Exploring the Peptide Potential of Genomes

Recent studies attribute a central role to the noncoding genome in the emergence of novel genes. The widespread transcription of noncoding regions and the pervasive translation of the resulting RNAs offer to the organisms a vast reservoir of novel peptides. Although the majority of these peptides are anticipated as deleterious or neutral, and thereby expected to be degraded right away or short-lived in evolutionary history, some of them can confer an advantage to the organism. The latter can be further subjected to natural selection and be established as novel genes. In any case, characterizing the structural properties of these pervasively translated peptides is crucial to understand (1) their impact on the cell and (2) how some of these peptides, derived from presumed noncoding regions, can give rise to structured and functional de novo proteins. Therefore, we present a protocol that aims to explore the potential of a genome to produce novel peptides. It consists in annotating all the open reading frames (ORFs) of a genome (i.e., coding and noncoding ones) and characterizing the fold potential and other structural properties of their corresponding potential peptides. Here, we apply our protocol to a small genome and show how to apply it to very large genomes. Finally, we present a case study which aims to probe the fold potential of a set of 721 translated ORFs in mouse lncRNAs, identified with ribosome profiling experiments. Interestingly, we show that the distribution of their fold potential is different from that of the nontranslated lncRNAs and more generally from the other noncoding ORFs of the mouse.