The dark genome in cardiovascular medicine

Only ∼1%-2% of the human genome directly codes for proteins. The remainder consists of non-coding DNA, often referred to as the 'dark genome'. This includes regulatory elements, transposable and repetitive sequences, structural genomic features, pseudogenes, intronic and intergenic regions, and non-coding RNA (ncRNA) genes. These components are increasingly recognized as major regulators of gene expression, cell identity, and disease susceptibility. Currently, dark genome elements, particularly ncRNAs are increasingly recognized as important regulators of cardiovascular health and disease. Advances in genome analysis technologies have greatly improved our understanding of these non-coding regions and revealed clearer connections between the dark genome and cardiovascular traits. This review highlights major parts of the dark genome involved in cardiovascular disease, with emphasis on those for which mechanistic understanding and translational relevance are beginning to emerge. As mechanistic insight into individual and collective components of the dark genome advances, it increasingly enables the development of new opportunities for targeted therapeutics for cardiovascular prevention and disease management.