RAPID: Probing SARS-CoV-2 evolution and vulnerabilities through its mutation and fitness landscape

RAPID：通过突变和适应度探索 SARS-CoV-2 的进化和脆弱性

• 批准号: 2032784
• 负责人: Marc Vermulst
• 金额: $ 19.83万
• 依托单位: University of Southern California
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2032784&HistoricalAwards=false
• 关键词: RAPID; Probing; SARS; CoV; evolution

A major challenge in the fight against viruses is their enormous amount of genetic diversity resulting from large population sizes combined with high mutation rates. However, the frequency at which such variants appear and the consequences of specific mutations on viral fitness are largely unknown for SARS-CoV-2. Researchers supported by this award will measure the mutation rate and fitness landscape of three SARS-CoV- 2 isolates from around the world. The work could be essential for accurately modeling the future evolution of SARS-CoV-2 and may help identify the virus’ vulnerabilities at the molecular level. Results from these studies will also be leveraged by undergraduate students and researchers for training in advanced genomic analyses. The findings and data from these studies will be published in peer-reviewed journals, presented at scientific meetings and in public STEM engagement activities, and shared on-line through blog posts and the popular press.Research supported by this award will measure variant frequencies in viral populations following several rounds of serial passaging in Vero E6 cells. Genome-wide measurements of all possible variants frequencies will be accomplished using the circle-sequencing to measure mutation rates and fitness landscape virus. Changes in variant frequencies over the course of serial passages will be used to derive the relative fitness of each variant. Knowing the mutation rate (and spectrum) of the virus is paramount to modeling its future evolution, including the rate at which resistant variants are expected to arise. By measuring the fitness of thousands of mutations across the genome, the researchers hope to identify residues and protein domains that are critical to the virus replication cycle and narrow the range of protein domains and residues to target with therapeutics. Among these sites, those for which no other mutation can rescue the viral fitness will be of particular interest. This RAPID award to University of Southern California is made by the Division of Biological Infrastructure 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.

抗击病毒的一个主要挑战是，它们由大量人口大小加上高突变率而导致的遗传多样性增加。然而，这种变体出现的频率以及特异性突变对病毒适应性的后果在很大程度上是SARS-COV-2所未知的。获得该奖项支持的研究人员将衡量来自世界各地的三个SARS-COV- 2个分离株的突变率和健身景观。这项工作对于准确建模SARS-COV-2的未来演变至关重要，并可能有助于确定病毒在分子水平上的脆弱性。本科生和研究人员还将利用这些研究的结果进行高级基因组分析的培训。这些研究的发现和数据将在经过同行评审的期刊上发表，在科学会议和公共STEM参与活动中介绍，并通​​过博客文章和流行的媒体在线共享。该奖项支持的研究将衡量在VERO E6细胞中多次通过的串行传递后，该奖项将衡量病毒种群中的变异频率。所有可能变体频率的全基因组测量值将使用圆末测量来测量突变率和适应性景观病毒。在串行通行过程中，变体频率的变化将用于得出每个变体的相对适应性。了解病毒的突变率（和光谱）对于对其未来进化进行建模至关重要，包括预期出现抗性变体的速率。通过测量整个基因组中数千个突变的适应性，研究人员希望鉴定出对病毒复制周期至关重要的残留物和蛋白质结构域，并缩小蛋白质结构域的范围，并通过治疗保留靶向靶向。在这些站点中，没有其他突变可以挽救病毒适应性的站点特别感兴趣。这项迅速颁发的南加州大学是由生物基础设施部使用冠状病毒援助，救济和经济安全（CARES）法案的资金颁发的。该奖项反映了NSF的法定任务，并被认为是通过基金会的知识分子优点和更广泛影响的审查标准来通过评估来通过评估来获得的支持。