Atlas of the Open Reading Frames in Human Diseases: Dark Matter of the Human Genome

Abstract

Background: The human genome encodes RNA and protein coding sequences, the non-coding RNAs, pseudogenes and uncharacterized Open Reading Frames (ORFs). The dark matter of the human genome encompassing the uncharacterized proteins and the non-coding RNAs are least well studied. However, they offer novel druggable targets and biomarkers discovery for diverse diseases. Methods: In this study, we have systematically dissected the dark matter of the human genome. Using diverse bioinformatics tools, an atlas of the dark matter of the genome was created. The ORFs were characterized for gene ontology, mRNA and protein expression, protein motif and domains and genome-wide association. Results: An atlas of disease-related ORFs (n=800) was generated. A complex landscape of involvement in multiple diseases was seen for these ORFs. Motif and domains analysis identified druggable targets and putative secreted biomarkers including enzymes, receptors and transporters as well as proteins with signal peptide sequence. About ten percent of the ORFs showed a correlation of gene expression at the mRNA and protein levels. Genome-Phenome association tools identified ORF's association with autoimmune, cardiovascular, cancer, diabetes, infection, metabolic, neurodegenerative and psychiatric disorders. Tumors encompassed largely heterozygous mutations. Conclusions: The dark matter human proteome atlas reported in this study should aid in the discovery of novel therapeutic and diagnostic targets for multiple diseases