The Genetic Signatures of Noncoding RNAs

By John S. Mattick. PLoS Genetics, 2009

721 citations recorded by the source corpus.

The majority of the genome in animals and plants is transcribed in a developmentally regulated manner to produce large numbers of non–protein-coding RNAs (ncRNAs), whose incidence increases with developmental complexity. There is growing evidence that these transcripts are functional, particularly in the regulation of epigenetic processes, leading to the suggestion that they compose a hitherto hidden layer of genomic programming in humans and other complex organisms. However, to date, very few have been identified in genetic screens. Here I show that this is explicable by an historic emphasis, both phenotypically and technically, on mutations in protein-coding sequences, and by presumptions about the nature of regulatory mutations. Most variations in regulatory sequences produce relatively subtle phenotypic changes, in contrast to mutations in protein-coding sequences that frequently cause catastrophic component failure. Until recently, most mapping projects have focused on protein-coding sequences, and the limited number of identified regulatory mutations have been interpreted as affecting conventional cis-acting promoter and enhancer elements, although these regions are often themselves transcribed. Moreover, ncRNA-directed regulatory circuits underpin most, if not all, complex genetic phenomena in eukaryotes, including RNA interference-related processes such as transcriptional and post-transcriptional gene silencing, position effect variegation, hybrid dysgenesis, chromosome dosage compensation, parental imprinting and allelic exclusion, paramutation, and possibly transvection and transinduction. The next frontier is the identification and functional characterization of the myriad sequence variations that influence quantitative traits, disease susceptibility, and other complex characteristics, which are being shown by genome-wide association studies to lie mostly in noncoding, presumably regulatory, regions. There is every possibility that many of these variations will alter the interactions between regulatory RNAs and their targets, a prospect that should be borne in mind in future functional analyses.

Subfields: Cancer Research, Molecular Biology, Plant Science

View Paper: https://www.semanticscholar.org/paper/82097f2afaa24280c9c52cd2fed4bc9ca2433061

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Citations in the corpus

Long Noncoding RNA MALAT1 Controls Cell Cycle Progression by Regulating the Expression of Oncogenic Transcription Factor B-MYB (2013, background): “The eukaryotic genome harbors a large number of noncoding RNAs, which include small and long noncoding RNAs (lncRNAs) [1,2,3,4].”
The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression (2012, neutral): “Mattick JS. 2009.”
A large intergenic non-coding RNA induced by p53 mediates global gene repression in the p53 response (2010, background): “It is clear that mammalian genomes encode numerous large noncoding RNAs (Carninci, 2008; Guttman et al., 2009; Mattick, 2009; Ponjavic et al., 2007).”
The Landscape of long non-coding RNA classification (2015, positive): “Its absence typical for lncRNAs [93] - does not universally imply lack of functionality [22, 24].”
The QTN Program and the Alleles That Matter for Evolution: All That’s Gold Does Not Glitter (2011, neutral): “A common theme in reviews of human GWAS findings is that a substantial fraction of associations fall in noncoding regions (Altshuler et al. 2008; McCarthy et al. 2008; Frazer et al. 2009; Manolio et al. 2009).”
Apoptosis, autophagy, necroptosis, and cancer metastasis (2015, background): “ncRNAs include multiple classes of RNA transcripts that are not translated into proteins but can regulate the transcription, stability or translation of protein-coding genes in the mammalian genome [147].”
The rise of regulatory RNA (2014, background): “Moreover, those loci expressing lncRNAs show all of the hallmarks of bona fide genes 4 , including conservation of promoters 169 , indicative chromatin structure 194 and regulation by conventional morphogens and transcription factors 195 .”
The Nuclear-Retained Noncoding RNA MALAT1 Regulates Alternative Splicing by Modulating SR Splicing Factor Phosphorylation (2010, background): “Mammalian genomes harbor fewer protein-coding genes than initially anticipated, and gene numbers do not proportionally increase with increased genome complexity (for review, see Amaral et al., 2008; Mattick, 2009).”