Genetic Variation at the N-acetyltransferase (NAT) Genes in Global Human Populations

Abstract

Currently, studies of the possible role of natural selection in shaping the observed variation at drug metabolizing enzyme (DME) loci remain limited. Functional variability at the N-acetyltransferase (NAT) genes is associated with adverse drug reactions and cancer susceptibility in humans. Previous studies of small sets of ethnic groups have indicated that the NAT genes have high levels of amino acid variation that differ in frequency across ethnic groups. I hypothesize that this functional variation may be adaptive in different environments and is maintained due to natural selection. Presumably, change in dietary patterns has been a strong selective pressure throughout the course of human evolution. The most extreme example of a shift in the dietary patterns of modern humans is most certainly the transition from a primarily hunter-gatherer subsistence to an agriculturalist lifestyle, within the past 10,000 years. Metabolism of grain and/or dairy products likely introduced new and foreign toxins to the human body. Although we can only speculate about the selective forces acting on the NAT genes in the past, it is possible that the observed pattern of phenotypic variation is associated with exposure to environmental, specifically dietary, toxins. The purpose of this study is: 1) to characterize nucleotide variation at the NAT drug-metabolizing genes (NAT1, NAT2) and the pseudo-gene (NATP1) in global human populations, including many previously under-represented African populations and 2) to understand the role that natural selection has played in shaping variation at NAT1 and NAT2 in human populations living in different environmental settings. I have resequenced ~3000 bp for each of the NAT1, NAT2 and NATP1 gene regions, in 182 African individuals and 155 individuals from a representative global panel (HGDP-CEPH), and have identified Single Nucleotide Polymorphisms (SNPs) at each locus (NAT1 (48), NATP1 (55) and NAT2 (46)). I have inferred haplotype phase and characterized patterns of haplotype diversity for each NAT locus. I have characterized nucleotide diversity and linkage disequilibrium for this ethnically diverse population dataset, as well as performed several tests of selective neutrality. This work will contribute to our understanding of how variation at the NAT loci may have been adaptive for dealing with changes in diet and exposure to toxins during human evolution.