Evolutionary conservation and selection of human disease gene orthologs in the rat and mouse genomes

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• dc.contributor.author Huang, Huica
• dc.contributor.author Winter, Eitan Eca
• dc.contributor.author Wang, Huajunca
• dc.contributor.author Weinstock, Keith Gca
• dc.contributor.author Xing, Hemingca
• dc.contributor.author Goodstadt, Leoca
• dc.contributor.author Stenson, Peter Dca
• dc.contributor.author Cooper, David Nca
• dc.contributor.author Smith, Douglasca
• dc.contributor.author Albà Soler, Marca
• dc.contributor.author Ponting, Chris Pca
• dc.contributor.author Fechtel, Kimca
• dc.date.accessioned 2014-12-18T10:46:07Z
• dc.date.available 2014-12-18T10:46:07Z
• dc.date.issued 2004ca
• dc.description.abstract Background: Model organisms have contributed substantially to our understanding of the etiology of human disease as well as having assisted with the development of new treatment modalities. The availability of the human, mouse and, most recently, the rat genome sequences now permit the comprehensive investigation of the rodent orthologs of genes associated with human disease. Here, we investigate whether human disease genes differ significantly from their rodent orthologs with respect to their overall levels of conservation and their rates of evolutionary change./nResults: Human disease genes are unevenly distributed among human chromosomes and are highly represented (99.5%) among human-rodent ortholog sets. Differences are revealed in evolutionary conservation and selection between different categories of human disease genes. Although selection appears not to have greatly discriminated between disease and non-disease genes, synonymous substitution rates are significantly higher for disease genes. In neurological and malformation syndrome disease systems, associated genes have evolved slowly whereas genes of the immune, hematological and pulmonary disease systems have changed more rapidly. Amino-acid substitutions associated with human inherited disease occur at sites that are more highly conserved than the average; nevertheless, 15 substituting amino acids associated with human disease were identified as wild-type amino acids in the rat. Rodent orthologs of human trinucleotide repeat-expansion disease genes were found to contain substantially fewer of such repeats. Six human genes that share the same characteristics as triplet repeat-expansion disease-associated genes were identified; although four of these genes are expressed in the brain, none is currently known to be associated with disease. Conclusions: Most human disease genes have been retained in rodent genomes. Synonymous nucleotide substitutions occur at a higher rate in disease genes, a finding that may reflect increased mutation rates in the chromosomal regions in which disease genes are found. Rodent orthologs associated with neurological function exhibit the greatest evolutionary conservation; this suggests that rodent models of human neurological disease are likely to most faithfully represent human disease processes. However, with regard to neurological triplet repeat expansion-associated human disease genes, the contraction, relative to human, of rodent trinucleotide repeats suggests that rodent loci may not achieve a 'critical repeat threshold' necessary to undergo spontaneous pathological repeat expansions. The identification of six genes in this study that have multiple characteristics associated with repeat expansion-disease genes raises the possibility that not all human loci capable of facilitating neurological disease by repeat expansion have as yet been identified.
• dc.description.sponsorship M.M.A. acknowledges program Ramón y Cajal and grant BIO2002-04426-C02-01 from the Spanish Ministry of Science and Technology.
• dc.format.mimetype application/pdfca
• dc.identifier.citation Huang H, Winter EE, Wang H, Weinstock KG, Xing H, Goodstadt L et al. Evolutionary conservation and selection of human disease gene orthologs in the rat and mouse genomes. Genome Biology. 2004 Jun;5(7):R47. DOI: 10.1186/gb-2004-5-7-r47ca
• dc.identifier.doi http://dx.doi.org/10.1186/gb-2004-5-7-r47
• dc.identifier.issn 1465-6906ca
• dc.identifier.uri http://hdl.handle.net/10230/22999
• dc.language.iso engca
• dc.publisher BioMed Centralca
• dc.relation.ispartof Genome Biology. 2004 Jun;5(7):R47
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PN/BIO2002-04426
• dc.rights © 2004 Huang et al.; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URLca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.subject.other Malalties
• dc.subject.other Neurologia
• dc.subject.other Gens humans
• dc.title Evolutionary conservation and selection of human disease gene orthologs in the rat and mouse genomesca
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/publishedVersionca