Strategies for studying heterogeneous genetic traits in humans by using a linkage map of restriction fragment length polymorphisms (original) (raw)

Abstract

Simple single-gene disorders in humans can be genetically mapped by using traditional methods of linkage analysis and increasingly abundant restriction fragment length polymorphisms (RFLPs). Many human diseases and traits, however, can be expected to be genetically heterogeneous (i.e., caused by any one of several genes), and traditional linkage analysis is much less effective in such circumstances. We present two methods, interval mapping and simultaneous search, designed to exploit the full power of a linkage map of the DNA markers. For the simplest situations, only 1/3 as many affected families are needed to map a heterogeneous trait by using these methods. Only 1/5-1/50 as many are needed to detect that genetic heterogeneity is present.

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Selected References

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  1. Botstein D., White R. L., Skolnick M., Davis R. W. Construction of a genetic linkage map in man using restriction fragment length polymorphisms. Am J Hum Genet. 1980 May;32(3):314–331. [PMC free article] [PubMed] [Google Scholar]
  2. Cavalli-Sforza L. L., King M. C. Detecting linkage for genetically heterogeneous diseases and detecting heterogeneity with linkage data. Am J Hum Genet. 1986 May;38(5):599–616. [PMC free article] [PubMed] [Google Scholar]
  3. Davies K. E., Pearson P. L., Harper P. S., Murray J. M., O'Brien T., Sarfarazi M., Williamson R. Linkage analysis of two cloned DNA sequences flanking the Duchenne muscular dystrophy locus on the short arm of the human X chromosome. Nucleic Acids Res. 1983 Apr 25;11(8):2303–2312. doi: 10.1093/nar/11.8.2303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Drayna D., Davies K., Hartley D., Mandel J. L., Camerino G., Williamson R., White R. Genetic mapping of the human X chromosome by using restriction fragment length polymorphisms. Proc Natl Acad Sci U S A. 1984 May;81(9):2836–2839. doi: 10.1073/pnas.81.9.2836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Jaspers N. G., Painter R. B., Paterson M. C., Kidson C., Inoue T. Complementation analysis of ataxia-telangiectasia. Kroc Found Ser. 1985;19:147–162. [PubMed] [Google Scholar]
  6. Knowlton R. G., Cohen-Haguenauer O., Van Cong N., Frézal J., Brown V. A., Barker D., Braman J. C., Schumm J. W., Tsui L. C., Buchwald M. A polymorphic DNA marker linked to cystic fibrosis is located on chromosome 7. 1985 Nov 28-Dec 4Nature. 318(6044):380–382. doi: 10.1038/318380a0. [DOI] [PubMed] [Google Scholar]
  7. MORTON N. E. Sequential tests for the detection of linkage. Am J Hum Genet. 1955 Sep;7(3):277–318. [PMC free article] [PubMed] [Google Scholar]
  8. Ott J. Linkage analysis and family classification under heterogeneity. Ann Hum Genet. 1983 Oct;47(Pt 4):311–320. doi: 10.1111/j.1469-1809.1983.tb01001.x. [DOI] [PubMed] [Google Scholar]
  9. Reeders S. T., Breuning M. H., Davies K. E., Nicholls R. D., Jarman A. P., Higgs D. R., Pearson P. L., Weatherall D. J. A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16. Nature. 1985 Oct 10;317(6037):542–544. doi: 10.1038/317542a0. [DOI] [PubMed] [Google Scholar]
  10. SMITH C. A. TESTING FOR HETEROGENEITY OF RECOMBINATION FRACTION VALUES IN HUMAN GENETICS. Ann Hum Genet. 1963 Nov;27:175–182. doi: 10.1111/j.1469-1809.1963.tb00210.x. [DOI] [PubMed] [Google Scholar]
  11. Tsui L. C., Buchwald M., Barker D., Braman J. C., Knowlton R., Schumm J. W., Eiberg H., Mohr J., Kennedy D., Plavsic N. Cystic fibrosis locus defined by a genetically linked polymorphic DNA marker. Science. 1985 Nov 29;230(4729):1054–1057. doi: 10.1126/science.2997931. [DOI] [PubMed] [Google Scholar]
  12. Wainwright B. J., Scambler P. J., Schmidtke J., Watson E. A., Law H. Y., Farrall M., Cooke H. J., Eiberg H., Williamson R. Localization of cystic fibrosis locus to human chromosome 7cen-q22. 1985 Nov 28-Dec 4Nature. 318(6044):384–385. doi: 10.1038/318384a0. [DOI] [PubMed] [Google Scholar]
  13. White R., Leppert M., Bishop D. T., Barker D., Berkowitz J., Brown C., Callahan P., Holm T., Jerominski L. Construction of linkage maps with DNA markers for human chromosomes. Nature. 1985 Jan 10;313(5998):101–105. doi: 10.1038/313101a0. [DOI] [PubMed] [Google Scholar]
  14. White R., Woodward S., Leppert M., O'Connell P., Hoff M., Herbst J., Lalouel J. M., Dean M., Vande Woude G. A closely linked genetic marker for cystic fibrosis. 1985 Nov 28-Dec 4Nature. 318(6044):382–384. doi: 10.1038/318382a0. [DOI] [PubMed] [Google Scholar]