The landscape of the A-to-I RNA editome from 462 human genomes

Abstract

A-to-I editing, as a post-transcriptional modification process mediated by ADAR, plays a crucial role in many biological processes in metazoans. However, how and to what extent A-to-I editing diversifies and shapes population diversity at the RNA level are largely unknown. Here, we used 462 mRNA-sequencing samples from five populations of the Geuvadis Project and identified 16,518 A-to-I editing sites, with false detection rate of 1.03%. These sites form the landscape of the RNA editome of the human genome. By exploring RNA editing within and between populations, we revealed the geographic restriction of rare editing sites and population-specific patterns of edQTL editing sites. Moreover, we showed that RNA editing can be used to characterize the subtle but substantial diversity between different populations, especially those from different continents. Taken together, our results demonstrated that the nature and structure of populations at the RNA level are illustrated well by RNA editing, which provides insights into the process of how A-to-I editing shapes population diversity at the transcriptomic level. Our work will facilitate the understanding of the landscape of the RNA editome at the population scale and will be helpful for interpreting differences in the distribution and prevalence of disease among individuals and across populations.

Genome-wide analysis of consistently RNA edited sites in human blood reveals interactions with mRNA processing genes and suggests correlations with cell types and biological variables

“…Recently, global editing level has been investigated across tissues and in different species [21, 22] and has also been correlated with the genetic background of human population [30, 50] and with common disease variants [29]. However, the published studies lack a detailed characterization of samples that allows assessing the role of biological and environmental factors.…”

Deciphering the principles of the RNA editing code via large-scale systematic probing

“…To date, all of the studies addressing this question have focused on sequence and structures in the immediate vicinity of the edited sites. These have revealed a degenerate sequence preference, including a bias against a G at the position immediately upstream of the edited site (Eggington et al, 2011;Matthews et al, 2016), a slight enrichment for G at the position following the edited site (Ouyang et al, 2018), and that adenosines in mismatched A-C pairs are preferably edited (Roth et al, 2019;Wong et al, 2001). Structurally, ADAR1 is known to edit long dsRNAs with a strong secondary structure (Morse et al, 2002).…”

Genome-wide analysis of consistently RNA edited sites in human blood reveals interactions with mRNA processing genes and suggests correlations with cell types and biological variables

“…Recently, global editing level has been investigated across tissues and in different species [21,22] and has also been correlated with the genetic background of human population [30,50] and with common disease variants [29]. However, the published studies lack a detailed characterization of samples that allows assessing the role of biological and environmental factors.…”