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. 1993 Nov;53(5):1038–1050.

Linkage disequilibrium in the neurofibromatosis 1 (NF1) region: implications for gene mapping.

L B Jorde 1, W S Watkins 1, D Viskochil 1, P O'Connell 1, K Ward 1
PMCID: PMC1682302  PMID: 8105688

Abstract

To test the usefulness of linkage disequilibrium for gene mapping, we compared physical distances and linkage disequilibrium among eight RFLPs in the neurofibromatosis 1 (NF1) region. Seven of the polymorphisms span most of the NF1 gene, while the remaining polymorphism lies approximately 70 kb 3' to a stop codon in exon 49. By using Centre d'Etude du Polymorphisme Humain (CEPH) kindreds, 91-110 unrelated parents were genotyped. A high degree of disequilibrium is maintained among the seven intragenic polymorphisms (r > .82, P < 10(-7)), even though they are separated by as much as 340 kb. The 3' polymorphism is only 68 kb distal to the next polymorphism, but disequilibrium between the 3' polymorphism and all others is comparatively low (magnitude of 4 < .33, P values .27-.001). This result was replicated in three sets of unrelated kindreds: the Utah CEPH families, the non-Utah CEPH families, and an independent set of NF1 families. Trigenic, quadrigenic, three-locus, and four-locus disequilibrium measures were also estimated. There was little evidence of higher-order linkage disequilibrium. As expected for a disease with multiple mutations, no disequilibrium was observed between the disease gene and any of the RFLPs. The observed pattern of high disequilibrium within the gene and a loss of disequilibrium 3' to the stop codon could have implications for gene mapping studies. These are discussed, and guidelines for linkage disequilibrium studies are suggested.

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Selected References

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  1. Barker D., Holm T., White R. A locus on chromosome 11p with multiple restriction site polymorphisms. Am J Hum Genet. 1984 Nov;36(6):1159–1171. [PMC free article] [PubMed] [Google Scholar]
  2. Bech-Hansen N. T., Linsley P. S., Cox D. W. Restriction fragment length polymorphisms associated with immunoglobulin C gamma genes reveal linkage disequilibrium and genomic organization. Proc Natl Acad Sci U S A. 1983 Nov;80(22):6952–6956. doi: 10.1073/pnas.80.22.6952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Begovich A. B., McClure G. R., Suraj V. C., Helmuth R. C., Fildes N., Bugawan T. L., Erlich H. A., Klitz W. Polymorphism, recombination, and linkage disequilibrium within the HLA class II region. J Immunol. 1992 Jan 1;148(1):249–258. [PubMed] [Google Scholar]
  4. Bell G. I., Karam J. H., Rutter W. J. Polymorphic DNA region adjacent to the 5' end of the human insulin gene. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5759–5763. doi: 10.1073/pnas.78.9.5759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Benlian P., Boileau C., Loux N., Pastier D., Masliah J., Coulon M., Nigou M., Ragab A., Guimard J., Ruidavets J. B. Extended haplotypes and linkage disequilibrium between 11 markers at the APOA1-C3-A4 gene cluster on chromosome 11. Am J Hum Genet. 1991 May;48(5):903–910. [PMC free article] [PubMed] [Google Scholar]
  6. Brown A. H. Sample sizes required to detect linkage disequilibrium between two or three loci. Theor Popul Biol. 1975 Oct;8(2):184–201. doi: 10.1016/0040-5809(75)90031-3. [DOI] [PubMed] [Google Scholar]
  7. Børresen A. L., Møller P., Berg K. Linkage disequilibrium analyses and restriction mapping of four RFLPs at the pro alpha 2(I) collagen locus: lack of correlation between linkage disequilibrium and physical distance. Hum Genet. 1988 Mar;78(3):216–221. doi: 10.1007/BF00291664. [DOI] [PubMed] [Google Scholar]
  8. Carothers A. D., Wright A. F. The effect of mutation on linkage disequilibrium. Ann Hum Genet. 1992 May;56(Pt 2):155–158. doi: 10.1111/j.1469-1809.1992.tb01141.x. [DOI] [PubMed] [Google Scholar]
  9. Cawthon R. M., Andersen L. B., Buchberg A. M., Xu G. F., O'Connell P., Viskochil D., Weiss R. B., Wallace M. R., Marchuk D. A., Culver M. cDNA sequence and genomic structure of EV12B, a gene lying within an intron of the neurofibromatosis type 1 gene. Genomics. 1991 Mar;9(3):446–460. doi: 10.1016/0888-7543(91)90410-g. [DOI] [PubMed] [Google Scholar]
  10. Cawthon R. M., O'Connell P., Buchberg A. M., Viskochil D., Weiss R. B., Culver M., Stevens J., Jenkins N. A., Copeland N. G., White R. Identification and characterization of transcripts from the neurofibromatosis 1 region: the sequence and genomic structure of EVI2 and mapping of other transcripts. Genomics. 1990 Aug;7(4):555–565. doi: 10.1016/0888-7543(90)90199-5. [DOI] [PubMed] [Google Scholar]
  11. Chakraborty R., Lidsky A. S., Daiger S. P., Güttler F., Sullivan S., Dilella A. G., Woo S. L. Polymorphic DNA haplotypes at the human phenylalanine hydroxylase locus and their relationship with phenylketonuria. Hum Genet. 1987 May;76(1):40–46. doi: 10.1007/BF00283048. [DOI] [PubMed] [Google Scholar]
  12. Chakravarti A., Buetow K. H., Antonarakis S. E., Waber P. G., Boehm C. D., Kazazian H. H. Nonuniform recombination within the human beta-globin gene cluster. Am J Hum Genet. 1984 Nov;36(6):1239–1258. [PMC free article] [PubMed] [Google Scholar]
  13. Chakravarti A., Elbein S. C., Permutt M. A. Evidence for increased recombination near the human insulin gene: implication for disease association studies. Proc Natl Acad Sci U S A. 1986 Feb;83(4):1045–1049. doi: 10.1073/pnas.83.4.1045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Chakravarti A., Li C. C., Buetow K. H. Estimation of the marker gene frequency and linkage disequilibrium from conditional marker data. Am J Hum Genet. 1984 Jan;36(1):177–186. [PMC free article] [PubMed] [Google Scholar]
  15. Chakravarti A., Phillips J. A., 3rd, Mellits K. H., Buetow K. H., Seeburg P. H. Patterns of polymorphism and linkage disequilibrium suggest independent origins of the human growth hormone gene cluster. Proc Natl Acad Sci U S A. 1984 Oct;81(19):6085–6089. doi: 10.1073/pnas.81.19.6085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Daiger S. P., Chakraborty R., Reed L., Fekete G., Schuler D., Berenssi G., Nasz I., Brdicka R., Kamarýt J., Pijácková A. Polymorphic DNA haplotypes at the phenylalanine hydroxylase (PAH) locus in European families with phenylketonuria (PKU). Am J Hum Genet. 1989 Aug;45(2):310–318. [PMC free article] [PubMed] [Google Scholar]
  17. Elbein S. C. Linkage disequilibrium among RFLPs at the insulin-receptor locus despite intervening Alu repeat sequences. Am J Hum Genet. 1992 Nov;51(5):1103–1110. [PMC free article] [PubMed] [Google Scholar]
  18. Estivill X., Farrall M., Scambler P. J., Bell G. M., Hawley K. M., Lench N. J., Bates G. P., Kruyer H. C., Frederick P. A., Stanier P. A candidate for the cystic fibrosis locus isolated by selection for methylation-free islands. 1987 Apr 30-May 6Nature. 326(6116):840–845. doi: 10.1038/326840a0. [DOI] [PubMed] [Google Scholar]
  19. Feinberg A. P., Vogelstein B. "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. doi: 10.1016/0003-2697(84)90381-6. [DOI] [PubMed] [Google Scholar]
  20. Hanauer A., Chery M., Fujita R., Driesel A. J., Gilgenkrantz S., Mandel J. L. The Friedreich ataxia gene is assigned to chromosome 9q13-q21 by mapping of tightly linked markers and shows linkage disequilibrium with D9S15. Am J Hum Genet. 1990 Jan;46(1):133–137. [PMC free article] [PubMed] [Google Scholar]
  21. Harley H. G., Brook J. D., Floyd J., Rundle S. A., Crow S., Walsh K. V., Thibault M. C., Harper P. S., Shaw D. J. Detection of linkage disequilibrium between the myotonic dystrophy locus and a new polymorphic DNA marker. Am J Hum Genet. 1991 Jul;49(1):68–75. [PMC free article] [PubMed] [Google Scholar]
  22. Haviland M. B., Kessling A. M., Davignon J., Sing C. F. Estimation of Hardy-Weinberg and pairwise disequilibrium in the apolipoprotein AI-CIII-AIV gene cluster. Am J Hum Genet. 1991 Aug;49(2):350–365. [PMC free article] [PubMed] [Google Scholar]
  23. Hedrick P. W. Gametic disequilibrium measures: proceed with caution. Genetics. 1987 Oct;117(2):331–341. doi: 10.1093/genetics/117.2.331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hegele R. A., Plaetke R., Lalouel J. M. Linkage disequilibrium between DNA markers at the low-density lipoprotein receptor gene. Genet Epidemiol. 1990;7(1):69–81. doi: 10.1002/gepi.1370070114. [DOI] [PubMed] [Google Scholar]
  25. Hill W. G., Weir B. S. Variances and covariances of squared linkage disequilibria in finite populations. Theor Popul Biol. 1988 Feb;33(1):54–78. doi: 10.1016/0040-5809(88)90004-4. [DOI] [PubMed] [Google Scholar]
  26. Hudson R. R. The sampling distribution of linkage disequilibrium under an infinite allele model without selection. Genetics. 1985 Mar;109(3):611–631. doi: 10.1093/genetics/109.3.611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hästbacka J., de la Chapelle A., Kaitila I., Sistonen P., Weaver A., Lander E. Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nat Genet. 1992 Nov;2(3):204–211. doi: 10.1038/ng1192-204. [DOI] [PubMed] [Google Scholar]
  28. Kaplan N., Weir B. S. Expected behavior of conditional linkage disequilibrium. Am J Hum Genet. 1992 Aug;51(2):333–343. [PMC free article] [PubMed] [Google Scholar]
  29. Kerem B., Rommens J. M., Buchanan J. A., Markiewicz D., Cox T. K., Chakravarti A., Buchwald M., Tsui L. C. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989 Sep 8;245(4922):1073–1080. doi: 10.1126/science.2570460. [DOI] [PubMed] [Google Scholar]
  30. Kupke K. G., Graeber M. B., Müller U. Dystonia-parkinsonism syndrome (XDP) locus: flanking markers in Xq12-q21.1. Am J Hum Genet. 1992 Apr;50(4):808–815. [PMC free article] [PubMed] [Google Scholar]
  31. Lalouel J. M., Jorde L. B. Idiopathic hemochromatosis: significance and implications of linkage and association to HLA. Ann N Y Acad Sci. 1988;526:34–46. doi: 10.1111/j.1749-6632.1988.tb55490.x. [DOI] [PubMed] [Google Scholar]
  32. Leitersdorf E., Chakravarti A., Hobbs H. H. Polymorphic DNA haplotypes at the LDL receptor locus. Am J Hum Genet. 1989 Mar;44(3):409–421. [PMC free article] [PubMed] [Google Scholar]
  33. Lewontin R C. The Interaction of Selection and Linkage. I. General Considerations; Heterotic Models. Genetics. 1964 Jan;49(1):49–67. doi: 10.1093/genetics/49.1.49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Litt M., Jorde L. B. Linkage disequilibria between pairs of loci within a highly polymorphic region of chromosome 2Q. Am J Hum Genet. 1986 Aug;39(2):166–178. [PMC free article] [PubMed] [Google Scholar]
  35. MacDonald M. E., Lin C., Srinidhi L., Bates G., Altherr M., Whaley W. L., Lehrach H., Wasmuth J., Gusella J. F. Complex patterns of linkage disequilibrium in the Huntington disease region. Am J Hum Genet. 1991 Oct;49(4):723–734. [PMC free article] [PubMed] [Google Scholar]
  36. MacDonald M. E., Novelletto A., Lin C., Tagle D., Barnes G., Bates G., Taylor S., Allitto B., Altherr M., Myers R. The Huntington's disease candidate region exhibits many different haplotypes. Nat Genet. 1992 May;1(2):99–103. doi: 10.1038/ng0592-99. [DOI] [PubMed] [Google Scholar]
  37. Mantel N. The detection of disease clustering and a generalized regression approach. Cancer Res. 1967 Feb;27(2):209–220. [PubMed] [Google Scholar]
  38. McLellan T., Jorde L. B., Skolnick M. H. Genetic distances between the Utah Mormons and related populations. Am J Hum Genet. 1984 Jul;36(4):836–857. [PMC free article] [PubMed] [Google Scholar]
  39. Messiaen L., De Bie S., Moens T., Van den Enden A., Leroy J. Lack of independence between five DNA polymorphisms in the NF1 gene. Hum Mol Genet. 1993 Apr;2(4):485–485. doi: 10.1093/hmg/2.4.485. [DOI] [PubMed] [Google Scholar]
  40. Migone N., de Lange G., Piazza A., Cavalli-Sforza L. L. Genetic analysis of eight linked polymorphisms within the human immunoglobulin heavy-chain region. Am J Hum Genet. 1985 Nov;37(6):1146–1163. [PMC free article] [PubMed] [Google Scholar]
  41. Miserez A. R., Schuster H., Chiodetti N., Keller U. Polymorphic haplotypes and recombination rates at the LDL receptor gene locus in subjects with and without familial hypercholesterolemia who are from different populations. Am J Hum Genet. 1993 Apr;52(4):808–826. [PMC free article] [PubMed] [Google Scholar]
  42. Murray J. C., Buetow K. H., Donovan M., Hornung S., Motulsky A. G., Disteche C., Dyer K., Swisshelm K., Anderson J., Giblett E. Linkage disequilibrium of plasminogen polymorphisms and assignment of the gene to human chromosome 6q26-6q27. Am J Hum Genet. 1987 Apr;40(4):338–350. [PMC free article] [PubMed] [Google Scholar]
  43. Murray J. C., Mills K. A., Demopulos C. M., Hornung S., Motulsky A. G. Linkage disequilibrium and evolutionary relationships of DNA variants (restriction enzyme fragment length polymorphisms) at the serum albumin locus. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3486–3490. doi: 10.1073/pnas.81.11.3486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. O'Connell P., Leach R. J., Ledbetter D. H., Cawthon R. M., Culver M., Eldridge J. R., Frej A. K., Holm T. R., Wolff E., Thayer M. J. Fine structure DNA mapping studies of the chromosomal region harboring the genetic defect in neurofibromatosis type I. Am J Hum Genet. 1989 Jan;44(1):51–57. [PMC free article] [PubMed] [Google Scholar]
  45. O'Connell P., Leach R., Cawthon R. M., Culver M., Stevens J., Viskochil D., Fournier R. E., Rich D. C., Ledbetter D. H., White R. Two NF1 translocations map within a 600-kilobase segment of 17q11.2. Science. 1989 Jun 2;244(4908):1087–1088. doi: 10.1126/science.2543077. [DOI] [PubMed] [Google Scholar]
  46. O'Connell P., Plaetke R., Matsunami N., Odelberg S., Jorde L., Chance P., Leppert M., Lalouel J. M., White R. An extended genetic linkage map and an "index" map for human chromosome 17. Genomics. 1993 Jan;15(1):38–47. doi: 10.1006/geno.1993.1007. [DOI] [PubMed] [Google Scholar]
  47. O'Connell P., Viskochil D., Buchberg A. M., Fountain J., Cawthon R. M., Culver M., Stevens J., Rich D. C., Ledbetter D. H., Wallace M. The human homolog of murine Evi-2 lies between two von Recklinghausen neurofibromatosis translocations. Genomics. 1990 Aug;7(4):547–554. doi: 10.1016/0888-7543(90)90198-4. [DOI] [PubMed] [Google Scholar]
  48. Oliver S. G., van der Aart Q. J., Agostoni-Carbone M. L., Aigle M., Alberghina L., Alexandraki D., Antoine G., Anwar R., Ballesta J. P., Benit P. The complete DNA sequence of yeast chromosome III. Nature. 1992 May 7;357(6373):38–46. doi: 10.1038/357038a0. [DOI] [PubMed] [Google Scholar]
  49. Ozelius L. J., Kramer P. L., de Leon D., Risch N., Bressman S. B., Schuback D. E., Brin M. F., Kwiatkowski D. J., Burke R. E., Gusella J. F. Strong allelic association between the torsion dystonia gene (DYT1) andloci on chromosome 9q34 in Ashkenazi Jews. Am J Hum Genet. 1992 Mar;50(3):619–628. [PMC free article] [PubMed] [Google Scholar]
  50. Pandolfo M., Sirugo G., Antonelli A., Weitnauer L., Ferretti L., Leone M., Dones I., Cerino A., Fujita R., Hanauer A. Friedreich ataxia in Italian families: genetic homogeneity and linkage disequilibrium with the marker loci D9S5 and D9S15. Am J Hum Genet. 1990 Aug;47(2):228–235. [PMC free article] [PubMed] [Google Scholar]
  51. Pound S. E., Carothers A. D., Pignatelli P. M., Macnicol A. M., Watson M. L., Wright A. F. Evidence for linkage disequilibrium between D16S94 and the adult onset polycystic kidney disease (PKD1) gene. J Med Genet. 1992 Apr;29(4):247–248. doi: 10.1136/jmg.29.4.247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Skraastad M. I., Van de Vosse E., Belfroid R., Höld K., Vegter-van der Vlis M., Sandkuijl L. A., Bakker E., van Ommen G. J. Significant linkage disequilibrium between the Huntington disease gene and the loci D4S10 and D4S95 in the Dutch population. Am J Hum Genet. 1992 Oct;51(4):730–735. [PMC free article] [PubMed] [Google Scholar]
  53. Sved J. A. Linkage disequilibrium and homozygosity of chromosome segments in finite populations. Theor Popul Biol. 1971 Jun;2(2):125–141. doi: 10.1016/0040-5809(71)90011-6. [DOI] [PubMed] [Google Scholar]
  54. Templeton A. R., Boerwinkle E., Sing C. F. A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping. I. Basic theory and an analysis of alcohol dehydrogenase activity in Drosophila. Genetics. 1987 Oct;117(2):343–351. doi: 10.1093/genetics/117.2.343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Theilmann J., Kanani S., Shiang R., Robbins C., Quarrell O., Huggins M., Hedrick A., Weber B., Collins C., Wasmuth J. J. Non-random association between alleles detected at D4S95 and D4S98 and the Huntington's disease gene. J Med Genet. 1989 Nov;26(11):676–681. doi: 10.1136/jmg.26.11.676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Thompson E. A., Deeb S., Walker D., Motulsky A. G. The detection of linkage disequilibrium between closely linked markers: RFLPs at the AI-CIII apolipoprotein genes. Am J Hum Genet. 1988 Jan;42(1):113–124. [PMC free article] [PubMed] [Google Scholar]
  57. Tzall S., Ellenbogen A., Eng F., Hirschhorn R. Identification and characterization of nine RFLPs at the adenosine deaminase (ADA) locus. Am J Hum Genet. 1989 Jun;44(6):864–875. [PMC free article] [PubMed] [Google Scholar]
  58. Viskochil D., Buchberg A. M., Xu G., Cawthon R. M., Stevens J., Wolff R. K., Culver M., Carey J. C., Copeland N. G., Jenkins N. A. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell. 1990 Jul 13;62(1):187–192. doi: 10.1016/0092-8674(90)90252-a. [DOI] [PubMed] [Google Scholar]
  59. Viskochil D., Cawthon R., O'Connell P., Xu G. F., Stevens J., Culver M., Carey J., White R. The gene encoding the oligodendrocyte-myelin glycoprotein is embedded within the neurofibromatosis type 1 gene. Mol Cell Biol. 1991 Feb;11(2):906–912. doi: 10.1128/mcb.11.2.906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Viskochil D., White R., Cawthon R. The neurofibromatosis type 1 gene. Annu Rev Neurosci. 1993;16:183–205. doi: 10.1146/annurev.ne.16.030193.001151. [DOI] [PubMed] [Google Scholar]
  61. Vnencak-Jones C. L., Phillips J. A., 3rd Hot spots for growth hormone gene deletions in homologous regions outside of Alu repeats. Science. 1990 Dec 21;250(4988):1745–1748. doi: 10.1126/science.1980158. [DOI] [PubMed] [Google Scholar]
  62. Walter M. A., Cox D. W. Nonuniform linkage disequilibrium within a 1,500-kb region of the human immunoglobulin heavy-chain complex. Am J Hum Genet. 1991 Nov;49(5):917–931. [PMC free article] [PubMed] [Google Scholar]
  63. Ward K., O'Connell P., Carey J. C., Leppert M., Jolley S., Plaetke R., Ogden B., White R. Diagnosis of neurofibromatosis I by using tightly linked, flanking DNA markers. Am J Hum Genet. 1990 May;46(5):943–949. [PMC free article] [PubMed] [Google Scholar]
  64. Watkins W. S., O'Connell P., Stevens J., Culver M., Ewart A., Jorde L. B. A BglII RFLP near the human neurofibromatosis type 1 (NF1) gene. Nucleic Acids Res. 1991 Dec 11;19(23):6662–6662. doi: 10.1093/nar/19.23.6662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Weir B. S., Hill W. G. Nonuniform recombination within the human beta-globin gene cluster. Am J Hum Genet. 1986 May;38(5):776–781. [PMC free article] [PubMed] [Google Scholar]
  66. Weir B. S. Inferences about linkage disequilibrium. Biometrics. 1979 Mar;35(1):235–254. [PubMed] [Google Scholar]
  67. Zerba K. E., Kessling A. M., Davignon J., Sing C. F. Genetic structure and the search for genotype-phenotype relationships: an example from disequilibrium in the Apo B gene region. Genetics. 1991 Oct;129(2):525–533. doi: 10.1093/genetics/129.2.525. [DOI] [PMC free article] [PubMed] [Google Scholar]

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