@article{Mai01112019,
author = {Mai, Te-Lun and Chuang, Trees-Juen}, 
title = {A-to-I RNA editing contributes to the persistence of predicted damaging mutations in populations},
volume = {29}, 
number = {11}, 
pages = {1766-1776}, 
year = {2019}, 
doi = {10.1101/gr.246033.118}, 
abstract ={Adenosine-to-inosine (A-to-I) RNA editing is a very common co-/posttranscriptional modification that can lead to A-to-G changes at the RNA level and compensate for G-to-A genomic changes to a certain extent. It has been shown that each healthy individual can carry dozens of missense variants predicted to be severely deleterious. Why strongly detrimental variants are preserved in a population and not eliminated by negative natural selection remains mostly unclear. Here, we ask if RNA editing correlates with the burden of deleterious A/G polymorphisms in a population. Integrating genome and transcriptome sequencing data from 447 human lymphoblastoid cell lines, we show that nonsynonymous editing activities (prevalence/level) are negatively correlated with the deleteriousness of A-to-G genomic changes and positively correlated with that of G-to-A genomic changes within the population. We find a significantly negative correlation between nonsynonymous editing activities and allele frequency of A within the population. This negative editing-allele frequency correlation is particularly strong when editing sites are located in highly important genes/loci. Examinations of deleterious missense variants from the 1000 Genomes Project further show a significantly higher proportion of rare missense mutations for G-to-A changes than for other types of changes. The proportion for G-to-A changes increases with increasing deleterious effects of the changes. Moreover, the deleteriousness of G-to-A changes is significantly positively correlated with the percentage of editing enzyme binding motifs at the variants. Overall, we show that nonsynonymous editing is associated with the increased burden of G-to-A missense mutations in healthy individuals, expanding RNA editing in pathogenomics studies.}, 
URL = {http://genome.cshlp.org/content/29/11/1766.abstract}, 
eprint = {http://genome.cshlp.org/content/29/11/1766.full.pdf+html}, 
journal = {Genome Research} 
}