the genetics of mexico recapitulates native american

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DOI: 10.1126/science.1251688, 1280 (2014);344Science

et al.Andrs Moreno-Estradaand affects biomedical traitsThe genetics of Mexico recapitulates Native American substructure

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HUMAN GENETICS

The genetics of Mexico recapitulatesNative American substructure andaffects biomedical traits

Andrs Moreno-Estrada,1*Christopher R. Gignoux,2Juan Carlos Fernndez-Lpez,3

Fouad Zakharia,1 Martin Sikora,1 Alejandra V. Contreras,3 Victor Acua-Alonzo,4,5

Karla Sandoval,1 Celeste Eng,6 Sandra Romero-Hidalgo,3 Patricia Ortiz-Tello,1

Victoria Robles,1 Eimear E. Kenny,1 Ismael Nuo-Arana,7Rodrigo Barquera-Lozano,4

Gastn Macn-Prez,4 Julio Granados-Arriola,8 Scott Huntsman,6 Joshua M. Galanter,6,9

Marc Via,6|| Jean G. Ford,10 Roco Chapela,11 William Rodriguez-Cintron,12

Jose R. Rodrguez-Santana,1,3 Isabelle Romieu,14 Juan Jos Sienra-Monge,15

Blanca del Rio Navarro,15 Stephanie J. London,16 Andrs Ruiz-Linares,5

Rodrigo Garcia-Herrera,3 Karol Estrada,3 Alfredo Hidalgo-Miranda,3

Gerardo Jimenez-Sanchez,3# Alessandra Carnevale,3 Xavier Sobern,3

Samuel Canizales-Quinteros,3,17 Hctor Rangel-Villalobos,7 Irma Silva-Zolezzi,3**

Esteban Gonzalez Burchard,6,9*Carlos D. Bustamante1*

Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of humangenome-wide variation from this region remain largely uncharacterized. We studied

genomic variation within Mexico from over 1000 individuals representing 20 indigenous

and 11 mestizo populations. We found striking genetic stratification among indigenous

populations within Mexico at varying degrees of geographic isolation. Some groups were as

differentiated as Europeans are from East Asians. Pre-Columbian genetic substructure is

recapitulated in the indigenous ancestry of admixed mestizo individuals across the

country. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican

Americans showed a significant association between subcontinental ancestry and lung

function. Thus, accounting for fine-scale ancestry patterns is critical for medical and

population genetic studies within Mexico, in Mexican-descent populations, and likely in

many other populations worldwide.

Understanding patterns of human popula-

tion structure, where regional surveys arekey for delineating geographically restricted

variation, is important for the design and

interpretation of medical genetic studies.

In particular, we expect rare genetic variants,

including functionally relevant sites, to exhibit

little sharing among diverged populations (1).

Native Americans display the lowest genetic

diversity of any continental group, but there is

high divergence among subpopulations (2). As

a result, present-day American indigenous pop-

ulations (and individuals with indigenous an-

cestry) may harbor local private alleles rare or

absent elsewhere, including functional and med-

ically relevant variants (3, 4). Mexico serves as

an important focal point for such analyses, be-cause it harbors one of the largest sources of

pre-Columbian diversity and has a long history

of complex civilizations with varying contribu-

tions to the present-day population.

Previous estimates of Native Mexican genetic

diversity examined single loci or were limited to

a reduced number of populations or small sam-

ple sizes (58). We examined local patterns of

variation from nearly 1 million genome-wide

autosomal single-nucleotode polymorphisms

(SNPs) for 511 Native Mexican individuals from

20 indigenous groups, covering most geographic

regions across Mexico (table S1). Standard prin-

cipal components analysis (PCA) summarizesthe major axes of genetic variation in the data

set [see (9)]. Whereas PC1 and PC2 separate

Africans and Europeans from Native Mexicans,

PC3 differentiates indigenous populations with-

in Mexico, following a clear northwest-southeast

cline (Fig. 1A). A total of 0.89% of the variation

is explained by PC3, nearly three times as much

as the variation accounted for by the north-south

axis of differentiation within Europe [0.30%, in

(10)]. The northernmost (Seri) and southern-

most (Lacandon) populations define the extremes

of the distribution, with very clear clustering

of individuals by population, indicating high

levels of divergence among groups (fig. S1).

Seri and Lacandon show the highest level ofpopulation differentiation as measured with

Wrights fixation index FST(0.136, Fig. 1B and

table S4), higher than the FST between Euro-

peans and Chinese populations in HapMap3

(0.11) (11). Other populations within Mexico

also show extreme FSTvalues; for example, the

Huichol and Tojolabal have a pairwise FST of

0.068, similar to that observed between the

Gujarati Indians and the Chinese in HapMap3

(0.076).

The high degree of differentiation between

populations measured byFST argues that these

populations have experienced high degrees

isolation. Indeed, when autozygosity is inferr

using runs of homozygosity (ROH), all popu

tions on average have long homozygous trac

with the Huichol, Lacandon, and Seri all havi

on average over 10% of the genome in ROH [fi

S2 and S3 (9)]. These populations are relativ

small, increasing the effects of genetic drift a

driving some of the high FSTvalues. In contra

the Mayan and Nahuan populations have mu

smaller proportions of the genome in ROH, co

sistent with ROH levels found in Near Easte

populations in HGDP (12). These populatio

are the descendants of large Mesoamerican

vilizations, and concordant with large histori

populations, have relatively low proportions

ROH. The high degree of variance in ROH amo

populations is an additional indicator of pop

lation substructure and suggests a large varian

in historical population sizes. Comparing the o

served ROH patterns to those derived from co

lescent simulations, we find that Native Americ

groups within Mexico are characterized by sm

effective population sizes under a model with

strong bottleneck, in agreement withother studof NativeAmerican populations(13). The degr

of population size recovery to the current day

consistent with the degree of isolation of the e

tant populations, ranging from 1196 chromosom

[95% confidence interval (CI) 317 to 1548] for t

Seri in the Sonora desert, to 3669 (95% CI 2588

5522) for the Mayans from Quintana Roo (figs.

to S6; (9)).

1Department of Genetics, Stanford University School ofMedicine, Stanford, CA, USA. 2Department of Bioengineerand Therapeutic Sciences, University of California, SanFrancisco, CA, USA. 3 Instituto Nacional de MedicinaGenmica (INMEGEN), Mexico City, Mexico. 4EscuelaNacional de Antropologa e Historia (ENAH), Mexico City,Mexico. 5Department of Genetics, Evolution andEnvironment, University College London, London, UK.6Department of Medicine, University of California, SanFrancisco, CA, USA. 7 Instituto de Investigacin en GenticMolecular, Universidad de Guadalajara, Ocotln, Mexico.8Instituto Nacional de Ciencias Mdicas y Nutricin SalvadZubirn, Mexico City, Mexico. 9Department of Bioengineerand Therapeutic Sciences, University of California, SanFrancisco, CA, USA. 10The Brooklyn Hospital Center,Brooklyn, NY, USA. 11Instituto Nacional de EnfermedadesRespiratorias (INER), Mexico City, Mexico. 12VeteransCaribbean Health Care System, San Juan, Puerto Rico.13Centro de Neumologa Pediatrica, San Juan, Puerto Rico14International Agency for Research on Cancer, Lyon, Fran15Hospital Infantil de Mxico Federico Gomez, Mexico CityMexico. 16National Institute of Environmental HealthSciences, National Institutes of Health, Department of Heaand Human Services, Research Triangle Park, NC, USA.17

Facultad de Qumica, Universidad Nacional Autnoma deMxico, Mexico City, Mexico.*Corresponding author. E-mail: [email protected]

(C.D.B.); [email protected] (A.M.-E.); esteban.burchard

ucsf.edu (E.G.B.) These authors contributed equally to this

work.Present address: Department of Genetics, Stanford Unive

School of Medicine, Stanford, CA, USA. (C.R.G.) Present address

Center for Statistical Genetics, Mount Sinai School of Medicine, N

York, USA. (E.E.K.) ||Present address: Department of Psychiatry

Clinical Psychobiology - IR3C, Universitat de Barcelona, Spain. (M

Present address: Analytic and Translational Genetics Unit,

Massachusetts General Hospital, Boston, USA. (K.E.) #Present

address: Harvard School of Public Health and Global Biotech

Consulting Group. (G.J.-S.) **Present address: Nutrition and

Health Department Nestec Ltd, Nestle Research Center, Lausa

Switzerland. (I.S.-Z.)

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Isolation also correlates with the degree of

relatedness within and between ethnic groups, ul-

timately shaping the pattern of genetic relation-

ships among populations. We built a relatedness

graph (Fig. 1C) of individuals sharing >13 cM of

the genome identically by descent (IBD) (cor-

responding to third/fourth cousins or closer

relatives). Almost all the connections are within-

versus among-population, consistent with the

populations being discrete rather than exhib-

iting large-scale gene flow [figs. S7 and S8 (9)].

As seen with the ROH calculations, the Mayan

and Nahuan groups have fewer internal connec-

tions. The few between-population connections

appear in populations close to each coastline,

such as the connections between the Campeche

Mayans and populations to the west along the

Gulf of Mexico.

The long-tract ROH and IBD analyses are es-

pecially relevant to the recent history of isolation

of Native American populations. We ran TreeMix

(14) to generate a probabilistic model of diver-

gence and migration among the Native Am

ican populations (Fig. 1D). The inferred tree w

no migration paths recapitulates the north/sou

and east/west gradients of differentiation fro

the PCA and IBD analyses, with populatio

with high ROH values also exhibiting long

tip branches. The primary branches divide po

ulations by geography. All northern populatio

(dark blue) branch from the same initial sp

at the root. We also find two additional maj

clades: a grouping of populations from the sout

ern states of Guerrero and Oaxaca (green labe

and aMayan clade composed of Mayan-speaki

populations from Chiapas and the Yucatan p

ninsula in the southeast (orange labels). Int

ducing migratory edges to the model conne

the Maya in Yucatan to a branch leading to t

Totonac, whose ancestors occupied the large p

Columbian city of El Tajin in Veracruz (15). Th

result points to an Atlantic coastal corridor

gene flow between the Yucatan peninsula a

central/northern Mexico (fig. S9), consistent w

our IBD analysis. Indeed, the only Mayan la

guage outside the Mayan territory is spoken

the Huastec, nearby in northern Veracruz, suporting a shared history (16).

These signals remain today as a legacy of t

pre-Columbian diversity of Mexican populatio

Over the past 500 years, population dynam

have changed drastically. Today, the majority

Mexicans are admixed and can trace their a

cestry back not only to indigenous groups b

also to Europe and Africa. To investigate patter

of admixture, we combined data from continen

source populations (including the 20 nat

Mexican groups, 16 European populations, a

50 West African Yorubas) with 500 admix

mestizo individuals from 10 Mexican sta

recruited by the National Institute of Genom

Medicine (INMEGEN) for this study, Mexicafrom Guadalajara in the POPRES collection (1

and individuals of Mexican descent from L

Angeles in the HapMap Phase 3 project (ta

S1). We ran the unsupervised mixture model

gorithm ADMIXTURE (18) to estimate ances

proportions for individuals in our combined da

set (Fig. 2, fig. S10, and table S5). Allowing

three ancestral clusters (K= 3), we find that mo

individuals have a large amount of Native a

European ancestry, with a small (typically


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Fig. 2. Mexican population structure.(A) Map of sampled pop-

ulations (detailed in table S1) and admixture average proportions

(table S5). Dots correspond to Native Mexican populations color-

coded according to K= 9 clusters identified in (B) (bottom), and

shaded areas denote states in which cosmopolitan populations

were sampled. Pie charts summarize per-state average propor-

tions of cosmopolitan samples at K= 3 (European in red, West

African in green, and Native American in gray). Bars show the

total Native American ancestry decomposed into average propor-

tions of the native subcomponents identified at K= 9. (B) Global

ancestry proportions at K= 3 (top) and K= 9 (bottom) estimated

with ADMIXTURE, including African, European, Native Mexican, and

cosmopolitan Mexican samples (tables S1 and S2). From left to right,

Mexican populations are displayed north-to-south. (C) Interpola-

tion maps showing the spatial distribution of the six native com-

ponents identified at K= 9. Contour intensities are proportional to

ADMIXTURE values observed in Native Mexican samples, with crosses indi-

cating sampling locations. Scatter plots with linear fits show ADMIXTURE

values observed in cosmopolitan samples versus a distance metric summariz-

ing latitude and longitude (long axis) for the sampled states. From left to right:

Yucatan, Campeche, Oaxaca, Veracruz, Guerrero, Tamaulipas, Guanajuato,

Zacatecas, Jalisco, Durango, and Sonora. Values are adjusted relative to

the total Native American ancestry of each individual (9).

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These changes due to ancestry are compar-

able to other factors affecting lung function. Com-

paring the expected effect of ancestry across

Mexico with the known effects of age in the

standard Mexican-American reference equa-

tions (28), the inferred 7.3% change in FEV1associated with subcontinental ancestry is sim-

ilar to the decline in FEV1 that a 30-year-old

Mexican-American individual of average height

would experience by aging 10.3 years if male

and 11.8 years if female. Similarly, comparing

our results from the Mexican data with the

model incorporating ancestry in African Amer-

icans, a difference of 7.3% in FEV1would corre-

spond to a 33% difference in African ancestry

(29). The association between FEV1 and ASPC1

is not an indicator of impaired lung function

on its ownrather, it contributes to the distribu-

tion of FEV1 values and would modify clinical

thresholds. This finding indicates that diagnoses

of diseases such as asthma and chronic obstruc-

tive pulmonary disease (COPD) relying on spe-

cific lung function thresholds may benefit from

taking finer-scale ancestry into consideration.

An important implication of our work is that

multi- and transethnic mapping efforts will

benefit from including individuals of Mexican

ancestry, because the Mexican population har-

bors rich amounts of genetic variation that may

underlie important biomedical phenotypes. A

key question in this regard is whether existing

catalogs of human genome variation capture

the genetic variation present in the samples

analyzed here. We performed targeted SNP tag-

ging and genome-wide haplotype sharing anal-

ysis within 100-kb sliding windows to assess

the degree to which haplotype diversity in the

Mexican mestizo samples could be captured

by existing reference panels [figs. S18 to 20 (9

Although Mexican-American samples (MXL) w

included in both the HapMap and 1000 G

nomes catalogs, average haplotype sharing f

the INMEGEN mestizo samples is limited

81.2 and 90.5% when combined with all con

nental HapMap populations. It is only after

cluding the Native American samples genotyp

here that nearly 100% of haplotypes are shar

maximizing the chances of capturing most of t

variation in Mexico.

Much effort has been invested in detecti

common genetic variants associated with co

plex disease and replicating associations acro

populations. However, functional and medica

relevant variation may be rare or populatio

specific, requiring studies of diverse hum

populations to identify new risk factors (

Without detailed knowledge of the geograph

Fig. 3. Subcontinental ancestry of admixed Mexican genomes and bio-

medical implications. (A) ASPCA of Native American segments from Mexican

cosmopolitan samples (colored circles) together with 20 indigenous Mexican

populations (population labels). Samples with >10% of non-native ad-

mixture were excluded from the reference panel, as well as population

outliers such as Seri, Lacandon, and Tojolabal. (B) Zoomed detail of the

distribution of the Native American fraction of cosmopolitan samples

throughout Mexico. Native ancestral populations were used to define PCA

space (prefixed by NAT) but removed from the background to highlight the

subcontinental origin of admixed genomes (prefixed by MEX). Each cir

represents the combined set of haplotypes called Native American alo

the haploid genome of each sample with >25% of Native American a

cestry. The inset map shows the geographic origin of cosmopolitan sa

ples per state, color-coded by region ( ). (C) Coefficients and 95% CIs

associations between ASPC1 and lung function (FEV1) from Mexic

participants in the GALA I study, and the MCCAS, as well as both stud

combined (table S6 and fig. S17) ( ). (D) Means and CIs of predict

change in FEV1 by state, extrapolated from the model in (C).

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