title: Transfer of noncoding DNA drives regulatory rewiring in bacteria.
abstract: Understanding the mechanisms that generate variation is a common pursuit unifying the life sciences. Bacteria represent an especially striking puzzle, because closely related strains possess radically different metabolic and ecological capabilities. Differences in protein repertoire arising from gene transfer are currently considered the primary mechanism underlying phenotypic plasticity in bacteria. Although bacterial coding plasticity has been extensively studied in previous decades, little is known about the role that regulatory plasticity plays in bacterial evolution. Here, we show that bacterial genes can rapidly shift between multiple regulatory modes by acquiring functionally divergent nonhomologous promoter regions. Through analysis of 270,000 regulatory regions across 247 genomes, we demonstrate that regulatory "switching" to nonhomologous alternatives is ubiquitous, occurring across the bacterial domain. Using comparative transcriptomics, we show that at least 16% of the expression divergence between Escherichia coli strains can be explained by this regulatory switching. Further, using an oligonucleotide regulatory library, we establish that switching affects bacterial promoter architecture. We provide evidence that regulatory switching can occur through horizontal regulatory transfer, which allows regulatory regions to move across strains, and even genera, independently from the genes they regulate. Finally, by experimentally characterizing the fitness effect of a regulatory transfer on a pathogenic E. coli strain, we demonstrate that regulatory switching elicits important phenotypic consequences. Taken together, our findings expose previously unappreciated regulatory plasticity in bacteria and provide a gateway for understanding bacterial phenotypic variation and adaptation.
authors.affiliation: Departments of Cell Research and Immunology and.
authors.forename: Yaara
authors.initials: Y
authors.lastname: Oren
authors.affiliation: Microbiology Graduate Program and.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Smith
authors.affiliation: Department of Systems Biology, Columbia University Medical Center, New York, NY 10032;
authors.forename: Nathan I
authors.initials: NI
authors.lastname: Johns
authors.affiliation: Departments of Cell Research and Immunology and.
authors.forename: Millie
authors.initials: M
authors.lastname: Kaplan Zeevi
authors.affiliation: Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel;
authors.forename: Dvora
authors.initials: D
authors.lastname: Biran
authors.affiliation: Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel; MIGAL, Galilee Research Institute, Kiryat Shmona 11016, Israel; and.
authors.forename: Eliora Z
authors.initials: EZ
authors.lastname: Ron
authors.affiliation: Department of Mathematics and Statistics, University of Helsinki, Helsinki, FIN-00014, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Corander
authors.affiliation: Department of Systems Biology, Columbia University Medical Center, New York, NY 10032;
authors.forename: Harris H
authors.identifier: http://orcid.org/0000-0003-2164-4318
authors.initials: HH
authors.lastname: Wang
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; ejalm@mit.edu talp@post.tau.ac.il.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Alm
authors.affiliation: Departments of Cell Research and Immunology and ejalm@mit.edu talp@post.tau.ac.il.
authors.forename: Tal
authors.initials: T
authors.lastname: Pupko
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D004269:DNA, Bacterial / Q000235:genetics* / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics* / Q000378:metabolism; D016680:Genome, Bacterial / Q000502:physiology*; D012045:Regulatory Sequences, Nucleic Acid / Q000502:physiology*; D013045:Species Specificity
chemical_list: D004269:DNA, Bacterial
keywords: HRT; bacterial evolution; core genes; regulatory evolution