Human genetics. The genetics of Mexico recapitulates Native American substructure and affects biomedical traits

Abstract

Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-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.

Fig. 1

Genetic differentiation of Native Mexican populations. (A) Principal component analysis of Native Mexicans with HapMap YRI and CEU samples. Population labels as in Table S1. (B) Pairwise F_ST values among Native Mexican populations ordered geographically (see also Table S4). (C) Relatedness graph of individuals sharing more than 13 cM of the genome as measured by the total of segments identical-by-descent (IBD). Each node represents a haploid genome and edges within clusters attract nodes proportionally to shared IBD. The spread of each cluster is thus indicative of the level of relatedness in each population as determined by a force-directed algorithm. Only the layout of nodes within each cluster is the result of the algorithm, as populations are localized to their approximate sampling locations to ease interpretation. Parentheses indicate the number of individuals represented out of the total sample size (2N). The full range of IBD thresholds are shown in fig. S8. (D) TreeMix graph representing population splitting patterns of the 20 Native Mexican groups studied. The length of the branch is proportional to the drift of each population. African, European, and Asian samples were used as outgroups to root the tree (fig. S9).

Fig. 2

Mexican population structure. (A) Map of sampled populations (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 proportions 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 proportions 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–S2). From left to right Mexican populations are displayed North-to-South. (C) Interpolation maps showing the spatial distribution of the six native components identified at K=9. Contour intensities are proportional to ADMIXTURE values observed in Native Mexican samples, with crosses indicating sampling locations. Scatter plots with linear fits show ADMIXTURE values observed in cosmopolitan samples versus a distance metric summarizing 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).

Fig. 3

Sub-continental ancestry of admixed Mexican genomes and biomedical implications. (A) Ancestry-specific PCA (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 admixture 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 sub-continental origin of admixed genomes (prefixed by MEX). Each circle represents the combined set of haplotypes called as Native American along the haploid genome of each sample with >25% of Native American ancestry. Inset map shows the geographic origin of cosmopolitan samples per state color-coded by region (9). (C) Coefficients and 95% confidence intervals for associations between ASPC1 and lung function (FEV₁) from Mexican participants of the Genetics of Asthma in Latino Americans (GALA I) study, and the Mexico City Childhood Asthma Study (MCCAS), as well as both studies combined (Table S6, Fig. S17) (9). (D) Means and confidence intervals of predicted change in FEV₁ by state extrapolated from the model in 3C.