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

Abstract

1 Essential genes (EGs) often form central nodes in protein-protein interaction (PPI) networks. 2 However, many reports have shown that numerous EGs are non-central, suggesting that another 3 principle governs gene essentiality. We propose link clustering as a distinct indicator of the essentiality 4 for non-central nodes. Specifically, in various human and yeast PPI networks, we found that 29 to 47% 5 of EGs were better characterized by link clustering than by centrality. Such non-central EGs with 6 clustered links have significant impacts on communities at lower hierarchical levels, suggesting that 7 their essentiality derives from functional dependency among relevant local neighbors, rather than their 8 implication on global connectivity. Moreover, these non-central EGs exhibited several distinct 9 characteristics: they tend to be younger and fast-evolving, and likely change their essentiality across 10 different human cell lines and between human and mouse than central-EGs.