Characterization of Genetic Variation and Natural Selection at the Arylamine N-Acetyltransferase Genes in Global Human Populations

Abstract

Functional variability at the arylamine N-acetyltransferase genes is associated with drug response in humans and may have been adaptive in the past owing to selection pressure from diet and exposure to toxins during human evolution. Aims: We have characterized nucleotide variation at the NAT1 and NAT2 genes, and at the NATP1 pseudogene in global human populations, including many previously under-represented African populations, in order to identify potential functional variants and to understand the role that natural selection has played in shaping variation at these loci in globally diverse populations. Materials & methods: We have resequenced approximately 2800 bp for each of the NAT1 and NAT2 gene regions, as well as the pseudogene NATP1, in 197 African and 132 nonAfrican individuals. Results & conclusion: We observe a signature of balancing selection maintaining variation in the 3‘-UTR of NAT1, suggesting that these variants may play a functional role that is currently undefined. In addition, we observed high levels of nonsynonymous functional variation at the NAT2 locus that differs amongst ethnically diverse populations.

Original submitted 13 April 2011; Revision submitted 28 June 2011

KEYWORDS::

• Africa
• arylamine N-acetyltransferase
• drug-metabolizing enzyme loci
• natural selection
• xenobiotic-metabolizing loci

Acknowledgements

The authors would first like to thank the Africans who contributed their samples to this study. Special thanks to Floyd Reed for his assistance in writing scripts and creating the program analysis pipeline used in the present study, Alessia Ranciaro for her contribution to the whole-genome re-amplification of samples, as well as Wen-Ya Ko and Michael Campbell for helpful discussion.

Financial & competing interests disclosure

This work was supported by the US National Science Foundation (NSF) IGERT grant 9987590 to Holly M Mortensen and Sarah A Tishkoff, NSF grants BCS 0196183, and BCS-0827436, NIH grants R01GM076637 and DP1-OD-006445-01 to Sarah A Tishkoff. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was supported by the US National Science Foundation (NSF) IGERT grant 9987590 to Holly M Mortensen and Sarah A Tishkoff, NSF grants BCS 0196183, and BCS-0827436, NIH grants R01GM076637 and DP1-OD-006445-01 to Sarah A Tishkoff. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.