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. 1991 Aug 1;174(2):335–349. doi: 10.1084/jem.174.2.335

A deletion map of the human immunoglobulin heavy chain variable region

PMCID: PMC2118905  PMID: 1649888

Abstract

Analysis of VH gene segments deleted in the process of immunoglobulin heavy chain (IGH) variable region assembly in three series of monoclonal B cell lines has been used to determine the human VH region organization. A deletion map of the relative positions of 21 different VH gene segments has been determined. The characterization of B cell lines from three unrelated adults of two racial groups yielded the same relative VH gene segment order, suggesting that the overall order of VH genes in the normal population is constant. This VH gene segment order was consistent with what we had previously generated from physical mapping techniques. DH segments from the second DH cluster, distinct from the major DH locus 3' of the VH region, were not observed to be used in 32 different rearrangements. Approximately 77% of the VH-(D)JH rearrangements involved VH gene segments within 500 kb of the JH region, indicating that human B cell lines preferentially rearrange JH- proximal VH gene segments. The switch, observed in mice, from the fetal use of JH-proximal VH gene segments to an adult VH use dependent upon VH family size may therefore not occur in humans. This detailed map of the VH gene segments is a necessary prerequisite for understanding VH usage in development and disease.

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Selected References

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  1. Alt F. W., Yancopoulos G. D., Blackwell T. K., Wood C., Thomas E., Boss M., Coffman R., Rosenberg N., Tonegawa S., Baltimore D. Ordered rearrangement of immunoglobulin heavy chain variable region segments. EMBO J. 1984 Jun;3(6):1209–1219. doi: 10.1002/j.1460-2075.1984.tb01955.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Benger J. C., Teshima I., Walter M. A., Brubacher M. G., Daouk G. H., Cox D. W. Localization and genetic linkage of the human immunoglobulin heavy chain genes and the creatine kinase brain (CKB) gene: identification of a hot spot for recombination. Genomics. 1991 Apr;9(4):614–622. doi: 10.1016/0888-7543(91)90354-h. [DOI] [PubMed] [Google Scholar]
  3. Berman J. E., Mellis S. J., Pollock R., Smith C. L., Suh H., Heinke B., Kowal C., Surti U., Chess L., Cantor C. R. Content and organization of the human Ig VH locus: definition of three new VH families and linkage to the Ig CH locus. EMBO J. 1988 Mar;7(3):727–738. doi: 10.1002/j.1460-2075.1988.tb02869.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Blackwell T. K., Alt F. W. Mechanism and developmental program of immunoglobulin gene rearrangement in mammals. Annu Rev Genet. 1989;23:605–636. doi: 10.1146/annurev.ge.23.120189.003133. [DOI] [PubMed] [Google Scholar]
  5. Blankenstein T., Krawinkel U. Immunoglobulin VH region genes of the mouse are organized in overlapping clusters. Eur J Immunol. 1987 Sep;17(9):1351–1357. doi: 10.1002/eji.1830170920. [DOI] [PubMed] [Google Scholar]
  6. Brodeur P. H., Osman G. E., Mackle J. J., Lalor T. M. The organization of the mouse Igh-V locus. Dispersion, interspersion, and the evolution of VH gene family clusters. J Exp Med. 1988 Dec 1;168(6):2261–2278. doi: 10.1084/jem.168.6.2261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brown N. A., Liu C., Berenson J. R., Garcia C. R., Wang R., Calame K. L. Immunoglobulin JH, C mu, and C gamma gene rearrangements in human B lymphocytes clonally transformed by Epstein-Barr virus. Proc Natl Acad Sci U S A. 1985 Jan;82(2):556–560. doi: 10.1073/pnas.82.2.556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Buluwela L., Albertson D. G., Sherrington P., Rabbitts P. H., Spurr N., Rabbitts T. H. The use of chromosomal translocations to study human immunoglobulin gene organization: mapping DH segments within 35 kb of the C mu gene and identification of a new DH locus. EMBO J. 1988 Jul;7(7):2003–2010. doi: 10.1002/j.1460-2075.1988.tb03039.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Buluwela L., Rabbitts T. H. A VH gene is located within 95 Kb of the human immunoglobulin heavy chain constant region genes. Eur J Immunol. 1988 Nov;18(11):1843–1845. doi: 10.1002/eji.1830181130. [DOI] [PubMed] [Google Scholar]
  10. Capra J. D., Tucker P. W. Human immunoglobulin heavy chain genes. J Biol Chem. 1989 Aug 5;264(22):12745–12748. [PubMed] [Google Scholar]
  11. Chen P. P., Siminovitch K. A., Olsen N. J., Erger R. A., Carson D. A. A highly informative probe for two polymorphic Vh gene regions that contain one or more autoantibody-associated Vh genes. J Clin Invest. 1989 Aug;84(2):706–710. doi: 10.1172/JCI114218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cox D. W., Markovic V. D., Teshima I. E. Genes for immunoglobulin heavy chains and for alpha 1-antitrypsin are localized to specific regions of chromosome 14q. Nature. 1982 Jun 3;297(5865):428–430. doi: 10.1038/297428a0. [DOI] [PubMed] [Google Scholar]
  13. Cuisinier A. M., Guigou V., Boubli L., Fougereau M., Tonnelle C. Preferential expression of VH5 and VH6 immunoglobulin genes in early human B-cell ontogeny. Scand J Immunol. 1989 Oct;30(4):493–497. doi: 10.1111/j.1365-3083.1989.tb02455.x. [DOI] [PubMed] [Google Scholar]
  14. Dosch H. M., Lam P., Guerin D. Differential regulation of activation, clonal expansion, and antibody secretion in human B cells. J Immunol. 1985 Dec;135(6):3808–3816. [PubMed] [Google Scholar]
  15. Dosch H. M., Lam P., Hui M. F., Hibi T. Concerted generation of Ig isotype diversity in human fetal bone marrow. J Immunol. 1989 Oct 15;143(8):2464–2469. [PubMed] [Google Scholar]
  16. Erikson J., Finan J., Nowell P. C., Croce C. M. Translocation of immunoglobulin VH genes in Burkitt lymphoma. Proc Natl Acad Sci U S A. 1982 Sep;79(18):5611–5615. doi: 10.1073/pnas.79.18.5611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fraizer G. C., Harrold T. R., Hofker M. H., Cox D. W. In-frame single codon deletion in the Mmalton deficiency allele of alpha 1-antitrypsin. Am J Hum Genet. 1989 Jun;44(6):894–902. [PMC free article] [PubMed] [Google Scholar]
  18. Hesse J. E., Lieber M. R., Gellert M., Mizuuchi K. Extrachromosomal DNA substrates in pre-B cells undergo inversion or deletion at immunoglobulin V-(D)-J joining signals. Cell. 1987 Jun 19;49(6):775–783. doi: 10.1016/0092-8674(87)90615-5. [DOI] [PubMed] [Google Scholar]
  19. Hibi T., Chan M. A., Petsche D., Dosch H. M. Phenotype, frequency, and EBV responsiveness of human marrow B and pre-B cells. J Immunol. 1986 May 1;136(9):3211–3218. [PubMed] [Google Scholar]
  20. Hibi T., Dosch H. M. Limiting dilution analysis of the B cell compartment in human bone marrow. Eur J Immunol. 1986 Feb;16(2):139–145. doi: 10.1002/eji.1830160206. [DOI] [PubMed] [Google Scholar]
  21. Honjo T., Kataoka T. Organization of immunoglobulin heavy chain genes and allelic deletion model. Proc Natl Acad Sci U S A. 1978 May;75(5):2140–2144. doi: 10.1073/pnas.75.5.2140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hui M. F., Lam P., Dosch H. M. Properties and heterogeneity of human fetal pre-B cells transformed by EBV. J Immunol. 1989 Oct 15;143(8):2470–2479. [PubMed] [Google Scholar]
  23. Ichihara Y., Abe M., Yasui H., Matsuoka H., Kurosawa Y. At least five DH genes of human immunoglobulin heavy chains are encoded in 9-kilobase DNA fragments. Eur J Immunol. 1988 Apr;18(4):649–652. doi: 10.1002/eji.1830180426. [DOI] [PubMed] [Google Scholar]
  24. Ichihara Y., Matsuoka H., Kurosawa Y. Organization of human immunoglobulin heavy chain diversity gene loci. EMBO J. 1988 Dec 20;7(13):4141–4150. doi: 10.1002/j.1460-2075.1988.tb03309.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Jeong H. D., Komisar J. L., Kraig E., Teale J. M. Strain-dependent expression of VH gene families. J Immunol. 1988 Apr 1;140(7):2436–2441. [PubMed] [Google Scholar]
  26. Johnson M. J., Natali A. M., Cann H. M., Honjo T., Cavalli-Sforza L. L. Polymorphisms of a human variable heavy chain gene show linkage with constant heavy chain genes. Proc Natl Acad Sci U S A. 1984 Dec;81(24):7840–7844. doi: 10.1073/pnas.81.24.7840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kleinfield R., Hardy R. R., Tarlinton D., Dangl J., Herzenberg L. A., Weigert M. Recombination between an expressed immunoglobulin heavy-chain gene and a germline variable gene segment in a Ly 1+ B-cell lymphoma. 1986 Aug 28-Sep 3Nature. 322(6082):843–846. doi: 10.1038/322843a0. [DOI] [PubMed] [Google Scholar]
  28. Kodaira M., Kinashi T., Umemura I., Matsuda F., Noma T., Ono Y., Honjo T. Organization and evolution of variable region genes of the human immunoglobulin heavy chain. J Mol Biol. 1986 Aug 20;190(4):529–541. doi: 10.1016/0022-2836(86)90239-1. [DOI] [PubMed] [Google Scholar]
  29. Krawinkel U., Christoph T., Blankenstein T. Organization of the Ig VH locus in mice and humans. Immunol Today. 1989 Oct;10(10):339–344. doi: 10.1016/0167-5699(89)90191-6. [DOI] [PubMed] [Google Scholar]
  30. Lawler A. M., Lin P. S., Gearhart P. J. Adult B-cell repertoire is biased toward two heavy-chain variable-region genes that rearrange frequently in fetal pre-B cells. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2454–2458. doi: 10.1073/pnas.84.8.2454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lee K. H., Matsuda F., Kinashi T., Kodaira M., Honjo T. A novel family of variable region genes of the human immunoglobulin heavy chain. J Mol Biol. 1987 Jun 20;195(4):761–768. doi: 10.1016/0022-2836(87)90482-7. [DOI] [PubMed] [Google Scholar]
  32. Logtenberg T., Schutte M. E., Inghirami G., Berman J. E., Gmelig-Meyling F. H., Insel R. A., Knowles D. M., Alt F. W. Immunoglobulin VH gene expression in human B cell lines and tumors: biased VH gene expression in chronic lymphocytic leukemia. Int Immunol. 1989;1(4):362–366. doi: 10.1093/intimm/1.4.362. [DOI] [PubMed] [Google Scholar]
  33. MacKenzie T., Dosch H. M. Clonal and molecular characteristics of the human IgE-committed B cell subset. J Exp Med. 1989 Feb 1;169(2):407–430. doi: 10.1084/jem.169.2.407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Matsuda F., Lee K. H., Nakai S., Sato T., Kodaira M., Zong S. Q., Ohno H., Fukuhara S., Honjo T. Dispersed localization of D segments in the human immunoglobulin heavy-chain locus. EMBO J. 1988 Apr;7(4):1047–1051. doi: 10.1002/j.1460-2075.1988.tb02912.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Meek K. D., Hasemann C. A., Capra J. D. Novel rearrangements at the immunoglobulin D locus. Inversions and fusions add to IgH somatic diversity. J Exp Med. 1989 Jul 1;170(1):39–57. doi: 10.1084/jem.170.1.39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Meek K., Rathbun G., Reininger L., Jaton J. C., Kofler R., Tucker P. W., Capra J. D. Organization of the murine immunoglobulin VH complex: placement of two new VH families (VH10 and VH11) and analysis of VH family clustering and interdigitation. Mol Immunol. 1990 Nov;27(11):1073–1081. doi: 10.1016/0161-5890(90)90095-h. [DOI] [PubMed] [Google Scholar]
  37. Nelson K. J., Haimovich J., Perry R. P. Characterization of productive and sterile transcripts from the immunoglobulin heavy-chain locus: processing of micron and muS mRNA. Mol Cell Biol. 1983 Jul;3(7):1317–1332. doi: 10.1128/mcb.3.7.1317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Nickerson K. G., Berman J., Glickman E., Chess L., Alt F. W. Early human IgH gene assembly in Epstein-Barr virus-transformed fetal B cell lines. Preferential utilization of the most JH-proximal D segment (DQ52) and two unusual VH-related rearrangements. J Exp Med. 1989 Apr 1;169(4):1391–1403. doi: 10.1084/jem.169.4.1391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Perlmutter R. M., Kearney J. F., Chang S. P., Hood L. E. Developmentally controlled expression of immunoglobulin VH genes. Science. 1985 Mar 29;227(4694):1597–1601. doi: 10.1126/science.3975629. [DOI] [PubMed] [Google Scholar]
  40. Rathbun G. A., Capra J. D., Tucker P. W. Organization of the murine immunoglobulin VH complex in the inbred strains. EMBO J. 1987 Oct;6(10):2931–2937. doi: 10.1002/j.1460-2075.1987.tb02597.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Rathbun G. A., Otani F., Milner E. C., Capra J. D., Tucker P. W. Molecular characterization of the A/J J558 family of heavy chain variable region gene segments. J Mol Biol. 1988 Aug 5;202(3):383–395. doi: 10.1016/0022-2836(88)90272-0. [DOI] [PubMed] [Google Scholar]
  42. Ravetch J. V., Siebenlist U., Korsmeyer S., Waldmann T., Leder P. Structure of the human immunoglobulin mu locus: characterization of embryonic and rearranged J and D genes. Cell. 1981 Dec;27(3 Pt 2):583–591. doi: 10.1016/0092-8674(81)90400-1. [DOI] [PubMed] [Google Scholar]
  43. Rechavi G., Bienz B., Ram D., Ben-Neriah Y., Cohen J. B., Zakut R., Givol D. Organization and evolution of immunoglobulin VH gene subgroups. Proc Natl Acad Sci U S A. 1982 Jul;79(14):4405–4409. doi: 10.1073/pnas.79.14.4405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Reth M. G., Jackson S., Alt F. W. VHDJH formation and DJH replacement during pre-B differentiation: non-random usage of gene segments. EMBO J. 1986 Sep;5(9):2131–2138. doi: 10.1002/j.1460-2075.1986.tb04476.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Sam M., Walter M. A., Cox D. W. RsaI polymorphism of a human immunoglobulin VH5 subclass locus. Nucleic Acids Res. 1988 Sep 12;16(17):8748–8748. doi: 10.1093/nar/16.17.8748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Sasso E. H., Van Dijk K. W., Milner E. C. Prevalence and polymorphism of human VH3 genes. J Immunol. 1990 Oct 15;145(8):2751–2757. [PubMed] [Google Scholar]
  47. Schroeder H. W., Jr, Hillson J. L., Perlmutter R. M. Early restriction of the human antibody repertoire. Science. 1987 Nov 6;238(4828):791–793. doi: 10.1126/science.3118465. [DOI] [PubMed] [Google Scholar]
  48. Schroeder H. W., Jr, Walter M. A., Hofker M. H., Ebens A., Willems van Dijk K., Liao L. C., Cox D. W., Milner E. C., Perlmutter R. M. Physical linkage of a human immunoglobulin heavy chain variable region gene segment to diversity and joining region elements. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8196–8200. doi: 10.1073/pnas.85.21.8196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Shen A., Humphries C., Tucker P., Blattner F. Human heavy-chain variable region gene family nonrandomly rearranged in familial chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8563–8567. doi: 10.1073/pnas.84.23.8563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Siebenlist U., Ravetch J. V., Korsmeyer S., Waldmann T., Leder P. Human immunoglobulin D segments encoded in tandem multigenic families. Nature. 1981 Dec 17;294(5842):631–635. doi: 10.1038/294631a0. [DOI] [PubMed] [Google Scholar]
  51. Souroujon M. C., Rubinstein D. B., Schwartz R. S., Barrett K. J. Polymorphisms in human H chain V region genes from the VHIII gene family. J Immunol. 1989 Jul 15;143(2):706–711. [PubMed] [Google Scholar]
  52. Takahashi N., Noma T., Honjo T. Rearranged immunoglobulin heavy chain variable region (VH) pseudogene that deletes the second complementarity-determining region. Proc Natl Acad Sci U S A. 1984 Aug;81(16):5194–5198. doi: 10.1073/pnas.81.16.5194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Walter M. A., Cox D. W. A method for two-dimensional DNA electrophoresis (2D-DE): application to the immunoglobulin heavy chain variable region. Genomics. 1989 Jul;5(1):157–159. doi: 10.1016/0888-7543(89)90102-x. [DOI] [PubMed] [Google Scholar]
  54. Walter M. A., Cox D. W. Analysis of genetic variation reveals human immunoglobulin VH-region gene organization. Am J Hum Genet. 1988 Mar;42(3):446–451. [PMC free article] [PubMed] [Google Scholar]
  55. Walter M. A., Linsley P. S., Cox D. W. Apa I polymorphism of a human immunoglobin VH3 subclass locus. Nucleic Acids Res. 1987 Jun 11;15(11):4697–4697. doi: 10.1093/nar/15.11.4697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Walter M. A., Surti U., Hofker M. H., Cox D. W. The physical organization of the human immunoglobulin heavy chain gene complex. EMBO J. 1990 Oct;9(10):3303–3313. doi: 10.1002/j.1460-2075.1990.tb07530.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Willems van Dijk K., Schroeder H. W., Jr, Perlmutter R. M., Milner E. C. Heterogeneity in the human Ig VH locus. J Immunol. 1989 Apr 1;142(7):2547–2554. [PubMed] [Google Scholar]
  58. Wu G. E., Atkinson M. J., Ramsden D. A., Paige C. J. VH gene repertoire. Semin Immunol. 1990 May;2(3):207–216. [PubMed] [Google Scholar]
  59. Wu G. E., Paige C. J. VH gene family utilization is regulated by a locus outside of the VH region. J Exp Med. 1988 Apr 1;167(4):1499–1504. doi: 10.1084/jem.167.4.1499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Yancopoulos G. D., Desiderio S. V., Paskind M., Kearney J. F., Baltimore D., Alt F. W. Preferential utilization of the most JH-proximal VH gene segments in pre-B-cell lines. Nature. 1984 Oct 25;311(5988):727–733. doi: 10.1038/311727a0. [DOI] [PubMed] [Google Scholar]
  61. Yancopoulos G. D., Malynn B. A., Alt F. W. Developmentally regulated and strain-specific expression of murine VH gene families. J Exp Med. 1988 Jul 1;168(1):417–435. doi: 10.1084/jem.168.1.417. [DOI] [PMC free article] [PubMed] [Google Scholar]

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