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Expandable and reversible copy number amplification drives rapid adaptation to antifungal drugs
Open accessAbstract
Previously, we identified long repeat sequences that are frequently associated with genome rearrangements, including copy number variation (CNV), in many diverse isolates of the human fungal pathogen Candida albicans (Todd et al., 2019). Here, we describe the rapid acquisition of novel, high copy number CNVs during adaptation to azole antifungal drugs. Single-cell karyotype analysis indicates that these CNVs appear to arise via a dicentric chromosome intermediate and breakage-fusion-bridge cycles that are repaired using multiple distinct long inverted repeat sequences. Subsequent removal of the antifungal drug can lead to a dramatic loss of the CNV and reversion to the progenitor genotype and drug susceptibility phenotype. These findings support a novel mechanism for the rapid acquisition of antifungal drug resistance and provide genomic evidence for the heterogeneity frequently observed in clinical settings.
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“In vitro evolution during fluconazole exposure is relatively slow, compared to C. albicans, and mainly composed of a single nucleotide polymorphism (SNP), with aneuploidy a minority effect [135,136].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [135]
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In the citing paper
“Under fluconazole exposure, C. albicans rapidly evolves CNVs and aneuploidy in vitro [135].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [135]
In the citing paper
“These complex CNVs are flanked by distinct long inverted repeat sequences and are found across the genome, often containing genes associated with drug resistance68.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [68]
In the citing paper
“Another significant source of genomic diversity that drives the rapid acquisition of azole resistance in C. albicans involves extensive copy number variations (CNVs), which amplify large genomic regions68.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [68]
In the citing paper
“our results suggest that GRs and CNVs around these genes are related to drug resistance, as previously proposed in C. albicans.36”
From Narrow mutational signatures drive acquisition of multidrug resistance in the fungal pathogen Candida glabrata (2021) · cites this paper as [36]
In the citing paper
“Intriguingly, our recent experiments demonstrate that azole tolerance and cross-tolerance to different azole drugs can evolve rapidly in vitro (Todd and Selmecki 2020; Kukurudz et al. 2022), yet the mechanisms that distinguish drug-resistant and drug-tolerant phenotypes in fungi are not fully characterized.”
From Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in Candida albicans (2023) · cites this paper as Todd and Selmecki 2020
In the citing paper
“The copy number breakpoints of all segmental aneuploidies occurred at long repeat sequences as described previously (Todd et al. 2019; Todd and Selmecki 2020).”
From Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in Candida albicans (2023) · cites this paper as Todd and Selmecki 2020
In the citing paper
“Todd and Selmecki (2020) did, however, identify 3 isolates evolved to FLC in an in vitro experiment that had increased copy number of a subset of efflux pump, multidrug transporters, and stress response genes on Chr3, leading to increased tolerance and resistance to several azoles.”
From Acquisition of cross-azole tolerance and aneuploidy in Candida albicans strains evolved to posaconazole (2022) · cites this paper as Todd and Selmecki (2020)
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Metadata
- Authors
- Todd, R. T., & Selmecki, A.
- Affiliations
- University of Minnesota (US)
- Corresponding author
- Selmecki, Anna
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2020-07-20
- Volume
- 9
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC7371428
- OpenAlex
- W3042508348
- Cited by
- 138
- References
- 184
- Citations by year
- 2026: 20 · 2025: 20 · 2024: 27 · 2023: 20 · 2022: 28 · 2021: 20 · 2020: 3
- FWCI
- 2.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Allergy and Infectious Diseases (AI143689)
- Nebraska Department of Health and Human Services (LB506-2017-55)
- Nebraska Established Program to Stimulate Competitive Research (First Award)
- National Center for Research Resources (COBRE P20RR018788 sub-award)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- Candida albicans, copy number variation, antifungal resistance, azole antifungals, breakage-fusion-bridge cycles, inverted repeats, drug sensitivity, genome rearrangement
- MeSH terms
- Adaptation, Biological, Antifungal Agents, Candida albicans, Genotype, Drug Resistance, Fungal, DNA Copy Number Variations, Single-Cell Analysis, Karyotype
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