State of the Interactomes: an evaluation of molecular networks for generating biological insights

Advancements in genomic and proteomic technologies have powered the use of gene and protein networks (“interactomes”) for understanding genotype-phenotype translation. However, the proliferation of interactomes complicates the selection of networks for specific applications. Here, we present a comprehensive evaluation of 46 current human interactomes, encompassing protein-protein interactions as well as gene regulatory, signaling, colocalization, and genetic interaction networks. Our analysis shows that large composite networks such as HumanNet, STRING, and FunCoup are most effective for identifying disease genes, while smaller networks such as DIP and SIGNOR demonstrate strong interaction prediction performance. These findings provide a benchmark for interactomes across diverse network biology applications and clarify factors that influence network performance. Furthermore, our evaluation pipeline paves the way for continued assessment of emerging and updated interaction networks in the future. ### Competing Interest Statement TI is a co-founder, member of the advisory board, and has an equity interest in Data4Cure and Serinus Biosciences. TI is a consultant for and has an equity interest in Ideaya Biosciences. The terms of these arrangements have been reviewed and approved by the University of California San Diego in accordance with its conflict-of-interest policies.