Coevolution within and between regulatory loci can preserve promoter function despite evolutionary rate acceleration

PLoS Genet. 2012 Sep;8(9):e1002961. doi: 10.1371/journal.pgen.1002961. Epub 2012 Sep 20.


Phenotypes that appear to be conserved could be maintained not only by strong purifying selection on the underlying genetic systems, but also by stabilizing selection acting via compensatory mutations with balanced effects. Such coevolution has been invoked to explain experimental results, but has rarely been the focus of study. Conserved expression driven by the unc-47 promoters of Caenorhabditis elegans and C. briggsae persists despite divergence within a cis-regulatory element and between this element and the trans-regulatory environment. Compensatory changes in cis and trans are revealed when these promoters are used to drive expression in the other species. Functional changes in the C. briggsae promoter, which has experienced accelerated sequence evolution, did not lead to alteration of gene expression in its endogenous environment. Coevolution among promoter elements suggests that complex epistatic interactions within cis-regulatory elements may facilitate their divergence. Our results offer a detailed picture of regulatory evolution in which subtle, lineage-specific, and compensatory modifications of interacting cis and trans regulators together maintain conserved gene expression patterns.

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 Sequence
  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans Proteins* / genetics
  • Caenorhabditis elegans Proteins* / metabolism
  • Conserved Sequence / genetics
  • Epistasis, Genetic
  • Evolution, Molecular*
  • Gene Expression Regulation / genetics
  • Molecular Sequence Data
  • Promoter Regions, Genetic*
  • Regulatory Sequences, Nucleic Acid / genetics*
  • Species Specificity
  • Vesicular Inhibitory Amino Acid Transport Proteins* / genetics
  • Vesicular Inhibitory Amino Acid Transport Proteins* / metabolism


  • Caenorhabditis elegans Proteins
  • Vesicular Inhibitory Amino Acid Transport Proteins
  • unc-47 protein, C elegans