Negative Correlation between Expression Level and Evolutionary Rate of Long Intergenic Noncoding RNAs

National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.
Genome Biology and Evolution (Impact Factor: 4.23). 11/2011; 3(1):1390-404. DOI: 10.1093/gbe/evr116
Source: PubMed


Mammalian genomes contain numerous genes for long noncoding RNAs (lncRNAs). The functions of the lncRNAs remain largely unknown but their evolution appears to be constrained by purifying selection, albeit relatively weakly. To gain insights into the mode of evolution and the functional range of the lncRNA, they can be compared with much better characterized protein-coding genes. The evolutionary rate of the protein-coding genes shows a universal negative correlation with expression: highly expressed genes are on average more conserved during evolution than the genes with lower expression levels. This correlation was conceptualized in the misfolding-driven protein evolution hypothesis according to which misfolding is the principal cost incurred by protein expression. We sought to determine whether long intergenic ncRNAs (lincRNAs) follow the same evolutionary trend and indeed detected a moderate but statistically significant negative correlation between the evolutionary rate and expression level of human and mouse lincRNA genes. The magnitude of the correlation for the lincRNAs is similar to that for equal-sized sets of protein-coding genes with similar levels of sequence conservation. Additionally, the expression level of the lincRNAs is significantly and positively correlated with the predicted extent of lincRNA molecule folding (base-pairing), however, the contributions of evolutionary rates and folding to the expression level are independent. Thus, the anticorrelation between evolutionary rate and expression level appears to be a general feature of gene evolution that might be caused by similar deleterious effects of protein and RNA misfolding and/or other factors, for example, the number of interacting partners of the gene product.

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Available from: David Managadze, Jun 26, 2014
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    • "Many of the putative functional ncRNAs are present at very low levels and thus unlikely to be of any importance with respect to cell or organism physiology. Additionally, the abundance of an ncRNA species shortly correlates with its level of conservation [10] "
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    ABSTRACT: In the last decade the role of noncoding RNAs (ncRNAs) emerges not only as key elements of posttranscriptional gene silencing, but also as important players of epigenetic regulation. New kind and new functions of ncRNAs are continuously discovered and one of their most important roles is the mediation of environmental signals, both physical and chemical. The activity of cytoplasmic short ncRNA is extensively studied, in spite of the fact that their function and role in the nuclear compartment are not yet completely unraveled. Cellular nucleus contains a multiplicity of long and short ncRNAs controlling at different levels transcriptional and epigenetic processes. In addition, some ncRNAs are involved in RNA editing and quality control. In this paper we review the existing knowledge dealing with how chemical stressors can influence the functionality of short nuclear ncRNAs. Furthermore, we perform bioinformatics analyses indicating that chemical environmental stressors not only induce DNA damage but also influence the mechanism of ncRNAs production and control.
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    • "Taking into account that some lincRNA genes originated from proteincoding genes [for example, Xist (Duret et al., 2006; Elisaphenko et al., 2008)], it appears likely that many properties of lincRNAs would generally resemble those of protein-coding genes, despite the typically lower level of constraint. In particular, protein-coding genes that are highly expressed in many tissues typically evolve slower than genes with lower expression level and breadth (Duret and Mouchiroud, 2000; Krylov et al., 2003; Drummond and Wilke, 2008), and a similar dependence has been observed for lincRNA genes (Managadze et al., 2011). Taken together, these findings imply that an unknown but substantial fraction of lincRNAs are functional molecules rather than transcriptional noise and have evolutionary properties similar to those of protein-coding genes. "
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    ABSTRACT: Transposable elements (TE) are abundant in mammalian genomes and appear to have contributed to the evolution of their hosts by providing novel regulatory or coding sequences. We analyzed different regions of long intergenic non-coding RNA (lincRNA) genes in human and mouse genomes to systematically assess the potential contribution of TEs to the evolution of the structure and regulation of expression of lincRNA genes. Introns of lincRNA genes contain the highest percentage of TE-derived sequences, followed by exons and then promoter regions although the density of TEs is not significantly different between exons and promoters. Higher frequencies of ancient TEs in promoters and exons compared to introns implies that many lincRNA genes emerged before the split of primates and rodents. The content of TE-derived sequences in lincRNA genes is substantially higher than that in protein-coding genes, especially in exons and promoter regions. A significant positive correlation was detected between the content of TEs and evolutionary rate of lincRNAs indicating that inserted TEs are preferentially fixed in fast-evolving lincRNA genes. These results are consistent with the RIDL (Repeat Insertion Domains of LncRNAs) hypothesis under which TEs have substantially contributed to the origin, evolution, and in particular functional diversification, of lincRNA genes.
    Full-text · Article · Jun 2015 · Frontiers in Bioengineering and Biotechnology
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    • "Many of the putative functional ncRNAs are present at very low levels and thus unlikely to be of any importance with respect to cell or organismal physiology. Importantly, the abundance of an ncRNA species roughly correlates with its level of conservation (Managadze et al., 2011), which is a good proxy for function (Doolittle et al., 2014; Elliott et al., 2014; however, see below); thus, determining the relative abundance of a given ncRNA in the relevant cell type is an important piece of information. However, one should keep in mind that if the ncRNA has catalytic activity or if it acts as a scaffold to regulate chromosomal architecture near its site of transcription, the RNA may not need to be present at very high levels to be able to perform its task. "
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    ABSTRACT: The genomes of large multicellular eukaryotes are mostly comprised of non-protein coding DNA. Although there has been much agreement that a small fraction of these genomes has important biological functions, there has been much debate as to whether the rest contributes to development and/or homeostasis. Much of the speculation has centered on the genomic regions that are transcribed into RNA at some low level. Unfortunately these RNAs have been arbitrarily assigned various names, such as "intergenic RNA," "long non-coding RNAs" etc., which have led to some confusion in the field. Many researchers believe that these transcripts represent a vast, unchartered world of functional non-coding RNAs (ncRNAs), simply because they exist. However, there are reasons to question this Panglossian view because it ignores our current understanding of how evolution shapes eukaryotic genomes and how the gene expression machinery works in eukaryotic cells. Although there are undoubtedly many more functional ncRNAs yet to be discovered and characterized, it is also likely that many of these transcripts are simply junk. Here, we discuss how to determine whether any given ncRNA has a function. Importantly, we advocate that in the absence of any such data, the appropriate null hypothesis is that the RNA in question is junk.
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