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1. Modifiers of meiotic NAHR and de-novo Copy Number Change
Recombination is a process that influences genetic variability and the efficacy of selection. Despite its essential role, recombination is an extremely variable phenotype. Modifiers of recombination rate evolve rapidly and segregate in natural populations. One of the most variable modifiers of recombination rate is the meiotic methyltransferase PRDM9, which marks specific sites for chromatin remodelling by epigenetic modifications. As a consequence of the rapid evolution of the DNA binding domain of PRDM9, dramatic reshuffling of recombination landscapes occurs over short evolutionary time scale, and even between individuals within the same population. Such newly evolved recombination landscapes can be selectively disadvantageous. PRDM9 only specifies the locations of recombination hotspots, but also minisatellites targeted for instability as well as rearrangement hotspots for nonallelic homologous recombination (NAHR). In order to gain an understanding of meiotic NAHR, we want to investigate PRDM9 mediated Copy Number Variation (CNV) hotspots.
2. The crossover/noncrossover decision in Prdm9 and Hstx2 mediated hybrid sterility
Reproductive isolation is a mechanism promoting speciation. Postzygotic isolation, and specifically the breakdown of meiosis is the main mechanisms responsible for hybrid sterility in mice, which appears to be under oligogenic control. Prdm9 remains the only characterized hybrid sterility gene identified to date in vertebrates. It interacts with a second hybrid sterility locus on the X-chromosome Hstx2, which modulates the extent of Prdm9-dependent F1 hybrid sterility and the frequency of global meiotic recombination. Male sterility of (PWD x B6) F1 hybrids is thus conferred by three factors, PRDM9, Hstx2 and autosomal heterozygosity. However, the underlying gene(s) and the precise role of the Hstx2 locus in hybrid male sterility remains elusive. PRDM9 mediated hybrid sterility, that is modulated by Hstx2, shows a distinct chromosome asynapsis phenotype at Prophase I of meiosis. Synapsis, in turn, appears dependent on non-crossover gene conversion, which occurs at ten-fold increased frequencies compared to crossover. In addition to initiation biases, Prdm9 and Hstx2 may possibly affect the crossover/non-crossover decision. Given that the crossover formation is not influenced by Hstx2, the effect may be on non-crossover resolution rather than on crossover resolution. Studying non-crossovers in addition to crossovers will reveal whether the approximate proportionality of breaks resolved as crossovers and non-crossovers, and whether a crossover independent pathway is active.