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 last few months we have been able to generate a genome-wide map for hotspots for double-strand breaks in mouse meiosis by using ChIP-Seq for Dmc1 and Rad51 foci, both of which mark these sites. Depending on the level of stastical significance as many as 40,000 of these hotspots can be enumerated and a large majority of both Rad51 and Dmc1 sites are identical.

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Brick, Kevin; Pratto, Florencia; Sun, Chi-Yu et al. (2018) Analysis of Meiotic Double-Strand Break Initiation in Mammals. Methods Enzymol 601:391-418
Thibault-Sennett, Sarah; Yu, Qi; Smagulova, Fatima et al. (2018) Interrogating the Functions of PRDM9 Domains in Meiosis. Genetics 209:475-487
Dai, Jieqiong; Voloshin, Oleg; Potapova, Svetlana et al. (2017) Meiotic Knockdown and Complementation Reveals Essential Role of RAD51 in Mouse Spermatogenesis. Cell Rep 18:1383-1394
Fayer, Shawn; Yu, Qi; Kim, Joongbaek et al. (2016) Robertsonian translocations modify genomic distribution of ?H2AFX and H3.3 in mouse germ cells. Mamm Genome 27:225-36
Smagulova, Fatima; Brick, Kevin; Pu, Yongmei et al. (2016) Erratum: The evolutionary turnover of recombination hot spots contributes to speciation in mice. Genes Dev 30:871
Davies, Benjamin; Hatton, Edouard; Altemose, Nicolas et al. (2016) Re-engineering the zinc fingers of PRDM9 reverses hybrid sterility in mice. Nature 530:171-6
Smagulova, Fatima; Brick, Kevin; Pu, Yongmei et al. (2016) The evolutionary turnover of recombination hot spots contributes to speciation in mice. Genes Dev 30:266-80
Pratto, Florencia; Brick, Kevin; Khil, Pavel et al. (2014) DNA recombination. Recombination initiation maps of individual human genomes. Science 346:1256442
Smagulova, Fatima; Brick, Kevin; Pu, Yongmei et al. (2013) Suppression of genetic recombination in the pseudoautosomal region and at subtelomeres in mice with a hypomorphic Spo11 allele. BMC Genomics 14:493
Khil, Pavel P; Smagulova, Fatima; Brick, Kevin M et al. (2012) Sensitive mapping of recombination hotspots using sequencing-based detection of ssDNA. Genome Res 22:957-65

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