Identification of evolutionarily meaningful information within the mammalian RNA editing landscape

Abstract

A large comparative genomic sequence study has determined the extent of conservation between RNA editing sites within the mammalian evolutionary tree.

Figure 1

An overview of RNA editing. (a) Specific RNA editing occurring in a pre-mRNA. The nascent transcript folds into a complex dsRNA structure, pairing coding sequences (blue) with highly conserved intronic sequences. Structural features (for example, bulges and loops) in the duplex region focus ADAR’s deaminase activity on a few or one adenosine residue. (b) Promiscuous editing of long repeat dsRNAs. Shown here is an inverted repeat of Alu elements whose transcription produces a long nearly perfect dsRNA. Numerous ADAR editing events can occur in such a substrate, altering its structure, and potentially interfering with downstream processes (for example, Dicer processing into endo-siRNAs). (c) A hypothetical scheme for conserved versus less-conserved RNA editing events. All RNA molecules can potentially form secondary structures, and thus potentially bind and be acted upon by ADAR. Those that are minimally structured will be edited poorly or not at all. The vast majority of RNAs will fall into this category, and be well below the action of serving as a variant incipient adaptation acted upon by natural selection (below dashed green line). Certain RNAs will more readily serve as ADAR targets, and will as a consequence also possess more dsRNA character. Such events can be acted upon by natural selection and serve as sources of variation in the expression of RNAs (for example, mRNAs, long non-coding dsRNA, miRNA precursors). Natural selection will preserve certain structural features, such as those in pre-mRNA and miRNA precursors, to ensure highly evolved edited structures. Other long dsRNAs, such as inverted repeat hairpin dsRNAs, will be edited as part of the regulation of host defenses to viruses and selfish genetic elements. ADAR, adenosine deaminase acting on RNA; dsRNA, double-stranded RNA; miRNA, microRNA, siRNA, small interfering RNA.