Tracing Antibody Repertoire Evolution by Systems Phylogeny

Abstract

Antibody evolution studies have been traditionally limited to either tracing a single clonal lineage (B cells derived from a single V-(D)-J recombination) over time or examining bulk functionality changes (e.g., tracing serum polyclonal antibody proteins). Studying a single B cell disregards the majority of the humoral immune response, whereas bulk functional studies lack the necessary resolution to analyze the co-existing clonal diversity. Recent advances in high-throughput sequencing (HTS) technologies and bioinformatics have made it possible to examine multiple co-evolving antibody monoclonal lineages within the context of a single repertoire. A plethora of accompanying methods and tools have been introduced in hopes of better understanding how pathogen presence dictates the global evolution of the antibody repertoire. Here, we provide a comprehensive summary of the tremendous progress of this newly emerging field of systems phylogeny of antibody responses. We present an overview encompassing the historical developments of repertoire phylogenetics, state-of-the-art tools, and an outlook on the future directions of this fast-advancing and promising field.

Keywords: B cell evolution; Ig-Seq; antibody lineage; phylogenetics; systems immunology.

Figure 1

Evolutionary dynamics of the Germinal center reaction. (A) Naïve and memory B cells are recruited into germinal center reactions where they undergo subsequent rounds of somatic hypermutation in the dark zone and selection via follicular dendritic cells in the light zone. This leads to successive rounds of division and mutations (shown by colored antibody receptors) or apoptosis (shown by gray cells). Different selection pressures can lead to either balanced selection, in which multiple independent clones expand and undergo SHM, or imbalanced selection where a few clones dominate the GC reaction and undergo many rounds of SHM. (B) Ig-Seq can capture the sequence diversity within populations of B cells. Systems phylogeny aims to assign the recovered sequences into clonal families, followed by the inference of evolutionary histories. The resulting phylogenetic trees can then be compared both within one host and between hosts.

Figure 2

Tree topologies for B cells. (A) The inclusion of polytomies in the phylogenetic tree allows a B cell to produce more than two distinct offspring at a given internal node. (B) Experimentally recovered sequences can be inferred as either internal nodes or tips in the phylogenetic tree. (C) Persisting ancestral sequences can be sampled at multiple time points while also producing distinct offspring. (D) Clonal frequencies have often been illustrated by the size of the nodes. Therefore, information regarding clonal expansion can be incorporated into the resulting topologies.