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Genetic recombination is directed away from functional genomic elements in mice

Abstract

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.

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Acknowledgements

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

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Authors

Contributions

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). https://doi.org/10.1038/nature11089

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