RAPID: Factors Contributing To Sequence Conservation in the SARS-CoV-2 Genome

一种新型冠状病毒（SARS-CoV-2）于2019年12月在中国湖北省出现，此后迅速蔓延，成为全球大流行病。迫切需要对这种病毒的生物学及其与人类宿主的相互作用进行基础研究，以遏制这种疾病的传播，减轻其对全球人口的破坏性影响。通过这个RAPID奖支持的研究将提高对这种病毒如何进化的认识，并可能提供有关其与人类宿主相互作用的重要线索。先前的研究表明，病毒基因组的一个关键区域是高度保守的，与基因组的其他部分相比，突变很少。探索这种序列保守性的潜在基础将揭示可能影响SARS-CoV-2传播，诊断和治疗的因素的新信息。该项目还为研究生和本科生提供培训机会，并将支持开发一个基于网络的工具，供社区研究病毒基因组进化。PI已经确定了SARS-Cov-2基因组的一个区域，其中包括RNA依赖性RNA聚合酶（RdRp），该区域在核苷酸水平上具有极高的保守性。这一发现表明，选择是为了维持该区域的序列基序，可能指向RdRp RNA或RNA介导的病毒与宿主之间的相互作用的结构限制。该项目将探索一系列关于选择因素的假设，包括非编码RNA、RNA二级结构和宿主蛋白质的RNA结合位点等，这些因素可能会解释序列保守性。该项目还将尝试进行一项研究，将这些因素与人类对SARS-CoV-2的易感性联系起来，如果能够获得关于基因组变异和相应感染严重程度的患者数据的话。该RAPID奖由分子和细胞生物科学部的遗传机制计划资助。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。

A novel coronavirus (SARS-CoV-2) emerged in Hubei, China in December 2019 and has since spread rapidly to become a global pandemic. There is a critical need for fundamental research on the biology of this virus and its interactions with the human host to stem the spread of the disease and mitigate its devastating impacts on the global human population. The research supported through this RAPID award will enhance knowledge of how this virus evolves, and it may provide vital clues about its interactions with the human host. Previous research has shown that a critical region of the viral genome is highly conserved, harboring very few mutations compared to the rest of the genome. Exploring the underlying basis for this sequence conservation will reveal new information on factors that could influence the spread, diagnostics and treatment of SARS-CoV-2. The project also offers training opportunities for graduate and undergraduate students, and will support development of a web-based tool for the community to study viral genome evolution. The PI has identified a region of the SARS-Cov-2 genome, which includes the RNA-dependent RNA polymerase (RdRp), which has extremely high conservation at the nucleotide level. This finding suggests that selection is acting to maintain sequence motifs in this region, possibly pointing to structural constraints on the RdRp RNA or RNA-mediated interactions between the virus and host. The project will explore a range of hypotheses about selection factors, including noncoding RNAs, RNA secondary structure and RNA binding sites for host proteins, among others, that could account for the sequence conservation. The project will also attempt a study relating these factors to human susceptibility to SARS-CoV-2, if access is gained to patient data on genome variation and corresponding infection severity. This RAPID award is funded by the Genetic Mechanisms Program in the Division of Molecular and Cellular Biosciences.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.