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

由于动物冠状病毒向人类传播，COVID-19疾病在过去二十年中引发了第三次重大疫情。其中，它是迄今为止最严重的。由于这种溢出效应，通常会出现新的疾病。然而，目前尚不清楚导致COVID-19的病毒的哪些基因变化使其感染人类。为了确定这些遗传变化，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的基因与感染其他动物宿主的冠状病毒的基因。这种病毒基因组的比较将有助于深入了解冠状病毒基因组中的哪些位点能够切换宿主物种，以及哪些位点在宿主切换后发生变化。了解这些遗传机制对于确定冠状病毒切换宿主的能力是否遵循一般规则，以及为冠状病毒基因组在人类感染发生后所经历的变化提供必要的历史背景至关重要。由此获得的知识为正在进行的有关疫苗设计和药物开发的决策提供了关于新目标的精确指导。这个项目的成果也将被纳入北卡罗来纳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揭示SARS-CoV-1、SARS-CoV-2以及从宿主宿主中测序的病毒的进化速度，揭示病毒基因组中与人畜共患病相近的位点之间的选择强度。首先，将从受感染的人类和动物宿主中收集的现有的sars致病、sars样病毒和covid -19致病病毒序列进行系统发育比较，以重建冠状病毒的进化历史。其次，将量化在动物储存库中传播的病毒、在SARS爆发期间在人类之间传播的病毒以及在COVID-19大流行期间在人类之间传播的病毒中，每个基因内每个核苷酸以及每个蛋白质内每个氨基酸位点的变化率。第三，将通过系统发育祖先状态重建方法估计SARS和COVID-19宿主转变事件前后的病毒基因序列。最后，应用一种新的计算方法，将重建祖先之间的差异与爆发期间存在的多态性进行比较，将确定与宿主转换相关的选择基因组位点。这种差异将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RAPID奖由环境生物学部的系统学和生物多样性科学集群利用《冠状病毒援助、救济和经济安全（CARES）法案》的资金设立。该奖项反映了美国国家科学基金会的法定使命，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.