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The majority of transcripts in the squid nervous system are extensively recoded by A-to-I RNA editing.

Alon S, Garrett SC, Levanon EY, Olson S, Graveley BR, Rosenthal JJ, Eisenberg E - Elife (2015)

Bottom Line: These studies on few established models have led to the general assumption that recoding by RNA editing is extremely rare.Here we employ a novel bioinformatic approach with extensive validation to show that the squid Doryteuthis pealeii recodes proteins by RNA editing to an unprecedented extent.Recoding is tissue-dependent, and enriched in genes with neuronal and cytoskeletal functions, suggesting it plays an important role in brain physiology.

View Article: PubMed Central - PubMed

Affiliation: George S Wise Faculty of Life Sciences, Department of Neurobiology, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
RNA editing by adenosine deamination alters genetic information from the genomic blueprint. When it recodes mRNAs, it gives organisms the option to express diverse, functionally distinct, protein isoforms. All eumetazoans, from cnidarians to humans, express RNA editing enzymes. However, transcriptome-wide screens have only uncovered about 25 transcripts harboring conserved recoding RNA editing sites in mammals and several hundred recoding sites in Drosophila. These studies on few established models have led to the general assumption that recoding by RNA editing is extremely rare. Here we employ a novel bioinformatic approach with extensive validation to show that the squid Doryteuthis pealeii recodes proteins by RNA editing to an unprecedented extent. We identify 57,108 recoding sites in the nervous system, affecting the majority of the proteins studied. Recoding is tissue-dependent, and enriched in genes with neuronal and cytoskeletal functions, suggesting it plays an important role in brain physiology.

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Recoding events are enriched in genes with neuronal and cytoskeletalfunctions and globally affect molecular pathways.(A) The top-scoring Gene Ontology (GO) terms (rated by falsediscovery rate, FDR), enriched in a list of squid ORFs ranked by thecumulative recoding level, that is the editing level summed over allrecoding sites (Eden et al., 2009).(B) All of the identifiable squid proteins present in theKEGG pathway ‘Circadian rhythm’ are edited, and many areheavily edited. We define ‘heavily edited proteins’ as thosefor which the cumulative recoding level exceeds unity (i.e., each copy ofthe protein is expected to have at least one modified amino acid, onaverage). These are marked red, other edited proteins in magenta, andproteins not identifiable in the squid transcriptome in green. This figurewas created using the KEGG (Kanehisa andGoto, 2000) pathway database website (http://www.genome.jp/kegg/pathway.html). Editing levels werecalculated using data from the Giant fiber lobe (GFL) and Optic lobe (OL)tissues combined.DOI:http://dx.doi.org/10.7554/eLife.05198.013
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fig4s1: Recoding events are enriched in genes with neuronal and cytoskeletalfunctions and globally affect molecular pathways.(A) The top-scoring Gene Ontology (GO) terms (rated by falsediscovery rate, FDR), enriched in a list of squid ORFs ranked by thecumulative recoding level, that is the editing level summed over allrecoding sites (Eden et al., 2009).(B) All of the identifiable squid proteins present in theKEGG pathway ‘Circadian rhythm’ are edited, and many areheavily edited. We define ‘heavily edited proteins’ as thosefor which the cumulative recoding level exceeds unity (i.e., each copy ofthe protein is expected to have at least one modified amino acid, onaverage). These are marked red, other edited proteins in magenta, andproteins not identifiable in the squid transcriptome in green. This figurewas created using the KEGG (Kanehisa andGoto, 2000) pathway database website (http://www.genome.jp/kegg/pathway.html). Editing levels werecalculated using data from the Giant fiber lobe (GFL) and Optic lobe (OL)tissues combined.DOI:http://dx.doi.org/10.7554/eLife.05198.013

Mentions: Consistent with other organisms (Stapleton et al.,2006), recoding events are enriched in genes with neuronal and cytoskeletalfunctions (Figure 4—figure supplement 1Aand Supplementary file1H). To gain insight on the effected pathways, squid ORFs were mapped to allhuman KEGG pathways (Kanehisa and Goto, 2000).Editing has a global effect on most pathways (Supplementary file 1I), and those related to the nervous systemare even more affected. For example, of the 27 proteins in the ‘Synaptic vesiclecycle’ pathway, 22 are edited and 14 heavily so (Figure 4A). Similarly, of the 39 proteins in the ‘Axonguidance’ pathway, 33 are edited and 19 heavily so. Other notable pathways are‘Regulation of actin cytoskeleton’ and ‘Circadian rhythm’(Figure 4—figure supplement 1B). Bycontrast, proteins in the pathways ‘Ribosome’ and ‘RNApolymerase’ are edited less than average (Supplementary file 1I), demonstrating that some pathways may beprotected from editing. Consistently, editing levels observed in non-nervous systemtissues are considerably lower (Alon et al.,2015).10.7554/eLife.05198.012Figure 4.Recoding due to RNA editing affects complete molecular pathways and islikely to be more advantageous in sites with high editing levels.


The majority of transcripts in the squid nervous system are extensively recoded by A-to-I RNA editing.

Alon S, Garrett SC, Levanon EY, Olson S, Graveley BR, Rosenthal JJ, Eisenberg E - Elife (2015)

Recoding events are enriched in genes with neuronal and cytoskeletalfunctions and globally affect molecular pathways.(A) The top-scoring Gene Ontology (GO) terms (rated by falsediscovery rate, FDR), enriched in a list of squid ORFs ranked by thecumulative recoding level, that is the editing level summed over allrecoding sites (Eden et al., 2009).(B) All of the identifiable squid proteins present in theKEGG pathway ‘Circadian rhythm’ are edited, and many areheavily edited. We define ‘heavily edited proteins’ as thosefor which the cumulative recoding level exceeds unity (i.e., each copy ofthe protein is expected to have at least one modified amino acid, onaverage). These are marked red, other edited proteins in magenta, andproteins not identifiable in the squid transcriptome in green. This figurewas created using the KEGG (Kanehisa andGoto, 2000) pathway database website (http://www.genome.jp/kegg/pathway.html). Editing levels werecalculated using data from the Giant fiber lobe (GFL) and Optic lobe (OL)tissues combined.DOI:http://dx.doi.org/10.7554/eLife.05198.013
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Related In: Results  -  Collection

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fig4s1: Recoding events are enriched in genes with neuronal and cytoskeletalfunctions and globally affect molecular pathways.(A) The top-scoring Gene Ontology (GO) terms (rated by falsediscovery rate, FDR), enriched in a list of squid ORFs ranked by thecumulative recoding level, that is the editing level summed over allrecoding sites (Eden et al., 2009).(B) All of the identifiable squid proteins present in theKEGG pathway ‘Circadian rhythm’ are edited, and many areheavily edited. We define ‘heavily edited proteins’ as thosefor which the cumulative recoding level exceeds unity (i.e., each copy ofthe protein is expected to have at least one modified amino acid, onaverage). These are marked red, other edited proteins in magenta, andproteins not identifiable in the squid transcriptome in green. This figurewas created using the KEGG (Kanehisa andGoto, 2000) pathway database website (http://www.genome.jp/kegg/pathway.html). Editing levels werecalculated using data from the Giant fiber lobe (GFL) and Optic lobe (OL)tissues combined.DOI:http://dx.doi.org/10.7554/eLife.05198.013
Mentions: Consistent with other organisms (Stapleton et al.,2006), recoding events are enriched in genes with neuronal and cytoskeletalfunctions (Figure 4—figure supplement 1Aand Supplementary file1H). To gain insight on the effected pathways, squid ORFs were mapped to allhuman KEGG pathways (Kanehisa and Goto, 2000).Editing has a global effect on most pathways (Supplementary file 1I), and those related to the nervous systemare even more affected. For example, of the 27 proteins in the ‘Synaptic vesiclecycle’ pathway, 22 are edited and 14 heavily so (Figure 4A). Similarly, of the 39 proteins in the ‘Axonguidance’ pathway, 33 are edited and 19 heavily so. Other notable pathways are‘Regulation of actin cytoskeleton’ and ‘Circadian rhythm’(Figure 4—figure supplement 1B). Bycontrast, proteins in the pathways ‘Ribosome’ and ‘RNApolymerase’ are edited less than average (Supplementary file 1I), demonstrating that some pathways may beprotected from editing. Consistently, editing levels observed in non-nervous systemtissues are considerably lower (Alon et al.,2015).10.7554/eLife.05198.012Figure 4.Recoding due to RNA editing affects complete molecular pathways and islikely to be more advantageous in sites with high editing levels.

Bottom Line: These studies on few established models have led to the general assumption that recoding by RNA editing is extremely rare.Here we employ a novel bioinformatic approach with extensive validation to show that the squid Doryteuthis pealeii recodes proteins by RNA editing to an unprecedented extent.Recoding is tissue-dependent, and enriched in genes with neuronal and cytoskeletal functions, suggesting it plays an important role in brain physiology.

View Article: PubMed Central - PubMed

Affiliation: George S Wise Faculty of Life Sciences, Department of Neurobiology, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
RNA editing by adenosine deamination alters genetic information from the genomic blueprint. When it recodes mRNAs, it gives organisms the option to express diverse, functionally distinct, protein isoforms. All eumetazoans, from cnidarians to humans, express RNA editing enzymes. However, transcriptome-wide screens have only uncovered about 25 transcripts harboring conserved recoding RNA editing sites in mammals and several hundred recoding sites in Drosophila. These studies on few established models have led to the general assumption that recoding by RNA editing is extremely rare. Here we employ a novel bioinformatic approach with extensive validation to show that the squid Doryteuthis pealeii recodes proteins by RNA editing to an unprecedented extent. We identify 57,108 recoding sites in the nervous system, affecting the majority of the proteins studied. Recoding is tissue-dependent, and enriched in genes with neuronal and cytoskeletal functions, suggesting it plays an important role in brain physiology.

Show MeSH
Related in: MedlinePlus