Human lncRNAs harbor conserved modules embedded in different sequence contexts

We analyzed the structure of human long non-coding RNA (lncRNAs) genes to investigate whether the non-coding transcriptome is organized in modular domains, as is the case for protein-coding genes. To this aim, we compared all known human lncRNA exons and identified 340 pairs of exons with high sequence and/or secondary structure similarity but embedded in a dissimilar sequence context. We grouped these pairs in 106 clusters based on their reciprocal similarities. These shared modules are highly conserved between humans and the four great ape species, display evidence of purifying selection and likely arose as a result of recent segmental duplications. Our analysis contributes to the understanding of the mechanisms driving the evolution of the non-coding genome and suggests additional strategies towards deciphering the functional complexity of this class of molecules. Author summary The Human genome includes more than 18,000 genes coding for RNAs that are not translated into proteins, called long non-coding RNAs (lncRNA). Mounting evolutionary and experimental evidence shows that a large amount of these RNAs have a specific function, mainly as regulators of a diverse set of biological processes. Here we set out to investigate whether these genes have a modular organization similar to that of protein-coding genes. Accordingly, we compared the sequence of all the exonic regions of human lncRNAs and identified 106 clusters of non-repetitive exonic modules shared between this class of genes. These modules display evidence of purifying selection, are highly conserved between humans and the four great ape species, and may represent distinct functional units that have been shuffled among multiple lncRNA genes, in a manner similar to the exon-shuffling process that is observed in the coding genome. ### Competing Interest Statement The authors have declared no competing interest.