Miguel Costa Coelho
Date: January 18, 2018. 11:00
Title: Experimental evolution of genetic instability: accelerating and controlling adaptation.
Affiliation: Department of Molecular an Celular Biology, Harvard University, USA.
Genetic instability, defined as an increase in the mutation rate, accelerates evolutionary adaptation and is universal in cancer. In mammals, instability is thought to arise primarily from inactivating or removing both copies of genes which function in DNA metabolism and cell cycle regulation. Repeatedly selecting for adaptive mutations selects for genetically unstable mutants in E. coli. I modified this approach to ask if single mutations could cause genetic instability in diploid strains of the budding yeast,Saccharomyces cerevisiae: I selected for the sequential inactivation of three groups of genes that can inhibit yeast proliferation. Our selection produced clones with increased point mutation, mitotic recombination, and chromosome loss rates. Genetic analysis identified candidate, heterozygous mutations. When these were engineered, individually, into the ancestral, genetically stable, diploid strain, they caused genetic instability. The genes harboring causative mutations were enriched for genes functioning in transport, protein quality control, and DNA metabolism, they differ from genes found in previous screens for genetic instability, and they include essential genes and homologs implicated in human cancer. I conclude that single genetic events can cause genetic instability in diploid yeast cells, and propose that similar, single-hit, mutations may initiate genetic instability in cancer. A human-based experimental evolution system to understand the role of instability during cancer development will be discussed, together with a small-molecule handles to quench adaptation and treatment resistance.