A universally observed feature of meiotic recombination is a highly non-uniform distribution of meiotic crossovers across the genome. Although it has become evident that hotspots of recombination are relatively unstable in evolution, the magnitude of the variation of recombination profiles on a genome-wide scale is unknown. To study the underlying mechanisms responsible for the birth, life and death of recombination hotspots we decided to estimate the genome-wide variation in profiles of recombination. This has become possible due to the recent confluence of two major developments: improvements in the computational approaches to calculate genome-wide recombination profiles from linkage disequilibrium data and the availability of a very dense catalog of genetic markers (single nucleotide polymorphisms, SNPs) in human beings (phase I of the HapMap, 106 SNPs). We found that a large fraction of hotspots of recombination varies between the four populations sampled by the HapMap project. Next, we showed that many (25%) present-day crossovers in one population are located in regions without historical hotspots. We conclude that profiles of human meiotic recombination are quickly changing over time. This absence-or-presence polymorphism of recombination hotspots is unlikely due to local DNA sequence variation but most likely reflects DNA sequence changes in distant elements or epigenetic factors. We are in the process of mapping the variability of the hotspots (epigenetic map) and/or the genetic determinants in trans responsible for this variability by generating a higher resolution recombination hotspot map from the phase II HapMap (5X106 SNPs) and from the ENCODE regions. Recently, we have expanded our analysis to a comparison of mouse and human recombination profiles comparing the human recombination profile computed from the HapMap at low resolution to the available mouse profiles from genetic maps. In the 18 months we have been able to generate a genome-wide map for hotspots for double-strand breaks in mouse meiosis by using Solexa/Illumina ChIP-Seq for Dmc1 and Rad51 foci, both of which mark these sites (all in collaboration with the laboratory of Galina Petukhova at the Department of Biochemistry and Molecular Biology at the Uniformed Services University of Health Sciences. Depending on the level of statistical significance as many as 40,000 of these hotspots can be enumerated and a large majority of both Rad51 and Dmc1 sites are identical. About 10,000 of these hotspots have a high degree of statistical significance. Compared to the LD recombination that has an accuracy of about 5 KB, our physical recombination map, the first for any multicellular organism, has an accuracy of about 200 bp. Using such a map has allowed to identify novel structural features for recombination hotspots. For example, we determined that recombination hotspots share a centrally distributed consensus motif (in the vast majority of hotspots), possess a nucleotide skew that changes polarity at the center of the hotspots, and have both a calculated and experimental preference to be occupied by a nucleosome. Finally, we find that the vast majority of recombination hotspots in mice are associated with testis-specific H3K4 trimethylation that do not overlap transcription start sites.
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