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Related Experiment Video

Updated: Oct 5, 2025

Analysis of Somatic Hypermutation in the JH4 intron of Germinal Center B cells from Mouse Peyer's Patches
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Tandem Substitutions in Somatic Hypermutation.

Julieta H Sepúlveda-Yáñez1,2, Diego Alvarez Saravia2, Bas Pilzecker3,4

  • 1Department of Hematology, Leiden University Medical Center, Leiden, Netherlands.

Frontiers in Immunology
|January 24, 2022
PubMed
Summary
This summary is machine-generated.

Activation-induced deaminase (AID) drives B-cell receptor affinity maturation via somatic hypermutation (SHM). This study reveals tandem substitutions, a distinct SHM type, occur at 5.7% of AID-induced mutations, potentially enhancing immune response.

Keywords:
apyrimidinic sitestrand slippagetandem dinucleotide substitutions (TDNS)tandem substitutiontranslesion synthesis (TLS)uracil-N-glycosylase (UNG)

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Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • B-cell receptor affinity maturation is crucial for adaptive immunity.
  • Somatic hypermutation (SHM), initiated by activation-induced deaminase (AID), introduces genetic diversity.
  • While single nucleotide substitutions are common in SHM, the occurrence and mechanisms of tandem substitutions were unclear.

Purpose of the Study:

  • To investigate the incidence and sequence context of tandem substitutions during SHM.
  • To elucidate the molecular mechanisms underlying tandem substitution generation.
  • To understand the potential role of tandem substitutions in B-cell receptor evolution and immune response.

Main Methods:

  • Massive parallel sequencing of V(D)J repertoires from healthy human donors.
  • Analysis of mutation patterns to identify and characterize tandem substitutions.
  • Comparison of observed mutation patterns with known SHM pathways.

Main Results:

  • Tandem substitutions constitute 5.7% of AID-induced mutations.
  • Mutation patterns indicate initiation of tandem substitutions by AID.
  • A proposed model suggests translesion synthesis across apyrimidinic sites, followed by strand decontraction and repair, predominantly generates tandem substitutions.

Conclusions:

  • Tandem substitutions are a significant, albeit less common, outcome of AID activity during SHM.
  • The proposed mechanism involving translesion synthesis and DNA repair pathways explains tandem substitution formation.
  • Tandem substitutions may contribute to B-cell receptor diversification by altering adjacent amino acid residues, potentially accelerating adaptive immune responses.