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A common sequence motif associated with recombination hot spots and genome instability in humans

Nature Genetics volume 40, pages 1124–1129 (2008)Cite this article

Abstract

In humans, most meiotic crossover events are clustered into short regions of the genome known as recombination hot spots. We have previously identified DNA motifs that are enriched in hot spots, particularly the 7-mer CCTCCCT. Here we use the increased hot-spot resolution afforded by the Phase 2 HapMap and novel search methods to identify an extended family of motifs based around the degenerate 13-mer CCNCCNTNNCCNC, which is critical in recruiting crossover events to at least 40% of all human hot spots and which operates on diverse genetic backgrounds in both sexes. Furthermore, these motifs are found in hypervariable minisatellites and are clustered in the breakpoint regions of both disease-causing nonallelic homologous recombination hot spots and common mitochondrial deletion hot spots, implicating the motif as a driver of genome instability.

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Figure 1: A common hot-spot motif acts across different repeat families.
Figure 2: The role of flanking sequence and motif degeneracy in determining hot-spot activity.
Figure 3: Hot-spot sequence motifs at STS deletion hot spot and common mitochondrial deletion endpoints.
Figure 4: Recombination and hypermutable minisatellites.

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Acknowledgements

We thank J. Lupski for help with compiling information on NAHR hot spots and G. Coop for discussion. We thank the Engineering and Physical Sciences Research Council (EPSRC), the Wolfson Foundation, the EU and the Wellcome Trust for financial support.

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Authors and Affiliations

  1. Broad Institute of Massachusetts Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Simon Myers

  2. Department of Statistics, Oxford University, 1 South Parks Road, Oxford, OX1 3TG, UK

    Simon Myers, Colin Freeman, Adam Auton, Peter Donnelly & Gil McVean

  3. Department of Biological Statistics and Computational Biology, 101 Biotechnology Building, Cornell University, Ithaca, 14853, New York, USA

    Adam Auton

  4. Wellcome Trust Centre for Human Genetics, Oxford University, Roosevelt Drive, OX3 7BN, Oxford, UK

    Peter Donnelly

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  5. Gil McVean
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Contributions

S.M., P.D. and G.M. designed the study; S.M., A.A. and C.F. performed the analyses; S.M. and G.M. wrote the paper.

Corresponding author

Correspondence to Simon Myers.

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Supplementary Figures 1 and 2, Supplementary Tables 1–4, Supplementary Methods and Supplementary Note (PDF 318 kb)

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Myers, S., Freeman, C., Auton, A. et al. A common sequence motif associated with recombination hot spots and genome instability in humans. Nat Genet 40, 1124–1129 (2008). https://doi.org/10.1038/ng.213

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