TY  - JOUR
A1  - Mai, Te-Lun
A1  - Chuang, Trees-Juen
T1  - A-to-I RNA editing contributes to the persistence of predicted damaging mutations in populations
Y1  - 2019/11/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 1766 
EP  - 1776 
DO  - 10.1101/gr.246033.118 
VL  - 29 
IS  - 11 
UR  - http://genome.cshlp.org/content/29/11/1766.abstract 
N2  - 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. 
ER  -