The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has triggered an unprecedented international effort to sequence complete viral genomes. We leveraged this wealth of information to characterize the substitution spectrum of SARS-CoV-2 and to compare it with those of other human and animal coronaviruses. We show that, once nucleotide composition is taken into account, human and most animal coronaviruses display a mutation spectrum dominated by C to U and G to U substitutions, a feature that is not shared by other positive-sense RNA viruses. However, the proportions of C to U and G to U substitutions tend to decrease as divergence increases, suggesting that, whatever their origin, a proportion of these changes is subsequently eliminated by purifying selection. Analysis of the sequence context of C to U substitutions showed little evidence of apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC)-mediated editing and such contexts were similar for SARS-CoV-2 and Middle East respiratory syndrome coronavirus sampled from different hosts, despite different repertoires of APOBEC3 proteins in distinct species. Conversely, we found evidence that C to U and G to U changes affect CpG dinucleotides at a frequency higher than expected. Whereas this suggests ongoing selective reduction of CpGs, this effect alone cannot account for the substitution spectra. Finally, we show that, during the first months of SARS-CoV-2 pandemic spread, the frequency of both G to U and C to U substitutions increased. Our data suggest that the substitution spectrum of SARS-CoV-2 is determined by an interplay of factors, including intrinsic biases of the replication process, avoidance of CpG dinucleotides and other constraints exerted by the new host.

中文翻译：

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冠状病毒基因组的取代谱


严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 大流行引发了前所未有的国际努力，对完整病毒基因组进行测序。我们利用这些丰富的信息来描述 SARS-CoV-2 的替代谱，并将其与其他人类和动物冠状病毒的替代谱进行比较。我们发现，一旦考虑到核苷酸组成，人类和大多数动物冠状病毒就会表现出以 C 到 U 和 G 到 U 取代为主的突变谱，这是其他正义 RNA 病毒所不具备的特征。然而，随着差异的增加，C 到 U 和 G 到 U 取代的比例往往会减少，这表明，无论其来源如何，这些变化的一部分随后会通过纯化选择而消除。对 C 到 U 替换的序列背景分析显示，几乎没有证据表明载脂蛋白 B mRNA 编辑催化多肽样 (APOBEC) 介导的编辑，并且从不同宿主采集的 SARS-CoV-2 和中东呼吸综合征冠状病毒的此类背景相似，尽管不同物种的 APOBEC3 蛋白具有不同的功能。相反，我们发现证据表明 C 到 U 和 G 到 U 的变化以高于预期的频率影响 CpG 二核苷酸。尽管这表明 CpG 正在进行选择性还原，但仅靠这种效应并不能解释取代谱。最后，我们发现，在 SARS-CoV-2 大流行传播的最初几个月，G 到 U 和 C 到 U 的替换频率均有所增加。我们的数据表明，SARS-CoV-2 的替代谱是由多种因素的相互作用决定的，包括复制过程的内在偏差、CpG 二核苷酸的避免以及新宿主施加的其他限制。