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Epistasis between promoter activity and coding mutations shapes gene evolvability
Open accessPreprint — published as 10.1126/sciadv.add9109 · Paper page
Abstract
Summary: The evolution of protein-coding genes proceeds as mutations act on two main dimensions: regulation of transcription level and the coding sequence. The extent and impact of the connection between these two dimensions are largely unknown because they have generally been studied independently. By measuring the fitness effects of all possible mutations on a protein complex at various levels of promoter activity, we show that expression at the optimal level for the WT protein masks the effects of both deleterious and beneficial coding mutations. Mutants that are deleterious at low expression but masked at optimal expression are slightly destabilizing for individual subunits and binding interfaces. Coding mutations that increase protein abundance are beneficial at low expression but incur a fitness cost at high expression. We thereby demonstrate that expression level can dictate which coding mutations are beneficial or deleterious.
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Metadata
- Authors
- Cisneros, A. F., Gagnon-Arsenault, I., Dubé, A. K., Després, P. C., Kumar, P., Lafontaine, K., Pelletier, J. N., & Landry, C. R.
- Affiliations
- PROTEO (CA)
- Indian Institute of Technology Roorkee (IN)
- Corresponding author
- Landry, Christian R.
- ORCID
- Venue
- Science Advances
- Publisher
- openRxiv
- Published
- 2022-06-08
- Volume
- 9
- Issue
- 5
- Pages
- eadd9109-eadd9109
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC9897669
- OpenAlex
- W4319069458
- Cited by
- 33
- References
- 1
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 9 · 2023: 5 · 2022: 1
- FWCI
- 5.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Science Advances (publishedVersion, cc-by-nc)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (387697)
- Natural Sciences and Engineering Research Council of Canada (RGPIN-N-2018-04686, 2018-04686)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Social Sciences › Arts and Humanities › History and Philosophy of Science › Philosophy of Biology and Scientific Explanation
- Keywords
- epistasis, promoter activity, coding mutations, transcriptional regulation, protein complex evolution, protein stability, binding interface, protein abundance, fitness effects of mutations, deleterious mutations, beneficial mutations
- MeSH terms
- Biochemical Phenomena, Epistasis, Genetic, Mutation, Promoter Regions, Genetic, Evolution, Molecular
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