Edgetic Perturbation Models of Human Inherited Disorders

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Edgetic Perturbation Models of Human Inherited Disorders

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dc.contributor.author Simonis, Nicolas
dc.contributor.author Li, Qian-Ru
dc.contributor.author Heuze, Fabien
dc.contributor.author Klitgord, Niels
dc.contributor.author Tam, Stanley
dc.contributor.author Venkatesan, Kavitha
dc.contributor.author Mou, Danny
dc.contributor.author Swearingen, Venus
dc.contributor.author Yildirim, Muhammed A
dc.contributor.author Dricot, Amélie
dc.contributor.author Szeto, David
dc.contributor.author Lin, Chenwei
dc.contributor.author Hao, Tong
dc.contributor.author Fan, Changyu
dc.contributor.author Milstein, Stuart
dc.contributor.author Dupuy, Denis
dc.contributor.author Brasseur, Robert
dc.contributor.author Zhong, Quan
dc.contributor.author Charloteaux, Benoit
dc.contributor.author Yu, Haiyuan
dc.contributor.author Yan, Han
dc.contributor.author Hill, David E.
dc.contributor.author Cusick, Michael
dc.contributor.author Vidal, Marc
dc.date.accessioned 2011-06-08T18:45:52Z
dc.date.issued 2009
dc.identifier.citation Zhong, Quan, Nicolas Simonis, Qian-Ru Li, Benoit Charloteaux, Fabien Heuze, Niels Klitgord, Stanley Tam, et al. 2009. Edgetic perturbation models of human inherited disorders. Molecular Systems Biology 5(1): 321. en_US
dc.identifier.issn 1744-4292 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:4908056
dc.description.abstract Cellular functions are mediated through complex systems of macromolecules and metabolites linked through biochemical and physical interactions, represented in interactome models as ‘nodes' and ‘edges', respectively. Better understanding of genotype-to-phenotype relationships in human disease will require modeling of how disease-causing mutations affect systems or interactome properties. Here we investigate how perturbations of interactome networks may differ between complete loss of gene products (‘node removal') and interaction-specific or edge-specific (‘edgetic') alterations. Global computational analyses of ~50 000 known causative mutations in human Mendelian disorders revealed clear separations of mutations probably corresponding to those of node removal versus edgetic perturbations. Experimental characterization of mutant alleles in various disorders identified diverse edgetic interaction profiles of mutant proteins, which correlated with distinct structural properties of disease proteins and disease mechanisms. Edgetic perturbations seem to confer distinct functional consequences from node removal because a large fraction of cases in which a single gene is linked to multiple disorders can be modeled by distinguishing edgetic network perturbations. Edgetic network perturbation models might improve both the understanding of dissemination of disease alleles in human populations and the development of molecular therapeutic strategies. en_US
dc.language.iso en_US en_US
dc.publisher Nature Publishing Group en_US
dc.relation.isversionof doi://10.1038/msb.2009.80 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2795474/pdf/ en_US
dash.license LAA
dc.subject binary protein interaction en_US
dc.subject genotype-to-phenotype relationships en_US
dc.subject human Mendelian disorders en_US
dc.subject network perturbation en_US
dc.title Edgetic Perturbation Models of Human Inherited Disorders en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal Molecular Systems Biology en_US
dash.depositing.author Vidal, Marc
dc.date.available 2011-06-08T18:45:52Z
dash.affiliation.other HMS^Genetics en_US
dash.affiliation.other HMS^Genetics en_US
dash.affiliation.other HMS^Genetics en_US
dash.affiliation.other HMS^Genetics en_US

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