Evidence for functional and non-functional classes of peptides translated from long non-coding RNAs

Abstract

Cells express thousands of transcripts that show weak coding potential. Known as long non-coding RNAs (lncRNAs), they typically contain short open reading frames 5 (ORFs) having no homology with known proteins. Recent studies show that a significant proportion of lncRNAs are translated, challenging the view that they are non-coding. These results are based on selective sequencing of ribosome-protected fragments, or ribosome profiling. The present study used ribosome profiling data from eight mouse tissues and cell types, combined with ~330,000 synonymous and 10 non-synonymous single nucleotide variants, to dissect the patterns of purifying selection in proteins translated from lncRNAs. Using the three-nucleotide read periodicity that characterizes actively translated regions, we identified 832 mouse translated lncRNAs. Overall, they produced 1,489 different proteins, most of them smaller than 100 amino acids. Nearly half of the ORFs then showed sequence 15 conservation in rat and/or human transcripts, and many of them are likely to encode functional micropeptides, including the recently discovered Myoregulin. For lncRNAs not conserved in rats or humans, the ORF codon usage bias distinguished between two classes, one with particularly high coding scores and evidence of purifying selection, consistent with the presence of lineage-specific functional proteins, and a 20 second, larger, class of ORFs producing peptides with no significant purifying selection signatures. We obtained evidence that the translation of these lncRNAs depends on the chance occurrence of ORFs with a favorable codon composition. Some of these lncRNAs may be precursors of novel protein-coding genes, filling a gap in our current understanding of de novo gene birth.

Comprehensive Peptide Analysis of Mouse Brain Striatum Identifies Novel sORF‐Encoded Polypeptides

“…sORF‐encoded polypeptides (SEPs), also referred to as non‐classical bio‐active peptides (NCBAPs), are directly translated from short open reading frames (sORFs) . In contrast to the CBAPs, where the peptides are processed through the secretory pathway, SEPs mostly lack a signaling sequence and are therefore directly synthesized and released into the cytoplasm . Erroneously, genome annotation efforts mostly assume that small ORFs <100 amino acids (AA) in length, do not have any coding potential.…”

New Genes and Functional Innovation in Mammals

“…These observations are consistent with a high rate of de novo gene emergence accompanied by frequent gene loss in the first stages of the evolutionary history of a gene ( Neme and Tautz 2014 ; Palmieri et al 2014 ). We also have to consider that some of the very young genes may not be functional even if translated ( Ruiz-Orera et al 2016 ).…”

Human Long Noncoding RNA Interactome: Detection, Characterization and Function

“…The detection of lncRNA-origin peptides is not easy, because computer analyses predict many Open Reading Frames (ORF), however, only a few of them are actively translated. It has been calculated that about 23% of the transcribed lncRNAs have been translated [182]. Moreover, the expression of many peptides is weak, and they are difficult to detect, especially in the case of peptides that lack sequence homologies to known proteins.…”