, Volume 30, Issue 4, pp 250–257 | Cite as

A human immunoglobulinIGHG3 allele (Gmb0, b1, c3, c5, u) with anIGHG4 converted region and three hinge exons

  • Sylvie Huck
  • Gérard Lefranc
  • Marie-Paule Lefranc


The five humanIGHG genes consist of three constant domain exons plus one of or four hinge exon(s), the quadruplicated hinge region being characteristic of theIGHG3 gene. Besides this structural difference, theIGHG genes are polymorphic, as demonstrated by the restriction fragment length polymorphism and, at the protein level, by the Gm allotypic antigenic determinants. In this paper, we report the sequence of theG3m(b0, b1, c3, c5, u) IGHG3 allele, typical of the Black African populations and of populations with Negroid admixture, found in a homozygous Tunisian designated as LAT. We demonstrate that thisG3 allele contains only three hinge exons instead of four (the probable result of an unequal crossing over) and thatIGHG3 genes with triplicated hinge exons (and therefore encoding shorter γ 3 chains) are present in healthy individuals from different populations. Moreover, we show that the LAT G3m (b0, b1, c3, c5, u) coding sequence results from the conversion, in the CH3 exon, of theG3m (b0, b1, b3, b4, b5, u, v) allele, the most frequentIGHG3 gene in the Negroid populations, by the homologous region of aIGHG4 gene. The structural features of theLAT IGHG3 allele, which are the lack of one hinge exon and its conversion by theIGHG4 gene, demonstrate that both crossing-over and gene conversion events occur in the evolution of the humanIGHG genes.


Length Polymorphism Restriction Fragment Length Polymorphism Restriction Fragment Fragment Length Polymorphism Gene Conversion 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bech-Hansen, N. T., Linsley, P. S., and Cox, D. W.: Restriction fragment polymorphisms associated with immunoglobulin Cγ genes reveal linkage disequilibrium and genomic organization.Proc Natl Acad Sci USA 80: 6952–6956, 1983PubMedGoogle Scholar
  2. Bensmana, M., Huck, S., Lefranc, G., and Lefranc, M.-P.: The human imunoglobulin pseudo-gamma IGHGP gene shows no major structural defect.Nucleic Acids Res 16: 3108, 1988PubMedGoogle Scholar
  3. Bentley, D. L., and Rabbitts, T. H.: Evolution of immunoglobulin V genes: evidence indicating that recently duplicated human Vk sequences have diverged by gene conversion.Cell 32: 181–189, 1983CrossRefPubMedGoogle Scholar
  4. Benton, W. D. and Davis, R. W.: Screening λgt recombinant clones by hybridization to single plaques in situ.Science 196: 180–182, 1977PubMedGoogle Scholar
  5. Buresi, C., Ghanem, N., Huck, S., Lefranc, G., and Lefranc, M.-P.: Exon duplication and triplication in the human T-cell receptor gamma constant region genes and RFLP in French, Lebanese, Tunisian, and Black African populations.Immunogenetics 29: 161–172, 1989CrossRefPubMedGoogle Scholar
  6. Burton, D. R.: Immunoglobulin G: functional sites.Mol Immunol 22: 161–206, 1985CrossRefPubMedGoogle Scholar
  7. Croce, C.M., Shander M., Martinis, J., Cicurel, M., D'Amona, G. G., Dolby, T. W., and Koprowski, H.: Chromosomal location of the genes for human immunoglobulin heavy chains.Proc Natl Acad Sci USA 76: 3416–3419, 1979PubMedGoogle Scholar
  8. Ellison J. W. and Hood, L. E.: Linkage and sequence homology of two human immunoglobulin γ heavy chain constant region genes.Proc Natl Acad Sci USA 79: 1984–1988, 1982PubMedGoogle Scholar
  9. Ellison J. W., Buxbaum, J., and Hood, L.: Nucleotide sequence of a human immunoglobulin C γ4 gene.DNA 1: 11–18, 1981PubMedGoogle Scholar
  10. Ellison, J. W., Berson, B. J., and Hood, L. E.: The nucleotide sequence of a human immunoglobulin Cγ1 gene.Nucleic Acids Res 10: 4071–4079, 1982PubMedGoogle Scholar
  11. Flanagan, J. G. and Rabbitts, T. H.: Arrangements of human immunoglobulin heavy chain constant region genes implies evolutionary duplication of a segment containing γ, ε and α genes.Nature 300: 709–713, 1982aCrossRefPubMedGoogle Scholar
  12. Flanagan, J. G. and Rabbitts, T. H.: The sequence of human immunoglobulin epsilon heavy chain constant region gene, and evidence for three non-allelic genes.EMBO J 1: 655–660, 1982bPubMedGoogle Scholar
  13. Flanagan, J. G., Lefranc, M.-P., and Rabbitts, T. H.: Mechanisms of divergence and convergence of the human immunoglobulin α 1 and α 2 constant region gene sequences.Cell 36: 681–688, 1984CrossRefPubMedGoogle Scholar
  14. Ghanem, N., Lefranc, M.-P., and Lefranc, G.: Definition of the RFLP alleles in the human immunoglobulin IGHG gene locus.Eur J Immunol 18: 1059–1065 1988aPubMedGoogle Scholar
  15. Ghanem, N., Dugoujon, J. M., Bensmana, M., Huck, S., Lefranc, M.-P., and Lefranc, G.: Restriction fragment haplotypes in the human immunoglobulin IGHG gene locus and their correlation with the Gm polymorphism.Eur J Immunol 18: 1067–1072, 1988bPubMedGoogle Scholar
  16. Ghanem, N., Bensmana, M., Dugoujon, J. M., Constans, J., Lefranc, M.-P., and Lefranc, G.: BamHI and SacI RFLPs of the human immunoglobulin IGHG genes with reference to the Gm polymorphism in African people: evidence for a major polymorphism.Hum Genet, in press, 1989aGoogle Scholar
  17. Ghanem, N., Dugoujon, J. M., Lefranc, M.-P., and Lefranc, G.: BstEII restriction fragment alleles and haplotypes of the human IGHG genes with reference to the BamHI/Sac I RFLPs and to the Gm polymorphism.Expl Clin Immunogenet 6: 39–54, 1989bGoogle Scholar
  18. Grubb, R.: The genetic markers of human immunoglobulins.Mol Biol Biochem Biophys 9: 1–143, 1970PubMedGoogle Scholar
  19. Guo, L. H., Yang, R. C. A., and Wu, R.: An improved strategy for rapid direct sequencing of both strands of long DNA molecules cloned in a plasmid.Nucleic Acids Res 11: 5521–5540, 1983PubMedGoogle Scholar
  20. Huber, R. and Bennett, W. S.: Antibody-antigen flexibility.Nature 326: 334–335, 1987CrossRefPubMedGoogle Scholar
  21. Huck, S., Fort, P., Crawford, D. H., Lefranc, M.-P., and Lefranc, G.: Sequence of a human immunoglobulin gamma 3 heavy chain constant region gene: comparison with the other human Cγ genes.Nucleic Acids Res 14: 1779–1789, 1986aPubMedGoogle Scholar
  22. Huck, S., Keyeux, G., Ghanem, N., Lefranc, M.-P., and Lefranc, G.: A gamma 3 hinge region probe: first specific human immunoglobulin subclass probe.FEBS Lett 208: 221–230, 1986bCrossRefPubMedGoogle Scholar
  23. Kabat, E. A., Wu, T. T., Reid-Miller, M., Perry, H. M., and Gottesman, K. S.:Sequences of Proteins of Immunological Interest, NIH, Bethesda, pp. 293–331, 1987Google Scholar
  24. Karn, J., Matthes, H. W. D., Gait, M. J., and Brenner, S.: A new selective phage cloning vector λ 2001 with sites for Xbal, BamHI, HindIII, EcoRI, Sstl and Xhol.Gene 32: 217–224, 1984CrossRefPubMedGoogle Scholar
  25. Kipps, T. J., Parham, P., Punt, J., and Herzenberg, L. A.: Importance of immunoglobulin isotype in human.J Exp Med 161: 1–17, 1985CrossRefPubMedGoogle Scholar
  26. Kirsch, I. R., Morton, C. C., Nakahara, K., and Leder, P.: Human immunoglobulin heavy chain genes map to a region of translocations in malignant B lymphocytes.Science 216: 301–303, 1982PubMedGoogle Scholar
  27. Krawinkel, U. and Rabbitts, T. H.: Comparison of the hinge coding segments in human immunoglobulin gamma heavy chain genes and the linkage of the gamma 2 and gamma 4 subclass genes.EMBO J 1: 403–407, 1982PubMedGoogle Scholar
  28. Lefranc, G., Rivat, L., Rivat, C., Loiselet, J., and Ropartz, C.: Evidence for “deleted” or “silent” genes homozygous at the locus coding for the constant region of the gamma 3 chain.Am J Hum Genet 28: 51–61, 1976PubMedGoogle Scholar
  29. Lefranc, G., Rivat, L., Salier, J. P., van Loghem, E., Aydenian, H., Zalzal, P., Chakhachiro, L., Loiselet, J., and Ropartz, C.: Recombination, mutaton or constitutive expression at a Gm locus and familial hypergammaglobulinemia.Am J Hum Genet 29: 523–536, 1977PubMedGoogle Scholar
  30. Lefranc, G., Rivat, L., Serre, J. L., Lalouel, J. M., Pison, G., Loiselet, J., Ropartz, C., de Lange, G., and van Loghem, E.: Common and uncommon immunoglobulin haplotypes among Lebanese communities.Hum Genet 41: 197–209, 1978CrossRefPubMedGoogle Scholar
  31. Lefranc, G., de Lange, G., Rivat, L., Langaney, A., Lefranc, M.-P., Ellouze, F., Sfar, G., Sfar, M., and van Loghem, E.: Gm, Am and Km immunoglobulin allotypes of two populations in Tunisia.Hum Genet 50: 199–211, 1979aCrossRefPubMedGoogle Scholar
  32. Lefranc, G., Dumitresco, S. M., Salier, J. P., Rivat, L., de Lange, G., van Loghem, E., and Loiselet, J.: Familial lack of the IgG3 subclass: gene elimination or turning off expression and neutral evolution in the immune system.J Immunogenet 6: 215–221, 1979bPubMedGoogle Scholar
  33. Lefranc, G., Lefranc, M.-P., Helal, A. N., Boukef, K., Chaabani, H., Sfar Gandoura, M., and van Loghem, E.: Unusual heavy chains of human IgG immunoglobulins: rearrangements of the CH domain exons.J Immunogenet 9: 1–9, 1982PubMedGoogle Scholar
  34. Lefranc, G., Chaabani, H., van Loghem, E., Lefranc, M.-P., de Lange, G., and Helal, A. N.: Simultaneous absence of the human IgG1, IgG2, IgG4 and IgA1 subclasses: immunological and immunogenetical considerations.Eur J Immunol 13: 240–244, 1983PubMedGoogle Scholar
  35. Lefranc, M.-P., and Lefranc, G.: Human immunoglobulin heavy chain multigene deletions in healthy individuals.FEBS Lett 213: 231–237, 1987CrossRefPubMedGoogle Scholar
  36. Lefranc, M.-P., Lefranc, G., and Rabbitts, T. H.: Inherited deletion of immunoglobulin heavy chain constant region genes in normal human individuals.Nature 300: 760–762, 1982CrossRefPubMedGoogle Scholar
  37. Lefranc, M.-P., Lefranc, G., de Lange, G., Out, T. A., van den Broek, P. J., van Nieuwkoop, J., Radl, J., Helal, A. N., Chaabani, H., van Loghem, E., and Rabbitts, T. H.: Instability of the human immunoglobulin heavy chain constant region locus indicated by different inherited chromosomal deletions.Mol Biol Med 1: 207–217, 1983PubMedGoogle Scholar
  38. Lefranc, M.-P., Helal, A. N., de Lange, G., Chaabani, H., van Loghem, E., and Lefranc, G.: Gene conversion in human immunoglobulin gamma locus shown by unusual location of IgG allotypes.FEBS Lett 196: 96–102, 1986aCrossRefPubMedGoogle Scholar
  39. Lefranc, M.-P., Forster, A., and Rabbitts, T. H.: Genetic polymorphism and exon changes of the constant regions of the human T-cell rearranging gene gamma.Proc Natl Acad Sci USA 83: 9596–9600, 1986bPubMedGoogle Scholar
  40. Littman, D. R., Newton, M., Crommie, D., Ang, S. L., Scidman, J. G., Gettner, S. N., and Weiss, A.: Characterization of an expressed CD3-associated Ti γ-chain reveals Cγ domain polymorphism.Nature 326: 85–88, 1987CrossRefPubMedGoogle Scholar
  41. Max, E. E., Battey, J., Ney, R., Kirsch, I. R., and Leder, P.: Duplication and deletion in the human immunoglobulin ε genes.Cell 29: 691–699, 1982CrossRefPubMedGoogle Scholar
  42. Messing, J. and Vieira, J.: A new pair of M13 vectors for selecting either strand of double-digest restriction fragments.Gene 19: 269–276, 1982CrossRefPubMedGoogle Scholar
  43. Michaelsen, T. E., Frangione, B., and Franklin, E. C.: Primary structure of the “Hinge” region of human IgG3. Probable quadruplication of a 15 amino acid residue basic unit.J Biol Chem 252: 883–889, 1977PubMedGoogle Scholar
  44. Milstein, C. P., Deverson, E. V., and Rabbitts, T. H.: The sequence of the human immunoglobulin μ-δ intron reveals possible vestigial switch segments.Nucleic Acids Res 12: 6523–6535, 1984PubMedGoogle Scholar
  45. Mount, S. M.: A catalogue of splice junction sequences.Nucleic Acids Res 10: 459–472, 1982PubMedGoogle Scholar
  46. Natvig, J. B. and Kunkel, H. G.: Human immunoglobulins: classes, subclasses, genetic variants and idiotypes.Adv Immunol 16: 1–59, 1973PubMedCrossRefGoogle Scholar
  47. Neuberger, M. S. and Rajewsky, K.: Activation of mouse complement by monoclonal mouse antibodies.Eur J Immunol 11: 1012–1016, 1981PubMedGoogle Scholar
  48. Oi, V. T., Vuong, T. M., Hardy, R., Reidler, J., Dangl, J., Herzenberg, L. A., and Stryer, L.: Correlation between segmental flexibility and effector function of antibodies.Nature 307: 136–140, 1984CrossRefPubMedGoogle Scholar
  49. Proudfoot, N. J. and Brownlee, G. G.: 3′ non-coding region sequences in eukaryotic messenger RNA.Nature 263: 211–214, 1976CrossRefPubMedGoogle Scholar
  50. Rabbitts, T. H., Forster, A., and Milstein, C. P.: Human immunoglobulin heavy chain genes: Evolutionary comparisons of Cμ, Cδ and Cγ genes and associated switch sequences.Nucleic Acids Res 9: 4509–4524, 1981PubMedGoogle Scholar
  51. Rigby, P. W. J., Dieckmann, M., Rhodes, C., and Berg, P.: Labelling deoxyribonucleic acid to high specific activity in vitro by nick translation with DNA polymerase I.J Mol Biol 113: 237–251, 1977CrossRefPubMedGoogle Scholar
  52. Salier, J. P., Rivat, L., Daveau, M., Lefranc, G., Breton, P., de Menibus, C. H., Henock, A., and Fudenberg, H. H.: Qunatitative studies of Gm allotypes. V. Simultaneous presence of latent Gm allotypes and deficient Gm genes in a family with hypogammaglobulinaemic probands.J Immunogenet 7: 123–135, 1980PubMedGoogle Scholar
  53. Sanger, F., Coulson, A. R., Barrell, B. G., Smith, A. J. H., and Roe, B. A.: Cloning in single stranded bacteriophage as an aid to rapid DNA sequencing.J Mol Biol 143: 161–178, 1980CrossRefPubMedGoogle Scholar
  54. Schneider, W. P., Wensel, T. G., Stryer, L., and Oi, V. T.: Genetically engineered immunoglobulins reveal structural features controlling segmental flexibility.Proc Natl Acad Sci USA 85: 2509–2513, 1988PubMedGoogle Scholar
  55. Shows, T. B., Mc Alpine, P. J., Boucheix, C., Collins, F. S., Conneally, P. M., Frezal, J., Gershowitz, H., Goodfellow, P. N., Hall, J. G., Issitt, P., Jones, C. A., Knowles, B. B., Lewis, M., McKusick, V. A., Meisler, M., Morton, N. E., Rubinstein, P., Schanfield, M. S., Schmickel, R. D., Skolnick, M. H., Spence, M. A., Sutherland, G. R., Traver, M., Van Cong, N., and Williard, H. F.: Guidelines for human gene nomenclature (ISGN, HGM9).Cytogenet Cell Genet 46: 11–28, 1987PubMedCrossRefGoogle Scholar
  56. Southern, E. M.: Detection of specific sequences among DNA fragments separated by gel electrophoresis.J Mol Biol 98: 503–517, 1975PubMedGoogle Scholar
  57. Steinberg, A. G.: Globulin polymorphisms in man.Annu Rev Genet 3: 25–52, 1969CrossRefGoogle Scholar
  58. Steinberg, A. G.: Contribution of the Gm and Inv allotypes to the characterization of human populations.Isr J Med Sci 9: 1249–1256, 1973PubMedGoogle Scholar
  59. Takahashi, N., Ueda, S., Obata, M., Nikaido, T., Nakai, S., and Honjo, T.: Structure of human immunoglobulin gamma genes: implications for evolution of a gene family.Cell 29: 671–679, 1982CrossRefPubMedGoogle Scholar
  60. Tunnacliffe, A., Kefford, R., Milstein, C., Forster, A., and Rabbitts, T. H.: Sequence and evolution of the human T-cell antigen receptor β-chain genes.Proc Natl Acad Sci USA 82: 5068–5072, 1985PubMedGoogle Scholar
  61. van Loghem, E.: Formal genetics of the immunoglobulin system.Ann NY Acad Sci 190: 136–149, 1971PubMedGoogle Scholar
  62. van Loghem, E., Natvig, J. B., and Matsumoto, H.: Genetic Markers of immunoglobulins in Japanese families. Inheritance of associated markers belonging to one IgA and three IgG subclasses.Ann Hum Genet 33: 351–359, 1970Google Scholar
  63. van Loghem, E., Sukernik, R. I., Osipova, L. P., Zegers, B. J. M., Matsumoto, H., de Lange, G., and Lefranc, G.: Gene deletion and gene duplication within the cluster of human heavy chain genes. Selective absence of IgG subclasses.J Immunogenet 7: 285–299, 1980PubMedGoogle Scholar
  64. van Loghem, E., de Lange, G., van Leeuwen, F., van Eede, P. H., Nijenhuis, L. E., Lefranc, M.-P., and Lefranc, G.: Human IgG allotypes co-occurring in more than one IgG subclass.Vox Sang 43: 301–309, 1982PubMedCrossRefGoogle Scholar
  65. Vieira, J. and Messing, J.: The pUC plasmids, an M13mp7-derived system for insertion mutagenesis and sequencing with synthetic universal primers.Gene 19: 259–268, 1982CrossRefPubMedGoogle Scholar
  66. White, M. B., Shen, A. L., Word, C. J., Tucker, P. W., and Blattner, F. R.: Human immunoglobulin D: genomic sequence of the delta heavy chain.Science 228: 733–737, 1985PubMedGoogle Scholar
  67. WHO meeting on human immunoglobulin allotypic markers: Review of the notation for the allotypic and related markers of human immunoglobulins.J Immunogenet 3: 357–362, 1976Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • Sylvie Huck
    • 1
  • Gérard Lefranc
    • 1
  • Marie-Paule Lefranc
    • 1
  1. 1.Laboratoire d'Immunogénétique Moléculaire, URA CNRS 1191Université Montpellier II-Sciences et Techniques du LanguedocMontpellier Cedex 1France

Personalised recommendations