Detecting Potentially Adaptive Mutations from the Parallel and Fixed Patterns in SARS-CoV-2 Evolution

Abstract

Early identification of adaptive mutations could provide timely help for the control and prevention of the COVID-19 pandemic. The fast accumulation of SARS-CoV-2 sequencing data provides important support, while also raising a great challenge for the recognition of adaptive mutations. Here, we proposed a computational strategy to detect potentially adaptive mutations from their fixed and parallel patterns in the phylogenetic trajectory. We found that the biological meanings of fixed substitution and parallel mutation are highly complementary, and can reasonably be integrated as a fixed and parallel (paraFix) mutation, to identify potentially adaptive mutations. Tracking the dynamic evolution of SARS-CoV-2, 37 sites in spike protein were identified as having experienced paraFix mutations. Interestingly, 70% (26/37) of them have already been experimentally confirmed as adaptive mutations. Moreover, most of the mutations could be inferred as paraFix mutations one month earlier than when they became regionally dominant. Overall, we believe that the concept of paraFix mutations will help researchers to identify potentially adaptive mutations quickly and accurately, which will provide invaluable clues for disease control and prevention.

Changes in endemic patterns of respiratory syncytial virus infection in pediatric patients under the pressure of nonpharmaceutical interventions for COVID‐19 in Beijing, China

“…This method has been validated in the presence of important mutant strains of SARS‐CoV‐2. 25 In our data, three paraFix mutations were “L” to “P,” as L274P, L298P, and L310P were identified in the RSV‐A subtype, which indicated that these sites might be the key amino acids on the G protein. In addition, the paraFix mutations were distributed mainly in HVR2 in both RSV‐A and RSV‐B subtypes.…”

“…The detection of paraFix mutations was performed with the R package sitePath. 25 Briefly, the phylogenetic tree and multisequence alignment files constructed by iqtree v1.6.12 as mentioned above based on all sequences of RSV Subtypes A and B, respectively, were sent to sitePath. Then, the paraFix mutations were detected with the recommended default parameter.…”

sitePath: a visual tool to identify polymorphism clades and help find fixed and parallel mutations

“…The result of its site 139 of the polyprotein, which was reported to be associated with enhanced virulence [ 2 ], is shown in Fig. 1 C. Moreover, sitePath was used on SARS-CoV-2 to find fixed and parallel mutations, which were found to be potentially adaptive for the virus [ 9 ].

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Attenuation and Degeneration of SARS-CoV-2 Despite Adaptive Evolution

“…Adaptive mutations of SARS-CoV-2 are characterized by 1) convergence or homoplasy, i.e., repeated, independent emergence of the same mutations in multiple strains [24]; 2) cooccurrence of two or more mutations in fixed strains suggesting epistasis and complementarity [25]; 3) concentration of mutations in hotspots, especially in the receptor-binding domain (RBD) of the spike protein that interacts with the human angiotensin-converting enzyme 2 (ACE2) receptor and neutralizing antibodies [26]; 4) competition between variants resulting in rapid selective sweeps, which leads to new variants replacing old ones in a matter of months [27,28].…”