Deciphering the Ancient and Complex Evolutionary History of Human Arylamine N-Acetyltransferase Genes

Abstract

The human N-acetyltransferase genes NAT1 and NAT2 encode two phase-II enzymes that metabolize various drugs and carcinogens. Functional variability at these genes has been associated with adverse drug reactions and cancer susceptibility. Mutations in NAT2 leading to the so-called slow-acetylation phenotype reach high frequencies worldwide, which questions the significance of altered acetylation in human adaptation. To investigate the role of population history and natural selection in shaping NATs variation, we characterized genetic diversity through the resequencing and genotyping of NAT1, NAT2, and the pseudogene NATP in a collection of 13 different populations with distinct ethnic backgrounds and demographic pasts. This combined study design allowed us to define a detailed map of linkage disequilibrium of the NATs region as well as to perform a number of sequence-based neutrality tests and the long-range haplotype (LRH) test. Our data revealed distinctive patterns of variability for the two genes: the reduced diversity observed at NAT1 is consistent with the action of purifying selection, whereas NAT2 functional variation contributes to high levels of diversity. In addition, the LRH test identified a particular NAT2 haplotype (NAT2*5B) under recent positive selection in western/central Eurasians. This haplotype harbors the mutation 341T-->C and encodes the "slowest-acetylator" NAT2 enzyme, suggesting a general selective advantage for the slow-acetylator phenotype. Interestingly, the NAT2*5B haplotype, which seems to have conferred a selective advantage during the past approximately 6,500 years, exhibits today the strongest association with susceptibility to bladder cancer and adverse drug reactions. On the whole, the patterns observed for NAT2 well illustrate how geographically and temporally fluctuating xenobiotic environments may have influenced not only our genome variability but also our present-day susceptibility to disease.

SPACE: An Algorithm to Predict and Quantify Alternatively Spliced Isoforms Using Microarrays

“…Indeed if most of the drugs have been introduced too recently to be directly responsible for selective pressures, they are often derived from nutrients that have been consumed by humans for a long time. Thus, genes involved in drug metabolism can potentially be involved in natural selection and this was confirmed by previous studies [39][40][41]. However, the implication of drug metabolism genes in SJS/TEN remains to be established.…”

A Homogenizing Process of Selection Has Maintained an “Ultra-Slow” Acetylation <em>NAT2</em> Variant in Humans

“…NAT2 acetylation has attracted much research interest in evolutionary biology and several population genetic studies have attempted to clarify the role that slow acetylation could have played in the adaptation of our species (Fuselli et al, 2007;Luca et al, 2008;Magalon et al, 2008;Mortensen et al, 2011;Patin et al, 2006;Sabbagh and Darlu, 2006;Sabbagh et al, 2011). The high prevalence of slow acetylators in humans (well above 50% worldwide) is thought to be a consequence of the shift in modes of subsistence and lifestyle in the last 10,000 years, which triggered significant changes in diet and human exposure to xenobiotic compounds.…”

“…The high prevalence of slow acetylators in humans (well above 50% worldwide) is thought to be a consequence of the shift in modes of subsistence and lifestyle in the last 10,000 years, which triggered significant changes in diet and human exposure to xenobiotic compounds. Several surveys of NAT2 sequence variation have indeed provided compelling evidence that at least some of the slow-causing variants of NAT2 have been driven to presentday frequencies through the action of natural selection (Luca et al, 2008;Magalon et al, 2008;Mortensen et al, 2011;Patin et al, 2006;Sabbagh et al, 2011). The slow acetylation phenotype may thus have been a key adaptation to increase our species fitness in response to the transition from foraging to farming.…”

“…Such a low level of geographic differentiation may rather suggest a homogenizing process of natural selection, promoting the same allelic variant in otherwise disparate populations (through either directional or balancing selection). Although many polymorphisms have been described in other regions of the NAT2 gene (Mortensen et al, 2011;Patin et al, 2006), limited data exist on the geographic distribution of these variants in worldwide populations.…”

N-acetyltransferase 2 Phenotype, Occupation, and Bladder Cancer Risk: Results from the EPIC Cohort

“…It is important to note that canids even lack NAT expression (42), and NAT knockout mice do not exhibit a different phenotype (43). Human NATs form a cluster of three genes, comprising a pseudogene and the functional genes NAT1 and NAT2 that share 81% of their sequence (44). Both isoforms catalyze Nand O-acetylation reactions but vary in substrate specificity (45).…”