Cited by 138Antifungal resistance and susceptibilityFungal and yeast genetics researchGenomic variations and chromosomal abnormalities

Expandable and reversible copy number amplification drives rapid adaptation to antifungal drugs

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Todd, Robert T, Selmecki, Anna·2020·eLife

Abstract

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 of C. auris during fluconazole exposure is relatively slow compared to C. albicans and mainly composed of SNPs, with aneuploidy a minority effect.

    “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]

    The Results section (page unavailable) reports rapid fluconazole adaptation in C. albicans: all 14 sequenced, resistance-increased isolates acquired chromosome or segmental aneuploidies. The Introduction and Conclusion mention copy-number variation in C. auris, but the paper does not compare its adaptation rate with C. albicans or establish that SNPs predominate and aneuploidy is a minority effect in C. auris. (LLM, conf=0.77)

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  • Under fluconazole exposure, C. albicans rapidly evolves CNVs and aneuploidy in vitro.

    “Under fluconazole exposure, C. albicans rapidly evolves CNVs and aneuploidy in vitro [135].”
  • These complex CNVs are flanked by distinct long inverted repeat sequences, found across the genome, and often contain genes associated with drug resistance.

    “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]

  • Extensive copy number variations (CNVs) amplify large genomic regions and drive rapid acquisition of azole resistance in C. albicans.

    “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]

  • GRs and CNVs around these genes are related to drug resistance.

    “our results suggest that GRs and CNVs around these genes are related to drug resistance, as previously proposed in C. albicans.36”

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Authors
Todd, R. T., & Selmecki, A.
Affiliations
University of Minnesota (US)
Corresponding author
Selmecki, Anna
Venue
eLife
Published
2020-07-20
Volume
9
ISSN
2050-084X (ISSN-L)
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
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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