Letter | Published:

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

Nature Genetics volume 31, pages 267271 (2002) | Download Citation

Subjects

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , & Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nature Genet. 29, 217–222 (2001).

  2. 2.

    , , & The double-strand-break repair model for recombination. Cell 33, 25–35 (1983).

  3. 3.

    , & The hotspot conversion paradox and the evolution of meiotic recombination. Proc. Natl Acad. Sci. USA 94, 8058–8063 (1997).

  4. 4.

    , & High-resolution mapping of crossovers in human sperm defines a minisatellite-associated recombination hotspot. Mol. Cell 2, 267–273 (1998).

  5. 5.

    , & High-resolution analysis of haplotype diversity and meiotic crossover in the human TAP2 recombination hotspot. Hum. Mol. Genet. 9, 725–733 (2000).

  6. 6.

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

  7. 7.

    & 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).

  8. 8.

    & Polarity of meiotic gene conversion in fungi: contrasting views. Experientia 50, 242–252 (1994).

  9. 9.

    , & 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).

  10. 10.

    & 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).

  11. 11.

    , & 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).

  12. 12.

    , & 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).

  13. 13.

    , , & An initiation site for meiotic gene conversion in the yeast Saccharomyces cerevisiae. Nature 338, 35–39 (1989).

  14. 14.

    , , , & 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).

  15. 15.

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

  16. 16.

    , & Long palindromic sequences induce double-strand breaks during meiosis in yeast. Mol. Cell. Biol. 20, 3449–3458 (2000).

  17. 17.

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

  18. 18.

    , & Mechanisms of meiotic drive. Annu. Rev. Genet. 4, 409–436 (1970).

  19. 19.

    Outline of Genetic Epidemiology (Karger, Basel, 1982).

  20. 20.

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

  21. 21.

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

  22. 22.

    , & Interaction between mismatch repair and genetic recombination in Saccharomyces cerevisiae. Genetics 137, 19–39 (1994).

  23. 23.

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

Download references

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.

Author information

Affiliations

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

    • Alec J. Jeffreys
    •  & Rita Neumann

Authors

  1. Search for Alec J. Jeffreys in:

  2. Search for Rita Neumann in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Alec J. Jeffreys.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng910

Further reading