A homogenizing process of selection has maintained an "ultra-slow" acetylation NAT2 variant in humans.

International audienceN-Acetyltransferase 2 (NAT2) is an important enzyme involved in the metabolism of a wide spectrum of naturally occurring xenobiotics, including therapeutic drugs and common environmental carcinogens. Extensive polymorphism in NAT2 gives rise to a wide interindividual variation in acetylation capacity, which influences individual susceptibility to various drug-induced adverse reactions and cancers. Striking patterns of geographic differentiation have been described for the main slow acetylation variants of the NAT2 gene, suggesting the action of natural selection at this locus. In the present study, we took advantage of whole-genome sequence data available from the 1000 Genomes project to investigate the global patterns of population genetic differentiation at NAT2 and determine whether they are atypical compared with the remaining variation of the genome. The nonsynonymous substitution c.590G>A (rs1799930) defining the slow NAT2*6 haplotype cluster exhibited an unusually low FST value compared with the genome average (FST = 0.006, P = 0.016). It was indicated as the most likely target of a homogenizing process of selection promoting the same allelic variant in globally distributed populations. The rs1799930 A allele has been associated with the slowest acetylation capacity in vivo, and its substantial correlation with the subsistence strategy adopted by past human populations suggests that it may have conferred a selective advantage in populations shifting from foraging to agricultural and pastoral activities in the Neolithic period. Results of neutrality tests further supported an adaptive evolution of the NAT2 gene through either balancing selection or directional selection acting on multiple standing slow acetylation variants

A homogenizing process of selection has maintained an "ultra-slow" acetylation NAT2 variant in humans.

International audienceN-Acetyltransferase 2 (NAT2) is an important enzyme involved in the metabolism of a wide spectrum of naturally occurring xenobiotics, including therapeutic drugs and common environmental carcinogens. Extensive polymorphism in NAT2 gives rise to a wide interindividual variation in acetylation capacity, which influences individual susceptibility to various drug-induced adverse reactions and cancers. Striking patterns of geographic differentiation have been described for the main slow acetylation variants of the NAT2 gene, suggesting the action of natural selection at this locus. In the present study, we took advantage of whole-genome sequence data available from the 1000 Genomes project to investigate the global patterns of population genetic differentiation at NAT2 and determine whether they are atypical compared with the remaining variation of the genome. The nonsynonymous substitution c.590G>A (rs1799930) defining the slow NAT2*6 haplotype cluster exhibited an unusually low FST value compared with the genome average (FST = 0.006, P = 0.016). It was indicated as the most likely target of a homogenizing process of selection promoting the same allelic variant in globally distributed populations. The rs1799930 A allele has been associated with the slowest acetylation capacity in vivo, and its substantial correlation with the subsistence strategy adopted by past human populations suggests that it may have conferred a selective advantage in populations shifting from foraging to agricultural and pastoral activities in the Neolithic period. Results of neutrality tests further supported an adaptive evolution of the NAT2 gene through either balancing selection or directional selection acting on multiple standing slow acetylation variants

Balancing immunity and tolerance : genetic footprint of natural selection in the transcriptional regulatory region of HLA-G

Human leukocyte antigen-G (HLA-G) has well-recognized immunosuppressive properties modulating the activity of many immune system cells, and polymorphisms observed at the HLA-G 5' upstream regulatory region (5'URR) may influence gene transcriptional regulation. In this study, we characterized the sequence variation and haplotype structure of the HLA-G 5'URR in worldwide populations to investigate the evolutionary history of the HLA-G promoter and shed some light into the mechanisms that may underlie HLA-G expression control. A 1.4-kb region, encompassing the known HLA-G regulatory elements, was sequenced in three African populations from Senegal, Benin and Congo, and data were combined with those available in the literature, resulting in a total of 1411 individuals from 21 worldwide populations. High levels of nucleotide and haplotype diversities, excess of intermediate-frequency variants and reduced population differentiation were observed at this locus when compared with the background genomic variation. These features support a strong molecular signature of balancing selection at HLA-G 5'URR, probably as a result of the competing needs to maintain both a maternal-fetal immune tolerance and an efficient host immune response to invading pathogens during human evolution. An extended analysis of a 300-kb region surrounding HLA-G revealed that this region is not involved in a hitchhiking effect and may be the direct target of selection

Balancing immunity and tolerance: genetic footprint of natural selection in the transcriptional regulatory region of HLA-G

Human leukocyte antigen-G (HLA-G) has well-recognized immunosuppressive properties modulating the activity of many immune system cells, and polymorphisms observed at the HLA-G 5'upstream regulatory region (5'URR) may influence gene transcriptional regulation. In this study, we characterized the sequence variation and haplotype structure of the HLA-G 5'URR in worldwide populations to investigate the evolutionary history of the HLA-G promoter and shed some light into the mechanisms that may underlie HLA-G expression control. A 1.4-kb region, encompassing the known HLA-G regulatory elements, was sequenced in three African populations from Senegal, Benin and Congo, and data were combined with those available in the literature, resulting in a total of 1411 individuals from 21 worldwide populations. High levels of nucleotide and haplotype diversities, excess of intermediate-frequency variants and reduced population differentiation were observed at this locus when compared with the background genomic variation. These features support a strong molecular signature of balancing selection at HLA-G 5'URR, probably as a result of the competing needs to maintain both a maternal-fetal immune tolerance and an efficient host immune response to invading pathogens during human evolution. An extended analysis of a 300-kb region surrounding HLA-G revealed that this region is not involved in a hitchhiking effect and may be the direct target of selection.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq