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

Elife. 2020 Jul 20:9:e58349. doi: 10.7554/eLife.58349.

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.

Keywords: Candida albicans; aneuploidy; copy number variation; dicentric chromosomes; drug resistance; drug tolerance; genetics; genomics; infectious disease; microbiology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Biological*
  • Antifungal Agents / pharmacology*
  • Candida albicans / drug effects
  • Candida albicans / genetics
  • Candida albicans / physiology*
  • DNA Copy Number Variations*
  • Drug Resistance, Fungal / genetics*
  • Genotype
  • Karyotype
  • Single-Cell Analysis

Substances

  • Antifungal Agents