Evolution shapes the mechanisms that promote the faithful transmission of genetic information during the reproduction of cells and organisms and errors in transmission are the raw material that drives evolutionary adaptation. Chromosome metabolism (the combination of chromosome replication, chromosome segregation, and the mechanisms that regulate them) changes over a wide range of time-scales. Over millions of years, mechanisms and components change, leading to cell biological differences between mammals and microbes that can exploited to treat infectious and parasitic disease. Over a human lifetime, cancer cells accumulate mutations that increase cell proliferation, survival, and migration and cause the genetic instability that accelerates cancer evolution and produces the mutant cells that resist many therapies. In meiosis, errors in chromosome segregation cause Down syndrome, the most common genetic birth defect. The combination of whole genome sequencing and genome engineering to test the effects of mutations makes experimental evolution a powerful tool to study the evolution of chromosome metabolism, its current mechanisms, and its plasticity. The budding yeast, Saccharomyces cerevisiae, with its rapid reproduction, compact genome, highly developed cell biology and genetics (both classical and molecular) is an ideal organism for these studies, which have already yielded insights into the evolution of both cancer and species. In this project, parallel populations will be evolved to respond to genetic perturbations, genome sequencing will find putative causative mutations, these mutations will be engineered, individually and in combination into ancestral strains, and cell biological assays will reveal the mechanisms by which the selected mutations repair or bypass the damaged pathways. The proposal has three aims, each studying how a cell biological process responds to genetic perturbations, with the twin goals of learning more about the process and its response to selective pressure: 1) Evolving improved survival and proliferation in response to replication stress, a ubiquitous feature of cancer. 2) Evolving two modifications of meiosis: alternative mechanisms to initiate recombination and accurate meiotic chromosome segregation in the absence of recombination. 3) Investigating a specific hypothesis for the mechanism of parasexuality, the process by which a variety of fungi, including pathogens such as Candida albicans, reduce their ploidy without passing through meiosis. All three aims will produce insights into disease, including cancer, inherited birth defects, and fungal pathogenesis.
Cancer is an evolutionary disease: our cells accumulate mutations that increase their growth, their proliferation, their survival, their migration, and their ability to resist therapy. To acquire these mutations, cancer cells are selected to mutate more often and this genetic instability both speeds their evolution and makes them more vulnerable. We use the advanced genetics and molecular biology of the baker?s yeast to study how genetic instability arises and how cells evolve to cope with it.
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