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Genetic recombination is directed away from functional genomic elements in mice


Genetic recombination occurs during meiosis, the key developmental programme of gametogenesis. Recombination in mammals has been recently linked to the activity of a histone H3 methyltransferase, PR domain containing 9 (PRDM9)1,2,3,4,5,6, the product of the only known speciation-associated gene in mammals7. PRDM9 is thought to determine the preferred recombination sites—recombination hotspots—through sequence-specific binding of its highly polymorphic multi-Zn-finger domain8. Nevertheless, Prdm9 knockout mice are proficient at initiating recombination9. Here we map and analyse the genome-wide distribution of recombination initiation sites in Prdm9 knockout mice and in two mouse strains with different Prdm9 alleles and their F1 hybrid. We show that PRDM9 determines the positions of practically all hotspots in the mouse genome, with the exception of the pseudo-autosomal region (PAR)—the only area of the genome that undergoes recombination in 100% of cells10. Surprisingly, hotspots are still observed in Prdm9 knockout mice, and as in wild type, these hotspots are found at H3 lysine 4 (H3K4) trimethylation marks. However, in the absence of PRDM9, most recombination is initiated at promoters and at other sites of PRDM9-independent H3K4 trimethylation. Such sites are rarely targeted in wild-type mice, indicating an unexpected role of the PRDM9 protein in sequestering the recombination machinery away from gene-promoter regions and other functional genomic elements.

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Figure 1: DSB hotspots localize to different loci in 9R and 13R mice.
Figure 2: PRDM9 redirects DSBs away from functional genomic elements.
Figure 3: PRDM9-independent hotspots in the PAR and flanking region.
Figure 4: Proposed role of the PRDM9 protein.

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Primary accessions

Gene Expression Omnibus

Data deposits

All data sets are fully described and available for download from the GEO under accession number GSE35498.


  1. Parvanov, E. D., Petkov, P. M. & Paigen, K. Prdm9 controls activation of mammalian recombination hotspots. Science 327, 835 (2010)

    Article  CAS  ADS  Google Scholar 

  2. Myers, S. et al. Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination. Science 327, 876–879 (2010)

    Article  CAS  ADS  Google Scholar 

  3. Baudat, F. et al. PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. Science 327, 836–840 (2010)

    Article  CAS  ADS  Google Scholar 

  4. Berg, I. L. et al. PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans. Nature Genet. 42, 859–863 (2010)

    Article  CAS  Google Scholar 

  5. Berg, I. L. et al. Variants of the protein PRDM9 differentially regulate a set of human meiotic recombination hotspots highly active in African populations. Proc. Natl Acad. Sci. USA 108, 12378–12383 (2011)

    Article  CAS  ADS  Google Scholar 

  6. Hinch, A. G. et al. The landscape of recombination in African–Americans. Nature 476, 170–175 (2011)

    Article  CAS  ADS  Google Scholar 

  7. Mihola, O., Trachtulec, Z., Vlcek, C., Schimenti, J. C. & Forejt, J. A mouse speciation gene encodes a meiotic histone H3 methyltransferase. Science 323, 373–375 (2009)

    Article  CAS  ADS  Google Scholar 

  8. Grey, C. et al. Mouse PRDM9 DNA-binding specificity determines sites of histone H3 lysine 4 trimethylation for initiation of meiotic recombination. PLoS Biol. 9, e1001176 (2011)

    Article  CAS  Google Scholar 

  9. Hayashi, K., Yoshida, K. & Matsui, Y. A histone H3 methyltransferase controls epigenetic events required for meiotic prophase. Nature 438, 374–378 (2005)

    Article  CAS  ADS  Google Scholar 

  10. Burgoyne, P. S. Genetic homology and crossing over in the X and Y chromosomes of mammals. Hum. Genet. 61, 85–90 (1982)

    Article  CAS  Google Scholar 

  11. Neale, M. J. & Keeney, S. Clarifying the mechanics of DNA strand exchange in meiotic recombination. Nature 442, 153–158 (2006)

    Article  CAS  ADS  Google Scholar 

  12. Smagulova, F. et al. Genome-wide analysis reveals novel molecular features of mouse recombination hotspots. Nature 472, 375–378 (2011)

    Article  CAS  ADS  Google Scholar 

  13. Khil, P. P., Smagulova, F., Brick, K. M., Camerini-Otero, R. D. & Petukhova, G. V. Sensitive mapping of recombination hotspots using sequencing-based detection of ssDNA. Genome Res. (2012)

  14. Borde, V. et al. Histone H3 lysine 4 trimethylation marks meiotic recombination initiation sites. EMBO J. 28, 99–111 (2009)

    Article  CAS  Google Scholar 

  15. Buard, J., Barthès, P., Grey, C. & de Massy, B. Distinct histone modifications define initiation and repair of meiotic recombination in the mouse. EMBO J. 28, 2616–2624 (2009)

    Article  CAS  Google Scholar 

  16. Guenther, M. G., Levine, S. S., Boyer, L. A., Jaenisch, R. & Young, R. A. A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130, 77–88 (2007)

    Article  CAS  Google Scholar 

  17. Ernst, J. et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473, 43–49 (2011)

    Article  CAS  ADS  Google Scholar 

  18. Pekowska, A. et al. H3K4 tri-methylation provides an epigenetic signature of active enhancers. EMBO J. 30, 4198–4210 (2011)

    Article  CAS  Google Scholar 

  19. Tan, M. et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146, 1016–1028 (2011)

    Article  CAS  Google Scholar 

  20. Pan, J. et al. A hierarchical combination of factors shapes the genome-wide topography of yeast meiotic recombination initiation. Cell 144, 719–731 (2011)

    Article  CAS  Google Scholar 

  21. Wu, T. C. & Lichten, M. Meiosis-induced double-strand break sites determined by yeast chromatin structure. Science 263, 515–518 (1994)

    Article  CAS  ADS  Google Scholar 

  22. Kauppi, L. et al. Distinct properties of the XY pseudoautosomal region crucial for male meiosis. Science 331, 916–920 (2011)

    Article  CAS  ADS  Google Scholar 

  23. Oliver, P. L. et al. Accelerated evolution of the Prdm9 speciation gene across diverse metazoan taxa. PLoS Genet. 5, e1000753 (2009)

    Article  Google Scholar 

  24. Bellott, D. W. & Page, D. C. Reconstructing the evolution of vertebrate sex chromosomes. Cold Spring Harb. Symp. Quant. Biol. 74, 345–353 (2009)

    Article  CAS  Google Scholar 

  25. Lim, F. L., Soulez, M., Koczan, D., Thiesen, H. J. & Knight, J. C. A KRAB-related domain and a novel transcription repression domain in proteins encoded by SSX genes that are disrupted in human sarcomas. Oncogene 17, 2013–2018 (1998)

    Article  CAS  Google Scholar 

  26. Margolin, J. F. et al. Krüppel-associated boxes are potent transcriptional repression domains. Proc. Natl Acad. Sci. USA 91, 4509–4513 (1994)

    Article  CAS  ADS  Google Scholar 

  27. Axelsson, E. et al. Death of PRDM9 coincides with stabilization of the recombination landscape in the dog genome. Genome Res. 22, 51–63 (2012)

    Article  CAS  Google Scholar 

  28. Muñoz-Fuentes, V., Di Rienzo, A. & Vilà, C. Prdm9, a major determinant of meiotic recombination hotspots, is not functional in dogs and their wild relatives, wolves and coyotes. PLoS ONE 6, e25498 (2011)

    Article  ADS  Google Scholar 

  29. Jothi, R., Cuddapah, S., Barski, A., Cui, K. & Zhao, K. Genome-wide identification of in vivo protein–DNA binding sites from ChIP-Seq data. Nucleic Acids Res. 36, 5221–5231 (2008)

    Article  CAS  Google Scholar 

  30. Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008)

    Article  Google Scholar 

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We thank S. Sharmeen and H. Smith for assistance with high-throughput sequencing. We also thank M. Lichten and P. Hsieh for critical discussion of the manuscript. This research was supported by the NIDDK Intramural Research Program; Basil O’Connor Starter Scholar Research Award Grant No. 5-FY07-667 from the March of Dimes Foundation (G.V.P.); NIH grant 1R01GM084104-01A1 from NIGMS (G.V.P.); and New Investigator Start-up Grants FS71HU, R071HU and CS71HU from USUHS (G.V.P.).

Author information

Authors and Affiliations



K.B. and P.K. performed data analyses. F.S. performed all experiments. K.B. and G.V.P. wrote the manuscript. G.V.P. and R.D.C.-O. designed and supervised the study. All authors contributed to experimental design, discussed the results and critiqued the manuscript.

Corresponding authors

Correspondence to R. Daniel Camerini-Otero or Galina V. Petukhova.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-14, Supplementary Materials and Methods, Supplementary Table 1 and Supplementary References. (PDF 2002 kb)

Supplementary Data

This file contains a list of meiotic DSB hotspots and H3K4me3 marks in all mouse strains. (ZIP 7400 kb)

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Brick, K., Smagulova, F., Khil, P. et al. Genetic recombination is directed away from functional genomic elements in mice. Nature 485, 642–645 (2012).

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