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Comparison of the theoretical and real-world evolutionary potential of a genetic circuit

Razo-Mejia, M. and Boedicker, J. Q. and Jones, D. and DeLuna, A. and Kinney, J. B. and Phillips, R. (2014) Comparison of the theoretical and real-world evolutionary potential of a genetic circuit. Physical Biology, 11 (2). Art. No. 026005. ISSN 1478-3967. PMCID PMC4051709. https://resolver.caltech.edu/CaltechAUTHORS:20140509-111341446

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1088/1478-3975/11/2/026005 DOIArticle
http://iopscience.iop.org/1478-3975/11/2/026005/PublisherArticle
http://iopscience.iop.org/1478-3975/11/2/026005/mediaPublisherSupplementary material
http://dx.doi.org/10.1101/003772DOISubmitted Article
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051709/PubMed CentralArticle
Additional Information:© 2014 IOP Publishing Ltd. Received 7 November 2013, revised 19 February 2014; Accepted for publication 5 March 2014; Published 1 April 2014. We would like to acknowledge Ron Milo, Niv Antonovsky, Adrian Jinich, Sushant Sundaresh, Joanna Robaszewski and Hernan Garcia for useful discussions. We are grateful to Valeria Souza (UNAM) for her kind donation of the E. coli strains. This work was supported by the National Institutes of Health, grant numbers DP1 OD000217A (Directors Pioneer Award), R01 GM085286 and R01 GM085286B (www.nih.gov). This work was also supported by the Donna and Benjamin M Rosen Center for Bioengineering at Caltech. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funders:
Funding AgencyGrant Number
NIHDP1 OD000217A
NIHR01 GM085286
NIHR01 GM085286B
Donna and Benjamin M. Rosen Center for BioengineeringUNSPECIFIED
Subject Keywords:thermodynamic models; lac operon; evolutionary potential; transcriptional regulation; natural variability
Issue or Number:2
Classification Code:PACS: 87.10.-e; 87.85.Xd; 87.15.Cc; 87.14.G-; 87.15.B-
PubMed Central ID:PMC4051709
Record Number:CaltechAUTHORS:20140509-111341446
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20140509-111341446
Official Citation:Comparison of the theoretical and real-world evolutionary potential of a genetic circuit M Razo-Mejia et al 2014 Phys. Biol. 11 026005
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:45641
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:09 May 2014 19:21
Last Modified:03 Oct 2019 06:33

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