Abstract CpG dinucleotides are under-represented in the genomes of single-stranded RNA viruses, and SARS-CoV-2 is no exception to this. Artificial modification of CpG frequency is a valid approach for live attenuated vaccine development; if this is to be applied to SARS-CoV-2, we must first understand the role CpG motifs play in regulating SARS-CoV-2 replication. Accordingly, the CpG composition of the SARS-CoV-2 genome was characterised. CpG suppression among coronaviruses does not differ between virus genera but does vary with host species and primary replication site (a proxy for tissue tropism), supporting the hypothesis that viral CpG content may influence cross-species transmission. Although SARS-CoV-2 exhibits overall strong CpG suppression, this varies considerably across the genome, and the Envelope (E) open reading frame (ORF) and ORF10 demonstrate an absence of CpG suppression. Across the Coronaviridae, E genes display remarkably high variation in CpG composition, with those of SARS and SARS-CoV-2 having much higher CpG content than other coronaviruses isolated from humans. This is an ancestrally derived trait reflecting their bat origins. Conservation of CpG motifs in these regions suggests that they have a functionality which over-rides the need to suppress CpG; an observation relevant to future strategies towards a rationally attenuated SARS-CoV-2 vaccine.

中文翻译：

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SARS-CoV-2 二核苷酸组成的基因组内变异


摘要 CpG 二核苷酸在单链 RNA 病毒基因组中的代表性不足，SARS-CoV-2 也不例外。人工修饰 CpG 频率是减毒活疫苗开发的有效方法；如果要将其应用于 SARS-CoV-2，我们必须首先了解 CpG 基序在调节 SARS-CoV-2 复制中所起的作用。因此，对 SARS-CoV-2 基因组的 CpG 组成进行了表征。冠状病毒中的 CpG 抑制在病毒属之间没有差异，但随宿主物种和初级复制位点（组织向性的代表）而变化，支持病毒 CpG 含量可能影响跨物种传播的假设。尽管 SARS-CoV-2 总体上表现出强烈的 CpG 抑制，但在整个基因组中差异很大，并且信封 (E) 开放阅读框 (ORF) 和 ORF10 表明不存在 CpG 抑制。在冠状病毒科中，E 基因在 CpG 组成方面表现出非常高的变异，其中 SARS 和 SARS-CoV-2 的 CpG 含量比从人类分离的其他冠状病毒高得多。这是祖先衍生的特征，反映了它们的蝙蝠起源。这些区域中 CpG 基序的保守性表明它们具有超越抑制 CpG 的需要的功能；与合理减毒 SARS-CoV-2 疫苗的未来策略相关的观察结果。