title: Quantifying evolutionary constraints on B-cell affinity maturation.
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.
authors.affiliation: Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Connor O
authors.initials: CO
authors.lastname: McCoy
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Trevor
authors.identifier: http://orcid.org/0000-0002-4039-5794
authors.initials: T
authors.lastname: Bedford
authors.affiliation: Departments of Statistics and Biology, University of Washington, Seattle, WA, USA.
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Minin
authors.affiliation: Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Philip
authors.identifier: http://orcid.org/0000-0002-0224-6464
authors.initials: P
authors.lastname: Bradley
authors.affiliation: Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Harlan
authors.identifier: http://orcid.org/0000-0001-5225-7076
authors.initials: H
authors.lastname: Robins
authors.affiliation: Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA matsen@fredhutch.org.
authors.forename: Frederick A
authors.identifier: http://orcid.org/0000-0003-0607-6025
authors.initials: FA
authors.lastname: Matsen
mesh_terms: D000916:Antibody Diversity; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D001499:Bayes Theorem; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D060966:Clonal Selection, Antigen-Mediated; D003198:Computer Simulation; D019143:Evolution, Molecular; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008957:Models, Genetic; D018448:Models, Immunological; D011947:Receptors, Antigen, B-Cell / Q000235:genetics; D013269:Stochastic Processes; D060152:V(D)J Recombination
chemical_list: D011947:Receptors, Antigen, B-Cell
keywords: B cell; affinity maturation; antibody; immunoglobulin; molecular evolution; natural selection