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

Mustonen, V., Kinney, J., Callan, C. G., Lassig, M. (August 2008) Energy-dependent fitness: a quantitative model for the evolution of yeast transcription factor binding sites. Proc Natl Acad Sci U S A, 105 (34). pp. 12376-81. ISSN 1091-6490 (Electronic)0027-8424 (Linking)

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DOI: 10.1073/pnas.0805909105


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.

Item Type: Paper
Uncontrolled Keywords: Binding Sites/ genetics Epistasis, Genetic Evolution, Molecular Fungal Proteins/ genetics Genome, Fungal Models, Genetic Mutation Quantitative Trait, Heritable Saccharomyces/genetics Selection, Genetic Stochastic Processes Thermodynamics Transcription Factors/ genetics
Subjects: evolution
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
organism description > yeast
CSHL Authors:
Communities: CSHL labs > Kinney lab
Depositing User: Matt Covey
Date: 26 August 2008
Date Deposited: 30 Apr 2015 18:52
Last Modified: 08 Nov 2017 21:03
PMCID: PMC2527919
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