title: Global Rebalancing of Cellular Resources by Pleiotropic Point Mutations Illustrates a Multi-scale Mechanism of Adaptive Evolution.
abstract: Pleiotropic regulatory mutations affect diverse cellular processes, posing a challenge to our understanding of genotype-phenotype relationships across multiple biological scales. Adaptive laboratory evolution (ALE) allows for such mutations to be found and characterized in the context of clear selection pressures. Here, several ALE-selected single-mutation variants in RNA polymerase (RNAP) of Escherichia coli are detailed using an integrated multi-scale experimental and computational approach. While these mutations increase cellular growth rates in steady environments, they reduce tolerance to stress and environmental fluctuations. We detail structural changes in the RNAP that rewire the transcriptional machinery to rebalance proteome and energy allocation toward growth and away from several hedging and stress functions. We find that while these mutations occur in diverse locations in the RNAP, they share a common adaptive mechanism. In turn, these findings highlight the resource allocation trade-offs organisms face and suggest how the structure of the regulatory network enhances evolvability.
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, 62210 Cuernavaca, Morelos, México.
authors.forename: Jose
authors.initials: J
authors.lastname: Utrilla
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: O'Brien
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: McCloskey
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY 10027, USA.
authors.forename: Jacky
authors.initials: J
authors.lastname: Cheung
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY 10027, USA.
authors.forename: Harris
authors.initials: H
authors.lastname: Wang
authors.affiliation: Departamento de Ingeniería Celular y Biocatálisis, Instituto de Biotecnología, UNAM, 62210 Cuernavaca, Morelos, Mexico.
authors.forename: Dagoberto
authors.initials: D
authors.lastname: Armenta-Medina
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Lyngby, Denmark.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Feist
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Lyngby, Denmark; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: palsson@eng.ucsd.edu.
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Palsson
mesh_terms: D000222:Adaptation, Physiological; D005075:Biological Evolution; D012321:DNA-Directed RNA Polymerases; D004926:Escherichia coli; D029968:Escherichia coli Proteins; D019143:Evolution, Molecular; D010641:Phenotype; D017354:Point Mutation
chemical_list: D029968:Escherichia coli Proteins; D012321:DNA-Directed RNA Polymerases