A Hidden Human Proteome Encoded by the “Non-Coding” Genes

It has been a long debate whether the 98% “non-coding” fraction of human genome can encode functional proteins besides a “random noise” of translation. We used our established translatome sequencing (RNC-seq) to analyze human cells and found that up to 3330 long non-coding RNAs (lncRNAs) were bound to ribosomes and thus might be translated into proteins (with more than 50 amino acids). These new protein-coding genes distributed universally in all human chromosomes. We then used various experimental methods including mass spectrometry, immunoblotting, subcellular localization and phenotype assessments to verify the existence of such a hidden human proteome encoded by purported lncRNAs that can express functional proteins. These new proteins deviate from the canonical proteins in various physical and chemical properties, and emerged mostly in primates during evolution. In sum, we experimentally evidenced a hidden human functional proteome encoded by purported lncRNAs, suggesting that the human genome has to be systematically re-annotated.