Interference with Prdm9-controlled meiotic chromosome asynapsis overrides hybrid sterility in mice

The infertility of hybrids between closely related (sub)species is one of the early reproductive isolation mechanisms leading to speciation. Since the genetic control of hybrid sterility (HS) is complex, only a few HS genes have been identified so far, including Prdm9, the only known vertebrate HS gene. Prdm9 causes infertility in male hybrids between PWD/Ph and C57BL/6J mouse strains derived from Mus m. musculus and Mus m. domesticus subspecies. However, within species Prdm9 determines the sites of programmed DNA double-strand breaks (DSBs) and meiotic recombination hotspots. In sterile hybrids, different PRDM9 variants do not bind both homologous chromosomes equally, suggesting that the asymmetry or lack of symmetry of binding sites could explain the failure of meiotic chromosomes to synapse. To investigate the relation between asynapsis and meiotic arrest, we prepared intersubspecific hybrids with stretches of consubspecific homology on several pairs of autosomes and analyzed their ability to form synaptonemal complexes. Eight examined autosomes with more than 27 Mb of consubspecific homology fully restored their synapsis and we predicted that a minimum of two symmetric DSBs per chromosome are necessary for successful meiosis. Moreover, targeted suppression of asynapsis in four chromosomes most sensitive to asynapsis partially rescued spermatogenesis, thus pointing to chromosomal quality of hybrid sterility. We hypothesize that reduced ability of meiotic chromosomes to synapse, determined by impaired recombination between evolutionary diverged homologous chromosomes could function as an ancient mechanism of hybrid sterility occurring in various sexually reproducing species.