Natural variation in the zinc-finger-encoding exon of Prdm9 affects hybrid sterility phenotypes in mice

PRDM9-mediated reproductive isolation was first described in the progeny of Mus musculus musculus (MUS) PWD/Ph and Mus musculus domesticus (DOM) C57BL/6J inbred strains. These male F1-hybrids fail to complete chromosome synapsis and arrest meiosis at prophase I, due to incompatibilities between the Prdm9 gene and hybrid sterility locus Hstx2. We identified fourteen alleles of Prdm9 in Exon 12, encoding the DNA-binding domain of the PRDM9 protein in outcrossed wild mouse populations from Europe, Asia, and the Middle East, eight of which are novel. The same Prdm9 allele was found in all mice bearing introgressed t-haplotypes, encompassing Prdm9 and inversions preventing recombination with wildtype Chr 17. We asked whether seven novel Prdm9 alleles in MUS populations and the t-haplotype allele in one MUS and three DOM populations induce Prdm9-mediated reproductive isolation. The results show that only combinations of the dom2 allele of DOM origin and the MUS msc1 allele ensure complete infertility of intersubspecific hybrids outside the context of inbred mouse strains. The results further indicate that the erasure of PRDM9 msc1 binding motifs may be shared by MUS mice from populations with different Prdm9 alleles, implicating that erased PRDM9 binding motifs may be uncoupled from their corresponding PRDM9 zinc finger arrays at the population level. Our data corroborate the model of Prdm9-mediated hybrid sterility beyond inbred strains of mice and suggest that sterility alleles of Prdm9 may be rare.