title: Modulating the frequency and bias of stochastic switching to control phenotypic variation.
abstract: Mechanisms that control cell-to-cell variation in gene expression ('phenotypic variation') can determine a population's growth rate, robustness, adaptability and capacity for complex behaviours. Here we describe a general strategy (termed FABMOS) for tuning the phenotypic variation and mean expression of cell populations by modulating the frequency and bias of stochastic transitions between 'OFF' and 'ON' expression states of a genetic switch. We validated the strategy experimentally using a synthetic fim switch in Escherichia coli. Modulating the frequency of switching can generate a bimodal (low frequency) or a unimodal (high frequency) population distribution with the same mean expression. Modulating the bias as well as the frequency of switching can generate a spectrum of bimodal and unimodal distributions with the same mean expression. This remarkable control over phenotypic variation, which cannot be easily achieved with standard gene regulatory mechanisms, has many potential applications for synthetic biology, engineered microbial ecosystems and experimental evolution.
authors.affiliation: 1] Department of Integrative Biology, University of California Berkeley, 3040 Valley Life Sciences Building, Mail code 3140, Berkeley, California 94720-3140, USA [2].
authors.forename: Michelle
authors.initials: M
authors.lastname: Hung
authors.affiliation: 1] Department of Integrative Biology, University of California Berkeley, 3040 Valley Life Sciences Building, Mail code 3140, Berkeley, California 94720-3140, USA [2].
authors.forename: Emily
authors.initials: E
authors.lastname: Chang
authors.affiliation: Department of Integrative Biology, University of California Berkeley, 3040 Valley Life Sciences Building, Mail code 3140, Berkeley, California 94720-3140, USA.
authors.forename: Razika
authors.initials: R
authors.lastname: Hussein
authors.affiliation: Department of Integrative Biology, University of California Berkeley, 3040 Valley Life Sciences Building, Mail code 3140, Berkeley, California 94720-3140, USA.
authors.forename: Katya
authors.initials: K
authors.lastname: Frazier
authors.affiliation: Department of Integrative Biology, University of California Berkeley, 3040 Valley Life Sciences Building, Mail code 3140, Berkeley, California 94720-3140, USA.
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Shin
authors.affiliation: Department of Integrative Biology, University of California Berkeley, 3040 Valley Life Sciences Building, Mail code 3140, Berkeley, California 94720-3140, USA.
authors.forename: Shiori
authors.initials: S
authors.lastname: Sagawa
authors.affiliation: Department of Integrative Biology, University of California Berkeley, 3040 Valley Life Sciences Building, Mail code 3140, Berkeley, California 94720-3140, USA.
authors.forename: Han N
authors.initials: HN
authors.lastname: Lim
mesh_terms: D003198:Computer Simulation; D004926:Escherichia coli / Q000235:genetics* / Q000378:metabolism; D010861:Fimbriae, Bacterial / Q000235:genetics* / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D005809:Genes, Regulator; D005838:Genotype; D008957:Models, Genetic; D010641:Phenotype; D013269:Stochastic Processes