Abstract
Linkage disequilibrium mapping in isolated populations provides a powerful tool for fine structure localization of disease genes. Here, Luria and Delbrück's classical methods for analysing bacterial cultures are adapted to the study of human isolated founder populations in order to estimate (i) the recombination fraction between a disease locus and a marker; (ii) the expected degree of allelic homogeneity in a population; and (iii) the mutation rate of marker loci. Using these methods, we report striking linkage disequilibrium for diastrophic dysplasia (DTD) in Finland indicating that the DTD gene should lie within 0.06 centimorgans (or about 60 kilobases) of the CSF1R gene. Predictions about allelic homogeneity in Finland and mutation rates in simple sequence repeats are confirmed by independent observations.
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References
Collins, F.S. Positional cloning: Let's not call it reverse anymore. Nature Genet. 1, 3–6 (1992).
Lander, E.S. & Botstein, D. Mapping complex genetic traits in humans: new methods using a complete RFLP linkage map. Cold Spring Harbor Symposia on Quantitative Biology 51, 49–62 (1986).
Kerem, B.-S. et al. Identification of cystic fibrosis gene: genetic analysis. Science 245, 1073–1080 (1989).
Nevanlinna, H.R. The Finnish population structure-A genetic and genealogical study. Hereditas 71, 195–236 (1972).
Norio, R., Nevanlinna, H.R. & Perheentupa, J. Hereditary diseases in Finland; rare flora in rare soil. Ann. clin. Res. 5, 109–141 (1973).
Norio, R. in Biocultural aspects of disease (eds H. Rotschild) 359–415 (Academic Press, New York, 1981).
Walker, B.A., Scott, C.I., Hall, J.G., Murdoch, J.L. & McKusick, V.A. Diastrophic dwarfism. Medicine 51, 41–59 (1972).
Hästbacka, J., Kaitila, I., Sistonen, P. & de la Chapelle, A. Diastrophic dysplasia gene maps to the distal long arm of chromosome 5. Proc. natn. Acad. Sci. U.S.A. 87, 8056–8059 (1990).
Hästbacka, J. et al. A linkage map spanning the locus for diastrophic dysplasia. Genomics 11, 968–973 (1991).
Luria, S.E. & Delbrück, M. Mutations of bacteria from virus sensitivity to virus resistance. Genetics 28, 491–511 (1943).
Cavalli-Sforza, L.L. & Bodmer, W.F. The Genetics of Human Populations. pages 71–110. (Freeman, San Francisco, 1971).
Stevenson, A.C. & Kerr, C.B. On the distribution of frequencies of mutations to genes determining harmful traits in man. Mut. Res. 4, 339–352 (1967).
Hill, W.G. & Weir, B.S. Variances and covariances of squared linkage disequilibria in finite populations. Theor. pop. Biol. 33: 54–78 (1988).
Kaplan, N. & Weir, B.S. Expected behavior of conditional linkage disequilibrium. Am. J. hum. Genet. 51: 333–343 (1992).
Morton, N.E. in Population structure and genetic disorders (eds A.W. Eriksson, H.R. Forsius, H.R. Nevanlinna, P.L. Workman & R.K. Norio) 43–56 (Academic Press, London, 1980).
Gedde-Dahl, T. Genetisk epidemiologi i Norge. Finska läkaresällskapets handlingar 135, 199–213 (1992).
Goodman, R.M. in Population structure and genetic disorders (eds A.W. Eriksson, H.R. Forsius, H.R. Nevanlinna, P.L. Workman & R.K. Norio) 337–351 (Academic Press, London, 1980).
Klein, D. & Rabinowicz, T. in Population structure and genetic disorders (eds. A.W. Eriksson, H.R. Forsius, H. R. Nevanlinna, P. L Workman & R. K. Norio) 367–382 (Academic Press, London, 1980).
Kirk, R.L. in Population structure and genetic disorders (eds. A. W. Eriksson, H.R. Forsius, H.R. Nevanlinna, P.L. Workman & R.K. Norio) 113–137 (Academic Press, London, 1980).
Sirugo, G. et al. Friedreich ataxia in Louisiana Acadians: demonstration of a founder effect by analysis of microsatellite-generated extended haplotypes. Am. J. hum. Genet. 50, 559–566 (1992).
Syvänen, A.-C. et al. Convenient and quantitative determination of the frequency of a mutant allele using solid-phase minisequencing: application to aspartylglucosaminuria in Finland. Genomics 12, 590–595 (1991).
Mononen, T., Mononen, I., Matilainen, R. & Airaksinen, E. High prevalence of aspartylglucosaminuria among school-age children in eastern Finland. Hum. Genet. 87, 266–268 (1991).
Mitchell, G.A. et al. At least two mutant alleles of ornithine--aminotransferase cause gyrate atrophy of the choriod and retina in Finns. Proc. natn. Acad. Sci. U.S.A. 86, 197–20 (1989).
Brody, L.C. et al. Ornithine -aminotransferase mutations in gyrate atrophy. J. biol. Chem. 267, 3302–3307 (1992).
Jeffreys, A.J., Royle, N.J., Wilson, V. & Wong, Z. Spontaneous mutation rates to new length alleles at tandem-repetitive hypervariable loci in human DNA. Nature 332, 278–281 (1988).
Roberts, W.M., Look, A.T., Roussel, M.F. & Sherr, C. Tanden linkage of human CSF-1 receptor (c-fms) and PDGF receptor genes. Cell 55, 655–661 (1988).
Sherr, C.J. Colony-stimulating factor-1 receptor. Blood 75, 1–12 (1990).
Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular Cloning, a Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989).
Dietrich, W. et al. A genetic map of the mouse suitable for typing intraspecific crosses. Genetics 131, 423–447 (1992).
Hampe, A., Shamoon, B.-M., Gobet, M., Sherr, C.J. & Galibert, F. Nucleotide sequence and structural organization of the human FMS proto-oncogene. Oncogene Res. 4, 9–17 (1989).
Xu, D.Q.X., Guilholt, S. & Galibert, F. Restriction fragment length polymorphism of the human c-fms gene. Proc. natn. Acad. Sci. U.S.A. 82, 2862–2865 (1985).
Verbeek, J.S., Roebroek, A.J.M., Van Den Ouweland, A.M.W., Bloemers, H.P.J. & Van De Ven, W.J.M. Human c-fms proto-oncogene: comparative analysis with an abnormal allele. Molec. cell Biol. 5, 422–426 (1985).
Polymeropoulos, M.H., Xiao, H., Rath, D.S., Merril, C.R. Dinucleotiderepeat polymorphism at the human proto-oncogene CFS-1 receptor (CSF1 R). Nucl. Acids Res. 19, 1160 (1991).
Weir, B.S. Genetic Data Analysis (Sinauer, Sunderland, Massachusetts, 1990).
Sahorta, S. Haldane's solution of the Luria-Delbruck distribution. Genetics 127, 257–261 (1991).
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Hästbacka, J., de la Chapelle, A., Kaitila, I. et al. Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nat Genet 2, 204–211 (1992). https://doi.org/10.1038/ng1192-204
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DOI: https://doi.org/10.1038/ng1192-204
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