Functional Overlap and Regulatory Links Shape Genetic Interactions between Signaling Pathways
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To understand relationships between phosphorylation-based signaling pathways, we analyzed 150 deletion mutants of protein kinases and phosphatases in S. cerevisiae using DNA microarrays. Downstream changes in gene expression were treated as a phenotypic readout. Double mutants with synthetic genetic interactions were included to investigate genetic buffering relationships such as redundancy. Three types of genetic buffering relationships are identified: mixed epistasis, complete redundancy, and quantitative redundancy. In mixed epistasis, the most common buffering relationship, different gene sets respond in different epistatic ways. Mixed epistasis arises from pairs of regulators that have only partial overlap in function and that are coupled by additional regulatory links such as repression of one by the other. Such regulatory modules confer the ability to control different combinations of processes depending on condition or context. These properties likely contribute to the evolutionary maintenance of paralogs and indicate a way in which signaling pathways connect for multiprocess control.
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A common neomorphic behavior, similar to one observed in yeast, occurred when a perturbation with little transcriptional effect alone enhanced the effects of a second perturbation (e.g., FEV/CBFA2T3, d=0.74).
“A common neomorphic behavior, similar to one observed in yeast (22), occurred when a perturbation that had little transcriptional effect on its own appeared to enhance the effects of a second perturbation (e.g. FEV/CBFA2T3, d = 0.74, fig. S11E).”
From Exploring genetic interaction manifolds constructed from rich single-cell phenotypes (2019) · cites this paper as [22]
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- Authors
- van Wageningen, S., Kemmeren, P., Lijnzaad, P., Margaritis, T., Benschop, J. J., de Castro, I. J., van Leenen, D., Groot Koerkamp, M. J. A., Ko, C. W., Miles, A. J., Brabers, N., Brok, M. O., Lenstra, T. L., Fiedler, D., Fokkens, L., Aldecoa, R., Apweiler, E., Taliadouros, V., Sameith, K., van de Pasch, L. A. L., van Hooff, S. R., Bakker, L. V., Krogan, N. J., Snel, B., & Holstege, F. C. P.
- Affiliations
- University Medical Center Utrecht (NL)
- Netherlands Bioinformatics Centre (NL)
- University of California, San Francisco (US)
- Utrecht University (NL)
- Corresponding author
- Holstege, Frank C.P.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 143
- Issue
- 6
- Pages
- 991-1004
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3073509
- OpenAlex
- W2112441403
- Cited by
- 133
- References
- 75
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 6 · 2021: 6 · 2020: 3 · 2019: 12 · 2018: 7 · 2017: 11 · 2016: 7 · 2015: 12 · 2014: 16 · 2013: 17 · 2012: 13
- FWCI
- 5.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (05071057, 81702015, 91106009, 016.108.607)
- National Institute of General Medical Sciences (R01GM084448)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- synthetic genetic interactions, functional overlap, regulatory modules, repression, paralogs, Saccharomyces cerevisiae, gene expression profiling
- MeSH terms
- Epistasis, Genetic, Phosphoric Monoester Hydrolases, Phosphorylation, Phosphotransferases, Saccharomyces cerevisiae, Signal Transduction, Gene Expression Profiling
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