Spatial regulation of meiotic recombination (360G-Wellcome-200843_Z_16_Z)

Our goal is to understand the mechanisms regulating the spatial distribution of genetic recombination during meiosis—a specialised cell division responsible for genome haploidisation during gametogenesis. We recently demonstrated that the distribution of meiotic DNA breaks (DSBs)—the precursors of genetic recombination—is non-random, being regulated by the evolutionarily-conserved DNA damage response (DDR) checkpoint protein Tel1 (ATM in mammals). In this proposal we will build upon this ground-breaking work, to test the manner in which chromosome structure shapes the distribution of meiotic recombination. First, we will determine the genome-wide distribution of clustered DSBs that arises when Tel1 activity is absent, and determine the functional association of such sites with higher-order chromosome loop structures. Second, we will monitor the 3D organisation of meiotic chromosomes, and of loop subdomains, and relate this information, mechanistically, to the location and spatial distribution of recombination. Third, we will investigate Tel1-independent mechanisms of spatial regulation, specifically testing the hypothesis that chromatin loop "clustering" mediates local DSB suppression. In many organisms, including humans, control of the initiation and spatial distribution of recombination is critical to both reproductive and evolutionary success. Our proposed work programme will shed mechanistic insight into the regulation of this fundamental process.