Mutation hypermutability

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. 

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. 

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. 

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). 

The final stage of B cell differentiation where the BCR repertoire is shaped is the germinal centre (GC) reaction. In the T cell dependent GC reaction, the BCR is adapted for its cognate antigen by somatic hypermutation (SMH) and class switch recombination (CSR), both of which are driven by activation induced cytidine deaminase (AID). Since AID induces targeted point mutations in the CDRs of the Ig HCs and Ig LCs, this can dramatically alter the BCR affinity or even its specificity. As AID activity may also result in the formation of an autoreactive BCR, a stringent counterselection of such self-reactive B cells is required. By analysis in human of the BCR repertoire of post-GC IgG+ memory B cells, it was demonstrated that indeed new auto-reactive B cells develop by SHM whereas 20% of naive B cells is self-reactive, up to 40% of the IgG+ memory B cells expressed a true de novo created self-reactive BCR. Apparently, lack of T cell help prevents activation of these self-... 

Low, N. M., ffolliger, P. H., and Winter, G. (1996). Mimicking somatic hypermutation affinity maturation of antibodies displayed on bacteriophage using a bacterial mutator strain. J. Mol. Biol., 260, 359-368. 

In other studies, Wain-Hobson and co-workers have selected active variants of dihydrofolate reductase (DHFR, 78 a.a.) from hypermutated libraries (Martinez et al., 1996). Amino acid substitutions were found in all but six residues. Three rounds of mutation and selection led to the isolation of DHFR mutants in which 22% of the amino acids had been substituted. Finally, Palzkill and co-workers have carried out a very systematic mutagenesis of nearly all codons in /1-lactamase (Huang et al., 1996). In this case 43 out of 263 residues were found to not tolerate amino acid substitutions. For DHFR and /8-lactamase, the two enzymes that have been subjected to systematic mutagenesis of nearly every residue, the fraction of invariable residues was roughly of the same order (9% and 16%, respectively). 

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