RAPID: Analyses of polymorphism and divergence to illuminate molecular evolution permissive of zoonoses in SARS and COVID-19

COVID-19疾病已经导致了过去二十年来的第三次大爆发，这是由动物冠状病毒向人类蔓延造成的。这其中，最为严重的是。新疾病的出现通常是因为这种溢出效应。然而，目前尚不清楚导致COVID-19的病毒中的基因变化使其能够感染人类。为了确定这些基因变化，该项目将使用新开发的计算方法来比较感染人类的冠状病毒中的基因与感染其他动物宿主的冠状病毒中的基因。病毒基因组的这种比较将有助于了解冠状病毒基因组中的哪些位点能够实现宿主物种的转换，以及哪些位点在宿主转换后发生变化。了解这些遗传机制对于确定冠状病毒转换宿主能力的一般规则是否是关键，以及为人类感染后冠状病毒基因组经历的变化提供必要的历史背景。随后的知识为疫苗设计和药物开发的持续决策提供了新目标的精确指导。该项目的成果也将被纳入北卡罗来纳州自然科学博物馆的多个引人入胜的教育展览中。该项目将应用分子进化方法来揭示SARS-CoV-1、SARS-CoV-2和从储存宿主测序的病毒的进化速率，揭示在病毒基因组中接近人畜共患病的位点之间的选择强度。首先，从受感染的人类和动物宿主中收集的现存SARS致病、SARS样和COVID-19致病病毒序列的系统发育比较将用于重建冠状病毒进化的历史。其次，在动物宿主中传播的病毒、SARS爆发期间在人类中传播的病毒以及COVID-19大流行期间在人类中传播的病毒中，每个基因内的每个核苷酸以及每个蛋白质内的每个氨基酸位点的变化率将被量化。第三，将通过系统发育祖先状态重建方法估计SARS和COVID-19宿主转换事件（前后）的病毒基因序列。最后，应用一种新的计算方法比较重建的祖先之间的分歧，在爆发期间存在的多态性将确定与宿主转换相关的选择下的基因组位点。这种分歧将被映射到已知的蛋白质结构域和结构，阐明对人类感染和传播重要的位点，从而有助于分子靶向疫苗和治疗的开发。该奖项由环境生物学部门的系统学和生物多样性科学集群颁发，使用冠状病毒援助，救济和经济安全（CARES）法案的资金。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

COVID-19 disease has caused the third major outbreak in the past two decades resulting from a spillover of an animal coronavirus to humans. Among them, it is by far the most severe. Novel diseases typically appear because of such spillovers. However, it is unknown what genetic changes in the virus causing COVID-19 enabled it to infect humans. To identify those genetic changes, this project will use newly developed computational methods to compare the genes in coronaviruses infecting humans to the genes in coronaviruses infecting other animal hosts. This comparison of viral genomes will provide insight into which sites within coronavirus genomes enable the switching of host species as well as which sites change following host switches. Awareness of these genetic mechanisms is critical to determining if general rules underlie the ability of coronaviruses to switch hosts, as well as to provide necessary historical context for the changes coronavirus genomes have experienced following the onset of human infections. The ensuing knowledge provides precise guidance on new targets for ongoing decisions regarding vaccine design and drug development. Results of this project will also be incorporated into multiple engaging and educational exhibits at the North Carolina Museum of Natural Sciences. This project will apply molecular evolutionary approaches to reveal the rates of evolution of SARS-CoV-1, SARS-CoV-2, and of viruses sequenced from reservoir hosts, revealing the strength of selection across sites occurring proximate to zoonosis within the viral genomes. First, phylogenetic comparisons of extant SARS-causing, SARS-like, and COVID-19-causing viral sequences collected from infected humans and from animal reservoirs will be used to reconstruct the history of coronavirus evolution. Second, the rate of change of each nucleotide within each gene—and each amino acid site within each protein—in viruses that were transmitting within the animal reservoir, in viruses transmitted among humans during the SARS outbreak, and in viruses transmitted among humans during the COVID-19 pandemic will quantified. Third, virus gene sequences that bracketed (pre- and post-) the host transition events for both SARS and COVID-19 will be estimated through phylogenetic ancestral state reconstruction methods. Finally, application of a novel computational approach comparing the divergence between reconstructed ancestors to the polymorphism present during the outbreak will identify genomic sites under selection that are associated with host transitions. This divergence will be mapped to known protein domains and structures, illuminating sites important to human infection and transmission, and thereby aiding molecularly targeted vaccine and therapy development. This RAPID award is made by the Systematics and Biodiversity Science Cluster in the Division of Environmental Biology, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.