Open Access Research

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 Szklarczyk1*, Bas FJ Wanschers12, Thomas D Cuypers13, John J Esseling4, Moniek Riemersma2, Mariël AM van den Brand2, Jolein Gloerich5, Edwin Lasonder1, Lambert P van den Heuvel2, Leo G Nijtmans2 and Martijn A Huynen1*

Author Affiliations

1 Centre for Molecular and Biomolecular Informatics, Radboud University Nijmegen Medical Centre, Nijmegen, 6500 HB, The Netherlands

2 Nijmegen Centre for Mitochondrial Disorders at the Department of Pediatrics, Radboud University Nijmegen Medical Centre, Nijmegen, 6500 HB, The Netherlands

3 Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, 3584 CH, The Netherlands

4 Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, 6500 HB, The Netherlands

5 Nijmegen Proteomics Facility, Department of Laboratory Medicine, Laboratory of Genetic, Endocrine and Metabolic Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, 6500 HB, The Netherlands

For all author emails, please log on.

Genome Biology 2012, 13:R12  doi:10.1186/gb-2012-13-2-r12

Published: 22 February 2012

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.