Use of LINKAGE Programs for Linkage Analysis

Marcy C. Speer1

1 Duke University Medical Center, Durham, North Carolina
Publication Name:  Current Protocols in Human Genetics
Unit Number:  Unit 1.7
DOI:  10.1002/0471142905.hg0107s48
Online Posting Date:  February, 2006
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Genetic linkage analysis remains a powerful tool for identifying regions of the genome that may harbor suceptibility loci. This unit describes the traditional approach of calculating two‐point and multipoint lod scores when the underlying genetic model is known. Components of the genetic model include whether a trait is dominant, recessive, or codominant, whether it is autosomal or sex linked, and whether there is mutation at the disease gene locus, as well as the disease and marker allele frequencies and the penetrance of the disease allele. The approach to genetic linkage analysis presented in this unit assumes that the markers are loosely spaced, so that there is no linkage disequilibrium between genetic markers. Practical examples and step‐by‐step guidelines are presented.

Keywords: Linkage analysis; lod score; genetic map; recombination fraction

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Table of Contents

  • Key Concepts
  • Programs for Linkage Analysis
  • Strategic Approach and Practical Examples
  • Commentary
  • Literature Cited
  • Figures
  • Tables
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Literature Cited

   Abecasis, G.R., Cherny, S.S., Cookson, W.O., and Cardon, L.R. 2002. Merlin: Rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30:97‐101.
   Bhat, A., Heath, S.C., and Ott, J. 1999. Heterogeneity for multiple disease loci in linkage analysis. Hum. Hered. 49:229‐231.
   Boehnke, M. 1991. Allele frequency estimation from data on relatives. Am. J. Hum. Genet. 48:22‐25.
   Boyles, A.L., Scott, W.K., Martin, E.R., Schmidt, S., Li, Y.‐J., Ashley‐Koch, A., Bass, M.P., Schmidt, M., Pericak‐Vance, M.A., Speer, M.C., and Hauser, E.R. 2005. Linkage disequilibrium inflates type I error rates in multipoint linkage analysis when parental genotypes are missing. Hum. Hered. 59:220‐227.
   Conneally, P.M., Edwards, J.H., Kidd, K.K., Lalouel, J.‐M., Morton, N.E., Ott, J., and White, R. 1985. Report of the committee on methods of linkage analysis and reporting. Cytogenet. Cell Genet. 40:356‐359.
   Cottingham, R.W., Idury, R.M., and Schaffer, A.A. 1993. Faster sequential genetic linkage computations. Am. J. Hum. Genet. 53:252‐263.
   Freimer, N.B., Sandkjiul, L.A., and Blower, S.M. 1993. Incorrect specification of marker allele frequencies: Effects on linkage analysis. Am. J. Hum. Genet. 52:1102‐1110.
   Gudbjartsson, D.F., Jonasson, K., Frigge, M. L., and Kong, A. 2000. Allegro, a new computer program for multipoint linkage analysis. Nat. Genet. 25:12‐13.
   Gudbjartsson, D.F., Thorvaldsson, T., Kong, A., Gunnarsson, G., and Ingolfsdottir, A. 2005. Allegro version 2. Nat. Genet. 37:1015‐1016.
   Haynes, C., Pericak‐Vance, M., and Dawson, D. 1986. Analysis of Huntington disease linkage and age‐of‐onset distributions. Genet. Epidemiol. 1:235‐239.
   Hodge, S.E., Morton, L.A., Tideman, S., Kidd, K.K., and Spence, M.A. 1979. Age‐at‐onset correction available for linkage analysis (LIPED). Am. J. Hum. Genet. 31:761‐762.
   Knowles, J.A., Vieland, V.J., and Gilliam, T.C. 1992. Perils of gene mapping with microsatellite markers. Am. J. Hum. Genet. 51:905‐909.
   Kruglyak, L., Daly, M.J., Reeve‐Daly, M.P., and Lander, E.S. 1996. Parametric and nonparametric linkage analysis: A unified multipoint approach. Am. J. Hum. Genet. 58:1347‐1363.
   O'Connell, J.R. and Weeks, D.E. 1995. The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set‐recoding and fuzzy inheritance. Nat. Genet. 11:402‐408.
   Ott, J. 1974. Estimation of the recombination fraction in human pedigrees: Efficient computation of the likelihood for human linkage studies. Am. J. Hum. Genet. 26:588‐597.
   Ott, J. 1978. A simple scheme for the analysis of HLA linkage in pedigrees. Ann. Hum. Genet. 42:255‐257.
   Ott, J. 1992. Strategies for characterizing highly polymorphic markers in human gene mapping. Am. J. Hum. Genet. 51:283‐290.
   Ott, J. 1999. Analysis of Human Genetic Linkage, 3rd ed. Johns Hopkins University Press, Baltimore.
   Ott, J., Bhattacharya, S., Chen, J.D., Denton, M.J., Donald, J., Dubay, C., Farrar, G.J., Fishman, G.A., Frey, D., Gal, A., Humphries, P., Jay, B., Jay, M., Litt, M., Machler, M., Musarella, M., Neugebauer, M., Nussbaum, R.L., Terwilliger, J.D., Weleber, R.G., Wirth, B., Wong, F., Worton, R.G., and Wright, A.F. 1990. Localizing multiple X chromosome‐linked retinitis pigmentosa loci using multilocus homogeneity tests. Proc. Natl. Acad. Sci. U.S.A. 87:701‐704.
   Renwick, J.I.H. 1971. The mapping of human chromosomes. Annu. Rev. Genet. 5:81‐120.
   Schaffer, A.A., Gupta, S.K., Shriram, K., and Cottingham, R.W. 1994. Avoiding recomputation in genetic linkage analysis. Hum. Hered. 44:225‐237.
   Sobel, E., Sengul, H., and Weeks, D.E. 2001. Multipoint estimation of identify‐by‐descent probabilities at arbitrary positions among marker loci on general pedigrees. Hum. Hered. 52: 121‐131.
   Terwilliger, J.D. and Ott, J. 1994. Handbook of Human Genetic Linkage. Johns Hopkins University Press, Baltimore.
Key References
   Ott, 1999. See above.
  A necessary reference book for human genetic linkage analysis, with both theoretical and practical perspectives.
   Terwilliger and Ott, 1994. See above.
  A beautifully documented, hands‐on guidebook for performing human linkage analysis.
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