An Evolutionary Landscape of A-to-I RNA Editome across Metazoan Species

Abstract

Adenosine-to-inosine (A-to-I) editing is widespread across the kingdom Metazoa. However, for the lack of comprehensive analysis in nonmodel animals, the evolutionary history of A-to-I editing remains largely unexplored. Here, we detect high-confidence editing sites using clustering and conservation strategies based on RNA sequencing data alone, without using single-nucleotide polymorphism information or genome sequencing data from the same sample. We thereby unveil the first evolutionary landscape of A-to-I editing maps across 20 metazoan species (from worm to human), providing unprecedented evidence on how the editing mechanism gradually expands its territory and increases its influence along the history of evolution. Our result revealed that highly clustered and conserved editing sites tended to have a higher editing level and a higher magnitude of the ADAR motif. The ratio of the frequencies of nonsynonymous editing to that of synonymous editing remarkably increased with increasing the conservation level of A-to-I editing. These results thus suggest potentially functional benefit of highly clustered and conserved editing sites. In addition, spatiotemporal dynamics analyses reveal a conserved enrichment of editing and ADAR expression in the central nervous system throughout more than 300 Myr of divergent evolution in complex animals and the comparability of editing patterns between invertebrates and between vertebrates during development. This study provides evolutionary and dynamic aspects of A-to-I editome across metazoan species, expanding this important but understudied class of nongenomically encoded events for comprehensive characterization.

Nonsynonymous A-to-I RNA editing contributes to burden of deleterious missense variants in healthy individuals

“…It was observed that the level of coding editing was generally less than 10% (Tan et al 2017) except for very few events of high editing levels (e.g., the editing site at position 607 of GRIA2 (Sommer et al 1991); or see the summary table in Hung el al. 's study (Hung et al 2018)). Most nonsynonymous editing events cannot fully posttranscriptionally compensate for the deleterious effects of G-to-A genomic mutations.…”

“…Adenosine-to-inosine (A-to-I) RNA editing is a very common mechanism in metazoans (Porath et al 2017a;Porath et al 2017b;Hung et al 2018). It is catalyzed by the protein families of adenosine deaminases acting on RNA (ADAR), which convert adenosine (A) to inosine (I), leading to differences between the RNA products and the corresponding genomic sequences.…”

“…Thus, it was suggested that RNA editing could contribute considerably to diversity and flexibility at both the RNA and protein levels, without the need for hardwired mutations at the DNA level (Walkley and Li 2017;Yablonovitch et al 2017). Although the majority of human RNA editing sites apparently occur in Alu repeat elements located in non-coding regions (Athanasiadis et al 2004;Peng et al 2012), the number of detected coding editing sites (including synonymous and nonsynonymous sites) is continuing to increase (Tan et al 2017;Hung et al 2018). Since nonsynonymous A-to-G RNA editing events can result in amino acid changes at the RNA level (even though most observed coding editing sites are edited at a very low level (Li et al 2009;Tan et al 2017)), they may compensate for G-to-A genomic mutations to a certain extent and thus partially reduce the deleteriousness of such mutations.…”

“…However, identification of RNA editing is often hampered by difficulties in distinguishing between true editing sites and A/G genomic variants because of the lack of genome and transcriptome sequencing data from the same samples at the population scale. To minimize false positives arising from single nucleotide polymorphisms (SNPs), sites overlapping with known SNPs (e.g., dbSNP) are generally discarded for detection of RNA editing events (Kurmangaliyev et al 2015;Walkley and Li 2017;Hung et al 2018). Thus, such a relationship between A-to-G RNA editing and the allele frequency of A/G genomic variants within a population remains uninvestigated.…”

Large-scale RNA editing profiling in different adult chicken tissues

“…al., applied RNA-Seq data from 20 metazoan species (including chicken), to identify high confidence editing sites. In chicken, 94 A-to-G editing sites were reported, which distribution of these sites had not been discussed in different tissues (Hung et al, 2017). Therefore, in spite of the biological importance of RNA editing, a few studies have been performed in chicken, which indicate much more work is needed to identify the extent of this mechanism in this species.…”