PMC:7519301 / 23839-26991
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7519301","sourcedb":"PMC","sourceid":"7519301","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7519301","text":"Sequence Identity with Potential Vaccine Candidates.\nTypical vaccine design strategies rely on either 1) selecting sequences sampled from infected individuals or 2) computationally deriving sequences that cover the diversity seen across circulating sequences and are, in theory, optimal compared to an individual isolate (38). Computationally derived sequences include consensus and ancestral sequences, such as the most recent common ancestor (MRCA) of a set of sequences. We inferred the MRCA corresponding to 1) SARS-CoV-2 S sequences sampled from Wuhan within the first month of the epidemic, 2) all currently circulating SARS-CoV-2 sequences, and 3) all SARS-CoV-2 sequences together with closely related sequences sampled from pangolins (n = 6) and a bat. There were 17 mutations between the human MRCA and the human−bat MRCA and 44 mutations between the human MRCA and human−pangolin MRCA. Overall, three segments in S reflected significant variability across species (AA 439 to 445, 482 to 501, and 676 to 690) (Fig. 5 A and C and SI Appendix, Fig. S11) (39). In contrast, when considering only human sequences, SARS-CoV-2 diversity was limited: Both MRCAs (derived from early sequences from Wuhan or from all circulating sequences) were identical to the initial reference sequence Wuhan-Hu-1. Comparing these sequences to the consensus sequence derived from all of the sequences sampled to date, there was only one mutation: D614G (Fig. 5B). Fig. 5D illustrates that mutations found across circulating S sequences were rare: Besides D614G (found in 69.4% of sequences), the next most frequent substitution is found in 1.96% of sequences (synonymous), with sequences sampled from infected individuals, on average, 0.55 mutations away from the consensus sequence (consisting of 0.12 synonymous and 0.43 nonsynonymous mutations). Across the genome, there were, on average, 4.05 nucleotide mutations per individual genome when compared to the consensus, with only P4715L and D614G found in \u003e50% of sequences.\nFig. 5. Mutations across SARS-CoV-2 S sequences. (A) Structure of SARS-CoV (5 × 58) (shown instead of SARS-CoV-2 for completeness of the Receptor Binding Motif [RBM]). (B–D) The three protomers in the closed SARS-CoV-2 S glycoprotein (Protein Data Bank ID code 6VXX) are colored in yellow, cyan, and white. Sites with mutations are shown as spheres. (B) Near-identity of potential vaccine candidates. The MRCA and Wuhan-Hu-1 reference sequences were identical, while the consensus derived from all circulating sequences showed a mutation (D614G). Site 614 is located at the interface between two subunits. (C) Sequence segments that differed between human and pangolin or bat hosts. Amino acid segments 439 to 455 and 482 to 501 impact receptor binding, while the 574 to 690 segment corresponds to the S2 cleavage site. (D) Sites with shared mutations across SARS-CoV-2 circulating sequences. The colors of the spheres correspond to the proportion of SARS-CoV-2 sequences that differed from the Wuhan-Hu-1 sequence (GISAID: EPI_ISL_402125, GenBank: NC_045512). 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