The Role of C-to-U RNA Editing in Human Biodiversity and Disease

Abstract

Intra-organism biodiversity is thought to arise from epigenetic modification of our constituent genes and post-translational modifications after mRNA is translated into proteins. We have found that post-transcriptional modification, also known as RNA editing, is also responsible for a significant amount of our biodiversity, substantively expanding this story. The APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) family RNA editing enzymes APOBEC3A and APOBEC3G catalyze the deamination of cytosines to uracils (C>U) in specific stem-loop structures.1,2 We used RNAsee (RNA site editing evaluation), a tool developed to predict the locations of APOBEC3A/G RNA editing sites, to determine whether known single nucleotide polymorphisms (SNPs) in DNA could be replicated in RNA via RNA editing. About 4.5% of non-synonymous SNPs which result in C>U changes in RNA, and about 5.4% of such SNPs labelled as pathogenic, were identified as probable sites for APOBEC3A/G editing. This suggests that the variant proteins created by these DNA mutations may also be created by transient RNA editing, with the potential to affect human health. Those SNPs identified as potential APOBEC3A/G-mediated RNA editing sites were disproportionately associated with cardiovascular diseases, digestive system diseases, and musculoskeletal diseases. Future work should focus on common sites of RNA editing, any variant proteins created by these RNA editing sites, and the effects of these variants on protein diversity and human health.