Genome-wide investigations into the consequences of gene and chromosome copy number changes

Abstract

Aneuploidy can have contradictory effects on organisms and cells, from developmental disorders and cancer in humans to drug resistance and adaptive advantage in yeast. Despite a long history of involvement in human health and innumerable cases in other model organisms, how aneuploidy confers seemingly paradoxical effects on cellular fitness remains debated. In this work, we examined the contributions individual genes may have on the fitness of aneuploid strains in environmental conditions normally detrimental to growth. We used a collection of ~1,800 Saccharomyces cerevisiae strains with large amplifications tiled across the genome to look at how aneuploidy impacts fitness in high temperature, prolonged stationary phase, and treatment with the Hsp90 inhibitor radicicol, as well as a normal temperature and DMSO only control. This screen revealed 91 candidate regions that may contain single genes that disproportionately impact fitness when amplified. Our candidate regions were identified using a new method to fit a piecewise constant model to fitness data across each chromosome arm. To validate potentially impactful genes, we developed a method to systematically test the contribution of each candidate gene in a pooled fashion. Finally we investigated the causes and consequences of the environmental stress response (ESR), a gene-expression signature exhibited by aneuploid cells. By controlling the growth rate of complex aneuploid strains, we show that the ESR is dependent on the proliferation rate of cells and results in decreased cell density of aneuploids via ribosome loss.