Whole genome sequencing of 1427 Mexican individuals from the oriGen cohort.

Latin American populations remain underrepresented in genomic research. To help address this, we present an analysis of high-coverage whole-genome data from 1481 volunteers recruited as part of the oriGen Project. We identify over 47.2 million SNVs and 8.1 million short indels, including nearly 3 million non-singleton short variants absent from dbSNP and the Mexico City Prospective Study. Admixture analysis indicates that a Mexican training dataset is needed to more accurately estimate ancestry compositions by genetic similarity. Analysis of copy number variation associated with MX-AMR highlights several loci, including LCE1D and RHD. Interestingly, while 3.1% of participants carry homozygous deletions in the RHD gene, which determines the Rh blood group, this frequency dropped to 0.6% among individuals with high MX-AMR. Since the RHD deletion is rare in East Asians, and the Rh-negative phenotype is rare in Indigenous American populations, our results support the hypothesis that the Rh-negative blood group increased in frequency during the Spanish conquest rather than by genetic drift. We also find that 10% of volunteers are heterozygotes for the 22-42128945-C-T Loss of Function variant in CYP2D6, an enzyme involved in metabolizing painkillers, and tamoxifen. This work helps address the underrepresentation of Mexican populations in genomic research.