Accessing the natural genetic diversity of species unveils hidden genetic traits, clarifies gene functions and allows the generalizability of laboratory findings to be assessed. One notable discovery made in natural isolates of Saccharomyces cerevisiae is that aneuploidy—an imbalance in chromosome copy numbers—is frequent^1,2 (around 20%), which seems to contradict the substantial fitness costs and transient nature of aneuploidy when it is engineered in the laboratory^3,4,5. Here we generate a proteomic resource and merge it with genomic¹ and transcriptomic⁶ data for 796 euploid and aneuploid natural isolates. We find that natural and lab-generated aneuploids differ specifically at the proteome. In lab-generated aneuploids, some proteins—especially subunits of protein complexes—show reduced expression, but the overall protein levels correspond to the aneuploid gene dosage. By contrast, in natural isolates, more than 70% of proteins encoded on aneuploid chromosomes are dosage compensated, and average protein levels are shifted towards the euploid state chromosome-wide. At the molecular level, we detect an induction of structural components of the proteasome, increased levels of ubiquitination, and reveal an interdependency of protein turnover rates and attenuation. Our study thus highlights the role of protein turnover in mediating aneuploidy tolerance, and shows the utility of exploiting the natural diversity of species to attain generalizable molecular insights into complex biological processes.

获取物种的自然遗传多样性可以揭示隐藏的遗传特征，阐明基因功能，并可以评估实验室研究结果的普遍性。在酿酒酵母天然分离株中发现的一个值得注意的发现是，非整倍性（染色体拷贝数的不平衡）很常见（约 20%），这似乎与非整倍性的巨大适应性成本和短暂性相矛盾。它是在实验室 ^3,4,5 设计的。在这里，我们生成蛋白质组资源，并将其与 796 个整倍体和非整倍体天然分离株的基因组 ¹ 和转录组 ⁶ 数据合并。我们发现天然和实验室生成的非整倍体在蛋白质组方面存在显着差异。在实验室生成的非整倍体中，一些蛋白质（尤其是蛋白质复合物的亚基）表现出表达减少，但总体蛋白质水平与非整倍体基因剂量相对应。相比之下，在天然分离物中，非整倍体染色体上编码的超过 70% 的蛋白质得到了剂量补偿，并且平均蛋白质水平在染色体范围内向整倍体状态转移。在分子水平上，我们检测到蛋白酶体结构成分的诱导、泛素化水平的增加，并揭示了蛋白质周转率和衰减的相互依赖性。因此，我们的研究强调了蛋白质周转在介导非整倍体耐受性中的作用，并展示了利用物种的自然多样性来获得对复杂生物过程的普遍分子见解的效用。