Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1994 Jan;54(1):104–113.

The 1.5-Mb region spanning the myotonic dystrophy locus shows uniform recombination frequency.

G G Shutler 1, A E MacKenzie 1, R G Korneluk 1
PMCID: PMC1918079  PMID: 8279459

Abstract

The myotonic dystrophy (DM) mutation has been identified as a heritable unstable CTG trinucleotide repeat sequence. The intergenerational amplification of this sequence is an example of a new class of dynamic mutations responsible for human genetic diseases. To ascertain whether recombination activity influences, or is affected by, the presence of this unique sequence, a comprehensive study of the physical and genetic mapping data for the 1.5-Mb region of human chromosome 19q13.3, which contains the DM locus, was conducted. The recombination rate for this region was examined by correlating genetic distance to physical distance for six selected marker loci. The following markers span the DM region: 19qCEN-p alpha 1.4 (D19S37)-APOC2-CKM-pE0.8 (D19S115)-pGB2.6 (DM)-p134c (D19S51)-19qTER. Initial linear regression analysis of these two parameters failed to reveal a significant linear correlation (coefficient of determination, r2 = .19), suggesting nonuniform rates of recombination. However, the presence of a recombination hot spot was believed to be unlikely, as the marker-to-marker pairs that showed the greatest deviation in recombination frequency were not restricted to a specific region of the 1.5 Mb studied and had relatively broad confidence intervals, as reflected by low LOD values. A second linear regression analysis using only marker intervals with high LOD scores (Zmax > 22) showed linear correlation (r2 = .68) for the entire 1.5-Mb region. This analysis indicated a relatively uniform recombination frequency in the 1.5-Mb region spanning the DM locus. Furthermore, the recombinations observed were neither under- nor overrepresented on DM chromosomes. Consequently, recombination activity is unlikely to influence, or be affected by, the presence of the DM mutation.

Full text

PDF
104

Images in this article

108Figure 2
on p.108
108Figure 3
on p.108
109Figure 4
on p.109

Selected References

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

  1. Aslanidis C., Jansen G., Amemiya C., Shutler G., Mahadevan M., Tsilfidis C., Chen C., Alleman J., Wormskamp N. G., Vooijs M. Cloning of the essential myotonic dystrophy region and mapping of the putative defect. Nature. 1992 Feb 6;355(6360):548–551. doi: 10.1038/355548a0. [DOI] [PubMed] [Google Scholar]
  2. Bachinski L. L., Krahe R., White B. F., Wieringa B., Shaw D., Korneluk R., Thompson L. H., Johnson K., Siciliano M. J. An informative panel of somatic cell hybrids for physical mapping on human chromosome 19q. Am J Hum Genet. 1993 Feb;52(2):375–387. [PMC free article] [PubMed] [Google Scholar]
  3. Birnboim H. C., Doly J. A rapid alkaline extraction procedure for screening recombinant plasmid DNA. Nucleic Acids Res. 1979 Nov 24;7(6):1513–1523. doi: 10.1093/nar/7.6.1513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brook J. D., Knight S. J., Roberts S. H., Harley H. G., Walsh K. V., Rundle S. A., Freyne K., Koch M. C., Epstein N. D., Wieringa B. The physical map of chromosome arm 19q: some new assignments, confirmations and re-assessments. Hum Genet. 1991 May;87(1):65–72. doi: 10.1007/BF01213095. [DOI] [PubMed] [Google Scholar]
  5. Brook J. D., McCurrach M. E., Harley H. G., Buckler A. J., Church D., Aburatani H., Hunter K., Stanton V. P., Thirion J. P., Hudson T. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member. Cell. 1992 Feb 21;68(4):799–808. doi: 10.1016/0092-8674(92)90154-5. [DOI] [PubMed] [Google Scholar]
  6. Buxton J., Shelbourne P., Davies J., Jones C., Van Tongeren T., Aslanidis C., de Jong P., Jansen G., Anvret M., Riley B. Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy. Nature. 1992 Feb 6;355(6360):547–548. doi: 10.1038/355547a0. [DOI] [PubMed] [Google Scholar]
  7. Coerwinkel-Driessen M., Schepens J., van Zandvoort P., van Oost B., Mariman E., Wieringa B. NcoI RFLP at the creatine kinase-muscle type gene locus (CKMM, chromosome 19). Nucleic Acids Res. 1988 Sep 12;16(17):8743–8743. doi: 10.1093/nar/16.17.8743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Feinberg A. P., Vogelstein B. "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. doi: 10.1016/0003-2697(84)90381-6. [DOI] [PubMed] [Google Scholar]
  9. Frossard P. M., Coleman R. T., Assmann G. NcoI RFLP at the human apolipoprotein CII gene locus. Nucleic Acids Res. 1986 Jun 25;14(12):5120–5120. doi: 10.1093/nar/14.12.5120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fu Y. H., Kuhl D. P., Pizzuti A., Pieretti M., Sutcliffe J. S., Richards S., Verkerk A. J., Holden J. J., Fenwick R. G., Jr, Warren S. T. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell. 1991 Dec 20;67(6):1047–1058. doi: 10.1016/0092-8674(91)90283-5. [DOI] [PubMed] [Google Scholar]
  11. Fu Y. H., Pizzuti A., Fenwick R. G., Jr, King J., Rajnarayan S., Dunne P. W., Dubel J., Nasser G. A., Ashizawa T., de Jong P. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science. 1992 Mar 6;255(5049):1256–1258. doi: 10.1126/science.1546326. [DOI] [PubMed] [Google Scholar]
  12. Harley H. G., Brook J. D., Rundle S. A., Crow S., Reardon W., Buckler A. J., Harper P. S., Housman D. E., Shaw D. J. Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Nature. 1992 Feb 6;355(6360):545–546. doi: 10.1038/355545a0. [DOI] [PubMed] [Google Scholar]
  13. Harley H. G., Walsh K. V., Rundle S., Brook J. D., Sarfarazi M., Koch M. C., Floyd J. L., Harper P. S., Shaw D. J. Localisation of the myotonic dystrophy locus to 19q13.2-19q13.3 and its relationship to twelve polymorphic loci on 19q. Hum Genet. 1991 May;87(1):73–80. doi: 10.1007/BF01213096. [DOI] [PubMed] [Google Scholar]
  14. Humphries S. E., Jowett N. I., Williams L., Rees A., Vella M., Kessling A., Myklebost O., Lydon A., Seed M., Galton D. J. A DNA polymorphism adjacent to the human apolipoprotein CII gene. Mol Biol Med. 1983 Dec;1(5):463–471. [PubMed] [Google Scholar]
  15. Jansen G., de Jong P. J., Amemiya C., Aslanidis C., Shaw D. J., Harley H. G., Brook J. D., Fenwick R., Korneluk R. G., Tsilfidis C. Physical and genetic characterization of the distal segment of the myotonic dystrophy area on 19q. Genomics. 1992 Jul;13(3):509–517. doi: 10.1016/0888-7543(92)90118-c. [DOI] [PubMed] [Google Scholar]
  16. Johnson K., Shelbourne P., Davies J., Buxton J., Nimmo E., Siciliano M. J., Bachinski L. L., Anvret M., Harley H., Rundle S. A new polymorphic probe which defines the region of chromosome 19 containing the myotonic dystrophy locus. Am J Hum Genet. 1990 Jun;46(6):1073–1081. [PMC free article] [PubMed] [Google Scholar]
  17. Korneluk R. G., MacKenzie A. E., Nakamura Y., Dubé I., Jacob P., Hunter A. G. A reordering of human chromosome 19 long-arm DNA markers and identification of markers flanking the myotonic dystrophy locus. Genomics. 1989 Oct;5(3):596–604. doi: 10.1016/0888-7543(89)90028-1. [DOI] [PubMed] [Google Scholar]
  18. Korneluk R. G., MacLeod H. L., McKeithan T. W., Brooks J. D., MacKenzie A. E. A chromosome 19 clone from a translocation breakpoint shows close linkage and linkage disequilibrium with myotonic dystrophy. Genomics. 1989 Feb;4(2):146–151. doi: 10.1016/0888-7543(89)90293-0. [DOI] [PubMed] [Google Scholar]
  19. Kremer E. J., Pritchard M., Lynch M., Yu S., Holman K., Baker E., Warren S. T., Schlessinger D., Sutherland G. R., Richards R. I. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science. 1991 Jun 21;252(5013):1711–1714. doi: 10.1126/science.1675488. [DOI] [PubMed] [Google Scholar]
  20. La Spada A. R., Wilson E. M., Lubahn D. B., Harding A. E., Fischbeck K. H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991 Jul 4;352(6330):77–79. doi: 10.1038/352077a0. [DOI] [PubMed] [Google Scholar]
  21. Lathrop G. M., Lalouel J. M., Julier C., Ott J. Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am J Hum Genet. 1985 May;37(3):482–498. [PMC free article] [PubMed] [Google Scholar]
  22. MacKenzie A. E., MacLeod H. L., Hunter A. G., Korneluk R. G. Linkage analysis of the apolipoprotein C2 gene and myotonic dystrophy on human chromosome 19 reveals linkage disequilibrium in a French-Canadian population. Am J Hum Genet. 1989 Jan;44(1):140–147. [PMC free article] [PubMed] [Google Scholar]
  23. Madisen L., Hoar D. I., Holroyd C. D., Crisp M., Hodes M. E. DNA banking: the effects of storage of blood and isolated DNA on the integrity of DNA. Am J Med Genet. 1987 Jun;27(2):379–390. doi: 10.1002/ajmg.1320270216. [DOI] [PubMed] [Google Scholar]
  24. Mahadevan M. S., Foitzik M. A., Surh L. C., Korneluk R. G. Characterization and polymerase chain reaction (PCR) detection of an Alu deletion polymorphism in total linkage disequilibrium with myotonic dystrophy. Genomics. 1993 Feb;15(2):446–448. doi: 10.1006/geno.1993.1087. [DOI] [PubMed] [Google Scholar]
  25. Mahadevan M., Tsilfidis C., Sabourin L., Shutler G., Amemiya C., Jansen G., Neville C., Narang M., Barceló J., O'Hoy K. Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene. Science. 1992 Mar 6;255(5049):1253–1255. doi: 10.1126/science.1546325. [DOI] [PubMed] [Google Scholar]
  26. Mendelsohn M. L., Mayall B. H., Bogart E., Moore D. H., 2nd, Perry B. H. DNA content and DNA-based centromeric index of the 24 human chromosomes. Science. 1973 Mar 16;179(4078):1126–1129. doi: 10.1126/science.179.4078.1126. [DOI] [PubMed] [Google Scholar]
  27. Miller S. A., Dykes D. D., Polesky H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. doi: 10.1093/nar/16.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Nakamura Y., Lathrop M., O'Connell P., Leppert M., Lalouel J. M., White R. A primary map of ten DNA markers and two serological markers for human chromosome 19. Genomics. 1988 Jul;3(1):67–71. doi: 10.1016/0888-7543(88)90161-9. [DOI] [PubMed] [Google Scholar]
  29. Nelson M., McClelland M. The effect of site-specific methylation on restriction-modification enzymes. Nucleic Acids Res. 1987;15 (Suppl):r219–r230. doi: 10.1093/nar/15.suppl.r219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Schonk D., Coerwinkel-Driessen M., van Dalen I., Oerlemans F., Smeets B., Schepens J., Hulsebos T., Cockburn D., Boyd Y., Davis M. Definition of subchromosomal intervals around the myotonic dystrophy gene region at 19q. Genomics. 1989 Apr;4(3):384–396. doi: 10.1016/0888-7543(89)90346-7. [DOI] [PubMed] [Google Scholar]
  31. Shaw D. J., Harley H. G., Brook J. D., McKeithan T. W. Long-range restriction map of a region of human chromosome 19 containing the apolipoprotein genes, a CLL-associated translocation breakpoint, and two polymorphic MluI sites. Hum Genet. 1989 Aug;83(1):71–74. doi: 10.1007/BF00274152. [DOI] [PubMed] [Google Scholar]
  32. Shaw D. J., Meredith A. L., Sarfarazi M., Huson S. M., Brook J. D., Myklebost O., Harper P. S. The apolipoprotein CII gene: subchromosomal localisation and linkage to the myotonic dystrophy locus. Hum Genet. 1985;70(3):271–273. doi: 10.1007/BF00273455. [DOI] [PubMed] [Google Scholar]
  33. Shutler G., Korneluk R. G., Tsilfidis C., Mahadevan M., Bailly J., Smeets H., Jansen G., Wieringa B., Lohman F., Aslanidis C. Physical mapping and cloning of the proximal segment of the myotonic dystrophy gene region. Genomics. 1992 Jul;13(3):518–525. doi: 10.1016/0888-7543(92)90119-d. [DOI] [PubMed] [Google Scholar]
  34. Shutler G., Leblond S., Bailly J., MacKenzie A. E., Tsilfidis C., Korneluk R. G. An insertion polymorphism identified by the probe pE0.8 (D19S115) at 19q13.3. Nucleic Acids Res. 1991 Mar 11;19(5):1159–1159. doi: 10.1093/nar/19.5.1159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Shutler G., MacKenzie A. E., Brunner H., Wieringa B., de Jong P., Lohman F. P., Leblond S., Bailly J., Korneluk R. G. Physical and genetic mapping of a novel chromosome 19 ERCC1 marker showing close linkage with myotonic dystrophy. Genomics. 1991 Mar;9(3):500–504. doi: 10.1016/0888-7543(91)90416-c. [DOI] [PubMed] [Google Scholar]
  36. Smeets H., Bachinski L., Coerwinkel M., Schepens J., Hoeijmakers J., van Duin M., Grzeschik K. H., Weber C. A., de Jong P., Siciliano M. J. A long-range restriction map of the human chromosome 19q13 region: close physical linkage between CKMM and the ERCC1 and ERCC2 genes. Am J Hum Genet. 1990 Mar;46(3):492–501. [PMC free article] [PubMed] [Google Scholar]
  37. Stallings R. L., Olson E., Strauss A. W., Thompson L. H., Bachinski L. L., Siciliano M. J. Human creatine kinase genes on chromosomes 15 and 19, and proximity of the gene for the muscle form to the genes for apolipoprotein C2 and excision repair. Am J Hum Genet. 1988 Aug;43(2):144–151. [PMC free article] [PubMed] [Google Scholar]
  38. Verkerk A. J., Pieretti M., Sutcliffe J. S., Fu Y. H., Kuhl D. P., Pizzuti A., Reiner O., Richards S., Victoria M. F., Zhang F. P. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 1991 May 31;65(5):905–914. doi: 10.1016/0092-8674(91)90397-h. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES