Data from: A global genetic interaction network maps a wiring diagram of cellular functionLink copied to clipboard!
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- Description:
- INTRODUCTION: Genetic interactions occur when mutations in two or more genes combine to generate an unexpected phenotype. An extreme negative or synthetic lethal genetic interaction occurs when two mutations, neither lethal individually, combine to cause cell death. Conversely, positive genetic interactions occur when two mutations produce a phenotype that is less severe than expected. Genetic interactions identify functional relationships between genes and can be harnessed for biological discovery and therapeutic target identification. They may also explain a considerable component of the undiscovered genetics associated with human diseases. Here, we describe construction and analysis of a comprehensive genetic interaction network for a eukaryotic cell. RATIONALE: Genome sequencing projects are providing an unprecedented view of genetic variation. However, our ability to interpret genetic information to predict inherited phenotypes remains limited, in large part due to the extensive buffering of genomes, making most individual eukaryotic genes dispensable for life. To explore the extent to which genetic interactions reveal cellular function and contribute to complex phenotypes, and to discover the general principles of genetic networks, we used automated yeast genetics to construct a global genetic interaction network. RESULTS: We tested most of the ~6000 genes in the yeast Saccharomyces cerevisiae for all possible pairwise genetic interactions, identifying nearly 1 million interactions, including ~550,000 negative and ~350,000 positive interactions, spanning ~90% of all yeast genes. Essential genes were network hubs, displaying five times as many interactions as nonessential genes. The set of genetic interactions or the genetic interaction profile for a gene provides a quantitative measure of function, and a global network based on genetic interaction profile similarity revealed a hierarchy of modules reflecting the functional architecture of a cell. Negative interactions connected functionally related genes, mapped core bioprocesses, and identified pleiotropic genes, whereas positive interactions often mapped general regulatory connections associated with defects in cell cycle progression or cellular proteostasis. Importantly, the global network illustrates how coherent sets of negative or positive genetic interactions connect protein complex and pathways to map a functional wiring diagram of the cell. CONCLUSION: A global genetic interaction network highlights the functional organization of a cell and provides a resource for predicting gene and pathway function. This network emphasizes the prevalence of genetic interactions and their potential to compound phenotypes associated with single mutations. Negative genetic interactions tend to connect functionally related genes and thus may be predicted using alternative functional information. Although less functionally informative, positive interactions may provide insights into general mechanisms of genetic suppression or resiliency. We anticipate that the ordered topology of the global genetic network, in which genetic interactions connect coherently within and between protein complexes and pathways, may be exploited to decipher genotype-to-phenotype relationships.
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- Author(s):
- Costanzo, Michael, VanderSluis, BenjaminUniversity of Toronto, Koch, Elizabeth N.University of Minnesota, Baryshnikova, AnastasiaUniversity of Minnesota, Pons, CarlesPrinceton University, Tan, GuihongUniversity of Minnesota, Wang, WenUniversity of Toronto, Usaj, MatejUniversity of Minnesota, Hanchard, JuliaUniversity of Toronto, Lee, Susan D.University of Toronto, Pelechano, VicentTufts University, Styles, Erin B.European Molecular Biology Laboratory, Billmann, MaximilianUniversity of Toronto, Van Leeuwen, JolandaHeidelberg University, Van Dyk, NydiaUniversity of Toronto, Lin, Zhen-YuanUniversity of Toronto, Kuzmin, ElenaMount Sinai Hospital, Nelson, JustinUniversity of Toronto, Piotrowski, Jeff S.University of Minnesota, Srikumar, TharanUniversity of Toronto, Bahr, SondraUniversity Health Network, Chen, YiqunUniversity of Toronto, Deshpande, RaameshUniversity of Toronto, Kurat, Christoph F.University of Minnesota, Li, Sheena C.University of Toronto, Li, ZhijianUniversity of Toronto, Mattiazzi Usaj, MojcaUniversity of Toronto, Okada, HirokiUniversity of Toronto, Pascoe, NatashaUniversity of Tokyo, San Luis, Bryan-JosephUniversity of Toronto, Sharifpoor, SaraUniversity of Toronto, Shuteriqi, EmiraUniversity of Toronto, Simpkins, Scott W.University of Toronto, Snider, JamieUniversity of Minnesota, Garadi Suresh, HarshaUniversity of Toronto, Tan, YizhaoUniversity of Toronto, Zhu, HongweiUniversity of Toronto, Malod-Dognin, NoelUniversity of Toronto, Janjic, VukUniversity College London Hospitals NHS Foundation Trust, Przulj, NatasaImperial College London, Troyanskaya, Olga G.University College London Hospitals NHS Foundation Trust, Stagljar, IgorSimons Foundation, Xia, TianUniversity of Toronto, Ohya, YoshikazuUniversity of Minnesota, Gingras, Anne-ClaudeUniversity of Tokyo, Raught, BrianUniversity of Toronto, Boutros, MichaelUniversity Health Network, Steinmetz, Lars M.Heidelberg University, Moore, Claire L.European Molecular Biology Laboratory, Rosebrock, Adam P.Tufts University, Caudy, Amy A.University of Toronto, Myers, Chad L.University of Toronto, Andrews, BrendaUniversity of Minnesota, and Boone, CharlesUniversity of TorontoUniversity of Toronto
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- Source Repository:
- Dryad
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- License:
- https://creativecommons.org/publicdomain/zero/1.0/
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- URL:
- https://doi.org/10.5061/dryad.4291s
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- Publication date:
- 2017-08-27
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- APA Citation:
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Costanzo, M., VanderSluis, B., Koch, E. N., Baryshnikova, A., Pons, C., Tan, G., Wang, W., Usaj, M., Hanchard, J., Lee, S. D., Pelechano, V., Styles, E. B., Billmann, M., Van Leeuwen, J., Van Dyk, N., Lin, Z.-Y., Kuzmin, E., Nelson, J., Piotrowski, J. S., … Boone, C. (2017). Data from: A global genetic interaction network maps a wiring diagram of cellular function [Data set]. Dryad. https://doi.org/10.5061/dryad.4291sCitation copied to clipboard
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