Fig. 5

Seventy-six dark genes (≥ 5% CDS) are associated with 326 human diseases, including autism, inflammatory bowel disease, and others. We found 76 genes ≥ 5% dark CDS that harbor mutations associated with 326 unique human diseases, according to the Human Gene Mutation Database (HGMD). a Some of the diseases with the most known associated genes include autism spectrum disorder, schizophrenia, hearing loss, spinal muscular atrophy, and inflammatory bowel disease. Word size represents the number of genes associated with each disease. These data demonstrate the number of diseases impacted by genes that are at least 5% dark CDS, and how important it is to completely resolve dark regions. We also performed an enrichment analysis, where the diseases most enriched for dark genes included color blindness (protan color vision defect), X-linked cone-rod dystrophy, and spinal muscular atrophy (Additional file 1: Figure S10). b Similarly, we quantified the number of diseases each gene was associated with and identified many disease-relevant genes with large portions of dark CDS regions that may harbor critical disease-modifying mutations that currently go undetected. Some of the genes with the most known disease associations include ARX (12.8% dark CDS), NEB (9.5% dark CDS), TBX1 (10.6% dark CDS), RPGR (8.6% dark CDS), HBA2 (9.5% dark CDS), and CR1 (26.0% dark CDS). CR1 is particularly notable for neuroscientists and Alzheimer’s disease geneticists, patients, and their caregivers, given that CR1 is a top-ten Alzheimer’s disease gene. Other notable genes include SMN1 (94.6% dark CDS) and SMN2 (88.0% dark CDS), which are known to harbor mutations (in camouflaged regions) that are involved in spinal muscular atrophy (SMA) and are implicated in ALS. HSPA1A (53.0% dark CDS) and HSPA1B (51.5% dark CDS) also encode two primary 70-kilodalton (kDa) heat-shock proteins. Heat-shock proteins have been implicated in ALS [31, 32]