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

RAPID：多态性和分歧分析以阐明 SARS 和 COVID-19 中人畜共患病的分子进化

• 批准号: 2031204
• 负责人: Jeffrey Townsend
• 金额: $ 12.27万
• 依托单位: Yale University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2031204&HistoricalAwards=false
• 关键词: RAPID; Analyses; polymorphism; divergence; illuminate

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.

新冠肺炎疾病在过去20年中引发了第三次大爆发，原因是一种动物冠状病毒对人类的溢出。其中，它是迄今为止最严重的。新疾病的出现通常是因为这种溢出效应。然而，目前尚不清楚导致新冠肺炎的病毒的哪些基因变化使其能够感染人类。为了识别这些基因变化，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的基因和感染其他动物宿主的冠状病毒的基因。病毒基因组的这种比较将提供关于冠状病毒基因组中哪些位置允许宿主物种切换以及哪些位置在宿主切换后发生变化的洞察力。对这些遗传机制的认识对于确定一般规则是否构成冠状病毒转换宿主能力的基础，以及为冠状病毒基因组在人类感染开始后经历的变化提供必要的历史背景至关重要。随后的知识为正在进行的疫苗设计和药物开发决策的新目标提供了准确的指导。该项目的成果还将纳入北卡罗来纳州自然科学博物馆的多个引人入胜和具有教育意义的展览中。该项目将应用分子进化方法来揭示SARS-CoV-1、SARS-CoV-2以及从存储宿主中测序的病毒的进化速度，揭示在病毒基因组内发生在人畜共患病附近的地点进行选择的力量。首先，从受感染的人和动物水库中收集的现有引起SARS的、类似SARS的和引起新冠肺炎的病毒序列的系统发育比较将用于重建冠状病毒的进化史。其次，在动物宿主内传播的病毒中，在SARS爆发期间在人类之间传播的病毒中，在新冠肺炎大流行期间在人与人之间传播的病毒中，每个基因中的每个核苷酸以及每个蛋白质中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包括SARS和新冠肺炎宿主过渡事件前后的病毒基因序列。最后，应用一种新的计算方法，将重建的祖先之间的差异与疫情爆发期间存在的多态进行比较，将识别与宿主转换相关的选择下的基因组位置。这种差异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置，从而帮助分子靶向疫苗和治疗的开发。这一快速奖项是由环境生物学部门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(CARE)法案的资金做出的。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。