Combinatorial effects of multiple genes contribute to beneficial aneuploidy phenotypes

Aneuploidy is one of the most common adaptive mechanisms to environmental selection in cells, yet its advantages over other genomic alterations remain unclear. We used budding yeast to determine if beneficial aneuploidy phenotypes are driven primarily by combinatorial expression changes of multiple genes. To determine the impact of complex aneuploidy on cellular fitness and drug resistance, we generated yeast collections with nearly every combination of two chromosome gains or losses. Additionally, we genetically dissected aneuploid chromosomes using partial deletions to identify chromosomal regions contributing to aneuploidy-driven drug resistance. Strong resistance phenotypes consistently came from combinations of chromosomes or chromosomal regions, with up to five regions on a chromosome contributing to resistance to a single drug. Gene ontology terms had limited predictive power in identifying the genes contributing to resistance phenotypes, as the combinatorial effects from different aneuploid regions act through multiple resistance pathways. The strongest phenotypes came from synergistic effects between copy number changes of different chromosomes or chromosomal regions, demonstrating how subtle gene expression changes of many genes combine to greatly impact cell survival.