The Heterogeneous Landscape and Early Evolution of Pathogen-Associated CpG Dinucleotides in SARS-CoV-2.
The Heterogeneous Landscape and Early Evolution of Pathogen-Associated CpG Dinucleotides in SARS-CoV-2.
复制标题
DOI：
10.2139/ssrn.3611280
复制
发表时间：
2020-05
期刊：
影响因子：
--
通讯作者：
A. Di Gioacchino;P. Šulc;A. Komarova;B. Greenbaum;R. Monasson;S. Cocco
中科院分区：
文献类型：
--
作者：
A. Di Gioacchino;P. Šulc;A. Komarova;B. Greenbaum;R. Monasson;S. Cocco
SARS-CoV-2 感染可导致患者出现急性呼吸综合征，部分原因是免疫信号失调。我们在这里分析 CpG 二核苷酸的出现，它们是沿着病毒序列的假定的病原体相关分子模式。通过与冠状病毒科中的其他 ssRNA 病毒进行比较分析，我们发现 SARS-CoV-2 的 CpG 含量虽然低于其他 β 冠状病毒，但其一级序列波动很大。虽然刺突蛋白 (S) 的 CpG 相对丰度及其相关的 CpG 力参数较低，与流行的季节性冠状病毒（如 HKU1）相当，但对于病毒基因组的 3' 端，它们的相对丰度及其相关的 CpG 力参数要大得多，并且与 SARS 和 MERS 相当。特别是核衣壳蛋白（N），其转录物在感染细胞的细胞质中相对丰富，并且存在于所有亚基因组RNA的3'UTR中，具有较高的CpG含量。我们推测 CpG 内容的这种双重性质可以赋予 SARS-CoV-2 进入宿主并在不同环境下触发模式识别受体 (PRR) 的高能力。然后，我们研究了自 COVID-19 大流行爆发以来同义突变的演变。使用二核苷酸选择性力的新应用来估计环境驱动的突变过程，我们发现同义突变似乎是由病毒密码子偏倚和 N 蛋白中 CpG 力的高值驱动的，导致 CpG 含量的损失。这些 CpG 丢失相关基因座匹配之前的序列基序最近鉴定了锌指抗病毒蛋白 (ZAP) 蛋白的结合模式。资助：这项工作得到了 ANR19 解密 CE30-0021-01 赠款的部分支持。 B.G.得到了美国国立卫生研究院赠款 7R01AI081848-04、1R01CA240924-01、抗击癌症 - Lustgarten 基金会融合梦之队赠款以及潘兴广场索恩奖 - 马克基金会研究员的支持，并得到了马克癌症研究基金会的资助。
SARS-CoV-2 infection can lead to acute respiratory syndrome in patients, which can be due in part to dysregulated immune signalling. We analyze here the occurrences of CpG dinucleotides, which are putative pathogen-associated molecular patterns, along the viral sequence. Carrying out a comparative analysis with other ssRNA viruses and within the Coronaviridae family, we find the CpG content of SARS-CoV-2, while low compared to other betacoronaviruses, widely fluctuates along its primary sequence. While the CpG relative abundance and its associated CpG force parameter are low for the spike protein (S) and comparable to circulating seasonal coronaviruses such as HKU1, they are much greater and comparable to SARS and MERS for the 3'-end of the viral genome. In particular, the nucleocapsid protein (N), whose transcripts are relatively abundant in the cytoplasm of infected cells and present in the 3'UTRs of all subgenomic RNA, has high CpG content. We speculate this dual nature of CpG content can confer to SARS-CoV-2 high ability to both enter the host and trigger pattern recognition receptors (PRRs) in different contexts. We then investigate the evolution of synonymous mutations since the outbreak of the COVID-19 pandemic. Using a new application of selective forces on dinucleotides to estimate context driven mutational processes, we find that synonymous mutations seem driven both by the viral codon bias and by the high value of the CpG force in the N protein, leading to a loss in CpG content. Sequence motifs preceding these CpG-loss-associated loci match recently identified binding patterns of the Zinc Finger anti-viral Protein (ZAP) protein. Funding: This work was partially supported by the ANR19 Decrypted CE30-0021-01 grants. B.G. was supported by National Institutes of Health grants 7R01AI081848-04, 1R01CA240924-01, a Stand Up to Cancer - Lustgarten Foundation Convergence Dream Team Grant, and The Pershing Square Sohn Prize - Mark Foundation Fellow supported by funding from The Mark Foundation for Cancer Research.