Genetic Modifiers of Hybrid Sterility during Meiosis in Subspecies of Mice (Mus musculus)

The exchange of genetic material between homologous chromosomes during meiosis is controlled by the protein “PR-domain containing 9” (PRDM9). The C2H2 zinc-finger domain of PRDM9 recognizes specific DNA sequence and initiate meiotic recombination. This domain is highly diverse and this diversity has been implicated in reproductive isolation, discovered in hybrids of laboratory inbred Mus musculus domesticus C57BL/6J (B6) and Mus musculus musculus PWD/Ph (PWD) strains. With several backcrossing experiments, “hybrid sterility on the X-chromosome”(Hstx2) was identified, which plays a role in hybrid sterility together with PRDM9. The mechanism of how PRDM9 and Hstx2 interact and leads to hybrid sterility is, however, not understood. This thesis aimed at investigating the role of the wild Prdm9 alleles in hybrid sterility in Mus musculus musculus and Mus musculus domesticus hybrids and to understand the function of Hstx2 in normal meiosis. I first determined the natural diversity of the zinc finger domain of PRDM9 in both subspecies of mice. This identified also a particular wild Prdm9 allele that is associated with chromosome 17 introgressed regions, called t-haplotypes, which we characterized in depth. To uncover whether wild Prdm9 alleles induce hybrid sterility I generated intersubspecific hybrids and measured their fertility, using as testis weight and sperm count as parameters. This revealed that all tested Prdm9 alleles found in wild mice don’t induce hybrid sterility. We also uncovered that hybrid sterility is nevertheless under major Prdm9 control, as Dom2 and MSc1, does induce hybrid sterility, even if the genetic background is partially wild. Furthermore, I tested whether “Hstx2” affects recombination in normal meiosis. I measured the testis expression of the Hstx2 candidate locus, the miRNA _465 cluster, and its computationally predicted target genes, using a droplet digital PCR (ddPCR) s. We revealed higher microRNA expression in mice with the sterility allele (Hstx2PWD), compared to mice with the fertility allele (Hstx2B6). Here, the two Hstx2 alleles differentially affected the expression of target genes active at the initiation of recombination.


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