title: Genome evolution predicts genetic interactions in protein complexes and reveals cancer drug targets.
abstract: Genetic interactions reveal insights into cellular function and can be used to identify drug targets. Here we construct a new model to predict negative genetic interactions in protein complexes by exploiting the evolutionary history of genes in parallel converging pathways in metabolism. We evaluate our model with protein complexes of Saccharomyces cerevisiae and show that the predicted protein pairs more frequently have a negative genetic interaction than random proteins from the same complex. Furthermore, we apply our model to human protein complexes to predict novel cancer drug targets, and identify 20 candidate targets with empirical support and 10 novel targets amenable to further experimental validation. Our study illustrates that negative genetic interactions can be predicted by systematically exploring genome evolution, and that this is useful to identify novel anti-cancer drug targets.
authors.affiliation: Department of Bioinformatics, Centre for Molecular Life Sciences, Radboud University Medical Centre, 6525GA Nijmegen, The Netherlands.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Lu
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kensche
authors.forename: Martijn A
authors.initials: MA
authors.lastname: Huynen
authors.forename: Richard A
authors.initials: RA
authors.lastname: Notebaart
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D004843:Epistasis, Genetic; D019143:Evolution, Molecular; D016681:Genome, Fungal; D006801:Humans; D053858:Metabolic Networks and Pathways; D008957:Models, Genetic; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D025941:Protein Interaction Mapping; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D049490:Systems Biology
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D029701:Saccharomyces cerevisiae Proteins