resolving the ortholog conjecture orthologs tend to be weakly, but significantly, more similar in function than paralogs解决直接同源猜想直接同源往往是弱,但值得注意的是,比假字相似的功能.pdfVIP

Resolving the Ortholog Conjecture: Orthologs Tend to Be Weakly, but Significantly, More Similar in Function than Paralogs Adrian M. Altenhoff1,2, Romain A. Studer2,3,4, Marc Robinson-Rechavi2,3, Christophe Dessimoz1,2,5* ¨ 1 ETH Zurich, Department of Computer Science, Zurich, Switzerland, 2 Swiss Institute of Bioinformatics, Lausanne, Switzerland, 3 Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland, 4 Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London, United Kingdom, 5 EMBL-European Bioinformatics Institute, Hinxton, Cambridge, United Kingdom Abstract The function of most proteins is not determined experimentally, but is extrapolated from homologs. According to the ‘‘ortholog conjecture’’, or standard model of phylogenomics, protein function changes rapidly after duplication, leading to paralogs with different functions, while orthologs retain the ancestral function. We report here that a comparison of experimentally supported functional annotations among homologs from 13 genomes mostly supports this model. We show that to analyze GO annotation effectively, several confounding factors need to be controlled: authorship bias, variation of GO term frequency among species, variation of background similarity among species pairs, and propagated annotation bias. After controlling for these biases, we observe that orthologs have generally more similar functional annotations than paralogs. This is especially strong for sub-cellular localization. We observe only a weak decrease in functional similarity with increasing sequence divergence. These findings hold over a large diversity of species; notably orthologs from model organisms such as E. coli, yeast or mouse have conserved functio