THE EFFECTS OF ANEUPLOIDY ON CELLULAR FITNESS AND AGING

Abstract

Aneuploidy plays an important role in myriad biological processes. In the case of multicellular organisms, germline and somatic aneuploidy, respectively, have been associated with atypical development and diseases such as cancer. In the case of asexually dividing cells, however, aneuploidy has been shown to influence adaptation and evolution. Despite the assumed advantage associated with aneuploidy under a certain circumstances, aneuploidy has generally been shown to decrease cellular fitness. In Chapter 1 of this thesis I present an overview of the field of aneuploidy research spanning its effects on cancer, metazoan development, adaptation and aging. In Chapter 2 I present work addressing the relationship between aneuploidy and cellular fitness. Specifically, I show that the majority of aneuploid events isolated from laboratory evolution experiments with the yeast <italic>Saccharomyces cerevisiae<italic> under nutrient-limited conditions result in increased fitness of the clones carrying them. In Chapter 2 I also describe a novel method for the development of thousands of yeast strains with diverse karyotypes. Using this method I generated a pool of >1,800 yeast strains each containing a different telomeric amplicon (i.e. segmental amplification initiating at diverse genomic positions and extending to the proximal telomere). I used this pool to test the fitness effects of this type of aneuploid event genome-wide and found that the fitness effects of telomeric amplicons are large, condition-specific and often driven by the fitness effects of a small number of genes along their lengths. I also used this dataset to generate lists of candidate driver genes important for increasing fitness under three different conditions. In Chapter 3 I studied the connection between aneuploidy and aging and show that haploid yeast disomic for a single yeast chromosome have shortened lifespans. A mutation in the ubiquitin ligase adaptor protein <italic>BUL1<italic> rescues this aging phenotype and connects the aging phenotypes of aneuploid yeast to disrupted proteostasis. In Chapter 4 I summarize the results of my thesis work and provide suggestions for future experiments and analyses concerning the data presented here. Aneuploidy's effects on cellular physiology are complex. The results presented in this thesis increase our understanding of aneuploidy's role in cellular adaptation and evolution and will hopefully inform the therapeutic approaches targeting the effects of aneuploidy on human health.