title: 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.
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.
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud University Nijmegen Medical Centre, Nijmegen, 6500 HB, The Netherlands. radek@cmbi.ru.nl
authors.forename: Radek
authors.initials: R
authors.lastname: Szklarczyk
authors.forename: Bas Fj
authors.initials: BF
authors.lastname: Wanschers
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Cuypers
authors.forename: John J
authors.initials: JJ
authors.lastname: Esseling
authors.forename: Moniek
authors.initials: M
authors.lastname: Riemersma
authors.forename: Mariël Am
authors.initials: MA
authors.lastname: van den Brand
authors.forename: Jolein
authors.initials: J
authors.lastname: Gloerich
authors.forename: Edwin
authors.initials: E
authors.lastname: Lasonder
authors.forename: Lambert P
authors.initials: LP
authors.lastname: van den Heuvel
authors.forename: Leo G
authors.initials: LG
authors.lastname: Nijtmans
authors.forename: Martijn A
authors.initials: MA
authors.lastname: Huynen
mesh_terms: D000595:Amino Acid Sequence; D019295:Computational Biology; D003576:Electron Transport Complex IV / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D012568:Schizosaccharomyces / Q000235:genetics; D017386:Sequence Homology, Amino Acid
chemical_list: C094357:COX14 protein, S cerevisiae; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; D003576:Electron Transport Complex IV