Tetraploidy accelerates adaptation under drug selection in a fungal pathogen.

Baseline ploidy significantly impacts evolutionary trajectories and, specifically, tetraploidy is associated with higher rates of adaptation relative to haploidy and diploidy. While the majority of experimental evolution studies investigating ploidy use the budding yeast Saccharomyces cerivisiae, the fungal pathogen Candida albicans is a powerful system to investigate ploidy dynamics, particularly in the context of acquiring antifungal drug resistance. C. albicans laboratory and clinical strains are predominantly diploid, but have been isolated as haploid and polyploid. Here, we evolved diploid and tetraploid C. albicans for ~60 days in the antifungal drug caspofungin. Tetraploid-evolved lines adapted faster than diploid-evolved lines and reached higher levels of caspofungin resistance. While diploid-evolved lines generally maintained their initial genome size, tetraploid-evolved lines rapidly underwent genome-size reductions and did so prior to caspofungin adaptation. While clinical resistance was largely due to mutations in FKS1, these mutations were caused by substitutions in diploid, and indels in tetraploid isolates. Furthermore, fitness costs in the absence of drug selection were significantly less in tetraploid-evolved lines compared to the diploid-evolved lines. Taken together, this work supports a model of adaptation in which the tetraploid state is transient but its ability to rapidly transition ploidy states improves adaptive outcomes and may drive drug resistance in fungal pathogens.