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Genome-wide analysis reveals novel molecular features of mouse recombination hotspots

Abstract

Meiotic recombination predominantly occurs at discrete genomic loci called recombination hotspots, but the features defining these areas are still largely unknown (reviewed in refs 1–5). To allow a comprehensive analysis of hotspot-associated DNA and chromatin characteristics, we developed a direct molecular approach for mapping meiotic DNA double-strand breaks that initiate recombination. Here we present the genome-wide distribution of recombination initiation sites in the mouse genome. Hotspot centres are mapped with approximately 200-nucleotide precision, which allows analysis of the fine structural details of the preferred recombination sites. We determine that hotspots share a centrally distributed consensus motif, possess a nucleotide skew that changes polarity at the centres of hotspots and have an intrinsic preference to be occupied by a nucleosome. Furthermore, we find that the vast majority of recombination initiation sites in mouse males are associated with testis-specific trimethylation of lysine 4 on histone H3 that is distinct from histone H3 lysine 4 trimethylation marks associated with transcription. The recombination map presented here has been derived from a homogeneous mouse population with a defined genetic background and therefore lends itself to extensive future experimental exploration. We note that the mapping technique developed here does not depend on the availability of genetic markers and hence can be easily adapted to other species with complex genomes. Our findings uncover several fundamental features of mammalian recombination hotspots and underline the power of the new recombination map for future studies of genetic recombination, genome stability and evolution.

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Figure 1: DSB hotspots in the mouse genome.
Figure 2: Characteristics of mouse DSB hotspots.
Figure 3: Specific H3K4me3 marks are associated with DSB hotspots.

Accession codes

Primary accessions

GenBank/EMBL/DDBJ

Gene Expression Omnibus

Data deposits

ChIP-Seq data have been deposited in the Gene Expression Omnibus under accession number GSE24438. Prdm9 complementary DNA sequences have been deposited in GenBank under accession numbers HQ704390 and HQ704391.

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Acknowledgements

We thank M. Lichten (NCI, NIH) and P. Hsieh (NIDDK, NIH) for comments and discussion. We are grateful to S. Sharmeen for her help with high-throughput sequencing. This work was supported in part by 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.); New Investigator Start-up Grants FS71HU, R071HU and CS71HU from USUHS (G.V.P.); and the NIDDK (NIH) Intramural Research Program (R.D.C.-O.).

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Authors and Affiliations

Authors

Contributions

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

The file contains Supplementary Text, Supplementary Figures 1-16 with legends, Supplementary Table 1, Supplementary Methods and Materials and additional references. (PDF 2679 kb)

Supplementary Data

This data file contains listings of the DSB hotspots. (XLS 585 kb)

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Smagulova, F., Gregoretti, I., Brick, K. et al. Genome-wide analysis reveals novel molecular features of mouse recombination hotspots. Nature 472, 375–378 (2011). https://doi.org/10.1038/nature09869

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