Adenosine-to-inosine (A-to-I) RNA editing alters the original genomic content of the human transcriptome and is essential for maintenance of normal life in mammals. A-to-I editing in Alu repeats is abundant in the human genome, with many thousands of expressed Alu sequences undergoing editing. Little is known so far about the contribution of Alu editing to transcriptome complexity. Transcripts derived from a single edited Alu sequence can be edited in multiple sites, and thus could theoretically generate a large number of different transcripts. Here we explored whether the combinatorial potential nature of edited Alu sequences is actually fulfilled in the human transcriptome. We analyzed datasets of editing sites and performed an analysis of a detailed transcript set of one edited Alu sequence. We found that editing appears at many more sites than detected by earlier genomic screens. To a large extent, editing of different sites within the same transcript is only weakly correlated. Thus, rather than finding a few versions of each transcript, a large number of edited variants arise, resulting in immense transcript diversity that eclipses alternative splicing as mechanism of transcriptome diversity, although with less impact on the proteome.
Bibliographical noteFunding Information:
EYL was supported by Rothschild fellowship from Yad Hanadiv foundation and by the Machiah Foundation. EE’s research was supported by the Israel Science Foundation, grant number 365/06. GR holds the Djerassi Chair in Oncology at the Sackler Faculty of Medicine, Tel Aviv University and his research was supported by the Kahn Family Foundation and the Flight Attendants Medical Research Institute (FAMRI). RM’s research was supported in parts by the following grants: Israel Science Foundation grants numbers 759/01-1 and 546, an Israel Cancer Research Fund project grant, a Systems Biology prize grant from Teva Pharmaceuticals, Human Frontiers Science Program—a Young Investigator Grant and a Research Grant, and a Swedish Foundation for Strategic Research grant funding the Strategic Research Center for studies on Integrative Recognition in the Immune System (IRIS), Karolinska Institute, Stockholm, Sweden. Funding for open access charge: The Israel Science Foundation.