Comparative modeling reveals the molecular determinants of aneuploidy fitness cost in a wild yeast model
Open accessPublished version of a preprint
Abstract
Although implicated as deleterious in many organisms, aneuploidy can underlie rapid phenotypic evolution. However, aneuploidy will be maintained only if the benefit outweighs the cost, which remains incompletely understood. To quantify this cost and the molecular determinants behind it, we generated a panel of chromosome duplications in Saccharomyces cerevisiae and applied comparative modeling and molecular validation to understand aneuploidy toxicity. We show that 74%-94% of the variance in aneuploid strains' growth rates is explained by the cumulative cost of genes on each chromosome, measured for single-gene duplications using a genomic library, along with the deleterious contribution of small nucleolar RNAs (snoRNAs) and beneficial effects of tRNAs. Machine learning to identify properties of detrimental gene duplicates provided no support for the balance hypothesis of aneuploidy toxicity and instead identified gene length as the best predictor of toxicity. Our results present a generalized framework for the cost of aneuploidy with implications for disease biology and evolution.
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- Authors
- Rojas, J., Hose, J., Dutcher, H. A., Place, M., Wolters, J. F., Hittinger, C. T., & Gasch, A. P.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Gasch, Audrey P.
- ORCID
- Venue
- Cell Genomics
- Publisher
- Elsevier BV
- Published
- 2024-10
- Volume
- 4
- Issue
- 10
- Pages
- 100656
- ISSN
- 2666-979X (ISSN-L)
- PMC
- PMC11602619
- OpenAlex
- W4402741295
- Cited by
- 22
- References
- 7
- Citations by year
- 2026: 11 · 2025: 4 · 2024: 7
- FWCI
- 5.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Genomics (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- SSRN Electronic Journal (acceptedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- PubMed Central (submittedVersion, cc-by-nc)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health (R01GM147271)
- Office of Science (DE\u2013SC0018409)
- National Human Genome Research Institute (T32GM007133, T32HG002760)
- National Institute of Food and Agriculture (7005101)
- National Science Foundation (DEB-2110403)
- Great Lakes Bioenergy Research Center
- Wisconsin Alumni Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- aneuploidy, fitness cost, chromosome duplication, Saccharomyces cerevisiae, gene dosage, small nucleolar RNA, tRNA, gene length, growth rate, phenotypic evolution, homology modeling
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