Sequence variation in human succinate dehydrogenase genes: evidence for long-term balancing selection on SDHA - PubMed (original) (raw)

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

Bora E Baysal et al. BMC Biol. 2007.

Abstract

Background: 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 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).

Results: We 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.

Conclusion: The 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.

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Figures

Figure 1

Figure 1

Minor allele frequency of each SDH subunit variant (also see Additional Table 1) is shown. Filled vertical bars refer to African American, unfilled vertical bars refer to European American samples. Synonymous and non-synonymous coding variants are marked by S and NS, respectively. ID refers to insertion/deletion polymorphisms.

Figure 2

Figure 2

Tajima's D statistic and nucleotide diversity in SDHA and SDHB genes (squares) relative to the 282 genes in SeattleSNP database are shown in the African American population. Positions of two highly polymorphic loci, ABO and FUT2, the latter of which encodes the alpha(1,2)fucosyltransferase, are shown.

Figure 3

Figure 3

Haplotypes of SDHA. Periods denote the identical SNP variant when compared to the most common haplotype of each haplogroup. @NC = non-coding, S = synonymous coding, NS = non-synonymous coding. I = insertion allele, D = deletion allele. ^AA = African-American samples, EA = European-American samples.

Figure 4

Figure 4

A median-joining network groups all SDHA haplotypes (Figure 3) on the basis of number of nucleotide differences. The haplotype RR is probably a recombinant between the two haplogroups. The pie chart for each haplotype depicts the proportional contribution of the African American (filled portion) and the European American (unfilled portion) samples.

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