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Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):16112-7. doi: 10.1073/pnas.1413272111. Epub 2014 Oct 13.

Transfer of noncoding DNA drives regulatory rewiring in bacteria.

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Departments of Cell Research and Immunology and.
Microbiology Graduate Program and.
Department of Systems Biology, Columbia University Medical Center, New York, NY 10032;
Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel;
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.
Department of Mathematics and Statistics, University of Helsinki, Helsinki, FIN-00014, Finland.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;
Departments of Cell Research and Immunology and


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.


HRT; bacterial evolution; core genes; regulatory evolution

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