Multiple Advantageous Amino Acid Variants in the NAT2 Gene in Human Populations

Abstract

BackgroundGenetic variation at NAT2 has been long recognized as the cause of differential ability to metabolize a wide variety of drugs of therapeutic use. Here, we explore the pattern of genetic variation in 12 human populations that significantly extend the geographic range and resolution of previous surveys, to test the hypothesis that different dietary regimens and lifestyles may explain inter-population differences in NAT2 variation.Methodology/Principal FindingsThe entire coding region was resequenced in 98 subjects and six polymorphic positions were genotyped in 150 additional subjects. A single previously undescribed variant was found (34T>C; 12Y>H). Several aspects of the data do not fit the expectations of a neutral model, as assessed by coalescent simulations. Tajima's D is positive in all populations, indicating an excess of intermediate alleles. The level of between-population differentiation is low, and is mainly accounted for by the proportion of fast vs. slow acetylators. However, haplotype frequencies significantly differ across groups of populations with different subsistence.Conclusions/SignificanceData on the structure of haplotypes and their frequencies are compatible with a model in which slow-causing variants were present in widely dispersed populations before major shifts to pastoralism and/or agriculture. In this model, slow-causing mutations gained a selective advantage in populations shifting from hunting-gathering to pastoralism/agriculture. We suggest the diminished dietary availability of folates resulting from the nutritional shift, as the possible cause of the fitness increase associated to haplotypes carrying mutations that reduce enzymatic activity.

SPACE: An Algorithm to Predict and Quantify Alternatively Spliced Isoforms Using Microarrays

“…Indeed if most of the drugs have been introduced too recently to be directly responsible for selective pressures, they are often derived from nutrients that have been consumed by humans for a long time. Thus, genes involved in drug metabolism can potentially be involved in natural selection and this was confirmed by previous studies [39][40][41]. However, the implication of drug metabolism genes in SJS/TEN remains to be established.…”

Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene

“…The search for an explanation for the presence of multiple common coding SNPs in NAT2 has been the source of intense investigation, and the prevalence of NAT2 haplotypes has been determined for a large number of human populations (38,45); the "rapid" acetylator NAT2*4 haplotype is considered ancestral and predominates in Southern Africa and East Asia, but higher frequencies of the most common "slow" acetylator haplotypes NAT2*5 (defined by the presence of rs1801280) and NAT2*6 (defined by the presence of rs1799930) predominate in Europe, Northern Africa, and the Middle East (47). Importantly, our analysis based on predicted acetylator status did not support a stronger association with insulin sensitivity for "slow" versus "rapid" acetylators, which suggests that the mechanism by which NAT2 may affect insulin sensitivity might be independent of the ability to acetylate the canonical drug substrates.…”

Comparative genomic and phylogenetic investigation of the xenobiotic metabolizing arylamine N‐acetyltransferase enzyme family

“…1,2 Sequences were also retrieved from the Fungal Genome Initiative databases 3 of the Broad Institute. Initial searches were performed by tBLASTn, using the protein sequences of: (a) Salmonella typhimurium NAT1 4,5 in order to update our previous catalogues of annotated NAT genes for these taxonomic groups [8]. The genomes of archaea, 1,4 protists 2,5 and fungi 2,3,5 were each one interrogated separately.…”