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RESEARCH PAPER

Regulatory circuit design and evolution using phage

Department of Biochemistry and Molecular Biophysics, University of Arizona, Tucson, Arizona 85721, USA

Bistable gene regulatory circuits can adopt more than one stable epigenetic state. To understand how natural circuits have this and other systems properties, several groups have designed regulatory circuits de novo. Here we describe an alternative approach. We have modified an existing bistable circuit, that of phage . With this approach, we used powerful genetic selections to identify functional circuits and selected for variants with altered behavior. The circuit involves two antagonistic repressors, CI and Cro. We replaced Cro with a module that included Lac repressor and several lac operators. Using a combinatorial approach, we isolated variants with different types of regulatory behavior. Several resembled wild-type —they could grow lytically, could form highly stable lysogens, and carried out prophage induction. Another variant could form stable lysogens in the presence of a ligand for Lac repressor but switched to the lytic state when the ligand was removed. Several isolates evolved toward a desired behavior under selective pressure. These results strongly support the idea that complex circuits can arise during the course of evolution by a combination of simpler regulatory modules. They also underscore the advantages of modifying a natural circuit as an approach to understanding circuit design, systems behavior, and circuit evolution.

[Keywords: Gene regulatory circuit; lambda phage; circuit design; Lac repressor; evolution of gene regulatory circuitry; systems behavior]

Received May 26, 2004; revised version accepted July 9, 2004.

Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1226004.

¹ Corresponding author. E-MAIL jlittle{at}u.arizona.edu; FAX (520) 621-5629.

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