Identification of a Global Aneuploidy-Associated Transcriptional and Phenotypic Signature in Budding Yeast

Aneuploidy, an unbalanced genome state with either gain or loss of chromosomes, is known to have dramatic effects on cellular physiology, ranging from detrimental effects including genetic disorders such as Down Syndrome to promoting adaptability under stress, such as drug resistance. This paradoxical nature of aneuploidy impedes the development of therapeutic strategies since a vast majority of tumors exhibit complex aneuploid karyotypes. Although the aneuploid cancer genome has been extensively studied, common transcriptional and phenotypic consequences of aneuploidy still remain elusive. To comprehensively study aneuploidy-specific features, we first generated karyotypically heterogeneous aneuploid populations in budding yeast Saccharomyces cerevisiae, based on our general statistical model. We then performed whole transcriptome sequencing on these heterogeneous aneuploid populations, to uncover a karyotype-independent, global aneuploidy-associated transcriptional response. The aneuploid transcriptome was similar to gene expression profiles of yeast cells subject to hypo-osmotic and cell-wall stresses. Furthermore, we observed that aneuploid cells indeed exhibited phenotypes characteristic of these stresses, including cell swelling, increased glycerol efflux, lower intracellular viscosity and a compromised cell wall. Finally, we also observed a significant reduction in endocytosis in the aneuploid population, resulting in perturbed cellular homeostasis. Interestingly, decreasing the effective turgor pressure by addition of sorbitol rescued the endocytosis defect. Thus, our results shed light on novel cellular consequences of aneuploidy that can be further studied to reveal detailed molecular mechanisms in aneuploidy and identify new potential targets for anticancer therapeutics