SUMMARY Just as reference genome sequences revolutionized human genetics, reference maps of interactome networks will be critical to fully understand genotype-phenotype relationships. Here, we describe a systematic map of ~14,000 high-quality human binary protein-protein interactions. At equal quality, this map is ~30% larger than what is available from small-scale studies published in the literature in the last few decades. While currently available information is highly biased and only covers a relatively small portion of the proteome, our systematic map appears strikingly more homogeneous, revealing a “broader” human interactome network than currently appreciated. The map also uncovers significant inter-connectivity between known and candidate cancer gene products, providing unbiased evidence for an expanded functional cancer landscape, while demonstrating how high quality interactome models will help “connect the dots” of the genomic revolution.

SUMMARY Chaperones are central to the proteostasis network (PN) and safeguard the proteome from misfolding, aggregation and proteotoxicity. We categorized the human chaperome of 332 genes into network communities using function, localization, interactome, and expression datasets. During human brain aging, expression of 32% of the chaperome corresponding to ATP-dependent chaperone machines is repressed, whereas 19.5% corresponding to ATP-independent chaperones and co-chaperones are induced. These repression and induction clusters are enhanced in Alzheimer's, Huntington's, and Parkinson's brains. Functional properties of the chaperome were assessed by perturbation in C. elegans and human cell models expressing Aβ, polyglutamine and Huntingtin. Of 219 C. elegans orthologs, knockdown of sixteen enhanced both Aβ and polyQ-associated toxicity. These correspond to 28 human orthologs, of which 52% and 41% are repressed, respectively, in brain aging and disease, and 37.5% affected Huntingtin aggregation in human cells. These results identify a critical chaperome sub-network that functions in aging and disease.