Skip to main content
SpringerLink
Log in

V(D)J Recombination: Of Mice and Sharks

  • Chapter
Book cover V(D)J Recombination

Part of the book series: Advances in Experimental Medicine and Biology ((volume 650))

Abstract

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.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Schatz DG, Oettinger MA, Baltimore D. The V(D)J recombination activating gene, RAG-1. Cell 1989; 59:1035–1048.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  4. Rast JP, Litman GW. Towards understanding the evolutionary origins and early diversification of rearranging antigen receptors. Immunol Rev 1998; 166:79–86.

    Article  CAS  PubMed  Google Scholar 

  5. Flajnik MF, Du Pasquier L. Evolution of innate and adaptive immunity: can we draw a line? Trends Immunol 2004; 25:640–644.

    Article  CAS  PubMed  Google Scholar 

  6. Spring J. Genome duplication strikes back. Nature Genetics 2002; 31:128–129.

    CAS  PubMed  Google Scholar 

  7. Furlong RF, Holland PWH. Were vertebrates octoploid? Philos Trans R Soc Lond B Biol Sci 2002; 357:531–544.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  12. van Gent DC, Mizuuchi K, Gellert M. Similarities between initiation of V(D)J recombination and retroviral integration. Science 1996; 271:1592–1594.

    Article  PubMed  Google Scholar 

  13. Kapitonov VV, Jurka J. RAG1 core and V(D)J recombination signal sequences were derived from Transib transposons. PLoS Biol 2005; 3:e181.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  19. Lewis SM, Wu GE. The old and the restless. J Exp Med 2000; 191:1631–1636.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  23. Flajnik MF. Comparative analyses of immunoglobulin genes: surprises and portents. Nat Rev Immunol 2002; 2:688–698.

    Article  CAS  PubMed  Google Scholar 

  24. Litman GW, Anderson MK, Rast JP. Evolution of antigen binding receptors. Annu Rev Immunol 1999; 17:109–147.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  32. Krangel MS. Gene segment selection in V(D)J recombination: accessibility and beyond. Nat Immunol 2003; 4:624–630.

    Article  CAS  PubMed  Google Scholar 

  33. Gellert M. V(D)J recombination: RAG proteins, repair factors and regulation. Annu Rev Biochemistry 2002; 71:101–132.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  35. Gilfillan S, Dierich A, Lemeur M et al. Mice lacking TdT: mature animals with an immature lymphocyte repertoire. Science 1993; 261:1175–1178.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  38. Beetz S, Diekhoff D, Steiner LA. Characterization of terminal deoxynucleotidyl transferase and polymerase mu in zebrafish. Immunogenetics 2007; 59:735–744.

    Article  CAS  PubMed  Google Scholar 

  39. Zhang SM, Adema CM, Kepler TB et al. Diversification of Ig superfamily genes in an invertebrate. Science 2004; 305:251–254.

    Article  CAS  PubMed  Google Scholar 

  40. Wu TT, Johnson G, Kabat EA. Length distribution of CDRH3 in antibodies. Proteins 1993; 16:1–7.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  42. Wedemayer GJ, Patten PA, Wang LH et al. Structural insights into the evolution of an antibody combining site. Science 1997; 276:1665–1669.

    Article  CAS  PubMed  Google Scholar 

  43. Wilson IA, Stanfield RL. Antibody-antigen interactions: new structures and new conformational changes. Curr Opin Struct Biol 1994; 4:857–867.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  47. Burnet FM. The clonal selection theory of acquired immunity. Cambridge: Cambridge University Press, 1959.

    Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  49. Yancopoulos GD, Alt FW. Regulation of the assembly and expression of variable-region genes. Annu Rev Immunol 1986; 4:339–368.

    Article  CAS  PubMed  Google Scholar 

  50. Alt FW, Yancopoulos GD, Blackwell TK et al. Ordered rearrangement of immunoglobulin heavy chain variable region segments. EMBO J 1984; 3:1209–1219.

    CAS  PubMed  Google Scholar 

  51. Chowdhury D, Sen R. Regulation of immunoglobulin heavy-chain gene rearrangements. Immunol Rev 2004; 200:182–196.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  53. Kosak ST, Skok JA, Medina KL et al. Subnuclear compartmentalization of immunoglobulin loci during lymphocyte development. Science 2002; 296:158–162.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  58. Tunyaplin C, Knight KL. IgH gene rearrangements on the unexpressed allele in rabbit B-cells. J Immunol 1997; 158:4805–4811.

    CAS  PubMed  Google Scholar 

  59. Lanning D, Jasper P, Knight K. IgH haplotype exclusion in rabbits. Semin Immunol 2002; 14:163–168.

    Article  CAS  PubMed  Google Scholar 

  60. Tunyaplin C, Knight KL. Fetal VDJ gene repertoire in rabbit: evidence for preferential rearrangement of VH1. Eur J Immunol 1995; 25:2583–2587.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  65. Weill JC, Reynaud CA. The chicken B-cell compartment. Science 1987; 238:1094–1098.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  67. Weill JC, Cocea L, Reynaud CA. Allelic exclusion: lesson from GALT species. Semin Immunol 2002; 14:213–215.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  74. Malecek K, Lee V, Feng W et al. Immunoglobulin heavy chain exclusion in the shark. PLoS Biol 2008; 6:e157.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  77. Mostoslavsky R, Singh N, Tenzen T et al. Asynchronous replication and allelic exclusion in the immune system. Nature 2001; 414:221–225.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  81. Lee SS, Fitch D, Flajnik MF et al. Rearrangement of immunoglobulin genes in shark germ cells. J Exp Med 2000; 191:1637–1648.

    Article  CAS  PubMed  Google Scholar 

  82. de Villartay J-P. Passera ou ne passera pas—accessibility is key. Nature Immunol 2006; 7:1019–1021.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  87. Nemazee D. Receptor editing in lymphocyte development and central tolerance. Nat Rev Immunol 2006; 6:728–740.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physiology and Pharmacology, State University of New York Health Science Center at Brooklyn, Brooklyn, New York, USA

    Ellen Hsu

Authors
  1. Ellen Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Centre d’Immunologie de Marseille-Luminy, Université d’Aix Marseille, Marseille, France

    Pierre Ferrier MD, PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Hsu, E. (2009). V(D)J Recombination: Of Mice and Sharks. In: Ferrier, P. (eds) V(D)J Recombination. Advances in Experimental Medicine and Biology, vol 650. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0296-2_14

Download citation

Publish with us

Policies and ethics

Search

Navigation