Abstract
Adenosine-to-inosine (A-to-I) editing is hypothesized to facilitate adaptive evolution by expanding proteomic diversity through an epigenetic approach. However, it is challenging to provide evidences to support this hypothesis at the whole editome level. In this study, we systematically characterized 2,114 A-to-I RNA editing sites in female and male brains of D. melanogaster, and nearly half of these sites had events evolutionarily conserved across Drosophila species. We detected strong signatures of positive selection on the nonsynonymous editing sites in Drosophila brains, and the beneficial editing sites were significantly enriched in genes related to chemical and electrical neurotransmission. The signal of adaptation was even more pronounced for the editing sites located in X chromosome or for those commonly observed across Drosophila species. We identified a set of gene candidates (termed “PSEB” genes) that had nonsynonymous editing events favored by natural selection. We presented evidence that editing preferentially increased mutation sequence space of evolutionarily conserved genes, which supported the adaptive evolution hypothesis of editing. We found prevalent nonsynonymous editing sites that were favored by natural selection in female and male adults from five strains of D. melanogaster. We showed that temperature played a more important role than gender effect in shaping the editing levels, although the effect of temperature is relatively weaker compared to that of species effect. We also explored the relevant factors that shape the selective patterns of the global editomes. Altogether we demonstrated that abundant nonsynonymous editing sites in Drosophila brains were adaptive and maintained by natural selection during evolution. Our results shed new light on the evolutionary principles and functional consequences of RNA editing.
Highlights
Genomic mutations are the major sources for phenotypic changes and adaptation [1,2,3,4]
We demonstrated that the expression level of Adar, together with the expression profiles of a set of genes that have editing sites favored by natural selection, were important in shaping the overall selective patterns of the global editomes at different developmental stages of D. melanogaster
Consistent with observations in primates that local nucleotide contexts affect the editing efficiencies [60, 88], we found that G immediately upstream a focal editing site was generally not favored, the nucleotide immediately downstream the editing site was slightly biased toward G, and other flanking nucleotides were generally not important, the overall patterns of preferences were weak in D. melanogaster (Fig 5A; we presented the frequencies of the tri-nucleotides centered with the editing sites and background adenosines in S19 Table)
Summary
Genomic mutations are the major sources for phenotypic changes and adaptation [1,2,3,4]. The “all-or-none” property of DNA mutations might incur pleiotropic effects that are antagonistic among cell types, tissues, developmental stages, sexes, or other aspects of life history [5,6,7], which would constrain the available genetic diversity for a species. Given the prevalence of pleiotropic effects in the genomes [8,9,10], the sequence space might be inaccessible to many mutations, which potentially slows down the rate of phenotypic evolution and adaptation [11]. The transcriptomic or proteomic diversity limited by mutation sequence space could be expanded by the alteration of RNA sequences in an epigenetic approach, such as RNA editing, which was hypothesized to facilitate adaptation [12,13,14]. RNA editing has the advantage to quickly respond to environmental stress and adjust the activity of final protein products [15, 16]
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