How and when the Americas were populated remains contentious. Using ancient and modern genome-wide data, we find that the ancestors of all present-day Native Americans, including Athabascans and Amerindians, entered the Americas as a single migration wave from Siberia no earlier than 23 thousand years ago (KYA), and after no more than 8,000-year isolation period in Beringia. Following their arrival to the Americas, ancestral Native Americans diversified into two basal genetic branches around 13 KYA, one that is now dispersed across North and South America and the other is restricted to North America. Subsequent gene flow resulted in some Native Americans sharing ancestry with present-day East Asians (including Siberians) and, more distantly, Australo-Melanesians. Putative ‘Paleoamerican’ relict populations, including the historical Mexican Pericúes and South American Fuego-Patagonians, are not directly related to modern Australo-Melanesians as suggested by the Paleoamerican Model.

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 1,000 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 sub-continental 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.

Relevant for various areas of human genetics, Y-chromosomal short tandem repeats (Y-STRs) are commonly used for testing close paternal relationships among individuals and populations, and for male lineage identification. However, even the widely used 17-loci Yfiler set cannot resolve individuals and populations completely. Here, 52 centers generated quality-controlled data of 13 rapidly mutating (RM) Y-STRs in 14,644 related and unrelated males from 111 worldwide populations. Strikingly, >99% of the 12,272 unrelated males were completely individualized. Haplotype diversity was extremely high (global: 0.9999985, regional: 0.99836–0.9999988). Haplotype sharing between populations was almost absent except for six (0.05%) of the 12,156 haplotypes. Haplotype sharing within populations was generally rare (0.8% nonunique haplotypes), significantly lower in urban (0.9%) than rural (2.1%) and highest in endogamous groups (14.3%). Analysis of molecular variance revealed 99.98% of variation within populations, 0.018% among populations within groups, and 0.002% among groups. Of the 2,372 newly and 156 previously typed male relative pairs, 29% were differentiated including 27% of the 2,378 father–son pairs. Relative to Yfiler, haplotype diversity was increased in 86% of the populations tested and overall male relative differentiation was raised by 23.5%. Our study demonstrates the value of RM Y-STRs in identifying and separating unrelated and related males and provides a reference database.

Over the last 500 years, admixture among Amerindians, Europeans, and Africans, principally, has come to shape the present-day gene pool of Mexicans, particularly Mestizos, who represent about 93% of the total Mexican population. In this work, we analyze the genetic data of 13 combined DNA index system-short tandem repeats (CODIS-STRs) in 1,984 unrelated Mestizos representing 10 population samples from different regions of Mexico, namely North, West, Central, and Southeast. The analysis of molecular variance (AMOVA) test demonstrated low but significant differentiation among Mestizos from different regions (F(ST) = 0.34%; P = 0.0000). Although the spatial analysis of molecular variance (SAMOVA) predicted clustering Mestizo populations into four well-delimited groups, the main differentiation was observed between Northwest when compared with Central and Southeast regions. In addition, we included analysis of individuals of Amerindian (Purepechas), European (Huelva, Spain), and African (Fang) origin. Thus, STRUCTURE analysis was performed identifying three well-differentiated ancestral populations (k = 3). STRUCTURE results and admixture estimations by means of LEADMIX software in Mestizo populations demonstrated genetic heterogeneity or asymmetric admixture throughout Mexico, displaying an increasing North-to-South gradient of Amerindian ancestry, and vice versa regarding the European component. Interestingly, this distribution of Amerindian ancestry roughly reflects pre-Hispanic Native-population density, particularly toward the Mesoamerican area. The forensic, epidemiological, and evolutionary implications of these findings are discussed herein.

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