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G3 (Bethesda). 2019 Jul 9;9(7):2199-2224. doi: 10.1534/g3.119.400223.

Humans and Chimpanzees Display Opposite Patterns of Diversity in Arylamine N-Acetyltransferase Genes.

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Department of Genetics and Evolution, Anthropology Unit, University of Geneva, Switzerland.
Departments of Pathology and Anthropology, CARTA (Center for Academic Research and Training in Anthropogeny), University of California San Diego, La Jolla.
Department of Comparative Genetics and Refinement, Biomedical Primate Research Centre, the Netherlands.
Zoologischer Garten Basel AG, Basel, Switzerland.
CNRS, Université Toulouse 3 UPS, ENFA, UMR 5174, Toulouse, France.
CNRS/Muséum National d'Histoire Naturelle, UMR 7206 Paris, France.
Institute of Genetics and Genomics in Geneva (IGE3), Switzerland.
UMR 216 MERIT, IRD, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Department of Genetics and Evolution, Anthropology Unit, University of Geneva, Switzerland


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. One member of this small gene family, NAT2, is established as the locus of the classic human acetylation polymorphism in drug metabolism. 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. 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. 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. 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. 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.


Arylamine N-acetyltransferases; drug metabolism; great apes; multigenic family; natural selection

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