Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Full Paper
  • Published:

Determination of gene organization in the human IGHV region on single chromosomes

Abstract

Organization of the IGHV genes (n=108) on single human chromosomes has been determined by detecting these sequences in single sperm using multiplex PCR amplification followed by microarray detection. A total of 374 single sperm samples from five Caucasian males were studied. Three deletion/insertion polymorphisms (Del I–Del III) with deletion allele frequencies ranging from 0.1 to 0.3 were identified. Del I is a previously reported polymorphism affecting three IGHV genes (IGHV1–8, IGHV3–9, and IGHV2–10). Del II affects a region 2–18 kb containing two pseudogenes IGHV(II)-28.1 and IGHV3–29, and Del III spans 21–53 kb involving genes IGHV4–39, IGHV7–40, IGHV(II)-40-1, and IGHV3–41. Deletion alleles of both Dels II and III were found in a heterozygous state, and therefore, could not be easily detected if haploid samples were not used in the study. Results of the present study indicate that deletions/insertions together with other possible chromosomal rearrangements may play an important role in forming the genetic structure of the IGHV region, and may significantly contribute to antibody diversity. Since these three polymorphisms are located within or next to the 3′ half of the IGHV region, they may have an important role in the expressed IGHV gene repertoire during immune response.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Croce CM, Shander M, Martinis J et al. Chromosomal location of the genes for human immunoglobulin heavy chains. Proc Natl Acad Sci USA 1979; 76: 3416–3419.

    Article  CAS  Google Scholar 

  2. Cox DW, Markovic VD, Teshima IE . Genes for immunoglobulin heavy chains and for alpha 1-antitrypsin are localized to specific regions of chromosome 14q. Nature 1982; 297: 428–430.

    Article  CAS  Google Scholar 

  3. Kirsch IR, Morton CC, Nakahara K, Leder P . Human immunoglobulin heavy chain genes map to a region of translocations in malignant B lymphocytes. Science 1982; 216: 301–303.

    Article  CAS  Google Scholar 

  4. Cherif D, Berger R . New localizations of VH sequences by in situ hybridization with biotinylated probes. Genes Chromosomes Cancer 1990; 2: 103–108.

    Article  CAS  Google Scholar 

  5. Matsuda F, Shin EK, Hirabayashi Y, Nagaoka H . Organization of variable region segments of the human immunoglobulin heavy chain: duplication of the D5 cluster within the locus and interchromosomal translocation of variable region segments. EMBO J 1990; 9: 2501–2506.

    Article  CAS  Google Scholar 

  6. Tomlinson IM, Cook GP, Carter NP et al. Human immunoglobulin VH and D segments on chromosomes 15q11.2 and 16p11.2. Hum Mol Genet 1994; 3: 853–860.

    Article  CAS  Google Scholar 

  7. Tomlinson IM, Walter G, Marks JD, Llewelyn MB, Winter G . The repertoire of human germline VH sequences reveals about fifty groups of VH segments with different hypervariable loops. J Mol Biol 1992; 227: 776–798.

    Article  CAS  Google Scholar 

  8. Cook GP, Tomlinson IM, Walter G et al. A map of the human immunoglobulin VH locus completed by analysis of the telomeric region of chromosome 14q. Nat Genet 1994; 7: 162–168.

    Article  CAS  Google Scholar 

  9. Williams SC, Frippiat JP, Tomlinson IM, Ignatovich O, Lefranc MP, Winter G . Sequence and evolution of the human germline V lambda repertoire. J Mol Biol 1996; 264: 220–232.

    Article  CAS  Google Scholar 

  10. Matsuda F, Shin EK, Nagaoka H et al. Structure and physical map of 64 variable segments in the 3′0.8-megabase region of the human immunoglobulin heavy-chain locus. Nat Genet 1993; 3: 88–94.

    Article  CAS  Google Scholar 

  11. Matsuda F, Ishii K, Bourvagnet P et al. The complete nucleotide sequence of the human immunoglobulin heavy chain variable region locus. J Exp Med 1998; 188: 2151–2162.

    Article  CAS  Google Scholar 

  12. Walter G, Tomlinson IM, Cook GP, Winter G, Rabbitts TH, Dear PH . HAPPY mapping of a YAC reveals alternative haplotypes in the human immunoglobulin VH locus. Nucleic Acids Res 1993; 21: 4524–4529.

    Article  CAS  Google Scholar 

  13. Tonegawa S . Somatic generation of antibody diversity. Nature 1983; 302: 575–581.

    Article  CAS  Google Scholar 

  14. Honjo T, Habu S . Origin of immune diversity: genetic variation and selection. Annu Rev Biochem 1985; 54: 803–830.

    Article  CAS  Google Scholar 

  15. Berek C, Milstein C . The dynamic nature of the antibody repertoire. Immunol Rev 1988; 105: 5–26.

    Article  CAS  Google Scholar 

  16. Jacob J, Kelsoe G, Rajewsky K, Weiss U . Intraclonal generation of antibody mutants in germinal centres. Nature 1991; 354: 389–392.

    Article  CAS  Google Scholar 

  17. Pham P, Bransteitter R, Petruska J, Goodman MF . Processive AID-catalysed cytosine deamination on single-stranded DNA simulates somatic hypermutation. Nature 2003; 424: 103–107.

    Article  CAS  Google Scholar 

  18. Nagaoka H, Muramatsu M, Yamamura N, Kinoshita K, Honjo T . Activation-induced deaminase (AID)-directed hypermutation in the immunoglobulin Smu region: implication of AID involvement in a common step of class switch recombination and somatic hypermutation. J Exp Med 2002; 195: 529–534.

    Article  CAS  Google Scholar 

  19. Jung D, Alt FW . Unraveling V(D)J recombination; insights into gene regulation. Cell 2004; 116: 299–311.

    Article  CAS  Google Scholar 

  20. Cui X, Li H . Human immunoglobulin VH4 sequences resolved by population-based analysis after enzymatic amplification and denaturing gradient gel electrophoresis. Eur J Immunogenet 2000; 27: 37–46.

    Article  CAS  Google Scholar 

  21. Cui X, Li H . Determination of gene organization in individual haplotypes by analyzing single DNA fragments from single spermatozoa. Proc Natl Acad Sci USA 1998; 95: 10791–10796.

    Article  CAS  Google Scholar 

  22. Cui X, Li H . Discriminating between allelic and interlocus differences among human immunoglobulin VH4 sequences by analyzing single spermatozoa. Hum Genet 1997; 100: 96–100.

    Article  CAS  Google Scholar 

  23. Li H, Cui X, Pramanik S, Chimge NO . Genetic diversity of the human immunoglobulin heavy chain VH region. Immunol Rev 2002; 190: 53–68.

    Article  CAS  Google Scholar 

  24. Pramanik S, Li H . Direct detection of insertion/deletion polymorphisms in an autosomal region by analyzing high-density markers in individual spermatozoa. Am J Hum Genet 2002; 71: 1342–1352.

    Article  CAS  Google Scholar 

  25. Lefranc M-P, Lefranc G . The Immunoglobulin Factsbook, Vol. xiv, Academic Press, San Diego, 2001, p. 457.

    Google Scholar 

  26. Li H, Hood L . Multiplex genotype determination at a DNA sequence polymorphism cluster in the human immunoglobulin heavy-chain region. Genomics 1995; 26: 199–206.

    Article  CAS  Google Scholar 

  27. den Dunnen JT, Antonarakis SE . Nomenclature for the description of human sequence variations. Hum Genet 2001; 109: 121–124.

    Article  CAS  Google Scholar 

  28. Shin EK, Matsuda F, Nagaoka H et al. Physical map of the 3′ region of the human immunoglobulin heavy chain locus: clustering of autoantibody-related variable segments in one haplotype. EMBO J 1991; 10: 3641–3645.

    Article  CAS  Google Scholar 

  29. Chen PP, Yang PM . A segment of human Vh gene locus is duplicated. Scand J Immunol 1990; 31: 593–599.

    Article  CAS  Google Scholar 

  30. Yang PM, Olsen NJ, Siminovitch KA et al. Possible deletion of a developmentally regulated heavy-chain variable region gene in autoimmune diseases. Proc Natl Acad Sci USA 1990; 87: 7907–7911.

    Article  CAS  Google Scholar 

  31. Sasso EH, Willems van Dijk K, Bull A, van der Maarel SM, Milner EC . VH genes in tandem array comprise a repeated germline motif. J Immunol 1992; 149: 1230–1236.

    CAS  PubMed  Google Scholar 

  32. Milner EC, Hufnagle WO, Glas AM, Suzuki I, Alexander C . Polymorphism and utilization of human VH Genes. Ann NY Acad Sci 1995; 764: 50–61.

    Article  CAS  Google Scholar 

  33. Tomlinson IM, Williams SC, Ignatovich O, Corbett SJ, Winter G . Vbase sequence directory, MRC Centre for Protein Engineering, 1998.

  34. Walter MA, Dosch HM, Cox DW . A deletion map of the human immunoglobulin heavy chain variable region. J Exp Med 1991; 174: 335–349.

    Article  CAS  Google Scholar 

  35. Ghanem N, Dariavach P, Bensmana M, Chibani J, Lefranc G, Lefranc MP . Polymorphism of immunoglobulin lambda constant region genes in populations from France, Lebanon and Tunisia. Exp Clin Immunogenet 1988; 5: 186–195.

    CAS  PubMed  Google Scholar 

  36. Taub RA, Hollis GF, Hieter PA, Korsmeyer S, Waldmann TA, Leder P . Variable amplification of immunoglobulin lambda light-chain genes in human populations. Nature 1983; 304: 172–174.

    Article  CAS  Google Scholar 

  37. Schaible G, Rappold GA, Pargent W, Zachau HG . The immunoglobulin kappa locus: polymorphism and haplotypes of Caucasoid and non-Caucasoid individuals. Hum Genet 1993; 91: 261–267.

    Article  CAS  Google Scholar 

  38. Ghanem N, Buresi C, Moisan JP et al. Deletion, insertion, and restriction site polymorphism of the T-cell receptor gamma variable locus in French, Lebanese, Tunisian, and black African populations. Immunogenetics 1989; 30: 350–360.

    Article  CAS  Google Scholar 

  39. Ghanem N, Soua Z, Zhang XG et al. Polymorphism of the T-cell receptor gamma variable and constant region genes in a Chinese population. Hum Genet 1991; 86: 450–456.

    Article  CAS  Google Scholar 

  40. Bohme J, Andersson M, Andersson G, Moller E, Peterson PA, Rask L . HLA-DR beta genes vary in number between different DR specificities, whereas the number of DQ beta genes is constant. J Immunol 1985; 135: 2149–2155.

    CAS  Google Scholar 

  41. Tokunaga K, Saueracker G, Kay PH, Christiansen FT, Anand R, Dawkins RL . Extensive deletions and insertions in different MHC supratypes detected by pusled field gel electrophoresis. J Exp Med 1988; 168: 933–940.

    Article  CAS  Google Scholar 

  42. Martin MP, Bashirova A, Traherne J, Trowsdale J, Carrington M . Cutting edge: expansion of the KIR locus by unequal crossing over. J Immunol 2003; 171: 2192–2195.

    Article  CAS  Google Scholar 

  43. Hikami K, Tsuchiya N, Yabe T, Tokunaga K . Variations of human killer cell lectin-like receptors: common occurrence of NKG2-C deletion in the general population. Genes Immun 2003; 4: 160–167.

    Article  CAS  Google Scholar 

  44. Lefranc MP, Lefranc G, Rabbitts TH . Inherited deletion of immunoglobulin heavy chain constant region genes in normal human individuals. Nature 1982; 300: 760–762.

    Article  CAS  Google Scholar 

  45. Migone N, Oliviero S, de Lange G et al. Multiple gene deletions within the human immunoglobulin heavy-chain cluster. Proc Natl Acad Sci USA 1984; 81: 5811–5815.

    Article  CAS  Google Scholar 

  46. Brusco A, Cinque F, Saviozzi S, Boccazzi C, De Marchi M, Carbonara AO . The G4 gene is duplicated in 44% of human immunoglobulin heavy chain constant region haplotypes. Hum Genet 1997; 100: 84–89.

    Article  CAS  Google Scholar 

  47. Brusco A, Cariota U, Bottaro A et al. Variability of the immunoglobulin heavy chain constant region locus: a population study. Hum Genet 1995; 95: 319–326.

    Article  CAS  Google Scholar 

  48. Bech-Hansen NT, Cox DW . Duplication of the human immunoglobulin heavy chain gamma 2 gene. Am J Hum Genet 1986; 38: 67–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Olsson PG, Rabbani H, Hammarstrom L, Smith CI . Novel human immunoglobulin heavy chain constant region gene deletion haplotypes characterized by pulsed-field electrophoresis. Clin Exp Immunol 1993; 94: 84–90.

    Article  CAS  Google Scholar 

  50. Cui XF, Li HH, Goradia TM et al. Single-sperm typing: determination of genetic distance between the G gamma-globin and parathyroid hormone loci by using the polymerase chain reaction and allele-specific oligomers. Proc Natl Acad Sci USA 1989; 86: 9389–9393.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Marco Azaro for help in preparation of illustrations, Drs Weichung Shih, Hui-Yun Wang and Xiangfeng Cui for helpful discussions and experimental help, and Danielle M Frikker for her comments on the paper. This work was supported in part by a grant (R01 AI045956) from the National Institute of Allergy and Infectious Diseases, NIH to HL.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to H Li.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chimge, NO., Pramanik, S., Hu, G. et al. Determination of gene organization in the human IGHV region on single chromosomes. Genes Immun 6, 186–193 (2005). https://doi.org/10.1038/sj.gene.6364176

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364176

Keywords

This article is cited by

Search

Quick links