Mechanisms of Adaptive Evolution of Aneuploid Cells

Alteration of normal ploidy (aneuploidy) is an important mechanism of evolution of species. It has been linked to a rapid response to stress and is regarded as a hallmark of cancer. While increased genomic instability of aneuploid cells can accelerate genetic diversification and facilitate adaptation, these cells also face the adverse effects of gene imbalance, resulting in fitness cost. Here, to understand the mechanisms through which cells respond to aneuploidy and develop tolerance leading to fitness restoration, we subjected disomic (i.e. with an extra chromosome copy) strains of yeast to long-term experimental evolution, forcing disomy maintenance with selection markers. We characterized mutations, karyotype alterations and gene expression changes throughout adaptive evolution, and analyzed them to dissect the associated molecular strategies. Cells with different extra chromosomes accumulated mutations at distinct rates, and endured a diverse array of adaptive events. Despite remarkable diversity of these events, cells tended to evolve towards normal ploidy through both chromosomal DNA loss and changes in gene expression. We identified genes commonly altered during the evolution of disomic strains, and genes recurrently mutated in multiple lines. Our analyses revealed protein translation, amino acid biosynthesis, transcription regulation, stress response, and nucleotide and protein degradation as key pathways for the adaptive response to aneuploidy and identified transcription factors that mediate this response. Together, these findings define cellular strategies that underlie tolerance to aneuploidy.