Several consequences of aneuploidy

Abstract

Whole-chromosome aneuploidy, or a karyotype that is not a multiple of the haploid complement, is the most common cause of miscarriage and developmental delay in humans. Aneuploidy is also a hallmark of cancer: greater than 90% of tumors display chromosomal copy number alterations. Thus, understanding the consequences of aneuploidy has broad relevance for human health and development. To that end, I have studied several distinct aspects of aneuploid cell biology. In the budding yeast Saccharomyces cerevisiae, I demonstrated that single-chromosome gains are sufficient to induce numerous forms of genomic instability. Aneuploid yeast strains displayed increased rates of forward mutation, mitotic recombination, chromosome loss, and double-strand break formation, which could significantly impact the evolution of tumor genomes. Secondly, I characterized the effects of aneuploidy on gene expression. I established that aneuploidy induced a transcriptional stress response that was independent of the identity of the extra chromosome and was remarkably well-conserved among eukaryotes. This gene expression program was apparent in trisomic primary cells as well as in chromosomally-unstable cancer cells. Thirdly, I compared the tumorigenicity of euploid and trisomic cell lines that were genetically-identical and differed only in karyotype. I discovered that under most circumstances, aneuploidy impeded proliferation, anchorage-independent growth, and tumor formation in xenografts. Thus, single-chromosome aneuploidy actually functions as a tumor suppressor, rather than a tumor-promoting agent. In total, these results shed light on the diverse ways that chromosomal imbalances can alter the physiology of normal cells and of cancer.