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

Abstract

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.

Population variability of rhesus macaque (Macaca mulatta) NAT1 gene for arylamine N-acetyltransferase 1: Functional effects and comparison with human

“…Here, we investigated NAT1 variability in a population sample of the Old World monkey rhesus macaque, also characterizing the possible functional consequences of detected variants. Our results are in accordance with the aforementioned study 60 , indicating high haplotypic diversity (Hd = 0.817) of (MACMU) NAT1 coding region for the specific rhesus macaque population studied, and with 16% of the haplotypes carrying at least one non-synonymous SNV with some functional impact. It appears that, in the rhesus macaque, polymorphic NAT1 alleles may modulate acetylation of arylamine xenobiotics more effectively compared with human, where population frequencies of non-synonymous SNVs in NAT1 coding region are extremely low (typically <1‰, with few exceptions) 104 .…”

“…paniscus ) compared with human. Genetic diversity was higher for NAT1 in the two Pan species and lower in human, with the opposite pattern observed for the NAT2 gene 60 . Here, we investigated NAT1 variability in a population sample of the Old World monkey rhesus macaque, also characterizing the possible functional consequences of detected variants.…”

“…The evolutionary history of human NAT1 gene indicates a dominant role of purifying selection, consistent with the presumed endogenous function of NAT1 enzyme 58,59 . However, a recent study suggests that the evolutionary pattern may be different for the NAT1 orthologues of other primate species 60 . We have recently analysed the NAT1 sequences of 35 non-human primate species and performed recombinant expression and comparative enzymatic analysis for ten of them, elucidating their genetic evolution and demonstrating functional variability across different phylogenetic lineages 61–63 .…”

The Exposome in Human Evolution: From Dust to Diesel

“…High-risk alleles existed at least 45,000 years ago in H. sapiens DNA from Ust'-Ishim (Siberia). N-acetyltransferases (NAT1,NAT2) are important for xenobiotic catabolism of modern drugs and ancient carcinogens such as PAHs in smoke from burning wood and tobacco (Zhou et al 2013;Aarts et al 2016;Vangenot et al 2019). Because the NAT variants alter cancer risk from cigarette smoke (Matejcic et al 2015;Sabbagh et al 2018) and red meat (Wang et al 2015), we suggest that NAT variants also modulate toxicity of domestic smoke from biomass burning used for cooking and warmth.…”

Similar patterns of genetic diversity and linkage disequilibrium in Western chimpanzees (Pan troglodytes verus) and humans indicate highly conserved mechanisms of MHC molecular evolution

“…Actually, the idea that Western chimpanzees underwent a substantial reduction in population size has been supported by analysing other parts of the genome. First, studies on both autosomal genes and whole genome sequences [ 44 , 66 , 67 , 70 , 86 – 88 ] have indicated that Western chimpanzees are generally less diverse than the other Pan sub-species, which sustains the hypothesis of several past bottlenecks in the former [ 44 , 79 ]; second, Western chimpanzees’ genomic diversity has been found to fall within the average observed for Non-African human populations, which show a much lower genetic diversity than African populations (Fig. 1 b of [ 44 ]).…”