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

Recent studies have shown that many essential genes (EGs) change their essentiality across various contexts. Finding contextual EGs in pathogenic conditions may facilitate the identification of therapeutic targets. We propose link clustering as an indicator of contextual EGs that are non-central in protein-protein interaction (PPI) networks. In various human and yeast PPI networks, we found that 29-47% of EGs were better characterized by link clustering than by centrality. Importantly, non-central EGs were prone to change their essentiality across different human cell lines and between species. Compared with central EGs and non-EGs, non-central EGs had intermediate levels of expression and evolutionary conservation. In addition, non-central EGs exhibited a significant impact on communities at lower hierarchical levels, suggesting that link clustering is associated with contextual essentiality, as it depicts locally important nodes in network structures.