Quantifying evolutionary constraints on B cell affinity maturation

TL;DR

This paper develops advanced statistical methods to analyze B cell receptor evolution, revealing conserved substitution processes and detailed selection patterns across gene segments using deep sequencing data.

Contribution

It introduces novel statistical tools for differentiating selection from mutation motifs in B cell evolution, applied to deep sequencing data for detailed constraint mapping.

Findings

Substitution process is conserved across individuals.

Significant variation in substitution across gene segments.

Detailed per-residue selection maps of B cell receptors.

Abstract

The antibody repertoire of each individual is continuously updated by the evolutionary process of B cell receptor mutation and selection. It has recently become possible to gain detailed information concerning this process through high-throughput sequencing. Here, we develop modern statistical molecular evolution methods for the analysis of B cell sequence data, and then apply them to a very deep short-read data set of B cell receptors. We find that the substitution process is conserved across individuals but varies significantly across gene segments. We investigate selection on B cell receptors using a novel method that side-steps the difficulties encountered by previous work in differentiating between selection and motif-driven mutation; this is done through stochastic mapping and empirical Bayes estimators that compare the evolution of in-frame and out-of-frame rearrangements. We use this new method to derive a per-residue map of selection, which provides a more nuanced view of the constraints on framework and variable regions.