Mutational activity of meiotic recombination

Recombination occurs in small localized regions 0.5-2 kilobases in size known as hotspots. Hotspot activity is highly variable among different individuals. Models about recombination hotspots are incomplete and controversial with several bizarre findings such as the hotspot paradox, rapid hotspot turnover during evolution and what appear to be heritable shifts in how hotspots are recruited for recombination. It has been argued that recombination leads to de novo mutations. Mutations could be an important driver of sequence evolution and influence hotspot activity. The observation that recombination is mutagenic is based on indirect sequence comparisons that have been quite controversial. The aim of this proposal is to experimentally investigate the mutagenic activity of meiosis in humans. Specifically, the number of new mutations introduced in recombination products will be measured and counted. The study includes the study of mutations in both crossovers and conversion products. These measurements will provide for the first time experimental verification whether recombination is mutagenic in humans. The results will be integrated into models of hotspot turnover and sequence evolution. This proposal addresses a small piece of the complexity of recombination hotspots, but it is crucial for understanding the bigger picture of what factors might influence recombination activity and its evolution.