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Abstract
Global insights into cellular organization and genome function require comprehensive understanding ofthe interactome networks that mediate genotypephenotype relationships1,2. Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRl'. With approximately 53,000 protein-protein interactions, HuRl has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies. The integration ofHuRl with genome3, transcriptome4 and proteome5 data enables cellular function to be studied within most physiological or pathological cellular contexts. We demonstrate the utility of HuRl in identifying the specific subcellular roles of protein-protein interactions. Inferred tissue-specific networks reveal general principles for the formation of cellular context-specific functions and elucidate potential molecular mechanisms that might underlie tissue-specific phenotypes of Mendelian diseases. HuRl is a systematic proteome-wide reference that links genomic variation to phenotypic outcomes.