Predicted and inferred waiting times for key mutations in the germinal centre reaction: evidence for stochasticity in selection.

Journal Article (Journal Article)

The germinal centre reaction (GCR) is a fundamental component of the immune response to T-dependent antigens, during which the immunoglobulin (Ig) genes of B cells experience somatic hypermutation and selection. A maximum-likelihood method on DNA sequence data from 16 individual germinal centres was used to infer that the waiting time for position 33 key (high-affinity) mutations in the anti-(4-hydroxy-3-nitrophenyl) acetyl (NP) response is 8.3 days. This is in marked contrast to the prediction of a key mutant each generation (waiting time about 1/3 day) obtained from a simple model and parameters available in the literature. This disagreement is resolved in part by the finding that the targeted base occurs in a cold spot for hypermutation, raising the predicted waiting time to 2.3 days, although this value remains significantly lower than that inferred from the sequence data. It is proposed that the remaining disparity is attributable to some further stochastic process in the GCR: many early key mutations arise but fail to 'take root' within the GC, either due to emigration or failure of cognate T cell/B cell interaction. Furthermore, it is argued that the frequency with which position 33 mutations are found in secondary responses to NP indicates the presence of selection after the GCR.

Full Text

Duke Authors

Cited Authors

  • Radmacher, MD; Kelsoe, G; Kepler, TB

Published Date

  • August 1998

Published In

Volume / Issue

  • 76 / 4

Start / End Page

  • 373 - 381

PubMed ID

  • 9723780

International Standard Serial Number (ISSN)

  • 0818-9641

Digital Object Identifier (DOI)

  • 10.1046/j.1440-1711.1998.00753.x


  • eng

Conference Location

  • United States