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. 1994 Jun;54(6):1110–1121.

Detection of tandem duplications and implications for linkage analysis.

T C Matise 1, A Chakravarti 1, P I Patel 1, J R Lupski 1, E Nelis 1, V Timmerman 1, C Van Broeckhoven 1, D E Weeks 1
PMCID: PMC1918201  PMID: 8198134

Abstract

The first demonstration of an autosomal dominant human disease caused by segmental trisomy came in 1991 for Charcot-Marie-Tooth disease type 1A (CMT1A). For this disorder, the segmental trisomy is due to a large tandem duplication of 1.5 Mb of DNA located on chromosome 17p11.2-p12. The search for the CMT1A disease gene was misdirected and impeded because some chromosome 17 genetic markers that are linked to CMT1A lie within this duplication. To better understand how such a duplication might affect genetic analyses in the context of disease gene mapping, we studied the effects of marker duplication on transmission probabilities of marker alleles, on linkage analysis of an autosomal dominant disease, and on tests of linkage homogeneity. We demonstrate that the undetected presence of a duplication distorts transmission ratios, hampers fine localization of the disease gene, and increases false evidence of linkage heterogeneity. In addition, we devised a likelihood-based method for detecting the presence of a tandemly duplicated marker when one is suspected. We tested our methods through computer simulations and on CMT1A pedigrees genotyped at several chromosome 17 markers. On the simulated data, our method detected 96% of duplicated markers (with a false-positive rate of 5%). On the CMT1A data our method successfully identified two of three loci that are duplicated (with no false positives). This method could be used to identify duplicated markers in other regions of the genome and could be used to delineate the extent of duplications similar to that involved in CMT1A.

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Selected References

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  1. Boehnke M. Allele frequency estimation from data on relatives. Am J Hum Genet. 1991 Jan;48(1):22–25. [PMC free article] [PubMed] [Google Scholar]
  2. Dausset J., Cann H., Cohen D., Lathrop M., Lalouel J. M., White R. Centre d'etude du polymorphisme humain (CEPH): collaborative genetic mapping of the human genome. Genomics. 1990 Mar;6(3):575–577. doi: 10.1016/0888-7543(90)90491-c. [DOI] [PubMed] [Google Scholar]
  3. Lange K., Weeks D., Boehnke M. Programs for Pedigree Analysis: MENDEL, FISHER, and dGENE. Genet Epidemiol. 1988;5(6):471–472. doi: 10.1002/gepi.1370050611. [DOI] [PubMed] [Google Scholar]
  4. Lathrop G. M., Lalouel J. M., Julier C., Ott J. Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3443–3446. doi: 10.1073/pnas.81.11.3443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Lupski J. R. An inherited DNA rearrangement and gene dosage effect are responsible for the most common autosomal dominant peripheral neuropathy: Charcot-Marie-Tooth disease type 1A. Clin Res. 1992 Dec;40(4):645–652. [PubMed] [Google Scholar]
  6. Lupski J. R., de Oca-Luna R. M., Slaugenhaupt S., Pentao L., Guzzetta V., Trask B. J., Saucedo-Cardenas O., Barker D. F., Killian J. M., Garcia C. A. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell. 1991 Jul 26;66(2):219–232. doi: 10.1016/0092-8674(91)90613-4. [DOI] [PubMed] [Google Scholar]
  7. Ott J. A simple scheme for the analysis of HLA linkages in pedigrees. Ann Hum Genet. 1978 Oct;42(2):255–257. doi: 10.1111/j.1469-1809.1978.tb00657.x. [DOI] [PubMed] [Google Scholar]
  8. Pentao L., Wise C. A., Chinault A. C., Patel P. I., Lupski J. R. Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit. Nat Genet. 1992 Dec;2(4):292–300. doi: 10.1038/ng1292-292. [DOI] [PubMed] [Google Scholar]
  9. Raeymaekers P., Timmerman V., De Jonghe P., Swerts L., Gheuens J., Martin J. J., Muylle L., De Winter G., Vandenberghe A., Van Broeckhoven C. Localization of the mutation in an extended family with Charcot-Marie-Tooth neuropathy (HMSN I). Am J Hum Genet. 1989 Dec;45(6):953–958. [PMC free article] [PubMed] [Google Scholar]
  10. Raeymaekers P., Timmerman V., Nelis E., Van Hul W., De Jonghe P., Martin J. J., Van Broeckhoven C. Estimation of the size of the chromosome 17p11.2 duplication in Charcot-Marie-Tooth neuropathy type 1a (CMT1a). HMSN Collaborative Research Group. J Med Genet. 1992 Jan;29(1):5–11. doi: 10.1136/jmg.29.1.5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Risch N., Giuffra L. Model misspecification and multipoint linkage analysis. Hum Hered. 1992;42(1):77–92. doi: 10.1159/000154047. [DOI] [PubMed] [Google Scholar]

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