{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T12:59:17Z","timestamp":1778763557398,"version":"3.51.4"},"reference-count":23,"publisher":"Oxford University Press (OUP)","issue":"13","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: The evolution of proteins cannot be fully understood without taking into account the coevolutionary linkages entangling them. From a practical point of view, coevolution between protein families has been used as a way of detecting protein interactions and functional relationships from genomic information. The most common approach to inferring protein coevolution involves the quantification of phylogenetic tree similarity using a family of methodologies termed mirrortree. In spite of their success, a fundamental problem of these approaches is the lack of an adequate statistical framework to assess the significance of a given coevolutionary score (tree similarity). As a consequence, a number of ad hoc filters and arbitrary thresholds are required in an attempt to obtain a final set of confident coevolutionary signals.<\/jats:p>\n               <jats:p>Results: In this work, we developed a method for associating confidence estimators (P values) to the tree-similarity scores, using a null model specifically designed for the tree comparison problem. We show how this approach largely improves the quality and coverage (number of pairs that can be evaluated) of the detected coevolution in all the stages of the mirrortree workflow, independently of the starting genomic information. This not only leads to a better understanding of protein coevolution and its biological implications, but also to obtain a highly reliable and comprehensive network of predicted interactions, as well as information on the substructure of macromolecular complexes using only genomic information.<\/jats:p>\n               <jats:p>Availability and implementation: The software and datasets used in this work are freely available at: http:\/\/csbg.cnb.csic.es\/pMT\/.<\/jats:p>\n               <jats:p>Contact: \u00a0pazos@cnb.csic.es<\/jats:p>\n               <jats:p>Supplementary Information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btv102","type":"journal-article","created":{"date-parts":[[2015,2,26]],"date-time":"2015-02-26T15:34:19Z","timestamp":1424964859000},"page":"2166-2173","source":"Crossref","is-referenced-by-count":37,"title":["Detection of significant protein coevolution"],"prefix":"10.1093","volume":"31","author":[{"given":"David","family":"Ochoa","sequence":"first","affiliation":[{"name":"1 Computational Systems Biology Group, National Centre for Biotechnology (CNB-CSIC), C\/ Darwin 3, 28049 Madrid and 2Structural Bioinformatics Group, Spanish National Cancer Research Centre (CNIO), C\/ Melchor Fern\u00e1ndez Almagro 3, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Juan","sequence":"additional","affiliation":[{"name":"1 Computational Systems Biology Group, National Centre for Biotechnology (CNB-CSIC), C\/ Darwin 3, 28049 Madrid and 2Structural Bioinformatics Group, Spanish National Cancer Research Centre (CNIO), C\/ Melchor Fern\u00e1ndez Almagro 3, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfonso","family":"Valencia","sequence":"additional","affiliation":[{"name":"1 Computational Systems Biology Group, National Centre for Biotechnology (CNB-CSIC), C\/ Darwin 3, 28049 Madrid and 2Structural Bioinformatics Group, Spanish National Cancer Research Centre (CNIO), C\/ Melchor Fern\u00e1ndez Almagro 3, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florencio","family":"Pazos","sequence":"additional","affiliation":[{"name":"1 Computational Systems Biology Group, National Centre for Biotechnology (CNB-CSIC), C\/ Darwin 3, 28049 Madrid and 2Structural Bioinformatics Group, Spanish National Cancer Research Centre (CNIO), C\/ Melchor Fern\u00e1ndez Almagro 3, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2015,2,24]]},"reference":[{"key":"2023020202134849900_btv102-B1","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/978-1-61779-276-2_11","article-title":"Using coevolution to predict protein-protein interactions","volume":"781","author":"Clark","year":"2011","journal-title":"Methods Mol. Biol."},{"key":"2023020202134849900_btv102-B2","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1093\/nar\/gkh340","article-title":"MUSCLE: multiple sequence alignment with high accuracy and high throughput","volume":"32","author":"Edgar","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"2023020202134849900_btv102-B3","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/nature11088","article-title":"Peroxiredoxins are conserved markers of circadian rhythms","volume":"485","author":"Edgar","year":"2012","journal-title":"Nature"},{"key":"2023020202134849900_btv102-B4","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.patrec.2005.10.010","article-title":"An introduction to ROC analysis","volume":"27","author":"Fawcett","year":"2006","journal-title":"Pattern Recogn. Lett."},{"key":"2023020202134849900_btv102-B5","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1093\/bioinformatics\/btn285","article-title":"MPIDB: the microbial protein interaction database","volume":"24","author":"Goll","year":"2008","journal-title":"Bioinformatics"},{"key":"2023020202134849900_btv102-B6","doi-asserted-by":"crossref","first-page":"D258","DOI":"10.1093\/nar\/gkh036","article-title":"The Gene Ontology (GO) database and informatics resource","volume":"32","author":"Harris","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"2023020202134849900_btv102-B7","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1016\/j.cell.2012.08.011","article-title":"A census of human soluble protein complexes","volume":"150","author":"Havugimana","year":"2012","journal-title":"Cell"},{"key":"2023020202134849900_btv102-B8","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1186\/1471-2105-12-363","article-title":"Selection of organisms for the co-evolution-based study of protein interactions","volume":"12","author":"Herman","year":"2011","journal-title":"BMC Bioinformatics"},{"key":"2023020202134849900_btv102-B9","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1093\/bioinformatics\/btr638","article-title":"PSICOV: precise structural contact prediction using sparse inverse covariance estimation on large multiple sequence alignments","volume":"28","author":"Jones","year":"2012","journal-title":"Bioinformatics"},{"key":"2023020202134849900_btv102-B10","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1073\/pnas.0709671105","article-title":"High-confidence prediction of global interactomes based on genome-wide coevolutionary networks","volume":"105","author":"Juan","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023020202134849900_btv102-B11","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/nrg3414","article-title":"Emerging methods in protein co-evolution","volume":"14","author":"Juan","year":"2013","journal-title":"Nat. Rev. Genet."},{"key":"2023020202134849900_btv102-B12","doi-asserted-by":"crossref","first-page":"D277","DOI":"10.1093\/nar\/gkh063","article-title":"The KEGG resource for deciphering the genome","volume":"32","author":"Kanehisa","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"2023020202134849900_btv102-B13","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1093\/molbev\/mst010","article-title":"MAFFT multiple sequence alignment software version 7: improvements in performance and usability","volume":"30","author":"Katoh","year":"2013","journal-title":"Mol. Biol. Evol."},{"key":"2023020202134849900_btv102-B14","doi-asserted-by":"crossref","first-page":"D334","DOI":"10.1093\/nar\/gki108","article-title":"EcoCyc: a comprehensive database resource for Escherichia coli","volume":"33","author":"Keseler","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"2023020202134849900_btv102-B15","doi-asserted-by":"crossref","first-page":"E1293","DOI":"10.1073\/pnas.1111471108","article-title":"Direct-coupling analysis of residue coevolution captures native contacts across many protein families, Proc","volume":"108","author":"Morcos","year":"2011","journal-title":"Natl. Acad. Sci. USA"},{"key":"2023020202134849900_btv102-B16","doi-asserted-by":"crossref","first-page":"e42057","DOI":"10.1371\/journal.pone.0042057","article-title":"Effect of reference genome selection on the performance of computational methods for genome-wide protein-protein interaction prediction","volume":"7","author":"Muley","year":"2012","journal-title":"PLoS One"},{"key":"2023020202134849900_btv102-B17","doi-asserted-by":"crossref","first-page":"14","DOI":"10.3389\/fcell.2014.00014","article-title":"Practical aspects of protein co-evolution","volume":"2","author":"Ochoa","year":"2014","journal-title":"Front Cell Dev. Biol."},{"key":"2023020202134849900_btv102-B18","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1016\/j.jmb.2005.07.005","article-title":"Assessing protein co-evolution in the context of the tree of life assists in the prediction of the interactome","volume":"352","author":"Pazos","year":"2005","journal-title":"J. Mol. Biol."},{"key":"2023020202134849900_btv102-B19","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1093\/protein\/14.9.609","article-title":"Similarity of phylogenetic trees as indicator of protein-protein interaction","volume":"14","author":"Pazos","year":"2001","journal-title":"Protein Eng."},{"key":"2023020202134849900_btv102-B20","doi-asserted-by":"crossref","first-page":"e9490","DOI":"10.1371\/journal.pone.0009490","article-title":"FastTree 2 \u2013 Approximately maximum-likelihood trees for large alignments","volume":"5","author":"Price","year":"2010","journal-title":"PLoS One"},{"key":"2023020202134849900_btv102-B21","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1039\/C2MB25317H","article-title":"Protein co-evolution: how do we combine bioinformatics and experimental approaches?","volume":"9","author":"Sandler","year":"2013","journal-title":"Mol. Biosyst."},{"key":"2023020202134849900_btv102-B22","doi-asserted-by":"crossref","first-page":"3482","DOI":"10.1093\/bioinformatics\/bti564","article-title":"The inference of protein-protein interactions by co-evolutionary analysis is improved by excluding the information about the phylogenetic relationships","volume":"21","author":"Sato","year":"2005","journal-title":"Bioinformatics"},{"key":"2023020202134849900_btv102-B23","doi-asserted-by":"crossref","first-page":"E406","DOI":"10.1073\/pnas.1108633109","article-title":"Tight coevolution of proliferating cell nuclear antigen (PCNA)-partner interaction networks in fungi leads to interspecies network incompatibility","volume":"109","author":"Zamir","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/31\/13\/2166\/49034602\/bioinformatics_31_13_2166.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/31\/13\/2166\/49034602\/bioinformatics_31_13_2166.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T03:40:40Z","timestamp":1675309240000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/31\/13\/2166\/195953"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,2,24]]},"references-count":23,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2015,7,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btv102","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2015,7,1]]},"published":{"date-parts":[[2015,2,24]]}}}