In this context, given the geographic distribution of the slow acetylator phenotype and the estimated expansion time of the slowest-encoding 341T>C mutation (5,797-7,005 years ago in West/Central Eurasians), it is tempting to hypothesize that the emergence of agriculture in West Eurasia could be at the basis of such environmental changes. Indeed, there is accumulating evidence that this major transition resulted in a profound modification of human diets and lifestyles (Cordain et al. 2005) and consequently, in the exposure to human chemical environment (Ferguson et al. 2002). Moreover, the highest frequencies of slow acetylators are observed in the Middle East (fig. 5), one of the first regions where agriculture originated ~10,000 years ago, and these frequencies decrease towards Western Europe, North Africa and India, three regions where agriculture was subsequently diffused from the Fertile Crescent (Harris 1996).American Journal of Human Genetics (in press)
Deciphering the ancient and complex evolutionary history of human arylamine N-acetyltransferase genes
Etienne Patin et al.
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, questioning 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 re-sequencing and genotyping of NAT1, NAT2 and the pseudogene NATP in a collection of 13 different populations with distinct ethnic background 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 while 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 ~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 illustrate well how geographically and temporally-fluctuating xenobiotic environments may have influenced not only our genome variability but also our present-day susceptibility to disease.