{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T22:38:12Z","timestamp":1781044692673,"version":"3.54.1"},"reference-count":57,"publisher":"Oxford University Press (OUP)","issue":"Supplement_1","license":[{"start":{"date-parts":[[2020,7,13]],"date-time":"2020-07-13T00:00:00Z","timestamp":1594598400000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"NSF","doi-asserted-by":"publisher","award":["DBI-1458477"],"award-info":[{"award-number":["DBI-1458477"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"NSF","doi-asserted-by":"publisher","award":["DBI-1564611"],"award-info":[{"award-number":["DBI-1564611"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Precision Health Initiative of Indiana University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>The computational prediction of gene function is a key step in making full use of newly sequenced genomes. Function is generally predicted by transferring annotations from homologous genes or proteins for which experimental evidence exists. The \u2018ortholog conjecture\u2019 proposes that orthologous genes should be preferred when making such predictions, as they evolve functions more slowly than paralogous genes. Previous research has provided little support for the ortholog conjecture, though the incomplete nature of the data cast doubt on the conclusions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We use experimental annotations from over 40\u00a0000 proteins, drawn from over 80\u00a0000 publications, to revisit the ortholog conjecture in two pairs of species: (i) Homo sapiens and Mus musculus and (ii) Saccharomyces cerevisiae and Schizosaccharomyces pombe. By making a distinction between questions about the evolution of function versus questions about the prediction of function, we find strong evidence against the ortholog conjecture in the context of function prediction, though questions about the evolution of function remain difficult to address. In both pairs of species, we quantify the amount of information that would be ignored if paralogs are discarded, as well as the resulting loss in prediction accuracy. Taken as a whole, our results support the view that the types of homologs used for function transfer are largely irrelevant to the task of function prediction. Maximizing the amount of data used for this task, regardless of whether it comes from orthologs or paralogs, is most likely to lead to higher prediction accuracy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>https:\/\/github.com\/predragradivojac\/oc.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Supplementary information<\/jats:title>\n                    <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btaa468","type":"journal-article","created":{"date-parts":[[2020,6,4]],"date-time":"2020-06-04T15:13:59Z","timestamp":1591283639000},"page":"i219-i226","source":"Crossref","is-referenced-by-count":68,"title":["The ortholog conjecture revisited: the value of orthologs and paralogs in function prediction"],"prefix":"10.1093","volume":"36","author":[{"given":"Moses","family":"Stamboulian","sequence":"first","affiliation":[{"name":"Department of Computer Science, Indiana University , Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael F","family":"Guerrero","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Indiana University , Bloomington, IN 47405, USA"},{"name":"Department of Biological Sciences, North Carolina State University , Raleigh, NC 27695, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew W","family":"Hahn","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Indiana University , Bloomington, IN 47405, USA"},{"name":"Department of Biology, Indiana University , Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Predrag","family":"Radivojac","sequence":"additional","affiliation":[{"name":"Khoury College of Computer Sciences, Northeastern University , Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,7,13]]},"reference":[{"key":"2024021913324012700_btaa468-B1","doi-asserted-by":"crossref","first-page":"e1002821","DOI":"10.1371\/journal.pgen.1002821","article-title":"Functional evolution of mammalian odorant receptors","volume":"8","author":"Adipietro","year":"2012","journal-title":"PLoS Genet"},{"key":"2024021913324012700_btaa468-B2","doi-asserted-by":"crossref","first-page":"e1002514","DOI":"10.1371\/journal.pcbi.1002514","article-title":"Resolving the ortholog conjecture: orthologs tend to be weakly, but significantly, more similar in function than paralogs","volume":"8","author":"Altenhoff","year":"2012","journal-title":"PLoS Comput. Biol"},{"key":"2024021913324012700_btaa468-B3","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: tool for the unification of biology. The Gene Ontology Consortium","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet"},{"key":"2024021913324012700_btaa468-B4","first-page":"15","article-title":"When should we not transfer functional annotation between sequence paralogs?","volume":"22","author":"Cao","year":"2017","journal-title":"Pac. Symp. Biocomput"},{"key":"2024021913324012700_btaa468-B5","doi-asserted-by":"crossref","first-page":"e1002784","DOI":"10.1371\/journal.pcbi.1002784","article-title":"The ortholog conjecture is untestable by the current gene ontology but is supported by RNA sequencing data","volume":"8","author":"Chen","year":"2012","journal-title":"PLoS Comput. Biol"},{"key":"2024021913324012700_btaa468-B6","doi-asserted-by":"crossref","first-page":"2086","DOI":"10.1002\/prot.23029","article-title":"Analysis of protein function and its prediction from amino acid sequence","volume":"79","author":"Clark","year":"2011","journal-title":"Proteins"},{"key":"2024021913324012700_btaa468-B7","doi-asserted-by":"crossref","first-page":"i53","DOI":"10.1093\/bioinformatics\/btt228","article-title":"Information-theoretic evaluation of predicted ontological annotations","volume":"29","author":"Clark","year":"2013","journal-title":"Bioinformatics"},{"key":"2024021913324012700_btaa468-B8","first-page":"D331","article-title":"Expansion of the Gene Ontology knowledgebase and resources","volume":"45","author":"Consortium","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2024021913324012700_btaa468-B9","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1101\/gr.163014.113","article-title":"Tempo and mode of regulatory evolution in Drosophila","volume":"24","author":"Coolon","year":"2014","journal-title":"Genome Res"},{"key":"2024021913324012700_btaa468-B10","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/978-1-4939-3743-1_5","article-title":"Computational methods for annotation transfers from sequence","volume":"1446","author":"Cozzetto","year":"2017","journal-title":"Methods Mol. Biol"},{"key":"2024021913324012700_btaa468-B11","doi-asserted-by":"crossref","first-page":"31865","DOI":"10.1038\/srep31865","article-title":"FFPred 3: feature-based function prediction for all Gene Ontology domains","volume":"6","author":"Cozzetto","year":"2016","journal-title":"Sci. Rep"},{"key":"2024021913324012700_btaa468-B12","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.tig.2013.09.005","article-title":"CAFA and the open world of protein function predictions","volume":"29","author":"Dessimoz","year":"2013","journal-title":"Trends Genet"},{"key":"2024021913324012700_btaa468-B13","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1146\/annurev.genet.40.110405.090439","article-title":"Orthology and functional conservation in eukaryotes","volume":"41","author":"Dolinski","year":"2007","journal-title":"Annu. Rev. Genet"},{"key":"2024021913324012700_btaa468-B14","article-title":"Species tree inference under the multispecies coalescent on data with paralogs is accurate","author":"Du","year":"2019","journal-title":"bioRxiv 498378"},{"key":"2024021913324012700_btaa468-B15","doi-asserted-by":"crossref","first-page":"E409","DOI":"10.1073\/pnas.1707515115","article-title":"Pairwise comparisons across species are problematic when analyzing functional genomic data","volume":"115","author":"Dunn","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2024021913324012700_btaa468-B16","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1371\/journal.pcbi.0010045","article-title":"Protein molecular function prediction by Bayesian phylogenomics","volume":"1","author":"Engelhardt","year":"2005","journal-title":"PLoS Comput. Biol"},{"key":"2024021913324012700_btaa468-B17","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1101\/gr.104687.109","article-title":"Genome-scale phylogenetic function annotation of large and diverse protein families","volume":"21","author":"Engelhardt","year":"2011","journal-title":"Genome Res"},{"key":"2024021913324012700_btaa468-B18","doi-asserted-by":"crossref","first-page":"e1000703","DOI":"10.1371\/journal.pcbi.1000703","article-title":"Getting started in gene orthology and functional analysis","volume":"6","author":"Fang","year":"2010","journal-title":"PLoS Comput. Biol"},{"key":"2024021913324012700_btaa468-B19","first-page":"99","article-title":"Distinguishing homologous from analogous proteins","volume":"19","author":"Fitch","year":"1970","journal-title":"Syst. Biol"},{"key":"2024021913324012700_btaa468-B20","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1038\/nrg3456","article-title":"Functional and evolutionary implications of gene orthology","volume":"14","author":"Gabald\u00f3n","year":"2013","journal-title":"Nat. Rev. Genet"},{"key":"2024021913324012700_btaa468-B21","doi-asserted-by":"crossref","first-page":"e1000252","DOI":"10.1371\/journal.pcbi.1000252","article-title":"Questioning the ubiquity of neofunctionalization","volume":"5","author":"Gibson","year":"2009","journal-title":"PLoS Comput. Biol"},{"key":"2024021913324012700_btaa468-B22","doi-asserted-by":"crossref","first-page":"ii3","DOI":"10.1093\/bioinformatics\/bti1201","article-title":"The choice of optimal distance measure in genome-wide datasets","volume":"21","author":"Glazko","year":"2005","journal-title":"Bioinformatics"},{"key":"2024021913324012700_btaa468-B23","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/S0168-9525(02)02837-8","article-title":"Rapid divergence in expression between duplicate genes inferred from microarray data","volume":"18","author":"Gu","year":"2002","journal-title":"Trends Genet"},{"key":"2024021913324012700_btaa468-B24","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1110\/ps.062153506","article-title":"Enhanced automated function prediction using distantly related sequences and contextual association by PFP","volume":"15","author":"Hawkins","year":"2006","journal-title":"Protein Sci"},{"key":"2024021913324012700_btaa468-B25","doi-asserted-by":"crossref","first-page":"10915","DOI":"10.1073\/pnas.89.22.10915","article-title":"Amino acid substitution matrices from protein blocks","volume":"89","author":"Henikoff","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2024021913324012700_btaa468-B26","doi-asserted-by":"crossref","first-page":"D1057","DOI":"10.1093\/nar\/gku1113","article-title":"The GOA database: gene ontology annotation updates for 2015","volume":"43","author":"Huntley","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"2024021913324012700_btaa468-B27","doi-asserted-by":"crossref","first-page":"i609","DOI":"10.1093\/bioinformatics\/btu472","article-title":"The impact of incomplete knowledge on the evaluation of protein function prediction: a structured-output learning perspective","volume":"30","author":"Jiang","year":"2014","journal-title":"Bioinformatics"},{"key":"2024021913324012700_btaa468-B28","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1186\/s13059-016-1037-6","article-title":"An expanded evaluation of protein function prediction methods shows an improvement in accuracy","volume":"17","author":"Jiang","year":"2016","journal-title":"Genome Biol"},{"key":"2024021913324012700_btaa468-B29","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1146\/annurev.genet.39.073003.114725","article-title":"Orthologs, paralogs, and evolutionary genomics","volume":"39","author":"Koonin","year":"2005","journal-title":"Annu. Rev. Genet"},{"key":"2024021913324012700_btaa468-B30","doi-asserted-by":"crossref","first-page":"e1005274","DOI":"10.1371\/journal.pcbi.1005274","article-title":"Tissue-specificity of gene expression diverges slowly between orthologs, and rapidly between paralogs","volume":"12","author":"Kryuchkova-Mostacci","year":"2016","journal-title":"PLoS Comput. Biol"},{"key":"2024021913324012700_btaa468-B31","doi-asserted-by":"crossref","first-page":"S8","DOI":"10.1186\/1471-2105-14-S3-S8","article-title":"MS-kNN: protein function prediction by integrating multiple data sources","volume":"14","author":"Lan","year":"2013","journal-title":"BMC Bioinformatics"},{"key":"2024021913324012700_btaa468-B32","article-title":"Humanization of yeast genes with multiple human orthologs reveals principles of functional divergence between paralogs","author":"Laurent","year":"2019","journal-title":"bioRxiv 668335"},{"key":"2024021913324012700_btaa468-B33","article-title":"Polynomial-time statistical estimation of species trees under gene duplication and loss","author":"Legried","year":"2019","journal-title":"bioRxiv 821439"},{"key":"2024021913324012700_btaa468-B34","doi-asserted-by":"crossref","first-page":"S8","DOI":"10.1186\/1471-2164-15-S1-S8","article-title":"Accumulation of CTCF-binding sites drives expression divergence between tandemly duplicated genes in humans","volume":"15","author":"Liao","year":"2014","journal-title":"BMC Genomics"},{"key":"2024021913324012700_btaa468-B35","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1101\/gr.1133803","article-title":"Divergence in the spatial pattern of gene expression between human duplicate genes","volume":"13","author":"Makova","year":"2003","journal-title":"Genome Res"},{"key":"2024021913324012700_btaa468-B36","doi-asserted-by":"crossref","first-page":"e79","DOI":"10.1371\/journal.pcbi.0020079","article-title":"Protein\u2013protein interactions more conserved within species than across species","volume":"2","author":"Mika","year":"2006","journal-title":"PLoS Comput. Biol"},{"key":"2024021913324012700_btaa468-B37","doi-asserted-by":"crossref","first-page":"e1000497","DOI":"10.1371\/journal.pcbi.1000497","article-title":"Influence of sequence changes and environment on intrinsically disordered proteins","volume":"5","author":"Mohan","year":"2009","journal-title":"PLoS Comput. Biol"},{"key":"2024021913324012700_btaa468-B38","doi-asserted-by":"crossref","first-page":"e1005011","DOI":"10.1371\/journal.pgen.1005011","article-title":"Pervasive variation of transcription factor orthologs contributes to regulatory network evolution","volume":"11","author":"Nadimpalli","year":"2015","journal-title":"PLoS Genet"},{"key":"2024021913324012700_btaa468-B39","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/0022-2836(70)90057-4","article-title":"A general method applicable to the search for similarities in the amino acid sequence of two proteins","volume":"48","author":"Needleman","year":"1970","journal-title":"J. Mol. Biol"},{"key":"2024021913324012700_btaa468-B40","doi-asserted-by":"crossref","first-page":"e1002073","DOI":"10.1371\/journal.pcbi.1002073","article-title":"Testing the ortholog conjecture with comparative functional genomic data from mammals","volume":"7","author":"Nehrt","year":"2011","journal-title":"PLoS Comput. Biol"},{"key":"2024021913324012700_btaa468-B41","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1002\/pro.143","article-title":"Evolutionary constraints on structural similarity in orthologs and paralogs","volume":"18","author":"Peterson","year":"2009","journal-title":"Protein Sci"},{"key":"2024021913324012700_btaa468-B42","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nmeth.2340","article-title":"A large-scale evaluation of computational protein function prediction","volume":"10","author":"Radivojac","year":"2013","journal-title":"Nat. Methods"},{"key":"2024021913324012700_btaa468-B43","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1093\/gbe\/evu051","article-title":"Gene family level comparative analysis of gene expression in mammals validates the ortholog conjecture","volume":"6","author":"Rogozin","year":"2014","journal-title":"Genome Biol. Evol"},{"key":"2024021913324012700_btaa468-B44","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1186\/1471-2105-7-302","article-title":"A new measure for functional similarity of gene products based on Gene Ontology","volume":"7","author":"Schlicker","year":"2006","journal-title":"BMC Bioinformatics"},{"key":"2024021913324012700_btaa468-B45","doi-asserted-by":"crossref","first-page":"e1000605","DOI":"10.1371\/journal.pcbi.1000605","article-title":"Annotation error in public databases: misannotation of molecular function in enzyme superfamilies","volume":"5","author":"Schnoes","year":"2009","journal-title":"PLoS Comput. Biol"},{"key":"2024021913324012700_btaa468-B46","doi-asserted-by":"crossref","first-page":"e1002533","DOI":"10.1371\/journal.pcbi.1002533","article-title":"Quality of computationally inferred gene ontology annotations","volume":"8","author":"\u0160kunca","year":"2012","journal-title":"PLoS Comput. Biol"},{"key":"2024021913324012700_btaa468-B47","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1186\/1471-2105-14-S3-S10","article-title":"Combining heterogeneous data sources for accurate functional annotation of proteins","volume":"14","author":"Sokolov","year":"2013","journal-title":"BMC Bioinformatics"},{"key":"2024021913324012700_btaa468-B48","doi-asserted-by":"crossref","first-page":"2993","DOI":"10.1093\/bioinformatics\/btu492","article-title":"Big data and other challenges in the quest for orthologs","volume":"30","author":"Sonnhammer","year":"2014","journal-title":"Bioinformatics"},{"key":"2024021913324012700_btaa468-B49","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1093\/molbev\/msu050","article-title":"Functional divergence for every paralog","volume":"31","author":"Soria","year":"2014","journal-title":"Mol. Biol. Evol"},{"key":"2024021913324012700_btaa468-B50","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.tig.2009.03.004","article-title":"How confident can we be that orthologs are similar, but paralogs differ?","volume":"25","author":"Studer","year":"2009","journal-title":"Trends Genet"},{"key":"2024021913324012700_btaa468-B51","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1126\/science.278.5338.631","article-title":"A genomic perspective on protein families","volume":"278","author":"Tatusov","year":"1997","journal-title":"Science"},{"key":"2024021913324012700_btaa468-B52","doi-asserted-by":"crossref","first-page":"e1002386.,","DOI":"10.1371\/journal.pcbi.1002386","article-title":"On the use of gene ontology annotations to assess functional similarity among orthologs and paralogs: a short report","volume":"8","author":"Thomas","year":"2012","journal-title":"PLoS Comput. Biol"},{"key":"2024021913324012700_btaa468-B53","doi-asserted-by":"crossref","first-page":"3484","DOI":"10.1038\/s41598-018-21849-1","article-title":"PANDA: protein function prediction using domain architecture and affinity propagation","volume":"8","author":"Wang","year":"2018","journal-title":"Sci. Rep"},{"key":"2024021913324012700_btaa468-B54","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1007\/s10618-019-00622-6","article-title":"A new class of metrics for learning on real-valued and structured data","volume":"33","author":"Yang","year":"2019","journal-title":"Data Min. Knowl. Disc"},{"key":"2024021913324012700_btaa468-B55","doi-asserted-by":"crossref","first-page":"D754","DOI":"10.1093\/nar\/gkx1098","article-title":"Ensembl 2018","volume":"46","author":"Zerbino","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"2024021913324012700_btaa468-B56","article-title":"ASTRAL-Pro: quartet-based species tree inference despite paralogy","author":"Zhang","year":"2019","journal-title":"bioRxiv 2019.12.12.874727"},{"key":"2024021913324012700_btaa468-B57","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1186\/s13059-019-1835-8","article-title":"The CAFA challenge reports improved protein function prediction and new functional annotations for hundreds of genes through experimental screens","volume":"20","author":"Zhou","year":"2019","journal-title":"Genome Biol"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/Supplement_1\/i219\/56702516\/bioinformatics_36_supplement1_i219.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/Supplement_1\/i219\/56702516\/bioinformatics_36_supplement1_i219.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,19]],"date-time":"2024-02-19T08:38:33Z","timestamp":1708331913000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/36\/Supplement_1\/i219\/5870499"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,1]]},"references-count":57,"journal-issue":{"issue":"Supplement_1","published-print":{"date-parts":[[2020,7,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btaa468","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2019.12.27.889691","asserted-by":"object"}]},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,7]]},"published":{"date-parts":[[2020,7,1]]}}}