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.

Covid-19疾病在过去二十年中引起了第三次重大爆发，这是由于动物冠状病毒向人类造成的。其中，它是迄今为止最严重的。新颖的疾病通常是由于这种间隙而出现的。然而，尚不清楚病毒的遗传变化导致Covid-19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​​冠状病毒中的基因与感染其他动物宿主的冠状病毒中的基因。这种病毒基因组的比较将提供有关冠状病毒基因组中哪些位点的洞察力，使宿主物种的切换以及宿主开关后哪些位点发生变化。对这些遗传机制的认识对于确定冠状病毒切换宿主的能力以及为冠状病毒基因组的变化提供必要的历史环境是否能力是否具有冠状病毒的能力是至关重要的。确保知识为有关疫苗设计和药物开发的持续决策提供了有关新目标的精确指导。该项目的结果还将在北卡罗来纳州自然科学博物馆的多次参与和教育展览中纳入。该项目将采用分子进化方法来揭示SARS-COV-1，SARS-COV-2和从储层宿主测序的病毒的进化速率，从而揭示了病毒基因组中接近人畜共患病的位点的选择强度。首先，将使用感染人类和动物储层收集的扩展的SARS引起SARS，类似SARS的和Covid-19引起的病毒序列进行系统发育比较，以重建冠状病毒进化的历史。其次，每个基因内的每个核苷酸的变化速率以及每种蛋白质中的每个氨基酸位点在动物储层内传播的病毒，在SARS爆发期间在人类之间传播的病毒以及在COVID-19大流行期间人类之间传播的病毒在人类之间传播的病毒。第三，将通过系统发育祖先重建方法估算SARS和COVID-19的宿主转变事件的病毒基因序列（前后）的宿主转变事件。最后，将一种新型计算方法的应用比较，将重建祖先与爆发过程中存在的多态性之间的差异进行比较将确定与宿主转变相关的基因组位点。这种差异将映射到已知的蛋白质结构域和结构，对人类感染和传播很重要的启发位点，从而有助于分子靶向疫苗和治疗的开发。该快速奖是由系统和生物多样性科学集群在环境生物学系中颁发的，使用冠状病毒援助，救济和经济安全（CARES）ACT的资金。该奖项反映了NSF的法定任务，并被认为是通过使用基金会的知识分子和更广泛影响的评估来审查Criteria通过评估来通过评估来获得支持的。