Abstract
The antibody repertoire of each individual is continuously updated by the evolutionary process of B-cell receptor (BCR) 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 dataset of BCRs. We find that the substitution process is conserved across individuals but varies significantly across gene segments. We investigate selection on BCRs 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.
Highlights
The antibody repertoire of each individual is continuously updated by the evolutionary process of B-cell receptor (BCR) mutation and selection
We investigate selection on BCRs 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
Antibodies encoded by somatically modified human B-cell receptor (BCR) genes bind a vast array of antigens, initiating an immune response or directly neutralizing their target
Summary
Antibodies encoded by somatically modified human B-cell receptor (BCR) genes bind a vast array of antigens, initiating an immune response or directly neutralizing their target. We develop modern statistical molecular evolution methods for the analysis of high-throughput B-cell sequence data, and apply them to a very deep short-read dataset of BCRs. we first apply model selection criteria to identify patterns in the single-nucleotide substitution process that occurs during affinity maturation and find that they are similar across individuals but vary significantly across gene segments. We develop the first statistical methodology and corresponding software for comprehensive per-residue selection estimates for BCRs. We leverage out-of-frame rearrangements carried along in B cells with a productively rearranged receptor on the second chromosome to estimate evolutionary rates under neutrality, avoiding difficulties encountered by previous work in differentiating between selection and motif-driven mutation. We are able to efficiently derive a per-residue map of selection on more than 15 million BCR sequences; we find that selection is dominated by negative selection with patterns that are consistent among individuals in our study
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