Testing the reverse transcriptase model of somatic mutation

Stephen Z. Sack, Philip D. Bardwell, Matthew D. Scharff

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Somatic hypermutation of the variable (V) regions of rearranged immunoglobulin genes leads to antibody affinity maturation. Although this process has been extensively studied, the mechanisms responsible for these multiple point mutations are still elusive. One mechanism that was proposed over 10 years ago by Steele and Pollard was that an intrinsic reverse transcriptase (RT) copies the nascent mRNA creating the large number of observed point mutations due to its high error rate. A cDNA copy of the mutated V region would then replace the endogenous DNA through a gene conversion-like event, thus integrating these point mutations into the genome. This model of hypermutation would account for the very high mutation rate, the presence of hotspots, strand bias, the requirement for transcription and localization of mutation within the immunoglobulin V region. Using AZT and ddC to inhibit endogenous RTs, we have assayed for somatic mutation using a murine in vivo model. Somatic mutation occurred at similar frequencies and with the same characteristics with or without treatment of RT inhibitors, suggesting that standard reverse transcription is not required for antibody V region hypermutation in the mouse.

Original languageEnglish (US)
Pages (from-to)303-311
Number of pages9
JournalMolecular Immunology
Volume38
Issue number4
DOIs
StatePublished - 2001

Fingerprint

RNA-Directed DNA Polymerase
Point Mutation
Mutation
Immunoglobulin Variable Region
Gene Conversion
Immunoglobulin Genes
Reverse Transcriptase Inhibitors
Antibody Affinity
Mutation Rate
Reverse Transcription
Complementary DNA
Genome
Messenger RNA
Antibodies
DNA

Keywords

  • Antibodies
  • B lymphocytes
  • Generation of diversity
  • MRNA

ASJC Scopus subject areas

  • Molecular Biology
  • Immunology

Cite this

Testing the reverse transcriptase model of somatic mutation. / Sack, Stephen Z.; Bardwell, Philip D.; Scharff, Matthew D.

In: Molecular Immunology, Vol. 38, No. 4, 2001, p. 303-311.

Research output: Contribution to journalArticle

Sack, Stephen Z. ; Bardwell, Philip D. ; Scharff, Matthew D. / Testing the reverse transcriptase model of somatic mutation. In: Molecular Immunology. 2001 ; Vol. 38, No. 4. pp. 303-311.
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