Combinatorial effects of multiple genes contribute to beneficial aneuploidy phenotypes

Aneuploidy is one of the most common mechanisms of adaptation to environmental selection in vegetatively growing cells. However, it is still unclear what advantages aneuploidy provides over other types of genomic alterations. In this study, we aimed to determine if beneficial aneuploidy phenotypes are driven primarily by combinatorial expression changes of multiple genes using budding yeast as a model system. To determine the impact of complex aneuploidy on cellular fitness and resistance to a variety of drug treatments, we generated yeast collections with nearly every possible combination of two chromosome gains or losses. In addition, we genetically dissected aneuploid chromosomes using partial deletions to identify chromosomal regions that contribute to aneuploidy-driven drug resistance. Strong resistance phenotypes consistently came from combinations of chromosomes or chromosomal regions. We identified up to five regions on a single chromosome that contribute to resistance to a single drug treatment. Finally, we found that the strongest aneuploidy phenotypes came from synergistic effects between copy number changes of different chromosomes or chromosomal regions. These results provide insights into how combining subtle gene expression changes across the genome impacts aneuploidy phenotypes.