Immunogenetics

, Volume 24, Issue 2, pp 79–83 | Cite as

Order of class III genes relative to HLA genes determined by the haplotype method

  • Alan N. Wilton
  • Brett Charlton
Article

Abstract

The B18 C4A3 C4BQ0 BfF1 DR3 haplotype was found to be ideal for determining the order of C4 and Bf relative to HLA-B and DR by the haplotype method. All the copies of this haplotype are assumed to be derived from a single ancestral haplotype. Sixteen of the twenty-six BfFl-containing haplotypes carried all of the alleles from this “ancestral” haplotype. Most of the other BfFl-containing haplotypes could be derived from the “ancestral” haplotype by a single crossover event for one of the two possible gene orders. This suggests that B18 C4A3 C4BQ0 BfFl DR3 is the sole source of the BfFl allele. The uncommon C4 type on B18 C4A3 C4BQ0 BfFl DR3 facilitates recognition of the BfFl-containing products of recombination between Bf and C4. One such recombinant haplotype was found which shows that the orientation of the class III genes is as follows: C4 is closest to HLA-B and Bf is closest to HLA-DR. This gene order is supported by all the earlier unequivocal results obtained using the haplotype method (Olaisen et al. 1983, Marshall et al. 1984a). Combining these results with the information on class III genes obtained from overlapping cosmid clones (Carroll et al. 1984) and earlier mapping studies (Robson and Lamm 1984) shows that HLA-B is telomeric to 21B. C4B, 21A, C4A, Bf and C2 then follow 21B in that order covering 120 kb. HLA-DR is located further toward the centromere.

Keywords

Gene Order Mapping Study Sole Source Early Mapping Crossover Event 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Alper, C. A., Raum, D., Karp, S., Awdeh, Z. L., and Yunis, E. J.: Serum complement ‘supergenes’ of the major histocompatibility complex in man (complotypes). Vox Sang. 45: 62–67, 1983Google Scholar
  2. Awdeh, Z. L., Raum, D., Yunis, E. J., and Alper, C. A.: Extended HLA complement-glyoxalase allele haplotypes: Evidence for T/t-like complex in man. Proc. Natl. Acad. Sci. U.S.A. 80: 259–263, 1983Google Scholar
  3. Baur, M. P. and Danilovs, J. A.: Reference tables of two and three locus haplotype frequencies for HLA-A, B, C, DR, Bf, and Glo. In P.I. Terasaki (ed.): Histocompatibility Testing 1980, pp. 994–1210, UCLA Tissue Typing Laboratory, Los Angeles, 1980Google Scholar
  4. Baur, M. P., Neugebauer, M., and Albert, E. D.: Reference table of two locus haplotype frequencies for all MHC marker loci. In E. D. Albert, M. P. Baur; and W. R. Mayr (eds): Histocompatibility Testing 1984, pp. 677–755, Springer-Verlag, Berlin, 1984Google Scholar
  5. Bender, K., Mayerovd, A., Frank, R., Hiller, C., and Wienker, T.: Haplotype analysis of linkage group HLAA: HLA-B: Bf and its bearing on the interpretation of linkage disequilibrium. Hum. Genet. 36: 191–196, 1977Google Scholar
  6. Bodmer, J. and Bodmer, W.: Histocompatibility 1984. Immunol. Today 5: 251–255, 1984Google Scholar
  7. Cambon-de Mouzon, A., Ohayon, E., Hauptman, G., Sevin, A., Abbal, M., Sommer, E., Vergnes, H., and Ducos, J.: HLA-A, B, C, DR antigens, Bf, C4 and glyoxalase I (GLO) polymorphisms in French Basques with insulin dependent diabetes mellitus (IDDM). Tissue Antigens 19: 366–379, 1982Google Scholar
  8. Carroll, M. C., Campbell, R. D., Bentley, D. R., and Porter, R. R.: A molecular map of the human major histocompatibility complex class III region linking complement genes C4, C2 and factor B. Nature 307: 237–240, 1984Google Scholar
  9. Carroll, M. C., Campbell, R. D., and Porter, R. R.: Mapping of steroid 21-hydroxylase genes adjacent to complement component C4 genes in HLA, the major histocompatibility complex in man. Proc. Natl. Acad. Sci. U.S.A. 82: 521–525, 1985aGoogle Scholar
  10. Carroll, M. C., Belt, K. T., Palsdottir, A., and Yu, Y.: Molecular genetics of the fourth component of human complement and steroid 21-hydroxylase. Immunol. Rev. 87: 39–60, 1985bGoogle Scholar
  11. Ceppellini, R., Curtoni, E. S., Mattiuz, P. L., Miggiano, V., Scudeller, G., and Serra, A.: Genetics of leukocyte antigens: A family study of segregation and linkage. In E. S. Curtoni, P. L. Mattiuz, and R. M. Tosi (eds.): Histocompatibility Testing 1967, pp. 149–187, Munksgaard, Copenhagen, 1967Google Scholar
  12. Chakravarti, A. and Buetow, K. H.: Fine structure mapping using linkage disequilibrium: HLA. Cytogenet. Cell Genet. 40: 603–604, 1986Google Scholar
  13. Dausset, J., Legrand, L., Lepage, V., Conto, L., Marcelli-Barge, A., Wildloecher, I., Benajam, A., Men, T., and Degos, L.: A haplotype study of HLA complex with special reference to the HLA-DR series and to Bf, C2 and glyoxalase I polymorphisms. Tissue Antigens 12: 297–307, 1978Google Scholar
  14. Dawkins, R. L., Christiansen, F.T., Kay, P. H., Garlepp, M., McCluskey, J., Hollingsworth, P. N., and Zilko, P. J.: Disease associations with complotypes, supratypes and haplotypes. Immunol. Rev. 70: 5–22, 1983Google Scholar
  15. Fisher, R. A. and Race, R. R.: Rh gene frequencies in Britain. Nature 157: 48–49, 1946Google Scholar
  16. Garlepp, M. J., Wilton, A. N., Dawkins, R. L., and White, P. C.: Rearrangement of 21-hydroxylase genes in disease-associated MHC supratypes. Immunogenetics 23: 100–105, 1986Google Scholar
  17. Kay, P. H., Wilton, A. N., and Dawkins, R. L.: Preferential paternal transmission in diabetogenic supratype marked by HLA B18, BfFl, DR3. J. Immunogenet., in press, 1986Google Scholar
  18. Kelly, H., McCann, V. J., Kay, P. H., and Dawkins, R. L.: Susceptibility to IDDM is marked by MHC supratypes rather than individual alleles. Immunogenetics 22: 643–651, 1985Google Scholar
  19. Lamm, L. U. and Olaisen, B.: Report of the committee on the genetic constitution of chromosomes 5 and 6. Cytogenet. Cell Genet. 40: 128–155, 1986Google Scholar
  20. Marshall, W. H., Barnard, J. M., Churchill, D., Farid, N. R., Grandy, R., Larsen, B., Payne, R. H., Skanes, V. M., Ebers, G. C., Paty, D. W., Mervart, H., and Schroeder, M. L.: Study of alleles of the second complement component (C2) on Canadian HLA haplotypes. Tissue Antigens 23: 229–239, 1984aGoogle Scholar
  21. Marshall, W. H., Neugebauer, M., Baur, M. P., and Albert, E. D.: The second complement component, C2, in the Ninth Workshop. In E. D. Albert, M. P. Baur, and W. R. Mayr (eds.): Histocompatibility Testing 1984, pp. 313–316, Springer-Verlag, Berlin, 1984bGoogle Scholar
  22. Matsui, Y., Alosco, S. M., Awdeh, Z., Duquesnoy, R. J., Page, P. L., Hartzman, R. J., Alper, C. A., and Yunis, E. J.: Linkage disequilibrium of HLA-SB1 with HLA-Al, B8, DR3, SC01 and of HLA-SB4 with the HLA-A26, Bw38, Dw10, DR4, SC21 extended haplotypes. Immunogenetics 20: 623–631, 1984Google Scholar
  23. Mauff, G., Alper, C. A., Awdeh, Z., Batchelor, J. R., Bertrams, J., Bruun-Petersen, G., Dawkins, R. L., Démant, P., Edwards, J., Grosse-Wilde, H., Hauptmann, G., Klouda, P., Lamm, L., Mollenhauer, E., Nerl, C., Olaisen, B., O'Neill, G., Rittner, C., Roos, M. H., Skanes, V., Teisberg, P., and Wells, L.: Statement on the nomenclature of human C4 allotypes. Immunobiology 164: 184–191, 1983Google Scholar
  24. McCluskey, J., Kay, P. H., Stuckey, M., Christiansen, F. T., Dawkins, R. L., and Wilson, G.: MHC “supratype” predicting heterozygous 21-hydroxylase deficiency. Lancet i: 764–765, 1983Google Scholar
  25. Morton, N. E., Green, A., Dunsworth, T., Svejgaard, A., Barbosa, J., Rich, S. S., Iselius, L., Platz, P., and Ryder, L. P.: Heterozygous expression of insulin-dependent diabetes mellitus (IDDM) deter minants in the HLA system. Am. J. Hum. Genet. 35: 210–213, 1983Google Scholar
  26. Neugebauer, M., Willems, J., and Baur, M. P.: Analysis of multilocus pedigree data by computer. In E. D. Albert, M. P. Baur, and W. R. Mayr (eds.): Histocompatibility Testing 1984, pp. 52–58, Springer-Verlag, Berlin, 1984Google Scholar
  27. Olaisen, B., Teisberg, P., Jonassen, R., Thorsby, E., and Gedde-Dahl, T.: Gene order and gene distances in the HLA region studied by the haplotype method. Ann. Hum. Genet. 47: 285–292, 1983Google Scholar
  28. O'Neill, G. J., Pollack, M. S., Yang, S. Y., Levine, L. S., New, M. I., and Dupont, B.: Gene frequencies and genetic linkage disequilibrium for HLA-linked genes Bf, C2, C4S, C4F, 21-hydroxylase deficiency, and glyoxalase I. Transplant. Proc. 11: 1713–1715, 1979Google Scholar
  29. O'Neill, G. J., Braun, D., Park, M. S., and Dupont, B.: HLA-linkedgenetic markers in HLA genotyped families. In P. I. Terasaki (ed.): Histocompatibility Testing 1980, pp. 142–147, UCLA Tissue Typing Laboratory, Los Angeles, 1980Google Scholar
  30. O'Neill, G. J., Dupont, B., Pollack, M. S., Levine, L. S., and New, M. L.: Complement C4 allotypes in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: Further evidence for different allelic variants at the 21-hydroxylase locus. Clin. Immunol. Immunopathol. 23: 312–322, 1982Google Scholar
  31. O'Neill, G. J., Nerl, C., and Pollack, M. S.: Analysis of active and inactive complement C4 complotypes associated with subtypes of HLA Bl7 in different racial groups. Am. J. Hum. Genet. 35: 309–317, 1983Google Scholar
  32. Raum, D. D., Awdeh, Z. L., Glass, D., Yunis, E., and Alper, C. A.: The location of C2, C4 and Bf relative to HLA-B and HLA-D. Immunogenetics 12: 473–483, 1981Google Scholar
  33. Raum, D., Awdeh, Z., Yunis, E. J., Alper, C. A., and Gabbay, K. H.: Extended major histocompatibility complex haplotypes in type I diabetes mellitus. J. Clin. Invest. 74: 449–454, 1984Google Scholar
  34. Rittner, C. and Mauff, G.: C4 polymorphisms. In E. D. Albert, M. P. Baur, and W. R. Mayr (eds.): Histocompatibility Testing 1984, pp. 318–324, Springer-Verlag, Berlin, 1984Google Scholar
  35. Robinson, M. A., Carroll, M. C., Johnson, A. H., Hartzman, R. J., Belt, K. T., and Kindt, T. J.: Localization of C4 genes within the HLA complex by molecular genotyping. Immunogenetics 21: 143–152, 1985Google Scholar
  36. Robson, E. B. and Lamm, L. U.: Report of the committee on the genetic constitution of chromosome 6. Cytogenet. Cell Genet. 37: 47–70, 1984Google Scholar
  37. Serjeantson, S. W.: Properdin factor B. In E. D. Albert, M. P. Baur, and W. R. Mayr (eds.): Histocompatibility Testing 1984, pp. 317–318, Springer-Verlag, Berlin, 1984Google Scholar
  38. Uring-Lambert, B., Goetz, J., Tongio, M. M., Mayer, S., and Hauptmann, G.: C4 haplotypes with duplications at the C4A or C4B loci: Frequency and associations with BF, C2, and HLA-A, B, C, DR alleles. Tissue Antigens 24: 70–72, 1984Google Scholar
  39. Welch, T. R. and Beischel, L.: 4 uremic variant: An acquired C4 allotype. Immunogenetics 22: 553–562, 1985Google Scholar
  40. White, P. C., Grossberger, D., Onufer, B. J., Chaplin, D. D., New, M. I., Dupont, B., and Strominger, J. L.: Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth compo nent of complement in man. Proc. Natl. Acad. Sci. U.S.A. 82: 1089–1093, 1985aGoogle Scholar
  41. White, P.C., New, M. I., and Dupont, B.: Adrenal 21-hydroxylase cytochrome P-450 genes within the MHC class III region. Immunol. Rev. 87: 123–150, 1985bGoogle Scholar
  42. Wilton, A. N., Christiansen, F. T., and Dawkins, R. L.: Influences of supratype matching on renal transplant survival. Transplant. Proc. 17: 2211–2216, 1985Google Scholar
  43. Yunis, E. J., Awdeh, Z., Johnson, A., Suciu-Foca, N., Robinson, M. A., Hartzman, R., Raum, D., Fleischnick, E., and Alper, C. A.: Complotype genetic loci segregate more frequently with HLA-DR than with HLA-B. Immunogenetics 21: 25–31, 1985Google Scholar

Copyright information

© Springer-Verlag 1986

Authors and Affiliations

  • Alan N. Wilton
    • 1
  • Brett Charlton
    • 1
  1. 1.Department of Clinical ImmunologyRoyal Perth HospitalPerthWestern Australia

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