A candidate complex approach to study functional mitochondrial DNA changes: Sequence variation and quaternary structure modeling of Drosophila simulans cytochrome c oxidase

Richard G. Melvin, Subhash D. Katewa, J. William O. Ballard

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

A problem with studying evolutionary dynamics of mitochondrial (mt) DNA is that classical population genetic techniques cannot identify selected substitutions because of genetic hitchhiking. We circumvented this problem by employing a candidate complex approach to study sequence variation in cytochrome c oxidase (COX) genes within and among three distinct Drosophila simulans mtDNA haplogroups. First, we determined sequence variation in complete coding regions for all COX mtDNA and nuclear loci and their isoforms. Second, we constructed a quaternary structure model of D. simulans COX. Third, we predicted that six of nine amino acid changes in D. simulans mtDNA are likely to be functionally important. Of these seven, genetic crosses can experimentally determine the functional significance of three. Fourth, we identified two single amino acid changes and a deletion of two consecutive amino acids in nuclear encoded COX loci that are likely to influence cytochrome c oxidase activity. These data show that linking population genetics and quaternary structure modeling can lead to functional predictions of specific mtDNA amino acid mutations and validate the candidate complex approach.

Original languageEnglish (US)
Pages (from-to)232-242
Number of pages11
JournalJournal of Molecular Evolution
Volume66
Issue number3
DOIs
StatePublished - Mar 2008
Externally publishedYes

Bibliographical note

Funding Information:
We thank M. Kreitman for comments on the manuscript. I. Ricafuente assisted with DNA sequencing. This work was supported by Grants NSF DEB-0444766 and NIH R01 GM067862-01.

Keywords

  • Candidate complex approach
  • Cytochrome c oxidase
  • Genetic hitchhiking

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