Negative feedback in genetic circuits confers evolutionary resilience and capacitance

Cell Rep. 2014 Jun 26;7(6):1789-95. doi: 10.1016/j.celrep.2014.05.018. Epub 2014 Jun 5.


Natural selection for specific functions places limits upon the amino acid substitutions a protein can accept. Mechanisms that expand the range of tolerable amino acid substitutions include chaperones that can rescue destabilized proteins and additional stability-enhancing substitutions. Here, we present an alternative mechanism that is simple and uses a frequently encountered network motif. Computational and experimental evidence shows that the self-correcting, negative-feedback gene regulation motif increases repressor expression in response to deleterious mutations and thereby precisely restores repression of a target gene. Furthermore, this ability to rescue repressor function is observable across the Eubacteria kingdom through the greater accumulation of amino acid substitutions in negative-feedback transcription factors compared to genes they control. We propose that negative feedback represents a self-contained genetic canalization mechanism that preserves phenotype while permitting access to a wider range of functional genotypes.

Publication types

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

MeSH terms

  • Amino Acid Substitution*
  • Bacterial Proteins / genetics
  • Biological Evolution*
  • Feedback
  • Gene Expression Regulation*
  • Models, Genetic
  • Selection, Genetic
  • Serine Endopeptidases / genetics


  • Bacterial Proteins
  • LexA protein, Bacteria
  • Serine Endopeptidases