Secondary structure impacts patterns of selection in human lncRNAs.

Cinta Pegueroles,Toni Gabaldón

doi:10.1186/s12915-016-0283-0

Abstract

BackgroundMetazoans transcribe many long non-coding RNAs (lncRNAs) that are poorly conserved and whose function remains unknown. This has raised the questions of what fraction of the predicted lncRNAs is actually functional, and whether selection can effectively constrain lncRNAs in species with small effective population sizes such as human populations.ResultsHere we evaluate signatures of selection in human lncRNAs using inter-specific data and intra-specific comparisons from five major populations, as well as by assessing relationships between sequence variation and predictions of secondary structure. In all analyses we included a reference of functionally characterized lncRNAs. Altogether, our results show compelling evidence of recent purifying selection acting on both characterized and predicted lncRNAs. We found that RNA secondary structure constrains sequence variation in lncRNAs, so that polymorphisms are depleted in paired regions with low accessibility and tend to be neutral with respect to structural stability.ConclusionsImportant implications of our results are that secondary structure plays a role in the functionality of lncRNAs, and that the set of predicted lncRNAs contains a large fraction of functional ones that may play key roles that remain to be discovered.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0283-0) contains supplementary material, which is available to authorized users.

Highlights

Metazoans transcribe many long non-coding RNAs that are poorly conserved and whose function remains unknown
Exons in long non-coding RNA (lncRNA) are enriched in conserved elements but do not show overall higher conservation than introns To provide a common background with previous studies using different sets of human lncRNAs, we first analyzed phastCons scores in exonic and intronic regions of lncRNAs and flanking protein coding genes, as well as in flanking intergenic regions
According to the authors, some lncRNAs of their functional set overlapped with protein coding genes or were classified as “protein coding” in a previous study [4], which may have resulted in an overestimation of their conservation

Summary

Introduction

Metazoans transcribe many long non-coding RNAs (lncRNAs) that are poorly conserved and whose function remains unknown. This has raised the questions of what fraction of the predicted lncRNAs is functional, and whether selection can effectively constrain lncRNAs in species with small effective population sizes such as human populations. Every search for lncRNAs in a metazoan genome has resulted in hundreds to thousands of predicted lncRNAs, with little overlap between studies. There is a relatively small but steadily growing set of functionally characterized transcripts. LncRNAdb v2 [5], a reference database for functionally validated lncRNAs, lists 136 experimentally characterized human lncRNAs, and for some

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Conclusion