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.

Whole-genome scans for natural selection signatures across Mexican indigenous populations remain underrepresented in the literature. Here, we conducted the first comparative analysis of genetic adaptation in Mexican indigenous populations using whole-genome sequencing data from 76 individuals representing 27 different ethnic groups in Mexico. We divided the cohort into northern, central, and southern populations and identified signals of natural selection within and across populations. We find evidence of adaptation to pathogenic environments in all our populations, including significant signatures in the Duffy blood group gene in central Mexican indigenous populations. Despite each region exhibiting unique local adaptation profiles, selection signatures on ARHGAP15, VGLL4, LINGO2, SYNDIG1, and TFAP2B were common to all populations. Our results also suggest that selection signatures falling within enhancers or promoters are usually connected to noncoding features, with notable exceptions like ARHGAP15 and GTDC1. This paper provides new evidence on the selection landscape of Mexican indigenous populations and lays the foundation for additional work on Mexican phenotypic characterization.

Indigenous people from the American continent, or Native Americans, are underrepresented in the collective genomic knowledge. A minimal percentage of individuals in international databases belong to these important minority groups. Yet, the study of native American genomics is a growing field. In this work, we reviewed 56 scientific publications where ancient or contemporary DNA of Native Americans across the continent was studied by array, whole-exome, or whole-genome technologies. In total, 13,706 native Americans have been studied with genomic technologies, of which 1292 provided whole genome samples. Data availability is lacking, with barely 3.6% of the contemporary samples clearly accessible for further studies; in striking contrast, 96.3% of the ancient samples are publicly available. We compiled census data on the home countries and found that 607 indigenous groups are still missing representation in genomic datasets. By analyzing authorship of the published works, we found that there is a need for more involvement of the home countries as leads in indigenous genomic studies. We provide this review to aid in the design of future studies that aim to reduce the missing diversity of indigenous Americans.

Whole genome scans for natural selection signatures across Mexican Indigenous (MI) Populations remain underrepresented in the literature. Here, we conducted the first comparative analysis of genetic adaptation in MI populations using whole genome sequencing (WGS) data from 76 individuals representing 27 different ethnic groups in Mexico. We divided the cohort into Northern, Central, and Southern populations and identified signals of natural selection within and across populations. We find evidence of adaptation to pathogenic environments in all our populations, including significant signatures in the Duffy blood group gene in Central MI populations. Despite each region exhibiting unique local adaptation profiles, selection signatures on ARHGAP15, VGLL4, LINGO2, SYNDIG1 , and TFAP2B were common to all populations. Our results also suggest that selection signatures falling within enhancers or promoters are usually connected to non-coding features, with notable exceptions like ARHGAP15 and GTDC1 . This paper provides new evidence on the selection landscape of Mexican Indigenous Populations and lays the foundation for additional work on Mexican phenotypic characterization. Significance statement: Previous research has identified distinct patterns of genomic adaptation across the different regions of Mexico, highlighting evidence of natural selection within metabolic and immune-related genes. However, the characterization of the Mexican selection landscape from a whole-genome perspective remains unexplored. Here, we conducted the first whole-genome scan for natural selection in 76 Mexican Indigenous individuals from 27 different ethnic groups divided into Northern, Central, and Southern populations. Our findings revealed distinct local adaptation profiles for each Mexican region, with different evidence of adaptation to pathogenic environments across these groups. In contrast, all populations had common selection signatures on ARHGAP15, VGLL4, LINGO2, SYNDIG1 , and TFAP2B . This paper provides new evidence on the genetic basis of adaptation of Indigenous groups in Mexico. Moreover, it provides a foundation for additional work on Mexican phenotypic characterization.

The Comcáac (also known as Seri) are an indigenous community from the central coast of the Sonoran Desert in Mexico. Genetic studies conducted on this population since the late 1990s have revealed marked genetic differentiation resulting from pronounced genetic drift caused by a historical bottleneck, which is consistent with anthropological and linguistic records. Research has examined allele frequencies and genetic variants associated with cirrhosis risk, pathogen adaptation, forensic markers, vitamin and sugar metabolism, body mass index, immune responses, cytochrome genes, genetic distances with other groups, and migration patterns. While early investigations relied on classical genetic approaches, more recent studies have employed omics technologies, including whole-genome sequencing. Analyses of the Comcáac genome provide valuable insights into the phenotypic traits and medical predispositions of this community.