Whole genome variation in 27 Mexican indigenous populations, demographic and biomedical insights

Abstract

There has been limited study of Native American whole genome diversity to date, which impairs effective implementation of personalized medicine and a detailed description of its demographic history. Here we report high coverage whole genome sequencing of 76 unrelated individuals, from 27 indigenous groups across Mexico, with more than 97% average Native American ancestry. On average, each individual has 3.26 million Single Nucleotide Variants and short indels, that together comprise a catalog of 9,737,152 variants, 44,118 of which are novel. We report 497 common Single Nucleotide Variants (with allele frequency > 5%) mapped to drug responses and 316,577 in enhancer or promoter elements; interestingly we found some of these enhancer variants in PPARG, a nuclear receptor involved in highly prevalent health problems in Mexican population, such as obesity, diabetes, and insulin resistance. By detecting signals of positive selection we report 24 enriched key pathways under selection, most of them related to immune mechanisms. No missense variants in ACE2, the receptor responsible for the entry of the SARS CoV-2 virus, were found in any individual. Population genomics and phylogenetic analyses demonstrated stratification in a Northern-Central-Southern axis, with major substructure in the Central region. The Seri, a northern group with the most genetic divergence in our study, showed a distinctive genomic context with the most novel variants, and the most population specific genotypes. Genome-wide analysis showed that the average haplotype blocks are longer in Native Mexicans than in other world populations. With this dataset we describe previously undetected population level variation in Native Mexicans, helping to reduce the gap in genomic data representation of such groups.

Imputation Performance in Latin American Populations: Improving Rare Variants Representation With the Inclusion of Native American Genomes

“…For example, the Ugandan Genome Resource ( Gurdasani et al, 2019 ) comprises genome-wide data for 6,400 individuals, including a subset of 1,978 whole genomes, which is enabling researchers to explore the genetic substructure of the region, improve imputation in African populations, and foster the discovery of novel association signals. In Latin America, recent sequencing efforts have generated whole-genome data from dozens of Native American genomes, including the Peruvian Genome Project (Harris et al, 2018) and the 12G and 100G-MX Projects ( Romero-Hidalgo et al, 2017 ; Aguilar-Ordoñez et al, 2021 ) from the National Institute of Genomic Medicine (INMEGEN) in Mexico. However, only a subset of the existing generated data is available to the scientific community given the data sharing mechanisms implemented in each country.…”

The Mitochondrial DNA Landscape of Modern Mexico

“…For these reasons, Mexico has been, and remains a rich source for anthropological and genetic studies, with the maternally inherited mitochondrial (mt)DNA as a classical marker. While some of the very first mitogenetic population studies already included individuals of Mexican descent [ 26 , 27 , 28 , 29 ], it has been repeatedly claimed since that country-wide mtDNA data from the general population was underrepresented in databases [ 13 , 18 , 20 , 30 , 31 , 32 ], together with Indigenous American genetic data in general [ 33 , 34 ]. Previous studies were either based on a small number of subjects (e.g., [ 35 , 36 ]), mtDNA segments shorter than the 1.1 kbp gold-standard control region (CR) range [ 37 ] (D-loop, nps 16024–16569 1–576; e.g., [ 16 , 18 ]), ancient DNA [ 38 , 39 ], data from geographically restricted or Indigenous population groups (e.g., [ 10 , 40 ]) where lineage representation could be heavily biased [ 41 ], US Mexicans (e.g., [ 20 , 21 ]), did not report the actual haplotypes (e.g., [ 4 , 42 ]), or a combination of these factors.…”

Fanconi Anemia Patients from an Indigenous Community in Mexico Carry a New Founder Pathogenic Variant in FANCG

“…Moreover, the high contribution of the native component of around 80% in these three patients contrasts with the average 46% found in the MXL group and supports the idea that these subjects who belong to the Mixe group have reduced genetic diversity (Figure 2). While only two of these patients have a native contribution of over 85%, sufficient to name them Mexican natives [31], the third one who does not reach this threshold also has the lower autosomic homozygosity and the more distant familial relationship, reflecting more mixture and illustrating the origin of mestizo-Mexicans [23].…”