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The rise and fall of a human recombination hot spot

Nature Genetics volume 41, pages 625–629 (2009)Cite this article

Abstract

Human meiotic crossovers mainly cluster into narrow hot spots1 that profoundly influence patterns of haplotype diversity2 and that may also affect genome instability3 and sequence evolution4,5,6. Hot spots also seem to be ephemeral7,8,9, but processes of hot-spot activation and their subsequent evolutionary dynamics remain unknown. We now analyze the life cycle of a recombination hot spot. Sperm typing revealed a polymorphic hot spot that was activated in cis by a single base change, providing evidence for a primary sequence determinant necessary, though not sufficient, to activate recombination. This activating mutation occurred roughly 70,000 y ago and has persisted to the present, most likely fortuitously through genetic drift despite its systematic elimination by biased gene conversion. Nonetheless, this self-destructive conversion will eventually lead to hot-spot extinction. These findings define a subclass of highly transient hot spots and highlight the importance of understanding hot-spot turnover and how it influences haplotype diversity.

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Figure 1: Identification of a sperm crossover hot spot from family linkage maps.
Figure 2: Variation between men in sperm crossover activity and biased gene conversion.
Figure 3: Active and suppressed haplotypes at hot-spot S2.
Figure 4: Evolutionary dynamics of hot-spot S2.

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References

  1. McVean, G.A. et al. The fine-scale structure of recombination rate variation in the human genome. Science 304, 581–584 (2004).

    Article  CAS  Google Scholar 

  2. Jeffreys, A.J., Kauppi, L. & Neumann, R. Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat. Genet. 29, 217–222 (2001).

    Article  CAS  Google Scholar 

  3. Lindsay, S.J., Khajavi, M., Lupski, J.R. & Hurles, M.E. A chromosomal rearrangement hotspot can be identified from population genetic variation and is coincident with a hotspot for allelic recombination. Am. J. Hum. Genet. 79, 890–902 (2006).

    Article  CAS  Google Scholar 

  4. Spencer, C.C.A. et al. The influence of recombination on human genetic diversity. PLoS Genet. 2, e148 (2006).

    Article  Google Scholar 

  5. Dreszer, T.R., Wall, G.D., Haussler, D. & Pollard, K.S. Biased clustered substitutions in the human genome: the footprints of male-driven biased gene conversion. Genome Res. 17, 1420–1430 (2007).

    Article  CAS  Google Scholar 

  6. Duret, L. & Arndt, P.F. The impact of recombination on nucleotide substitutions in the human genome. PLoS Genet. 4, e1000071 (2008).

    Article  Google Scholar 

  7. Ptak, S.E. et al. Fine-scale recombination patterns differ between chimpanzees and humans. Nat. Genet. 37, 429–434 (2005).

    Article  CAS  Google Scholar 

  8. Winckler, W. et al. Comparison of fine-scale recombination rates in humans and chimpanzees. Science 308, 107–111 (2005).

    Article  CAS  Google Scholar 

  9. Jeffreys, A.J., Neumann, R., Panayi, M., Myers, S. & Donnelly, P. Human recombination hot spots hidden in regions of strong marker association. Nat. Genet. 37, 601–606 (2005).

    Article  CAS  Google Scholar 

  10. Webb, A.J., Berg, I.L. & Jeffreys, A. Sperm cross-over activity in regions of the human genome showing extreme breakdown of marker association. Proc. Natl. Acad. Sci. USA 105, 10471–10476 (2008).

    Article  CAS  Google Scholar 

  11. Coop, G., Wen, X., Ober, C., Pritchard, J.K. & Przeworski, M. High-resolution mapping of crossovers reveals extensive variation in fine-scale recombination patterns among humans. Science 319, 1395–1398 (2008).

    Article  CAS  Google Scholar 

  12. The International HapMap Consortium. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).

  13. Maniatis, N. et al. The first linkage disequilibrium (LD) maps: delineation of hot and cold blocks by diplotype analysis. Proc. Natl. Acad. Sci. USA 99, 2228–2233 (2002).

    Article  CAS  Google Scholar 

  14. Jeffreys, A.J. & Neumann, R. Reciprocal crossover asymmetry and meiotic drive in a human recombination hot spot. Nat. Genet. 31, 267–271 (2002).

    Article  CAS  Google Scholar 

  15. Jeffreys, A.J. & Neumann, R. Factors influencing recombination frequency and distribution in a human meiotic crossover hotspot. Hum. Mol. Genet. 14, 2277–2287 (2005).

    Article  CAS  Google Scholar 

  16. Jeffreys, A.J. & May, C.A. Intense and highly localized gene conversion activity in human meiotic crossover hot spots. Nat. Genet. 36, 151–156 (2004).

    Article  CAS  Google Scholar 

  17. Myers, S., Freeman, C., Auton, A., Donnelly, P. & McVean, G. A common sequence motif associated with recombination hot spots and genome instability in humans. Nat. Genet. 40, 1124–1129 (2008).

    Article  CAS  Google Scholar 

  18. Neumann, R. & Jeffreys, A.J. Polymorphism in the activity of human crossover hotspots independent of local DNA sequence variation. Hum. Mol. Genet. 15, 1401–1411 (2006).

    Article  CAS  Google Scholar 

  19. Peters, A.D. A combination of cis and trans control can solve the hotspot conversion paradox. Genetics 178, 1579–1593 (2008).

    Article  CAS  Google Scholar 

  20. Coop, G. & Myers, S.R. Live hot, die young: transmission distortion in recombination hotspots. PLoS Genet. 3, e35 (2007).

    Article  Google Scholar 

  21. Pineda-Krch, M. & Redfield, R.J. Persistence and loss of meiotic recombination hotspots. Genetics 169, 2319–2333 (2005).

    Article  CAS  Google Scholar 

  22. Boulton, A., Myers, R.S. & Redfield, R.J. The hotspot conversion paradox and the evolution of meiotic recombination. Proc. Natl. Acad. Sci. USA 94, 8058–8063 (1997).

    Article  CAS  Google Scholar 

  23. Jeffreys, A.J., Murray, J. & Neumann, R. High-resolution mapping of crossovers in human sperm defines a minisatellite-associated recombination hotspot. Mol. Cell 2, 267–273 (1998).

    Article  CAS  Google Scholar 

  24. Jeffreys, A.J., Ritchie, A. & Neumann, R. High resolution analysis of haplotype diversity and meiotic crossover in the human TAP2 recombination hotspot. Hum. Mol. Genet. 9, 725–733 (2000).

    Article  CAS  Google Scholar 

  25. Hudson, R.R. & Kaplan, N.L. Statistical properties of the number of recombination events in the history of a sample of DNA sequences. Genetics 111, 147–164 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Arndt, P.F., Hwa, T. & Petrov, D.A. Substantial regional variation in substitution rates in the human genome: importance of GC content, gene density, and telomere-specific effects. J. Mol. Evol. 60, 748–763 (2005).

    Article  CAS  Google Scholar 

  27. Thomson, R., Pritchard, J.K., Shen, P., Oefner, P.J. & Feldman, M.W. Recent common ancestry of human Y chromosomes: evidence from DNA sequence data. Proc. Natl. Acad. Sci. USA 97, 7360–7365 (2000).

    Article  CAS  Google Scholar 

  28. Hudson, R.R. The variance of coalescent time estimates from DNA sequences. J. Mol. Evol. 64, 702–705 (2007).

    Article  CAS  Google Scholar 

  29. Morton, N.E. Outline of Genetic Epidemiology (Karger, Basel, Switzerland, 1982).

    Google Scholar 

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Acknowledgements

We thank J. Blower and volunteers for providing semen samples, T.E. King and P. Balaresque for DNA samples, A. Webb for bioinformatics support, colleagues for helpful discussions, and the Medical Research Council, the Wellcome Trust (ref. 081227/Z/06/Z), the Royal Society and the Louis-Jeantet Foundation for funding support.

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  1. Department of Genetics, University of Leicester, Leicester, UK

    Alec J Jeffreys & Rita Neumann

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  1. Alec J Jeffreys
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A.J.J. and R.N. designed the study and performed the analyses, and A.J.J. wrote the paper.

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Correspondence to Alec J Jeffreys.

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Jeffreys, A., Neumann, R. The rise and fall of a human recombination hot spot. Nat Genet 41, 625–629 (2009). https://doi.org/10.1038/ng.346

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