Enrichment and aggregation of topological motifs are independent organizational principles of integrated interaction networks

TL;DR

This study introduces a new method to analyze biological interaction networks, revealing that motif aggregation and enrichment are independent principles of network organization, challenging traditional views.

Contribution

The paper presents a novel statistical method to assess motif aggregation significance and demonstrates that aggregation and enrichment are independent organizational principles.

Findings

Motif aggregation reflects local modularity independent of enrichment.

Identified novel functional network themes not associated with enrichment.

Challenges the view that motif enrichment is the primary organizational principle.

Abstract

Topological network motifs represent functional relationships within and between regulatory and protein-protein interaction networks. Enriched motifs often aggregate into self-contained units forming functional modules. Theoretical models for network evolution by duplication-divergence mechanisms and for network topology by hierarchical scale-free networks have suggested a one-to-one relation between network motif enrichment and aggregation, but this relation has never been tested quantitatively in real biological interaction networks. Here we introduce a novel method for assessing the statistical significance of network motif aggregation and for identifying clusters of overlapping network motifs. Using an integrated network of transcriptional, posttranslational and protein-protein interactions in yeast we show that network motif aggregation reflects a local modularity property which is independent of network motif enrichment. In particular our method identified novel functional network themes for a set of motifs which are not enriched yet aggregate significantly and challenges the conventional view that network motif enrichment is the most basic organizational principle of complex networks.