title: Edgetic perturbation models of human inherited disorders.
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 approximately 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.
authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhong
authors.forename: Nicolas
authors.initials: N
authors.lastname: Simonis
authors.forename: Qian-Ru
authors.initials: QR
authors.lastname: Li
authors.forename: Benoit
authors.initials: B
authors.lastname: Charloteaux
authors.forename: Fabien
authors.initials: F
authors.lastname: Heuze
authors.forename: Niels
authors.initials: N
authors.lastname: Klitgord
authors.forename: Stanley
authors.initials: S
authors.lastname: Tam
authors.forename: Haiyuan
authors.initials: H
authors.lastname: Yu
authors.forename: Kavitha
authors.initials: K
authors.lastname: Venkatesan
authors.forename: Danny
authors.initials: D
authors.lastname: Mou
authors.forename: Venus
authors.initials: V
authors.lastname: Swearingen
authors.forename: Muhammed A
authors.initials: MA
authors.lastname: Yildirim
authors.forename: Han
authors.initials: H
authors.lastname: Yan
authors.forename: Amélie
authors.initials: A
authors.lastname: Dricot
authors.forename: David
authors.initials: D
authors.lastname: Szeto
authors.forename: Chenwei
authors.initials: C
authors.lastname: Lin
authors.forename: Tong
authors.initials: T
authors.lastname: Hao
authors.forename: Changyu
authors.initials: C
authors.lastname: Fan
authors.forename: Stuart
authors.initials: S
authors.lastname: Milstein
authors.forename: Denis
authors.initials: D
authors.lastname: Dupuy
authors.forename: Robert
authors.initials: R
authors.lastname: Brasseur
authors.forename: David E
authors.initials: DE
authors.lastname: Hill
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cusick
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
mesh_terms: D000483:Alleles; D004194:Disease / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics