Dataset Information

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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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.

SUBMITTER: Luca F

PROVIDER: S-EPMC2527519 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Multiple advantageous amino acid variants in the NAT2 gene in human populations.

Luca Francesca F Bubba Giuseppina G Basile Massimo M Brdicka Radim R Michalodimitrakis Emmanuel E Rickards Olga O Vershubsky Galina G Quintana-Murci Lluis L Kozlov Andrey I AI Novelletto Andrea A

PloS one 20080905 9

<h4>Background</h4>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.<h4>Methodology/principal findings</h4>The entire ...[more]

PMID: 18773084

Similar Datasets

Project description:Introduction: Several polymorphisms altering the NAT2 activity have already been identified. The geographical distribution of NAT2 variants has been extensively studied and has been demonstrated to vary significantly among different ethnic population. Here, we describe the genetic variability of human N-acetyltransferase 2 (NAT2) gene and the predominant genotype-deduced acetylation profiles of Brazilians. Methods: A total of 964 individuals, from five geographical different regions, were genotyped for NAT2 by sequencing the entire coding exon. Results: Twenty-three previously described NAT2 single nucleotide polymorphisms (SNPs) were identified, including the seven most common ones globally (c.191G>A, c.282C>T, c.341T>C, c.481C>T, c.590G>A, c.803A>G and c.857G>A). The main allelic groups were NAT2*5 (36%) and NAT2*6 (18.2%), followed to the reference allele NAT2*4 (20.4%). Combined into genotypes, the most prevalent allelic groups were NAT2*5/*5 (14.6%), NAT2*5/*6 (11.9%) and NAT2*6/*6 (6.2%). The genotype deduced NAT2 slow acetylation phenotype was predominant but showed significant variability between geographical regions. The prevalence of slow acetylation phenotype was higher in the Northeast, North and Midwest (51.3%, 45.5% and 41.5%, respectively) of the country. In the Southeast, the intermediate acetylation phenotype was the most prevalent (40.3%) and, in the South, the prevalence of rapid acetylation phenotype was significantly higher (36.7%), when compared to other Brazilian states (p < 0.0001). Comparison of the predicted acetylation profile among regions showed homogeneity among the North and Northeast but was significantly different when compared to the Southeast (p = 0.0396). The Southern region was significantly different from all other regions (p < 0.0001). Discussion: This study contributes not only to current knowledge of the NAT2 population genetic diversity in different geographical regions of Brazil, but also to the reconstruction of a more accurate phenotypic picture of NAT2 acetylator profiles in those regions.

Project description:BACKGROUND: Urodele amphibians like the axolotl are unique among vertebrates in their ability to regenerate and their resistance to develop cancers. It is unknown whether these traits are linked at the molecular level. RESULTS: Blocking p53 signaling in axolotls using the p53 inhibitor, pifithrin-alpha, inhibited limb regeneration and the expression of p53 target genes such as Mdm2 and Gadd45, suggesting a link between tumor suppression and regeneration. To understand this relationship we cloned the p53 gene from axolotl. When comparing its sequence with p53 from other organisms, and more specifically human we observed multiple amino acids changes found in human tumors. Phylogenetic analysis of p53 protein sequences from various species is in general agreement with standard vertebrate phylogeny; however, both mice-like rodents and teleost fishes are fast evolving. This leads to long branch attraction resulting in an artefactual basal emergence of these groups in the phylogenetic tree. It is tempting to assume a correlation between certain life style traits (e.g. lifespan) and the evolutionary rate of the corresponding p53 sequences. Functional assays of the axolotl p53 in human or axolotl cells using p53 promoter reporters demonstrated a temperature sensitivity (ts), which was further confirmed by performing colony assays at 37 degrees C. In addition, axolotl p53 was capable of efficient transactivation at the Hmd2 promoter but has moderate activity at the p21 promoter. Endogenous axolotl p53 was activated following UV irradiation (100 j/m2) or treatment with an alkylating agent as measured using serine 15 phosphorylation and the expression of the endogenous p53 target Gadd45. CONCLUSION: Urodele p53 may play a role in regeneration and has evolved to contain multiple amino acid changes predicted to render the human protein defective in tumor suppression. Some of these mutations were probably selected to maintain p53 activity at low temperature. However, other significant changes in the axolotl proteins may play more subtle roles on p53 functions, including DNA binding and promoter specificity and could represent useful adaptations to ensure p53 activity and tumor suppression in animals able to regenerate or subject to large variations in oxygen levels or temperature.

Dataset Information

Multiple advantageous amino acid variants in the NAT2 gene in human populations.

Publications

Multiple advantageous amino acid variants in the NAT2 gene in human populations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets