Iterative orthology prediction uncovers new mitochondrial proteins and identifies C12orf62 as the human ortholog of COX14, a protein involved in the assembly of cytochrome c oxidase

Radek Szklarczyk*, Bas F.J. Wanschers, Thomas D. Cuypers, John J. Esseling, Moniek Riemersma, Mariël A.M. Van Den Brand, Jolein Gloerich, Edwin Lasonder, Lambert P. van den Heuvel, Leo G. Nijtmans, Martijn A. Huynen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

68 Citations (Scopus)

Abstract

Background: Orthology is a central tenet of comparative genomics and ortholog identification is instrumental to protein function prediction. Major advances have been made to determine orthology relations among a set of homologous proteins. However, they depend on the comparison of individual sequences and do not take into account divergent orthologs.Results: We have developed an iterative orthology prediction method, Ortho-Profile, that uses reciprocal best hits at the level of sequence profiles to infer orthology. It increases ortholog detection by 20% compared to sequence-to-sequence comparisons. Ortho-Profile predicts 598 human orthologs of mitochondrial proteins from Saccharomyces cerevisiae and Schizosaccharomyces pombe with 94% accuracy. Of these, 181 were not known to localize to mitochondria in mammals. Among the predictions of the Ortho-Profile method are 11 human cytochrome c oxidase (COX) assembly proteins that are implicated in mitochondrial function and disease. Their co-expression patterns, experimentally verified subcellular localization, and co-purification with human COX-associated proteins support these predictions. For the human gene C12orf62, the ortholog of S. cerevisiae COX14, we specifically confirm its role in negative regulation of the translation of cytochrome c oxidase.Conclusions: Divergent homologs can often only be detected by comparing sequence profiles and profile-based hidden Markov models. The Ortho-Profile method takes advantage of these techniques in the quest for orthologs.

Original languageEnglish
Article numberR12
Number of pages14
JournalGenome Biology
Volume13
Issue number2
DOIs
Publication statusPublished - 22 Feb 2012
Externally publishedYes

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