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Reciprocal crossover asymmetry and meiotic drive in a human recombination hot spot

Nature Genetics volume 31, pages 267–271 (2002)Cite this article

Abstract

Human DNA diversity arises ultimately from germline mutation that creates new haplotypes that can be reshuffled by meiotic recombination. Reciprocal crossover generates recombinant haplotypes but should not influence the frequencies of alleles in a population. We demonstrate crossover asymmetry at a recombination hot spot in the major histocompatibility complex1, whereby reciprocal exchanges in sperm map to different locations in the hot spot. We identify a single-nucleotide polymorphism at the center of the hot spot and show that, when heterozygous, it seems sufficient to cause this asymmetry, apparently by influencing the efficiency of highly localized crossover initiation. As a consequence, crossovers in heterozygotes are accompanied by biased gene conversion, most likely occurring by gap repair2, that can also affect nearby polymorphisms through repair of an extended gap. The result is substantial over-transmission of the recombination-suppressing allele and neighboring markers to crossover products. Computer simulations show that this meiotic drive, although weak at the population level, is sufficient to favor eventual fixation of the recombination-suppressing variant. These findings provide an explanation for the relatively uniform widths of human crossover hot spots and suggest that hot spots may be generally prone to extinction by meiotic drive3.

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Figure 1: Crossover asymmetry and transmission distortion in recombination hot-spot DNA2.
Figure 2: Influence of haplotype on transmission ratio distortion in hot-spot DNA2.
Figure 3: Crossover asymmetry arising from suppression of the initiation of DSB repair.
Figure 4: Crossover and gap-size distribution under the DSB-repair model.
Figure 5: Population effects of recombination-based meiotic drive.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Szostak, J.W., Orr-Weaver, T.L., Rothstein, R.J. & Stahl, F.W. The double-strand-break repair model for recombination. Cell 33, 25–35 (1983).

    Article  CAS  PubMed  Google Scholar 

  3. 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  PubMed  PubMed Central  Google Scholar 

  4. 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  PubMed  Google Scholar 

  5. 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  PubMed  Google Scholar 

  6. Petes, T.D. Meiotic recombination hot spots and cold spots. Nature Rev. Genet. 2, 360–369 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Schultes, N.P. & Szostak, J.W. Decreasing gradients of gene conversion on both sides of the initiation site for meiotic recombination at the ARG4 locus in yeast. Genetics 126, 813–822 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Nicolas, A. & Petes, T.D. Polarity of meiotic gene conversion in fungi: contrasting views. Experientia 50, 242–252 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Liu, J., Wu, T.C. & Lichten, M. The location and structure of double-strand DNA breaks induced during yeast meiosis: evidence for a covalently linked DNA-protein intermediate. EMBO J. 14, 4599–4608 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Xu, L. & Kleckner, N. Sequence non-specific double-strand breaks and interhomolog interactions prior to double-strand break formation at a meiotic recombination hot spot in yeast. EMBO J. 14, 5115–5128 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. de Massy, B., Rocco, V. & Nicolas, A. The nucleotide mapping of DNA double-strand breaks at the CYS3 initiation site of meiotic recombination in Saccharomyces cerevisiae. EMBO J. 14, 4589–4598 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sun, H., Treco, D. & Szostak, J.W. Extensive 3′-overhanging, single-stranded DNA associated with the meiosis-specific double-strand breaks at the ARG4 recombination initiation site. Cell 64, 1155–1161 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Nicolas, A., Treco, D., Schultes, N.P. & Szostak, J.W. An initiation site for meiotic gene conversion in the yeast Saccharomyces cerevisiae. Nature 338, 35–39 (1989).

    Article  CAS  PubMed  Google Scholar 

  14. Kon, N., Krawchuk, M.D., Warren, B.G., Smith, G.R. & Wahls, W.P. Transcription factor Mts1/Mts2 (Atf1/Pcr1, Gad7/Pcr1) activates the M26 meiotic recombination hotspot in Schizosaccharomyces pombe. Proc. Natl Acad. Sci. USA 94, 13765–13770 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Beck, S. et al. Complete sequence and gene map of a human major histocompatibility complex. Nature 401, 921–923 (1999).

    Article  Google Scholar 

  16. Nasar, F., Jankowski, C. & Nag, D.K. Long palindromic sequences induce double-strand breaks during meiosis in yeast. Mol. Cell. Biol. 20, 3449–3458 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Murray, J. et al. Comparative sequence analysis of human minisatellites showing meiotic repeat instability. Genome Res. 9, 130–136 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Zimmering, S., Sandler, L. & Nicoletti, B. Mechanisms of meiotic drive. Annu. Rev. Genet. 4, 409–436 (1970).

    Article  CAS  PubMed  Google Scholar 

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

  20. Cullen, M. et al. Characterization of recombination in the HLA class II region. Am. J. Hum. Genet. 60, 397–407 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Newton, C.R. et al. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res. 17, 2503–2516 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Alani, E., Reenan, R.A. & Kolodner, R.D. Interaction between mismatch repair and genetic recombination in Saccharomyces cerevisiae. Genetics 137, 19–39 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Kimura, M. The Neutral Theory of Molecular Evolution (Cambridge University Press, 1983).

    Book  Google Scholar 

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Acknowledgements

We thank J. Blower and numerous volunteers for supplying semen and blood samples, S. Mistry for assistance with automated sequencing and oligonucleotide synthesis, J. Stead for website construction and R. Badge, R. Borts, L. Kauppi, C. Yauk and colleagues for helpful discussions. This work was supported by grants to A.J.J. from the Medical Research Council and Royal Society, UK.

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  1. Department of Genetics, University of Leicester, Leicester, LE1 7RH, UK

    Alec J. Jeffreys & Rita Neumann

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  1. Alec J. Jeffreys
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Correspondence to Alec J. Jeffreys.

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Jeffreys, A., Neumann, R. Reciprocal crossover asymmetry and meiotic drive in a human recombination hot spot. Nat Genet 31, 267–271 (2002). https://doi.org/10.1038/ng910

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