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Mode of Selection and Experimental Evolution of Antifungal Drug Resistance in Saccharomyces cerevisiae
Abstract
We show that mode of selection, degree of dominance of mutations, and ploidy are determining factors in the evolution of resistance to the antifungal drug fluconazole in yeast. In experiment 1, yeast populations were subjected to a stepwise increase in fluconazole concentration over 400 generations. Under this regimen, two mutations in the same two chromosomal regions rose to high frequency in parallel in three replicate populations. These mutations were semidominant and additive in their effect on resistance. The first of these mutations mapped to PDR1 and resulted in the overexpression of the ABC transporter genes PDR5 and SNQ2. These mutations had an unexpected pleiotropic effect of reducing the residual ability of the wild type to reproduce at the highest concentrations of fluconazole. In experiment 2, yeast populations were subjected to a single high concentration of fluconazole. Under this regimen, a single recessive mutation appeared in each of three replicate populations. In a genome-wide screen of approximately 4700 viable deletion strains, 13 were classified as resistant to fluconazole (ERG3, ERG6, YMR102C, YMR099C, YPL056C, ERG28, OSH1, SCS2, CKA2, SML1, YBR147W, YGR283C, and YLR407W). The mutations in experiment 2 all mapped to ERG3 and resulted in the overexpression of the gene encoding the drug target ERG11, but not PDR5 and SNQ2. Diploid hybrids from experiments 1 and 2 were less fit than the parents in the presence of fluconazole. In a variation of experiment 2, haploids showed a higher frequency of resistance than diploids, suggesting that degree of dominance and ploidy are important factors in the evolution of antifungal drug resistance.
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In the citing paper
“The impact of drug concentration on the spectrum and effect of mutations acquired during adaptation is not known for any fungal pathogen, and how the specific level of a given stress influences the distribution of beneficial mutations has been poorly explored in general.”
From Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in Candida albicans (2023) · cites this paper as Anderson et al. 2003
In the citing paper
“In a similar example, three lineages from one genetic background of haploid S. cerevisiae were exposed to increasing concentrations of FLC over the span of 400 generations, starting at 16 μg/ml FLC and increasing every 100 generations to 32 μg/ml, 64 μg/ml, and 128 μg/ml FLC (Anderson et al. 2003).”
From Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in Candida albicans (2023) · cites this paper as Anderson et al. 2003
In the citing paper
“Prior studies into how antifungal drugs impact the spectrum of mutations observed during adaption primarily focused on increasing FLC concentrations or on short-term evolution experiments in a single concentration of FLC (Cowen et al. 2000; Anderson et al. 2003; Mount et al. 2018; Rybak et al. 2020; Burrack et al. 2022).”
From Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in Candida albicans (2023) · cites this paper as Anderson et al. 2003
In the citing paper
“Overall, the impact of genetic and environmental factors, including FLC concentration, on the acquisition of drug resistance and tolerance phenotypes is not known.”
From Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in Candida albicans (2023) · cites this paper as Anderson et al. 2003
In the citing paper
“Several studies have shown a high consistency between results obtained in vivo and in vitro in yeasts like C. albicans and S. cerevisiae [147,148].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [148]
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Metadata
- Authors
- Anderson, J. B., Sirjusingh, C., Parsons, A. B., Boone, C., Wickens, C., Cowen, L. E., & Kohn, L. M.
- Affiliations
- University of Toronto (CA)
- Corresponding author
- Anderson, James B
- Venue
- Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2003-04-01
- Volume
- 163
- Issue
- 4
- Pages
- 1287-1298
- ISSN
- 0016-6731 (ISSN-L)
- 1943-2631
- OpenAlex
- W2143154997
- Cited by
- 156
- References
- 31
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 11 · 2020: 10 · 2019: 10 · 2018: 5 · 2017: 10 · 2016: 5 · 2015: 6 · 2014: 10 · 2013: 5 · 2012: 10
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Keywords
- antifungal resistance, fluconazole resistance, Saccharomyces cerevisiae, experimental evolution, ploidy, PDR1, PDR5, ERG3, ERG11, pleiotropy
- MeSH terms
- Diploidy, Dose-Response Relationship, Drug, Biological Evolution, Haploidy, Saccharomyces cerevisiae, Selection, Genetic, Fluconazole, Drug Resistance, Fungal
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