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

ELife
Robert T Todd, Anna Selmecki

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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Citations

Jul 30, 2020·Nature Reviews. Microbiology·Andrea Du Toit
Dec 3, 2020·Frontiers in Microbiology·Eric DelarzeDominique Sanglard
Sep 8, 2021·MBio·Samuel Vega-EstévezAlessia Buscaino

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Datasets Mentioned

BETA
AMS3051
PRJNA613282

Methods Mentioned

BETA
electrophoresis
restriction digest
PCR
Ligation

Software Mentioned

HaplotypeCaller
SplitThreader
Sniffles
samtools view
Samtools
R package Growthcurver
MEM
Fastq
CHEF
ImageJ

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