Abstract
BackgroundADAR proteins are among the most extensively studied RNA binding proteins. They bind to their target and deaminate specific adenosines to inosines. ADAR activity is essential, and the editing of a subset of their targets is critical for viability. Recently, a huge number of novel ADAR targets were detected by analyzing next generation sequencing data. Most of these novel editing sites are located in lineage-specific genomic repeats, probably a result of overactivity of editing enzymes, thus masking the functional sites. In this study we aim to identify the set of mammalian conserved ADAR targets.ResultsWe used RNA sequencing data from human, mouse, rat, cow, opossum, and platypus to define the conserved mammalian set of ADAR targets. We found that the conserved mammalian editing sites are surprisingly small in number and have unique characteristics that distinguish them from non-conserved ones. The sites that constitute the set have a distinct genomic distribution, tend to be located in genes encoding neurotransmitter receptors or other synapse related proteins, and have higher editing and expression levels. We also found a high consistency of editing levels of this set within mice strains and between human and mouse. Tight regulation of editing in these sites across strains and species implies their functional importance.ConclusionsDespite the discovery of numerous editing targets, only a small number of them are conserved within mammalian evolution. These sites are extremely highly conserved and exhibit unique features, such as tight regulation, and probably play a pivotal role in mammalian biology.
Highlights
Adeonsine deaminase acting on RNA (ADAR) proteins are among the most extensively studied RNA binding proteins
In the last few years, the total number of known human editing sites jumped by several orders of magnitude; many expected that the number of functional sites would grow at the same rate
In order to find sites that are highly conserved between species, we retrieved for each site the 80 bp flanking genomic sequence (40 nucleotides upstream and 40 downstream) and aligned each of the human sequences to all mouse sequences using the standard Basic local alignment tool (BLAST) [51] alignment tool
Summary
ADAR proteins are among the most extensively studied RNA binding proteins. They bind to their target and deaminate specific adenosines to inosines. A huge number of novel ADAR targets were detected by analyzing generation sequencing data Most of these novel editing sites are located in lineage-specific genomic repeats, probably a result of overactivity of editing enzymes, masking the functional sites. The current rapid progress in sequencing technologies, led to the publication of a huge number of editing sites, more than a million in human [20,28], and thousands of additional ones in mouse [4,29] and Drosophila [5,30] Most of these sites are consequences of double-stranded RNA structures formed by inverted, usually lineage specific, repeats (for example, Alu pairs [12,31,32,33] in human, and B1 in mouse [29]). It is not clear which of the sites have functional importance, and how many are only the outcomes of residual ADAR activity, with no selective advantage
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