Tuesday, December 18, 2007

NAT2 variants and the transition to agriculture in Central Asia

First what is NAT2? It's a gene involved in the acetylation of xenobiotics (foreign substances) and carcinogens - basically getting rid of toxins. They hypothesize that they will find different versions of this gene depending on whether a group is traditionally pastoralist or agriculturalist. They focus in on Central Asia where there is still some diversity among groups in subsistence. They don't really explain why there would have been selection for getting rid of foreign substances with an agricultural diet. They mention cooking meat at high temperatures, but that doesn't really seem to make the case... so, what is it about an agricultural, sedentary lifestyle that would select for the ability to neutralize or get rid of foreign stuff? This may be kinda obvious, like in the case of parasites, but they don't really seem to focus on that, so I wish they would have mentioned some other examples of what they meant. Anyway, their choice of populations to study seemed appropriate and interesting.
From the discussion section, mentioning converging evidence among groups in Africa:
A similar dichotomous pattern at the NAT2 gene has been observed among sub-Saharan Africans, where the Bantu-speaking agriculturalists presented a higher frequency of slow acetylators, as compared to the Pygmy hunter-gatherers (0.46 and 0.10, respectively).33 These significant differences in the frequency distribution of slow/fast acetylation phenotypes depending on lifestyle, attested by significant FST estimates, strongly suggest that being slow acetylator has been an advantage in long-term agriculturalist populations in Central Asia.
They then discuss the alternative hypotheses for their findings:
This observation can be explained by three different, non-mutually exclusive hypotheses: (1) demographic processes, (2) balancing selection or (3) directional selection on standing variation.
They go through each one and discuss it in light of their findings. All in all, I liked the general idea of the study, and I think that we will see many more such studies about recent selection due to novel environments. However, in this specific case, I am left to wonder about what exactly the selective advantage is in the environment of agricultural groups (what xenobiotics?, carcinogens?), and if it is linked to the variants of this particular gene... probably beyond the scope and purpose of this particular study.

Population genetic diversity of the NAT2 gene supports a role of acetylation in human adaptation to farming in Central Asia

Hélène Magalon, Etienne Patin, Frédéric Austerlitz, Tatyana Hegay, Almaz Aldashev, Lluís Quintana-Murci and Evelyne Heyer

European Journal of Human Genetics Advance online publication
Abstract: The arylamine N-acetyltransferase 2 (NAT2) enzyme detoxifies a wide spectrum of naturally occurring xenobiotics including carcinogens and drugs. Variation at the NAT2 gene has been linked to the human acetylation capacity, either 'slow' or 'fast', which modifies susceptibility to cancer and adverse drug reactions. We investigated the possible influence of natural selection in shaping the acetylation phenotype and the NAT2 gene variability in six Central Asian populations, who are either long-term sedentary agriculturalists (two Tajik populations), recent sedentary agriculturalists (Kazakhs, Uzbeks) or nomad pastoralists (two Kirghiz populations). To this end, we sequenced the entire NAT2 coding exon, as well as genotyping nine intergenic SNPs covering a 200-kb region. Our results revealed that the two Tajik populations exhibited significantly higher proportions of slow acetylators than the nomadic populations. In addition, sequence-based neutrality tests yielded significantly positive values in Central Asian populations following an agriculturalist lifestyle, due to an excess of haplotypes at intermediate frequencies. Taken together, our data suggest that balancing selection, and/or directional selection on standing low-frequency alleles, have shaped NAT2 genetic diversity and the human acetylation phenotype in Central Asian agriculturalists. These results further support the hypothesis that a major transition in human lifestyle, such as the emergence of farming has dramatically changed human chemical environments and the selective pressures they imposed.

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