Genetic Dissection of Quantitative Control of Recombination

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DESCRIPTION (provided by applicant): The central question addressed in this proposal is to identify the nature of a regulatory system controlling the quantitative activity of recombination hotspots during mammalian meiosis, a system of whose significant features remain largely unexplained. Meiosis is essential, assuring continued reproductive success of a species. Gaining a further understanding of the genetic system behind this regulation has substantial implications on public health. Failure to properly execute meiosis can result in aneuploid gametes causing the majority of spontaneously aborted pregnancies and sterility in humans. Meiosis is responsible for the shuffling of genetic material between generations and the positions of meiotic recombination determine the blocks of inheritance in human populations. To date the only known regulator of hotspots, Prdm9, functions qualitatively by directing the position of recombination along chromosomes. In contrast, the identity of the trans-acting quantitative regulatory genes influencing the rate of recombination at hotspots remains unknown. Experiments outlined here will remedy this deficit by combining the power of mouse genetics with an innovative method to accurately measure the products of recombination by leveraging high-throughput DNA sequencing to map these quantitative regulatory genes. Additional genetic strategies will be applied to survey the naturally occurring allelic diversity found in mice for modifiers of Prdm9 activities and differentiate between Prdm9- dependent and independent pathways. Together, results from these experiments will further advance our understanding of the system controlling the position and relative activates of mammalian recombination hotspots. PUBLIC HEALTH RELEVANCE: Meiosis is a specialized developmental process, required for sexual reproduction, giving rise to germ cells (sperm and egg). Aberrant meiosis results in the majority of spontaneous abortions in human pregnancies due to improper disjunction of chromosomes during a process called meiotic recombination. Research set out in this proposal seeks to identify the underlying genetic regulatory system controlling the position and rate of meiotic recombination.