Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs.

By J. Ponjavic, Chris P. Ponting, Gerton A. Lunter. Genome Research, 2007

740 citations recorded by the source corpus.

Long transcripts that do not encode protein have only rarely been the subject of experimental scrutiny. Presumably, this is owing to the current lack of evidence of their functionality, thereby leaving an impression that, instead, they represent "transcriptional noise." Here, we describe an analysis of 3122 long and full-length, noncoding RNAs ("macroRNAs") from the mouse, and compare their sequences and their promoters with orthologous sequence from human and from rat. We considered three independent signatures of purifying selection related to substitutions, sequence insertions and deletions, and splicing. We find that the evolution of the set of noncoding RNAs is not consistent with neutralist explanations. Rather, our results indicate that purifying selection has acted on the macroRNAs' promoters, primary sequence, and consensus splice site motifs. Promoters have experienced the greatest elimination of nucleotide substitutions, insertions, and deletions. The proportion of conserved sequence (4.1%-5.5%) in these macroRNAs is comparable to the density of exons within protein-coding transcripts (5.2%). These macroRNAs, taken together, thus possess the imprint of purifying selection, thereby indicating their functionality. Our findings should now provide an incentive for the experimental investigation of these macroRNAs' functions.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/32f8898f7074b77259e274f38ec56aa047a96d09

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Molecular Biology

Citations in the corpus

Genome regulation by long noncoding RNAs (2012, background): “LincRNAs show sequence conservation throughout evolution over introns or untranscribed intergenic sequences, further suggesting their functionality (24, 44, 45).”
Pervasive Transcription of the Human Genome Produces Thousands of Previously Unidentified Long Intergenic Noncoding RNAs (2013, neutral): “tethered together by nonconserved sequence [25,31,32].”
Localization and abundance analysis of human lncRNAs at single-cell and single-molecule resolution (2015, background): “Yet, no study has systematically applied single molecule RNA FISH to explore lncRNA localization and abundance from cDNA and RNA-seq catalogs, such as those in [9,33-38].”
Long non-coding RNAs: insights into functions (2009, background): “The binding of transcription factors to non-coding loci, together with evidence of purifying selection acting on ncRNA promoters, suggests that this type of expression is explicitly regulate”
Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. (2011, background): “In particular, recent studies have focused on large intergenic noncoding RNAs (lincRNAs) (Ponjavic et al. 2007; Guttman et al. 2009; Khalil et al. 2009; Orom et al. 2010), which do not overlap annotated protein-coding regions, as this facilitates experimental manipulation and computational analysis.”
The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression (2012, background): “These findings are in agreement with studies of other lncRNA catalogs (Ponjavic et al. 2007; Guttman et al. 2009; Marques and Ponting 2009; Ørom et al. 2010).”
Long noncoding RNAs: Cellular address codes in development and disease (2013, neutral): “Interestingly, the promoters of lncRNAs are the region of the lncRNA gene under higher selective pressure, displaying levels of selection comparable to the promoters of proteincoding genes (Derrien et al., 2012; Guttman et al., 2009;Marques and Ponting, 2009; Ørom et al., 2010; Ponjavic et al., 2007”
Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation. (2008, background): “This is supported by recent work showing that ncRNA promoters are subject to purifying selection (Ponjavic et al. 2007), are on average more conserved than promoters of protein-coding genes (Carninci et al.”
Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression (2009, background): “Discussion It is becoming clear that the mammalian genome encodes thousands of lincRNAs that are highly conserved and, thus, biologically functional (1, 27).”
Comparative Genomics (2007, neutral): “The contribution of transfrags to constrained sequences in human is matter of current study (e.g. Ponjavic et al. 2007; The ENCODE Project Consortium 2007).”
Genome-wide computational identification and manual annotation of human long noncoding RNA genes. (2010, background): “…are unlikely to simply represent transcriptional noise because they are expressed in a tissue-and developmental-specific manner, and their sequence displays phylogenetic conservation consistent with negative evolutionary selection, which indicates functional constraint (Ponjavic et al. 2007).”