title: 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.
authors.affiliation: Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 52900, Israel;
authors.forename: Lily
authors.initials: L
authors.lastname: Bazak
authors.forename: Ami
authors.initials: A
authors.lastname: Haviv
authors.forename: Michal
authors.initials: M
authors.lastname: Barak
authors.forename: Jasmine
authors.initials: J
authors.lastname: Jacob-Hirsch
authors.forename: Patricia
authors.initials: P
authors.lastname: Deng
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Farren J
authors.initials: FJ
authors.lastname: Isaacs
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: Jin Billy
authors.initials: JB
authors.lastname: Li
authors.forename: Eli
authors.initials: E
authors.lastname: Eisenberg
authors.forename: Erez Y
authors.initials: EY
authors.lastname: Levanon
mesh_terms: D000241:Adenosine / Q000235:genetics*; D020087:Alu Elements; D000818:Animals; D001483:Base Sequence; D005786:Gene Expression Regulation; D005796:Genes; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007288:Inosine / Q000378:metabolism*; D011323:Primates / Q000235:genetics*; D017393:RNA Editing; D059467:Transcriptome
chemical_list: D007288:Inosine; D000241:Adenosine