Non-immunoglobulin genes would have low mutability under somatic hypermutation

As mentioned in the previous chapter, the nature of the somatic hypermutation mechanism is not known. Attempts to show the involvement of mismatch repair mechanisms, that is, the mechanisms that recognize and repair base pairs other than Watson-Crick A-T and G-C, in this process led to ambiguous results (). There is a sense though, that an error-prone polymerase might be involved (1998), or, more generally, that normally expressed gene products have been recruited in the somatic hypermutation mechanism (1998). In order to test the involvement of these general mutation/repair mechanisms in somatic hypermutation, I stated the following hypothesis. If both:

• more general mutation/repair mechanisms have been recruited for somatic hypermutation, and
• genes tend to evolve mutational robustness (Wagner, 1999, and E. van Nimwegen, personal communication, 1999)

then I might be able to detect optimization features with respect to the somatic mutator in non-immunoglobulin genes. Concretely, in light of my previous results, I would expect to detect codon usage bias consistent with low mutability in non-immunoglobulin genes.

In the following sections I will show that such codon bias is indeed present in a large fraction of the non-immunoglobulin sequences that I analyzed. It is not a random codon bias that the somatic hypermutation mechanism happens to reveal; none of 100 other codon biases that I analyzed produced as many sequences with very low mutability as the codon bias present in the genome. If non-immunoglobulin genes were to undergo somatic hypermutation, they would generally have a low propensity to mutate. A striking finding is that their mutability would be correlated with the A and T nucleotide composition, and that this correlation is not entirely observable in the mutability model that I used. This finding may be a small step towards revealing the nature of the somatic hypermutation mechanism, that virtually every laboratory that studies somatic mutation is trying to identify.