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2011), and, in turn, the cellular machinery that creates DSBs is thought to be recruited ( Baudat et al. PRDM9 trimethylates histone H3 at Lys4 ( Hayashi et al. DNA sequence-specific binding of PRDM9 dictates hot spot locations, and this binding specificity is conferred by multiple adjacent zinc fingers (ZFs), each of which recognizes a preferred DNA sequence. In most mammals, meiotic DSBs are targeted to a small subset of genomic loci, known as hot spots, by the histone-lysine N-methyltransferase PRDM9 protein ( Baudat et al. Each DSB is subsequently repaired as either a crossover, where there is a reciprocal exchange between parental chromosomes, or a noncrossover, where a nonreciprocal exchange known as a gene conversion occurs. Recombination is initiated by the formation of DNA double-strand breaks (DSBs), and this triggers a search for homologous DNA sequence that leads to the pairing and synapsis of homologous chromosomes. Meiotic recombination ensures accurate segregation of homologous chromosomes during meiosis and drives genetic diversity in sexually reproducing organisms. As crossovers are disfavored at such hot spots, we propose that sequence divergence generated by hot spot turnover may create an impediment for recombination in hybrids, potentially leading to reduced fertility and, eventually, speciation. We found that hot spot erosion governs the preferential usage of some Prdm9 alleles over others in hybrid mice and increases sequence diversity specifically at hot spots that become active in the hybrids. To better understand the evolutionary turnover of recombination hot spots and its consequences, we mapped DSB hot spots in four major subspecies of Mus musculus with different Prdm9 alleles and in their F1 hybrids. Rapid evolution of the DNA-binding specificity of PRDM9 and gradual erosion of PRDM9-binding sites by gene conversion will alter the recombination landscape over time. In most mammals, the DNA double-strand breaks (DSBs) that initiate meiotic recombination are directed to a subset of genomic loci (hot spots) by sequence-specific binding of the PRDM9 protein. Meiotic recombination is required for the segregation of homologous chromosomes and is essential for fertility.