Repertoire-wide phylogenetic models of B cell molecular evolution reveal evolutionary signatures of aging and vaccination

Significance High-affinity antibodies that protect us from infection are produced by B cells through an evolutionary process of mutation and selection during adaptive immune responses. B cell repertoire sequencing combined with phylogenetic methods has provided unprecedented potential to study B cells as an evolving population. However, phylogenetic models operate on individual lineages rather than the thousands of lineages often found in B cell repertoires. Here, we develop an evolutionary framework that incorporates B cell-specific features and combines information across lineages to characterize mutation and selection dynamics of entire repertoires. We use this technique to demonstrate evidence of age-associated changes in somatic hypermutation targeting and uncover a general trend within our datasets toward negative selection over the course of affinity maturation.
In order to produce effective antibodies, B cells undergo rapid somatic hypermutation (SHM) and selection for binding affinity to antigen via a process called affinity maturation. The similarities between this process and evolution by natural selection have led many groups to use phylogenetic methods to characterize the development of immunological memory, vaccination, and other processes that depend on affinity maturation. However, these applications are limited by the fact that most phylogenetic models are designed to be applied to individual lineages comprising genetically diverse sequences, while B cell repertoires often consist of hundreds to thousands of separate low-diversity lineages. Further, several features of affinity maturation violate important assumptions in standard phylogenetic models. Here, we introduce a hierarchical phylogenetic framework that integrates information from all lineages in a repertoire to more precisely estimate model parameters while simultaneously incorporating the unique features of SHM. We demonstrate the power of this repertoire-wide approach by characterizing previously undescribed phenomena in affinity maturation. First, we find evidence consistent with age-related changes in SHM hot-spot targeting. Second, we identify a consistent relationship between increased tree length and signs of increased negative selection, apparent in the repertoires of recently vaccinated subjects and those without any known recent infections or vaccinations. This suggests that B cell lineages shift toward negative selection over time as a general feature of affinity maturation. Our study provides a framework for undertaking repertoire-wide phylogenetic testing of SHM hypotheses and provides a means of characterizing dynamics of mutation and selection during affinity maturation.