Movements in the Amino Acid Network - Differential Changeability of Germline Sequences Provide Insight into Distinct Strategies for Germline and Somatic Variation in k and l Light Chains
Uri Hershberg (Yale University)
(April 28, 2005 10:30 AM - 11:30 AM)
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 mutation and selection, and as a control at CD8 - a light chain homologue that does not mutate. Our results suggest three new ideas about selection: First, the chemical properties shared by groups of AA (i.e. "traits") 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. k and l 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, the codons of which tend to mutate into each other. We have found an over expression of codons belonging to a single neighborhood in those regions of the light chain that contact antigen. 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.