Organismal ploidy state and environmental stress impact the mutational spectrum and the mutational rate. The human fungal pathogen Candida albicans, serves as a clinically relevant model for studying the interaction between eukaryotic ploidy and stress-induced mutagenesis. In this study, we compared the rates and types of genome perturbations in diploid and tetraploid C. albicans following exposure to two classes of antifungal drugs, azoles and echinocandins. We measured mutations at three different scales: point mutation, loss-ofheterozygosity (LOH), and genome size changes in cells treated with fluconazole and caspofungin. We find that caspofungin induced higher rates of mutation than fluconazole, likely an indirect result from the stress associated with cell wall perturbations rather than an inherent genotoxicity. Furthermore, we found disproportionately elevated rates of LOH and genome size changes in response to both antifungals in tetraploid C. albicans compared to diploid C.albicans, suggesting that the magnitude of stress-induced mutagenesis results from an interaction between ploidy state and the environment. These results have both clinical and evolutionary implications for how fungal pathogens generate mutations in response to antifungal drug stress, and may facilitate the emergence of antifungal resistance.

The ability to generate genetic variation facilitates rapid adaptation in stressful environments. The opportunistic fungal pathogen Candida albicans frequently undergoes large-scale genomic changes, including aneuploidy and loss-of heterozygosity (LOH), following exposure to physiological stressors and host environments. However, the specific host factors that induce C. albicans genome instability remains largely unknown. Here, we leveraged genetically-tractable nematode hosts to specifically investigate the innate immune components driving host-associated C. albicans genome instability, which include host production of antimicrobial peptides (AMPs) and reactive oxygen species (ROS). C. albicans associated with wildtype, immunocompetent hosts carried multiple large-scale genomic changes including LOH, whole chromosome, and segmental aneuploidies. In contrast, C. albicans associated with immunocompromised hosts deficient in AMPs or ROS production had reduced LOH frequencies and fewer, if any, additional genomic changes. We also found that C. albicans cap1∆/∆ strains deficient in ROS detoxification, were more susceptible to host-produced ROS genome instability compared to wildtype C. albicans. Further, genomic perturbations resulting from host-produced ROS are mitigated by the addition of antioxidants. Taken together, this work suggests that host-produced ROS and AMPs induces genotypic plasticity in C. albicans which may facilitate rapid adaptation and lead to phenotypic changes.