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

Robert T. Todd, Anna Selmecki

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article numbere58349
Pages (from-to)1-33
Number of pages33
JournaleLife
Volume9
DOIs
StatePublished - Jul 2020

Bibliographical note

Funding Information:
We thank Curtis Focht from our lab for assistance developing multiple bioinformatics pipelines, and Hung-ji Tsai, Laura Burrack, and Dana Davis for helpful discussions and feedback on the manuscript. We are grateful to Leah Cowen and her lab for the isolates detailed in Figure 3. Support for this research was provided by NIH grant R01 AI143689, NE Established Program to Stimulate Competitive Research (EPSCoR) First Award, NE Department of Health and Human Services (LB506-2017-55) award, and NIH-NCRR COBRE grant P20RR018788 sub-award. The sequencing datasets generated during this study are available in the Sequence Read Archive repository under BioProject PRJNA613282.

Funding Information:
We thank Curtis Focht from our lab for assistance developing multiple bioinformatics pipelines, and Hung-ji Tsai, Laura Burrack, and Dana Davis for helpful discussions and feedback on the manuscript. We are grateful to Leah Cowen and her lab for the isolates detailed in Figure 3. Support for this research was provided by NIH grant R01 AI143689, NE Established Program to Stimulate Competitive Research (EPSCoR) First Award, NE Department of Health and Human Services (LB506-2017-55) award, and NIH-NCRR COBRE grant P20RR018788 sub-award. The sequencing datasets generated during this study are available in the Sequence Read Archive repository under BioProject PRJNA613282. National Institute of Allergy and Infectious Diseases AI143689 Anna Selmecki Nebraska Department of Health and Human Services LB506-2017-55 Anna Selmecki Nebraska Established Program to Stimulate Competitive Research First Award Anna Selmecki National Center for Research Resources COBRE P20RR018788 sub-award Anna Selmecki.

Publisher Copyright:
© Todd and Selmecki.

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