Abstract
In his book “What is life?” which was so influential at the tinne, Erwin Schrödinger (1944) mused, “In orderte be suitable material for the work of natural selection, mutations must be rare events.” That is, stability is one of the most important properties of the gene. A decade and a half later, the visionary Joshua Lederberg (1959) was musing about the origin of antibody diversity. He proposed that the instability of genes, i.e., from somatic mutation, was crucial in this process.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
Allegrucci M, Young-Cooper GO, Alexander CB, Newman BA, Mage RG (1991) Preferential rearrangement in normal rabbits of the 3’ VHa allotype gene that is deleted in Alicia mutants; somatic hypermutation conversion may play a major role in generating the heterogeneity of rabbit heavy chain variable region sequences. Eur J Immunol 21:411–417
Bachi J, Wabi M (1995) Hypermutation in T cells questioned. Nature 375:285–286
Bachi J, Wabi M (1996) An immunoglobulin mutator that preferentially targets G-C base pairs. Proc Natl Acad Sci USA 93:851–855
Baker SM, Bronner CE, Zhang L, Plug AW, Robatzek M, Warren G, Elliott EAYJ, Ashley T, Arnheim N, Flavell RA, Liskay RM (1995) Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis. Cell 82:309–319
Baumal R, Birshtein BK, Coffino P, Scharff MD (1973) Mutations in immunoglobulin-producing mouse myeloma cells. Science 182:164–166
Berek C, Milstein C (1987) Mutation drift and repertoire shift in the maturation of the immune response. Immunol Rev 96:23–41
Berek C, Griffiths GM, Milstein C (1985) Molecular events during maturation of the immune response to oxazolone. Nature 316:412–418
Berinstein N, Campbell MJ, Lam K, Carswell C, Levy S, Levy R (1990) Idiotypic variation in a human B lymphoma cell line. J Immunol 144:752–758
Bernard O, Hozumi N, Tonegawa S (1978) Sequences of mouse immunoglobulin light chain genes before and after somatic changes. Cell 15:1133–1144
Betz AG, Rada C, Pannell R, Milstein C, Neubörger MS (1993) Passenger transgenes reveal intrinsic specificity of the antibody hypermutation mechanism: clustering, polarity and specific hotspots. Proc Natl Acad Sci USA 90:2385–2388
Betz AG, Milstein C, Gonzalez-Fernandez A, Pannell R, Larson T, Neubörger MS (1994) Elements regulating somatic hypermutation of an immunoglobulin kappa gene: critical role for the intron enhancer/matrix attachment region. Cell 77:239–248
Bothwell ALM, Paskind M, Reth M, Imanishi-Kari T, Rajewsky K, Baltimore D (1981) Heavy chain variable region contribution to the NPb family of antibodies:somatic mutation evident in a gamma 2a variable region. Cell 24:625–637
Brenner S, Milstein C (1966) Origin of antibody variation. Nature 211:242–243
Chen C, Roberts VA, Rittenberg MB (1992) Generation and analysis of random point mutations in an antibody CDR2 sequence: many mutated antibodies lose their ability to bind antigen. J Exp Med 176:855–866
Chen C, Nagy Z, Radic MZ, Hardy RR, Huszar D, Camper SA, Weigert M (1995) The site and stage of anti-DNA B-cell deletion. Nature 373:252–255
Clarke SH, Huppi K, Ruezinsky D, Staudt L, Gerhard W, Weigert M (1985) Inter- and intraclonal diversity in the antibody response to influenza hennagglutinin. J Exp Med 161:687–704
Coffino P, Scharff MD (1971) Rate of sonnatic mutation in immunoglobulin production by mouse myeloma cells. Proc Natl Acad Sci USA 68:219–223
Crews S, Griffin J, Huang H, Calame K, Hood L (1981) A single VH gene segment encodes the immune response to phosphorylcholine:somatic mutation is correlated with the class of the antibody Cell 25:59–704
Cunningham AJ, Fordham SA (1974) Antibody cell daughters can produce antibody of different specificities. Nature 250:669–671
Desiderio SV Yancopoulos GD, Paskind M, Thomas E, Boss MA, Landau N, Alt FW, Baltimore D (1984) Insertion of N regions into heavy-chain genes is correlated with expression of terminal deoxytransferase in B cells. Nature 311:752–755
Du Pasquier L (1993) Phylogeny of B-cell development. Curr Biol 5:185–193
Eigen M (1993) Viral quasi-species. Sci Am 269:42–49
Gay D, Saunders T Camper S, Weigert M (1993) Receptor editing: an approach by autoreactive B cells to escape tolerance. J Exp Med 177:999–1008
Gearhart PJ (1993) Somatic mutation and affinity maturation. In: Paul WE (ed) Fundamental immunology, 3rd edn. Raven, New York, pp 865–885
Gearhart PJ, Bogenhagen, DF (1983) Clusters of point mutations are found exclusively around rearranged antibody variable genes. Proc Natl Acad Sci USA 80:3439–3443
Gearhart PJ, Johnson ND, Douglas R, Hood L (1981). IgG antibodies to phosphorylcholine exhibit more diversity than their IgM counterparts. Nature 291:29–34
Gershenfeld HK, Tsukamato A, Weissman IL, Joho R (1981) Somatic diversification is required to generate VK genes of M0PC511 and MOPC167 myeloma proteins. Proc Natl Acad Sci USA 78:7674–7678
Gonzalez-Fernandez A, Gupta SK, Pannell R, Neubörger MS, Milstein C (1994) Somatic mutation of immunoglobulin lambda chains: a segment of the major intron hypermutates as much as the complementarity-determining regions. Proc Natl Acad Sci USA 91:12614–12618
Goodnow CC (1992) Transgenic mice and analysis of B-cell tolerance. Ann Rev Immunol 10:489–518
Goodnow CC, Crosbie J, Jorgensen H, Brink RA, Basten A (1989) Induction of self-tolerance in mature peripheral B lymphocytes. Nature 342:385–391
Green NS, Rabinowitz JL, Zhu M, Kobrin BJ, Scharff MD (1995) Immunoglobulin variable region hypermutation in hybrids derived from a pre-B- and a myeloma cell line. Proc Natl Acad Sci USA 92:6304–6308
Griffiths GM, Berek C, Kaartinen M, Milstein C (1984) Somatic mutation and the maturation of immune response to 2-phenyloxazolone. Nature 312:271–275
Grossehedl R, Baltimore D (1985) Cell-type specificity of immunoglobulin gene expression is regulated by at least three DNA sequence elements. Cell 41:885–897
Gu H, Tarlinton D, Muller W, Rajewsky K, Forster I (1991) Most peripheral B cells in mice are ligand selected. J Exp Med 173:1357–1371
Hanawalt PC (1994) Transcription-coupled repair and human disease. Science 266:1957–1958
Harriman W, Volk H, Defranoux N, Wabi M (1993) Immunoglobulin class switch recombination. Annu Rev Immunol 11:361–384
Hartley SB, Crosbie J, Brink R, Kantor AB, Basten A, Goodnow CC (1991) Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens. Nature 353:765–769
Hengstschlager M, Williams M, Maizels N (1994) A lambda 1 transgene under the control of a heavy chain promoter and enhancer does not undergo somatic hypermutation. Eur J Immunol 24:1649–1656
Hinds-Frey KR, Nishikata H, Litman RX Litman GW (1993) Somatic variation precedes extensive diversification of germline sequences and combinatorial joining in the evolution of immunoglobulin heavy chain diversity J Exp Med 178:815–824
Jäck HM, Wabi M (1987). High rates of deletions in the constant region segment of the immunoglobulin mu gene. Proc Natl Acad Sci USA 84:4934–4938
Jacob J, Kelsoe G (1992) In situ studies of the primary immune response to (4-hydroxy-3-nitrophe- nyl)acetyl. II. A common clonal origin for periarteriolar lymphoid sheath-associated foci and germinal centers. J Exp Med 176:679–687
Jacob J, Kelsoe G, Rajewsky K, Weiss U (1991) Intraclonal generation of antibody mutants in germinal centres. Nature 354:389–392
Jacob J, Przylepa J, Miller C, Kelsoe G (1993) In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. III. The kinetics of V region mutation and selection in germinal center B cells. J Exp Med 178:1293–307
Jerne NK (1971) The somatic generation of immune recognition. Eur J Immunol 1:1–9
Kelsoe G, Zheng B (1993) Sites of B-cell activation in vivo. Curr Opin Immunol 5:418–422
Kim S, Davis M, Sinn E, Patten R Hood L (1981) Antibody diversity: somatic hypermutation of rearranged VH genes. Cell 27:573–581
Knight KL, Becker RS (1990) Molecular basis of the allelic inheritance of rabbit immunoglobulin VH allotypes:implications for the generation of antibody diversity Cell 60:963–970
Knight KL, Becker RS, DiPietro LA (1991) Restricted utilization of germ-line VH genes in rabbits:im- plications for inheritance of VH allotypes and generation of antibody diversity. Adv Exp Med Biol 292:235–424
Küppers R, Zhao M, Hansmann ML, Rajewsky K (1993) Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J 12:4955–4967
Küppers R, Rajewsky K, Zhao M, Simons G, Laumann R, Fischer R, Hansmann ML (1994) Hodgkin disease: Hodgkin and Reed-Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development. Proc Natl Acad Sci USA 91:10962–10966
Lederberg J (1959). Genes and antibodies. Do antigens bear instructions for antibody specifity or do they select cell lines that arise by mutation? Science 129:1649–1653
Levy S, Mendel E, Kon S, Avnur Z, Levy R (1988) Mutational hot spots in Ig V region genes of human follicular lymphomas. J Exp Med 168:475–89
Lieber MR (1992) The mechanism of V(D)J recombination: a balance of diversity specificity, and stability Cell 70:873–876
Linton PJL, Decker DJ, Klinman NR (1989) Primary antibody-forming cells and secondan/ B cells are generated from separate precursor cell subpopulations. Cell 59:1049–1059
Maizels N (1989) Might gene conversion be the mechanism of somatic hypermutation of mammalian immunoglobulin genes? Trends Genet 5:4–8
Manser T (1990) The efficiency of antibody affinity maturation:can the rate of B-cell division be limiting? Immunol Today 11:305–308
Manser T, Huang SY, Gefter ML (1984) Influence of clonal selection on the expression of immunoglobulin variable region genes. Science 226:1283–1288
McKean D, Huppi K, Bell M, Staudt L, Gerhard W, Weigert M (1984) Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin. Proc Natl Acad Sci USA 81:3180–3184
Meyer J, Jäck HM, Ellis N, Wabi M (1986) High rate of somatic point mutation in vitro in and near the variable-region segment of an immunoglobulin heavy chain gene. Proc Natl Acad Sci USA 83:6950–6953
Milstein C, Adetugbo K, Cowan NJ, Kohier G, Secher DS (1978) Expression of antibody genes in tissue culture:structural mutants and hybrid cells. National Cancer Institute Monographs 48:321–330
Nemazee D (1993) Promotion and prevention of autoimmunity by B lymphocytes. Curr Opin Immunol 5:866–72
Radic MZ, Erikson J, Litwin S, Weigert M (1993) B lymphocytes may escape tolerance by revising their antigen receptors. J Exp Med 177:1165–1173
Reynaud CA, Anquez V Grimal H, Weill JC (1987) A hyperconversion mechanism generates the chicken light chain preimmune repertoire. Cell 48:379–88
Reynaud CA, Dahan A, Anquez V Weill JC (1989) Somatic hyperconversion diversifies the single Vh gene of the chicken with a high incidence in the D region. Cell, 59:171–183
Reynaud CA, Mackay CR, Muller RG, Weill JC (1991) Somatic generation of diversity in a mammalian primary lymphoid organ:the sheep ileal Peyer’s patches. Cell 64:995–1005
Reynaud CA, Garcia C, Hein WR, Weill JC (1995) Hypermutation generating the sheep immunoglobulin repertoire is an antigen-independent process. Cell 80:115–125
Ritchie KA, Brinster RL, Storb U (1984) Allelic exclusion and control of endogenous immunoglobulin gene rearrangement in kappa transgenic mice. Nature 312:517–520
Rogerson B, Hackett J Jr, Peters A, Haasch D, Storb U (1991) 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 10:4331–4341
Rogozin IB, Kolchanov NA (1992) Somatic hypermutagenesis in immunoglobulin genes. II. Influence of neighbouring base sequences on mutagenesis. Biochim Biophys Acta 1171:11–18
Rudikoff S, Pawlita M, Pumphrey J, Heller M (1984) Somatic diversification of immunoglobulins. Proc Natl Acad Sci USA 81:2162–2165
Russell DM, Dembic Z, Morahan G, Miller JF; Burki K, Nemazee D (1991) Peripheral deletion of self-reactive B cells. Nature 354:308–311
Sablitzky F, Wildner G, Rajewsky K (1985) Somatic mutation and clonal expansion of B cells in an antigen-driven immune response. EMBO J. 4:345–350
Scharff MD, Aguila HL, Behar SM, Chien NC, DePinho R, French DL, Pollock RR, Shin SU (1987) Studies on the somatic instability of immunoglobulin genes in vivo and in cultured cells. Immunol Rev 96:75–90
Schrödinger E (1944) What is life? Cambridge University Press, Cambridge Scising E, Storb U (1981) Somatic mutation of immunoglobulin light-chain variable-region genes. Cell 25:47–58
Sharpe MJ, Milstein C, Jarvis JM, Neuberger MS (1991) Somatic hypermutation of immunoglobulin K L chain may depend on sequences 3’ of C kappa and occurs on passenger transgenes. EMBO J 10:2139–2145
Shokat KM, Goodnow CC (1995) Antigen-induced B-cell death and elimination during germinal-centre immune responses. Nature 375:334–338
Siekevitz M, Kocks C, Rajewsky K, Dildrop R (1987) Analysis of somatic mutation and class switching in naive and memory B cells generating adoptive primary and secondary responses. Cell 48:757–770
Sprent J (1994) T and B memory cells. Cell 76:315–322
Tiegs SL, Russell DM, Nemazee D (1993) Receptor editing in self-reactive bone marrow B cells. J Exp Med 177:1009–1020
Thompson CB, Neimen PE (1987) Somatic diversification of the chicken immunoglobulin light chain gene is limited to the rearranged variable gene segment. Cell 48:369–378
Umar A, Schweitzer PA, Levy NS, Gearhart JD, Gearhart PJ (1991) Mutation in a reporter gene depends on proximity to and transcription of immunoglobulin variable transgenes. Proc Natl Acad Sci USA 88:4902–4906
Vescio RA, Cao J, Hong CH, Lee JC, Wu CH, Der Danielian M, Wu V Newman R, Lichtenstein AK, Berenson, J (1995) Myeloma Ig heavy chain region sequences reveal prior antigenic selection and marked somatic mutation but no intraclonal diversity J Immunol 155:2487–2497
von Borstel RC, Cain KT, Steinberg C (1971) Inheritance of spontaneous mutability in yeast. Genetics 69:17–27
Wabi M, Burrows PD, von Gabain A, Steinberg C (1985) Hypermutation at the immunoglobulin heavy chain locus in a pre-B-cell line. Proc Natl Acad Sci USA 82:479–482
Wabi M, Jäck HM, Meyer J, Beck-Engeser G, von Borstel R, Steinberg C (1987) Measurements of mutation rates in B lymphocytes. Immunol Rev 96:91–107
Wabi M, Harriman W, Fischer E, Steinberg C (1994) Can we outlive Methuselah? Cybernet Sys 25:373–387
Weigert MG, Cesari IM, Yonkovich SJ, Cohn M (1970) Variability in the lambda light chain sequences of mouse antibody Nature 228:1045–1047
Weinstein PD, Anderson AO, Mage RG (1994) Rabbit IgH sequences in appendix germinal centers:VH diversification by gene conversion-like and hypermutation mechanisms. Immunity 1:647–659
Wilson M, Hsu E, Marcuz A, Courtet M, Du Pasquier L, Steinberg C (1992) What limits affinity maturation of antibodies in Xenopus — the rate of somatic mutation or the ability to select mutants? EMBO J 11:4337–4347
Wilson M, Marcuz A, Du Pasquier L (1995) Somatic mutations during an immune response in Xenopus tadpoles. Dev Immunol (in press)
Xu B, Scising E (1994) Analysis of sequence transfers resembling gene conversion in a mouse antibody transgene. Science 265:1590–1593
Yelamos J, Klix N, Goyenechea B, Lozano F, Chui YL, Gonzalez-Fernandez A, Panell R, Neuberger MS, Milstein C (1995) Targeting of non-lg sequences in place of the V segment by somatic hypermutation. Nature 376:225–229
Zhang LH, Vrieling H, van Zeeland AA, Jenssen D (1992) Spectrum of spontaneously occurring mutations in the hprt gene of V79 Chinese hamster cells. J Mol. Biol 223:627–635
Zheng B, Xue W, Kelsoe G (1994) Locus-specific somatic hypermutation in germinal centre T cells. Nature 372:556–559
Zhu M, Rabinowitz JL, Green NS, Kobrin BJ, Scharff MD (1995) A well-differentiated B-cell line is permissive for somatic mutation of a transfected immunoglobulin heavy-chain gene. Proc Natl Acad Sci USA 92:2810–2814
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1996 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Wabl, M., Steinberg, C. (1996). Somatic Hypermutability. In: Jessberger, R., Lieber, M.R. (eds) Molecular Analysis of DNA Rearrangements in the Immune System. Current Topics in Microbiology and Immunology, vol 217. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-50140-1_14
Download citation
DOI: https://doi.org/10.1007/978-3-642-50140-1_14
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-50142-5
Online ISBN: 978-3-642-50140-1
eBook Packages: Springer Book Archive