In humans, its two functional members, NAT1 and NAT2, show differences in expression patterns and substrate specificity, while the third member ( NATP) is a pseudogene. 2012).Īrylamine N-acetyltransferases ( NATs) genes are members of a small multigene family coding for enzymes that biotransform numerous compounds. Indeed, physiological differences between species, whether they emerged through demographic processes or as adaptive responses might offer insights into present-day questions regarding human health and disease ( Olson and Varki 2003 O’Bleness et al. ![]() As foreseen by Olson and Varki (2003), analyzing genetic and genomic diversity in the great apes is also providing novel insights of medical interest ( e.g., ( Enard et al. This potential to answer evolutionary questions regarding all hominid species, including our own, is extensively exploited, and notably so in the last half decade thanks to the accelerated pace at which whole genome sequences are generated ( Kuhlwilm et al. Hominid species, the so-called “great apes”, share a recent common history that makes the genomic diversity of our closest relatives highly informative in evolutionary studies on our own species and more broadly on all great apes. Overall, the results point to the evolution of divergent functions of these highly homologous genes in the different primate species, possibly related to their specific chemical/dietary environment (exposome) and we hypothesize that this is likely linked to the emergence of controlled fire use in the human lineage.Īrylamine N-acetyltransferases, multigenic family, drug metabolism, great apes, natural selection This pattern was also reflected in the results returned by selective neutrality tests, which suggest, in agreement with the predicted functional impact of mutations detected in non-human primates, stronger directional selection, presumably purifying selection, at NAT1 in modern humans, and at NAT2 in chimpanzees. Little polymorphism sharing was found among hominids, yet all species displayed high NAT diversity, but distributed in an opposite fashion in chimpanzees and bonobos ( Pan genus) compared to modern humans, with higher diversity in Pan species at NAT1 and lower at NAT2, while the reverse is observed in humans. To shed new light on such hypotheses, we investigated the genetic diversity of the three members of the NAT gene family in seven hominid species, including modern humans, Neanderthals and Denisovans. ![]() Current hypotheses hold that selective processes favoring haplotypes conferring lower NAT2 activity have been operating in modern humans’ recent history as an adaptation to local chemical and dietary environments. One member of this small gene family, NAT2, is established as the locus of the classic human acetylation polymorphism in drug metabolism. ![]() ![]() Among the many genes involved in the metabolism of therapeutic drugs, human arylamine N-acetyltransferases ( NATs) genes have been extensively studied, due to their medical importance both in pharmacogenetics and disease epidemiology.
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