A Comprehensive Map of Non-Alu RNA Editing Sites Across the Human Genome

A-to-I RNA editing by ADAR enzymes in the human genome is very ubiquitous and was shown to have a major effect on the innate immune system, as well as being a prominent factor in various pathologies, such as cancer. Editing activity in the human genome is well detected inside Alu elements, where it serves as an important immunoregulator of the cellular innate immunity of the MDA5\MAV pathway. Other specific sites, outside Alus, presumed to be numerous, were virtually invisible, obscured by sequencing errors and genomic variations. Such editing targets have great potential to have distinctive effects, as demonstrated by the already known sites, such as AZIN recoding site, that contributes to cancer progression, the recoding of NEIL1 that reduce the thymine glycol cleavage rate by 30-fold, and the FLNA recoding which regulates blood pressure. We applied our newly published method on the GTEx project, to produce a comprehensive high-quality atlas of editing sites across the entire genome outside Alu repeats. In addition, our approach also enabled the detection of APOBECs catalyzed C-to-U RNA editing sites. These sites are normally completely overshadowed by DNA editing by the same enzyme group, and spontaneous de-methylations, to the point that they are undetectable. We present here a first characterization of these sites across the genome.