Cellular factors modulating recombination – PolARe

Homologous recombination (HR) is a major and ubiquitous DNA repair mechanism. It is essential to maintain genome integrity throughout the cell cycle and plays a key role in genome dynamics by generating gene conversions (loss of heterozygosity (LOH) regions) associated or not with crossovers. Most mechanistic studies on homologous recombination did not address in detail the effects of sequence polymorphism, a naturally occurring property of the genome, nor replicative and chronological cell age, properties of the cell. Here, we will address these knowledge gaps primarily through the characterization of mitotic and meiotic genome-wide recombination patterns in designed Saccharomyces cerevisiae hybrids with varying levels of heterozygosity. Comparison of recombination patterns from cells proficient and deficient for the mismatch repair (MMR) machinery will inform on the types and densities of sequence polymorphisms required to drive the anti-recombinogenic effect of MMR. Through both replicative lifespan and chronological lifespan-based experiments, comparison of recombination patterns from young and old cells will inform on the recombination defects in old cells and their implication in triggering genomic instability. Finally, through sequence analysis around recombination hotspots and haplotypes boundaries across the S. cerevisiae population, we will project our findings into a population genomics framework to infer how recombination has shaped genome evolution and use genome editing to test such predictions. Overall, based on extensive preliminary results and proven expertise, we have the ambition to unveil the interplay between DNA sequence Polymorphisms, Aging and Recombination (PolARe).