Decoding the dark genome reveals its organisation into modular disease networks.

The biological functions and disease relevance of the 'dark genome'-over one-third of all protein-coding genes-remain largely unknown. Here, we use integrative network and functional analyses to construct a systems-level map of dark gene contributions to human genetic diseases. We identify 16 hub dark genes, including R3HDM2 and RPUSD4, that are central to disease networks and are overwhelmingly enriched for roles in mitochondrial protein synthesis. These hubs form modular networks connecting major inflammatory conditions like psoriasis and tuberculosis, driven by specific transcription factors. Furthermore, we demonstrate that the expression of these hubs is controlled in a tissue-specific manner by thousands of genetic variants (eQTLs), providing direct mechanistic links to phenotypes such as myocardial infarction and diabetes. Our results provide a functional landscape for the dark genome, revealing its critical role in mitochondrial pathways and presenting a rich resource of novel therapeutic targets.