Graphlet eigencentralities capture novel central roles of genes in pathways

Graphlet adjacency extends regular node adjacency in a network by considering a pair of nodes being adjacent if they participate in a given graphlet (small, connected, induced subgraph). Graphlet adjacencies captured by different graphlets were shown to contain complementary biological functions and cancer mechanisms. To further investigate the relationships between the topological features of genes participating in molecular networks, as captured by graphlet adjacencies, and their biological functions, we build more descriptive pathway-based approaches.

We introduce a new graphlet-based definition of eigencentrality of genes in a pathway, graphlet eigencentrality, to identify pathways and cancer mechanisms described by a given graphlet adjacency. We compute the centrality of genes in a pathway either from the local perspective of the pathway or from the global perspective of the entire network.

We show that in molecular networks of human and yeast, different local graphlet adjacencies describe different pathways (i.e., all the genes that are functionally important in a pathway are also considered topologically important by their local graphlet eigencentrality). Pathways described by the same graphlet adjacency are functionally similar, suggesting that each graphlet adjacency captures different pathway topology and function relationships. Additionally, we show that different graphlet eigencentralities describe different cancer driver genes that play central roles in pathways, or in the crosstalk between them (i.e. we can predict cancer driver genes participating in a pathway by their local or global graphlet eigencentrality). This result suggests that by considering different graphlet eigencentralities, we can capture different functional roles of genes in and between pathways.