Hypermutation

Somatic hypermutation High frequency of mutation that occurs in the gene segments encoding the variable regions of antibodies during the differentiation of B lymphocytes into antibody-producing plasma cells. 

Wang L, Jackson WC, Steinbach PA, Tsien RY (2004) Evolution of new nonantibody proteins via iterative somatic hypermutation. Proc Natl Acad Sci USA 101 16745-16749... 

Buard.J., andVergnaud, G. (1994). Complex recombination events at the hypermutable minisatellite CEB1 (D2S90). EMBO J. 13, 3203-3210. 

The mechanism of strand-directed mismatch correction has been demonstrated in E. coli (see, e.g., Wagner and Meselson, 1976). In this organism, adenine methyla-tion of d(G-A-T-C) sequences determines the strand on which repair occurs. Thus, parental DNA is fully methylated, while newly synthesized DNA is undermethylated, for a period sufficient for mismatch correction. By this means the organism preserves the presumed correct sequence, i.e., that present on the original DNA strand, and removes the aberrant base on the newly synthesized strand. Adenine methylation is achieved in E. coli by the dam methylase, which is dependent on S-adenosylmethionine. Mutants (dam) lacking this methylase are hypermutable, as would be expected by this model (Marinus and Morris, 1974). 

Somatic hypermutation Mutations occurring in the variable region genes of the light and heavy chains during the formation of memory B cells. Those B cells whose affinity is increased by such mutations are positively selected by interaction with antigen, and this leads to an increase in the average affinity of the antibodies produced. 

As compared to DCs, B cells are very poor APCs and play a major role as source for antibodies. Upon stimulation by antigens and in the presence of T cells at the border of the T-cell-B-cell area, adjacent to follicles, B cells become antibody-secreting cells and eventually form a germinal center (GC) response. GCs are specialized follicles for B-cell expansion, somatic hypermutation, and class switch recombination, processes that are regulated by T cells, follicular DCs, and other cells. In this process of B-cell maturation, Tregs seem to play a critical role, as in several immune diseases, which are characterized by aberrant antibody... 

With one exception, all the mechanisms used by B cells to generate antibody diversity are also used by T cells to generate T-cell receptor diversity. The one mechanism that does not appear to operate in T-cell receptor diversification is somatic hypermutation. This is presumably because mutation would be likely to generate killer T cells that would wantonly attack self-molecules. This is much less of a problem for B cells, since most self-reactive B cells could not be activated without the aid of specific helper T cells. 

Somatic Hypermutation in Clonally Related B Cell Products Changes in Antibody Affinity... 

The molecular mechanism of somatic hypermutation is not yet understood, nor have the enzyme(s) involved been identified. Nevertheless, a considerable amount of descriptive information about the process has accumulated (see reviews by Milstein and Neuberger, 1996 Storb, 1996). 

Observations that the 5 end of the mutation domain is near the transcriptional promoter stimulated speculation that the initiation of transcription is in some way involved in the generation of mutations. Betz et al. (1994) showed that the two transcriptional enhancer elements in the K locus, one in the JC intron and the other 9 kb 3 to CK, are important for effective hypermutation. The intron enhancer appeared to be absolutely required, whereas deletion of the 3 enhancer reduced but did not abolish mutation. The promoter 5 of the VK transcription start site (Falkner and Zachau, 1984 Parslow et al., 1984) was replaced by the human P-globin promoter without deleterious effect on mutation, indicating that specific promoter elements may not be required. Heavy chain transgenes with a heterologous promoter can also undergo mutation (Tumas-Brundage and Manser, 1997). 

Somatic hypermutation has been studied in detail in mice and humans, but no doubt operates in a similar fashion in a variety of other species, modifying the repertoire that is initially established by V(D)J recombination before the introduction of antigen. In the case of V regions of K light chains in sheep, somatic hypermutation also contributes toward the generation of the preimmune repertoire in an antigen-independent process (Reynaud et al., 1991, 1995). 

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