Evolutionary conservation of long non-coding RNAs; sequence, structure, function

Background: Recent advances in genomewide studies have revealed the abundance of long non-coding RNAs (IncRNAs) in mammalian transcriptomes. The ENCODE Consortium has elucidated the prevalence of human IncRNA genes, which are as numerous as protein-coding genes. Surprisingly, many IncRNAs do not show the same pattern of high interspecies conservation as protein-coding genes. The absence of functional studies and the frequent lack of sequence conservation therefore make functional interpretation of these newly discovered transcripts challenging. Many investigators have suggested the presence and importance of secondary structural elements within IncRNAs, but mammalian IncRNA secondary structure remains poorly understood. It is intriguing to speculate that in this group of genes, RNA secondary structures might be preserved throughout evolution and that this might explain the lack of sequence conservation among many IncRNAs. Scope of review: Here, we review the extent of interspecies conservation among different IncRNAs, with a focus on a subset of IncRNAs that have been functionally investigated. The function of IncRNAs is widespread and we investigate whether different forms of functionalities may be conserved. Major conclusions: Lack of conservation does not imbue a lack of function. We highlight several examples of IncRNAs where RNA structure appears to be the main functional unit and evolutionary constraint. We survey existing genomewide studies of mammalian IncRNA conservation and summarize their limitations. We further review specific human IncRNAs which lack evolutionary conservation beyond primates but have proven to be both functional and therapeutically relevant. General significance: Pioneering studies highlight a role in IncRNAs for secondary structures, and possibly the presence of functional modules, which are interspersed with longer and less conserved stretches of nucleotide sequences. Taken together, high-throughput analysis of conservation and functional composition of the still-mysterious IncRNA genes is only now becoming feasible. (C) 2013 Elsevier B.V. All rights reserved.