Linda Odenthal-Hesse

January 12, 2022

Please refer to and contact Linda <> for further information on the projects.

(Epi)genetic control of meiotic recombination

Project 1

While nearly all eukaryotic organisms reproduce sexually and genetic recombination is universally present – the regulation of meiotic recombination has remained enigmatic. Regulatory proteins and entire pathways involved in repairing meiotic double-stranded DNA breaks appear highly conserved across metazoans and are largely involved also in mitotic DNA repair. However, this high level of conservation creates a conundrum because eukaryotic genomes have meanwhile evolved tremendously to differ in size, ploidy, repeat content, complexity, and higher-order chromatin structure. Genetic and epigenetic factors are emerging in critical roles regulating the correct placement of meiotic recombination. The offered research projects are situated at the interface of genetics and epigenetics and aim to understand the evolution, specificity, and plasticity of meiotic recombination regulation across time and space.

Meiotic recombination is a highly variable phenotype, and modifiers of recombination rate evolve rapidly and segregate in natural populations. Project 1 requires previous bioinformatic training and characterizes the diversity and evolution of newly identified candidate meiotic recombination regulators in mice and humans. Here you will initially analyse existing epigenetic and genomic data, including Chromatin-Immunoprecipitation sequencing (ChIP-seq) and transcriptomic datasets to characterize protein evolution in-silico. Furthermore, you will test whether successful recombination and repair are impacted different protein variants with diverse genotypes are combined via crossing experiments. You will then test the impact of varying combinations of factors on the chromatin landscape and meiotic transcriptome.

Project 2

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.

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