Article

European Journal of Human Genetics (2008) 16, 243–251; doi:10.1038/sj.ejhg.5201963; published online 28 November 2007

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

Hélène Magalon1,6, Etienne Patin1,2,6, Frédéric Austerlitz3, Tatyana Hegay4, Almaz Aldashev5, Lluís Quintana-Murci2 and Evelyne Heyer1

  1. 1Unité d’Eco-Anthropologie et Ethnobiologie, CNRS UMR 5145, Musée de l’Homme, Paris, France
  2. 2Human Evolutionary Genetics, CNRS URA 3012, Institut Pasteur, Paris, France
  3. 3Laboratoire Ecologie Systématique et Evolution, CNRS UMR 8079, Orsay, France
  4. 4Institute of Immunology, Academy of Sciences, Tashkent, Uzbekistan
  5. 5National Academy of Sciences, Bishkek, Kyrgyz Republic

Correspondence: Dr E Patin, Human Evolutionary Genetics, Metchnikoff Building, 5th floor, 25 rue du Dr Roux Paris, Institut Pasteur, Cedex 15, Paris 75724, France. Tel: +33 1 44 38 94 41; Fax: +33 1 45 68 86 39; E-mail: epatin@pasteur.fr

6Joint first authors.

Received 16 July 2007; Revised 23 October 2007; Accepted 25 October 2007; Published online 28 November 2007.

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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.

Keywords:

NAT2, Neolithic transition, Central Asia, natural selection