Abstract
Humans living in the Andes Mountains have been historically exposed to arsenic from natural sources, including drinking water. Enzymatic methylation of arsenic allows it to be excreted more efficiently by the human body. Adaptation to high-arsenic environments via enhanced methylation and excretion of arsenic was first reported in indigenous women in the Argentinean Andes, but whether adaptation to arsenic is a general phenomenon across native populations from the Andes Mountains remains unclear. Therefore, we evaluated whether adaptation to arsenic has occurred in the Bolivian Andes by studying indigenous groups who belong to the Aymara-Quechua and Uru ethnicities and have lived in the Bolivian Andes for generations. Our population genetics methods, including genome-wide selection scans based on linkage disequilibrium patterns and allele frequency differences, in combination with targeted and whole-genome sequencing and genotype–phenotype association analyses, detected signatures of positive selection near the gene encoding arsenite methyltransferase (AS3MT), the main arsenic methylating enzyme. This was among the strongest selection signals (top 0.5% signals via locus-specific branch length and extended haplotype homozygosity tests) at a genome-wide level in the Bolivian study groups. We found a large haplotype block of 676 kb in the AS3MT region and identified candidate functional variants for further analysis. Moreover, our analyses revealed associations between AS3MT variants and the fraction of mono-methylated arsenic in urine and showed that the Bolivian study groups had the highest frequency of alleles associated with more efficient arsenic metabolism reported so far. Our data support the idea that arsenic exposure has been a driver for human adaptation to tolerate arsenic through more efficient arsenic detoxification in different Andean populations.