Sequence variation in human succinate dehydrogenase genes: evidence for long-term balancing selection on SDHA.

Bora E Baysal,Elizabeth C Lawrence,Robert E Ferrell

doi:10.1186/1741-7007-5-12

Abstract

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 (% π = 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.

Highlights

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
3828 coding and 7013 non-coding nucleotides were sequenced for each sample, and 52 polymorphisms were detected (Table 1)
Inclusion of the SDHA indels, by recoding them as single nucleotide polymorphisms (SNPs), increased all SDHA test statistics and reduced the p values that the Y629F and V657I variants originate from two distinct genetic loci because these missense variants are encoded by a single, highly polymorphic SDHA gene

Summary

Introduction

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. SDHA encodes the major catalytical subunit (flavoprotein, Fp) of the succinate dehydrogenase enzyme complex (SDH; mitochondrial complex II). 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). The identification of the SDHD subunit gene as the hereditary paraganglioma type 1 locus (PGL1) has uncovered unexpected links between SDH and tumor susceptibility, and highlighted the role of mitochondria in cancer [4]. Mutations in SDHB, SDHC, and SDHD subunit genes (PGL genes) have been established as an important cause of sporadic and familial paragangliomas [5,6,7,8,9,10]. The paraganglia specificity of PGL tumors [4] and data from global gene-expression analysis [11], cell biology [12], animal-model studies [13], and gene-environment interaction and population genetics [14] support the hypothesis that constitutive hypoxic stimulation underlies the pathogenesis of PGL

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