Immunoglobulin genes evolved plasticity for somatic hypermutation

The basic mechanism that is responsible for fine-tuning of antigen receptors has been described. It is termed affinity maturation, and it involves rounds of essentially random mutagenesis followed by selection. In chapter , I introduced a new method for analyzing the plasticity of individual immunoglobulin genes under somatic hypermutation. I showed that codon bias consistent with low framework, and high complementarity-determining region, mutability is found in individual V region genes in a variety of species. I also showed that the codon composition of the genes is a good predictor of their mutability. The methods that I introduced in this chapter can be applied both to the analysis of individual gene sequences, as well to sets of genes. These are both important issues. In somatic hypermutation experiments there is always the question of the intrinsic mutability of the gene relative to selection pressures that operate on the protein product. Also, the study of the immunoglobulin gene family is generally difficult due to the close genealogical relationship between these genes. These problems are explicitly addressed in the tests that I designed. I further analyzed the sequence specificity of the somatic hypermutation mechanism by applying it to a set of non-immunoglobulin genes. Intriguingly, I found that these genes have a codon bias consistent with low mutability under somatic hypermutation as well. This result suggests a possible connection between the somatic hypermutation mechanism and more general processes that operate throughout the genome. I provided further supporting evidence, by showing that the somatic hypermutation mechanism reveals the A/T content of the gene. That the evolutionary stability of A/T-rich nucleic acids, and the proteins they encode, is lower than their G/C-rich counterparts has already been shown, though the factors that may be responsible for it are debated.