Identification of widespread ultra-edited human RNAs.
Identification of widespread ultra-edited human RNAs.
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识别广泛的超编辑人类RNA。
DOI：
10.1371/journal.pgen.1002317
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发表时间：
2011-10
期刊：
影响因子：
4.5
通讯作者：
Levanon EY
中科院分区：
文献类型：
--
作者：
Carmi S;Borukhov I;Levanon EY
RNA 分子的腺苷到肌苷修饰（A 到 I RNA 编辑）是增加转录组多样性的重要机制。当 ADAR 蛋白将基因组编码的腺苷 (A) 转化为肌苷 (I) 时，就会发生这种情况。测序反应将肌苷读取为鸟苷（G）；因此，目前检测 A 到 I 编辑位点的方法是将 RNA 序列与其相应的 DNA 区域对齐并识别 A 到 G 错配。然而，此类方法对于经过大量编辑（“超”编辑）的 RNA 表现不佳，因为大量的错配掩盖了这些 RNA 的基因组起源。因此，到目前为止，仅发现了一些传闻中的超编辑RNA。在这里，我们介绍并应用一种新的计算方法来识别超编辑的 RNA。我们检测到 760 个 EST，包含 15,646 个编辑位点（平均每个 EST 超过 20 个位点），其中 13,668 个是新颖的。超编辑的 RNA 表现出 ADAR 的已知序列基序，并且倾向于定位于有义链 Alu 元件中。与轻度编辑位点相比，超编辑主要发生在富含 Alu 的区域，其中与邻近的反向 Alu 的潜在碱基配对会产生特别长的双链 RNA 结构。超编辑位点在古老的 Alu 亚家族中代表性不足，往往是不保守的，并且避免外显子，这表明超编辑通常是有害的。超编辑的一个可能的生物学功能可以通过编辑位点附近的 RNA 的非规范剪接和切割来介导。自从发现众多 RNA 加工途径以来，过去几十年来，将 mRNA 作为 DNA 和蛋白质之间的纯粹中间体的传统观点发生了变化。常见的 RNA 修饰是 A 至 I 编辑，或将腺苷 (A) 转化为肌苷 (I)。由于肌苷被解读为鸟苷 (G)，A 到 I 编辑会导致 RNA 序列发生变化，从而改变其编码蛋白质的功能。近年来，通过计算比较 RNA 序列与人类基因组并搜索 A 到 G 错配，发现了数以万计的人类 A 到 I 编辑位点。然而，以前的筛选通常忽略了经过极端编辑的RNA序列，因为这些RNA携带的大量A到G错配掩盖了它们的基因组起源。我们开发了一种新的计算框架来检测极端的 A-to-I 编辑或超编辑，其基础是在与基因组比对之前屏蔽潜在的编辑位点。我们的方法检测到大约 14,000 个编辑位点，每个编辑过的分子平均有超过 20 个核苷酸受到影响。我们证明，对这些序列进行超编辑的可能原因是它们有可能折叠成特别长的双链结构，这是编辑酶的首选目标。
Adenosine-to-inosine modification of RNA molecules (A-to-I RNA editing) is an important mechanism that increases transciptome diversity. It occurs when a genomically encoded adenosine (A) is converted to an inosine (I) by ADAR proteins. Sequencing reactions read inosine as guanosine (G); therefore, current methods to detect A-to-I editing sites align RNA sequences to their corresponding DNA regions and identify A-to-G mismatches. However, such methods perform poorly on RNAs that underwent extensive editing (“ultra”-editing), as the large number of mismatches obscures the genomic origin of these RNAs. Therefore, only a few anecdotal ultra-edited RNAs have been discovered so far. Here we introduce and apply a novel computational method to identify ultra-edited RNAs. We detected 760 ESTs containing 15,646 editing sites (more than 20 sites per EST, on average), of which 13,668 are novel. Ultra-edited RNAs exhibit the known sequence motif of ADARs and tend to localize in sense strand Alu elements. Compared to sites of mild editing, ultra-editing occurs primarily in Alu-rich regions, where potential base pairing with neighboring, inverted Alus creates particularly long double-stranded RNA structures. Ultra-editing sites are underrepresented in old Alu subfamilies, tend to be non-conserved, and avoid exons, suggesting that ultra-editing is usually deleterious. A possible biological function of ultra-editing could be mediated by non-canonical splicing and cleavage of the RNA near the editing sites. The traditional view of mRNA as a pure intermediate between DNA and protein has changed in the last decades since the discovery of numerous RNA processing pathways. A frequent RNA modification is A-to-I editing, or the conversion of adenosine (A) to inosine (I). Since inosine is read as a guanosine (G), A-to-I editing leads to changes in the RNA sequence that can alter the function of its encoded protein. In recent years, tens of thousands of human A-to-I editing sites were discovered by computationally comparing RNA sequences to the human genome and searching for A-to-G mismatches. However, previous screens usually ignored RNA sequences that were edited to extreme, because the large number of A-to-G mismatches carried by these RNAs obscured their genomic origin. We developed a new computational framework to detect extreme A-to-I editing, or ultra-editing, based on masking potential editing sites before the alignment to the genome. Our method detected about 14,000 editing sites, with each edited molecule affected, on average, in more than 20 nucleotides. We demonstrated that the likely reason for the ultra-editing of those sequences is their potential to fold back into a particularly long double-stranded structure, which is the preferred target of the editing enzymes.
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