title: Comparison of the theoretical and real-world evolutionary potential of a genetic circuit.
abstract: With the development of next-generation sequencing technologies, many large scale experimental efforts aim to map genotypic variability among individuals. This natural variability in populations fuels many fundamental biological processes, ranging from evolutionary adaptation and speciation to the spread of genetic diseases and drug resistance. An interesting and important component of this variability is present within the regulatory regions of genes. As these regions evolve, accumulated mutations lead to modulation of gene expression, which may have consequences for the phenotype. A simple model system where the link between genetic variability, gene regulation and function can be studied in detail is missing. In this article we develop a model to explore how the sequence of the wild-type lac promoter dictates the fold-change in gene expression. The model combines single-base pair resolution maps of transcription factor and RNA polymerase binding energies with a comprehensive thermodynamic model of gene regulation. The model was validated by predicting and then measuring the variability of lac operon regulation in a collection of natural isolates. We then implement the model to analyze the sensitivity of the promoter sequence to the regulatory output, and predict the potential for regulation to evolve due to point mutations in the promoter region.
authors.affiliation: Ingenieria Biotecnologica, Instituto Politecnico Nacional, Av Mineral de Valenciana No 200 Col Fracc Industrial Puerto Interior, Silao de la Victoria, Guanajuato, 36275, Mexico. Department of Applied Physics, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.
authors.forename: M
authors.initials: M
authors.lastname: Razo-Mejia
authors.forename: J Q
authors.initials: JQ
authors.lastname: Boedicker
authors.forename: D
authors.initials: D
authors.lastname: Jones
authors.forename: A
authors.initials: A
authors.lastname: DeLuna
authors.forename: J B
authors.initials: JB
authors.lastname: Kinney
authors.forename: R
authors.initials: R
authors.lastname: Phillips
mesh_terms: D005075:Biological Evolution; D012321:DNA-Directed RNA Polymerases / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics*; D015964:Gene Expression Regulation, Bacterial; D014644:Genetic Variation; D007763:Lac Operon; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D013816:Thermodynamics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D014157:Transcription Factors; D012321:DNA-Directed RNA Polymerases