| Summary: | <p>Abstract</p> <p>Background</p> <p>Balancing 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 <it>SDHA </it>gene is under long-term balancing selection. <it>SDHA </it>encodes the major catalytical subunit (flavoprotein, Fp) of the succinate dehydrogenase enzyme complex (SDH; mitochondrial complex II). The inhibition of Fp by homozygous <it>SDHA </it>mutations or by 3-nitropropionic acid poisoning causes central nervous system pathologies. In contrast, heterozygous mutations in <it>SDHB</it>, <it>SDHC</it>, and <it>SDHD</it>, the other SDH subunit genes, cause hereditary paraganglioma (PGL) tumors, which show constitutive activation of pathways induced by oxygen deprivation (hypoxia).</p> <p>Results</p> <p>We sequenced the four SDH subunit genes (10.8 kb) in 24 African American and 24 European American samples. We also sequenced the <it>SDHA </it>gene (2.8 kb) in 18 chimpanzees. Increased nucleotide diversity distinguished the human <it>SDHA </it>gene from its chimpanzee ortholog and from the PGL genes. Sequence analysis uncovered two common <it>SDHA </it>missense variants and refuted the previous suggestions that these variants originate from different genetic loci. Two highly dissimilar <it>SDHA </it>haplotype clusters were present in intermediate frequencies in both racial groups. The <it>SDHA </it>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 (% π = 0.231) and the Tajima statistics (<it>D </it>= 1.954) in the <it>SDHA </it>gene were comparable with the most outstanding cases for balancing selection in the African American population.</p> <p>Conclusion</p> <p>The <it>SDHA </it>gene has a strong signature of balancing selection. The <it>SDHA </it>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.</p>
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