A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes

Abstract

RNA molecules transmit the information encoded in the genome and generally reflect its content. Adenosine-to-inosine (A-to-I) RNA editing by ADAR proteins converts a genomically encoded adenosine into inosine. It is known that most RNA editing in human takes place in the primate-specific Alu sequences, but the extent of this phenomenon and its effect on transcriptome diversity are not yet clear. Here, we analyzed large-scale RNA-seq data and detected~1.6 million editing sites. As detection sensitivity increases with sequencing coverage, we performed ultradeep sequencing of selected Alu sequences and showed that the scope of editing is much larger than anticipated. We found that virtually all adenosines within Alu repeats that form double-stranded RNA undergo A-to-I editing, although most sites exhibit editing at only low levels (<1%). Moreover, using high coverage sequencing, we observed editing of transcripts resulting from residual antisense expression, doubling the number of edited sites in the human genome. Based on bioinformatic analyses and deep targeted sequencing, we estimate that there are over 100 million human Alu RNA editing sites, located in the majority of human genes. These findings set the stage for exploring how this primate-specific massive diversification of the transcriptome is utilized.

Single-cell transcriptomics reveals specific RNA editing signatures in the human brain

“…The vast majority of RNA editing sites detected here and in previous studies (Bazak et al 2014a;Picardi et al 2015) reside in Alu repetitive elements. To provide a more realistic estimate of global editing activity per cell, we calculated the Alu editing index (AEI) per cell because it represents the weighted average editing level across all expressed Alu sequences (PazYaacov et al 2015).…”

Editing of Cellular Self-RNAs by Adenosine Deaminase ADAR1 Suppresses Innate Immune Stress Responses

“…However, such highly specific A-to-I editing events within exonic ORF sequences are the exception in the context of present understanding. Of the several thousand A-to-I-editing sites identified through next generation sequencing studies, the vast majority is found within noncoding sequences of genes that are not inducible by IFN (56,(73)(74)(75)(76)(77)(78). What then is the molecular basis of the IFN-induced, dsRNA-dependent innate responses exemplified by eIF2␣ phosphorylation and SG formation that we now find are suppressed by A-to-I editing but are de-repressed in the absence of ADAR1 following IFN treatment?…”

C-to-U editing and site-directed RNA editing for the correction of genetic mutations

“…A-to-I deamination has been observed at hundreds of thousands of sites and mostly occurs in non-coding and intronic regions, especially in targets containing Alu repeat sequences (8,9). When A-to-I editing occurs in coding regions, it has most commonly been associated with the recoding of brain proteins (10).…”