Pathology Presents: Genetic Entropy and the Evolution of Mutation Rate: Implications for Cancer

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Speaker

Alan Herr, PhD
Research Assistant Professor
Department of Pathology
University of Washington

Faculty Sponsor

Larry Loeb, MD, PhD


Date & Time

March 2, 2016 at 4:30pm - 5:30pm

Location

Health Sciences Building, T-739

Calendar

Pathology Presents

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Add to Calendar 03/02/2016 04:30 PM 03/02/2016 05:30 PM America/Los_Angeles Pathology Presents: Genetic Entropy and the Evolution of Mutation Rate: Implications for Cancer Pathology Presents: Genetic Entropy and the Evolution of Mutation Rate: Implications for Cancer

Alan Herr, PhD
Research Assistant Professor
Department of Pathology
University of Washington
Why Attend? Genetic Entropy and the Evolution of Mutation Rate: Implications for Cancer Microbes or human cancer cells with a “mutator phenotype” evolve novel traits more rapidly due to defects in DNA replication fidelity or DNA repair.  But such mutators suffer from genetic entropy, defined as the random accumulation of deleterious mutations.  At the extreme, excessive genetic entropy can drive extinction of mutator clones.  We have used the budding yeast, Saccharomyces cerevisiae, to model mutator genotypes found in human cancers and to define the maximum mutation rate of haploid and diploid cells.  We find that the number of essential genes determines the threshold for extinction in both haploids and diploids.  Intriguingly, the maximum mutation burden of diploid yeast cells mirrors that found in some mutator-driven malignancies, suggesting that these cancer cells exist near an extinction threshold.  We also find that excessive genetic entropy provides strong selection pressure for mutants that either attenuate the mutator phenotype or buffer cells from the mutations.  We hope to use the “antimutator” mutants to investigate our recent discovery that mutator cells can adopt different mutator states as they pass through the cell cycle.  Understanding what determines this volatility may provide new insight into how to treat mutator-driven malignancies.
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Description

Why Attend?

Genetic Entropy and the Evolution of Mutation Rate: Implications for Cancer

Microbes or human cancer cells with a “mutator phenotype” evolve novel traits more rapidly due to defects in DNA replication fidelity or DNA repair.  But such mutators suffer from genetic entropy, defined as the random accumulation of deleterious mutations.  At the extreme, excessive genetic entropy can drive extinction of mutator clones.  We have used the budding yeast, Saccharomyces cerevisiae, to model mutator genotypes found in human cancers and to define the maximum mutation rate of haploid and diploid cells.  We find that the number of essential genes determines the threshold for extinction in both haploids and diploids.  Intriguingly, the maximum mutation burden of diploid yeast cells mirrors that found in some mutator-driven malignancies, suggesting that these cancer cells exist near an extinction threshold.  We also find that excessive genetic entropy provides strong selection pressure for mutants that either attenuate the mutator phenotype or buffer cells from the mutations.  We hope to use the “antimutator” mutants to investigate our recent discovery that mutator cells can adopt different mutator states as they pass through the cell cycle.  Understanding what determines this volatility may provide new insight into how to treat mutator-driven malignancies.