Quantifying evolutionary constraints on B-cell affinity maturation |
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Authors: | Connor O. McCoy Trevor Bedford Vladimir N. Minin Philip Bradley Harlan Robins Frederick A. Matsen IV |
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Affiliation: | 1.Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;2.Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;3.Departments of Statistics and Biology, University of Washington, Seattle, WA, USA |
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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. |
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Keywords: | B cell antibody immunoglobulin affinity maturation molecular evolution natural selection |
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