Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland

An Erratum to this article was published on 01 December 1992

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

  1. 1

    Collins, F.S. Positional cloning: Let's not call it reverse anymore. Nature Genet. 1, 3–6 (1992).

    CAS  Article  Google Scholar 

  2. 2

    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).

    Article  Google Scholar 

  3. 3

    Kerem, B.-S. et al. Identification of cystic fibrosis gene: genetic analysis. Science 245, 1073–1080 (1989).

    CAS  Article  Google Scholar 

  4. 4

    Nevanlinna, H.R. The Finnish population structure-A genetic and genealogical study. Hereditas 71, 195–236 (1972).

    CAS  Article  Google Scholar 

  5. 5

    Norio, R., Nevanlinna, H.R. & Perheentupa, J. Hereditary diseases in Finland; rare flora in rare soil. Ann. clin. Res. 5, 109–141 (1973).

    CAS  PubMed  Google Scholar 

  6. 6

    Norio, R. in Biocultural aspects of disease (eds H. Rotschild) 359–415 (Academic Press, New York, 1981).

    Google Scholar 

  7. 7

    Walker, B.A., Scott, C.I., Hall, J.G., Murdoch, J.L. & McKusick, V.A. Diastrophic dwarfism. Medicine 51, 41–59 (1972).

    CAS  Article  Google Scholar 

  8. 8

    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).

    Article  Google Scholar 

  9. 9

    Hästbacka, J. et al. A linkage map spanning the locus for diastrophic dysplasia. Genomics 11, 968–973 (1991).

    Article  Google Scholar 

  10. 10

    Luria, S.E. & Delbrück, M. Mutations of bacteria from virus sensitivity to virus resistance. Genetics 28, 491–511 (1943).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Cavalli-Sforza, L.L. & Bodmer, W.F. The Genetics of Human Populations. pages 71–110. (Freeman, San Francisco, 1971).

    Google Scholar 

  12. 12

    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).

    CAS  Article  Google Scholar 

  13. 13

    Hill, W.G. & Weir, B.S. Variances and covariances of squared linkage disequilibria in finite populations. Theor. pop. Biol. 33: 54–78 (1988).

    CAS  Article  Google Scholar 

  14. 14

    Kaplan, N. & Weir, B.S. Expected behavior of conditional linkage disequilibrium. Am. J. hum. Genet. 51: 333–343 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    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).

    Google Scholar 

  16. 16

    Gedde-Dahl, T. Genetisk epidemiologi i Norge. Finska läkaresällskapets handlingar 135, 199–213 (1992).

    Google Scholar 

  17. 17

    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).

    Google Scholar 

  18. 18

    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).

    Google Scholar 

  19. 19

    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).

    Google Scholar 

  20. 20

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    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).

    Article  Google Scholar 

  22. 22

    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).

    CAS  Article  Google Scholar 

  23. 23

    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).

    CAS  Article  Google Scholar 

  24. 24

    Brody, L.C. et al. Ornithine -aminotransferase mutations in gyrate atrophy. J. biol. Chem. 267, 3302–3307 (1992).

    CAS  PubMed  Google Scholar 

  25. 25

    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).

    CAS  Article  Google Scholar 

  26. 26

    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).

    CAS  Article  Google Scholar 

  27. 27

    Sherr, C.J. Colony-stimulating factor-1 receptor. Blood 75, 1–12 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular Cloning, a Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989).

    Google Scholar 

  29. 29

    Dietrich, W. et al. A genetic map of the mouse suitable for typing intraspecific crosses. Genetics 131, 423–447 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    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).

    CAS  PubMed  Google Scholar 

  31. 31

    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).

    CAS  Article  Google Scholar 

  32. 32

    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).

    CAS  Article  Google Scholar 

  33. 33

    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).

    CAS  Article  Google Scholar 

  34. 34

    Weir, B.S. Genetic Data Analysis (Sinauer, Sunderland, Massachusetts, 1990).

    Google Scholar 

  35. 35

    Sahorta, S. Haldane's solution of the Luria-Delbruck distribution. Genetics 127, 257–261 (1991).

    Google Scholar 

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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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