Dissecting the influence of genetic background on aneuploidy tolerance in the model eukaryote Saccharomyces cerevisiae

ABSTRACT Chromosome segregation errors can produce cells with an incorrect number of one or more chromosomes, known as aneuploidy. Aneuploidy is therefore a special class of mutation that can have immediate phenotypic effects. Although aneuploidy is detrimental during mammalian development, it is common in many cancers and a driver in the evolution of drug resistant tumors and fungal pathogens. A major unaddressed question is the degree to which different individuals vary in their ability to tolerate aneuploidy. Understanding how genetic differences influence aneuploidy tolerance has far reaching implications for genetics, human biology, and evolution. But studying this topic mammalian systems is extremely challenging, since it is not possible to systematically manipulate karyotypes in a large number of genetic backgrounds. Here we will address the fundamental question of how genetic variation influences the ability of cells to tolerate chromosome duplications, in the model eukaryote Saccharomyces cerevisiae. Using the power of yeast genetics, we adapted a method to duplicate specific yeast chromosomes in the near absence of selection. We will apply this method to explore the breadth and mechanisms of genetic variation in tolerating chromosome duplications (herein referred to as aneuploidy). Aim 1 will use this approach to duplicate each of the 16 chromosomes in yeast, in dozens of non-laboratory strains across the yeast phylogeny. Results will characterize the range of natural variation in aneuploidy tolerance and will test if this variation occurs sporadically due to rare alleles or persists across many strains within specific lineages. Preliminary results suggest lineage-specific variation in aneuploidy tolerance. Aim 2 will test if variations in aneuploidy sensitivity are due to differences in “generalized” aneuploidy tolerance, in which cells are sensitive regardless of which chromosome is duplicated, versus chromosome-specific sensitivities that are likely driven by the effects of duplicated genes encoded on those chromosomes. We will test how well chromosome-specific sensitivities are explained by an additive gene model that is based on measured fitness costs of the genes’ over-expression, measured here from a gene over-expression library expressed in each strain. Aim 3 will begin to uncover the physiological and genetic mechanisms for variable aneuploidy tolerance. We will first test our hypothesis that genetic variation in aneuploidy tolerance is due to variations in the ability to manage proteostasis stress. We will then use bulk- segregant mapping to study the genetic architecture of that variance and identify casual genes. Yeast is an outstanding model in which to study this fundamental question, since many cellular mechanisms and genetic principles are conserved in other organisms including humans. This project will generate important insights into aneuploidy tolerance that will have broad implications for genetics, human health, and evolution.