Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Complex gene conversion events in germline mutation at human minisatellites

Abstract

Mutation at the human minisatellites MS32, MS205 and MS31A has been investigated by characterizing mutant alleles in pedigrees and in the case of MS32 by direct analysis of mutant molecules in single sperm. Most mutations at all three loci are polar, involving the preferential gain of a few repeat units at one end of the tandem repeat array. Incoming repeats can be derived from the same allele or the homologous chromosome, though they are frequently rearranged during mutation. Lack of exchange of flanking markers suggests the involvement of complex conversion–like events in the generation of mutant alleles. At MS32, high frequency mutation processes in sperm appear to be largely germline specific and to occur at a constant rate irrespective of allele size. Together with mutational polarity, this implies that germline instability is controlled by elements outside the tandem repeat array.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Armour, J.A.L. & Jeffreys, A.J. Biology and applications of human minisatellite loci. Curr. Opin. Genet. Dev. 2, 850–856 (1992).

    Article  CAS  Google Scholar 

  2. Jeffreys, A.J., Royle, N.J., Wilson, V. & Wong, Z. Spontaneous mutation rates to new length alleles at tandem-repetitive hypervariable loci in human DNA. Nature 332, 278–281 (1988).

    Article  CAS  Google Scholar 

  3. Vergnaud, G. et al. The use of synthetic tandem repeats to isolate new VNTR loci: cloning of a human hypermutable sequence. Genomics 11, 135–144 (1991).

    Article  CAS  Google Scholar 

  4. Jeffreys, A.J., Turner, M. & Debenham, P. The efficiency of multilocus DNA fingerprint probes for individualization and establishment of family relationships, determined from extensive casework. Am. J. hum. Genet. 48, 824– 840 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Henke, J., Fimmers, R., Baur, M.P. & Henke, L. DNA-minisatellite mutations: recent investigations concerning distribution and impact on parentage testing. Int. J. leg. Med. 105, 217–222 (1993).

    Article  CAS  Google Scholar 

  6. Wolff, R., Nakamura, Y. & White, R. Molecular characterization of a spontaneously generated new allele at a VNTR locus: no exchange of flanking DNA sequences. Genomics 3, 347–351 (1988).

    Article  CAS  Google Scholar 

  7. Wolff, R.K., Plaetke, R., Jeffreys, A.J. & White, R. Unequal crossingover between homologous chromosomes is not the major mechanism involved in the generation of new alleles at VNTR loci. Genomics 5, 382–384 (1989).

    Article  CAS  Google Scholar 

  8. Jeffreys, A.J., MacLeod, A., Tamaki, K., Neil, D.L. & Monckton, D.G. Minisatellite repeat coding as a digital approach to DNA typing. Nature 354, 204–209 (1991).

    Article  CAS  Google Scholar 

  9. Jeffreys, A.J., Neumann, R. & Wilson, V. Repeat unit sequence variation in minisatellites: a novel source of DNA polymorphism for studying allelic variation and mutation by single molecule analysis. Cell 60, 473–485 (1990).

    Article  CAS  Google Scholar 

  10. Armour, J.A.L., Harris, P.C. & Jeffreys, A.J. Allelic variation at minisatellite MS205 (D16S309):) evidence for polarized variability. Hum. molec. Genet. 2, 1137– 1145 (1993).

    Article  CAS  Google Scholar 

  11. Neil, D.L. & Jeffreys, A.J. Digital DNA typing at a second hypervariable locus by minisatellite variant repeat mapping. Hum. molec. Genet. 2, 1129–1135 (1993).

    Article  CAS  Google Scholar 

  12. Wong, Z., Wilson, V., Patel, I., Povey, S. & Jeffreys, A.J. Characterization of a panel of highly variable minisatellites cloned from human DNA. A. J. hum. Genet. 51, 269–288 (1987).

    Article  CAS  Google Scholar 

  13. Royle, N.J., Clarkson, R.E., Wong, Z. & Jeffreys, A.J. Clustering of hypervariable minisatellites in the proterminal region of human autosomes. Genomics 3, 352–360 (1988).

    Article  CAS  Google Scholar 

  14. Armour, J.A.L., Wong, Z., Wilson, V., Royle, N.J. & Jeffreys, A.J. Sequences flanking the repeat arrays of human minisatellites: association with tandem and dispersed repeat elements. Nucl. Acids Res. 17, 4925–4935 (1989).

    Article  CAS  Google Scholar 

  15. Gray, I.C. & Jeffreys, A.J. Evolutionary transience of hypervariable minisatellites in man and the primates. Proc. R. Soc. Land. B. 243, 241–253 (1991).

    Article  CAS  Google Scholar 

  16. Tamaki, K., Monckton, D.G., MacLeod, A., Allen, M. & Jeffreys, A.J. Four-state MVR-PCR: increased discrimination of digital DNA typing by simultaneous analysis of two polymorphic sites within minisatellite variant repeats at D1S8. Hum. molec. Genet. 2, 1629–1632 (1993).

    Article  CAS  Google Scholar 

  17. Monckton, D.G., Tamaki, K., MacLeod, A., Neil, D.L. & Jeffreys, A.J. Allele-specific MVR-PCR analysis at minisatellite D1S8. Hum. molec. Genet. 2, 513–519 (1993).

    Article  CAS  Google Scholar 

  18. Royle, N.J., Armour, J.A.L., Webb, M., Thomas, A. & Jeffreys, A.J. A hypervariable locus D1SS309 located at the distal end of 16p. Nucl. Acids Res. 20, 1164 (1992).

    Article  CAS  Google Scholar 

  19. Rack, K.A. et al. Characterization of three de novo derivative chromosomes 16 by “reverse chromosome painting” and molecular analysis. Am. J. hum. Genet. 52, 987–997 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Monckton, D.G. & Jeffreys, A.J. Minisatellite “isoallele” discrimination in pseudohomozygotes by single molecule PCR and variant repeat mapping. Genomics 11, 465–467 (1991).

    Article  CAS  Google Scholar 

  21. Harding, R.M., Boyce, A.J. & Clegg, J.B. The evolution of tandemly repetitive DNA: recombination rules. Genetics 132, 847–859 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Caskey, C.T., Pizzuti, A., Fu, Y.-H., Fenwick, R.G. & Nelson, D.L. Triplet repeat mutations in human disease. Science 256, 784–789 (1992).

    Article  CAS  Google Scholar 

  23. Huntington's Disease Collaborative Reasearch Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's Disease chromosomes. Cell 72, 971–983 (1993).

    Article  Google Scholar 

  24. Orr, H.T. et al. Expansion of an unstable trinucleotide GAG repeat in spinocerebellar ataxia type I. Nature Genet. 4, 221–226 (1993).

    Article  CAS  Google Scholar 

  25. 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  Google Scholar 

  26. Schultes, N.P. & Szostak, J.W. A poly (dA.dT) tract is a component of the recombination initiation site at the ARG4 locus in Saccharomyces cerevisiae. Molec. Cell Biol. 11, 322–328 (1991).

    Article  CAS  Google Scholar 

  27. Massey, B. & Nicholas, A. The control in cis of the position and the amount of the ARG4 meiotic double-strand break of Saccharamyces cerevisiae. EMBO J. 12, 1459–1466 (1993).

    Article  Google Scholar 

  28. Carpenter, A.T.C. Gene conversion, recombination nodules, and the initiation of meiotic synapsis. BioEssays 6, 232–236 (1987).

    Article  CAS  Google Scholar 

  29. Knight, S.J.L. et al. Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation. Cell 74, 127–134 (1993).

    Article  CAS  Google Scholar 

  30. Hansen, R.S., Canfield, T.K., Lamb, M.M., Gartier, S.M. & Laird, C.D. Association of Fragile X syndrome with delayed replication of the FMR1 gene. Cell 73, 1403–1409 (1993).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jeffreys, A., Tamaki, K., MacLeod, A. et al. Complex gene conversion events in germline mutation at human minisatellites. Nat Genet 6, 136–145 (1994). https://doi.org/10.1038/ng0294-136

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0294-136

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing