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Evolution to the rescue: using comparative genomics to understand long non-coding RNAs

Nature Reviews Genetics volume 17, pages 601–614 (2016)Cite this article

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This article has been updated

Key Points

  • Long non-coding RNAs (lncRNAs) are emerging as important regulators in multiple key pathways. Thousands of lncRNA genes have now been identified in dozens of species, including animals, plants and single-celled organisms.

  • Unlike protein-coding genes and non-coding RNAs such as microRNAs, lncRNAs are rapidly lost and gained during evolution, raising questions about how many of them are functional.

  • Within conserved lncRNAs, exon–intron architectures and sequences are also rapidly turned over with only short regions evolving under purifying selection.

  • Across long evolutionary distances, there are numerous lncRNAs that are found in syntenic regions, but exhibit no detectable sequence similarity. These can correspond to loci where only the act of transcription is important, or to lncRNAs that depend on very short sequence elements for their functions.

  • Evolutionary trajectories can be used to classify lncRNAs into groups with different characteristics and probably different modes of action.

  • In most cases tested so far, lncRNA function was maintained across large evolutionary distances even when the lncRNA sequence substantially diverged.

Abstract

Long non-coding RNAs (lncRNAs) have emerged in recent years as major players in a multitude of pathways across species, but it remains challenging to understand which of them are important and how their functions are performed. Comparative sequence analysis has been instrumental for studying proteins and small RNAs, but the rapid evolution of lncRNAs poses new challenges that demand new approaches. Here, I review the lessons learned so far from genome-wide mapping and comparisons of lncRNAs across different species. I also discuss how comparative analyses can help us to understand lncRNA function and provide practical considerations for examining functional conservation of lncRNA genes.

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Figure 1: A generic pipeline for the identification of lncRNAs from RNA-seq data.
Figure 2: Classes of lncRNA conservation.
Figure 3: Pathways for origination and diversification of lncRNA loci.
Figure 4: Manifestations of conserved functionality in lncRNA genes.

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Change history

  • 06 September 2016

    In the original version of this article, the sentence “A study using a different background model recently reported more than 4 million regions that are evolving under selection to preserve secondary structure” (section ‘Secondary structure and its conservation’) was missing a citation of reference 65 (Smith, M. A., Gesell, T., Stadler, P. F. & Mattick, J. S. Widespread purifying selection on RNA structure in mammals. Nucleic Acids Res. 41, 8220–8236 (2013)). This citation dropped out during journal typesetting of the article and has now been reinstated. The editors apologize for this error.

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Acknowledgements

The author thanks A. Shkumatava, A. Mallory, M. Garber, E. Hornstein, H. Hezroni and N. Gil for discussions and comments on the manuscript. I.U. is the Sygnet Career Development Chair for Bioinformatics and recipient of an Alon Fellowship from The Council for Higher Education of Israel. Work in the Ulitsky laboratory is supported by grants to I.U. from the European Research Council (Project lincSAFARI), the Israeli Science Foundation (1242/14 and 1984/14), the Israeli Centers of Research Excellence (I-CORE) Program of the Planning and Budgeting Committee and The Israel Science Foundation (1796/12), the Minerva Foundation, the Fritz-Thyssen Foundation and by research grants from Lapon Raymond and the Abramson Family Center for Young Scientists.

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  1. Department of Biological Regulation, Weizmann Institute of Science, 234 Herzl Street, Rehovot, 76100, Israel

    Igor Ulitsky

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Glossary

Expressed sequence tag

(EST). Typically 3′-biased Sanger-sequencing read of approximately 700 nucleotides.

Full-length cDNA

A cDNA that ideally captures a full-length mRNA transcript from the 5′ cap to the 3′ polyadenylated tail; sequenced by multiple Sanger sequencing runs.

Homologues

A pair of genes that descended from a common ancestral gene.

Purifying selection

(Also called negative selection). Selective removal of deleterious alleles.

Effective population size

The size of an idealized population that would experience genetic drift in a similar way to the actual population.

Triplex

An RNA structure formed by three strands of RNA, two that form a Watson–Crick duplex and a third that binds in the major groove of the duplex forming Hoogsteen and reverse Hoogsteen hydrogen bonds.

Syntenic

Preserving order and orientation of genes or other genomic elements between species.

Orthologous

Pertains to homologous genes in different species that have evolved from a common ancestral gene by speciation.

Trans-acting

Regulation that is not cis acting; for example, regulation by diffusible factors that can comparably regulate both homologous loci in a diploid organism.

Cis-acting

Acting from the same molecule, typically interpreted as regulation occurring on the same physical chromosome.

Paralogues

Homologous genes related by duplication within a genome.

Nonsense mutations

Mutations in which a codon encoding an amino acid is mutated into a stop codon.

Exaptation

Co-option of a functionally unrelated DNA sequence for a novel function.

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Ulitsky, I. Evolution to the rescue: using comparative genomics to understand long non-coding RNAs. Nat Rev Genet 17, 601–614 (2016). https://doi.org/10.1038/nrg.2016.85

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