RNA editome in rhesus macaque shaped by purifying selection.
RNA editome in rhesus macaque shaped by purifying selection.
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通过纯化选择塑造恒河猴的RNA编辑组
DOI：
10.1371/journal.pgen.1004274
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发表时间：
2014-04
期刊：
影响因子：
4.5
通讯作者：
Li CY
中科院分区：
文献类型：
--
作者：
Chen JY;Peng Z;Zhang R;Yang XZ;Tan BC;Fang H;Liu CJ;Shi M;Ye ZQ;Zhang YE;Deng M;Zhang X;Li CY
下一代测序技术大大拓宽了人们对 RNA 编辑过程的理解；然而，有关这一监管步骤的几个问题仍未解决——准确描述编辑组的策略、维持其概况的机制以及其进化和功能相关性。在此，我们报告了人类近亲恒河猴的 RNA 编辑组的准确定量图谱。通过结合同一动物多个组织的基因组和转录组测序，我们鉴定了 31,250 个编辑位点，其中 99.8% 是 A 到 G 的转换。我们通过多种独立手段验证了编码区96.6%的编辑位点和非编码区97.5%的随机选择位点，以及相应的编辑水平，证明了我们的实验范式的可行性。多项证据支持这样的观点，即腺苷脱氨基与猕猴编辑组相关——A 到 G 编辑位点的两侧是具有 ADAR 底物属性的序列，并且 ADAR 的序列背景和表达谱都是确定不同位点和组织类型之间 RNA 编辑的定量差异的相关因素。为了支持其中一些编辑位点的功能相关性，在编辑位点周围检测到发散减少的取代谷，这表明维持这些编辑底物中的一些具有双链结构的进化限制。因此，这些发现补充了“持续探测”模型，该模型假设一小部分功能编辑位点的起源是基于修补的。总之，本文报道的猕猴编辑组强调了 RNA 编辑作为灵长类动物进化中广泛的功能调节，并为进一步了解人类 RNA 编辑提供了信息框架。 RNA 编辑是一种共转录过程，它引入了 RNA 及其相应 DNA 序列之间的差异。目前，下一代测序已经能够以全面、高效的方式研究编辑组。然而，涉及编辑组准确定位及其调控和功能结果的基本问题仍未解决。为了从进化的角度进一步揭示潜在机制，我们在此报告了恒河猴（我们最接近的进化亲戚之一）的编辑组概况。我们确定了 31,250 个 RNA 编辑位点的列表，并破译了跨多个组织和动物的准确且信息丰富的编辑组。我们发现腺苷脱氨与猕猴编辑组相关，因为 ADAR 的序列背景和表达谱都是确定不同位点和组织类型之间 RNA 编辑定量差异的相关因素。重要的是，这些RNA编辑事件中的一些代表功能调节，而不是中性信号，正如在编辑位点周围检测到的发散减少的取代谷所表明的那样，这表明在维持这些编辑底物中的一些具有双链结构方面存在选择性限制。因此，猕猴编辑组为深入了解 RNA 编辑调控提供了信息丰富的进化背景。
Understanding of the RNA editing process has been broadened considerably by the next generation sequencing technology; however, several issues regarding this regulatory step remain unresolved – the strategies to accurately delineate the editome, the mechanism by which its profile is maintained, and its evolutionary and functional relevance. Here we report an accurate and quantitative profile of the RNA editome for rhesus macaque, a close relative of human. By combining genome and transcriptome sequencing of multiple tissues from the same animal, we identified 31,250 editing sites, of which 99.8% are A-to-G transitions. We verified 96.6% of editing sites in coding regions and 97.5% of randomly selected sites in non-coding regions, as well as the corresponding levels of editing by multiple independent means, demonstrating the feasibility of our experimental paradigm. Several lines of evidence supported the notion that the adenosine deamination is associated with the macaque editome – A-to-G editing sites were flanked by sequences with the attributes of ADAR substrates, and both the sequence context and the expression profile of ADARs are relevant factors in determining the quantitative variance of RNA editing across different sites and tissue types. In support of the functional relevance of some of these editing sites, substitution valley of decreased divergence was detected around the editing site, suggesting the evolutionary constraint in maintaining some of these editing substrates with their double-stranded structure. These findings thus complement the “continuous probing” model that postulates tinkering-based origination of a small proportion of functional editing sites. In conclusion, the macaque editome reported here highlights RNA editing as a widespread functional regulation in primate evolution, and provides an informative framework for further understanding RNA editing in human. RNA editing is a co-transcriptional process that introduces differences between RNA and its corresponding DNA sequence. Currently, the next generation sequencing have allowed study of the editome in a comprehensive and efficient manner. However, fundamental issues involving accurate mapping of the editome as well as its regulation and functional outcome remain unresolved. To further unveil the underlying mechanisms from the evolutionary perspective, we report here the editome profile in rhesus macaque, one of our closest evolutionary relatives. We identified a list of 31,250 RNA-editing sites and deciphered an accurate and informative editome across multiple tissues and animals. We found that the adenosine deamination is associated with the macaque editome, in that both the sequence context and the expression profile of ADARs are relevant factors in determining the quantitative variance of RNA editing across different sites and tissue types. Importantly, some of these RNA-editing events represent functional regulation, rather than neutral signals, as suggested by substitution valley of decreased divergence detected around the editing sites, an indication of selective constraint in maintaining some of these editing substrates with their double-stranded structure. The macaque editome thus provides an informative evolutionary context for an in-depth understanding of RNA editing regulation.