Background Mobile elements comprise a large fraction of metazoan genomes. Accumulation of mobile elements is bound to produce multiple putative double-stranded RNA (dsRNA) structures within the transcriptome. These endogenous dsRNA structures resemble viral RNA and may trigger false activation of the innate immune response, leading to severe damage to the host cell. Adenosine to inosine (A-to-I) RNA editing is a common post-transcriptional modification, abundant within repetitive elements of all metazoans. It was recently shown that a key function of A-to-I RNA editing by ADAR1 is to suppress the immunogenic response by endogenous dsRNAs. Results Here, we analyze the transcriptomes of dozens of species across the Metazoa and identify a strong genomic selection against endogenous dsRNAs, resulting in their purification from the canonical transcriptome. This purifying selection is especially strong for long and nearly perfect dsRNAs. These are almost absent from mRNAs, but not pre-mRNAs, supporting the notion of selection due to cytoplasmic processes. The few long and nearly perfect structures found in human transcripts are weakly expressed and often heavily edited. Conclusion Purifying selection of long dsRNA is an important defense mechanism against false activation of innate immunity. This newly identified principle governs the integration of mobile elements into the genome, a major driving force of genome evolution. Furthermore, we find that most ADAR1 activity is not required to prevent an immune response to endogenous dsRNAs. The critical targets of ADAR1 editing are, likely, to be found mostly in non-canonical transcripts.

中文翻译：

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长 dsRNA 的纯化选择是防止先天免疫错误激活的第一道防线

背景 移动元件构成后生动物基因组的很大一部分。移动元件的积累必然会在转录组内产生多个假定的双链 RNA (dsRNA) 结构。这些内源性 dsRNA 结构类似于病毒 RNA，可能会触发先天免疫反应的错误激活，从而导致宿主细胞严重受损。腺苷至肌苷 (A-to-I) RNA 编辑是一种常见的转录后修饰，在所有后生动物的重复元件中大量存在。最近的研究表明，ADAR1 进行 A 到 I RNA 编辑的一个关键功能是抑制内源 dsRNA 的免疫原性反应。结果在这里，我们分析了后生动物中数十个物种的转录组，并确定了针对内源 dsRNA 的强大基因组选择，从而从规范转录组中纯化了它们。这种纯化选择对于长且近乎完美的 dsRNA 来说尤其有效。这些在 mRNA 中几乎不存在，但前体 mRNA 中却没有，这支持了由于细胞质过程而进行选择的概念。在人类转录本中发现的少数长且近乎完美的结构表达较弱，并且经常被大量编辑。结论 长 dsRNA 的纯化选择是防止先天免疫错误激活的重要防御机制。这一新发现的原理控制着移动元件与基因组的整合，这是基因组进化的主要驱动力。此外，我们发现大多数 ADAR1 活性并不是阻止对内源 dsRNA 的免疫反应所必需的。ADAR1 编辑的关键目标很可能主要存在于非规范转录本中。