Resistance to the limited number of available antifungal drugs is a serious problem in the treatment of Candida albicans. We found that aneuploidy in general and a specific segmental aneuploidy, consisting of an isochromosome composed of the two left arms of chromosome 5, were associated with azole resistance. The isochromosome forms around a single centromere flanked by an inverted repeat and was found as an independent chromosome or fused at the telomere to a full-length homolog of chromosome 5. Increases and decreases in drug resistance were strongly associated with gain and loss of this isochromosome, which bears genes expressing the enzyme in the ergosterol pathway targeted by azole drugs, efflux pumps, and a transcription factor that positively regulates a subset of efflux pump genes.

Polyploidy is observed across the tree of life, yet its influence on evolution remains incompletely understood1–4. Polyploidy, usually whole genome duplication (WGD), is proposed to alter the rate of evolutionary adaptation. This could occur through complex effects on the frequency or fitness of beneficial mutations 2,5–7. For example, in diverse cell types and organisms, immediately after a WGD, newly formed polyploids missegregate chromosomes and undergo genetic instability8–13. The instability following WGDs is thought to provide adaptive mutations in microorganisms13,14 and can promote tumorigenesis in mammalian cells11,15. Polyploidy may also affect adaptation independent of beneficial mutations through ploidy-specific changes in cell physiology16. Here, we performed in vitro evolution experiments to directly test whether polyploidy can accelerate evolutionary adaptation. Compared to haploids and diploids, tetraploids underwent significantly faster adaptation. Mathematical modeling suggested that rapid adaptation of tetraploids was driven by higher rates of beneficial mutations with stronger fitness effects, which was supported by whole-genome sequencing and phenotypic analyses of evolved clones. Chromosome aneuploidy, concerted chromosome loss, and point mutations all provided large fitness gains. We identified several mutations whose beneficial effects were manifest specifically in the tetraploid strains. Together, these results provide direct quantitative evidence that in some environments polyploidy can accelerate evolutionary adaptation.