Bibliography

Amit, A., Mariuzza, R., Phillips, S., and Poljak, R. (1986).

Three dimensional structure of an antigen-antibody complex at 2.8 $\AA$ resolution.
Science 233:747-753.

Argos, P., Rossmann, M., Grau, U., Zuber, A., Franck, G., and Tratschin, J. (1979).

Thermal stability and protein structure.
Biochemistry 18:5698-5703.

B-Rao, C. and Stewart, J. (1996).

Inverse analysis of empirical matrices of idiotypic network interactions.
Bull. Math. Biol. 58:1123-1153.

Bachl, J. and Wabl, M. (1996).

An immunoglobulin mutator that targets G.C base pairs.
Proc. Natl. Acad. Sci. USA 93:851-855.

Bartlett, M. (1978).

An introduction to stochastic processes.
Cambridge University Press, Cambridge, 3rd edition.

Beck, G. and Habicht, G. (1996).

Immunity and the invertebrates.
Sci. Am. 275:60-66.

Berek, C., Berger, A., and Apel, M. (1991).

Maturation of the immune response in the germinal centers.
Cell 67:1121-1129.

Bernard, O., Hozumi, N., and Tonegawa, S. (1978).

Sequences of mouse immunoglobulin light chain gene before and after somatic changes.
Cell 15:1133-1144.

Bernardi, G. and Bernardi, G. (1986).

Compositional constraints and genome evolution.
J. Mol. Evol. 22:363-365.

Betz, A., Rada, C., Pannell, R., Milstein, C., and Neuberger, M. (1993).

Passenger transgenes reveal intrinsic specificity of the antibody hypermutation mechanism: clustering, polarity and specific hot spots.
Proc. Natl. Acad. Sci. USA 90:2385-2388.

Bill, C., Duran, W., Miselis, N., and Nickoloff, J. (1998).

Efficient repair of all types of single-base mismatches in recombination intermediates in Chinese hamster ovary cells. Competition between long-patch and G-T glycosylase-mediated repair of G-T mismatches.
Genetics 149:1935-1943.

Brooks, R., Bennett, D., and Smith, J. (1980).

Mammalian cell cycles need two random transitions.
Cell 19:493-504.

Cairns, J., Overbaugh, J., and Miller, S. (1988).

The origin of mutants.
Nature 335:142-145.

Carneiro, J. and Stewart, J. (1994).

Rethinking "shape space": evidence from simulated docking suggests that steric shape complementarity is not limiting for antibody-antigen recognition and idiotypic interactions.
J. Theor. Biol. 169:391-402.

Cascalho, M., Wong, J., Steinberg, C., and Wabl, M. (1998).

Mismatch repair co-opted by hypermutation.
Science 279:1207-1210.

Cohn, M. and Langman, R. (1990).

The protecton: the unit of humoral immunity selected by evolution.
Immunol. Rev. 115:11-147.

Cowell, L., Kim, H., Humaljoki, T., Berek, C., and Kepler, T. (1998).

Enhanced evolvability in immunoglobulin v genes under somatic hypermutation.
J.Molec.Evol. (to appear) .

Dal Porto, J., Haberman, A., Shlomchik, M., and Kelsoe, G. (1998).

Antigen drives very low affinity B cells to become plasmacytes and enter the germinal centers.
J. Immunol. 161:5373-5381.

Davis, M., Boniface, J., Reich, Z., Lyons, D., Hampl, J., Arden, B., and Chien, Y. (1998).

Ligand recognition by $\alpha \beta$ T cell receptors.
Annu. Rev. Immunol. 16:523-544.

De Boer, R., Segel, L., and Perelson, A. (1992).

Pattern formation in one- and two-dimensional shape-space models of the immune system.
J. Theor. Biol. 155:295-333.

Derrida, B. (1984).

Random-energy model: An exactly solvable model of disordered systems.
Phys. Rev. B 24:2613-2626.

Detours, V., Bersini, H., Stewart, J., and Varela, F. (1994).

Development of an idiotypic network in shape space.
J. Theor. Biol. 170:401-414.

Diaz, M. and Flajnik, M. (1998).

Evolution of somatic hypermutation and gene conversion in adaptive immunity.
Immunol. Rev. 162:13-24.

Dörner, T., Brezinschek, H., Foster, S., Brezinschek, R., Farner, N., and Lipsky, P. (1998).

Delineation of selective influences shaping the mutated expressed human Ig heavy chain repertoire.
J. Immunol. 160:2831-2841.

Dörner, T., Brezinschek, H.-P., Foster, S., Domiati-Saad, R., and Lipsky, P. (1997).

Analysis of the frequency pattern of somatic mutations within nonproductively rearranged human variable heavy chain genes.
J. Immunol. 158:2779-2789.

Dunn-Walters, D., Dogan, A., Boursier, L., MacDonald, C., and Spencer, J. (1998).

Base-specific sequences that bias somatic hypermutation deduced by analysis of out-of-frame human IgVH genes.
J. Immunol. 160:2360-2364.

Feeney, A. (1992).

Predominance of V_H-D-J_H junctions occuring at sites of short sequence homology results in limited junctional diversity in neonatal antibodies.
J. Immunol. 149:222-229.

Fisher, R. (1930).

The genetical theory of natural selection.
Oxford University Press.

Foote, J. and Winter, G. (1992).

Antibody framework residues affecting the conformation of the hypervariable loops.
J. Mol. Biol. 224:487-499.

Frey, S., Bertocci, B., Delbos, F., Quint, L., Weill, J.-C., and Raynaud, C.-A. (1998).

Mismatch repair deficiency interferes with the accumulation of mutations in chronically stimulated B cells and not with the hypermutation process.
Immunity 9:127-134.

Gilfillan, S., Bachmann, M., Trembleau, S., Adorini, L., Kalinke, U., Zinkernagel, R., Benoist, C., and Mathis, D. (1995).

Efficient immune responses in mice lacking N-region diversity.
Eur. J. Immunol. 25:3115-3122.

Gilfillan, S., Dierich, A., Lemeur, M., Benoist, C., and Mathis, D. (1993).

Mice lacking TdT: mature animals with an immature lymphocyte repertoire.
Science 261:1175-1178.

Giudicelli, V., Chaume, D., Bodmer, J., Muller, W., Busin, C., Marsh, S., Bontrop, R., Marc, L., Malik, A., and M.P., L. (1997).

IMGT, the international ImMunoGeneTics database.
Nucleic Acids Res. 25:206-211.

Goodlad, J. and Macartney, J. (1995).

Regulation of murine germinal centre cell proliferation in vivo: A stathmokinetic study examining the effect of differently timed doses of cyclosporin A.
J. Pathol. 176:87-97.

Hanna, M. (1964).

An autoradiographic study of the germinal center in spleen white pulp during early intervals of the immune response.
Lab. Invest. 13:95-104.

Higgins, D. and Sharp, P. (1988).

CLUSTAL: a package for performing multiple sequence alignments on a microcomputer.
Gene 73:237-244.

Hightower, R. (1996).

Computational aspect of antibody gene families.
Ph.D. thesis, University of New Mexico.

Hinds-Frey, K., Nishikata, H., Litman, R., and Litman, G. (1993).

Somatic variation preceeds extensive diversification of germline sequences and combinatorial joining in the evolution of immunoglobulin heavy chain diversity.
J. Exp. Med. 178:815-824.

Hsu, E. (1998).

Mutation, selection, and memory in b lymphocytes of exothermic vertebrates.
Immunol. Rev. 162:25-36.

Huisman, G., Siegele, D., Zambrano, M., and Kolter, R. (1996).

Morphological and physiological changes during stationary phase.
In Escherichia coli and Salmonella, F. Neidhardt, ed., pp. 1672-1682. ASM Press, Washington, D.C.

Ikemura, T. (1981).

Correlation between the abundance of Escherichia coli transfer RNAs and the occurence of the respective codons in its protein genes: a proposal for a synonymous codon choice that is optimal for the E. coli translational system.
J. Mol. Evol. 151:389-409.

Ikemura, T. (1985).

Codon usage and tRNA content in unicellular and multicellular organisms.
Mol. Biol. Evol. 2:13-34.

Insel, R., Adderson, E., and Carroll, W. (1992).

The repertoire of human antibody to the Haemophilus influenzae type b capsular polysaccharide.
Int. Rev. Immunol. 9:25-42.

Insel, R. and Varade, W. (1998).

Characteristics of somatic hypermutation of human immunoglobulin genes.
Curr. Top. Microbiol. Immunol. 229:33-44.

Jacob, J., Kassir, R., and Kelsoe, G. (1991).

In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. I. The architecture and dynamics of responding cell populations.
J. Exp. Med. 173:1165-1175.

Jacob, J. and Kelsoe, G. (1992).

In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. II. A common clonal origin for periarteriolar lymphoid sheath-associated foci and germinal centers.
J. Exp. Med. 176:679-687.

Jones, M., Thomas, S., and Rogers, A. (1994).

Luria-Delbrück fluctuation experiments: design and analysis.
Genetics 136:1209-1216.

Kearney, J., Bartels, J., Hamilton, A., Lehuen, A., Solvason, N., and Vakil, M. (1992).

Development and function of the early B cell repertoire.
Intern. Rev. Immunol. 8:247-257.

Kelly, C. and Rahn, O. (1932).

The growth of individual bacterial cells.
J. Bacteriol. 23:147-153.

Kelsoe, G. (1998).

V(D)J hypermutation and DNA mismatch repair: Vexed by fixation.
Proc. Natl. Acad. Sci. USA 95:6576-6577.

Kendall, D. (1948).

On the role of variable generation time in the development of a stochastic birth process.
Biometrika 35:316-330.

Kendall, D. (1952).

Les procesus stochastiques de croissance in biologie.
Ann. Inst. H. Poincaré 13:43-108.

Kepler, T. (1997).

Codon bias and plasticity in immunoglobulins.
Mol. Biol. Evol. 14:637-643.

Kepler, T. and Bartl, S. (1998).

Plasticity under somatic mutation in antigen receptors.
Curr. Top. Microbiol. Immunol. 229:149-162.

Kepler, T. and Perelson, A. (1993).

Cyclic re-entry of germinal center B cells and the efficiency of affinity maturation.
Immunol.Today 14:412-415.

Knuth, D. (1973).

The art of computer programming, vol. 2.
Addison-Wesley Publishing Company, Inc.

Kroese, F., Wubenna, A., Seijen, H., and Nieuwenhuis, P. (1987).

Germinal centers develop oligoclonally.
Eur. J. Immunol. 17:1069-1072.

Langman, R. and Cohn, M. (1993).

Two signal models of lymphocyte activation?
Immunol. Today 14:235-237.

Lea, D. and Coulson, C. (1949).

The distribution of the number of mutants in bacterial populations.
J. Genetics 49:264-284.

Lebecque, S. and Gearhart, P. (1990).

Boundaries of somatic mutation in rearranged immunoglobulin genes: 5' boundary is near the promoter, and 3' boundary is approximately 1 kb from V(D)J gene.
J. Exp. Med. 172:1717-1727.

Lee, W., Cosenza, H., and Köhler, H. (1974).

Clonal restriction of the immune response to phosphorylcholine.
Nature 247:55-61.

Li, W.-H. (1997).

Molecular evolution.
Sinauer Associates, Inc. Sunderland Massachusetts 01375 USA.

Liu, Y. J., Zhang, J., Lane, P. J. L., Chan, E. Y.-T., and MacLennan, I. C. M. (1991).

Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens.
Eur. J. Immunol. 21:2951-2962.

Luria, S. and Delbrück, M. (1943).

Mutations of bacteria from virus sensitivity to virus resistance.
Genetics 28:491-511.

MacLennan, I. (1991).

The centre of hypermutation.
Nature 354:352-353.

MacLennan, I. C. M. (1994).

Germinal centers.
Annu. Rev. Immunol. 12:117-139.

MacLennan, I. C. M., Liu, Y. J., Olfield, S., Zhang, J., and Lane, P. J. L. (1990).

The evolution of B-cell clones.
Curr. Top. Microbiol. Immunol. 159:37-63.

MacWilliams, F. and Sloane, N. (1986).

The theory of error correcting codes.
Elsevier Science Publishers, B.V.

Matzinger, P. (1994).

Tolerance, danger and the extended family.
Annu. Rev. Immunol. 12:991-1045.

McKean, D. M., Huppi, K., Bell, M., Staudt, L., Gerhard, W., and 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.

Milstein, C., Neuberger, M., and Staden, R. (1998).

Both DNA strands of antibody genes are hypermutation targets.
Proc. Natl. Acad. Sci. USA 95:8791-8794.

Minar, N. (1994).

Suboptimal solutions in a simple GA problem and the underuse of genetic material (unpublished manuscript).
http://www.santafe.edu/$\tilde{ }$nelson/gaimmune .

Mitchell, M. (1996).

An introduction to genetic algorithms.
The MIT Press, Cambridge, Massachusetts.

Motoyama, N., Okada, H., and Azuma, T. (1991).

Somatic mutation in constant regions of mouse $\lambda_1$ light chains.
Proc. Natl. Acad. Sci. USA 88:7933-7937.

Nossal, G. (1971).

Antibodies and immunity.
Pelican Books, Ltd., Harmondsworth, Middlesex, England.

Nossal, G. (1992).

The molecular and cellular basis of affinity maturation in the antibody response.
Cell 68:1-2.

Oprea, M. and Perelson, A. (1997).

Somatic mutation leads to efficient affinity maturation when centrocytes recycle back to centroblasts.
J. Immunol. 158:5155-5162.

Perelson, A. (1989).

Immune network theory.
Immunol. Rev. 110:5-36.

Perelson, A. and Oster, G. (1979).

Theoretical studies of clonal selection: minimal antibody repertoire size and reliability of self-non-self discrimination.
J. Theor. Biol. 81:645-670.

Phung, Q., Winter, D., Cranston, A., Tarone, R., Bohr, V., Fishel, R., and Gearhart, P. (1998).

Increased hypermutation at G and C nucleotides in immunoglobulin variable genes from mice deficient in the MSH2 mismatch repair protein.
J. Exp. Med. 187:1745-1751.

Press, W., Flannery, B., Teukolsky, S., and Vetterling, W. (1988).

Numerical recipes in C.
Cambridge University Press, Cambridge.

Radmacher, M., Kelsoe, G., and Kepler, T. (1998).

Predicted and inferred waiting times for key mutations in the germinal center reaction: Evidence for stochasticity in selection.
Immunol. Cell Biol. 76:373-381.

Reynaud, C., Garcia, C., and J.C., W. (1995).

Hypermutation generating the sheep immunoglobulin repertoire is an antigen-independent process.
Cell 80:115-125.

Rogozin, I. and Kolchanov, N. (1992).

Somatic hypermutagenesis in immunoglobulin genes. II. Influence of neighboring base sequences on mutagenesis.
Biochim. Biophys. Acta 1171:11-18.

Roux, K., Greenberg, A. S., Greene, L., Strelets, L., Avila, D., McKinney, E., and Flajnik, M. (1998).

Structural analysis of the nurse shark (new) antigen receptor (NAR): Molecular convergence of NAR and unusual mammalian immunoglobulins.
Proc. Natl. Acad. Sci. USA 95:11804-11809.

Sarkar, S. A. (1992).

On fluctuation analysis: a new, simple and efficient method for computing the expected number of mutants.
Genetica 85:173-179.

Segel, L. and Perelson, A. (1989).

Shape space: an approach to the evaluation of cross-reactivity effects, stability and controllability in the immune system.
Immunol. Lett. 22:91-99.

Seidman, J., Leder, A., Edgell, M., Polsky, F., Tilghman, S., Tiemeier, D., and Leder, P. (1978).

Multiple related immunoglobulin variable region genes identified by cloning and sequence analysis.
Proc. Natl. Acad. Sci. USA 75:3881-3885.

Smith, D., Creadon, G., Jena, P., Portanova, J., Kotzin, B., and Wysocki, L. (1996).

Di- and trinucleotide target preferences in somatic mutagenesis in normal and autoreactive B cells.
J. Imunol. 156:2642-2652.

Smith, D., Forrest, S., Hightower, R., and Perelson, A. (1997).

Deriving shape space parameters from immunological data.
J. Theor. Biol. 189:141-150.

Smith, J. and Martin, L. (1973).

Do cells cycle?
Proc. Natl. Acad. Sci. USA 70:1263-1267.

Stewart, F., Gordon, D., and Levin, B. (1990).

Fluctuation analysis: the probability distribution of the number of mutants under different conditions.
Genetics 124:175-185.

Van der Stoep, N., Van der Linden, J., and Logtenberg, T. (1993).

Molecular evolution of the human immunoglobulin E response: high incidence of shared mutations and clonal relatedness among V_H5 transcripts from three unrelated patients with atopic dermatitis.
J. Exp. Med. 177:99-107.

Takahashi, Y., Dutta, P., Cerasoli, D., and Kelsoe, G. (1998).

In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. V. Affinity maturation develops in two stages of clonal selection.
J. Exp. Med. 187:885-895.

Tanaka, T. and Nei, M. (1989).

Positive Darwinian selection observed at the variable region genes of immunoglobulins.
Mol. Biol. Evol. 6:447-459.

Tew, J. and Mandel, T. (1979).

Prolonged antigen half-life in the lymphoid follicles of specifically immunized mice.
Immunology 37:69-76.

Tew, J., Mandel, T., and Miller, G. (1979).

Immune retention: immunological requirements for maintaining an easily degradable antigen in vivo.
Australian J. Exp. Biol. Med. Sci. 57:401-414.

Tonegawa, S. (1983).

Somatic generation of antibody diversity.
Nature 302:575-581.

Torkelson, J., Harris, R., Lombardo, M., Nagendran, J., Thulin, C., and Rosenberg, M. (1997).

Genome-wide hypermutation in a subpopulation of stationary-phase cells underlies recombination-dependent adaptive mutation.
EMBO J. 16:3303-3311.

Travisano, M. and Lenski, R. (1996).

Long-term experimental evolution in Escherichia coli. IV. Targets of selection and the specificity of adaptation.
Genetics 143:15-26.

Van Zoelen, E., Van Der Saag, P., and De Laat, S. (1981).

Family tree analysis of a transformed cell line and the transition probability model for the cell cycle.
Exp. Cell Res. 131:395-406.

Varade, W., Carnahan, J., Kingsley, P., and Insel, R. (1998).

Inherent properties of somatic hypermutation as revealed by human non-productive VH6 immunoglobulin rearrangements.
Immunology 93:171-176.

Varade, W., Marin, E., Kittelberger, A., and Insel, R. (1993).

Use of the most proximal J_H-proximal human Ig H chain V region gene, V_H6 in the expressed immune repertoire.
J. Immunol. 150:4985-4995.

Wagner, S., Milstein, C., and Neuberger, M. (1995).

Codon bias targets mutation.
Nature 376:732.

Weigert, M., Cesari, I., Yonkovitch, S., and Cohn, M. (1970).

Variability in the light chain sequences of mouse antibody.
Nature 228:1045-1047.

Wilson, M., Hsu, E., Marcuz, A., Courtet, L., Du Pasquier, L., and 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.

Winter, D., Phung, Q., Umar, A., Baker, S., Tarone, R., Tanaka, K., Liskay, R., Kunkel, T., Bohr, V., and Gearhart, P. (1998).

Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2.
Proc. Natl. Acad. Sci. USA 95:6953-6958.

Wolfe, K., Sharp, P., and Li, W.-H. (1989).

Mutation rates differ among regions of the mammalian genome.
Nature 337:283-285.

Wu, T. and Kabat, E. (1970).

An a analysis of the sequences of the variable regions of the Bence-Jones proteins and myeloma light chains and their implications for antibody complementarity.
J. Exp. Med. 132:211-250.

Zhang, J., MacLennan, I., Liu, Y.-J., and Lane, P. (1988).

Is rapid proliferation in B centroblasts linked to somatic mutation in memory B-cell clones?
Immunol. Lett. 18:297-299.

Zheng, B., Xue, W., and Kelsoe, G. (1994).

Locus-specific somatic hypermutation in germinal centre T cells.
Nature 372:556-559.

Zuber, H. (1981).

Structure and function of thermophilic enzymes.
In Structural and functional aspects of enzyme catalysis, H. Eggerer and R. Huber, eds., pp. 114-127. Springer-Verlag, Berlin.