Human A-to-I RNA editing SNP loci are enriched in GWAS signals for autoimmune diseases and under balancing selection
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RESEARCH
Open Access
Human A-to-I RNA editing SNP loci are enriched in GWAS signals for autoimmune diseases and under balancing selection Hui Zhang1,2†, Qiang Fu1†, Xinrui Shi1†, Ziqing Pan1, Wenbing Yang1, Zichao Huang1, Tian Tang3, Xionglei He1 and Rui Zhang1,4* * Correspondence: zhangrui3@mail. sysu.edu.cn † Hui Zhang, Qiang Fu and Xinrui Shi contributed equally to this work. 1 Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, People’s Republic of China 4 RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China Full list of author information is available at the end of the article
Abstract 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. Keywords: A-to-I RNA editing, Autoimmune and immune-related diseases, Transcriptome, Balancing selection
Introduction RNA editing is a process through which the sequence of an RNA is posttranscriptionally altered from that encoded in the DNA [1, 2]. A-to-I RNA editing is the most common type of RNA editing in metazoans [3]. It is mediated by Adenosine Deaminases Acting on RNA (ADARs), which bind dsRNA regions of protein-coding and non-coding RNAs and deaminate adenosine to inosine [2, 4, 5]. Inosine pairs © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, pro
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