In Search of the Biological Significance of Modular Structures in Protein Networks

Abstract

Many complex networks such as computer and social networks exhibit modular structures, where links between nodes are much denser within modules than between modules. It is widely believed that cellular networks are also modular, reflecting the relative independence and coherence of different functional units in a cell. While many authors have claimed that observations from the yeast protein–protein interaction (PPI) network support the above hypothesis, the observed structural modularity may be an artifact because the current PPI data include interactions inferred from protein complexes through approaches that create modules (e.g., assigning pairwise interactions among all proteins in a complex). Here we analyze the yeast PPI network including protein complexes (PIC network) and excluding complexes (PEC network). We find that both PIC and PEC networks show a significantly greater structural modularity than that of randomly rewired networks. Nonetheless, there is little evidence that the structural modules correspond to functional units, particularly in the PEC network. More disturbingly, there is no evolutionary conservation among yeast, fly, and nematode modules at either the whole-module or protein-pair level. Neither is there a correlation between the evolutionary or phylogenetic conservation of a protein and the extent of its participation in various modules. Using computer simulation, we demonstrate that a higher-than-expected modularity can arise during network growth through a simple model of gene duplication, without natural selection for modularity. Taken together, our results suggest the intriguing possibility that the structural modules in the PPI network originated as an evolutionary byproduct without biological significance. Many complex networks are naturally divided into communities or modules, where links within modules are much denser than those across modules. For example, human individuals belonging to the same ethnic groups interact more than those from different ethnic groups. Cellular functions are also organized in a highly modular manner, where each module is a discrete object composed of a group of tightly linked components and performs a relatively independent task. It is interesting to ask whether this modularity in cellular function arises from modularity in molecular interaction networks such as the transcriptional regulatory network and protein–protein interaction (PPI) network. We analyze the yeast PPI network and show that it is indeed significantly more modular than randomly rewired networks. However, we find little evidence that the structural modules correspond to functional units. We also fail to observe any evolutionary conservation among yeast, fly, and nematode PPI modules. We then show by computer simulation that modular structures can arise during network growth via a simple model of gene duplication, without natural selection for modularity. Thus, it appears that the structural modules in the PPI network may have originated as an evolutionary byproduct without much biological significance.