National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.
mSystems. 2022 Jun 28;7(3):e0017922. doi: 10.1128/msystems.00179-22. Epub 2022 May 18.
Insertions in the SARS-CoV-2 genome have the potential to drive viral evolution, but the source of the insertions is often unknown. Recent proposals have suggested that human RNAs could be a source of some insertions, but the small size of many insertions makes this difficult to confirm. Through an analysis of available direct RNA sequencing data from SARS-CoV-2-infected cells, we show that viral-host chimeric RNAs are formed through what are likely stochastic RNA-dependent RNA polymerase template-switching events. Through an analysis of the publicly available GISAID SARS-CoV-2 genome collection, we identified two genomic insertions in circulating SARS-CoV-2 variants that are identical to regions of the human 18S and 28S rRNAs. These results provide direct evidence of the formation of viral-host chimeric sequences and the integration of host genetic material into the SARS-CoV-2 genome, highlighting the potential importance of host-derived insertions in viral evolution. Throughout the COVID-19 pandemic, the sequencing of SARS-CoV-2 genomes has revealed the presence of insertions in multiple globally circulating lineages of SARS-CoV-2, including the Omicron variant. The human genome has been suggested to be the source of some of the larger insertions, but evidence for this kind of event occurring is still lacking. Here, we leverage direct RNA sequencing data and SARS-CoV-2 genomes to show that host-viral chimeric RNAs are generated in infected cells and two large genomic insertions have likely been formed through the incorporation of host rRNA fragments into the SARS-CoV-2 genome. These host-derived insertions may increase the genetic diversity of SARS-CoV-2 and expand its strategies to acquire genetic material, potentially enhancing its adaptability, virulence, and spread.
SARS-CoV-2 基因组中的插入有可能推动病毒进化，但插入的来源通常未知。最近的研究表明，人类 RNA 可能是某些插入的来源，但许多插入的片段很小，这使得确认这一点变得困难。通过对来自 SARS-CoV-2 感染细胞的可用直接 RNA 测序数据进行分析，我们表明，病毒-宿主嵌合 RNA 是通过可能的随机 RNA 依赖性 RNA 聚合酶模板转换事件形成的。通过对公开的 GISAID SARS-CoV-2 基因组集合进行分析，我们在循环的 SARS-CoV-2 变体中鉴定出两个与人类 18S 和 28S rRNA 区域相同的基因组插入。这些结果提供了病毒-宿主嵌合序列形成和宿主遗传物质整合到 SARS-CoV-2 基因组中的直接证据，突出了宿主衍生插入在病毒进化中的潜在重要性。 在整个 COVID-19 大流行期间，对 SARS-CoV-2 基因组的测序揭示了多个全球循环的 SARS-CoV-2 谱系中存在插入，包括奥密克戎变体。人类基因组被认为是一些较大插入的来源，但这种事件发生的证据仍然缺乏。在这里，我们利用直接 RNA 测序数据和 SARS-CoV-2 基因组表明，在感染细胞中生成了宿主-病毒嵌合 RNA，并且两个大的基因组插入很可能是通过将宿主 rRNA 片段整合到 SARS-CoV-2 基因组中形成的。这些宿主衍生的插入可能会增加 SARS-CoV-2 的遗传多样性，并扩大其获取遗传物质的策略，从而可能增强其适应性、毒力和传播能力。
