title: The mutation patterns in B-cell immunoglobulin receptors reflect the influence of selection acting at multiple time-scales.
abstract: During the several-week course of an immune response, B cells undergo a process of clonal expansion, somatic hypermutation of the immunoglobulin (Ig) genes and affinity-dependent selection. Over a lifetime, each B cell may participate in multiple rounds of affinity maturation as part of different immune responses. These two time-scales for selection are apparent in the structure of B-cell lineage trees, which often contain a 'trunk' consisting of mutations that are shared across all members of a clone, and several branches that form a 'canopy' consisting of mutations that are shared by a subset of clone members. The influence of affinity maturation on the B-cell population can be inferred by analysing the pattern of somatic mutations in the Ig. While global analysis of mutation patterns has shown evidence of strong selection pressures shaping the B-cell population, the effect of different time-scales of selection and diversification has not yet been studied. Analysis of B cells from blood samples of three healthy individuals identifies a range of clone sizes with lineage trees that can contain long trunks and canopies indicating the significant diversity introduced by the affinity maturation process. We here show that observed mutation patterns in the framework regions (FWRs) are determined by an almost purely purifying selection on both short and long time-scales. By contrast, complementarity determining regions (CDRs) are affected by a combination of purifying and antigen-driven positive selection on the short term, which leads to a net positive selection in the long term. In both the FWRs and CDRs, long-term selection is strongly dependent on the heavy chain variable gene family.
authors.affiliation: Bioengineering Program, Faculty of Engineering, Bar-Ilan University, Ramat Gan 5290002, Israel.
authors.forename: Gur
authors.initials: G
authors.lastname: Yaari
authors.affiliation: Department of Mathematics, Bar-Ilan University, Ramat Gan 5290002, Israel.
authors.forename: Jennifer I C
authors.initials: JI
authors.lastname: Benichou
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06511, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Vander Heiden
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06511, USA Departments of Pathology and Immunobiology, Yale School of Medicine, New Haven, CT 06511, USA steven.kleinstein@yale.edu.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Kleinstein
authors.affiliation: Department of Mathematics, Bar-Ilan University, Ramat Gan 5290002, Israel Gonda Brain Research Center, Bar-Ilan University, Ramat Gan 5290002, Israel louzouy@math.biu.ac.il.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Louzoun
mesh_terms: D000915:Antibody Affinity / Q000235:genetics; D000916:Antibody Diversity; D001402:B-Lymphocytes / Q000276:immunology*; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D060966:Clonal Selection, Antigen-Mediated; D022801:Complementarity Determining Regions; D005803:Genes, Immunoglobulin; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D008957:Models, Genetic; D018448:Models, Immunological; D009154:Mutation; D011947:Receptors, Antigen, B-Cell / Q000235:genetics*; D027041:Somatic Hypermutation, Immunoglobulin; D013997:Time Factors
chemical_list: D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell
keywords: B-cell receptor; affinity maturation; antigen-driven selection; lineage trees; mutations; next generation sequencing