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). As the HapMap is the major resource being used for Genome-Wide Association Studies (GWAS) knowing how well historic recombination is reflected in recombination in current individuals is important in assessing the strength of these associations. Recently, we have computed historic recombination maps for several populations. We have shown that although for a given population we find only about 60% of present-day recombination (crossovers) at recombination hotspots (roughly equivalent to the edges of haplotype blocks) in the historical computed map, nearly all crossovers in present-day individuals are predicted by including computed hotspots from several populations (Khil and Camerini-Otero (2010) PLoS Genetics 6, 1). We have hypothesized that this reflects the existence of a universal human recombinome. In the last two years 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 even though these sites are well-known to be marked by H3K4 trimethylation. Thus, H3K4 trimethylation per se is not a sufficient mark for directing the meiotic double-strand break machinery.

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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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