How Particular RNA Editing Sites Can be Selectively Superior to Heterozygous SNPs Independent of Temporospatial Regulation

Abstract A-to-I RNA editing introduces A-to-G variation at post-transcriptional level, but it remains mysterious. What is the advantage of functional RNA editing compared to an A/G heterozygous SNP? Here, we provide the following situations that particular RNA editing sites can be superior to heterozygous SNPs even independent of its temporospatial regulation. (1) Assume a site with A/G heterozygote advantage. RNA editing does not undergo Mendelian segregation and recombination that inevitably produce homozygotes of lower fitness. (2) Graded RNA editing level. A snapshot of editing profile shows strong tissue-specific editing levels, providing flexible stoichiometry of edited/unedited versions, while heterozygous SNPs generally produce similar expression of two alleles. (3) Higher molecular diversity. N RNA editing sites in a gene theoretically produce a dramatic number of X = 2N mRNA haplotypes, but all SNPs in a gene can only produce two alleles. Nevertheless, we emphasize that these advantageous sites may emerge through complicated evolutionary process and remain rare across the genome. We systematically discussed the pros and cons of RNA editing versus heterozygous SNPs, deepening our understanding of the biological functions of cis-regulatory mechanisms. We provide putative answers to why evolution chose RNA editing instead of a genomic mutation at particular sites. ARTICLE HIGHLIGHTS RNA editing offers greater flexibility and diversity compared to heterozygous SNPs. RNA editing does not undergo Mendelian segregation and recombination like heterozygous SNPs. Unlike the binary and 0.5 level of SNPs, RNA editing level is graded from 0 to 1. N RNA editing sites potentially produce X = 2N mRNA haplotypes, while all SNPs produce two alleles only. These advantages of particular editing sites come with costs like off-targeting.