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Sequence tolerance of the phage lambda PRM promoter: implications for evolution of gene regulatory circuitry.

ABSTRACT: Much of the gene regulatory circuitry of phage lambda centers on a complex region called the O(R) region. This approximately 100-bp region is densely packed with regulatory sites, including two promoters and three repressor-binding sites. The dense packing of this region is likely to impose severe constraints on its ability to change during evolution, raising the question of how the specific arrangement of sites and their exact sequences could evolve to their present form. Here we ask whether the sequence of a cis-acting site can be widely varied while retaining its function; if it can, evolution could proceed by a larger number of paths. To help address this question, we developed a lambda cloning vector that allowed us to clone fragments spanning the O(R) region. By using this vector, we carried out intensive mutagenesis of the P(RM) promoter, which drives expression of CI repressor and is activated by CI itself. We made a pool of fragments in which 8 of the 12 positions in the -35 and -10 regions were randomized and cloned this pool into the vector, making a pool of P(RM) variant phage. About 10% of the P(RM) variants were able to lysogenize, suggesting that the lambda regulatory circuitry is compatible with a wide range of P(RM) sequences. Analysis of several of these phages indicated a range of behaviors in prophage induction. Several isolates had induction properties similar to those of the wild type, and their promoters resembled the wild type in their responses to CI. We term this property of different sequences allowing roughly equivalent function "sequence tolerance " and discuss its role in the evolution of gene regulatory circuitry.

SUBMITTER: Michalowski CB

PROVIDER: S-EPMC529058 | biostudies-literature | 2004 Dec

REPOSITORIES: biostudies-literature

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Sequence tolerance of the phage lambda PRM promoter: implications for evolution of gene regulatory circuitry.

Michalowski Christine B CB Short Megan D MD Little John W JW

Journal of bacteriology 20041201 23

Much of the gene regulatory circuitry of phage lambda centers on a complex region called the O(R) region. This approximately 100-bp region is densely packed with regulatory sites, including two promoters and three repressor-binding sites. The dense packing of this region is likely to impose severe constraints on its ability to change during evolution, raising the question of how the specific arrangement of sites and their exact sequences could evolve to their present form. Here we ask whether th ...[more]

PMID: 15547271

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Project description:BackgroundGene regulatory networks can be modelled in various ways depending on the level of detail required and biological questions addressed. One of the earliest formalisms used for modeling is a Boolean network, although these models cannot describe most temporal aspects of a biological system. Differential equation models have also been used to model gene regulatory networks, but these frameworks tend to be too detailed for large models and many quantitative parameters might not be deducible in practice. Hybrid models bridge the gap between these two model classes - these are useful when concentration changes are important while the information about precise concentrations and binding site affinities is partial.ResultsIn this paper we study the stable behaviours of phage λ via a hybrid system based model. We identify wild type and mutant behaviours that arise for various orderings of binding site affinities. We propose experiments for detecting these behaviours: we suggest several ways of altering binding affinities with either mutations or genome rearrangements to achieve modified behaviours. The feasibility of these experiments is assessed. The interplay between the qualitative aspects of a network, e.g. network topology, and quantitative parameters, e.g. growth and degradation rates of proteins, is demonstrated. We also provide a software for exploring all feasible states of a hybrid system model and identifying all attractors.ConclusionsThe behaviours of phage λ are determined mainly by the topology of this network and by the mutual order of binding affinities. Exact affinities and growth and degradation rates of proteins fine tune the system. We show that only two stable behaviours are possible for phage λ if the main constraints of λ switch are preserved - these behaviours correspond to lysis and lysogeny. We identify several variants of both lysis and lysogeny - one wild type and one modified behaviour for each. We elucidate the necessary constraints for binding site affinities to achieve both wild type lysis and lysogeny. Our software is applicable to a wide range of biological models described as a hybrid system.

Dataset Information

Sequence tolerance of the phage lambda PRM promoter: implications for evolution of gene regulatory circuitry.

Publications

Sequence tolerance of the phage lambda PRM promoter: implications for evolution of gene regulatory circuitry.

Similar Datasets

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