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. © 2008 Luca et al.

Luca, F., Bubba, G., Basile, M., Brdicka, R., Michalodimitrakis, E., Rickards, O., et al. (2008). Multiple advantageous amino acid variants in the NAT2 gene in human populations. PLOS ONE, 3(9) [10.1371/journal.pone.0003136].

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

RICKARDS, OLGA;NOVELLETTO, ANDREA
2008

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. © 2008 Luca et al.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/18 - Genetica
Settore BIO/08
English
Con Impact Factor ISI
amino acid; arylamine acetyltransferase; cysteine; histidine; threonine; tyrosine; folic acid; NAT2 protein, human; allele; amino acid substitution; article; controlled study; enzyme activity; gene frequency; gene mutation; gene sequence; genetic polymorphism; genetic variability; genotype; geographic distribution; haplotype; human; lifestyle; population differentiation; population research; biological model; chemistry; genetics; geography; metabolism; molecular evolution; mutation; phenotype; population genetics; Alleles; Arylamine N-Acetyltransferase; Evolution, Molecular; Folic Acid; Gene Frequency; Genetic Variation; Genetics, Population; Genotype; Geography; Haplotypes; Humans; Models, Genetic; Mutation; Phenotype; Polymorphism, Genetic
Luca, F., Bubba, G., Basile, M., Brdicka, R., Michalodimitrakis, E., Rickards, O., et al. (2008). Multiple advantageous amino acid variants in the NAT2 gene in human populations. PLOS ONE, 3(9) [10.1371/journal.pone.0003136].
Luca, F; Bubba, G; Basile, M; Brdicka, R; Michalodimitrakis, E; Rickards, O; Vershubsky, G; Quintana, M; L, K; Ai, ; Novelletto, A
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/30687
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