One Year of SARS-CoV-2: How Much Has the Virus Changed?

SIMPLE SUMMARY: Now that vaccines have been developed and are being deployed to address the COVID-19 pandemic, a major concern is the emergence of mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that confer immune escape or enhanced fitness. As such, it is important to assess how rapidly the virus is mutating to gauge the likelihood of such an event. Using ≈290,000 SARS-CoV-2 proteome sequences deposited in a resource known as the Global Initiative on Sharing All Influenza Data (GISAID), we show that 27 of the proteins comprising the SARS-CoV-2 virus are mutating at different rates, with most exhibiting little to no mutational variability. Specifically, we observe that the principal targets of COVID-19 vaccines and therapeutics, the Spike and Nucleocapsid proteins, have the highest mutational variability. Additionally, we provide the foremost assessment of SARS-CoV-2 mutations in terms of time, geography, and their location in the available 3D protein structure. Together, these data demonstrate that the SARS-CoV-2 proteome is slowly accumulating mutations. These finding suggest that extant vaccines and therapies will likely remain effective for the foreseeable future, but the continued surveillance for mutations in primary viral targets is warranted. ABSTRACT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide crisis with profound effects on both public health and the economy. In order to combat the COVID-19 pandemic, research groups have shared viral genome sequence data through the Global Initiative on Sharing All Influenza Data (GISAID). Over the past year, ≈290,000 full SARS-CoV-2 proteome sequences have been deposited in the GISAID. Here, we used these sequences to assess the rate of nonsynonymous mutants over the entire viral proteome. Our analysis shows that SARS-CoV-2 proteins are mutating at substantially different rates, with most of the viral proteins exhibiting little mutational variability. As anticipated, our calculations capture previously reported mutations that arose in the first months of the pandemic, such as D614G (Spike), P323L (NSP12), and R203K/G204R (Nucleocapsid), but they also identify more recent mutations, such as A222V and L18F (Spike) and A220V (Nucleocapsid), among others. Our comprehensive temporal and geographical analyses show two distinct periods with different proteome mutation rates: December 2019 to July 2020 and August to December 2020. Notably, some mutation rates differ by geography, primarily during the latter half of 2020 in Europe. Furthermore, our structure-based molecular analysis provides an exhaustive assessment of SARS-CoV-2 mutation rates in the context of the current set of 3D structures available for SARS-CoV-2 proteins. This emerging sequence-to-structure insight is beginning to illuminate the site-specific mutational (in)tolerance of SARS-CoV-2 proteins as the virus continues to spread around the globe.