A study reveals that natural proteome diversity links aneuploidy tolerance to protein turnover. Researchers analyzed 796 natural yeast isolates, finding that natural aneuploids differ from lab-generated ones at the proteome level. In lab-generated aneuploids, some proteins show reduced expression, but overall protein levels match the gene dosage. In contrast, natural isolates show dosage compensation, with 70% of proteins on aneuploid chromosomes adjusted to euploid levels. The study highlights the role of protein turnover in aneuploidy tolerance, showing that natural isolates have strategies to mitigate fitness costs. The proteomes of natural isolates were analyzed using a high-throughput proteomics pipeline, revealing increased ubiquitination and proteasome activity. The study also found that proteins with higher turnover rates are more likely to be dosage compensated. These findings suggest that protein turnover plays a key role in aneuploidy tolerance, and that natural diversity can provide insights into complex biological processes. The study underscores the importance of natural genetic diversity in understanding gene function and the generalizability of laboratory findings.A study reveals that natural proteome diversity links aneuploidy tolerance to protein turnover. Researchers analyzed 796 natural yeast isolates, finding that natural aneuploids differ from lab-generated ones at the proteome level. In lab-generated aneuploids, some proteins show reduced expression, but overall protein levels match the gene dosage. In contrast, natural isolates show dosage compensation, with 70% of proteins on aneuploid chromosomes adjusted to euploid levels. The study highlights the role of protein turnover in aneuploidy tolerance, showing that natural isolates have strategies to mitigate fitness costs. The proteomes of natural isolates were analyzed using a high-throughput proteomics pipeline, revealing increased ubiquitination and proteasome activity. The study also found that proteins with higher turnover rates are more likely to be dosage compensated. These findings suggest that protein turnover plays a key role in aneuploidy tolerance, and that natural diversity can provide insights into complex biological processes. The study underscores the importance of natural genetic diversity in understanding gene function and the generalizability of laboratory findings.