The molecular basis of somatic hypermutation of immunoglobulin genes

Current Opinion in Immunology

Volumn 8, Issue 2, 1996, Pages 206-214

  Storb, Ursula ^a  

^a UNIVERSITY OF CHICAGO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DNA REPAIR; DNA REPLICATION; GENE CONVERSION; GENETIC TRANSCRIPTION; IMMUNOGLOBULIN GENE; MOLECULAR MODEL; REVIEW; SOMATIC MUTATION; TRANSCRIPTION INITIATION;

EID: 0029888843     PISSN: 09527915     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0952-7915(96)80059-8     Document Type: Article

References (88)

1. Apel M, Berek C: Somatic mutations in antibodies expressed by germinal center B cells early after primary immunization. Int Immunol 1990, 2:813-819.
2. Jacob J, Kelsoe GKR, Weiss U: Intraclonal generation of antibody mutants in germinal centers. Nature 1991, 354:389-392.
3. MacIennan ICM, Liu YJ, Johnson GD: Maturation and dispersal of B-cell clones during T-cell-dependent antibody responses. Immunol Rev 1992, 126; 143-161.
4. Kelsoe G: In situ studies of germinal center reaction. Adv Immunol 1995, 60:267-288.
5. 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.
6. 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.
7. Zou X, Xian J, Popov A, Rosewell I, Mueller M, Brueggemann M: Subtle differences in antibody responses and hypermutation of lambda light chains in mice with a disrupted kappa constant region. Eur J Immunol 1995, 25:2154-2162.
8. Gonzales-Fernandes A, Milstein C: Analysis of somatic hypermutation in mouse Peyer's patches using immunoglobulin κ light-chain transgenes. Proc Natl Acad Sci USA 1993, 90:9862-9866.
9. Rogerson B: Somatic hypermutation of VHS107 genes is not associated with gene conversion among family members. Int Immunol 1995, 7:1225-1235.
10. 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.
11. Miller C, Kelsoe G: Ig VH hypermutation is absent in the germinal centers of aged mice. J Immunol 1995, 155:3377-3384.
12. Jacobson E, Corporale L, Thorbecke J: Effect of thymus cell injections on germinal center formation in lymphoid issues of nude (thymus-less) mice. Cell Immunol 1974, 13:416-430.
13. + cells limit germinal center formation? Immunology 1990, 69:487-489.
14. Miller C, Stedra J, Kelsoe G, Cerny J: Facultative role of germinal centers and T cells in the somatic diversification of IgVH genes. J Exp Med 1995, 181:1319-1331.
15. Han S, Hathcock K, Zheng B, Kepler T, Hodes R, Kelsoe G: Cellular interaction in germinal centers. Roles of CD40 ligand and B7-2 in established germinal centers. J Immunol 1995, 155:556-567.
16. Han S, Zheng B, Dal Porto J, Kelsoe G: In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. IV. Affinity-dependent antigen-driven B cell apoptosis in germinal centers as a mechanism for maintaining self tolerance. J Exp Med 1995, in press.
17. Hinds-Frey K, Nishikata H, Litman R, Litman G: Somatic variation precedes extensive diversification of germline sequences and combinatorial joining in the evolution of Ig heavy chain diversity. J Exp Med 1993, 178:815-824.
18. 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, 374:168-173.
19. Zheng B, Xue W, Kelsoe G: Locus-specific somatic hypermutation in germinal centre T cells. Nature 1994, 372:556-559.
20. McHeyzer-Williams M, Davis M: Antigen-specific development of primary and memory T cells in vivo. Science 1995, 268:106-110.
21. 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 USA 1984, 81:3180-3184.
22. Golding G, Gearhart P, Glockman B: Patterns of somatic mutation in immunoglobulin variable genes. Genetics 1987, 115:169-176.
23. Gearhart PJ, Levy NS: Kinetics and molecular model for somatic mutation in immunoglobulin variable genes. In Somatic Hypermutation in V-Regions. Edited by Steele EJ: Boca Raton: CRC Press; 1991:29-39.
24. Gonzalez-Fernandez A, Gupta S, Pannell R, Neuberger M, Milstein C: Somatic mutation of immunoglobulin lambda chains: a segment of the major intron hypermutates as much as the complementarity-determining region. Proc Natl Acad Sci 1994, 91:12614-12618.
25. Azuma T, Motoyama N, Fields L, Loh D: Mutations of the chloramphenicol acetyl transferase transgene driven by the immunoglobulin promoter and intron enhancer. Int Immunol 1993, 5:121-130.
26. •] show that transgenic constructs expressed under the control of both an Ig promoter and an Ig enhancer and containing extraneous sequences (bacterial genes and a globin gene) are subject to somatic hypermutation. These studies clearly show that Ig V genes and their flanks are not the only mutation targets and suggest, that any DNA sequence may be a target under the right circumstances.
27. Betz AG, Neuberger MS, Milstein C: Discriminating intrinsic and antigen-selected mutational hotspots in immunoglobulin V genes. Immunol Today 1993, 14:405-411.
28. Wagner S, Milstein C, Neuberger M: Codon bias targets mutation. Nature 1995, 376:732.
29. Reynaud C, Garcia C, Hein W, Weill J: Hypermutation generating the sheep immunoglobulin repertoire is an antigen-independent process. Cell 1995, 80:115-125.
30. Both G, Taylor L, Pollard J, Steele E: Distribution of mutations around rearranged heavy-chain antibody variable-region genes. Mol Cell Biol 1990, 10:5187-5196.
31. Rada C, Gonzalez-Fernandez A, Jarvis JM, Milstein C: The 5′ boundary of somatic hypermutation in a Vκ gene is in the leader intron. Eur J Immunol 1994, 24:1453-1457.
32. Rogerson B: Mapping the upstream boundary of somatic mutations in rearranged immunoglobulin transgenes and endogenous genes. Mol Immunol 1994, 31:83-98.
33. Lebecque S, Gearhart P: Boundaries of somatic mutation in rearranged immunoglobulin genes: 5′ boundary is near the promoter, and 3′ boundary is ∼1 kb from V(D)J gene. J Exp Med 1990, 172:1717-1727.
34. Motoyama N, Okada H, Azuma T: Somatic mutation in constant region of mouse λ1 light chains. Proc Natl Acad Sci USA 1991, 88:7933-7937.
35. Weber JS, Berry J, Litwin S, Claflin JL: Somatic hypermutation of the JC intron is markedly reduced in unrearranged κ and H alleles and is unevenly distributed in rearranged alleles. J Immunol 1991, 146:3218-3226.
36. Weber JS, Berry J, Manser T, Claflin JL: Position of the rearranged VK and its 5′ flanking sequences determines the location of somatic mutations in the Jκ locus. J Immunol 1991, 146:3652-3655.
37. 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.
38. Selsing E, Storb U: Somatic mutation of immunoglobulin light-chain variable-region genes. Cell 1981, 47-58.
39. Gorski J, Rollini P, Mach B: Somatic mutations of immunoglobulin variable genes are restricted to the rearranged V gene. Science 1983, 220:1179-1181.
40. 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.
41. Motoyama N, Miwa T, Suzuki Y, Okada M, Azuma T: Comparison of somatic mutation frequency among immunoglobulin genes. J Exp Med 1994, 179:395-403.
42. Storb U, Haasch D, Arp B, Sanchez P, Cazenave P, Miller J: Physical linkage of mouse λ genes by pulsed-field gel electrophoresis suggests that the rearrangement process favors proximate target sequences. Mol Cell Biol 1989, 9:711-718.
43. Picard D, Schaffner W: Unrearranged immunoglobulin lambda variable region is transcribed in kappa-producing myelomas. EMBO J 1984, 3:3031-3035.
44. Mather E, Perry R: Transcriptional regulation of immunoglobulin V genes. Nucleic Acids Res 1981, 9:6855-6867.
45. 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.
46. 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.
47. Green N, Rabinowitz J, Zhu M, Kobrin B, Scharff M: Immunoglobulin variable region hypermutation in hybrids derived from a pre-B- and a myeloma cell line. Proc Natl Acad Sci USA 1995, 92:6304-6308.
48. Zhu M, Rabinowiz J, Green N, Kobrin B, Scharff M: A well-differentiated B-cell line is permissive for somatic mutation of a transfected immunoglobulin heavy-chain gene. Proc Natl Acad Sci USA 1995, 92:2810-2814.
49. O'Brien R, Brinster R, Storb U: Somatic hypermutation of an immunoglobulin transgene in κ transgenic mice. Nature 1987, 326:405-409.
50. 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.
51. κ promoter can be replaced by a β-globin promoter without loss of mutation efficiency. The κ-3′ enhancer is dispensible for the basic process, but its deletion greatly decreases the frequency of mutations. However, deletion of the κ-intron enhancer eliminates detectable mutations; it remains to be determined if it is specifically required, or if it is replaceable by another enhancer that is expressed in germinal center B cells.
52. κ transcription promoter is duplicated upstream of the C region, leading to transcripts initiating within the gene as well as at the normal initiation site. This transgene shows somatic mutations of the C region in addition to the normal V region mutations, but no mutations betwen these two regions. This is the first evidence linking somatic mutation to the initiation of transcription and suggests that an error factor is loaded at the initiating transcription complex and carried into the gene with the elongating complex. The restriction of mutations to a stretch of about 1.5 kb from the promoter may be explained by early action of the mutator factor during elongation and its irreversible dissociation from the transcription complex after each mutation event.
53. Chui Y, Lozano F, Jarvis J, Pannell R, Milstein C: A reporter gene to analyse the hypermutation of immunoglobulin genes. J Mol Biol 1995, 249:555-563.
54. Maizels N: Might gene conversion be the mechanism of somatic hypermutation of mammalian Ig genes? Trends Genet 1989, 5:4-8.
55. 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.
56. Manser T: The efficiency of antibody maturation; can the rate of B cell division be limiting? Immunol Today 1990, 11:305-308.
57. 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 J 1991, 10:4331-4341.
58. Brenner S, Milstein C: Origin of antibody variation. Nature 1966, 211:242-243.
59. 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.
60. Reynaud C, Anquez V, Dahan A, Weill J: A single rearrangement event generates most of the chicken Ig light chain diversity. Cell 1985, 40:283-291.
61. Carlson L, McCormack W, Postema C, Humphries E, Thompson C: Templated insertion in the rearranged chicken IgL V gene segment arise by intrachromosomal gene conversion. Genes Dev 1990, 4:536-547.
62. Becken R, Knight K: Somatic diversification of Ig heavy chain VDJ genes: evidence for somatic gene conversion in rabbits. Cell 1990, 63:987-997.
63. Reynaud C, Anquez V, Grimal H, Weill J-C: A hyperconversion mechanism generates the chicken light chain preimmune repertoire. Cell 1987, 48:379-388.
64. McCormack W, Thompson C: Chicken IgL variable region gene conversions display pseudogene donor preference and 5′ to 3′ polarity. Genes Dev 1990, 4:546-558.
65. Baltimore D: Gene conversion: some implications for immunoglobulin genes. Cell 1981, 24:592-594.
66. Chien N, Pollock R, Desaymard C, Schraff M: Point mutations cause the somatic diversification of IgM and IgG2a antiphosphorylcholine antibodies. J Exp Med 1988, 167:954-973.
67. Wysocki L, Gefter M, Margolies M: Parallel evolution of antibody variable regions by somatic processes: consecutive shared somatic alterations in VH genes expressed by independently generated hybridomas apparently acquired by point mutation and selection rather than by gene conversion. J Exp Med 1990, 172:315-323.
68. Xu B, Selsing E: Analysis of sequence transfers resembling gene conversion in a mouse antibody transgene. Science 1994, 265:1590-1593.
69. Ford J, McHeyzer-Williams M, Lieber M: Analysis of individual immunoglobulin lambda light chain genes amplified from single cells is inconsistent with variable region gene conversion in germinal-center B cell somatic mutation. Eur J Immunol 1994, 24:1816-1822.
70. Selsing E, Miller J, Wilson R, Storb U: Evolution of mouse immunoglobulin lambda genes. Proc Natl Acad Sci USA 1982, 79:4681-4685.
71. Gilboa E, Mitra S, Goff S, Baltimore D: A detailed model of reverse transcription and tests of crucial aspects. Cell 1979, 18:93-100.
72. Fulton R, Van Ness B: Kappa immunoglobulin promoters and enhancers display developmentally controlled interactions. Nucleic Acids Res 1993, 21:4941-4947.
73. 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.
74. Morse B, South V, Rothberg P, Astrin S: Somatic mutation and transcriptional deregulation of myc in endemic Burkitt's lymphoma disease: heptamer-noname recognition mistakes? Mol Cell Biol 1989, 9:74-82.
75. 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, 92:6577-6581. c-myc genes translocated to the heavy chain locus in peripheral blood lymphocytes contained point mutations with indications of strand bias as in somatic mutations of Ig genes. The myc mutations shown here and in previous publications are a natural example of somatic point mutations under the control of a non-Ig transcription promoter. Furthermore, evidence indicates that the mutations most probably occurred after the translocation event: separate cell clones with identical breaks in c-myc and the heavy chain locus have multiple, different point mutations.
76. 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 κ-3′ enhancer activation. Mol Cell Biol 1992, 12:368-378.
77. Rudin C, Storb U: Two conserved essential motifs of the murine immunoglobulin λ enhancers bind B-cell-specific factors. Mol Cell Biol 1992, 12:309-320.
78. Eisenbeis C, Singh H, Storb U: PU.1 is a component of a multiprotein complex which binds en essential site in the murine immunoglobulin λ2-4 enhancer. Mol Cell Biol 1993, 13:6452-6461.
79. Sohn J, Gerstein R, Hsieh C, Lemer M, Selsing E: Somatic hypermutation of an immunoglobulin μ heavy chain transgene. J Exp Med 1993, 177:493-504.
80. Taylor L, Carmack C, Huszar D, Higgins K, Masahyekh R, Sequar G, Schramm S, Chiung-Chi K, O'Donnell S, Kay R, Woodhouse C, Lonberg N: Human immunoglobulin transgenes undergo rearrangement, somatic mutation and class switching in mice that lack endogenous IgM. Int Immunol 1994, 6:579-591.
81. 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.
82. Hackett J, Rogerson B, O'Brien R, Storb U: Analysis of somatic mutations in κ transgenes. J Exp Med 1990, 172:131-137.
83. Friedberg E: Relationships between DNA repair and transcription. Annu Rev Biochem 1996, in press.
84. Hanawalt PC: Transcription-coupled repair and human disease. Science 1994, 266:1957-1958.
85. Hanawalt PC: DNA repair comes of age. Mutation Res 1995, 336:101-113.
86. Donahue B, Yin S, Taylor J, Reines D, Hanawalt P: Transcript leavage by RNA polymerase II arrested by a cyclobutane pyrimidine dimer in the DNA template. Proc Natl Acad Sci USA 1994, 91:8502-8506.
87. Kornberg A, Baker T: DNA Replication. New York: WH Freeman; 1992.
88. Von Hippel PH, Yager TD: The elongation-termination decision in transcription. Science 1992, 255:809-812.