{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T14:21:52Z","timestamp":1790259712538,"version":"4.1.0"},"reference-count":60,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2015,2,13]],"date-time":"2015-02-13T00:00:00Z","timestamp":1423785600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"DOI":"10.1371\/journal.pgen.1004967","type":"journal-article","created":{"date-parts":[[2015,2,13]],"date-time":"2015-02-13T16:05:09Z","timestamp":1423843509000},"page":"e1004967","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":33,"title":["Evolutionary Signatures amongst Disease Genes Permit Novel Methods for Gene Prioritization and Construction of Informative Gene-Based Networks"],"prefix":"10.1371","volume":"11","author":[{"given":"Nolan","family":"Priedigkeit","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Wolfe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan L.","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2015,2,13]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/nrg3523","article-title":"Bringing genome-wide association findings into clinical use","volume":"14","author":"TA Manolio","year":"2013","journal-title":"Nat Rev Genet"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1056\/NEJMe1303816","article-title":"The beginning of the end of the beginning in cancer genomics","volume":"368","author":"DP Steensma","year":"2013","journal-title":"N Engl J Med"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nrg2918","article-title":"Network medicine: a network-based approach to human disease","volume":"12","author":"A-L Barab\u00e1si","year":"2011","journal-title":"Nat Rev Genet"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.cell.2013.08.030","article-title":"A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk","volume":"155","author":"DR Blair","year":"2013","journal-title":"Cell"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"W214","DOI":"10.1093\/nar\/gkq537","article-title":"The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function","volume":"38","author":"D Warde-Farley","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"D808","DOI":"10.1093\/nar\/gks1094","article-title":"STRING v9.1: protein-protein interaction networks, with increased coverage and integration","volume":"41","author":"A Franceschini","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"D561","DOI":"10.1093\/nar\/gks1114","article-title":"BioGPS and MyGene.info: organizing online, gene-centric information","volume":"41","author":"C Wu","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"D408","DOI":"10.1093\/nar\/gkt1100","article-title":"UniHI 7: an enhanced database for retrieval and interactive analysis of human molecular interaction networks","volume":"42","author":"RKR Kalathur","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/ni.2008","article-title":"Phosphoproteomic analysis reveals an intrinsic pathway for the regulation of histone deacetylase 7 that controls the function of cytotoxic T lymphocytes","volume":"12","author":"MN Navarro","year":"2011","journal-title":"Nat Immunol"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/nature10989","article-title":"Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations","volume":"485","author":"BJ O'Roak","year":"2012","journal-title":"Nature"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1002\/pmic.201100607","article-title":"Combining many interaction networks to predict gene function and analyze gene lists","volume":"12","author":"S Mostafavi","year":"2012","journal-title":"Proteomics"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/nrg3253","article-title":"Computational tools for prioritizing candidate genes: boosting disease gene discovery","volume":"13","author":"Y Moreau","year":"2012","journal-title":"Nat Rev Genet"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"e82154","DOI":"10.1371\/journal.pone.0082154","article-title":"A Novel Null Homozygous Mutation ConfirmsCACNA2D2 as a Gene Mutated in Epileptic Encephalopathy","volume":"8","author":"T Pippucci","year":"2013","journal-title":". PLoS ONE"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"e64468","DOI":"10.1371\/journal.pone.0064468","article-title":"Identification of the causative gene for Simmental arachnomelia syndrome using a network-based disease gene prioritization approach","volume":"8","author":"S Jiao","year":"2013","journal-title":"PLoS ONE"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"3761","DOI":"10.1093\/hmg\/ddn272","article-title":"Mutation of Hairy-and-Enhancer-of-Split-7 in humans causes spondylocostal dysostosis","volume":"17","author":"DB Sparrow","year":"2008","journal-title":"Human Molecular Genetics"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"e1000874","DOI":"10.1371\/journal.pgen.1000874","article-title":"Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4) due to PTRF-CAVIN mutations","volume":"6","author":"A Rajab","year":"2010","journal-title":"PLoS Genet"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1101\/gr.117143.110","article-title":"Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis","volume":"21","author":"Y Erlich","year":"2011","journal-title":"Genome Res"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"D793","DOI":"10.1093\/nar\/gkn665","article-title":"McKusick's Online Mendelian Inheritance in Man (OMIM)","volume":"37","author":"J Amberger","year":"2009","journal-title":"Nucleic Acids Res"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1056\/NEJMe078114","article-title":"Network medicine\u2014from obesity to the "diseasome"","volume":"357","author":"A-L Barab\u00e1si","year":"2007","journal-title":"N Engl J Med"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"9880","DOI":"10.1073\/pnas.0802208105","article-title":"The implications of human metabolic network topology for disease comorbidity","volume":"105","author":"D-S Lee","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref21","first-page":"e1000353","article-title":"A Dynamic Network Approach for the Study of Human Phenotypes","volume":"5","author":"CA Hidalgo","year":"2009","journal-title":"A Dynamic Network Approach for the Study of Human Phenotypes"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"e4346","DOI":"10.1371\/journal.pone.0004346","article-title":"A pathway-based view of human diseases and disease relationships","volume":"4","author":"Y Li","year":"2009","journal-title":"PLoS ONE"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1093\/bib\/bbr013","article-title":"Exploiting drug-disease relationships for computational drug repositioning","volume":"12","author":"JT Dudley","year":"2011","journal-title":"Briefings in Bioinformatics"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/clpt.2013.1","article-title":"Computational drug repositioning: from data to therapeutics","volume":"93","author":"MR Hurle","year":"2013","journal-title":"Clin Pharmacol Ther"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.1093\/molbev\/msq144","article-title":"An integrated view of molecular coevolution in protein-protein interactions","volume":"27","author":"SC Lovell","year":"2010","journal-title":"Mol Biol Evol"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1101\/gr.132647.111","article-title":"Evolutionary rate covariation reveals shared functionality and coexpression of genes","volume":"22","author":"NL Clark","year":"2012","journal-title":"Genome Res"},{"key":"ref27","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":"D Juan","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1534\/genetics.112.145979","article-title":"Evolutionary rate covariation in meiotic proteins results from fluctuating evolutionary pressure in yeasts and mammals","volume":"193","author":"NL Clark","year":"2013","journal-title":"Genetics"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1093\/molbev\/msp324","article-title":"A novel method to detect proteins evolving at correlated rates: identifying new functional relationships between coevolving proteins","volume":"27","author":"NL Clark","year":"2010","journal-title":"Mol Biol Evol"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"e1000570","DOI":"10.1371\/journal.pgen.1000570","article-title":"Coevolution of interacting fertilization proteins","volume":"5","author":"NL Clark","year":"2009","journal-title":"PLoS Genet"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"e1004108","DOI":"10.1371\/journal.pgen.1004108","article-title":"Evolutionary rate covariation identifies new members of a protein network required for Drosophila melanogaster female post-mating responses","volume":"10","author":"GD Findlay","year":"2014","journal-title":"PLoS Genet"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"9440","DOI":"10.1073\/pnas.1530509100","article-title":"Statistical significance for genomewide studies","volume":"100","author":"JD Storey","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1038\/ng.958","article-title":"Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3","volume":"43","author":"S Macgregor","year":"2011","journal-title":"Nat Genet"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"3516","DOI":"10.1073\/pnas.90.8.3516","article-title":"MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2","volume":"90","author":"KM Kozopas","year":"1993","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"3081","DOI":"10.1093\/bioinformatics\/bts581","article-title":"An unbiased evaluation of gene prioritization tools","volume":"28","author":"D Bornigen","year":"2012","journal-title":"Bioinformatics"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.ajhg.2011.10.001","article-title":"Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19","volume":"89","author":"C Bredrup","year":"2011","journal-title":"Am J Hum Genet"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1002\/ajmg.c.31336","article-title":"Ciliary disorder of the skeleton","volume":"160C","author":"C Huber","year":"2012","journal-title":"Am J Med Genet"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1091\/mbc.E04-09-0851","article-title":"ATP-2 interacts with the PLAT domain of LOV-1 and is involved in Caenorhabditis elegans polycystin signaling","volume":"16","author":"J Hu","year":"2005","journal-title":"Mol Biol Cell"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1172\/JCI40076","article-title":"Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy","volume":"120","author":"JF O'Toole","year":"2010","journal-title":"J Clin Invest"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"24496","DOI":"10.1074\/jbc.M600651200","article-title":"Correction of Pulmonary Abnormalities in Sftpd-\/- Mice Requires the Collagenous Domain of Surfactant Protein D","volume":"281","author":"PS Kingma","year":"2006","journal-title":"Journal of Biological Chemistry"},{"issue":"Suppl","key":"ref41","doi-asserted-by":"crossref","first-page":"S43","DOI":"10.1016\/j.resp.2010.04.023","article-title":"Recent advances in alveolar biology: evolution and function of alveolar proteins","volume":"173","author":"S Orgeig","year":"2010","journal-title":"Respir Physiol Neurobiol"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1093\/jnci\/dji253","article-title":"Association between endothelin receptor B nonsynonymous variants and melanoma risk","volume":"97","author":"N Soufir","year":"2005","journal-title":"J Natl Cancer Inst"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"4909","DOI":"10.1158\/0008-5472.CAN-12-2194","article-title":"Roles for endothelin receptor B and BCL2A1 in spontaneous CNS metastasis of melanoma","volume":"72","author":"W Cruz-Mu\u00f1oz","year":"2012","journal-title":"Cancer Research"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1158\/0008-5472.CAN-09-2838","article-title":"A Novel Mouse Model for De novo Melanoma","volume":"70","author":"MY Kumasaka","year":"2010","journal-title":"Cancer Research"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1158\/0008-5472.CAN-06-2606","article-title":"Endothelin-1 and endothelin-3 promote invasive behavior via hypoxia-inducible factor-1alpha in human melanoma cells","volume":"67","author":"F Spinella","year":"2007","journal-title":"Cancer Research"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.dnarep.2010.02.018","article-title":"Mice with DNA repair gene Ercc1 deficiency in a neural crest lineage are a model for late-onset Hirschsprung disease","volume":"9","author":"J Selfridge","year":"2010","journal-title":"DNA Repair (Amst)"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"2412","DOI":"10.1038\/onc.2011.426","article-title":"Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance","volume":"31","author":"W Li","year":"2012","journal-title":"Oncogene"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0140-6736(12)61023-X","article-title":"Noonan syndrome","volume":"381","year":"2013","journal-title":"The Lancet"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1111\/j.1365-2141.2008.07269.x","article-title":"Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference","volume":"142","author":"A Vlachos","year":"2008","journal-title":"British Journal of Haematology"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.clim.2013.02.014","article-title":"Targeting the complement system in systemic lupus erythematosus and other diseases","volume":"148","author":"M-L Barilla-LaBarca","year":"2013","journal-title":"Clinical Immunology"},{"key":"ref51","first-page":"476","article-title":"Gene-function studies in systemic lupus erythematosus","volume":"9","author":"JC Crisp\u00edn","year":"2013","journal-title":"Nature Publishing Group"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"8685","DOI":"10.1073\/pnas.0701361104","article-title":"The human disease network","volume":"104","author":"K-I Goh","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"3881","DOI":"10.1172\/JCI36625","article-title":"Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters","volume":"118","author":"S Br\u00f6er","year":"2008","journal-title":"J Clin Invest"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"e1000662","DOI":"10.1371\/journal.pcbi.1000662","article-title":"Network-Based Elucidation of Human Disease Similarities Reveals Common Functional Modules Enriched for Pluripotent Drug Targets","volume":"6","author":"S Suthram","year":"2010","journal-title":"PLoS Comput Biol"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"D561","DOI":"10.1093\/nar\/gkq973","article-title":"The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored","volume":"39","author":"D Szklarczyk","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"ref56","doi-asserted-by":"crossref","unstructured":"Kouskoumvekaki I, Shublaq N, Brunak S (2013) Facilitating the use of large-scale biological data and tools in the era of translational bioinformatics. Briefings in Bioinformatics.","DOI":"10.1093\/bib\/bbt055"},{"key":"ref57","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1093\/molbev\/mst080","article-title":"Evidence for polygenic adaptation to pathogens in the human genome","volume":"30","author":"JT Daub","year":"2013","journal-title":"Mol Biol Evol"},{"key":"ref58","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1093\/molbev\/msm088","article-title":"PAML 4: Phylogenetic Analysis by Maximum Likelihood","volume":"24","author":"Z Yang","year":"2007","journal-title":"Mol Biol Evol"},{"key":"ref59","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":"T Sato","year":"2005","journal-title":"Bioinformatics"},{"key":"ref60","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1093\/bioinformatics\/btn209","article-title":"fdrtool: a versatile R package for estimating local and tail area-based false discovery rates","volume":"24","author":"K Strimmer","year":"2008","journal-title":"Bioinformatics"}],"container-title":["PLOS Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pgen.1004967","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,8,20]],"date-time":"2019-08-20T18:55:59Z","timestamp":1566327359000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1004967"}},"subtitle":[],"editor":[{"given":"Joshua M.","family":"Akey","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2015,2,13]]},"references-count":60,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2015,2,13]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1004967","relation":{},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,2,13]]}}}