V(D)J Recombination: Of Mice and Sharks

  • Ellen Hsu
Part of the Advances in Experimental Medicine and Biology book series (volume 650)


The adaptive immune system of jawed vertebrates is based on a vast, anticipatory repertoire of specific antigen receptors, immunoglobulins (Ig) in B-lymphocytes and T-cell receptors (TCR) in T-lymphocytes. The Ig and TCR diversity is generated by a process called V(D)J recombination, which is initiated by the RAG recombinase. Although RAG activity is very well conserved, the regulated accessibility of the antigen receptor genes to RAG has evolved with the species’ organizational structure, which differs most significantly between fishes and tetrapods. V(D)J recombination was primarily characterized in developing lymphocytes of mice and human beings and is often described as an ordered, two-stage program. Studies in rabbit, chicken and shark show that this process does not have to be ordered, nor does it need to take place in two stages to generate a diverse repertoire and enable the expression of a single species of antigen receptor per cell, a restriction called allelic exclusion.


Gene Segment Antigen Receptor Cartilaginous Fish Immunoglobulin Light Chain Recombination Signal Sequence 
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. 1.
    Tonegawa S. Somatic generation of antibody diversity. Nature 1983; 302:575–581.CrossRefPubMedGoogle Scholar
  2. 2.
    Schatz DG, Oettinger MA, Baltimore D. The V(D)J recombination activating gene, RAG-1. Cell 1989; 59:1035–1048.CrossRefPubMedGoogle Scholar
  3. 3.
    Oettinger MA, Schatz DG, Gorka C et al. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 1990; 248:1517–1523.CrossRefPubMedGoogle Scholar
  4. 4.
    Rast JP, Litman GW. Towards understanding the evolutionary origins and early diversification of rearranging antigen receptors. Immunol Rev 1998; 166:79–86.CrossRefPubMedGoogle Scholar
  5. 5.
    Flajnik MF, Du Pasquier L. Evolution of innate and adaptive immunity: can we draw a line? Trends Immunol 2004; 25:640–644.CrossRefPubMedGoogle Scholar
  6. 6.
    Spring J. Genome duplication strikes back. Nature Genetics 2002; 31:128–129.PubMedGoogle Scholar
  7. 7.
    Furlong RF, Holland PWH. Were vertebrates octoploid? Philos Trans R Soc Lond B Biol Sci 2002; 357:531–544.CrossRefPubMedGoogle Scholar
  8. 8.
    Holland PWH, Garcia-Fernandez J, Williams NA et al. Gene duplications and the origins of vertebrate development. Development Suppl 1994; 125–133.Google Scholar
  9. 9.
    Escriva H, Manzon L, Youson J et al. Analysis of lamprey and hagfish genes reveals a complex history of gene duplications during early vertebrate evolution. Mol Biol Evol 2002; 19:1440–14506.PubMedGoogle Scholar
  10. 10.
    Kasahara M, Suzuki T, Du Pasquier L. On the origins of the adaptive immune system: novel insights from invertebrates and cold-blooded vertebrates. Trends Immunol 2004; 25:105–111.CrossRefPubMedGoogle Scholar
  11. 11.
    Sakano H, Huppi K, Heinrich G et al. Sequences at the somatic recombination sites of immunoglobulin light-chain genes. Nature 1979; 280:288–294.CrossRefPubMedGoogle Scholar
  12. 12.
    van Gent DC, Mizuuchi K, Gellert M. Similarities between initiation of V(D)J recombination and retroviral integration. Science 1996; 271:1592–1594.CrossRefPubMedGoogle Scholar
  13. 13.
    Kapitonov VV, Jurka J. RAG1 core and V(D)J recombination signal sequences were derived from Transib transposons. PLoS Biol 2005; 3:e181.CrossRefPubMedGoogle Scholar
  14. 14.
    Fugmann SD, Messier C, Novack LA et al. An ancient evolutionary origin of the Rag1/2 gene locus. Proc Natl Acad Sci USA 2006; 103:3728–3733.CrossRefPubMedGoogle Scholar
  15. 15.
    Agrawal A, Eastman QM, Schatz DG. Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature 1998; 394:744–751.CrossRefPubMedGoogle Scholar
  16. 16.
    Hiom K, Melek M, Gellert M. DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations. Cell 1998; 94:463–470.CrossRefPubMedGoogle Scholar
  17. 17.
    Thompson CB. New insights into V(D)J recombination and its role in the evolution of the immune system. Immunity 1995; 3:531–539.CrossRefPubMedGoogle Scholar
  18. 18.
    Fugmann SD, Lee AI, Shockett PE et al. The RAG proteins and V(D)J recombination: complexes, ends and transposition. Annu Rev Immunol 2000; 18:495–527.CrossRefPubMedGoogle Scholar
  19. 19.
    Lewis SM, Wu GE. The old and the restless. J Exp Med 2000; 191:1631–1636.CrossRefPubMedGoogle Scholar
  20. 20.
    Greenberg AS, Avila D, Hughes M et al. A new antigen receptor gene family that undergoes rearrangement and extensive somatic diversification in sharks. Nature 1995; 374:168–173.CrossRefPubMedGoogle Scholar
  21. 21.
    Criscitiello MF, Saltis M, Flajnik MF. An evolutionarily mobile antigen receptor variable region gene: doubly rearranging NAR-TcR genes in sharks. Proc Natl Acad Sci USA 2006; 103:5036–5041.CrossRefPubMedGoogle Scholar
  22. 22.
    Parra ZE, Baker ML, Schwarz RS et al. A unique T-cell receptor discovered in marsupials. Proc Natl Acad Sci USA 2007; 104:9776–9781.CrossRefPubMedGoogle Scholar
  23. 23.
    Flajnik MF. Comparative analyses of immunoglobulin genes: surprises and portents. Nat Rev Immunol 2002; 2:688–698.CrossRefPubMedGoogle Scholar
  24. 24.
    Litman GW, Anderson MK, Rast JP. Evolution of antigen binding receptors. Annu Rev Immunol 1999; 17:109–147.CrossRefPubMedGoogle Scholar
  25. 25.
    Rast JP, Anderson MK, Strong SJ et al. α, β, ψ and σ T-cell antigen receptor genes arose early in vertebrate phylogeny. Immunity 1997; 6:1–11.CrossRefPubMedGoogle Scholar
  26. 26.
    Wilson MR, Zhou H, Bengtén E et al. T-cell receptors in channel catfish: structure and expression of TCR alpha and beta genes. Mol Immunol 1998; 35:545–557.CrossRefPubMedGoogle Scholar
  27. 27.
    Haire RN, Kitzan Haindfield MK et al. Structure and diversity of T-lymphocyte antigen receptors alpha and gamma in Xenopus. Immunogenetics 2002; 54:431–438.CrossRefPubMedGoogle Scholar
  28. 28.
    André S, Kerfourn F, Affaticati P et al. Highly restricted diversity of TCR delta chains of the amphibian Mexican axolotl (Ambystoma mexicanum) in peripheral tissues. Eur J Immunol 2007; 37:1621–1633.CrossRefPubMedGoogle Scholar
  29. 29.
    Kubota T, Wang J, Göbel TW et al. Characterization of an avian (Gallus gallus domesticus) TCR alpha delta gene locus. J Immunol 1999; 163:3858–3866.PubMedGoogle Scholar
  30. 30.
    Parra ZE, Baker ML, Hathaway J et al. Comparative genomic analysis and evolution of the T-cell receptor loci in the opossum Monodelphis domestica. BMC Genomics 2008; 9:111.CrossRefPubMedGoogle Scholar
  31. 31.
    Parra ZE, Arnold T, Nowak MA et al. TCR gamma chain diversity in the spleen of the duckbill platypus (Ornithorhynchus anatinus). Dev Comp Immunol 2006; 30:699–710.CrossRefPubMedGoogle Scholar
  32. 32.
    Krangel MS. Gene segment selection in V(D)J recombination: accessibility and beyond. Nat Immunol 2003; 4:624–630.CrossRefPubMedGoogle Scholar
  33. 33.
    Gellert M. V(D)J recombination: RAG proteins, repair factors and regulation. Annu Rev Biochemistry 2002; 71:101–132.CrossRefGoogle Scholar
  34. 34.
    Komori T, Okada A, Stewart V et al. Lack of N regions in antigen receptor variable region genes of TdT-deficient lymphocytes. Science 1993; 261:1171–1175.CrossRefPubMedGoogle Scholar
  35. 35.
    Gilfillan S, Dierich A, Lemeur M et al. Mice lacking TdT: mature animals with an immature lymphocyte repertoire. Science 1993; 261:1175–1178.CrossRefPubMedGoogle Scholar
  36. 36.
    Bertocci B, De Smet A, Weill JC et al. Nonoverlapping functions of DNA polymerases mu, lambda and terminal deoxynucleotidyltransferase during immunoglobulin V(D)J recombination in vivo. Immunity 2006; 25:31–41.CrossRefPubMedGoogle Scholar
  37. 37.
    Domínguez O, Ruiz JF, Laín de Lera T et al. DNA polymerase mu (Pol mu), homologous to TdT, could act as a DNA mutator in eukaryotic cells. EMBO J 2000; 19:1731–1742.CrossRefPubMedGoogle Scholar
  38. 38.
    Beetz S, Diekhoff D, Steiner LA. Characterization of terminal deoxynucleotidyl transferase and polymerase mu in zebrafish. Immunogenetics 2007; 59:735–744.CrossRefPubMedGoogle Scholar
  39. 39.
    Zhang SM, Adema CM, Kepler TB et al. Diversification of Ig superfamily genes in an invertebrate. Science 2004; 305:251–254.CrossRefPubMedGoogle Scholar
  40. 40.
    Wu TT, Johnson G, Kabat EA. Length distribution of CDRH3 in antibodies. Proteins 1993; 16:1–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Fleurant M, Changchien L, Chen CT et al. Shark Ig light chain junctions are as diverse as in heavy chains. J Immunol 2004; 173:5574–5582.PubMedGoogle Scholar
  42. 42.
    Wedemayer GJ, Patten PA, Wang LH et al. Structural insights into the evolution of an antibody combining site. Science 1997; 276:1665–1669.CrossRefPubMedGoogle Scholar
  43. 43.
    Wilson IA, Stanfield RL. Antibody-antigen interactions: new structures and new conformational changes. Curr Opin Struct Biol 1994; 4:857–867.CrossRefPubMedGoogle Scholar
  44. 44.
    Stanfield RL, Dooley H, Verdino P et al. Maturation of shark single-domain (IgNAR) antibodies: evidence for induced-fit binding. J Mol Biol 2007; 367:358–372.CrossRefPubMedGoogle Scholar
  45. 45.
    Nguyen VK, Hamers R, Wyns L et al. Camel heavy-chain antibodies: diverse germline V(H)H and specific mechanisms enlarge the antigen-binding repertoire. EMBO J 2000; 19:921–930.CrossRefPubMedGoogle Scholar
  46. 46.
    Achour I, Cavelier P, Tichit M et al. Tetrameric and homodimeric camelid IgGs originate from the same IgH locus. J Immunol 2008; 181:2001–2009.PubMedGoogle Scholar
  47. 47.
    Burnet FM. The clonal selection theory of acquired immunity. Cambridge: Cambridge University Press, 1959.Google Scholar
  48. 48.
    Stanhope-Baker P, Hudson KM, Shaffer AL et al. Cell type-specific chromatin structure determines the targeting of V(D)J recombinase activity in vitro. Cell 1996; 85:887–897.CrossRefPubMedGoogle Scholar
  49. 49.
    Yancopoulos GD, Alt FW. Regulation of the assembly and expression of variable-region genes. Annu Rev Immunol 1986; 4:339–368.CrossRefPubMedGoogle Scholar
  50. 50.
    Alt FW, Yancopoulos GD, Blackwell TK et al. Ordered rearrangement of immunoglobulin heavy chain variable region segments. EMBO J 1984; 3:1209–1219.PubMedGoogle Scholar
  51. 51.
    Chowdhury D, Sen R. Regulation of immunoglobulin heavy-chain gene rearrangements. Immunol Rev 2004; 200:182–196.CrossRefPubMedGoogle Scholar
  52. 52.
    Fuxa M, Skok J, Souabni A et al. Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene. Genes Dev 2004; 18:411–422.CrossRefPubMedGoogle Scholar
  53. 53.
    Kosak ST, Skok JA, Medina KL et al. Subnuclear compartmentalization of immunoglobulin loci during lymphocyte development. Science 2002; 296:158–162.CrossRefPubMedGoogle Scholar
  54. 54.
    Jhunjhunwala S, van Zelm MC, Peak MM et al. The 3D structure of the immunoglobulin heavy-chain locus: implications for long-range genomic interactions. Cell 2008; 133:265–279.CrossRefPubMedGoogle Scholar
  55. 55.
    Roldán E, Fuxa M, Chong W et al. Locus “decontraction” and centromic recruitment contribute to allelic exclusion of the immunoglobulin heavy-chain gene. Nat Immunol 2005; 6:31–41.CrossRefPubMedGoogle Scholar
  56. 56.
    Schlingen RJ, Reddy KL, Singh H et al. Initiation of allelic exclusion by stochastic interaction of Tcrb alleles with repressive nuclear compartments. Nat. Immunol 2008; 9:802–809.CrossRefGoogle Scholar
  57. 57.
    Perlot T, Alt FW, Bassing CH et al. Elucidation of IgH intronic enhancer functions via germ-line deletion. Proc Natl Acad Sci USA 2005; 102:14362–4367.CrossRefPubMedGoogle Scholar
  58. 58.
    Tunyaplin C, Knight KL. IgH gene rearrangements on the unexpressed allele in rabbit B-cells. J Immunol 1997; 158:4805–4811.PubMedGoogle Scholar
  59. 59.
    Lanning D, Jasper P, Knight K. IgH haplotype exclusion in rabbits. Semin Immunol 2002; 14:163–168.CrossRefPubMedGoogle Scholar
  60. 60.
    Tunyaplin C, Knight KL. Fetal VDJ gene repertoire in rabbit: evidence for preferential rearrangement of VH1. Eur J Immunol 1995; 25:2583–2587.CrossRefPubMedGoogle Scholar
  61. 61.
    Mage RG, Lanning D, Knight KL. B-cell and antibody repertoire development in rabbits: the requirement of gut-associated lymphoid tissues. Dev Comp Immunol 2006; 30:137–153.CrossRefPubMedGoogle Scholar
  62. 62.
    Yancopoulos GD, Desiderio SV, Paskind M et al. Preferential utilization of the most JH-proximal VH gene segments in preB-cell lines. Nature 1984; 311:727–733.CrossRefPubMedGoogle Scholar
  63. 63.
    Knight KL, Becker RS. Molecular basis of the allelic inheritance of rabbit immunoglobulin VH allotypes: implications for the generation of antibody diversity. Cell 1990; 60:963–970.CrossRefPubMedGoogle Scholar
  64. 64.
    Reynaud CA, Imhof BA, Anquez V et al. Emergence of committed B-lymphoid progenitors in the developing chicken embryo. EMBO J 1992; 11:4349–4358.PubMedGoogle Scholar
  65. 65.
    Weill JC, Reynaud CA. The chicken B-cell compartment. Science 1987; 238:1094–1098.CrossRefPubMedGoogle Scholar
  66. 66.
    Benatar T, Tkalec K, Ratcliffe MJ. Stochastic rearrangement of immunoglobulin variable-region genes in chicken B-cell development. Proc Natl Acad Sci USA 1992; 89:7615–7619.CrossRefPubMedGoogle Scholar
  67. 67.
    Weill JC, Cocea L, Reynaud CA. Allelic exclusion: lesson from GALT species. Semin Immunol 2002; 14:213–215.CrossRefPubMedGoogle Scholar
  68. 68.
    Du Pasquier L, Hsu E. Immunoglobulin expression in diploid and polyploid interspecies, hybrid of Xenopus: evidence for allelic exclusion. Eur J Immunol 1983; 13:585–590.CrossRefPubMedGoogle Scholar
  69. 69.
    Barreto V, Meo T, Cumano A. Mice triallelic for the Ig heavy chain locus: implications for VHDJH recombination. J Immunol 2001; 166:5638–5645.PubMedGoogle Scholar
  70. 70.
    Du Pasquier L, Blomberg B. The expression of antibody diversity in natural and laboratory-made polyploid individuals of the clawed toad Xenopus. Immunogenetics 1982; 15:251–60.CrossRefPubMedGoogle Scholar
  71. 71.
    Hoegg S, Brinkmann H, Taylor JS et al. Phylogenetic timing of the fish-specific genome duplication correlates with the diversification of teleost fish. J Mol Evol 2004; 59:190–203.CrossRefPubMedGoogle Scholar
  72. 72.
    Lee V, Huang JL, Lui MF et al. The evolution of multiple isotypic IgM heavy chain genes in the shark. J Immunol 2008; 180:7461–7470.PubMedGoogle Scholar
  73. 73.
    Anderson M, Amemiya C, Luer C et al. Complete genomic sequence and patterns of transcription of a member of an unusual family of closely related, chromosomally dispersed Ig gene clusters in Raja. Int Immunol 1994; 6:1661–1670.CrossRefPubMedGoogle Scholar
  74. 74.
    Malecek K, Lee V, Feng W et al. Immunoglobulin heavy chain exclusion in the shark. PLoS Biol 2008; 6:e157.CrossRefPubMedGoogle Scholar
  75. 75.
    Eason DD, Litman RT, Luer CA et al. Expression of individual immunoglobulin genes occurs in an unusual system consisting of multiple independent loci. Eur J Immunol 2004; 34:2551–2558.CrossRefPubMedGoogle Scholar
  76. 76.
    Mostoslavsky R, Singh N, Kirillov A et al. Kappa chain monoallelic demethylation and the establishment of allelic exclusion. Genes Dev 1998; 12:1801–1811.CrossRefPubMedGoogle Scholar
  77. 77.
    Mostoslavsky R, Singh N, Tenzen T et al. Asynchronous replication and allelic exclusion in the immune system. Nature 2001; 414:221–225.CrossRefPubMedGoogle Scholar
  78. 78.
    Kokubo F, Litman R, Shamblott MJ et al. Diverse organization of immunoglobulin VH gene loci in a primitive vertebrate. EMBO J 1988; 7:3413–3422.Google Scholar
  79. 79.
    Ghaffari SH, Lobb CJ. Structure and genomic organization of a second cluster of immunoglobulin heavy chain gene segments in the channel catfish. J Immunol 1999; 162:1519–1529.PubMedGoogle Scholar
  80. 80.
    Reynaud CA, Dahan A, Anquez V et al. Somatic hyperconversion diversifies the single VH gene of the chicken with a high incidence on the D region. Cell 1989; 40:283–291.CrossRefGoogle Scholar
  81. 81.
    Lee SS, Fitch D, Flajnik MF et al. Rearrangement of immunoglobulin genes in shark germ cells. J Exp Med 2000; 191:1637–1648.CrossRefPubMedGoogle Scholar
  82. 82.
    de Villartay J-P. Passera ou ne passera pas—accessibility is key. Nature Immunol 2006; 7:1019–1021.CrossRefGoogle Scholar
  83. 83.
    Criscitiello MF, Flajnik MF. Four primordial immunoglobulin light chain isotypes, including lambda and kappa, identified in the most primitive living jawed vertebrates. Eur J Immunol 2007; 37:2683–2694.CrossRefPubMedGoogle Scholar
  84. 84.
    Hsu E, Criscitiello MF. Diverse immunoglobulin light chain organizations in fish retain potential to revise B-cell receptor specificities. J Immunol 2006; 177:2452–2462.PubMedGoogle Scholar
  85. 85.
    Zimmerman AM, Yeo G, Howe K et al. Immunoglobulin light chain (IgL) genes in zebrafish: Genomic configurations and inversional rearrangements between (VL-JL-CL) gene clusters. Dev Comp Immunol 2008; 32:421–434.CrossRefPubMedGoogle Scholar
  86. 86.
    Bengtén E, Stromberg S, Daggfeldt A et al. Transcriptional enhancers of immunoglobulin light chain genes in Atlantic cod (Gadus morhua) Immunogenetics 2000; 51:647–658.CrossRefPubMedGoogle Scholar
  87. 87.
    Nemazee D. Receptor editing in lymphocyte development and central tolerance. Nat Rev Immunol 2006; 6:728–740.CrossRefPubMedGoogle Scholar
  88. 88.
    Danilova N, Bussmann J, Jekosch K et al. The immunoglobulin heavy-chain locus in zebrafish; identification and expression of a previously unknown isotype, immunoglobulin Z. Nat Immunol 2005; 6:295–302.CrossRefPubMedGoogle Scholar
  89. 89.
    Daggfeldt A, Bengtén E, Pilstrom L. A cluster type organization of the loci of the immunoglobulin light chain in Atlantic cod (Gadus morhua L.) and rainbow trout (Oncorhynchus mykiss Walbaum) indicated by nucleotide sequences of cDNAs and hybridization analysis. Immunogenetics 1993; 38:199–209.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  • Ellen Hsu
    • 1
  1. 1.Department of Physiology and PharmacologyState University of New York Health Science Center at BrooklynBrooklynUSA

Personalised recommendations