title: Sequence-Intrinsic Mechanisms that Target AID Mutational Outcomes on Antibody Genes.
abstract: In activated B lymphocytes, AID initiates antibody variable (V) exon somatic hypermutation (SHM) for affinity maturation in germinal centers (GCs) and IgH switch (S) region DNA breaks (DSBs) for class-switch recombination (CSR). To resolve long-standing questions, we have developed an in vivo assay to study AID targeting of passenger sequences replacing a V exon. First, we find AID targets SHM hotspots within V exon and S region passengers at similar frequencies and that the normal SHM process frequently generates deletions, indicating that SHM and CSR employ the same mechanism. Second, AID mutates targets in diverse non-Ig passengers in GC B cells at levels similar to those of V exons, definitively establishing the V exon location as "privileged" for SHM. Finally, Peyer's patch GC B cells generate a reservoir of V exons that are highly mutated before selection for affinity maturation. We discuss the implications of these findings for harnessing antibody diversification mechanisms.
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine at Boston Children's Hospital, and Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Leng-Siew
authors.initials: LS
authors.lastname: Yeap
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine at Boston Children's Hospital, and Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Joyce K
authors.initials: JK
authors.lastname: Hwang
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine at Boston Children's Hospital, and Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Du
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine at Boston Children's Hospital, and Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Meyers
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine at Boston Children's Hospital, and Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Fei-Long
authors.initials: FL
authors.lastname: Meng
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine at Boston Children's Hospital, and Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Agnė
authors.initials: A
authors.lastname: Jakubauskaitė
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine at Boston Children's Hospital, and Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Mengyuan
authors.initials: M
authors.lastname: Liu
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine at Boston Children's Hospital, and Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Vinidhra
authors.initials: V
authors.lastname: Mani
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Boston, MA 02215, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Kepler
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine at Boston Children's Hospital, and Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Jing H
authors.initials: JH
authors.lastname: Wang
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine at Boston Children's Hospital, and Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: alt@enders.tch.harvard.edu.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D003564:Cytidine Deaminase / Q000235:genetics*; D006801:Humans; D017578:Immunoglobulin Class Switching; D051379:Mice; D009154:Mutation; D027041:Somatic Hypermutation, Immunoglobulin; D060152:V(D)J Recombination; D055544:beta-Globins / Q000235:genetics; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D055544:beta-Globins; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase