Link clustering explains non-central essential genes in protein interaction networks

Essential genes (EGs) often form central nodes in protein-protein interaction (PPI) networks. However, many reports have shown that numerous EGs are non-central, suggesting that another principle governs gene essentiality. We propose link clustering as a distinct indicator of the essentiality for non-central nodes. Specifically, in various human and yeast PPI networks, we found that 29 to 47% of EGs were better characterized by link clustering than by centrality. Such non-central EGs with clustered links have significant impacts on communities at lower hierarchical levels, suggesting that their essentiality derives from functional dependency among relevant local neighbors, rather than their implication on global connectivity. Moreover, these non-central EGs exhibited several distinct characteristics: they tend to be younger and fast-evolving, and likely change their essentiality across different human cell lines and between human and mouse than central-EGs.