title: Multiple advantageous amino acid variants in the NAT2 gene in human populations.
abstract: BACKGROUND
  Genetic 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.
  
  
  RESULTS
  The 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
  Data 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.
authors.affiliation: Department of Cell Biology, University of Calabria, Rende, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Luca
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Bubba
authors.forename: Massimo
authors.initials: M
authors.lastname: Basile
authors.forename: Radim
authors.initials: R
authors.lastname: Brdicka
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Michalodimitrakis
authors.forename: Olga
authors.initials: O
authors.lastname: Rickards
authors.forename: Galina
authors.initials: G
authors.lastname: Vershubsky
authors.forename: Lluis
authors.initials: L
authors.lastname: Quintana-Murci
authors.forename: Andrey I
authors.initials: AI
authors.lastname: Kozlov
authors.forename: Andrea
authors.initials: A
authors.lastname: Novelletto
mesh_terms: D000483:Alleles; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D019143:Evolution, Molecular; D005492:Folic Acid / Q000737:chemistry; D005787:Gene Frequency; D014644:Genetic Variation; D005828:Genetics, Population; D005838:Genotype; D005843:Geography; D006239:Haplotypes; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic
chemical_list: D005492:Folic Acid; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human
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