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

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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.