PMC:7519301 / 12459-17848 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7519301","sourcedb":"PMC","sourceid":"7519301","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7519301","text":"One S Mutation (D614G) Has Become Dominant.\nSince the beginning of the pandemic, two mutations across the genome have become consensus: P4715L in ORF1ab (nucleotide 14,143, C to T) and D614G in S (nucleotide 23,403, A to G) (Fig. 1B) (a third consensus mutation, at nucleotide 3,037, is not reported as the site was masked during our sequence-filtering procedure). These mutations were found in 69.3% and 69.4% of sequences, respectively, and are in linkage (Fig. 2B). Given the importance of S for virus entry and as a target of the host neutralizing response, the biologic implications of the D614G mutation are under intense scrutiny (24–28). This mutation was first observed in a sequence from China dated January 24, with seven more sequences sampled until February 8. Then, the D614G mutation was not observed in China until March 13. In contrast, the D614G mutation was introduced in Europe at the end of January (first sequence identified in Germany, dated January 28), and it rapidly became dominant on that continent and at every location where the virus subsequently spread (Fig. 2A). The phylogenetic tree (Fig. 2B) and the distribution of sequences (Fig. 2C) are suggestive of a founder effect. The rapid spread of sequences carrying the D614G mutation implies that the growing viral population should become more homogeneous, that is, the frequency of sequences with shared polymorphisms will increase. We found a median of seven substitutions (based on a comparison of 18,514 sequences) between two independent SARS-CoV-2 genomes (SI Appendix, Fig. S2). Yet, genomes with the D614G mutation showed a median of five substitutions, whereas those with D at position 614 differed by eight substitutions (Fig. 2D).\nFig. 2. The S mutation D614G quickly became dominant. The mutation D614G was found in 69% of sequences sampled globally as of May 18, 2020, the second most frequent mutation in S was only found in ∼2% of sequences. (A) Number of sequences with D (gray) or G (purple) by continent and sampling date shown cumulatively through the outbreak. (B) Phylogenetic tree reconstructed from all of the ORFs showing the linkage between D614G in S and P4715L in ORF1ab. Tips are colored by continent. The phylogeny suggests that these mutations were linked to a bottleneck event when SARS-CoV-2 viruses were introduced in Europe; this mutation was first seen in Europe in a sequence sampled in Germany at the end of January. There is no evidence that the increasing predominance of this mutation was caused by convergent selection events that would have occurred in multiple individuals. (C) Overall number of sequences with D614 or D614G across continents; the predominance of D614G in Europe is suggestive of a founder event. (D) Distribution of Hamming distances between sequences with D614, G614 or discordant pairs. The median is marked with a dashed line. To test whether this site was under selection, we used likelihood-based, phylogenetically informed models that assume branch-specific substitution rates (29) and implemented a sampling strategy to circumvent computational limitations imposed by the large number of sequences. Subsampled alignments (100 times at a 10% sampling fraction) had diversity estimates statistically similar to the complete alignment for each gene (Mann−Whitney U test, P \u003e 0.09; SI Appendix, Fig. S3). In S, only site 614 was estimated to be under diversifying selection in a majority of subsampled alignments (58%); evidence of diversifying selection indicates that genetic diversity increases in the viral population (i.e., there was a higher proportion of mutations causing an amino acid change than not at site 614, or, the nonsynonymous/synonymous substitution rates ratio, dN/dS, was over 1, P \u003c 0.1) (SI Appendix, Fig. S4). Because diversifying selection is often associated with the host adaptive response, we considered whether the D614G mutation coincided with targets of antibody and T cell responses. Site 614 is at the interface between the S1 and S2 subunits and is thus not highly accessible to antibodies (SI Appendix, Fig. S5). Therefore, we predict that antibodies to the native S protein would cross-react with S containing the D614G mutation, in agreement with recent reports (24, 25, 27, 28). Many known neutralizing antibodies target the RBD, yet we found little evidence that mutations could affect binding to the ACE2 receptor, as only five shared mutations were identified at contact sites with the ACE2 receptor, and all were found in 10 or fewer sequences. Of these, one mutation, at position 489, was synonymous and found in three sequences (0.02%). The others were nonsynonymous: G476S (n = 10 sequences, 0.05%), Y453F (n = 5, 0.02%), G446V (n = 3, 0.02%), and A475V (n = 2, 0.01%). To predict the potential immune pressure linked to T cell responses, we developed a T cell immunogenicity index which takes into account the CD8 and CD4 epitope repertoires in the structural proteins of SARS-CoV-2 (S, N, M, E) and the frequency of human leukocyte antigen (HLA) alleles or haplotypes in a given population. We found that sites with mutations, including 614 in S, were not colocalized with T cell epitopes frequently identified in different populations (SI Appendix, Figs. S6 and S7), and there was no significant relationship between the number of mutations and the immunogenicity index (SI Appendix, Fig. 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