Energy-dependent fitness: A quantitative model for the evolution of yeast transcription factor binding sites

Ville Mustonen, Justin Kinney, Curtis Gove Callan, Michael Lässig

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


We present a genomewide cross-species analysis of regulation for broad-acting transcription factors in yeast. Our model for binding site evolution is founded on biophysics: the binding energy between transcription factor and site is a quantitative phenotype of regulatory function, and selection is given by a fitness landscape that depends on this phenotype. The model quantifies conservation, as well as loss and gain, of functional binding sites in a coherent way. Its predictions are supported by direct cross-species comparison between four yeast species. We find ubiquitous compensatory mutations within functional sites, such that the energy phenotype and the function of a site evolve in a significantly more constrained way than does its sequence. We also find evidence for substantial evolution of regulatory function involving point mutations as well as sequence insertions and deletions within binding sites. Genes lose their regulatory link to a given transcription factor at a rate similar to the neutral point mutation rate, from which we infer a moderate average fitness advantage of functional over nonfunctional sites. In a wider context, this study provides an example of inference of selection acting on a quantitative molecular trait.

Original languageEnglish (US)
Pages (from-to)12376-12381
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number34
StatePublished - Aug 26 2008

All Science Journal Classification (ASJC) codes

  • General


  • Binding energy
  • Quantitative molecular trait
  • Transcriptional regulation


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