigure1(shownasblacktriangles).
considerabledifferentiationbetweencontinental popula-tions[66,67].VariationinLatinAmericansforthesetraits
can span the range seen in the parental populations
involved in the admixture and there is a significant
correlation between ancestry and phenotypic variation
[27].In addition to replicating associationspreviously
reportedintheGWASscarriedoutinEuropeans,studies
inLatinAmericanshaveidentifiedanumberofnoveltrait
lociand,asanticipated,thesenewlocioftenshowmarked
differencesinallelefrequenciesbetweenEuropeansand
Native Americans[63,64,65]. Figure 4 presents the
exampleofnoseprotrusion.Thistraithas84%
herita-bility,showsconsiderabledifferentiationbetweenNative
AmericansandEuropeans(withgreaterprotrusion
corre-lating with European ancestry) [65]. About 5.5% of
variationinthistraitisexplainedbybasiccovariatessuch
as age and sex, 12.2% being explained by the genetic
PrincipalComponents(i.e.continentaland
sub-continen-talancestry)[65].About1%ofthephenotypicvariance
is explained by a SNP (rs2045323) showing
genome-wide significant association in the DCHS2 (Dachsous
Cadherin-Related 2) gene region in 4q31 [65]. This
SNP shows a 57% difference in allele frequencies
be-tweenEuropeansandNativeAmericans.
Thusfar,GWASs havebeencarried outmostlyin
Eur-opeans,thusrepresentingarelativelynarrowsamplingof
humandiversity[68,69].Bycomparison,studiesinLatin
Americans allow analyses of much wider genetic and
phenotypicscope.Trans-ethnicgenome-wideassociation
studieshave been advocatedas a toolfor fine-mapping
traitlocisharedbycontinentalpopulations[70].As
illus-tratedbytherecentstudiesmentionedabove,themixed
ancestryof LatinAmericanscanin addition leadto the
identificationofnoveltraitlocicharacterizedby
differen-tiatedallelefrequenciesbetweenthecontinentalgroups
that admixed in Latin America. Noticeably, in the
ex-tremecaseoftraitlociwithdifferentallelesfixed across
continents,suchtraitlociwouldbedetectableby
associ-ationtestsinadmixedsamplesbutnotintheun-admixed
parentalgroups.Insum,thehighgeneticandphenotypic
diversity of Latin Americans can empower genetic
(a) (b)
(c) 0.05
0.04
0.03
(d) (e)
90
60
30
0
8
6
4
2
0
1 2 3 4 5 6 7 8
Chromosome
Nose Protr
usion (P
.D
.)
European Ancestry
Human Genome Diversity Project
SNP: rs2045323
Ancestral Allele: G Derived Allele: A
–log
10
(
p
)
9 1011 12 13 14 15 16 17 18 2022X 0.03 0.04 0.05 0.06
Highly European Highly Native Rest
Nose protrusion (P.D.)
Density
0.06 r = 0.36
0.05
0.04
0.03
0.00 0.25 0.50 0.75
30º
60º
30º
0º
–30º
0º 30º 60º 90º 120º 150º 0º
270º 300º 1.00
Current Opinion in Genetics & Development
PhenotypicvariationinLatinAmericansandalocusfornoseprotrusion.(a)Densityplotsfornoseprotrusionforindividualsincludedinthe
analysesofFigures2and3.ToillustratethephenotypicdifferentiationbetweenpopulationscontributingtoLatinAmericanadmixtureseparate
plotsareshownforindividualswith>95%Nativeancestry(inred)or>95%Europeanancestry(inblue).Variationintherestofthesampleis
shownintheyellowplot.NoseprotrusionwasmeasuredasaProcrustesDistance(PD)(calculatedasdetailedinAdhikarietal.(2016)[65]).(b)
ScatterplotcomparingindividualnoseprotrusionwithEuropeanancestryandevidencingasignificantcorrelation(r=0.36;P-value=210 16).As
acorollary,panel(c)showsthatgeographicvariationinnoseprotrusioninChileansmatchesvariationinEuropeanancestryinthiscountry(as
reportedinRuiz-Linaresetal.[27]).(d)Manhattanplotidentifying4q31asaregionincludingSNPssignificantlyassociatedwithnoseprotrusion
inLatinAmericans.(e)AllelefrequenciesintheCEPH-HGDPpopulationpanelfortheindexSNP(rs2045323)inthe4q31regionassociatedwith
noseprotrusion(obtainedfromhttp://genome.ucsc.edu/).
drawafullerpictureof thegeneticarchitectureof
com-plex traitsin humans.
Conclusions
and
future
work
StudiesperformedinLatinAmericansampleshave
estab-lishedthatgeneticanalysesprovideanenriching
perspec-tiveonthedemographichistoryoftheregionandresults
fromthesestudiesareofgeneralrelevancefor the
char-acterizationofthegeneticarchitectureofhuman
pheno-types, including disease. High marker-density analyses
arelikelytocontinuetoincreaseingeographiccoverage,
providing more refinedevolutionaryanalyses across the
region. In areas where there are few extant ethnically
defined native populations(e.g. Caribbeanislands), the
studyofadmixedLatin-Americanscancontributetoour
understanding of the pre-Columbian patterns of
settle-ment. Itwill be interesting to evaluate furtherthe role
that selection couldhave played in shaping patterns of
diversityatthetraitlociidentifiedbytherecentGWAS.
Other than investigating pre-Columbian evolutionary
events, an interesting area of work is the analysis of
post-Columbianfactors,otherthanadmixture,potentially
impacting on the genetic make-up of Latin American
populations, including patterns of mating [71,72] and
recentselection.Ithaslong beenrealizedthatthe
colo-nization of the Americas resulted in the exposure of
natives and immigrants to novel environmental
chal-lenges, including many infectious diseases [73], which
couldhaveimpactedonthegeneticmakeupofadmixed
Latin Americans. Thus, admixture mapping has been
usedtoexplore thepossibilitythatselectioncouldhave
shaped variationin regionalancestry along thegenome
[74,75].Resultsobtainedsofarincludeamarkedvariation
inancestryaroundtheHLAregion,whichcouldrelateto
selection of HLA haplotypesby infectious agents [76].
These observations are contentious[77,78] and require
furthervalidation,includingrelatingspecificgenetic
var-iantswithparticularenvironmentalfactorsanddetailing
themechanismof thisinteraction.
Animportanttopicofresearch,particularlyforthefuture
development of precision medicine initiatives targeting
LatinAmericans,istheextenttowhichcontinental
sub-structure could impact on disease-related phenotypes
(beyondtheeffectsofcontinentalancestry)[79,80].This
is particularlyrelevant forthe NativeAmerican
compo-nentofLatin-Americansas thehighgenetic
differentia-tionof manyNativepopulationspotentiallyinvolvedin
historic admixture could result in alleles impacting on
trait phenotypes beinggeographically localized[28]. In
view of these developments it is important to bear in
mindthatthehistoryofLatinAmericahasimpactednot
onlyonitspresentgeneticdiversitybuthasalsohadmajor
socioeconomic effects. The area has historically been
highly structured both genetically and socially, Latin
America beingtheregionwiththemostunequalwealth
late with each other and with phenotypic diversity,
in-cluding major disease patterns [27,82–84]. Latin
Americansthuspresentanumberofresearchchallenges
on how the interaction of genetic and socioeconomic
factors impinge on biologicaldiversity and disease
sus-ceptibility [85–89]. Further research on these topics
should be of general significance for the development
of effectivegenomicapplicationsin biomedicine.
Acknowledgements
OurworkwasfundedbygrantsfromtheLeverhulmeTrust(F/07134/DF) andBBSRC(BB/I021213/1)toA.R.-L.
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