Dissecting the genetic determinants of aneuploidy's effect on cellular proliferat

University Of Washington, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): An abnormal karyotype, including both segmental and whole chromosomal aneuploidies, is a hallmark of cancer. Many tumors are aneuploidy and there is evidence that aneuploidy may be a driver of tumorigenesis [27]. Despite these close ties to cancer, aneuploidy is paradoxically associated with a cell cycle delay and decreased growth rates [25, 29]. Aneuploidy results in the coordinated copy-number change of tens to thousands of genes. This genetic complexity has made it difficult to understand how aneuploidy might promote tumorigenesis and cellular proliferation. Saccharomyces cerevisiae is a well-studied model organism with many elements of its cellular biology conserved with mammalian cells. The study of complex genetic problems is simplified in S. cerevisiae due to the relative simplicity of the yeast genome and by the many available strain collections. In a process with many parallels to tumorigenesis, our laboratory has isolated aneuploid clones of S. cerevisiae from a subset of 24 independent long-term evolution experiments [7]. Just as aneuploidies frequently represented in a population of cancer cells are hypothesized to be associated with a proliferative advantage [17], similarly, in Aim 1 we plan to identify high-frequency aneuploid clones isolated from these evolution experiments and in Aim 2 determine their proliferative advantage. Population-level analysis of the evolution experiments will be carried out using array comparative genomic hybridization (aCGH) of population DNA while the relative proliferative advantage of different strains will be determined by direct competition experiments. In Aim 3 we will exploit bar-coded yeast collections spanning more than 90% of the protein coding genome [10, 30] and the novel high-throughput sequencing technology Bar-seq [21] to determine how the coordinated copy- number change of multiple genes within an aneuploid region combines to affect cellular proliferation. We hope that the rigorous genetic analysis of aneuploidy proposed here will help us better understand the role of aneuploidy in tumorigenesis and cancer progression. PUBLIC HEALTH RELEVANCE: Aneuploidy is a genetic abnormality where a cell has an abnormal number of chromosomes. Cancer is a disease characterized by unbridled cellular growth and many cancer cells themselves are aneuploid [reviewed in 28]. In this proposal we will use yeast to identify the genetic basis for aneuploidy's effects on cellular growth.