SSS-test: a novel test for detecting positive selection on RNA secondary structure

Marko Dunjić,Peter F Stadler,Katja Nowick,Maria Beatriz Walter Costa,Christian Höner Zu Siederdissen

doi:10.1186/s12859-019-2711-y

Abstract

BackgroundLong non-coding RNAs (lncRNAs) play an important role in regulating gene expression and are thus important for determining phenotypes. Most attempts to measure selection in lncRNAs have focused on the primary sequence. The majority of small RNAs and at least some parts of lncRNAs must fold into specific structures to perform their biological function. Comprehensive assessments of selection acting on RNAs therefore must also encompass structure. Selection pressures acting on the structure of non-coding genes can be detected within multiple sequence alignments. Approaches of this type, however, have so far focused on negative selection. Thus, a computational method for identifying ncRNAs under positive selection is needed.ResultsWe introduce the SSS-test (test for Selection on Secondary Structure) to identify positive selection and thus adaptive evolution. Benchmarks with biological as well as synthetic controls yield coherent signals for both negative and positive selection, demonstrating the functionality of the test. A survey of a lncRNA collection comprising 15,443 families resulted in 110 candidates that appear to be under positive selection in human. In 26 lncRNAs that have been associated with psychiatric disorders we identified local structures that have signs of positive selection in the human lineage.ConclusionsIt is feasible to assay positive selection acting on RNA secondary structures on a genome-wide scale. The detection of human-specific positive selection in lncRNAs associated with cognitive disorder provides a set of candidate genes for further experimental testing and may provide insights into the evolution of cognitive abilities in humans.AvailabilityThe SSS-test and related software is available at: https://github.com/waltercostamb/SSS-test. The databases used in this work are available at: http://www.bioinf.uni-leipzig.de/Software/SSS-test/.

Highlights

Long non-coding RNAs play an important role in regulating gene expression and are important for determining phenotypes
Benchmarking Biological controls: SSS-scores indicating negative selection for small (small) non-coding RNA (ncRNA) and positive selection for human Human Accelerated Region 1 (HAR1) As a plausibility check for the SSS-test we used collections of small ncRNAs, which are known to be structurally conserved [14, 61]: miRNAs, Small nucleolar RNA (snoRNA), and tRNAs
Despite the lack of direct experimental evidence for HAR1 functioning based on its structure, we applied our test to HAR1 as the only, at least putative example of a positively selected structure

Summary

Introduction

Long non-coding RNAs (lncRNAs) play an important role in regulating gene expression and are important for determining phenotypes. Selection pressures acting on the structure of non-coding genes can be detected within multiple sequence alignments. Approaches of this type, have so far focused on negative selection. The question remains, what fraction of the detectable lncRNAs convey biological functions, as opposed to being coherently transcribed and processed byproducts without biological relevance (“junk RNA”). Without experimental testing this question is currently difficult to answer because, in contrast to their protein-coding counterparts, most lncRNAs exhibit only low levels of sequence conservation. Recent studies found that lncRNAs are often located in syntenic positions and display similar expression patterns across species [24,25,26]

Results

Discussion

Conclusion