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. 2011 Nov;12(11):1545-58.
doi: 10.2217/pgs.11.88. Epub 2011 Oct 13.

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

Free PMC article

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

Holly M Mortensen et al. Pharmacogenomics. .
Free PMC article


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.

Conflict of interest statement

Financial & competing interests disclosure

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.


Figure 1
Figure 1. Multidimensional scaling plots of population pairwise FST values for the (A) NAT1, (B) NAT2 and (C) NATP1 gene regions
Analysis of molecular variance results are indicated in the inset, where variance among groups = FCT, variance among populations within groups = FSC, and variance among populations = FST. Yellow = Africa; Purple = Europe; Blue = Asia; Red = Americas. Population structure is specified according to the population groupings listed in Table 1. MDS: Multidimensional scaling.
Figure 2
Figure 2. NAT2-inferred acetylator phenotype distribution for all populations in the current study
Phenotype inference was made based on SNPs known to affect acetylator phenotype [103]. Each individual is represented according to their inferred diploid haplotype, where light blue = slow/slow; turquoise = slow/rapid; dark blue = rapid/rapid; light gray = unknown/slow; dark gray = unknown/rapid; black = unknown/unknown. Inset shows NAT2-inferred acetylator phenotype distribution within Africa for each population group. Populations shown flanking Africa are those sampled from Cameroon and Tanzania (highlighted in gray). Refer to Table 1 for population counts included in the present study.
Figure 3
Figure 3. Median-joining network for NAT2-inferred acetylator phenotypes
For all nodes, dark blue = rapid acetylators, light blue = slow acetylators, gray = haplotypes where acetylator phenotype could not be inferred, and red indicates the chimpanzee (Pan troglodytes) outgroup. All nomenclature follows that recommended by the NAT nomenclature committee (e.g., NAT2*Major haplotype/sub-haplotype). Bold sub-haplotypes represent haplotypes that are novel to the current dataset.

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