Somatic hypermutation

Somatic hypermutation, or SHM, is an important mechanism of the immune system to generate high-affinity antibodies to defend against pathogens. With the exception of sporadic extrafollicular events, somatic hypermutation occurs mainly during the germinal center reaction of B cells. In this process, the antigen-binding domains of immunoglobulin genes are mutated at a rate of 10 ³ to 10 ⁴ mutations per base pair per generation. Because this rate is approximately one million times higher than the basal, natural mutation rate of somatic cells (McKean et al. 1984; Berek and Milstein, 1988), this phenomenon is referred to as somatichypermutation.

There are three immunoglobulin gene loci in our genome:

• the locus for the heavy chain ("Ig heavy chain"; IgH)
• the locus for the lambda light chain
• the locus for the kappa light chains ("Ig light chain"; IgLλ and IgLκ).

In order to form a functional B cell receptor, B cells in their early developmental stages must first rearrange their Ig gene segments at these loci (Janeway et al. 2005). In the course of this rearrangement, a V and a J segment are fused in the case of the light chain and a V, a D and a J gene segment are fused in the case of the heavy chain, each of which then forms a common exon (V(D)J recombination). Between the rearranged exon of the variable region and the exons of the constant region lies a long, non-coding region.

Somatic hypermutation occurs only on a relatively distinct segment of the three immunoglobulin genes. It begins approximately 150 bp downstream of the transcription initiation site of the variable region, then extends across the entire coding sequence of the rearranged V, (D) and J exons of the variable region and beyond, and ends relatively diffusely approximately 1.5 - 2 kb downstream of the transcription initiation start in the non-coding region still upstream of the intron enhancer and constant region (Rada & Milstein, 2001). The strength of the hypermutation (or the rate of hypermutation) depends on the transcription rate of the locus (Bachl et al. 2001). Ig enhancers are therefore considered essential elements for hypermutation. The mutations themselves are usually single base exchanges, with only occasional insertions and deletions (Wilson et al. 1998).

1. Bachl J et al. (2001) Increased transcription levels induce higher mutation rates in a hypermutating cell line. J Immunol 166: 5051- 5057.
2. Berek C and Milstein C (1988) The dynamic nature of the antibody repertoire. Immunol Rev 105: 5-26.
3. Janeway C et al (2005) Immunobiology: the immune system in healt and disease, 6th ed, Garland Science Publishing, New York.
4. McKean D et al (1984) Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin. Proc Natl Acad Sci U S A 81
5. Michael N et al (2003) The E box motif CAGGTG enhances somatic hypermutation without enhancing transcription. Immunity 19: 235-242
6. Rada C et al (2001) The intrinsic hypermutability of antibody heavy and light chain genes decays exponentially. Embo J 20: 4570-4576
7. Wilson PC et al (1998) Somatic hypermutation introduces insertions and deletions into immunoglobulin V genes. J Exp Med 187: 59-70