Insights into the consequences of chromosome gains and losses in S. cerevisiae

Abstract

When cells divide, they must properly duplicate and segregate their genome to generate two identical daughter cells with faithful transmission of the genomic content. Errors in chromosome segregation lead to aneuploidy, a state of chromosomal imbalance where the karyotype is not an exact multiple of the haploid complement. At an organismal level, aneuploidy is the leading cause of miscarriage and developmental defects, while at a cellular level, aneuploidy causes proliferative defects and is detrimental to cell fitness. However, aneuploidy is also associated with cancer, a disease of uncontrolled proliferation. Understanding the effects of aneuploidy on cellular physiology has broad implications for many areas of human health. Here, I have characterized the G1 delay in aneuploid S. cerevisiae. Aneuploid yeast exhibited a growth defect in G1. Additionally, aneuploid cells displayed a cell cycle entry delay due to delayed accumulation of G1 cyclins. Like other cellular stresses, aneuploidy interferes with the cell's ability to grow and to enter the cell cycle. I also developed a novel method to systematically examine the immediate consequences of gaining and-for the first time-losing single or multiple chromosomes. Using this system, I found that phenotypes wide-spread among aneuploid cells develop immediately following chromosome mis-segregation. Also, phenotypes common to chromosome gains are also wide-spread among cells that lost chromosomes, indicating that chromosome gains and losses fundamentally affect cells in similar ways. Finally, cell cycle analyses following chromosome mis-segregation revealed a surprising phenotypic variability among cells harboring the same aneuploidies. Together, these results provide insights into the mechanisms for the observed consequences of chromosome gains and losses on cellular physiology.