How cells leverage their phenotypic potential to adapt and survive in a changing environment is a complex biological problem, with important implications for pathogenesis and species evolution. One particularly fascinating adaptive approach is the bet hedging strategy known as phenotype switching, which introduces phenotypic variation into a population through stochastic processes. Phenotype switching has long been observed in species across the tree of life, yet the mechanistic causes of

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... ing in these organisms have remained difficult to define. Here we describe the causative basis of colony morphology phenotype switching which occurs among cells of the pathogenic isolate of Saccharomyces cerevisiae, YJM311. From clonal populations of YJM311 cells grown in identical conditions, we identified colonies which displayed altered colony architectures, yet could revert to the wild-type morphology after passaging. Whole genome sequence analysis revealed that these variant clones had all acquired whole chromosome copy number alterations (i.e., aneuploidies). Cumulatively, the variant clones we characterized harbored an exceptional spectrum of karyotypic alterations, with individual variants carrying between 1 and 16 aneuploidies. Most variants harbored unique collections of aneuploidies, indicating that numerous distinct karyotypes could manifest in the same morphological variation. Intriguingly, the genomic stability of these newly aneuploid variant clones modulated how often cells reverted back to the wild-type phenotypic state. We found that such revertant switches were also driven by chromosome missegregation events, and in some cases occurred through a return to euploidy. Together, our results demonstrate that colony morphology switching in this yeast strain is driven by stochastic and systemic aneuploidization events. These findings add an important new perspective to our current understanding of phenotype switching and bet hedging strategies, as well as how environmental pressures perpetuate organismal adaption and genome evolution.