Cancers are commonly characterized as having an abnormal number of chromosomes, termed aneuploidy, which arise due to genomic instability. There is still debate over whether aneuploidy is a driving force of the disease or a resulting phenotype; however, the presence of aneuploidy can be used to grade the malignant potential of certain types of cancer. A simple hypothesis is that genome instability itself is tumorigenic in that it results in alterations in the number of chromosomes, which alters gene copy number and ultimately affects gene expression in cells. Many gene disruptions that result in a propensity for cells to become aneuploid were first identified through mutagenesis screens designed to generate null or missense mutations in haploid strains ofSaccharomyces cerevisiae. In contrast, the susceptibility to develop cancer can be transmitted as an autosomal dominant trait with affected individuals being heterozygous carriers of null mutations. In this chapter, we will describe a technique that can be used to identify heterozygous mutations in dosage-sensitive genes that mediate genomic stability by performing genome-wide screens in yeast.
