Open Access Research article

Rapid birth-and-death evolution of the xenobiotic metabolizing NAT gene family in vertebrates with evidence of adaptive selection

Audrey Sabbagh128*, Julie Marin34, Charlotte Veyssière34, Emilie Lecompte34, Sotiria Boukouvala5, Estella S Poloni6, Pierre Darlu7 and Brigitte Crouau-Roy34

Author Affiliations

1 Institut de Recherche pour le Développement (IRD), UMR216-Mère et enfant face aux infections tropicales, Paris, France

2 PRES Paris Sorbonne Cité, Université Paris Descartes, Paris, France

3 CNRS, Université Paul Sabatier, ENFA, UMR5174EDB (Laboratoire Évolution & Diversité Biologique), Toulouse F-31062, France

4 Université de Toulouse 3, UMR5174EDB, Toulouse F-31062, France

5 Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece

6 Laboratory of Anthropology, Genetics and Peopling History, Anthropology Unit, Department of Genetics and Evolution, University of Geneva, Geneva, Switzerland

7 UMR 7206 Eco-anthropologie et ethnobiologie, MNHN-CNRS-Université Denis Diderot, Paris, France

8 IRD UMR 216, Université Paris Descartes, Paris, France

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BMC Evolutionary Biology 2013, 13:62  doi:10.1186/1471-2148-13-62

Published: 7 March 2013



The arylamine N-acetyltransferases (NATs) are a unique family of enzymes widely distributed in nature that play a crucial role in the detoxification of aromatic amine xenobiotics. Considering the temporal changes in the levels and toxicity of environmentally available chemicals, the metabolic function of NATs is likely to be under adaptive evolution to broaden or change substrate specificity over time, making NATs a promising subject for evolutionary analyses. In this study, we trace the molecular evolutionary history of the NAT gene family during the last ~450 million years of vertebrate evolution and define the likely role of gene duplication, gene conversion and positive selection in the evolutionary dynamics of this family.


A phylogenetic analysis of 77 NAT sequences from 38 vertebrate species retrieved from public genomic databases shows that NATs are phylogenetically unstable genes, characterized by frequent gene duplications and losses even among closely related species, and that concerted evolution only played a minor role in the patterns of sequence divergence. Local signals of positive selection are detected in several lineages, probably reflecting response to changes in xenobiotic exposure. We then put a special emphasis on the study of the last ~85 million years of primate NAT evolution by determining the NAT homologous sequences in 13 additional primate species. Our phylogenetic analysis supports the view that the three human NAT genes emerged from a first duplication event in the common ancestor of Simiiformes, yielding NAT1 and an ancestral NAT gene which in turn, duplicated in the common ancestor of Catarrhini, giving rise to NAT2 and the NATP pseudogene. Our analysis suggests a main role of purifying selection in NAT1 protein evolution, whereas NAT2 was predicted to mostly evolve under positive selection to change its amino acid sequence over time. These findings are consistent with a differential role of the two human isoenzymes and support the involvement of NAT1 in endogenous metabolic pathways.


This study provides unequivocal evidence that the NAT gene family has evolved under a dynamic process of birth-and-death evolution in vertebrates, consistent with previous observations made in fungi.

N-acetyltransferases; Gene family; Vertebrates; Gene duplication; Adaptive selection