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.

  • Review
  • Published:

The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease

Genes & Immunity volume 13, pages 363–373 (2012)Cite this article

Subjects

Abstract

The immunoglobulin (IG) loci consist of repeated and highly homologous sets of genes of different types, variable (V), diversity (D) and junction (J), that rearrange in developing B cells to produce an individual’s highly variable repertoire of expressed antibodies, designed to bind to a vast array of pathogens. This repeated structure makes these loci susceptible to a high frequency of insertion and deletion events through evolutionary time, and also makes them difficult to characterize at the genomic level or assay with high-throughput techniques. Given the central role of antibodies in the adaptive immune system, it is not surprising that early candidate gene approaches showed that germline polymorphisms in these regions correlated with susceptibility to both infectious and autoimmune diseases. However, more recent studies, particularly those using high-throughput genome-wide arrays, have failed to implicate these loci in disease. In this review of the IG heavy chain variable gene cluster (IGHV), we examine how poorly we understand the distribution of haplotype variation in this genomic region, and we argue that this lack of information may mask candidate loci in the IGHV gene cluster as causative factors for infectious and autoimmune diseases.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Murphy KM, Travers P, Walport M . Janeway’s Immunobiology 7th edn. Garland Science London, 2007.

    Google Scholar 

  2. Lefranc M-P, Lefranc G . The Immunoglobulin FactsBook. Academic Press London, 2001.

    Google Scholar 

  3. Lefranc M-P, Lefranc G . The T Cell Receptor FactsBook. Academic Press London, 2001.

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Liu L, Lucas AH . IGH V3-23*01 and its allele V3-23*03 differ in their capacity to form the canonical human antibody combining site specific for the capsular polysaccharide of Haemophilus influenzae type B. Immunogenetics 2003; 55: 336–338.

    CAS  PubMed  Google Scholar 

  6. Boyd SD, Gaeta BA, Jackson KJ, Fire AZ, Marshall EL, Merker JD et al. Individual variation in the germline Ig gene repertoire inferred from variable region gene rearrangements. J Immunol 2010; 184: 6986–6992.

    CAS  PubMed  Google Scholar 

  7. Glanville J, Kuo TC, von Budingen HC, Guey L, Berka J, Sundar PD et al. Naive antibody gene-segment frequencies are heritable and unaltered by chronic lymphocyte ablation. Proc Natl Acad Sci USA 2011; 108: 20066–20071.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 1000 Genomes Project Consortium A map of human genome variation from population-scale sequencing. Nature 2010; 467: 1061–1073.

    Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  10. IMGT. The International ImMunoGeneTics information system: http://www.imgt.org.

  11. Pallarès N, Lefebvre S, Contet V, Matsuda F, Lefranc MP . The human immunoglobulin heavy variable genes. Exp Clin Immunogenet 1999; 16: 36–60.

    PubMed  Google Scholar 

  12. Ruiz M, Pallarès N, Contet V, Barbi V, Lefranc MP . The human immunoglobulin heavy diversity (IGHD) and joining (IGHJ) segments. Exp Clin Immunogenet 1999; 16: 173–184.

    CAS  PubMed  Google Scholar 

  13. Lefranc MP . Nomenclature of the human immunoglobulin heavy (IGH) genes. Exp Clin Immunogenet 2001; 18: 100–116.

    CAS  PubMed  Google Scholar 

  14. Lefranc MP . Nomenclature of the human immunoglobulin heavy (IGH) genes. In: Current Protocols in Immunology. John Wiley and Sons Hoboken, 2001.

    Google Scholar 

  15. Giudicelli V, Chaume D, Lefranc MP . IMGT/GENE-DB: a comprehensive database for human and mouse immunoglobulin and T cell receptor genes. Nucleic Acids Res 2005; 33: D256–D261.

    CAS  PubMed  Google Scholar 

  16. The Immunoglobulin Polymorphism Database: cgi.cse.unsw.edu.au/∼ihmmune/IgPdb/.

  17. Wang Y, Jackson KJ, Gaeta B, Pomat W, Siba P, Sewell WA et al. Genomic screening by 454 pyrosequencing identifies a new human IGHV gene and sixteen other new IGHV allelic variants. Immunogenetics 2011; 63: 259–265.

    PubMed  Google Scholar 

  18. Romo-Gonzalez T, Morales-Montor J, Rodriguez-Dorantes M, Vargas-Madrazo E . Novel substitution polymorphisms of human immunoglobulin VH genes in Mexicans. Hum Immunol 2005; 66: 732–740.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  20. Lefranc G, Chaabani H, Van Loghem E, Lefranc MP, De Lange G, Helal AN . Simultaneous absence of the human IgG1, IgG2, IgG4 and IgA1 subclasses: immunological and immunogenetical considerations. Eur J Immunol 1983; 13: 240–244.

    CAS  PubMed  Google Scholar 

  21. Lefranc MP, Lefranc G, de Lange G, Out TA, van den Broek PJ, van Nieuwkoop J et al. Instability of the human immunoglobulin heavy chain constant region locus indicated by different inherited chromosomal deletions. Mol Biol Med 1983; 1: 207–217.

    CAS  PubMed  Google Scholar 

  22. Keyeux G, Lefranc G, Lefranc MP . A multigene deletion in the human IGH constant region locus involves highly homologous hot spots of recombination. Genomics 1989; 5: 431–441.

    CAS  PubMed  Google Scholar 

  23. Lefranc MP, Hammarström L, Smith CI, Lefranc G . Gene deletions in the human immunoglobulin heavy chain constant region locus: molecular and immunological analysis. Immunodefic Rev 1991; 2: 265–281.

    CAS  PubMed  Google Scholar 

  24. Wiebe V, Helal A, Lefranc MP, Lefranc G . Molecular analysis of the T17 immunoglobulin CH multigene deletion (del A1-GP-G2-G4-E). Hum Genet 1994; 93: 520–528.

    CAS  PubMed  Google Scholar 

  25. Hammarström L, Ghanem N, Smith CI, Lefranc G, Lefranc MP . RFLP of human immunoglobulin genes. Exp Clin Immunogenet 1990; 7: 7–19.

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  27. Sasso EH, Willems van Dijk K, Bull AP, Milner EC . A fetally expressed immunoglobulin VH1 gene belongs to a complex set of alleles. J Clin Invest 1993; 91: 2358–2367.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Shin EK, Matsuda F, Ozaki S, Kumagai S, Olerup O, Ström H et al. Polymorphism of the human immunoglobulin variable region segment V1-4.1. Immunogenetics 1993; 38: 304–306.

    CAS  PubMed  Google Scholar 

  29. Sasso EH, Buckner JH, Suzuki LA . Ethnic differences in VH gene polymorphism. Ann NY Acad Sci 1995; 764: 72–73.

    CAS  PubMed  Google Scholar 

  30. 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.

    CAS  PubMed  Google Scholar 

  31. Walter MA, Surti U, Hofker MH, Cox DW . The physical organization of the human immunoglobulin heavy chain gene complex. EMBO J 1990; 9: 3303–3313.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Shin EK, Matsuda F, Nagaoka H, Fukita Y, Imai T, Yokoyama K 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Cook GP, Tomlinson IM, Walter G, Riethman H, Carter NP, Buluwela L 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.

    CAS  PubMed  Google Scholar 

  35. Cook GP, Tomlinson IM . The human immunoglobulin VH repertoire. Immunol Today 1995; 16: 237–242.

    CAS  PubMed  Google Scholar 

  36. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Chimge NO, Pramanik S, Hu G, Lin Y, Gao R, Shen L et al. Determination of gene organization in the human IGHV region on single chromosomes. Genes Immun 2005; 6: 186–193.

    CAS  PubMed  Google Scholar 

  39. Pramanik S, Cui X, Wang HY, Chimge NO, Hu G, Shen L et al. Segmental duplication as one of the driving forces underlying the diversity of the human immunoglobulin heavy chain variable gene region. BMC Genomics 2011; 12: 78.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Kidd MJ, Chen Z, Wang Y, Jackson KJ, Zhang LN, Boyd SD et al. The inference of phased haplotypes for the immunoglobulin H chain V region gene loci by analysis of VDJ gene rearrangements. J Immunol 2012; 188: 1333–1340.

    CAS  PubMed  Google Scholar 

  41. Cho CS, Wang X, Zhao Y, Carson DA, Chen PP . Genotyping by PCR-ELISA of a complex polymorphic region that contains one to four copies of six highly homologous human VH3 genes. Proc Assoc Am Physicians 1997; 109: 558–564.

    CAS  PubMed  Google Scholar 

  42. Romo-Gonzalez T, Vargas-Madrazo E . Structural analysis of substitution patterns in alleles of human immunoglobulin VH genes. Mol Immunol 2005; 42: 1085–1097.

    CAS  PubMed  Google Scholar 

  43. Lefranc MP . IMGT unique numbering for the variable (V), constant (C), and groove (G) domains of IG, TR, MH, IgSF, and MhSF. Cold Spring Harb Protoc 2011; 2011: 633–642.

    PubMed  Google Scholar 

  44. Lefranc MP . IMGT Collier de Perles for the variable (V), constant (C), and groove (G) domains of IG, TR, MH, IgSF, and MhSF. Cold Spring Harb Protoc 2011; 2011: 643–651.

    PubMed  Google Scholar 

  45. Ehrenmann F, Lefranc MP . IMGT/3D structure-DB: querying the IMGT database for 3D structures in immunology and immunoinformatics (IG or antibodies, TR, MH, RPI, and FPIA). Cold Spring Harb Protoc 2011; 2011: 750–761.

    PubMed  Google Scholar 

  46. Scott MG, Crimmins DL, McCourt DW, Zocher I, Thiebe R, Zachau HG et al. Clonal characterization of the human IgG antibody repertoire to Haemophilus influenzae type b polysaccharide. III. A single VKII gene and one of several JK genes are joined by an invariant arginine to form the most common L chain V region. J Immunol 1989; 143: 4110–4116.

    CAS  PubMed  Google Scholar 

  47. Feeney AJ, Atkinson MJ, Cowan MJ, Escuro G, Lugo G . A defective Vkappa A2 allele in Navajos which may play a role in increased susceptibility to Haemophilus influenzae type b disease. J Clin Invest 1996; 97: 2277–2282.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Nadel B, Tang A, Lugo G, Love V, Escuro G, Feeney AJ . Decreased frequency of rearrangement due to the synergistic effect of nucleotide changes in the heptamer and nonamer of the recombination signal sequence of the V kappa gene A2b, which is associated with increased susceptibility of Navajos to Haemophilus influenzae type b disease. J Immunol 1998; 161: 6068–6073.

    CAS  PubMed  Google Scholar 

  49. Sasso EH, Johnson T, Kipps TJ . Expression of the immunoglobulin VH gene 51p1 is proportional to its germline gene copy number. J Clin Invest 1996; 97: 2074–2080.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sasso EH, Ghillani P, Musset L, Piette JC, Cacoub P . Effect of 51p1-related gene copy number (V1-69 locus) on production of hepatitis C-associated cryoglobulins. Clin Exp Immunol 2001; 123: 88–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Watson CT, Ramagopalan SV, Morrison KM, Ebers GC, Breden F . IGHV4-39 deletion polymorphism does not associate with risk or outcome of multiple sclerosis. J Neuroimmunol 2010; 225: 164–166.

    CAS  PubMed  Google Scholar 

  52. van Zelm MC, Geertsema C, Nieuwenhuis N, de Ridder D, Conley ME, Schiff CC et al. Gross deletions involving IGHM, BTK, or Artemis: a model for genomic lesions mediated by transposable elements. Am J Hum Genet 2008; 82: 320–332.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Prabakaran P, Chen W, Singarayan MG, Stewart CC, Streaker E, Feng Y et al. Expressed antibody repertoires in human cord blood cells: 454 sequencing and IMGT/HighV-QUEST analysis of germline gene usage, junctional diversity, and somatic mutations. Immunogenetics 2011; 5: 337–350.

    Google Scholar 

  54. Foreman AL, Van de Water J, Gougeon ML, Gershwin ME . B cells in autoimmune diseases: insights from analyses of immunoglobulin variable (Ig V) gene usage. Autoimmun Rev 2007; 6: 387–401.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Scheid JF, Mouquet H, Feldhahn N, Seaman MS, Velinzon K, Pietzsch J et al. Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature 2009; 458: 636–640.

    CAS  PubMed  Google Scholar 

  56. Gorny MK, Wang XH, Williams C, Volsky B, Revesz K, Witover B et al. Preferential use of the VH5-51 gene segment by the human immune response to code for antibodies against the V3 domain of HIV-1. Mol Immunol 2009; 46: 917–926.

    CAS  PubMed  Google Scholar 

  57. Breden F, Lepik C, Longo NS, Montero M, Lipsky PE, Scott JK . Comparison of antibody repertoires produced by HIV-1 infection, other chronic and acute infections, and systemic autoimmune disease. PLoS One 2011; 6: e16857.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Huang CC, Venturi M, Majeed S, Moore MJ, Phogat S, Zhang MY et al. Structural basis of tyrosine sulfation and VH-gene usage in antibodies that recognize the HIV type 1 coreceptor-binding site on gp120. Proc Natl Acad Sci USA 2004; 101: 2706–2711.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Kashyap AK, Steel J, Oner AF, Dillon MA, Swale RE, Wall KM et al. Combinatorial antibody libraries from survivors of the Turkish H5N1 avian influenza outbreak reveal virus neutralization strategies. Proc Natl Acad Sci USA 2008; 105: 5986–5991.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Throsby M, van den Brink E, Jongeneelen M, Poon LL, Alard P, Cornelissen L et al. Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells. PLoS One 2008; 3: e3942.

    PubMed  PubMed Central  Google Scholar 

  61. Sui J, Hwang WC, Perez S, Wei G, Aird D, Chen LM et al. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat Struct Mol Biol 2009; 16: 265–273.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Lerner RA . Rare antibodies from combinatorial libraries suggests an S.O.S. component of the human immunological repertoire. Mol Biosyst 2011; 7: 1004–1012.

    CAS  PubMed  Google Scholar 

  63. Sui J, Sheehan J, Hwang WC, Bankston LA, Burchett SK, Huang CY et al. Wide prevalence of heterosubtypic broadly neutralizing human anti-influenza A antibodies. Clin Infect Dis 2011; 52: 1003–1009.

    CAS  PubMed  Google Scholar 

  64. Wrammert J, Koutsonanos D, Li GM, Edupuganti S, Sui J, Morrissey M et al. Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med 2011; 208: 181–193.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Cho ML, Chen PP, Seo YI, Hwang SY, Kim WU, Min DJ et al. Association of homozygous deletion of the Humhv3005 and the VH3-30.3 genes with renal involvement in systemic lupus erythematosus. Lupus 2003; 12: 400–405.

    CAS  PubMed  Google Scholar 

  66. Olee T, Yang PM, Siminovitch KA, Olsen NJ, Hillson J, Wu J et al. Molecular basis of an autoantibody-associated restriction fragment length polymorphism that confers susceptibility to autoimmune diseases. J Clin Invest 1991; 88: 193–203.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Mo L, Leu SJ, Berry C, Liu F, Olee T, Yang YY et al. The frequency of homozygous deletion of a developmentally regulated Vh gene (Humhv3005) is increased in patients with chronic idiopathic thrombocytopenic purpura. Autoimmunity 1996; 24: 257–263.

    CAS  PubMed  Google Scholar 

  68. Gregersen PK, Olsson LM . Recent advances in the genetics of autoimmune disease. Annu Rev Immunol 2009; 27: 363–391.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Vencovsky J, Zd'arsky E, Moyes SP, Hajeer A, Ruzickova S, Cimburek Z et al. Polymorphism in the immunoglobulin VH gene V1-69 affects susceptibility to rheumatoid arthritis in subjects lacking the HLA-DRB1 shared epitope. Rheumatology (Oxford) 2002; 41: 401–410.

    CAS  Google Scholar 

  70. Tsai FJ, Lee YC, Chang JS, Huang LM, Huang FY, Chiu NC et al. Identification of novel susceptibility Loci for kawasaki disease in a Han chinese population by a genome-wide association study. PLoS One 2011; 6: e16853.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Walter MA, Gibson WT, Ebers GC, Cox DW . Susceptibility to multiple sclerosis is associated with the proximal immunoglobulin heavy chain variable region. J Clin Invest 1991; 87: 1266–1273.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Hashimoto LL, Walter MA, Cox DW, Ebers GC . Immunoglobulin heavy chain variable region polymorphisms and multiple sclerosis susceptibility. J Neuroimmunol 1993; 44: 77–83.

    CAS  PubMed  Google Scholar 

  73. Sawcer S, Jones HB, Feakes R, Gray J, Smaldon N, Chataway J et al. A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nat Genet 1996; 13: 464–468.

    CAS  PubMed  Google Scholar 

  74. Feakes R, Chataway J, Sawcer S, Jones HB, Clayton D, Goodfellow PN et al. Susceptibility to multiple sclerosis and the immunoglobulin heavy chain gene cluster. Ann Neurol 1998; 44: 984.

    CAS  PubMed  Google Scholar 

  75. Feakes R, Sawcer S, Smillie B, Chataway J, Broadley S, Compston A . No evidence for the involvement of interleukin 2 or the immunoglobulin heavy chain gene cluster in determining genetic susceptibility to multiple sclerosis. J Neurol Neurosurg Psychiatry 2000; 68: 679.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Walter MA, Cox DW . Nonuniform linkage disequilibrium within a 1500-kb region of the human immunoglobulin heavy-chain complex. Am J Hum Genet 1991; 49: 917–931.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Terwilliger JD, Hiekkalinna T . An utter refutation of the ‘fundamental theorem of the HapMap’. Eur J Hum Genet 2006; 14: 426–437.

    CAS  PubMed  Google Scholar 

  78. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    CAS  PubMed  Google Scholar 

  79. de Bakker PI, Yelensky R, Pe'er I, Gabriel SB, Daly MJ, Altshuler D . Efficiency and power in genetic association studies. Nat Genet 2006; 37: 1217–1223.

    Google Scholar 

  80. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ et al. Finding the missing heritability of complex diseases. Nature 2009; 461: 747–753.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Eichler EE, Flint J, Gibson G, Kong A, Leal SM, Moore JH et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet 2010; 11: 446–450.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Conrad DF, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y et al. Origins and functional impact of copy number variation in the human genome. Nature 2010; 464: 704–712.

    CAS  PubMed  Google Scholar 

  83. Craddock N, Hurles ME, Cardin N, Pearson RD, Plagnol V, Robson S et al. Genome-wide association study of CNV in 16 000 cases of eight common diseases and 3 000 shared controls. Nature 2010; 464: 713–720.

    CAS  PubMed  Google Scholar 

  84. Kato M, Kawaguchi T, Ishikawa S, Umeda T, Nakamichi R, Shapero MH et al. Population-genetic nature of copy number variations in the human genome. Hum Mol Genet 2010; 19: 761–773.

    CAS  PubMed  Google Scholar 

  85. Campbell CD, Sampas N, Tsalenko A, Sudmant PH, Kidd JM, Malig M et al. Population-genetic properties of differentiated human copy-number polymorphisms. Am J Hum Genet 2011; 88: 317–332.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Levy S, Sutton G, Ng PC, Feuk L, Halpern AL, Walenz BP et al. The diploid genome sequence of an individual human. PLoS Biol 2007; 5: e254.

    PubMed  PubMed Central  Google Scholar 

  87. Axelrod N, Lin Y, Ng PC, Stockwell TB, Crabtree J, Huang J et al. The HuRef Browser: a web resource for individual human genomics. Nucleic Acids Res 2009; 37 (Database issue) D1018–D1024.

    CAS  PubMed  Google Scholar 

  88. Alkan C, Sajjadian S, Eichler EE . Limitations of next-generation genome sequence assembly. Nat Methods 2011; 8: 61–65.

    CAS  PubMed  Google Scholar 

  89. Tuzun E, Sharp AJ, Bailey JA, Kaul R, Morrison VA, Pertz LM et al. Fine-scale structural variation of the human genome. Nat Genet 2005; 37: 727–732.

    CAS  PubMed  Google Scholar 

  90. Kidd JM, Cooper GM, Donahue WF, Hayden HS, Sampas N, Graves T et al. Mapping and sequencing of structural variation from eight human genomes. Nature 2008; 453: 56–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Kidd JM, Sampas N, Antonacci F, Graves T, Fulton R, Hayden HS et al. Characterization of missing human genome sequences and copy-number polymorphic insertions. Nat Methods 2010; 7: 365–371.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Mills RE, Walter K, Stewart C, Handsaker RE, Chen K, Alkan C et al. Mapping copy number variation by population-scale genome sequencing. Nature 2011; 470: 59–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Huang DF, Siminovitch KA, Liu XY, Olee T, Olsen NJ, Berry C et al. Population and family studies of three disease-related polymorphic genes in systemic lupus erythematosus. J Clin Invest 1995; 95: 1766–1772.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Veijola R, Knip M, Puukka R, Reijonen H, Cox DW, Ilonen J . The immunoglobulin heavy-chain variable region in insulin-dependent diabetes mellitus: affected-sib-pair analysis and association studies. Am J Hum Genet 1996; 59: 462–470.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Field LL, Larsen Z, Pociot F, Nerup J, Tobias R, Bonnevie-Nielsen V . Evidence for a locus (IDDM16) in the immunoglobulin heavy chain region on chromosome 14q32.3 producing susceptibility to type 1 diabetes. Genes Immun 2002; 3: 338–344.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Dr Bernard Crespi for helpful comments on early drafts of this manuscript, as well as three anonymous reviewers for their many useful suggestions for improvement of our original submission. We would also like to thank Dr Marie-Paule Lefranc, founder and director of IMGT, for ongoing encouragement and support of our continued research efforts in the immunoglobulin regions.

Author information

Authors and Affiliations

  1. Department of Biological Sciences, Simon Fraser University, Burnaby, BC, Canada

    C T Watson & F Breden

Authors
  1. C T Watson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F Breden
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to C T Watson or F Breden.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Watson, C., Breden, F. The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease. Genes Immun 13, 363–373 (2012). https://doi.org/10.1038/gene.2012.12

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2012.12

Keywords

This article is cited by

Search

Advanced search

Quick links