Skip to main content
Log in

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

  • Published:
Immunogenetics Aims and scope Submit manuscript

Abstract

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.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • 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, 1983

    CAS  PubMed  Google Scholar 

  • 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, 1988

    CAS  PubMed  Google Scholar 

  • Bentley, D. L., and Rabbitts, T. H.: Evolution of immunoglobulin V genes: evidence indicating that recently duplicated human V k sequences have diverged by gene conversion.Cell 32: 181–189, 1983

    Article  CAS  PubMed  Google Scholar 

  • Benton, W. D. and Davis, R. W.: Screening λgt recombinant clones by hybridization to single plaques in situ.Science 196: 180–182, 1977

    CAS  PubMed  Google Scholar 

  • 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, 1989

    Article  CAS  PubMed  Google Scholar 

  • Burton, D. R.: Immunoglobulin G: functional sites.Mol Immunol 22: 161–206, 1985

    Article  CAS  PubMed  Google Scholar 

  • 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, 1979

    CAS  PubMed  Google Scholar 

  • 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, 1982

    CAS  PubMed  Google Scholar 

  • Ellison J. W., Buxbaum, J., and Hood, L.: Nucleotide sequence of a human immunoglobulin C γ4 gene.DNA 1: 11–18, 1981

    CAS  PubMed  Google Scholar 

  • 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, 1982

    CAS  PubMed  Google Scholar 

  • 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, 1982a

    Article  CAS  PubMed  Google Scholar 

  • 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, 1982b

    CAS  PubMed  Google Scholar 

  • 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, 1984

    Article  CAS  PubMed  Google Scholar 

  • 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 1988a

    CAS  PubMed  Google Scholar 

  • 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, 1988b

    CAS  PubMed  Google Scholar 

  • 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, 1989a

  • 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, 1989b

    CAS  Google Scholar 

  • Grubb, R.: The genetic markers of human immunoglobulins.Mol Biol Biochem Biophys 9: 1–143, 1970

    CAS  PubMed  Google Scholar 

  • 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, 1983

    CAS  PubMed  Google Scholar 

  • Huber, R. and Bennett, W. S.: Antibody-antigen flexibility.Nature 326: 334–335, 1987

    Article  CAS  PubMed  Google Scholar 

  • 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, 1986a

    CAS  PubMed  Google Scholar 

  • 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, 1986b

    Article  CAS  PubMed  Google Scholar 

  • 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, 1987

    Google Scholar 

  • 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, 1984

    Article  CAS  PubMed  Google Scholar 

  • Kipps, T. J., Parham, P., Punt, J., and Herzenberg, L. A.: Importance of immunoglobulin isotype in human.J Exp Med 161: 1–17, 1985

    Article  CAS  PubMed  Google Scholar 

  • 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, 1982

    CAS  PubMed  Google Scholar 

  • 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, 1982

    CAS  PubMed  Google Scholar 

  • 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, 1976

    PubMed  CAS  Google Scholar 

  • 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, 1977

    CAS  PubMed  Google Scholar 

  • 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, 1978

    Article  CAS  PubMed  Google Scholar 

  • 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, 1979a

    Article  CAS  PubMed  Google Scholar 

  • 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, 1979b

    CAS  PubMed  Google Scholar 

  • 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, 1982

    CAS  PubMed  Google Scholar 

  • 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, 1983

    CAS  PubMed  Google Scholar 

  • Lefranc, M.-P., and Lefranc, G.: Human immunoglobulin heavy chain multigene deletions in healthy individuals.FEBS Lett 213: 231–237, 1987

    Article  CAS  PubMed  Google Scholar 

  • 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, 1982

    Article  CAS  PubMed  Google Scholar 

  • 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, 1983

    CAS  PubMed  Google Scholar 

  • 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, 1986a

    Article  CAS  PubMed  Google Scholar 

  • 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, 1986b

    CAS  PubMed  Google Scholar 

  • 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, 1987

    Article  CAS  PubMed  Google Scholar 

  • 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, 1982

    Article  CAS  PubMed  Google Scholar 

  • Messing, J. and Vieira, J.: A new pair of M13 vectors for selecting either strand of double-digest restriction fragments.Gene 19: 269–276, 1982

    Article  CAS  PubMed  Google Scholar 

  • 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, 1977

    CAS  PubMed  Google Scholar 

  • 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, 1984

    CAS  PubMed  Google Scholar 

  • Mount, S. M.: A catalogue of splice junction sequences.Nucleic Acids Res 10: 459–472, 1982

    CAS  PubMed  Google Scholar 

  • Natvig, J. B. and Kunkel, H. G.: Human immunoglobulins: classes, subclasses, genetic variants and idiotypes.Adv Immunol 16: 1–59, 1973

    Article  CAS  PubMed  Google Scholar 

  • Neuberger, M. S. and Rajewsky, K.: Activation of mouse complement by monoclonal mouse antibodies.Eur J Immunol 11: 1012–1016, 1981

    CAS  PubMed  Google Scholar 

  • 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, 1984

    Article  CAS  PubMed  Google Scholar 

  • Proudfoot, N. J. and Brownlee, G. G.: 3′ non-coding region sequences in eukaryotic messenger RNA.Nature 263: 211–214, 1976

    Article  CAS  PubMed  Google Scholar 

  • 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, 1981

    CAS  PubMed  Google Scholar 

  • 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, 1977

    Article  CAS  PubMed  Google Scholar 

  • 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, 1980

    CAS  PubMed  Google Scholar 

  • 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, 1980

    Article  CAS  PubMed  Google Scholar 

  • 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, 1988

    CAS  PubMed  Google Scholar 

  • 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, 1987

    Article  CAS  PubMed  Google Scholar 

  • Southern, E. M.: Detection of specific sequences among DNA fragments separated by gel electrophoresis.J Mol Biol 98: 503–517, 1975

    CAS  PubMed  Google Scholar 

  • Steinberg, A. G.: Globulin polymorphisms in man.Annu Rev Genet 3: 25–52, 1969

    Article  CAS  Google Scholar 

  • Steinberg, A. G.: Contribution of the Gm and Inv allotypes to the characterization of human populations.Isr J Med Sci 9: 1249–1256, 1973

    CAS  PubMed  Google Scholar 

  • 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, 1982

    Article  CAS  PubMed  Google Scholar 

  • 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, 1985

    CAS  PubMed  Google Scholar 

  • van Loghem, E.: Formal genetics of the immunoglobulin system.Ann NY Acad Sci 190: 136–149, 1971

    PubMed  Google Scholar 

  • 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, 1970

    Google Scholar 

  • 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, 1980

    PubMed  Google Scholar 

  • 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, 1982

    Article  PubMed  Google Scholar 

  • 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, 1982

    Article  CAS  PubMed  Google Scholar 

  • 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, 1985

    CAS  PubMed  Google Scholar 

  • 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, 1976

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

The nucleotide sequence data reported in this paper have been submitted to the GenBank nucleotide sequence database and have been assigned the accession number X16110.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huck, S., Lefranc, G. & Lefranc, MP. A human immunoglobulinIGHG3 allele (Gmb0, b1, c3, c5, u) with anIGHG4 converted region and three hinge exons. Immunogenetics 30, 250–257 (1989). https://doi.org/10.1007/BF02421328

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02421328

Keywords

Navigation