title: Accurate quantification of functional analogy among close homologs.
abstract: Correctly evaluating functional similarities among homologous proteins is necessary for accurate transfer of experimental knowledge from one organism to another, and is of particular importance for the development of animal models of human disease. While the fact that sequence similarity implies functional similarity is a fundamental paradigm of molecular biology, sequence comparison does not directly assess the extent to which two proteins participate in the same biological processes, and has limited utility for analyzing families with several parologous members. Nevertheless, we show that it is possible to provide a cross-organism functional similarity measure in an unbiased way through the exclusive use of high-throughput gene-expression data. Our methodology is based on probabilistic cross-species mapping of functionally analogous proteins based on Bayesian integrative analysis of gene expression compendia. We demonstrate that even among closely related genes, our method is able to predict functionally analogous homolog pairs better than relying on sequence comparison alone. We also demonstrate that the landscape of functional similarity is often complex and that definitive "functional orthologs" do not always exist. Even in these cases, our method and the online interface we provide are designed to allow detailed exploration of sources of inferred functional similarity that can be evaluated by the user.
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Chikina
authors.forename: Olga G
authors.initials: OG
authors.lastname: Troyanskaya
mesh_terms: D000818:Animals; D001499:Bayes Theorem; D019295:Computational Biology; D019143:Evolution, Molecular; D020869:Gene Expression Profiling / Q000706:statistics & numerical data; D053263:Gene Regulatory Networks; D006801:Humans; D034882:Lamins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis / Q000706:statistics & numerical data; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D040681:Structural Homology, Protein; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D050825:Synaptosomal-Associated Protein 25 / Q000737:chemistry / Q000235:genetics / Q000502:physiology
chemical_list: D034882:Lamins; D011506:Proteins; D029701:Saccharomyces cerevisiae Proteins; D050825:Synaptosomal-Associated Protein 25; D013482:Superoxide Dismutase