A homogenizing process of selection has maintained an "ultra-slow" acetylation NAT2 variant in humans.

B Patillon; P Luisi; E S Poloni; S Boukouvala; P Darlu; E Genin; A Sabbagh

A homogenizing process of selection has maintained an "ultra-slow" acetylation NAT2 variant in humans.

B Patillon ¹ P Luisi E S Poloni S Boukouvala P Darlu ² E Genin A Sabbagh ^{3, 1}

1 MERIT - UMR_D 216 - Mère et enfant face aux infections tropicales

2 Inserm U535 - Génétique épidémiologique et structures des populations humaines

3 IRD - Institut de Recherche pour le Développement

Abstract : N-Acetyltransferase 2 (NAT2) is an important enzyme involved in the metabolism of a wide spectrum of naturally occurring xenobiotics, including therapeutic drugs and common environmental carcinogens. Extensive polymorphism in NAT2 gives rise to a wide interindividual variation in acetylation capacity, which influences individual susceptibility to various drug-induced adverse reactions and cancers. Striking patterns of geographic differentiation have been described for the main slow acetylation variants of the NAT2 gene, suggesting the action of natural selection at this locus. In the present study, we took advantage of whole-genome sequence data available from the 1000 Genomes project to investigate the global patterns of population genetic differentiation at NAT2 and determine whether they are atypical compared with the remaining variation of the genome. The nonsynonymous substitution c.590G>A (rs1799930) defining the slow NAT2*6 haplotype cluster exhibited an unusually low FST value compared with the genome average (FST = 0.006, P = 0.016). It was indicated as the most likely target of a homogenizing process of selection promoting the same allelic variant in globally distributed populations. The rs1799930 A allele has been associated with the slowest acetylation capacity in vivo, and its substantial correlation with the subsistence strategy adopted by past human populations suggests that it may have conferred a selective advantage in populations shifting from foraging to agricultural and pastoral activities in the Neolithic period. Results of neutrality tests further supported an adaptive evolution of the NAT2 gene through either balancing selection or directional selection acting on multiple standing slow acetylation variants.

Keywords : ACETYLATION POLYMORPHISM LINKAGE DISEQUILIBRIUM NAT2 NATURAL SELECTION POPULATION DIFFERENTIATION

Type de document :

Article dans une revue

Human Biology, Wayne State University Press, 2013, 86 (3), pp.185-214

Domaine :

Sciences du Vivant [q-bio]

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http://hal.univ-brest.fr/hal-01315459
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Soumis le : vendredi 13 mai 2016 - 11:32:58
Dernière modification le : jeudi 11 janvier 2018 - 06:20:15

A homogenizing process of selection has maintained an "ultra-slow" acetylation NAT2 variant in humans.

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A homogenizing process of selection has maintained an "ultra-slow" acetylation NAT2 variant in humans.

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