Functional alignment of regulatory networks: a study of temperate phages

Abstract

The relationship between the design and functionality of molecular networks is now a key issue in biology. Comparison of regulatory networks performing similar tasks can provide insights into how network architecture is constrained by the functions it directs. Here, we discuss methods of network comparison based on network architecture and signaling logic. Introducing local and global signaling scores for the difference between two networks, we quantify similarities between evolutionarily closely and distantly related bacteriophages. Despite the large evolutionary separation between phage lambda and 186, their networks are found to be similar when difference is measured in terms of global signaling. We finally discuss how network alignment can be used to pinpoint protein similarities viewed from the network perspective.

Figure 1. The Genetic Regulatory Networks for Phage 186, Phage λ, and Phage P22, All of Which Are Temperate and Infect E. coli

The proteins are colored according to their functions and expression mode in the lysis–lysogeny life cycle of the phages. We summarize the influence of one protein on another by either a green arrow (positive, e.g., transcriptional activation) or a red arrow (negative, e.g., repression). The dashed lines show relatively weak regulations.

Figure 2. Illustration of the Differences between the Real 186 and λ Networks (Top) and an Example of Their Randomized Counterparts (Bottom)

These examples of randomized networks show that it possible to preserve local properties, yet obtain different network structures.

Figure 3. Alignment of Two Phage Networks

Placement of proteins is based on our knowledge [–9,13,22], and the lines connecting them are associated with the minimal D_S alignment. Proteins that perform similar functions or are regulated similarly are placed on the same level; thus, horizontal lines mark ideal matching. Blue lines correspond to meaningful alignments, and red lines are the misalignments. The numbers above the lines, d_i, reflect the differences in signaling between the aligned proteins and are the contributions to the minimal difference . The numbers in the parentheses indicate multiple equivalent proteins, making the sum of all shown signaling differences equal to 2 × 43. The key regulators RecA, LexA, and CI are identified correctly, whereas the misidentification of CII with CIII is reasonable since both favor entry into lysogeny through the same pathway. The major discrepancy is associated with the different roles of Cro and Apl during lysis (the weak links from Cro to Q and N in λ).