Cited by 156Evolution and Genetic DynamicsFungal and yeast genetics researchAntifungal resistance and susceptibility

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Mode of Selection and Experimental Evolution of Antifungal Drug Resistance in Saccharomyces cerevisiae

Anderson, James B, Sirjusingh, Caroline, Parsons, Ainslie B, Boone, Charles, Wickens, Claire, Cowen, Leah E, Kohn, Linda M·2003·Genetics

DOI 10.1093/genetics/163.4.1287

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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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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
ORCID: Anderson, James B
Boone, Charles
Cowen, Leah E
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
DOI: 10.1093/genetics/163.4.1287
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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Mode of Selection and Experimental Evolution of Antifungal Drug Resistance in Saccharomyces cerevisiae

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