Genome-wide analysis reveals novel molecular features of mouse recombination hotspots

Meiotic recombination predominantly occurs at discrete genomic loci called recombination hotspots, but the features defining these areas are still largely unknown (reviewed in1-5). To enable a comprehensive analysis of hotspot-associated DNA and chromatin characteristics we developed a direct molecular approach for mapping meiotic DNA double stranded breaks that initiate recombination. Here, we present the genome-wide distribution of recombination initiation sites in the mouse genome, constituting the first physical map of recombination hotspots in a multi-cellular organism. Hotspot centres are mapped with approximately 200-nucleotide precision that enables analysis of the fine structural details of the preferred recombination sites. We determine that hotspots share a centrally distributed consensus motif, possess a nucleotide skew that changes polarity at the centre of hotspots, and have an intrinsic preference to be occupied by a nucleosome. Furthermore, we find that the vast majority of recombination initiation sites in mouse males are associated with testis-specific trimethylation of lysine 4 on histone H3 that is distinct from histone H3 lysine 4 trimethylation marks associated with transcription. The recombination map presented here has been derived from a homogeneous mouse population with a defined genetic background and therefore, lends itself to extensive future experimental exploration. Importantly, the mapping technique developed here does not depend on availability of genetic markers and hence can be easily adapted for other species with complex genomes. Our findings uncover several fundamental features of mammalian recombination hotspots and underline the power of the new recombination map for future studies of genetic recombination, genome stability and evolution.