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Evidence for balancing selection from nucleotide sequence analyses of human G6PD.

ABSTRACT: Glucose-6-phosphate dehydrogenase (G6PD) mutations that result in reduced enzyme activity have been implicated in malarial resistance and constitute one of the best examples of selection in the human genome. In the present study, we characterize the nucleotide diversity across a 5.2-kb region of G6PD in a sample of 160 Africans and 56 non-Africans, to determine how selection has shaped patterns of DNA variation at this gene. Our global sample of enzymatically normal B alleles and A, A-, and Med alleles with reduced enzyme activities reveals many previously uncharacterized silent-site polymorphisms. In comparison with the absence of amino acid divergence between human and chimpanzee G6PD sequences, we find that the number of G6PD amino acid polymorphisms in human populations is significantly high. Unlike many other G6PD-activity alleles with reduced activity, we find that the age of the A variant, which is common in Africa, may not be consistent with the recent emergence of severe malaria and therefore may have originally had a historically different adaptive function. Overall, our observations strongly support previous genotype-phenotype association studies that proposed that balancing selection maintains G6PD deficiencies within human populations. The present study demonstrates that nucleotide sequence analyses can reveal signatures of both historical and recent selection in the genome and may elucidate the impact that infectious disease has had during human evolution.

SUBMITTER: Verrelli BC

PROVIDER: S-EPMC385087 | biostudies-literature | 2002 Nov

REPOSITORIES: biostudies-literature

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Evidence for balancing selection from nucleotide sequence analyses of human G6PD.

Verrelli Brian C BC McDonald John H JH Argyropoulos George G Destro-Bisol Giovanni G Froment Alain A Drousiotou Anthi A Lefranc Gerard G Lefranc Gerard G Helal Ahmed N AN Loiselet Jacques J Tishkoff Sarah A SA

American journal of human genetics 20021011 5

Glucose-6-phosphate dehydrogenase (G6PD) mutations that result in reduced enzyme activity have been implicated in malarial resistance and constitute one of the best examples of selection in the human genome. In the present study, we characterize the nucleotide diversity across a 5.2-kb region of G6PD in a sample of 160 Africans and 56 non-Africans, to determine how selection has shaped patterns of DNA variation at this gene. Our global sample of enzymatically normal B alleles and A, A-, and Med ...[more]

PMID: 12378426

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Project description:BackgroundBalancing selection operating for long evolutionary periods at a locus is characterized by the maintenance of distinct alleles because of a heterozygote or rare-allele advantage. The loci under balancing selection are distinguished by their unusually high polymorphism levels. In this report, we provide statistical and comparative genetic evidence suggesting that the SDHA gene is under long-term balancing selection. SDHA encodes the major catalytical subunit (flavoprotein, Fp) of the succinate dehydrogenase enzyme complex (SDH; mitochondrial complex II). The inhibition of Fp by homozygous SDHA mutations or by 3-nitropropionic acid poisoning causes central nervous system pathologies. In contrast, heterozygous mutations in SDHB, SDHC, and SDHD, the other SDH subunit genes, cause hereditary paraganglioma (PGL) tumors, which show constitutive activation of pathways induced by oxygen deprivation (hypoxia).ResultsWe sequenced the four SDH subunit genes (10.8 kb) in 24 African American and 24 European American samples. We also sequenced the SDHA gene (2.8 kb) in 18 chimpanzees. Increased nucleotide diversity distinguished the human SDHA gene from its chimpanzee ortholog and from the PGL genes. Sequence analysis uncovered two common SDHA missense variants and refuted the previous suggestions that these variants originate from different genetic loci. Two highly dissimilar SDHA haplotype clusters were present in intermediate frequencies in both racial groups. The SDHA variation pattern showed statistically significant deviations from neutrality by the Tajima, Fu and Li, Hudson-Kreitman-Aguadé, and Depaulis haplotype number tests. Empirically, the elevated values of the nucleotide diversity (% pi = 0.231) and the Tajima statistics (D = 1.954) in the SDHA gene were comparable with the most outstanding cases for balancing selection in the African American population.ConclusionThe SDHA gene has a strong signature of balancing selection. The SDHA variants that have increased in frequency during human evolution might, by influencing the regulation of cellular oxygen homeostasis, confer protection against certain environmental toxins or pathogens that are prevalent in Africa.

Project description:Bacterial lineages that populate the human gut microbiota contend with spatial and temporal fluctuations in numerous environmental variables, including bouts of extreme selective agents such as antibiotics. Oscillations in the adaptive landscape can impose balancing selection on populations, leaving characteristic signatures in the sequence variation of functionally significant genomic loci. Despite their potential importance for gut bacterial adaptation, the metagenomic targets of balancing selection have not been identified. Here, I present population genetic evidence that balancing selection maintains allelic diversity in multidrug efflux pumps of multiple predominant gut bacterial species. Metagenome-wide scans of 566,958 genes from 287 bacterial species represented by 118,617 metagenome-assembled genomes indicated that most genes have been conserved by purifying selection. However, dozens of core open reading frames (CORFs) displayed positive Tajima's D values that deviated significantly from their species' genomic backgrounds, indicating the action of balancing selection. Multidrug efflux pumps (MEPs) from a diversity of bacterial species were significantly enriched among the CORFs with Tajima's D values >3 in industrialized, but not nonindustrialized, human populations. The AcrB subunit of an MEP from Bacteroides dorei displayed the highest Tajima's D of any CORF. Divergent haplotypes of this CORF displayed evidence of positive selection and homology to an Escherichia coli AcrB subunit that binds tetracycline and macrolide antibiotics, suggesting functional significance and implicating medical antibiotics as an agent of selection acting on this locus. Other proteins identified as targets of balancing selection included peptidoglycan/LPS O-acetylases and ion transporters. Intriguingly, the degree of balancing selection acting on gut bacterial species was associated with species abundance in the gut based on metagenomic data, further suggesting fitness benefits of the allelic variation identified.

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Evidence for balancing selection from nucleotide sequence analyses of human G6PD.

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Evidence for balancing selection from nucleotide sequence analyses of human G6PD.

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