Aneuploidy enables adaptation to brefeldin A in Candida albicans

Candida albicans is the most prevalent opportunistic fungal pathogen. Both in vivo and in vitro studies have demonstrated that genome plasticity is a hallmark of C. albicans. While aneuploidy formation is a well-documented adaptive mechanism under various stress conditions, the response to brefeldin A-a compound that induces endoplasmic reticulum stress-remains poorly understood. In this study, we demonstrate that C. albicans adapts to subinhibitory and inhibitory concentrations of brefeldin A, primarily through the formation of chromosome 3 trisomy. These aneuploid strains were found to be unstable, reverting to euploidy in the absence of stress, accompanied by a loss of brefeldin A tolerance. We identified at least two genes on chromosome 3, SEC7 and CDR1, that contribute to this adaptive response. Notably, higher concentrations of brefeldin A selected for strains with increasingly complex aneuploidies. Our findings underscore the remarkable genomic plasticity of C. albicans and reveal aneuploidy as a reversible mechanism for adapting to brefeldin A stress. This study provides new insights into the role of aneuploidy in fungal adaptation and offers potential implications for understanding drug resistance mechanisms in pathogenic fungi.