The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has motivated an intensive analysis of its molecular epidemiology following its worldwide spread. To understand the early evolutionary events following its emergence, a data set of 985 complete SARS-CoV-2 sequences was assembled. Variants showed a mean of 5.5 to 9.5 nucleotide differences from each other, consistent with a midrange coronavirus substitution rate of 3 × 10⁻⁴ substitutions/site/year. Almost one-half of sequence changes were C→U transitions, with an 8-fold base frequency normalized directional asymmetry between C→U and U→C substitutions. Elevated ratios were observed in other recently emerged coronaviruses (SARS-CoV, Middle East respiratory syndrome [MERS]-CoV), and decreasing ratios were observed in other human coronaviruses (HCoV-NL63, -OC43, -229E, and -HKU1) proportionate to their increasing divergence. C→U transitions underpinned almost one-half of the amino acid differences between SARS-CoV-2 variants and occurred preferentially in both 5′ U/A and 3′ U/A flanking sequence contexts comparable to favored motifs of human APOBEC3 proteins. Marked base asymmetries observed in nonpandemic human coronaviruses (U ≫ A > G ≫ C) and low G+C contents may represent long-term effects of prolonged C→U hypermutation in their hosts. The evidence that much of sequence change in SARS-CoV-2 and other coronaviruses may be driven by a host APOBEC-like editing process has profound implications for understanding their short- and long-term evolution. Repeated cycles of mutation and reversion in favored mutational hot spots and the widespread occurrence of amino acid changes with no adaptive value for the virus represent a quite different paradigm of virus sequence change from neutral and Darwinian evolutionary frameworks and are not incorporated by standard models used in molecular epidemiology investigations.

中文翻译：

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SARS-CoV-2 和其他冠状病毒基因组中猖獗的 C→U 超突变：其短期和长期进化轨迹的原因和后果。


严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 在全球范围内传播后，引发了对其分子流行病学的深入分析。为了了解其出现后的早期进化事件，我们收集了 985 个完整 SARS-CoV-2 序列的数据集。变体之间平均存在 5.5 至 9.5 个核苷酸差异，这与 3 × 10 ^-4个替换/位点/年的中等冠状病毒替换率一致。几乎一半的序列变化是 C→U 转换，C→U 和 U→C 取代之间的基频归一化方向不对称性为 8 倍。在其他最近出现的冠状病毒（SARS-CoV、中东呼吸综合征 [MERS]-CoV）中观察到比率升高，在其他人类冠状病毒（HCoV-NL63、-OC43、-229E 和 -HKU1）中观察到比率下降。导致他们的分歧越来越大。 C→U 转换支撑了 SARS-CoV-2 变体之间近一半的氨基酸差异，并且优先发生在 5'U/A 和 3'U/A 侧翼序列环境中，与人类 APOBEC3 蛋白的偏好基序相当。在非大流行人类冠状病毒中观察到的明显碱基不对称性（U≫A>G≫C）和低G+C含量可能代表了宿主中长期C→U超突变的长期影响。 SARS-CoV-2 和其他冠状病毒的大部分序列变化可能是由宿主 APOBEC 样编辑过程驱动的证据对于理解它们的短期和长期进化具有深远的意义。 在有利的突变热点中重复的突变和回复循环以及对病毒没有适应性价值的氨基酸变化的广泛发生代表了与中性和达尔文进化框架完全不同的病毒序列变化范式，并且没有被纳入用于病毒的标准模型中。分子流行病学调查。