Purifying selection on splice-related motifs, not expression level nor RNA folding, explains nearly all constraint on human lincRNAs

Andreas Schüler, Avazeh T. Ghanbarian, Laurence D. Hurst

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

There are two strong and equally important predictors of rates of human protein evolution: The amount the gene is expressed and the proportion of exonic sequence devoted to control splicing, mediated largely by selection on exonic splice enhancer (ESE) motifs. Is the same true for noncoding RNAs, known to be under very weak purifying selection? Prior evidence suggests that selection at splice sites in long intergenic noncoding RNAs (lincRNAs) is important. We now report multiple lines of evidence indicating that the great majority of purifying selection operating on lincRNAs in humans is splice related. Splice-related parameters explain much of the between-gene variation in evolutionary rate in humans. Expression rate is not a relevant predictor, although expression breadth is weakly so. In contrast to proteincoding RNAs, we observe no relationship between evolutionary rate and lincRNA stability. As in protein-coding genes, ESEs are especially abundant near splice junctions and evolve slower than non-ESE sequence equidistant from boundaries. Nearly all constraint in lincRNAs is at exon ends (N.B. the same is not witnessed in Drosophila). Although we cannot definitely answer the question as to why splice-related selection is so important, we find no evidence that splicing might enable the nonsense-mediated decay pathway to capture transcripts incorrectly processed by ribosomes. We find evidence consistent with the notion that splicing modifies the underlying chromatin through recruitment of splice-coupled chromatin modifiers, such as CHD1, which in turn might modulate neighbor gene activity. We conclude that most selection on human lincRNAs is splice mediated and suggest that the possibility of splice-chromatin coupling is worthy of further scrutiny.

LanguageEnglish
Pages3164-3183
Number of pages20
JournalMolecular Biology and Evolution
Volume31
Issue number12
DOIs
StatusPublished - 1 Dec 2014

Fingerprint

RNA Folding
Long Noncoding RNA
folding
RNA
Chromatin
chromatin
gene
genes
Genes
enhancer elements
Untranslated RNA
modifiers (genes)
ribosomes
protein
Ribosomes
Drosophila
exons
Exons
Proteins
proteins

Keywords

  • ncRNA
  • Rate of evolution
  • Splicing

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics

Cite this

Purifying selection on splice-related motifs, not expression level nor RNA folding, explains nearly all constraint on human lincRNAs. / Schüler, Andreas; Ghanbarian, Avazeh T.; Hurst, Laurence D.

In: Molecular Biology and Evolution, Vol. 31, No. 12, 01.12.2014, p. 3164-3183.

Research output: Contribution to journalArticle

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