Abstract
Arylamine N-acetyltransferase 2 (NAT2) is involved in human physiological responses to a variety of xenobiotic compounds, including common therapeutic drugs and exogenous chemicals present in the diet and the environment. Many questions remain about the evolutionary mechanisms that have led to the high prevalence of slow acetylators in the human species. Evidence from recent surveys of NAT2 gene variation suggests that NAT2 slow-causing variants might have become targets of positive selection as a consequence of the shift in modes of subsistence and lifestyle in human populations in the last 10,000 years. We aimed to test more extensively the hypothesis that slow acetylation prevalence in humans is related to the subsistence strategy adopted by the past populations. To this end, published frequency data on the most relevant genetic variants of NAT2 were collected from 128 population samples (14,679 individuals) representing different subsistence modes and dietary habits, allowing a thorough analysis at both a worldwide and continent scale. A significantly higher prevalence of the slow acetylation phenotype was observed in populations practicing farming (45.4%) and herding (48.2%) as compared to populations mostly relying on hunting and gathering (22.4%) (P = 0.0007). This was closely mirrored by the frequency of the slow 590A variant that was found to occur at a three-fold higher frequency in food producers (25%) as compared to hunter-gatherers (8%). These findings are consistent with the hypothesis that the Neolithic transition to subsistence economies based on agricultural and pastoral resources modified the selective regime affecting the NAT2 acetylation pathway. Furthermore, the vast amount of data collected enabled us to provide a comprehensive and up-to-date description of NAT2 worldwide genetic diversity, thus building up a useful resource of frequency data for further studies interested in epidemiological or anthropological research questions involving NAT2.
Highlights
The arylamine N-acetyltransferase 2 (NAT2) gene is involved in human physiological responses to a wide range of xenobiotic compounds, including many clinically useful drugs and a variety of exogenous chemicals present in the diet and the environment
A intriguing aspect of NAT2 gene variation is the high prevalence of slow acetylators in humans which calls into question the role that slow acetylation has played in the adaptation of our species
We created a comprehensive resource of frequency data for the seven most important genetic variants of the NAT2 gene by systematically retrieving data from the literature (Table S1)
Summary
The arylamine N-acetyltransferase 2 (NAT2) gene is involved in human physiological responses to a wide range of xenobiotic compounds, including many clinically useful drugs and a variety of exogenous chemicals present in the diet and the environment. A first possible explanation is that NAT2 may be a neutrally evolving gene, the NAT2 enzyme having become dispensable or redundant with other detoxifying enzymes such as NAT1, and being no more essential to human life and health [7] Under such a model, the variants conferring a slow acetylator phenotype are not more detrimental to the individual’s survival than neutral polymorphisms and they may have reached high frequencies in human populations just ‘by chance’, through genetic drift. Considering a global advantage of being a slow acetylator (and a roughly equivalent effect of all slowcausing mutations on phenotype and fitness), this model assumes that the different slow variants of NAT2 may have simultaneously become targets of directional selection, thereby generating an excess of intermediate-frequency haplotypes. This, in turn, would explain why conventional tests of selection have failed to detect signatures of positive selection at the NAT2 locus [6,8]
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