Intricate targeting of immunoglobulin somatic hypermutation maximizes the efficiency of affinity maturation. Academic Article uri icon

Overview

abstract

  • It is believed that immunoglobulin-variable region gene (IgV) somatic hypermutation (SHM) is initiated by activation-induced cytidine deaminase (AID) upon deamination of cytidine to deoxyuracil. Patch-excision repair of these lesions involving error prone DNA polymerases such as poleta causes mutations at all base positions. If not repaired, the deaminated nucleotides on the coding and noncoding strands result in C-to-T and G-to-A exchanges, respectively. Herein it is reported that IgV gene evolution has been considerably influenced by the need to accommodate extensive C deaminations and the resulting accumulation of C-to-T and G-to-A exchanges. Although seemingly counterintuitive, the precise placement of C and G nucleotides causes most C-to-T and G-to-A mutations to be silent or conservative. We hypothesize that without intricate positioning of C and G nucleotides the efficiency of affinity maturation would be significantly reduced due to a dominance of replacements caused by C and G transition mutations. The complexity of these evolved biases in codon use are compounded by the precise concomitant hotspot/coldspot targeting of AID activity and Poleta errors to maximize SHM in the CDRs and minimize mutations in the FWRs.

publication date

  • May 2, 2005

Research

keywords

  • B-Lymphocytes
  • Codon
  • Cytosine Deaminase
  • DNA Repair
  • Evolution, Molecular
  • Immunoglobulin Variable Region
  • Mutation
  • Somatic Hypermutation, Immunoglobulin

Identity

PubMed Central ID

  • PMC2213188

Scopus Document Identifier

  • 18644366944

Digital Object Identifier (DOI)

  • 10.1084/jem.20042483

PubMed ID

  • 15867095

Additional Document Info

volume

  • 201

issue

  • 9