A-to-I RNA editing contributes to the persistence of predicted damaging mutations in populations

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.

A-to-I RNA editing in honeybees shows signals of adaptation and convergent evolution

“…However, these interesting examples notwithstanding, the extent to which the recoding phenomenon is actually used as a means for proteome diversification is still under debate. In fact, several recent studies have raised the possibility that nonsynonymous editing may be used to compensate for otherwise deleterious G-to-A mutations, rather than allowing for the two alleles (A and G) to co-exist (Jiang and Zhang 2019;Mai and Chuang 2019;Popitsch et al, 2020). Thus, a high N/S ratio is not sufficient to prove that editing serves for adaptation through proteome diversification.…”

Somatic A‐to‐I RNA‐edited RHOA isoform 2 specific‐R176G mutation promotes tumor progression in lung adenocarcinoma

“…Here, our results demonstrate an interesting mechanism by which alternatively spliced RHOAiso2 harbors a unique cryptic Alu‐rich exon at the 3′ RHOA mRNA for A‐to‐I editing not only to increase mutations and proteomic diversity but also to potentiate oncogenic RHOA‐ROCK signaling during LUAD tumorigenesis and metastasis. Importantly, the increased expression of somatic A‐to‐I RNA editing‐derived neoantigens and increased mutation burden in cancers has been suggested to impact the therapeutic efficacy of ICI treatments 39–42 …”

“…Importantly, the increased expression of somatic A-to-I RNA editing-derived neoantigens and increased mutation burden in cancers has been suggested to impact the therapeutic efficacy of ICI treatments. [39][40][41][42] Nevertheless, with millions of A-to-I RNA editing events detected with various omics approaches, only limited A-to-I editing events have been functionally characterized for mechanistic participation in cancer progression. 43,44 For instance, the AZIN1-S367G mutation is a well-studied A-to-I editing event with increased affinity to neutralize antizyme, a protease that degrades cell cycling proteins such as ornithine decarboxylase (ODC1) and cyclin D1 (CCND1), to enhance cell proliferation and tumor growth.…”

“…Importantly, the increased expression of somatic A‐to‐I RNA editing‐derived neoantigens and increased mutation burden in cancers has been suggested to impact the therapeutic efficacy of ICI treatments. 39 , 40 , 41 , 42 …”