Detection of tandam duplications and implications for linkage analysis
- Univ. of Pittsburgh, PA (United States)
- Case Western Reserve Univ., Cleveland, OH (United States)
- Baylor College of Medicine, Houston, TX (United States)
- Univ. of Antwerp (Belgium)
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, the authors 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. They 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, they devised a likelihood-based method for detecting the presence of a tandemly duplicated marker when one is suspected. They tested their methods through computer simulations and on CMT1A pedigrees genotyped at several chromosome 17 markers. On the simulated data, the method detected 96% of duplicated markers (with a false-positive rate of 5%). On the CMT1A data the 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. 18 refs., 5 figs., 6 tabs.
- OSTI ID:
- 7075782
- Journal Information:
- American Journal of Human Genetics; (United States), Vol. 54:6; ISSN 0002-9297
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE
BIOLOGICAL MARKERS
GENETIC MAPPING
DISEASES
STATISTICAL MODELS
COMPUTERIZED SIMULATION
HEREDITARY DISEASES
HUMAN CHROMOSOME 17
MUSCLES
NERVOUS SYSTEM DISEASES
CHROMOSOMES
HUMAN CHROMOSOMES
MAPPING
MATHEMATICAL MODELS
SIMULATION
550400* - Genetics
990200 - Mathematics & Computers