Somatic Hypermutation of Immunoglobulin Genes

  • U. Storb


The first convincing evidence for somatic mutation of Ig genes was a study of mouse λ genes carried out by Weigert and collaborators in the early 7os.1 Comparing the amino acid sequences of λ light chain variable (V) regions in nine mouse myelomas, they found that six were identical, and three had one, two, or three amino acid changes. They concluded that there was only a single variable gene for mouse lambda, and that the three altered sequences must have arisen by some process of somatic mutation.


Somatic Mutation Immunoglobulin Gene Somatic Hypermutation Heavy Chain Gene Class Switch Recombination 
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  1. 1.
    Weigert M, Cesari IM, Yonkovich SJ, Cohn M. Variability in the lambda light chain sequences of mouse antibody. Nature 1970; 228: 1045–1047.PubMedCrossRefGoogle Scholar
  2. 2.
    Bernard O, Hozumi N, Tonegawa S. Sequences of mouse immunoglobulin light chain genes before and after somatic changes. Cell 1978; 15: 1133–1144.PubMedCrossRefGoogle Scholar
  3. 3.
    Selsing E, Storb U. Somatic mutation of immunoglobulin light-chain variable-region genes. Cell 1981; 25:47-58.Google Scholar
  4. 4.
    Crews S, Griffin J, Huang H, Calame K, Hood L. A single VH gene segment encodes the immune response to phosphorylcholine: Somatic mutation is correlated with the class of the antibody. Cell 1981; 25: 59–66.PubMedCrossRefGoogle Scholar
  5. 5.
    Gorski J, Rollini P, Mach B. Somatic mutations of immunoglobulin variable genes are restricted to the rearranged V gene. Science 1983; 220: 1179–1181.PubMedCrossRefGoogle Scholar
  6. 6.
    Engler P, Klotz E, Storb U. N region diversity of a transgenic substrate in fetal and adult lymphoid cells. J Exp Med 1992; 176: 1399–1404.Google Scholar
  7. 7.
    Lewis SM. The mechanism of V(D)J joining: Lessons from molecular, immunological and comparative analyses. Adv Immunol 1994; 56: 27–150.Google Scholar
  8. 8.
    Bogue M, Roth DB. Mechanism of V(D)J recombination. Curr Op Immunol 1996; 8x75–180.Google Scholar
  9. 9.
    Green N, Rabinowitz J, Zhu M, Kobrin B, Scharff M. Immunoglobulin variable region hypermutation in hybrids derived from a pre-Band a myeloma cell line. Proc Natl Acad Sci USA 1995; 92: 6304–6308.Google Scholar
  10. 10.
    Wabl M, Burrows P, von Gabain A, Steinberg C. Hypermutation at the immunoglobulin heavy chain locus in a pre-B-cell line. Proc Natl Acad Sci USA 1985; 82: 479–482.Google Scholar
  11. 11.
    Jaeck H-M, McDowell M, Steinberg C, Wabl M. Looping out an deletion mechanism for the immunoglobulin heavy-chain class switch. Proc Natl Acad Sci USA 1988; 85: 1581–1585.CrossRefGoogle Scholar
  12. 12.
    Manser T, Gefter M. The molecular evolution of the immune response: Idiotype specific suppression indicates that B cells express germline encoded V genes prior to antigenic stimulation. Eur J Immunol 1986; 16:1439-1444.Google Scholar
  13. 13.
    Klein U, Kueppers U, Rajewsky K. Human IgM+IgD+ B cells, the major B cell subset in the peripheral blood, express V-kappa genes with no or little somatic mutation throughout life. Eur J Immunol 1993; 23: 3272–3277.Google Scholar
  14. 14.
    Liu Y-J, Zhang J, Lane P, Chan E, MacLennan I. Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens. Eur J Immunol 1991; 21: 2951–2962.PubMedCrossRefGoogle Scholar
  15. 15.
    Kimoto H, Nagaoka H, Adachi Y et al. Accumulation of somatic hypermutation and antigen-driven selection in rapidly cycling surface Ig+ germinal center (GC) B cells which occupy GC at a high frequency during the primary anti-hapten response in mice. Eur J Immunol 1997; 27: 268–279.Google Scholar
  16. 16.
    Vonderheide R, Hunt S. Comparison of IgD+ and IgD- thoracic duct B lymphocytes as germinal center precursor cells in the rat. Internatl Immunol 1991; 3: 1273–1281.CrossRefGoogle Scholar
  17. 17.
    Liu Y-J, de Bouteiller O, Arpin C et al. Normal human IgD+IgMgerminal center B cells can express up to 8o mutations in the variabale region of their IgD transcripts. Immunity 1996; 4: 603–613.Google Scholar
  18. 18.
    Liu Y, Malisan F, de Bouteiller O et al. Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation. Immunity 1996; 4: 241–250.Google Scholar
  19. 19.
    Shan H, Schlomchik M, Weigert M. Heavy-chain class switch does not terminate somatic mutation. J Exp Med 1990; 172: 531–536.PubMedCrossRefGoogle Scholar
  20. 20.
    Gearhart P, Johnson N, Douglas R, Hood L. IgG antibodies to phosphorylcholine exhibit more diversity than their IgM counterparts. Nature 1981; 291:29-34.Google Scholar
  21. 21.
    Klein U, Kueppers R, Rajewsky K. Variable region gene analysis of B cell subsets derived from a 4-year-old child: Somatically mutated memory B cells accumulate in the peripheral blood already at a young age. J Exp Med 1994; 180: 1383–1393.Google Scholar
  22. 22.
    Pascual V, Liu Y, Magalski A, de Bouteiller O, Banchereau J, Capra D. Analysis of somatic mutation in five B cell subsets of human tonsil. J Exp Med 1994; 180:329-339.Google Scholar
  23. 23.
    Peters A, Storb U. Somatic hypermutation of immunoglobulin genes is linked to transcription initiation. Immunity 1996; 4: 57–65.Google Scholar
  24. 24.
    MacLennan I, Liu Y, Oldfield S, Zhang J, Lane P. The evolution of B cell clones. Curr Top Microbiol Immunol 1990; 159: 37–60.Google Scholar
  25. 25.
    Berek C, Berger A, Apel M. Maturation of the immune response in germinal centers. Cell 1991; 67: 1121–1129.PubMedCrossRefGoogle Scholar
  26. 26.
    Tew JG, Kosko MH, Burton GF, Szakal AK. Follicular dendritic cells as accessory cells. Immunol Rev 1990; 117: 185–211.PubMedCrossRefGoogle Scholar
  27. 27.
    Kelsoe G. In situ studies of germinal center reaction. Adv Immunol 1995; 60:267–288.Google Scholar
  28. 28.
    Jacob J, Kelsoe G, K. R, Weiss U. Intraclonal generation of antibody mutants in germinal centers. Nature 1991; 354: 389–392.Google Scholar
  29. 29.
    Jacob J, Kassir R, Kelsoe G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. I. The architecture and dynamics of responding cell polulations. J Exp Med 1991; 173: 1165–1175.Google Scholar
  30. 30.
    Reynaud C, Garcia C, Hein W, Weill J. Hypermutation generating the sheep immunoglobulin repertoire is an antigen-independent process. Cell 1995; 80: 115–125.Google Scholar
  31. 31.
    Carter M, Li S, Wilkinson M. A splicing-dependent regulatory mechanism that detects translation signals. EMBO J 1996; 15: 5965-5975.Google Scholar
  32. 32.
    Shlomchik MJ, Marshak-Rothstein A, Wofowicz CB, Rothstein TL, Weigert M. The role of clonal selection and somatic mutation in autoimmunity. Nature 1987; 328: 805–811.PubMedCrossRefGoogle Scholar
  33. 33.
    Siekevitz M, Kocks C, Rajewsky K, Dildrop R. Analysis of somatic mutation and class switching in naive and memory B cells generating adoptive primary and secondary responses. Cell 1987; 48757-770.Google Scholar
  34. 34.
    Griffiths G, Berek C, Kaartinen M, Milstein C. Somatic mutation and the maturation of immune reponse to 2-phenyl oxazolone. Nature 1984; 312: 271–275.PubMedCrossRefGoogle Scholar
  35. 35.
    Decker D, Linton P, Zaharevitz S, Biery M, Gingeras T, Klinman N. Defining subsets of naive and memory B cells based on the ability of their progeny to somatically mutate in vitro. Immunity 1995; 2: 195–203.Google Scholar
  36. 36.
    Bothwell A, Tao W, Blier P. A model for the development of somatic variants in memory B cells. In: Steele EJ, ed. Somatic Hypermutation in V Regions. Boca Raton, FL: CRC Press, 1991: 55–67.Google Scholar
  37. 37.
    Kipps TJ. The CD5 B cell. Adv Immunol 1988; 47: 117–185.CrossRefGoogle Scholar
  38. 38.
    Ebeling S, Schutte M, Logtenberg T. Peripheral human CD5+ and CD5- B cells may express somatically mutated VH5- and VH6-encoded IgM receptors. J Immunol 1993; 151: 6891–6899.Google Scholar
  39. 39.
    Hashimoto S, Dono M, Wakai M et al. Somatic diversification and selection of Ig heavy and light chain variable region genes in IgG+ CD5+ chronic lymphocytic leukemia B cells. J Exp Med 1995; 181: 1507–1517.Google Scholar
  40. 40.
    Zheng B, Xue W, Kelsoe G. Locus-specific somatic hypermutation in germinal centre T cells. Nature 1994; 372: 556–559.Google Scholar
  41. 41.
    Vitetta E, Berton M, Burger C, Kepron M, Lee W, Yin X-M. Memory B and T cells. Ann. Rev Immunol 1991; 9: 193–217.CrossRefGoogle Scholar
  42. 42.
    McHeyzer-Williams M, Davis M. Antigen-specific development of primary and memory T cells in vivo. Science 1995; 268: 106–110.Google Scholar
  43. 43.
    Vescio R, Cao J, Hong C et al. Myeloma Ig heavy chain V region sequences reveal prior antigenic selection and marked somatic mutation but no intraclonal diversity. J Immunol 1995; 155: 2487–2497.Google Scholar
  44. 44.
    Klein U, Klein G, Ehlin-Hendricksson B, Rajewsky K, Kueppers R. Burkitt’s lymphoma is a malignancy of mature B cells expressing somatically mutated V region genes. Mol Med 1995; 1495-505.Google Scholar
  45. 45.
    Kueppers R, Hajadi M, Plank L, Rajewsky K, Hansmann M-L. Molecular Ig gene analysis reveals that monocytoid B cell lymphoma is a malignancy of mature B cells carrying somatically mutated V region genes and suggests that rearrangment of the kappa-deleting element (resulting in the deletion of the Ig kappa enhancers) abolishes somatic hypermutation in the human. Eur J Immunol 1996; 26: 1794–1800.CrossRefGoogle Scholar
  46. 46.
    Levy R, Levy S, Cleary M et al. Somatic mutation in human B-cell tumors. Imm Rev 1987; 96: 43–58.CrossRefGoogle Scholar
  47. 47.
    Bahler D, Levy R. Clonal evolution of a follicular lymphoma: Evidence for antigen selection. Proc Natl Acad Sci USA 1992; 89: 6770–6774.Google Scholar
  48. 48.
    Cuisinier A, Gauthier L, Boubli L, Fougerau M, Tonnelle C. Mechanisms that generate human Ig diversity operate from the 8th week of gestation in fetal liver. Eur J Immunol 1993; 23: 110–118.Google Scholar
  49. 49.
    Reynaud C, Mackay C, Mueller R, Weill J. Somatic generation of diversity in a mammalian primary lymphoid organ: The sheep ileal Peyer’s patches. Cell 1991; 64: 995–1005.Google Scholar
  50. 50.
    Maybaum T, Reynolds J. B cells selected for apoptosis in the sheep ileal Peyer’s patch have enhanced mutational diversity in the Ig V-lambda licht chain. J Immunol 1996; 157:1474-1484.Google Scholar
  51. 51.
    Becker R, Knight K. Somatic diversification of Ig heavy chain VDJ genes: Evidence for somatic gene conversion in rabbits. Cell 1990; 63: 987–997.PubMedCrossRefGoogle Scholar
  52. 52.
    Reynaud C, Anquez V, Grimai H, Weill J-C. A hyperconversion mechanism generates the chicken light chain preimmune repertoire. Cell 1987; 48: 379–388.Google Scholar
  53. 53.
    Storb U. The molecular basis of somatic hypermutation of immunoglobulin genes. Curr Op Immunol 1996; 8: 206–214.CrossRefGoogle Scholar
  54. 54.
    Lanning DK, Knight K. Somatic hypermutation: Mutations 3’ of rabbit VDJ h-chain genes. J Immunol 1997; submitted.Google Scholar
  55. 55.
    Parvari R, Ziv E, Lantner F, Heller D, Schechter I. Somatic diversification of chicken immunoglobulin light chains by point mutations. Proc Natl Acad Sci USA 1990; 87: 3072–3076.PubMedCrossRefGoogle Scholar
  56. 56.
    Wilson M, Hsu E, Marcuz A, Courtet M, Du Pasquier L, Steinberg C. What limits affinity maturation of antibodies in Xenopus—the rate of somatic mutation or the ability to select mutants? EMBO J 1992; 11:4337-4347.Google Scholar
  57. 57.
    Greenberg A, Avilla D, Hughes M, Hughes A, McKinney E, Flajnik M. A new antigen receptor gene family that undergoes rearrangement and extensive somatic diversification in sharks. Nature 1995; 374168–173.Google Scholar
  58. 58.
    Gearhart P. Somatic muttion and affinity maturation. In: Paul WE, ed. Fundamental Immunology. 3rd ed. New York: Raven Press, Ltd., 1993:865-885.Google Scholar
  59. 59.
    Levy N, Malipiero U, Lebeque S, Gearhart P. Early onset of somatic mutation in immunoglobulin VH genes during the primary immune response. J Exp Med 1989; 169: 2007–2019.PubMedCrossRefGoogle Scholar
  60. 60.
    Cumano A, Rajewsky K. Clonal recruitment and somatic mutation in the generation of immunological memory to the hapten NP. EMBO J 1986; 5: 2459–2468.PubMedGoogle Scholar
  61. 61.
    Wysocki L, Manser T, Gefter M. Somatic evolution of variable region structures during an immune response. Proc Natl Acad Sci USA 1986; 83: 1847–1851.PubMedCrossRefGoogle Scholar
  62. 62.
    O’Brien R, Brinster R, Storb U. Somatic hypermutation of an immunoglobulin transgene in x transgenic mice. Nature 1987; 326:405-409.Google Scholar
  63. 63.
    Hackett J, Rogerson B, O’Brien R, Storb U. Analysis of somatic mutations in x transgenes. J Exp Med 1990; 172: 131–137.PubMedCrossRefGoogle Scholar
  64. 64.
    Hackett J, Stebbins C, Rogerson B, Davis M, Storb U. Analysis of a T cell receptor gene as a target of the somatic hypermutation mechanism. J Exp Med 1992; 176: 225–231.PubMedCrossRefGoogle Scholar
  65. 65.
    Sharpe M, Milstein C, Jarvis J, Neuberger M. Somatic hypermutation of immunoglobulin x may depend on sequences 3’ of Cx and occurs on passenger transgenes. EMBO J 1991; 10:2139-2145.Google Scholar
  66. 66.
    Sharpe M, Neuberger M, Pannell R, Surami A, Milstein C. Lack of somatic mutation in a x light chain transgene. Eur J Immunol 1990; 20:1379-1385.Google Scholar
  67. 67.
    Carmack C, Camper S, Mackle J, Gerhard W, Weigert M. Influence of a Vx8 L chain transgene on endogenous rearrangements and the immune response to the HA(SB) determinant of influenza virus. J Immunol 1991; 147: 2024–2033.PubMedGoogle Scholar
  68. 68.
    Betz A, Milstein C, Gonzalez-Fernandes R, Pannell R, Larson T, Neuberger M. Elements regulating somatic hypermutation of an immunoglobulin K gene: Critical role for the intron enhancer/matrix attachment region. Cell 1994; 77: 239–248.Google Scholar
  69. 69.
    Giusti A, Manser T. Hypermutation is observed only in antibody H chain V region transgenes that have recombined with endogenous immunoglobulin H DNA: Implications for the location of cis-acting elements required for somatic mutation. j Exp Med 1993; 177:797-809.Google Scholar
  70. 70.
    Sohn J, Gerstein R, Hsieh C, Lemer M, Selsing E. Somatic hyper-mutation of an immunoglobulin 11 heavy chain transgene. J Exp Med 1993; 177: 493–504.Google Scholar
  71. 71.
    Yelamos J, Klix N, Goyenechea B et al. Targeting of non-Ig sequences in place of the V segment by somatic hypermutation. Nature 1995; 376: 225–229.Google Scholar
  72. 72.
    Johnston J, Ihyer S, Smitch R et al. Analysis of hypermutation in immunoglobulin heavy chain passenger transgenes. Eur J Immunol 1996; 26: 1058–1062.PubMedCrossRefGoogle Scholar
  73. 73.
    Klotz E, Storb U. Somatic hypermutation of a lambda-2 transgene under the control of the lambda enhancer or the heavy chain intron enhancer. J Immunol 1996; 157: 4458–4463.Google Scholar
  74. 74.
    Klotz E, Hackett JJ, Storb U. Somatic hypermutation of an artificial test substrate within an Ig kappa transgene. Immunol 1998; (in press).Google Scholar
  75. 75.
    Carter M, Li S, Wilkinson M. A splicing-dependent regulatory mechanism that detects translation signals. EMBO J 1996; 15: 5965-5975.Google Scholar
  76. 76.
    Rose M, Birbeck S, Wallis V, Forrester J, Davies A. Peanut lectin binding properties of germinal centers of mouse lymphoid tissue. Nature 1980; 284: 364–366.PubMedCrossRefGoogle Scholar
  77. 77.
    Apel M, Berek C. Somatic mutations in antibodies expressed by germinal center B cells early after primary immunization. Internatl Immunol 1990; 2: 813–819.CrossRefGoogle Scholar
  78. 78.
    Gonzales-Fernandes A, Milstein C. Analysis of somatic hyper-mutation in mouse Peyer’s patches using immunoglobulin K light-chain transgenes. Proc Natl Acad Sci USA 1993; 90: 9862–9866.Google Scholar
  79. 79.
    Gonzalez-Fernandez A, Gilmore D, Milstein C. Age-related decrease in the proportion of germinal center B cells from mouse Peyer’s patches is accompanied by an accumulation of somatic mutations in their immunoglobulin genes. Eur J Immunol 1994; 24: 2918–2921.Google Scholar
  80. 80.
    Wagner S, Elvin J, Norris P, McGregor J, Neuberger M. Somatic hypermutation of Ig genes in patients with xeroderma pigmentosum (XP-D). Internatl Immunol 1996; 8: 701–705.CrossRefGoogle Scholar
  81. 81.
    Chu Y, Marin E, Fuleihan R et al. Somatic mutation of human Ig V genes in the X-linked hyperIgM syndrome. J Clin Invest 1995; 951389-1393.Google Scholar
  82. 82.
    Timmers E, Hermans M, Kraakman M, Hendriks R, Schuurman R. Diversity of immunoglobulin kappa light chain gene rearrangements and evidence for somatic mutation in V-kappa IV family gene segments in X-linked agammaglobulenemia. Eur J Immunol 1993; 23: 619–624.Google Scholar
  83. 83.
    Kim N, Kage K, Matsuda F, Lefranc M-P, Storb U. B lymphocytes of xeroderma pigmentosum or Cockayne syndrome patients with inherited defects in nucleotide excision repair are fully capable of somatic hypermutation of immunoglobulin genes. J Exp Med 1997; 186: 413–419.Google Scholar
  84. 84.
    Varade W, Insel R. Isolation of germinal centerlike events from human spleen RNA. J Clin Invest 1993; 91: 1838–1842.Google Scholar
  85. 85.
    Insel R, Varade W, Marin E. Human splenic IgM Ig transcripts are mutated at high frequency. Mol Immunol 1994: 383–392.Google Scholar
  86. 86.
    Insel R, Varade W. Bias in somatic hypermutation of human VH genes. Internatl Immunol 1994; 61437-1443.Google Scholar
  87. 87.
    Kueppers R, Zhao M, Hansmann M, Rajewsky K. Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J 1993: 4955–4967.Google Scholar
  88. 88.
    Dunn-Walters D, Isaacson P, Spencer J. Analysis of mutations in Ig heavy chain V region genes of microdissected marginal zone (MGZ) B cells suggests that the MGZ of human spleen is a reservoir of memory b cells. J Exp Med 1995; 182:559-566.Google Scholar
  89. 89.
    Bachl J, Wabl M. An immunoglobulin mutator that targets G/C base pairs. Proc Natl Acd Sci USA 1996; 93:85i-855.Google Scholar
  90. 90.
    McHeyzer-Williams M, Nossal G, Lalor P. Molecular characterization of single memory B cells. Nature 1991; 350:502-505.Google Scholar
  91. 91.
    Kaellberg E, Jainandunsing S, Gray D, Leanderson T. Somatic mutation of immunoglobulin V genes in vitro. Science 1996; 271: 1285–1289.CrossRefGoogle Scholar
  92. 92.
    Razanajaona D, Denepoux S, Blanchard D et al. In vitro triggering of somatic mutation in human naive B cells. J Immunol 1997; 1593347-3353.Google Scholar
  93. 93.
    Denepoux S, Razanajaona D, Blanchard D et al. Induction of somatic mutation in a human B cell line in vitro. Immunity 1997; 6: 35–46.Google Scholar
  94. 94.
    McKean D, Huppi K, Bell M, Staudt L, Gerhard W, Weigert M. Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutination. Proc Natl Acad Sci 1984; 81: 3180–3184.PubMedCrossRefGoogle Scholar
  95. 95.
    Kunkel T. Hypermutation during DNA synthesis in vitro. In: Steele EJ, ed. Somatic Hypermutation in V-Regions. Boca Raton Ann Arbor, Boston: CRC Press, 1991: 159–178.Google Scholar
  96. 96.
    Golding G, Gearhart P, Glockman B. Patterns of somatic mutation in immunoglobulin variable genes. Genetics 1987; 115: 169–176.PubMedGoogle Scholar
  97. 97.
    Neuberger MS, Milstein C. Somatic hypermutation. Curr Op Imm 1995; 7248–254.Google Scholar
  98. 98.
    Smith D, Creadon G, Jena P, Portanova J, Kotzin B, Wysocki L. Di-and trinucleotide target preferences of somatic mutagenesis in normal and autoreactive B cells. J Immunol 1996; 156: 2642–2652.PubMedGoogle Scholar
  99. 99.
    Storb U, Peters A, Klotz E et al. Somatic hypermutation of immunoglobulin genes is linked to transcription. Curr. Topics Microbiol Immunol 1998; 22911–19.Google Scholar
  100. 100.
    Betz AG, Rada C, R. P, Milstein C, Neuberger M. Passenger transgenes reveal intrinsic specificity of the antibody hypermutation mechanism: Clustering, polarity and specific hotspots. Proc Natl Acad Sci 1993; 902385-2388.Google Scholar
  101. 101.
    Doerner T, Brezinschek H-P, Brezinschek R, Foster S, Domiati-Saad R, Lipsky P. Analysis of the frequency and pattern of somatic mutations ithin nonproductively rearranged human variable heavy chain genes. J Immunol 1997; 158: 2779–2789.Google Scholar
  102. 102.
    Wagner S, Milstein C, Neuberger M. Codon bias targets mutation. Nature 1995; 376: 732.Google Scholar
  103. 103.
    Azuma T, Motoyama N, Fields L, Loh D. Mutations of the chloramphenicol acetyl transferase transgene driven by the immunoglobulin promoter and intron enhancer. Internatl Immunol 1993; 5: 121–130.Google Scholar
  104. 104.
    Klotz E. An analysis of molcular requirements for somatic hyper-mutation using immunoglobulin light chain transgenes [Ph.D.]. Chicago: University of Chicago, 1997: 132.Google Scholar
  105. 105.
    Winter D, Sattar N, Mai J-J, Gearhart P. Insertion of 2 kb of bacteriophage DNA between an immunoglobulin promoter and leader exon stops somatic hypermutation in a kappa transgene. Mol Immunol 1997; 34: 359–366.Google Scholar
  106. 106.
    Weiss S, Wu G. Somatic point mutations in unrearranged immunoglobulin gene segments encoding the variable region of lambda light chains. EMBO J 1987; 6: 927–932.Google Scholar
  107. 107.
    Motoyama N, Miwa T, Suzuki Y, Okada H, Azuma T. Comparison of somatic mutation frequency among immunoglobulin genes. J Exp Med 1994; 179: 395–403.Google Scholar
  108. 108.
    Storb U, Haasch D, Arp B, Sanchez P, Cazenave P, Miller J. Physical linkage of mouse A genes by pulsed-field gel electrophoresis suggests that the rearrangement process favors proximate target sequences. Mol Cell Biol 1989; 9: 711–718.Google Scholar
  109. 109.
    Carson S, Wu G. A linkage map of the mouse immunoglobulin A light chain locus. Immunogenetics 1989; 29: 173–179.Google Scholar
  110. 110.
    Picard D, Schaffner W. Unrearranged immunoglobulin lambda variable region is transcribed in kappa-producing myelomas. EMBO J 1984; 3: 3031–3035.Google Scholar
  111. 111.
    Mather E, Perry R. Transcriptional regulation of immunoglobulin V genes. Nucleic Acids Res 1981; 9: 6855–6867.PubMedCrossRefGoogle Scholar
  112. 112.
    Roes J, Hueppi K, Rajewsky K, Sablitzky F. V gene rearrangement is required to fully activate the hypermutation mechanism in B cells. J Immunol 1989; 142: 1022–1026.PubMedGoogle Scholar
  113. 113.
    Both G, Taylor L, J. P, Steele E. Distribution of mutations around rearranged heavy-chain antibody variable-region genes. Mol Cell Biol 1990; 10: 5187–5196.Google Scholar
  114. 114.
    Gearhart PJ, Levy NS. Kinetics and molecular model for somatic mutation in immunoglobulin variable genes. In: Steele EJ, ed. Somatic hypermutation in V-regions. Boca Raton: CRC Press, 1991: 29-39.Google Scholar
  115. 115.
    Rada C, Gonzalez-Fernandez A, Jarvis JM, Milstein C. The 5’ boundary of somatic hypermutation in a Vk gene is in the leader intron. Eur J immunol 1994; 24: 1453–1457.Google Scholar
  116. 116.
    Rogerson B. Mapping the upstream boundary of somatic mutations in rearranged immunoglobulin transgenes and endogenous genes. Mol Immunol 1994; 3183-98.Google Scholar
  117. 117.
    Lebecque S, Gearhart P. Boundaries of somatic mutation in rearranged immunoglobulin genes: 5’ boundary is near the promoter, and 3’ boundary is -1kb from V(D)J gene. J Exp Med 1990; 172: 1717–1727.PubMedCrossRefGoogle Scholar
  118. 118.
    Motoyama N, Okada H, Azuma T. Somatic mutation in constant region of mouse Xi light chains. Proc Natl Acad Sci USA 1991; 88:7933-7937.Google Scholar
  119. 119.
    Weber JS, Berry J, Litwin S, Claflin JL. Somatic hypermutation of the JC intron is markedly reduced in unrearranged x and H alleles and is unevenly distributed in rearranged alleles. J Immunol 1991; 146: 3218–3226.PubMedGoogle Scholar
  120. 120.
    Weber JS, Berry J, Manser T, Claflin JL. Position of the rearranged Vx and its 5’ flanking sequences determines the location of somatic mutations in the Jx locus. J Immunol 1991; 146: 3652–3655.PubMedGoogle Scholar
  121. 121.
    Rothenfluth H, Taylor L, Bothwell A, Both G, Steele E. Somatic hypermutation in 5’ flanking regions of heavy chain antibody variable regions. Eur J Immunol 1993; 23: 2152–2159.CrossRefGoogle Scholar
  122. 122.
    Gearhart PJ, Bogenhagen DF. Clusters of point mutations are found exclusively around rearranged antibody variable genes. Proc Natl Acad Sci USA 1983; 80: 3439–3443.PubMedCrossRefGoogle Scholar
  123. 123.
    Goyenechea B, Klix N, Yelamos J et al. Cells strongly expressing Igkappa transgenes show clonal recruitment of hypermutation: A role for both MAR and the enhancers. EMBO J 1997; i6:3987-3994.Google Scholar
  124. 124.
    Fulton R, Van Ness B. Kappa immunoglobulin promoters and enhancers display developmentally controlled interactions. Nucleic Acids Res 1993; 21:4941-4947.Google Scholar
  125. 125.
    Tumas-Brundage K, Manser T. The transcriptional promoter regulates hypermutation of the antibody heavy chain locus. J Exp Med 1997; 185: 239–250.Google Scholar
  126. 126.
    Rabbits T, Forster A, Hamlyn P, Baer R. Effect of somatic mutation within translocated c-myc genes in Burkitt’s lymphoma. Nature 1984; 309: 592–597.CrossRefGoogle Scholar
  127. 127.
    Morse B, South V, Rothberg P, Astrin S. Somatic mutation and transcriptional deregulation of myc in endemic Burkitt’s lymphoma disease: Heptamer-nonamer recognition mistakes? Mol. Cell Biol 1989; 9:74-82.Google Scholar
  128. 128.
    Mueller J, Janz S, Goedert J, Potter M, Rabkin C. Persistence of immunoglobulin heavy chain/c-myc recombination-positive lymphocyte clones in the blood of human immunodeficiency virus infected homosexual men. Proc Natl Acad Sci USA 1995; 92t6577-6581.Google Scholar
  129. 129.
    Migliazza A, Martinotti S, Chen W et al. Frequent somatic hyper-mutation of the 5’ noncoding region of the BCL6 gene in B-cell lymphoma. Proc Natl Acad Sci USA 1995; 92: 12520–12524.Google Scholar
  130. 130.
    Pongubala J, Nagulapalli M, Klemsz S, McKercher S, Maki R, Atchison M. PU.1 recruits a second nuclear factor to a site important for immunoglobulin K 3’ enhancer activation. Mol Cell Biol 1992; 12: 368–378.Google Scholar
  131. 131.
    Rudin C, Storb U. Two conserved essential motifs of the murine immunoglobulin X enhancers bind B-cell-specific factors. Mol Cell Biol 1992; 12: 309–320.PubMedGoogle Scholar
  132. 132.
    Eisenbeis C, Singh H, Storb U. PU.1 is a component of a multiprotein complex which binds an essential site in the murine immunoglobulin A.2–4 enhancer. Mol Cell Biol 1993; 13: 6452–6461.Google Scholar
  133. 133.
    Taylor L, Carmack C, Huszar D et al. Human immunoglobulin transgenes undergo rearrangement, somatic mutation and class switching in mice that lack endogenous IgM. Internatl Imm 1994; 6: 579–591.Google Scholar
  134. 134.
    Szajnert M, Saule S, Bornkamm G, Wajcman H, Lenoir G, Kaplan J. Clustered somatic mutations in and around first exon of non-rearranged c-myc in Burkitt lymphoma with t(8; 22) translocation. Nucleic Acids Res 1987; 15: 4553–4565.Google Scholar
  135. 135.
    Ye B, Cattoretti G, Shen Q et al. The Bd-6 proto-oncogene controls germinal-center formation and Th2-type inflammation. Nature Genetics 1997; 16: 161–170.PubMedCrossRefGoogle Scholar
  136. 136.
    Brenner S, Milstein C. Origin of antibody variation. Nature 1966; 211: 242–243.PubMedCrossRefGoogle Scholar
  137. 137.
    Steele E, Pollard J. Hypothesis: Somatic mutation by gene conversion via the error prone DNA> RNA > DNA information loop. Mol Immunol 1987; 24: 667–673.PubMedCrossRefGoogle Scholar
  138. 138.
    Maizels N. Might gene conversion be the mechanism of somatic hypermutation of mammalian Ig genes? Trends in Genetics 1989; 5: 4–8.Google Scholar
  139. 139.
    Manser T. The efficiency of antibody maturation; can the rate of B cell division be limiting? Immunol Today 1990; 11: 305–308.PubMedCrossRefGoogle Scholar
  140. 140.
    Rogerson B, Hackett J, Peters A, Haasch D, Storb U. Mutation pattern of immunoglobulin transgenes is compatible with a model of somatic hypermutation in which targeting of the mutator is linked to the direction of DNA replication. EMBO Journal 1991; 10:4331-4341.Google Scholar
  141. 141.
    Storb U, Peters A, Klotz E, Rogerson B, Hackett J. The mechanism of somatic hypermutation studied with transgenic and transfected target genes. Semin Immunol 1996; 8x31–140.Google Scholar
  142. 142.
    Shen HM, Cheo DL, Friedberg E, Storb U. The inactivation of the XP-C gene does not affect somatic hypermutation or class switch recombination of immunoglobulin genes. Mol Immunol 1997a; 34:527-533.Google Scholar
  143. 143.
    Mellon I, Rajpal D, Koi M, Boland C, Champe G. Transcription-coupled repair deficiency and mutations in human mismatch repair genes. Science 1996; 272:557-560.Google Scholar
  144. 144.
    Storb U, Klotz E, Hackett J, Kage K, Bozek G, Martin TE. A hypermutable insert in an immunoglobulin transgene contains hotspots of somatic mutation and sequences predicting highly stable structures in the RNA transcript. 1998; (submitted).Google Scholar
  145. 145.
    Rogozin I, Kolchanov N. Somatic hypermutagenesis in immunoglobulin genes. II. Influence of neighboring base sequences on mutagenesis. Biochim Biophys Acta 1992; 1171: 11–18.Google Scholar
  146. 146.
    Shen H, Peters A, Baron B, Zhu X, Storb U. Mutation of Bd-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science 1998; (in press).Google Scholar

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© Springer-Verlag Berlin Heidelberg 1998

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  • U. Storb

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