Complementary base pairing and the origin of substitution mutations

Nature. 1976 Sep 23;263(5575):285-9. doi: 10.1038/263285a0.


On the basis of chemical considerations and model building, the Watson-Crick concept of complementary base pairing is extended to a wider range of DNA pairs that A-T and G-C (including A-C, G-T, A-A, G-G and G-A) by invoking imino or enol tautomers (or protonated species) and synisomers. The virtual absence of these additional base pairs from DNA is explained in terms of the low frequency with which these unfavoured forms occur and the two-step mechanism of DNA synthesis, whereby residues are first incorporated by the DNA polymerase and then checked. This base-pairing hypothesis is used to explain the origin, nature and level of spontaneous substitution mutations, their enhancement by base analogues, and the unique effects of certain mutator alleles.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 2-Aminopurine / metabolism
  • Bromodeoxyuridine / metabolism
  • Chemical Phenomena
  • Chemistry
  • DNA Nucleotidyltransferases / metabolism
  • DNA Replication
  • DNA*
  • Exonucleases / metabolism
  • Hydrogen Bonding
  • Models, Biological*
  • Mutation*
  • Templates, Genetic


  • 2-Aminopurine
  • DNA
  • DNA Nucleotidyltransferases
  • Exonucleases
  • Bromodeoxyuridine