title: Growth condition dependency is the major cause of non-responsiveness upon genetic perturbation.
abstract: Investigating the role and interplay between individual proteins in biological processes is often performed by assessing the functional consequences of gene inactivation or removal. Depending on the sensitivity of the assay used for determining phenotype, between 66% (growth) and 53% (gene expression) of Saccharomyces cerevisiae gene deletion strains show no defect when analyzed under a single condition. Although it is well known that this non-responsive behavior is caused by different types of redundancy mechanisms or by growth condition/cell type dependency, it is not known what the relative contribution of these different causes is. Understanding the underlying causes of and their relative contribution to non-responsive behavior upon genetic perturbation is extremely important for designing efficient strategies aimed at elucidating gene function and unraveling complex cellular systems. Here, we provide a systematic classification of the underlying causes of and their relative contribution to non-responsive behavior upon gene deletion. The overall contribution of redundancy to non-responsive behavior is estimated at 29%, of which approximately 17% is due to homology-based redundancy and 12% is due to pathway-based redundancy. The major determinant of non-responsiveness is condition dependency (71%). For approximately 14% of protein complexes, just-in-time assembly can be put forward as a potential mechanistic explanation for how proteins can be regulated in a condition dependent manner. Taken together, the results underscore the large contribution of growth condition requirement to non-responsive behavior, which needs to be taken into account for strategies aimed at determining gene function. The classification provided here, can also be further harnessed in systematic analyses of complex cellular systems.
authors.affiliation: Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.|Center for Molecular Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Saman
authors.initials: S
authors.lastname: Amini
authors.affiliation: Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
authors.forename: Frank C P
authors.initials: FC
authors.lastname: Holstege
authors.affiliation: Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.|Center for Molecular Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Patrick
authors.identifier: http://orcid.org/0000-0003-2237-7354
authors.initials: P
authors.lastname: Kemmeren
mesh_terms: D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D046912:Multiprotein Complexes / Q000145:classification / Q000235:genetics*; D016296:Mutagenesis / Q000235:genetics; D010641:Phenotype; D000072417:Protein Domains / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development*; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D046912:Multiprotein Complexes; D012333:RNA, Messenger