Genetic mapping uncovers cis-regulatory landscape of RNA editing

Ramaswami, Gokul; Deng, Patricia; Zhang, Rui; Carbone, Mary Anna; Mackay, Trudy F. C.; Li, Jin Billy

doi:10.1038/ncomms9194

Cited by 77 publications

(84 citation statements)

References 41 publications

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“…melanogaster were located in pre-mRNA regions that formed stable secondary structures. These results also well explain why the A-to-I editing sites are located in clusters, as commonly observed in previous studies [41, 47–49, 62]. By clustering the editing sites with distances smaller than 100 nucleotides, we identified a total of 1,320 editing sites that form 413 clusters in brains of D .…”

Section: Resultssupporting

confidence: 89%

“…melanogaster as previously observed [41]. Notably, we found a considerable number of sites at which editing events was readily detected in certain strains while absent in the other strains.…”

Section: Resultssupporting

confidence: 88%

“…melanogaster [41, 92]. Here we ask whether we can find SNPs associated with the variations in editing levels across the five strains of D .…”

Section: Resultsmentioning

confidence: 99%

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Adaptation of A-to-I RNA editing in Drosophila

et al. 2017

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Adenosine-to-inosine (A-to-I) editing is hypothesized to facilitate adaptive evolution by expanding proteomic diversity through an epigenetic approach. However, it is challenging to provide evidences to support this hypothesis at the whole editome level. In this study, we systematically characterized 2,114 A-to-I RNA editing sites in female and male brains of D. melanogaster, and nearly half of these sites had events evolutionarily conserved across Drosophila species. We detected strong signatures of positive selection on the nonsynonymous editing sites in Drosophila brains, and the beneficial editing sites were significantly enriched in genes related to chemical and electrical neurotransmission. The signal of adaptation was even more pronounced for the editing sites located in X chromosome or for those commonly observed across Drosophila species. We identified a set of gene candidates (termed “PSEB” genes) that had nonsynonymous editing events favored by natural selection. We presented evidence that editing preferentially increased mutation sequence space of evolutionarily conserved genes, which supported the adaptive evolution hypothesis of editing. We found prevalent nonsynonymous editing sites that were favored by natural selection in female and male adults from five strains of D. melanogaster. We showed that temperature played a more important role than gender effect in shaping the editing levels, although the effect of temperature is relatively weaker compared to that of species effect. We also explored the relevant factors that shape the selective patterns of the global editomes. Altogether we demonstrated that abundant nonsynonymous editing sites in Drosophila brains were adaptive and maintained by natural selection during evolution. Our results shed new light on the evolutionary principles and functional consequences of RNA editing.

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Section: Resultssupporting

confidence: 89%

Section: Resultssupporting

confidence: 88%

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Adaptation of A-to-I RNA editing in Drosophila

et al. 2017

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“…6e). Collectively, our data suggest that cis -acting elements exert a greater effect on RNA editing than trans -acting factors, consistent with our recent observations in Drosophila 24,25 , although non-repetitive sites are more directed by trans -acting factors. These results parallel recent findings that RNA splicing is primarily cis -directed 26,27 and are in sharp contrast to gene expression programs, which exhibit tissue-specific signatures 26,27 .…”

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confidence: 92%

Dynamic landscape and regulation of RNA editing in mammals

Tan

Shanmugam

et al. 2017

Nature

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518

628

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Adenosine-to-inosine (A-to-I) RNA editing is a conserved post-transcriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules1. Although many editing sites have recently been discovered2–7, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood8–10. Here we report dynamic spatiotemporal patterns and new regulators of RNA editing, discovered through an extensive profiling of A-to-I RNA editing in 8,551 human samples (representing 53 body sites from 552 individuals) from the Genotype-Tissue Expression (GTEx) project and in hundreds of other primate and mouse samples. We show that editing levels in non-repetitive coding regions vary more between tissues than editing levels in repetitive regions. Globally, ADAR1 is the primary editor of repetitive sites and ADAR2 is the primary editor of non-repetitive coding sites, whereas the catalytically inactive ADAR3 predominantly acts as an inhibitor of editing. Cross-species analysis of RNA editing in several tissues revealed that species, rather than tissue type, is the primary determinant of editing levels, suggesting stronger cis-directed regulation of RNA editing for most sites, although the small set of conserved coding sites is under stronger trans-regulation. In addition, we curated an extensive set of ADAR1 and ADAR2 targets and showed that many editing sites display distinct tissue-specific regulation by the ADAR enzymes in vivo. Further analysis of the GTEx data revealed several potential regulators of editing, such as AIMP2, which reduces editing in muscles by enhancing the degradation of the ADAR proteins. Collectively, our work provides insights into the complex cis- and trans-regulation of A-to-I editing.

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“…Alternative splicing is assessed by comparing the abundance of individual transcript isoforms and components of the isoforms, i.e., exons, untranslated regions, and splicing junctions [46][47][48]. Other traits and features being explored for disease association include RNA-editing quantitative trait loci (edQTL) [49], RNA decay quantitative trait loci (rdQTL) [50], and small regulatory RNAs [51,52].…”

Section: Interpretation Validation and Characterization Of Functionmentioning

confidence: 99%

RNA Sequencing and Genetic Disease

et al. 2016

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Purpose of Review Next-generation sequencing is a revolutionary approach for highly accurate identification of gene associations with specific human disease phenotypes. RNA sequencing (RNA-seq) holds great promise for identifying distinct gene expression ''signatures'' for the detection, prognosis, and chemosensitivity of human disease. However, this technique has yet to be adopted as a standard medical practice. Recent Findings The recent emergence of high-throughput, next-generation sequencing technology has facilitated significant advancements in understanding evolutionary diversity and disease. RNA-seq in particular is an invaluable tool for profiling transcription across the entire human genome (i.e., the ''transcriptome'') at high resolution, providing the means to quantitatively study links among genotypes, transcript abundance, and other transcript-based features and human phenotypes. RNA-seq technology provides an essential layer of molecular information providing investigators and clinicians a systems genetics prospective of human disease. Integrated analysis of DNA-and RNA-seq data allows elucidation of the causal and regulatory mechanisms of the complex traits of human disease. Summary Here, we review RNA-seq technology and present a summary of different methods and their application to the study of human genetic disease. We further illustrate the utility of RNA-seq technology as an important tool for identifying novel transcriptomic biomarkers, and how these link to the pathological phenotypes of human disease initiation and progression. Advanced machine learning techniques for RNA-seq data analysis are also discussed.

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Genetic mapping uncovers cis-regulatory landscape of RNA editing

Cited by 77 publications

References 41 publications

Adaptation of A-to-I RNA editing in Drosophila

Adaptation of A-to-I RNA editing in Drosophila

Dynamic landscape and regulation of RNA editing in mammals

RNA Sequencing and Genetic Disease

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