The genetic makeup of Indigenous populations inhabiting Mexico has been strongly influenced by geography and demographic history. Here, we perform a genome-wide analysis of 716 newly genotyped individuals from 60 of the 68 recognized ethnic groups in Mexico. We show that the genetic structure of these populations is strongly influenced by geography, and our demographic reconstructions suggest a decline in the population size of all tested populations in the last 15–30 generations. We find evidence that Aridoamerican and Mesoamerican populations diverged roughly 4–9.9 ka, around the time when sedentary farming started in Mesoamerica. Comparisons with ancient genomes indicate that the Upward Sun River 1 (USR1) individual is an outgroup to Mexican/South American Indigenous populations, whereas Anzick-1 was more closely related to Mesoamerican/South American populations than to those from Aridoamerica, showing an even more complex history of divergence than recognized so far.

The Mexican population is characterized by high and particular admixture, and the picture of variants associated with disease remains unclear. Here we investigated the distribution of single nucleotide polymorphisms (SNPs) in the Mexican population. We focused on two non-synonymous and three synonymous SNPs in the beta-2 adrenergic receptor gene (ADRB2), which plays key roles in energy balance regulation. These SNPs were genotyped in 2,011 Mexican Amerindians (MAs) belonging to 62 ethnic groups and in 1,980 geographically matched Mexican Mestizos (MEZs). The frequency distribution of all five ADRB2 variants significantly differed between MAs, MEZs, and other continental populations (CPs) from the 1000 Genomes database. Allele frequencies of the three synonymous SNPs rs1042717A, rs1042718A, and rs1042719C were significantly higher in Mexican individuals, particularly among MAs, compared to in the other analyzed populations (P<0.05). The non-synonymous ADRB2 Glu27 allele (rs1042714G), which is associated with several common conditions, showed the lowest frequency in MAs (0.03) compared to other populations worldwide. Among MEZs, this allele showed a frequency of 0.15, intermediate between that in MAs and in Iberians (0.43). Moreover, Glu27 was the only SNP exhibiting a geographic gradient within the MEZ population (from 0.22 to 0.11), reflecting admixed mestizo ancestry across the country. Population differentiation analysis demonstrated that Glu27 had the highest F_ST value in MAs compared with Europeans (CEU) (0.71), and the lowest between MAs and Japanese (JPT) (0.01), even lower than that observed between MAs and MEZs (0.08). This analysis demonstrated the genetic diversity among Amerindian ethnicities, with the most extreme F_ST value (0.34) found between the Nahuatls from Morelos and the Seris. This is the first study of ADRB2 genetic variants among MA ethnicities. Our findings add to our understanding of the genetic contribution to variability in disease susceptibility in admixed populations.

Molecular diagnosis of cystic fibrosis (CF) is challenging in Mexico due to the population's high genetic heterogeneity. To date, 46 pathogenic variants (PVs) have been reported, yielding a detection rate of 77%. We updated the spectrum and frequency of PVs responsible for this disease in mexican patients. We extracted genomic DNA from peripheral blood lymphocytes obtained from 297 CF patients and their parents. First, we analyzed the five most frequent PVs in the Mexican population using PCR-mediated site-directed mutagenesis. In patients with at least one identified allele, CFTR sequencing was performed using next-generation sequencing tools and multiplex ligation-dependent probe amplification. For variants not previously classified as pathogenic, we used a combination of in silico prediction, CFTR modeling, and clinical characteristics to determine a genotype–phenotype correlation. We identified 95 PVs, increasing the detection rate to 87.04%. The most frequent variants were p.(PheF508del) (42.7%), followed by p.(Gly542*) (5.6%), p.(Ser945Leu) (2.9%), p.(Trp1204*) and p.(Ser549Asn) (2.5%), and CFTRdel25–26 and p.(Asn386Ilefs*3) (2.3%). The remaining variants had frequencies of <2.0%, and some were exclusive to one family. We identified 10 novel PVs localized in different exons (frequency range: 0.1–0.8%), all of which produced structural changes, deletions, or duplications in different domains of the protein, resulting in dysfunctional ion flow. The use of different in silico software and American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) criteria allowed us to assume that all of these PVs were pathogenic, causing a severe phenotype. In a highly heterogeneous population, combinations of different tools are needed to identify the variants responsible for CF and enable the establishment of appropriate strategies for CF diagnosis, prevention, and treatment.

Background: In several populations CFTR mutations, as well as IVS8-Tn CFTR polymorphism, have been associated with congenital bilateral absence of the vas deferens (CBAVD) and idiopathic obstructive azoospermia diseases. However, the involvement of these mutations in infertility of Mexican males has not been elucidated. Aims: We investigated whether CFTR mutations and IVS8-Tn(TG)m polymorphisms are associated with infertility in azoospermic Mexican patients. Methods: Sixteen CBAVD and 33 idiopathic azoospermic cases were included. The CFTR gene was sequenced in all CBAVD cases. In the idiopathic azoospermic patients, the p.F508del, p.G542X, p.N1303K, p.S549N, p.I507del, and p.R117H mutations and those detected in our CBAVD cases were screened. Results: The p.F508del, p.G85E, p.D1152H, and p.W1089X mutations were found in 3 CBAVD patients (18.8%). None of the 9 CFTR mutations screened for in idiopathic azoospermic were found; however, we documented a high frequency of the Gln1463Gln polymorphism in comparison with healthy controls (20% vs 6%; p=0.0029). Conclusions: These data showed that the CFTR mutations but not the IVS8-Tn polymorphism are involved in CBAVD etiology in a Mexican population. Nevertheless, other screening strategies should be used to rule out the implication of CFTR mutations in idiopathic azoospermic disease.