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.

中文翻译：

---

A-to-I RNA 编辑有助于预测的破坏性突变在人群中的持续存在。

腺苷至肌苷 (A-to-I) RNA 编辑是一种非常常见的共转录/转录后修饰，可导致 RNA 水平上的 A 至 G 变化，并在一定程度上补偿 G 至 A 基因组变化。程度。研究表明，每个健康个体都可以携带数十种预计会严重有害的错义变异。为什么强烈有害的变异会保留在群体中，并且不会被负性自然选择所消除，目前仍不清楚。在这里，我们询问 RNA 编辑是否与人群中有害的 A/G 多态性负担相关。整合 447 个人类淋巴母细胞系的基因组和转录组测序数据，我们发现非同义编辑活动（流行率/水平）与 A 到 G 基因组变化的有害性呈负相关，与 G 到 A 基因组变化的有害性呈正相关人口内部的变化。我们发现群体中非同义编辑活动与 A 等位基因频率之间存在显着负相关。当编辑位点位于非常重要的基因/位点时，这种负编辑-等位基因频率相关性特别强。对 1000 个基因组计划的有害错义变异的检查进一步表明，G 到 A 变化的罕见错义突变比例明显高于其他类型的变化。G 到 A 变化的比例随着变化的有害影响的增加而增加。此外，G 到 A 变化的有害性与变体上编辑酶结合基序的百分比显着正相关。总体而言，我们表明非同义编辑与健康个体中 G 到 A 错义突变负担的增加有关，从而扩大了病原学研究中的 RNA 编辑。