Sequence-Intrinsic Mechanisms that Target AID Mutational Outcomes on Antibody Genes

Cell. 2015 Nov 19;163(5):1124-1137. doi: 10.1016/j.cell.2015.10.042. Epub 2015 Nov 12.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism*
  • Cytidine Deaminase / genetics*
  • Humans
  • Immunoglobulin Class Switching*
  • Mice
  • Mutation
  • Somatic Hypermutation, Immunoglobulin*
  • V(D)J Recombination*
  • beta-Globins / genetics


  • beta-Globins
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase