Natural variation in Prdm9 affecting hybrid sterility phenotypes

Abstract PRDM9-mediated reproductive isolation was first described in offspring of Mus musculus musculus strain PWD/Ph and Mus musculus domesticus strain C57BL/6J. Male F 1 -hybrids do not complete chromosome synapsis and arrest meiosis at Prophase I. Currently, all data supports an oligogenic control of hybrid sterility based on incompatibilities between PRDM9 and hybrid-sterility locus Hstx2 in Mus musculus hybrids. Erosion of PRDM9 binding sites was proposed to result in asymmetric binding on diverged homologs of intersubspecific F 1 hybrids. Numerous alleles of Prdm9 have been characterized for different subspecies of Mus musculus , but only a few were analyzed for their impact on hybrid sterility. We analyzed Prdm9 diversity in natural wild mouse populations from Europe, Asia, and the Middle East and identified several novel Prdm9 alleles. We established that a single Prdm9 allele is associated with t -haplotype Chromosome 17 in all three subspecies of Mus musculus and characterized the phylogenetic relationships of novel Prdm9 alleles with established sterility alleles. Novel wild Prdm9 alleles produced F 1 -hybrid male offspring that were either fertile or showed Prdm9 -dependent reduction of fertility and high levels of asynapsis. Fertility or sterility phenotypes segregated purely with the Prdm9 genotype, although the Mus musculus musculus background varied. Our data substantiate that hybrid sterility is under oligogenic control with Prdm9 as the leading player but is consistent with a nonbinary regulation of hybrid sterility and gradual fertility decline when homologs diverge.