Recent population genomic insights into the genetic basis of arsenic tolerance in humans: the difficulties of identifying positively selected loci in strongly bottlenecked populations

Abstract

Recent advances in genomics have enabled researchers to shed light on the evolutionary processes driving human adaptation, by revealing the genetic architectures underlying traits ranging from lactase persistence, to skin pigmentation, to hypoxic response, to arsenic tolerance. Complicating the identification of targets of positive selection in modern human populations is their complex demographic history, characterized by population bottlenecks and expansions, population structure, migration, and admixture. In particular, founder effects and recent strong population size reductions, such as those experienced by the indigenous peoples of the Americas, have severe impacts on genetic variation that can lead to the accumulation of large allele frequency differences between populations due to genetic drift rather than natural selection. While distinguishing the effects of demographic history from selection remains challenging, neglecting neutral processes can lead to the incorrect identification of candidate loci. We here review the recent population genomic insights into the genetic basis of arsenic tolerance in Andean populations, and utilize this example to highlight both the difficulties pertaining to the identification of local adaptations in strongly bottlenecked populations, as well as the importance of controlling for demographic history in selection scans.

Arsenic Methyltransferase and Methylation of Inorganic Arsenic

“…A similar phenomenon had been described in several different populations living in the Atacama Desert region (i.e., southern Peru, Bolivia, northern Chile, and Argentina) for thousands of years [ 77 ]. One population from Quebrada Valley of Chile, where arsenic levels in drinking water reache in excess of 200 μg/L, can metabolize arsenic efficiently and can rapidly reduce arsenic burden via urination [ 78 ].…”

Synonymous single nucleotide polymorphism in arsenic (+3) methyltransferase of the Western mosquitofish (Gambusia affinis) and its gene expression among field populations

“…We found three exonic SNPs on G. affinis as3mt in this study. Those SNPs have not been previously reported in humans, and this is the first report of an SNP on exon 4 (Wood et al 2006;Fujihara et al 2010;Schlebusch et al 2013;Antonelli et al 2014;Agusa et al 2015;Apata and Pfeifer 2020). Interestingly, the three exonic SNPs in G. affinis as3mt found in this study are all synonymous SNPs unlike known human exonic SNPs (Wood et al 2006).…”

“…Interestingly, the three exonic SNPs in G. affinis as3mt found in this study are all synonymous SNPs unlike known human exonic SNPs (Wood et al 2006). In human populations exposed to high arsenic concentrations over many generations, the frequency of protective mutations is often higher than those seen in populations living with lower levels of exposure, and differences in relative urinary production of MMA and DMA is a representative phenotype of AS3MT SNP variation and alterations in enzyme methylation activity (Engström et al 2007(Engström et al , 2011Watanabe and Hirano 2013;Antonelli et al 2014;Apata and Pfeifer 2020). For example, women from populations where water resources contain high arsenic concentrations exhibit populationspecific AS3MT haplotypes; the haplotypes differ in whether they lead to a higher percentage of MMA or DMA in urine samples (Engström et al 2011).…”

“…In humans, decreased activity of AS3MT is linked to a SNP (T > C), resulting in a Met287Thr amino acid change (Drobna et al 2009). Several other studies show allelic variation within human populations (Schlebusch et al 2015;Apata and Pfeifer 2020), with polymorphisms detected in the AS3MT 5ʹ-UTR that affect the conversion of inorganic arsenic to its organic forms (Wood et al 2006;Valenzuela et al 2009;Antonelli et al 2014). Despite the widespread distribution of arsenic in nature, unlike studies in human populations, there are relatively few studies on whether mutations in AS3MT impact wildlife (Boyle et al 2008;Ye et al 2014;Hallauer et al 2016).…”

Methylmercury and Polycyclic Aromatic Hydrocarbons in Mediterranean Seafood: A Molecular Anthropological Perspective

“…Through analyses of ancient human remains from the Camarones Valley, it has been shown that the inhabitants of the area have been exposed to arsenic-contaminated drinking water for the last 7000 years [107]. Interestingly, a decreasing trend has been detected in the average hair and bone arsenic levels, starting from Archaic hunter-gatherers and leading to the current populations, and this evidence has been interpreted as the potential result of an adaptive increasingly efficient metabolic detoxification [108]. In support of the above scenario, analyses carried out through polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), targeting SNPs strongly associated with arsenic metabolization, showed that, contrary to alleles associated with increased toxicity risk, protective variants are much more frequent in exposed populations compared to a southern Chilean community [109].…”