Identification of genetic variants controlling RNA editing and their effect on RNA structure stabilization

Post-transcriptional modification of RNA (RNA editing, RNAe) results in differences between the RNA transcript and the genomic DNA sequence (RDD). Enzymatic modification of adenosine to inosine (A2I) by ADAR is the most studied type of RNAe. However, few genetic association studies with A2I RNAe events have been conducted. Some studies have analyzed the inter-population RNAe-QTL diversity in humans, but the sample size of these studies was limited. Other types of RNA and DNA differences have been reported but are largely understudied. Here, we report a comprehensive analysis of all types of RDD, based on two independent datasets. We found that A2I was by far the most observed type of RDD. Moreover, manual curation suggests that A2I is likely the only enzymatically driven RNAe type observed in blood derived DNA, all other non-A2I RDD could either be attributed to sequencing and processing artifacts, or are a result of somatic DNA rearrangements. We then conducted an in-cis genetic association study and identified 472 genetic associations (RNAe-QTL), that were replicated in both datasets. We confirm the potential effect of the RNAe-QTL on RNA structure by showing that allele specific RNAe occurs in heterozygotes. Although the generally assumed function of RNAe is to destabilize double stranded RNA structure, we found clear evidence for the potential additional involvement of RNAe in maintaining RNA hairpin that has been altered by the RNAe-QTL. Our study confirms, in two independent datasets, the potential role of RNAe in maintaining RNA structure in the presence of genetic variation.