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

We provide statistical and comparative genetic evidence suggesting that the SDHA gene is under long-term balancing selection

Bora E Baysal; Elizabeth C Lawrence; Robert E Ferrell


Scholarcy 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
  • succinate dehydrogenase enzyme complex is composed of four subunits encoded by the nuclear genes SDHA, SDHB, SDHC, and SDHD
  • Our findings indicate that the variation pattern in SDHA is characterized by the presence of higher sequence diversity, two common and highly dissimilar haplogroups, and statistical and empirical support for the operation of a balancing selection mechanism
  • Inclusion of the SDHA indels, by recoding them as single nucleotide polymorphisms, 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
  • Our findings suggest that the high nucleotide diversity of the human SDHA gene is a consequence of persistence of two distinct haplogroups for long periods during human evolution, leading to acquisition of a distinct set of polymorphisms by each haplogroup
  • A major finding of our study is the unexpectedly high nucleotide diversity in the SDHA gene in the African American samples
  • Our findings demonstrate that the SDHA gene carries a strong signature of balancing selection in the African American population and that PGL and SDHA gene products are subject to distinct selective constraints
  • These data provide new insights into succinate dehydrogenase enzyme complex biology and may catalyze further research on the causes and the consequences of the unexpectedly high sequence diversity in the SDHA subunit gene

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