FROM MODULE TO MYOCARDIUM: A GRAPH THEORETIC ANALYSIS OF THE HUMAN PROTEOME

Abstract

Nature is built on hierarchy. It falls to biologists to study this hierarchy and uncover the emergent properties which enable Life. In this thesis, we focus on the significance of modules in protein-protein interaction (PPI) networks and make two key claims. First, we devise a novel hierarchical clustering algorithm which yields the module topology of the clustered graph. The module topology is a tree which mathematically describes the hierarchical organization of modularity in the original graph. By annotating the module topologies of tissue-specific human PPI networks with Gene Ontology terms, we uncover the existence of at least two levels of biologically meaningful super-modules (modules of modules). Second, we theorize a novel graph construction for modeling the similarities between abstract mathematical sets, which we call the de Bruijn set graph. By using de Bruijn set graphs to model human PPI modules, we find that the diversity of PPI modules parallels the diversity of differentiated tissues. Further, we suggest that each connected component within the de Bruijn set graph represents a collection of PPI module isoforms which descended evolutionarily from an ancestral proto-module via the exchange of homologous proteins. From these results, we conclude that PPI modules are a fundamental unit of biological function and suggest a mechanism for modular proteomic evolution.