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. 1998 Jun 15;17(12):3495–3502. doi: 10.1093/emboj/17.12.3495

Influences of array size and homogeneity on minisatellite mutation.

J Buard 1, A Bourdet 1, J Yardley 1, Y Dubrova 1, A J Jeffreys 1
PMCID: PMC1170686  PMID: 9628885

Abstract

Unstable minisatellites display high frequencies of spontaneous gain and loss of repeats in the human germline. Most length changes arise through complex recombination events including intra-allelic duplications/deletions and inter-allelic transfers of repeats. Definition of the factors modulating instability requires both measurement of mutation rate and detailed analysis of mutant structures at the level of individual alleles. We have measured mutation rates in sperm for a wide range of alleles of the highly unstable human minisatellite CEB1. Instability varies by three orders of magnitude between alleles and increases steadily with the size of the tandem array. Structural analysis of mutant molecules derived from six alleles revealed that it is the rate of intra-allelic rearrangements which increases with array size and that intra-allelic duplication events tend to cluster within homogeneous segments of alleles; both phenomena resemble features of trinucleotide repeat instability. In contrast, inter-allelic transfers occur at a fairly constant rate, irrespective of array length, and show a mild polarity towards one end of the minisatellite, suggesting the possible influence of flanking DNA on these conversion-like events.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andreassen R., Egeland T., Olaisen B. Mutation rate in the hypervariable VNTR g3 (D7S22) is affected by allele length and a flanking DNA sequence polymorphism near the repeat array. Am J Hum Genet. 1996 Aug;59(2):360–367. [PMC free article] [PubMed] [Google Scholar]
  2. Andrew S. E., Goldberg Y. P., Hayden M. R. Rethinking genotype and phenotype correlations in polyglutamine expansion disorders. Hum Mol Genet. 1997 Nov;6(12):2005–2010. doi: 10.1093/hmg/6.12.2005. [DOI] [PubMed] [Google Scholar]
  3. Buard J., Jeffreys A. J. Big, bad minisatellites. Nat Genet. 1997 Apr;15(4):327–328. doi: 10.1038/ng0497-327. [DOI] [PubMed] [Google Scholar]
  4. Buard J., Vergnaud G. Complex recombination events at the hypermutable minisatellite CEB1 (D2S90). EMBO J. 1994 Jul 1;13(13):3203–3210. doi: 10.1002/j.1460-2075.1994.tb06619.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chung M. Y., Ranum L. P., Duvick L. A., Servadio A., Zoghbi H. Y., Orr H. T. Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I. Nat Genet. 1993 Nov;5(3):254–258. doi: 10.1038/ng1193-254. [DOI] [PubMed] [Google Scholar]
  6. Eichler E. E., Holden J. J., Popovich B. W., Reiss A. L., Snow K., Thibodeau S. N., Richards C. S., Ward P. A., Nelson D. L. Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nat Genet. 1994 Sep;8(1):88–94. doi: 10.1038/ng0994-88. [DOI] [PubMed] [Google Scholar]
  7. Gacy A. M., Goellner G., Juranić N., Macura S., McMurray C. T. Trinucleotide repeats that expand in human disease form hairpin structures in vitro. Cell. 1995 May 19;81(4):533–540. doi: 10.1016/0092-8674(95)90074-8. [DOI] [PubMed] [Google Scholar]
  8. Heery D. M., Gannon F., Powell R. A simple method for subcloning DNA fragments from gel slices. Trends Genet. 1990 Jun;6(6):173–173. doi: 10.1016/0168-9525(90)90158-3. [DOI] [PubMed] [Google Scholar]
  9. Jeffreys A. J., Bois P., Buard J., Collick A., Dubrova Y., Hollies C. R., May C. A., Murray J., Neil D. L., Neumann R. Spontaneous and induced minisatellite instability. Electrophoresis. 1997 Aug;18(9):1501–1511. doi: 10.1002/elps.1150180903. [DOI] [PubMed] [Google Scholar]
  10. Jeffreys A. J., MacLeod A., Tamaki K., Neil D. L., Monckton D. G. Minisatellite repeat coding as a digital approach to DNA typing. Nature. 1991 Nov 21;354(6350):204–209. doi: 10.1038/354204a0. [DOI] [PubMed] [Google Scholar]
  11. Jeffreys A. J., Neumann R. Somatic mutation processes at a human minisatellite. Hum Mol Genet. 1997 Jan;6(1):129–136. doi: 10.1093/hmg/6.1.129. [DOI] [PubMed] [Google Scholar]
  12. Jeffreys A. J., Neumann R., Wilson V. Repeat unit sequence variation in minisatellites: a novel source of DNA polymorphism for studying variation and mutation by single molecule analysis. Cell. 1990 Feb 9;60(3):473–485. doi: 10.1016/0092-8674(90)90598-9. [DOI] [PubMed] [Google Scholar]
  13. 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. 1988 Mar 17;332(6161):278–281. doi: 10.1038/332278a0. [DOI] [PubMed] [Google Scholar]
  14. Jeffreys A. J., Tamaki K., MacLeod A., Monckton D. G., Neil D. L., Armour J. A. Complex gene conversion events in germline mutation at human minisatellites. Nat Genet. 1994 Feb;6(2):136–145. doi: 10.1038/ng0294-136. [DOI] [PubMed] [Google Scholar]
  15. May C. A., Jeffreys A. J., Armour J. A. Mutation rate heterogeneity and the generation of allele diversity at the human minisatellite MS205 (D16S309). Hum Mol Genet. 1996 Nov;5(11):1823–1833. doi: 10.1093/hmg/5.11.1823. [DOI] [PubMed] [Google Scholar]
  16. Mitas M. Trinucleotide repeats associated with human disease. Nucleic Acids Res. 1997 Jun 15;25(12):2245–2254. doi: 10.1093/nar/25.12.2245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Monckton D. G., Neumann R., Guram T., Fretwell N., Tamaki K., MacLeod A., Jeffreys A. J. Minisatellite mutation rate variation associated with a flanking DNA sequence polymorphism. Nat Genet. 1994 Oct;8(2):162–170. doi: 10.1038/ng1094-162. [DOI] [PubMed] [Google Scholar]
  18. Monckton D. G., Tamaki K., MacLeod A., Neil D. L., Jeffreys A. J. Allele-specific MVR-PCR analysis at minisatellite D1S8. Hum Mol Genet. 1993 May;2(5):513–519. doi: 10.1093/hmg/2.5.513. [DOI] [PubMed] [Google Scholar]
  19. Monckton D. G., Wong L. J., Ashizawa T., Caskey C. T. Somatic mosaicism, germline expansions, germline reversions and intergenerational reductions in myotonic dystrophy males: small pool PCR analyses. Hum Mol Genet. 1995 Jan;4(1):1–8. doi: 10.1093/hmg/4.1.1. [DOI] [PubMed] [Google Scholar]
  20. Vergnaud G., Mariat D., Apiou F., Aurias A., Lathrop M., Lauthier V. The use of synthetic tandem repeats to isolate new VNTR loci: cloning of a human hypermutable sequence. Genomics. 1991 Sep;11(1):135–144. doi: 10.1016/0888-7543(91)90110-z. [DOI] [PubMed] [Google Scholar]
  21. Warren S. T. The expanding world of trinucleotide repeats. Science. 1996 Mar 8;271(5254):1374–1375. doi: 10.1126/science.271.5254.1374. [DOI] [PubMed] [Google Scholar]

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