Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Linkage disequilibrium and extended haplotypes in the HLA-A to D6S105 region: implications for mapping the hemochromatosis gene (HFE)

Abstract

The hemochromatosis gene (HFE) maps to 6p21.3, in close linkage with the HLA Class I genes. Linkage disequilibrium (LD) studies were designed to narrow down the most likely candidate region for HFE, as an alternative to traditional linkage analysis. However, both the HLA-A and D6S105 subregions, which are situated 2–3 cM and approximately 3 Mb apart, have been suggested to contain HFE. The present report extends our previous study based upon the analysis of a large number of HFE and normal chromosomes from 66families of Breton ancestry. In addition to the previously used RFLP markers spanning the 400-kb surrounding HLA-A, we examined three microsatellites: D6S510, HLA-F, and D6S105. Our combined data not only confirm a peak of LD at D6S105, but also reveal a complex pattern of LD over the i82 to D6S105 interval. Within our ethnically well-defined population of Brittany, the association of HFE with D6S105 is as great as that with HLA-A, while the internal markers display a lower LD. Fine haplotype analysis enabled us to identify two categories of haplotypes segregating with HFE. In contrast to the vast majority of normal haplotypes, 50% of HFE haplotypes are completely conserved over the HLA-A to D6S105 interval. These haplotypes could have been conserved through recombination suppression, selective forces and/or other evolutionary factors. This particular haplotypic configuration might account for the apparent inconsistencies between genetic linkage and LD data, and additionally greatly complicates positional cloning of HFE through disequilibrium mapping.

This is a preview of subscription content, log in to check access.

References

  1. Abderrahim H, Sambucy JL, Iris F, Ouguen P, Billault A, Chumakov IM, Dausset J, Cohen D, Le Paslier D (1994) Cloning the human major histocompatibility complex in YACS. Genomics 23: 520–527

  2. Andrew S, Theilmann J, Hedrick A, Mah D, Weber B, Hayden MR (1992) Nonrandom association between Huntington disease and two loci separated by about 3 Mb on 4p16.3. Genomics 13: 301–311

  3. Andrew S, Theilmann J, Almqvist E, Norremolle A, Lucotte G, Anvret M, Sorensen SA, Turpin JC, Hayden MR (1993) DNA analysis of distinct populations suggests multiple origins for the mutation causing Huntington disease. Clin Genet 43: 286–294

  4. Awdeh ZL, Raum D, Yunis EJ, Alper CA (1983) Extended HLA/complement allele haplotypes: evidence for T/t-like complex in man. Proc Natl Acad Sci USA 80: 259–263

  5. Bengtsson BO, Thomson G (1981) Measuring the strength of associations between HLA antigens and diseases. Tissue Antigens 18: 356–363

  6. Boretto J, Jouanolle AM, Yaouanq J, El Kahloun A, Mauvieux V, Blayau M, Perichon M, Le Treut A, Clayton J, Borot N, Le Gall JY, Pontarotti P, David V (1992) Anonymous markers located on chromosome 6 between HLA-A and B: allelic distribution in genetic hemochromatosis. Hum Genet 89: 33–36

  7. Christiansen FT, Zhang WJ, Griffiths M, Mallal SA, Dawkins RL (1991) Major histocompatibility complex (MHC) complement deficiency, ancestral haplotypes and systemic lupus erythematosus (SLE): C4 deficiency explains some but not all of the influence of the MHC. J Rheumatol 18: 1350–1358

  8. Cooper DN, Clayton JF (1988) DNA polymorphism and the study of disease association. Hum Genet 78: 299–312

  9. David V, Paul P, Simon M, Le Gall JY, Fauchet R, Gicquel I, Dugast I, Le Mignon L, Yaouanq J, Cohen D, Bourel M (1986) DNA polymorphism related to the idiopathic hemochromatosis gene: evidence in a recombinant family. Hum Genet 74: 113–120

  10. David V, Boretto J, Jouanolle AM, Mauvieux V, El Kahloun A, Perichon M, Blayau M, Pontarotti P (1990) Two polymorphisms at the locus D6S98 defined by a YAC. Nucleic Acids Res 18: 5582

  11. Edwards CQ, Griffin LM, Dadone MM, Skolnick MH, Kushner JP (1986) Mapping the locus for hereditary hemochromatosis: localization between HLA-B and HLA-A. Am J Hum Genet 38: 805–811

  12. El Kahloun A, Jouanolle AM, Chorney M, Mauvieux V, Gicquel I, Pontarotti P, David V (1991) A new polymorphic probe close to HLA-A. Nucleic Acids Res 19: 5100

  13. El Kahloun A, Vernet C, Jouanolle AM, Boretto J, Mauvieux V, Le Gall JY, David V, Pontarotti P (1992) A continuous restriction map from HLA-E to HLA-F. Structural comparison between different HLA-A haplotypes. Immunogenetics 35: 183–189

  14. El Kahloun A, Chauvel B, Mauvieux V, Dorval I, Jouanolle AM, Gicquel I, Le Gall JY, David V (1993) Localization of seven new genes around the HLA-A locus. Hum Mol Genet 2: 55–60

  15. Gandon G, Lelaure V, Pichon L, Jouanolle AM, Le Gall JY, David V (1994) Dinucleotide repeat polymorphism at the D6S510 locus. Hum Mol Genet 3: 1210

  16. Gasparini P, Borgato L, Piperno A, Girelli D, Olivieri O, Gottardi E, Roetto A, Dianzani I, Fargion S, Schinaia G, Ceppellini MD, Gandini G, Pignatti PF, Fiorelli G, De Sandre G, Camaschella C (1993) Linkage analysis of 6p21 polymorphic markers and the hereditary hemochromatosis: localisation of the gene centromeric to HLA-F. Hum Mol Genet 2: 571–576

  17. Geraghty DE, Pein J, Lipsky B, Hansen JA, Taillon-Miller P, Bronson SK, Chaplin DD (1992) Cloning and physical mapping of the HLA-class I region spanning the HLA-E-to-HLA-F interval by using yeast artificial chromosomes. Proc Natl Acad Sci USA 89: 2669–2673

  18. Goei VL, Parimoo S, Capossel A, Chu TW, Gruen JR (1994) Isolation of novel non-HLA gene fragments from the hemochromatosis region (6p21. 3) by cDNA hybridization selection. Am J Hum Genet 54: 244–251

  19. Gruen JR, Goei VL, Summers KM, Capossela A, Powell L, Halliday J, Zoghbi H, Shukla H, Weissman SM (1992) Physical and genetic mapping of the telomeric major histocompatibility complex region in man and relevance to the primary hemochromatosis gene. Genomics 14: 232–240

  20. Hästabacka J, Chapelle A de la, Kaitila I, Sistonen P, Weaver A, Lander E (1992) Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nature Genet 2: 204–211

  21. Hill WG (1975) Linkage disequilibrium among multiple neutral alleles produced by mutation in finite population. Theor Popul Biol 8: 117–126

  22. Hill WG, Robertson A (1968) Linkage disequilibrium in finite populations. Theor Appl Genet 38: 226–231

  23. Hill WG, Weir BS (1994) Maximum likelihood estimation of gene location by linkage disequilibrium. Am J Hum Genet 54: 705–714

  24. Huntington's Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72: 971–983

  25. Jazwinska EC, Lee SC, Webb SI, Halliday JW, Powell LW (1993) Localization of the hemochromatosis gene close to D6S105. Am J Hum Genet 53: 347–352

  26. Jorde LB, Watkins WS, Viskochil D, O'Connell P, Ward K (1993) Linkage disequilibrium in the neurofibromatosis I (NFI) region: implication for gene mapping. Am J Hum Genet 53: 1038–1050

  27. Kerem BS, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui LC (1989) Identification of the cystic fibrosis gene: genetic analysis. Science 245: 1073–080

  28. Knapp M, Seuchter SA, Baur MP (1993) The haplotype relative risk (HRR) method for analysis of association in nuclear families. Am J Hum Genet 52: 1085–1093

  29. Lalouel JM, Jorde LB (1988) Idiopathic hemochromatosis: significance and implications of linkage and association to HLA. Ann NY Acad Sci 526: 34–46

  30. Lalouel JM, Le Mignon L, Simon M, Fauchet R, Bourel M, Rao DC, Morton NE (1985) Genetic analysis of idiopathic hemochromatosis using both qualitative (disease status) and quantitative (serum iron) information. Am J Hum Genet 37: 700–718

  31. Lehesjoki AE, Koskiniemi M, Norio R, Tirrito S, Sistonene P, Lander E, Chapelle A de la (1993) Localisation of the EPM1 gene for progressive myoclonus epilepsy on chromosome 21: linkage disequilibrium allows high resolution mapping. Hum Mol Genet 2: 1229–1234

  32. Litt M, Jorde LB (1986) Linkage disequilibria between pairs of loci within a highly polymorphic region of chromosome 2q. Am J Hum Genet 39: 166–178

  33. Mayo O, Street DJ (1986) Heterogeneity in disease associations. Hum Hered 36: 89–92

  34. Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampish HJ, Stromeyer G (1985) Survival and causes of death in cirrhotic and non-cirrhotic patients with primary hemochromatosis. N Engl J Med 14: 1256–1262

  35. Powell LW, Bassett ML, Axelsen E, Ferluga J, Halliday JW (1988) Is all hereditary hemochromatosis HLA-associated? Ann NY Acad Sci 526: 23–33

  36. Powell LW, Summers KM, Board PG, Axelsen E, Webb S, Halliday JW (1990) Expression of hemochromatosis in homozygous subjects. Implication for early diagnosis and prevention. Gastroenterology 98: 1625–1632

  37. Silver LM, Artzt K (1981) Recombination suppression of mouse thaplotypes due to chromatin mismatching. Nature 290: 68–70

  38. Simon M (1990) Disorders of iron metabolism and related disorders. In: Emery AE, Rimoin DL (eds) Principle and practice of medical genetics, 2nd edn. Churchill Livingstone, Edinburgh London Melbourne New York, pp 1783–1796

  39. Simon M, Bourel M, Fauchet R, Genetet B (1976) Association of HLA A3 and HLA B14 antigens with idiopathic haemochromatosis. Gut 17: 332–334

  40. Simon M, Bourel M, Genetet B, Fauchet R (1977) Idiopathic hemochromatosis. Demonstration of recessive inheritance and early detection by family HLA typing. N Engl J Med 297: 1017–1021

  41. Simon M, Le Mignon L, Fauchet R, Yaouanq J, David V, Edan G, Bourel M (1987) A study of 609 haplotypes marking for the hemochromatosis gene: (1) mapping of the gene near the HLAA locus and characters required to define a heterozygous population and (2) hypothesis concerning the underlying cause of hemochromatosis-HLA association. Am J Hum Genet 41: 89–105

  42. Simon M, Yaouanq J, Le Gall JY, Fauchet R, Brissot P, Bourel M (1988) Genetics of hemochromatosis: HLA association and mode of inheritance. Ann NY Acad Sci 526: 11–22

  43. Sirugo G, Cocozza S, Brice A, Cavalcanti F, De Michele G, Doues I, Filla A, Koenig M, Lorenzetti D, Monticelli A, Pianese L, Redolfi E, Rousseau F, Mandel JL, Di Donato S, Pandolfo M (1993) Linkage disequilibrium analysis of Friedreich's ataxia in 140 Caucasian families: positioning ot the disease locus and evaluation of allelic heterogeneity. Eur J Hum Genet 1: 133–143

  44. Stone C, Pointon J, Jazwinska EC, Halliday JW, Powell LW, Robson KJH, Monaco AP, Weatherall DJ (1994) Isolation of CA dinucleotide repeats close to D6S105; linkage disequilibrium with haemochromatosis. Hum Mol Genet 3: 2043–2046

  45. Tokunaga K, Saueracker G, Kay PH, Christiansen FT, Anand R, Dawkins RL (1988) Extensive deletions and insertions in different MHC supratypes detected by pulse fields gel electrophoresis. J Exp Med 168: 933–940

  46. Trent JM, Ziegler A (1993) Report of the first international workshop on human chromosome 6 mapping. Cytogenet Cell Genet 62: 66–75

  47. Venditti CP, Chorney MJ (1992) Class I gene contraction within the HLA-A subresion on the human MHC. Genomics 14: 1003–1009

  48. Venditti CP, Harris JM, Geraghty DE, Chorney MJ (1994) Mapping and characterization of non-HLA multigene assemblages in the human MHC class 1 region. Genomics 22: 257–266

  49. Voltz A, Boyle JM, Cann HM, Cottingham RW, Orr H, Ziegler A (1994) Report on the second international workshop on human chromosome 6. Genomics 21: 464–472

  50. Weir BS, Cockerham CC (1978) Testing hypothesis about linkage disequilibrium with multiple alleles. Genetics 88: 633–642

  51. Wilkie PJ, Polymeropoulos MH, Trent JM, Small KW, Weber JL (1993) Genetic and physical map of 11 short tandem repeat polymorphisms on human chromosome 6. Genomics 15: 225–227

  52. Worwood M, Raha-Chowdhury R, Dorak MT, Darke C, Bowen DJ, Burnett AK (1994) Alleles at D6S265 and D6S105 define a hemochromatosis-specific genotype. Br J Haematol 86: 863–866

  53. Yaouanq J (1993) Hémochromatose génétique: étude de prévalence en Bretagne, marqueurs moléculaires associés au gène et leurs applications au conseil génétique. PhD thesis, Mention Sciences Biologiques, University of Rennes I, France

  54. Yaouanq J, El Kahloun A, Chorney M, Jouanolle AM, Mauvieux V, Perichon M, Blayau M, Pontarotti P, Le Gall JY, David V (1992) Familial screening of genetic hemochromatosis by means of DNA markers. J Med Genet 29: 320–322

  55. Yaouanq J, Perichon M, Chorney M, Pontarotti P, Le Treut A, El Kahloun A, Mauvieux V, Blayau M, Jouanolle AM, Chauvel B, Moirand R, Nouel O, Le Gall JY, Feingold J, David V (1994) Anonymous marker loci within 400 kb of HLA-A generate haplotypes in linkage disequilibrium with the hemochromatosis gene (HFE). Am J Hum Genet 54: 252–263

  56. Zhang WJ, Degli-Esposi MA, Cobain TJ, Cameron PU, Christiansen FT, Dawkins RL (1990) Differences in gene copy number carried by different MHC ancestral haplotypes. J Exp Med 171: 2101–2114

  57. Zouros E, Golding GB, MacKay TFC (1977) The effect of combining alleles into electrophoretic classes on detecting linkage disequilibrium. Genetics 85: 543–550

Download references

Author information

Additional information

The authors contributed equally to this work

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gandon, G., Jouanolle, A.M., Chauvel, B. et al. Linkage disequilibrium and extended haplotypes in the HLA-A to D6S105 region: implications for mapping the hemochromatosis gene (HFE). Hum Genet 97, 103–113 (1996). https://doi.org/10.1007/BF00218843

Download citation

Keywords

  • Linkage Disequilibrium
  • Hemochromatosis
  • RFLP Marker
  • Normal Chromosome
  • Evolutionary Factor