Evolving ribonucleocapsid assembly/packaging signals in the genomes of the human and animal coronaviruses: targeting, transmission and evolution

A world-wide COVID-19 pandemic intensified strongly the studies of molecular mechanisms related to the coronaviruses. The origin of coronaviruses and the risks of human-to-human, animal-to-human and human-to-animal transmission of coronaviral infections can be understood only on a broader evolutionary level by detailed comparative studies. In this paper, we studied ribonucleocapsid assembly-packaging signals (RNAPS) in the genomes of all seven known pathogenic human coronaviruses, SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-OC43, HCoV-HKU1, HCoV-229E and HCoV-NL63 and compared them with RNAPS in the genomes of the related animal coronaviruses including SARS-Bat-CoV, MERS-Camel-CoV, MHV, Bat-CoV MOP1, TGEV and one of camel alphacoronaviruses. RNAPS in the genomes of coronaviruses were evolved due to weakly specific interactions between genomic RNA and N proteins in helical nucleocapsids. Combining transitional genome mapping and Jaccard correlation coefficients allows us to perform the analysis directly in terms of underlying motifs distributed over the genome. In all coronaviruses, RNAPS were distributed quasi-periodically over the genome with the period about 54 nt biased to 57 nt and to 51 nt for the genomes longer and shorter than that of SARS-CoV, respectively. The comparison with the experimentally verified packaging signals for MERS-CoV, MHV and TGEV proved that the distribution of particular motifs is strongly correlated with the packaging signals. We also found that many motifs were highly conserved in both characters and positioning on the genomes throughout the lineages that make them promising therapeutic targets. The mechanisms of encapsidation can affect the recombination and co-infection as well. Communicated by Ramaswamy H. Sarma

全球新型冠状病毒肺炎（COVID-19）大流行极大地推动了冠状病毒（coronaviruses）相关分子机制的研究。唯有通过更广阔进化视角下的详细比较研究，我们才能阐明冠状病毒的起源，以及冠状病毒感染的人际、动物传人及人传动物传播风险。本研究针对已知7株致病性人类冠状病毒的基因组，分析了其中的核糖核衣壳组装包装信号（ribonucleocapsid assembly-packaging signals, RNAPS），这7株病毒分别为：严重急性呼吸综合征冠状病毒（SARS-CoV）、新型冠状病毒（SARS-CoV-2）、中东呼吸综合征冠状病毒（MERS-CoV）、人类冠状病毒OC43（HCoV-OC43）、人类冠状病毒HKU1（HCoV-HKU1）、人类冠状病毒229E（HCoV-229E）以及人类冠状病毒NL63（HCoV-NL63）；同时将这些信号与相关动物冠状病毒基因组中的RNAPS进行了比对分析，相关动物冠状病毒包括蝙蝠源严重急性呼吸综合征冠状病毒（SARS-Bat-CoV）、骆驼源中东呼吸综合征冠状病毒（MERS-Camel-CoV）、鼠肝炎病毒（MHV）、蝙蝠冠状病毒MOP1（Bat-CoV MOP1）、猪传染性胃肠炎病毒（TGEV）以及一种骆驼源甲型冠状病毒（camel alphacoronaviruses）。冠状病毒基因组中的RNAPS是通过基因组RNA与螺旋形核衣壳（helical nucleocapsids）中核衣壳蛋白（N protein）之间的弱特异性相互作用演化而来的。结合过渡基因组映射与雅卡尔相关系数（Jaccard correlation coefficients），我们可直接基于分布于基因组的核心基序开展分析。在所有冠状病毒中，RNAPS均以准周期性分布于基因组，其周期约为54 nt；对于长度长于、短于严重急性呼吸综合征冠状病毒基因组的病毒株，该周期分别偏向57 nt与51 nt。通过与经实验验证的中东呼吸综合征冠状病毒、鼠肝炎病毒以及猪传染性胃肠炎病毒的包装信号进行比对，证实了特定基序的分布与包装信号具有显著相关性。本研究还发现，在各进化谱系中，诸多基序的序列特征及其在基因组上的位置均高度保守，这使得这些基序成为极具潜力的治疗靶点。病毒衣壳装配机制同样会对重组与共感染过程产生影响。本文由Ramaswamy H. Sarma转交。