Genetic Plasiticity of V Genes Under Somatic Hypermutation: Statistical Analyses Using a New Resampling-Based Methodology

Evidence for somatic hypermutation of immunoglobulin genes has been observed in all the species in which immunoglobulins have been found. Previous studies have suggested that codon usage in Ig V genes is such that the sequence-specificity of somatic hypermutation results in greater mutability in complementarity-determining regions of the gene than in the framework regions. We have developed a new resampling-based methodology to explore genetic plasticity in individual V genes and in V gene families in a statistically meaningful way. We determine what factors contribute to this mutability difference, and characterize the strength of selection for this effect. We find that although the codon usage in Ig V genes renders them distinct among translationally equivalent sequences with random codon usage, they are nevertheless far from being optimal in this regard. We find that the mutability patterns in a number of species are similar to those we find for human sequences. Interestingly, sheep sequences show extremely strong mutability differences, consistent with the role of somatic hypermutation as a primary diversification in these animals. Human TCR Vbeta sequences ressemble Ig in mutability pattern, suggesting one of several alternatives: That hypermutation is functionally operating in TCR; that it was once operating in TCR or in the common precursor of TCR and Ig, or that the hypermutation mechanism has evolved to exploit the codon usage in Ig (and fortuitously, TCR) rather than vice versa.<p> <p> Appears in Genome Research9: pp. 1294-1304.