Transfer of noncoding DNA drives regulatory rewiring in Bacteria

Yaara Oren, Mark B. Smith, Nathan I. Johns, Millie Kaplan Zeevi, Dvora Biran, Eliora Z. Ron, Jukka Corander, Harris H. Wang, Eric J. Alm, Tal Pupko*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Understanding the mechanisms thatgenerate variationisacommon 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 inbacteria. 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 analysisof 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.

Original languageEnglish
Pages (from-to)16112-16117
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number45
StatePublished - 11 Nov 2014


  • Bacterial evolution
  • Core genes
  • HRT
  • Regulatory evolution


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