Codon bias and plasticity in immunoglobulins

Abstract

Immunoglobulin genes experience Darwinian evolution twice. In addition to the germline evolution all genes experience, immunoglobulins are subjected, upon exposure to antigen, to somatic hypermutation. This is accompanied by selection for high affinity to the eliciting antigen and frequently results in a significant increase in the specificity of the responding population. The hypermutation mechanism displays a strong sequence specificity. Thus arises the opportunity to manipulate codon bias in a site-specific manner so as to direct hypermutation to those parts of the gene that encode the antigen-binding portions of the molecule and away from those that encode the structurally conserved regions. This segregation of mutability would clearly be advantageous; it would enhance the generation of potentially useful variants while keeping mutational loss to acceptably low levels. But it is not clear that the advantage gained would be large enough to produce a measurable effect within the background stochasticity of the evolutionary process. I have performed a pair of statistical tests to determine whether site-specific codon bias in human immunoglobulin genes is correlated with the sequence specificity of the somatic mutation mechanism. The sequence specificity of the mutator was determined by analysis of a database of published immunoglobulin intron sequences that had experienced somatic mutation but not selection. The site-specific codon bias was determined by analysis of published sequences of human germline immunoglobulin V genes. Both tests strongly suggest that evolution has acted to enhance the plasticity of immunoglobulin genes under somatic hypermutation.

Evolution of Ig DNA Sequence to Target Specific Base Positions Within Codons for Somatic Hypermutation

“…In calculating the mutability of a given base in a V codon, we averaged its mutability in all three triplet reading frames, thus taking into account the three triplets that encompass a given nucleotide. This contrasts with earlier analyses (36,38) that only considered the translational reading frame despite no evidence supporting a coincidental mutational reading frame. The example calculation in Fig.…”

The Nucleotide-Replacement Spectrum Under Somatic Hypermutation Exhibits Microsequence Dependence That Is Strand-Symmetric and Distinct from That Under Germline Mutation

“…Codon bias differs between framework and complementarity-determining regions, with the result that the framework nucleotides are less mutable than those in the complementarity-determining regions (5)(6)(7). Direct counting of mutations accumulated in nonproductively rearranged Ig genes confirms that this difference hypothesized under relatively simple empirical models for mutability is indeed realized in a significant and observable way (8).…”

Genetic Plasticity ofVGenes Under Somatic Hypermutation: Statistical Analyses Using a New Resampling-Based Methodology

“…That CDR are inherently more susceptible to (somatic) mutations has been suggested by various authors (Motoyama et al 1991;Varade et al 1993), and later supported by statistical evidence (Wagner et al 1995;Kepler 1997;Dörner et al 1998;Cowell et al 1999). In this study, we develop a novel resamplingbased methodology and use it to analyze several aspects of this genetic plasticity.…”