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.正常倍性改变（非整倍性，aneuploidy）是物种进化的重要机制之一。其与物种对胁迫的快速应答密切相关，同时被视为癌症的标志性特征。尽管非整倍体细胞的基因组不稳定性升高可加速遗传多样化并促进适应性演化，但这类细胞也会面临基因失衡带来的负面影响，进而产生适合度代价（fitness cost）。为解析细胞响应非整倍性并产生耐受以恢复适合度的潜在机制，本研究将二体（disomic，即携带一条额外染色体拷贝的）酵母菌株置于长期实验进化体系中，并通过筛选标记强制维持其二体状态。我们对适应性进化过程中的突变、核型改变与基因表达变化进行了系统表征，并通过整合分析解析其中涉及的分子调控策略。携带不同额外染色体的细胞，其突变积累速率存在显著差异，并经历了多样的适应性演化事件。尽管这类事件存在丰富的多样性，但细胞倾向于通过染色体DNA丢失与基因表达调控两种途径，向正常倍性状态回归。我们鉴定出在二体菌株进化过程中普遍发生改变的基因，以及在多个进化谱系中反复出现突变的基因。分析结果显示，蛋白质翻译、氨基酸生物合成、转录调控、应激反应、核苷酸与蛋白质降解等通路，是细胞响应非整倍性的关键调控通路，并鉴定出介导该响应的转录因子。综上，本研究明确了介导非整倍性耐受的核心细胞策略。