Germline codon usage as an indicator of immune selection dynamics

Uri Hershberg

Laboratory Medicine and Immunobiology, Yale University School of Medicine

The form of the amino acid (AA) table, and the relationship between genotype and phenotype that it implies, are at the basis of all processes of evolution. We have developed a network view of the AA table in which every codon is a node and every edge is a mutation. We have used the measures this view generates to study the process of affinity maturation in the immune reaction. In this enclosed process of selection, B-lymphocytes triggered by a pathogen, undergo rapid mutation, proliferation and death over a short period of time. This process leads to the selection of those cells, which produce high affinity receptors to the pathogen. Due to the short time scale we expect the process to be dependent on the connectivity of the AA network.
We looked at the germline DNA of two light chain types that undergo affinity maturation, and as a control at CD8 - a light chain homologue that does not undergo it. Our results suggest three new ideas about selection: First, the traits of AA and the potential to change them are a meaningful signal for selection. Second, we found that while all light chains have evolved to generate variable progeny under high rates of mutation. Kappa and Lambda gene families differ in the extent to which they will risk their potential viability. Finally, the existence of a transition bias in mutations means that not all movements on the AA network are equal, dividing it into Transition Neighborhoods, whose codons tend to mutate into each other. We have found over expression of codons belonging to a single neighborhood. This is another method to balance viability and variability as it constrains the extent to which mutations will change the structure of the light chain.