Design principles of molecular networks revealed by global comparisons and composite motifs

Background: Molecular networks are of great current interest, particularly with the publication of many large-scale data sets in yeast. Previous analyses have focused on the topological structure of individual networks.

Results: Here, we present a global comparison of the four basic molecular networks: regulatory, co-expression, interaction, and metabolic.

Conclusions: We find that in terms of overall topological correlation -- whether nearby proteins in one network tend to be close in another -- all four networks are quite similar. However, focusing on the occurrence of more local features, we first introduce the concept of composite hubs ¨C hubs shared by more than one network. We find that the four networks can be divided into two different classes: regulation and action. The later group -- comprising metabolic, co-expression, and interaction networks -- share the same scaffolding of central hubs, whereas the regulatory network uses distinctly different regulator hubs. Finally, we examine the inter-relationship between the regulatory network and each of the three action networks, focusing on 3 basic composite motifs -- triangles, trusses, and bridges -- that involve different levels of regulation of a pair of separated genes. The analysis of these shows that action networks further divide into two groups. On the one hand, interaction and co-expression networks tend to have short-range relationships, with directly interacting and co-expressed proteins sharing common regulators. On the other, the metabolic network contains many long-distance relationships: far-away enzymes in the same pathway often have time-delayed expression relationships that are well-coordinated by bridging connections between their regulators.