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

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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access

through your institution Subscribe to this journal Receive 51 print issues and online access $199.00 per year only $3.90 per issue Learn more Buy this article * Purchase on SpringerLink *

Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional

subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS 3D CHROMATIN REMODELLING IN THE GERM LINE MODULATES GENOME EVOLUTIONARY PLASTICITY Article

Open access 11 May 2022 INTERFERENCE LENGTH REVEALS REGULARITY OF CROSSOVER PLACEMENT ACROSS SPECIES Article Open access 17 October 2024 GENOME-WIDE HIGH-RESOLUTION MAPPING OF MITOTIC DNA

SYNTHESIS SITES AND COMMON FRAGILE SITES BY DIRECT SEQUENCING Article 19 June 2020 ACCESSION CODES PRIMARY ACCESSIONS GENBANK/EMBL/DDBJ * HQ704390 * HQ704391 GENE EXPRESSION OMNIBUS *

GSE24438 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. REFERENCES * Arnheim, N., Calabrese, P. & Tiemann-Boege, I. Mammalian meiotic recombination hot spots. _Annu. Rev. Genet._ 41, 369–399

(2007) Article  CAS  Google Scholar  * Buard, J. & de Massy, B. Playing hide and seek with mammalian meiotic crossover hotspots. _Trends Genet._ 23, 301–309 (2007) Article  CAS  Google

Scholar  * Lichten, M. Meiotic chromatin: the substrate for recombination initiation. _Genome Dynam. Stabil._ 3, 165–193 (2008) Article  Google Scholar  * Paigen, K. & Petkov, P.

Mammalian recombination hot spots: properties, control and evolution. _Nature Rev. Genet._ 11, 221–233 (2010) Article  CAS  Google Scholar  * Clark, A. G., Wang, X. & Matise, T.

Contrasting methods of quantifying fine structure of human recombination. _Annu. Rev. Genom. Hum. Genet._ 11, 45–64 (2010) Article  CAS  Google Scholar  * Kauppi, L., May, C. A. &

Jeffreys, A. J. Analysis of meiotic recombination products from human sperm. _Methods Mol. Biol._ 557, 323–355 (2009) Article  CAS  Google Scholar  * The. International HapMap Consortium. A

haplotype map of the human genome. _Nature_ 437, 1299–1320 (2005) * Durbin, R. M. et al. A map of human genome variation from population-scale sequencing. _Nature_ 467, 1061–1073 (2010)

Article  ADS  CAS  Google Scholar  * Frazer, K. A. et al. A second generation human haplotype map of over 3.1 million SNPs. _Nature_ 449, 851–861 (2007) Article  ADS  CAS  Google Scholar  *

Kong, A. et al. Fine-scale recombination rate differences between sexes, populations and individuals. _Nature_ 467, 1099–1103 (2010) Article  ADS  CAS  Google Scholar  * Myers, S., Bottolo,

L., Freeman, C., McVean, G. & Donnelly, P. A fine-scale map of recombination rates and hotspots across the human genome. _Science_ 310, 321–324 (2005) Article  ADS  CAS  Google Scholar 

* Neale, M. J. & Keeney, S. Clarifying the mechanics of DNA strand exchange in meiotic recombination. _Nature_ 442, 153–158 (2006) Article  ADS  CAS  Google Scholar  * Petukhova, G. V.,

Romanienko, P. J. & Camerini-Otero, R. D. The Hop2 protein has a direct role in promoting interhomolog interactions during mouse meiosis. _Dev. Cell_ 5, 927–936 (2003) Article  CAS 

Google Scholar  * Qin, J., Richardson, L. L., Jasin, M., Handel, M. A. & Arnheim, N. Mouse strains with an active H2-Ea meiotic recombination hot spot exhibit increased levels of

H2-Ea-specific DNA breaks in testicular germ cells. _Mol. Cell. Biol._ 24, 1655–1666 (2004) Article  CAS  Google Scholar  * Paigen, K. et al. The recombinational anatomy of a mouse

chromosome. _PLoS Genet._ 4, e1000119 (2008) Article  Google Scholar  * Cox, A. et al. A new standard genetic map for the laboratory mouse. _Genetics_ 182, 1335–1344 (2009) Article  CAS 

Google Scholar  * 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  * Khambata, S., Mody,

J., Modzelewski, A., Heine, D. & Passmore, H. C. Ea recombinational hot spot in the mouse major histocompatibility complex maps to the fourth intron of the Ea gene. _Genome Res._ 6,

195–201 (1996) Article  CAS  Google Scholar  * Francino, M. P. & Ochman, H. Strand asymmetries in DNA evolution. _Trends Genet._ 13, 240–245 (1997) Article  CAS  Google Scholar  * Duret,

L. & Galtier, N. Biased gene conversion and the evolution of mammalian genomic landscapes. _Annu. Rev. Genom. Hum. Genet._ 10, 285–311 (2009) Article  CAS  Google Scholar  * 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  ADS  CAS  Google

Scholar  * Wang, Z., Schones, D. E. & Zhao, K. Characterization of human epigenomes. _Curr. Opin. Genet. Dev._ 19, 127–134 (2009) Article  CAS  Google Scholar  * Borde, V. et al. Histone

H3 lysine 4 trimethylation marks meiotic recombination initiation sites. _EMBO J._ 28, 99–111 (2008) Article  Google Scholar  * Buard, J., Barthes, 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  * Parvanov, E. D., Petkov, P. M. &

Paigen, K. _Prdm9_ controls activation of mammalian recombination hotspots. _Science_ 327, 835 (2010) Article  ADS  CAS  Google Scholar  * Myers, S. et al. Drive against hotspot motifs in

primates implicates the PRDM9 gene in meiotic recombination. _Science_ 327, 876–879 (2010) Article  ADS  CAS  Google Scholar  * Baudat, F. et al. PRDM9 is a major determinant of meiotic

recombination hotspots in humans and mice. _Science_ 327, 836–840 (2010) Article  ADS  CAS  Google Scholar  * Myers, S., Freeman, C., Auton, A., Donnelly, P. & McVean, G. A common

sequence motif associated with recombination hot spots and genome instability in humans. _Nature Genet._ 40, 1124–1129 (2008) Article  CAS  Google Scholar  * 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  * Kaplan, N. et al. The

DNA-encoded nucleosome organization of a eukaryotic genome. _Nature_ 458, 362–366 (2009) Article  ADS  CAS  Google Scholar  Download references 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.). AUTHOR INFORMATION Author notes * Fatima Smagulova and Ivan V. Gregoretti: These authors

contributed equally to this work. AUTHORS AND AFFILIATIONS * Uniformed Services University of the Health Sciences, Bethesda, 20814, Maryland, USA Fatima Smagulova & Galina V. Petukhova *

National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, 20892, Maryland, USA Ivan V. Gregoretti, Kevin Brick, Pavel Khil & R. Daniel Camerini-Otero Authors *

Fatima Smagulova View author publications You can also search for this author inPubMed Google Scholar * Ivan V. Gregoretti View author publications You can also search for this author

inPubMed Google Scholar * Kevin Brick View author publications You can also search for this author inPubMed Google Scholar * Pavel Khil View author publications You can also search for this

author inPubMed Google Scholar * R. Daniel Camerini-Otero View author publications You can also search for this author inPubMed Google Scholar * Galina V. Petukhova View author publications

You can also search for this author inPubMed Google Scholar 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. ETHICS DECLARATIONS COMPETING INTERESTS 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) POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2

POWERPOINT SLIDE FOR FIG. 3 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 05 October 2010 * Accepted:

24 January 2011 * Published: 03 April 2011 * Issue Date: 21 April 2011 * DOI: https://doi.org/10.1038/nature09869 SHARE THIS ARTICLE Anyone you share the following link with will be able to

read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing

initiative