Background Adenosine-to-inosine (A-to-I) RNA editing plays important roles in diversifying the transcriptome and preventing MDA5 sensing of endogenous dsRNA as nonself. To date, few studies have investigated the population genomic signatures of A-to-I editing due to the lack of editing sites overlapping with SNPs. Results In this study, we applied a pipeline to robustly identify SNP editing sites from population transcriptomic data and combined functional genomics, GWAS, and population genomics approaches to study the function and evolution of A-to-I editing. We find that the G allele, which is equivalent to edited I, is overrepresented in editing SNPs. Functionally, A/G editing SNPs are highly enriched in GWAS signals of autoimmune and immune-related diseases. Evolutionarily, derived allele frequency distributions of A/G editing SNPs for both A and G alleles as the ancestral alleles are skewed toward intermediate frequency alleles relative to neutral SNPs, a hallmark of balancing selection, suggesting that both A and G alleles are functionally important. The signal of balancing selection is confirmed by a number of additional population genomic analyses. Conclusions We uncovered a hidden layer of A-to-I RNA editing SNP loci as a common target of balancing selection, and we propose that the maintenance of such editing SNP variations may be at least partially due to constraints on the resolution of the balance between immune activity and self-tolerance.

中文翻译：

---

人类 A-to-I RNA 编辑 SNP 位点富含用于自身免疫性疾病的 GWAS 信号和平衡选择

背景腺苷到肌苷 (A-to-I) RNA 编辑在使转录组多样化和阻止 MDA5 将内源性 dsRNA 感知为非自身方面发挥着重要作用。迄今为止，由于缺乏与 SNP 重叠的编辑位点，很少有研究调查 A-to-I 编辑的群体基因组特征。结果在这项研究中，我们应用了一个管道从群体转录组数据中可靠地识别 SNP 编辑位点，并结合功能基因组学、GWAS 和群体基因组学方法来研究 A-to-I 编辑的功能和进化。我们发现 G 等位基因，相当于编辑的 I，在编辑 SNP 中的比例过高。在功能上，A/G 编辑 SNP 在自身免疫和免疫相关疾病的 GWAS 信号中高度富集。进化上，A/G 编辑 SNP 的 A/G 等位基因的等位基因频率分布，因为祖先等位基因相对于中性 SNP 偏向中频等位基因，这是平衡选择的标志，表明 A 和 G 等位基因在功能上都很重要。许多额外的群体基因组分析证实了平衡选择的信号。结论我们发现了一个隐藏的 A-to-I RNA 编辑 SNP 位点作为平衡选择的共同目标，我们提出这种编辑 SNP 变异的维持可能至少部分是由于对平衡之间平衡分辨率的限制免疫活性和自我耐受性。表明 A 和 G 等位基因在功能上都很重要。许多额外的群体基因组分析证实了平衡选择的信号。结论我们发现了一个隐藏的 A-to-I RNA 编辑 SNP 位点作为平衡选择的共同目标，我们提出这种编辑 SNP 变异的维持可能至少部分是由于对平衡之间平衡分辨率的限制免疫活性和自我耐受性。表明 A 和 G 等位基因在功能上都很重要。许多额外的群体基因组分析证实了平衡选择的信号。结论我们发现了一个隐藏的 A-to-I RNA 编辑 SNP 位点作为平衡选择的共同目标，我们提出这种编辑 SNP 变异的维持可能至少部分是由于对平衡之间平衡分辨率的限制免疫活性和自我耐受性。