key: cord-0916591-8rwq2mwn
authors: Li, H.; Chen, Z.; Liu, X.; Hu, P.
title: Spike mutations of the SARS-CoV-2 Omicron: more likely to occur in the epitopes
date: 2022-03-06
journal: nan
DOI: 10.1101/2022.03.03.22271159
sha: 9896099b346f6f72cd46a900dbc6732d6f7f1669
doc_id: 916591
cord_uid: 8rwq2mwn

Almost two years since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak in 2019, and it is still pandemic over the world. SARS-COV-2 continuing to mutate and evolve, which further exacerbated the spread of the epidemic. Omicron variant, as an emerging mutation recently in South Africa, spreaded fastly to other countries worldwide. However, the gene charicterstic of Omicron and the effect on epitopes are still unclear. In this study, we retrieved 800 SARS-CoV-2 full-length sequences from GISAID database on 14 December 2021 (Alpha 110, Beta 101, Gamma 108, Delta 110, Omicron 107, Lambda 98, Mu 101, GH/490R 65). Overall, 1320 amino acid (AA) sites were mutated in these 800 SARS-CoV-2 sequences. Covariant network analysis showed that the covariant network of Omicron variant was significantly different from other variants. Further, 218 of the 1320 AA sites were occurred in the S gene, including 78 high-frequency mutations (>90%). Notably, we identified 25 unique AA mutations in Omicron, which may affect the transmission and pathogenicity of SARS-CoV-2. Finally, we analyzed the effect of Omicron on epitope peptide. As expected, 64.1% mutations (25/39) of Omicron variants were in epitopes, which was significantly higher than in other variants. These mutations may cause a poor response to vaccines to Omicron variants. In conclusion, Omicron variants, as an emerging mutation, should be alerted for us due that it may lead to poor vaccine response, and more data is needed to evaluate the virulence and vaccines responses to this variants.

). Of these mutations, 791 (59.92%) was in ORF1ab, followed by ORF2 (218, 16.52%), ORF9 (99, 7.50%), ORF3 (88, 6.67%), the mutations in other ORFs were infrequent (all < 5%).

The protein-coding region of SARS-CoV-2 was used to analyze covariant pairs of amino acid position. Covarying positions were identified using OMES algorithms 2 .

And an OMES score of 3 was used as the cutoff for analyses. Amino-acid covariant networks were visualized by Cytoscape version 3.7.2. Sequences enrolled in this study were used to analyze covarying pairs according to different variants ( Figure   S1 ). Significant differences in covariant residue networks among different reuse, remix, or adapt this material for any purpose without crediting the original authors. preprint (which was not certified by peer review) in the Public Domain. It is no longer restricted by copyright. Anyone can legally share,

The copyright holder has placed this this version posted March 6, 2022. ; https://doi.org/10.1101/2022.03.03.22271159 doi: medRxiv preprint SARS-CoV-2 variants were observed. Then we identified 2268 covarying amino acid pairs most highly represented in 161 isolates (including 20 randomly selected isolates of each subtype and a reference sequence) and found these form small closed networks within and between protein. Amino acid covarying network in the SARS-CoV-2 shown in Figure 1B , which revealed that several mutations in the spike protein are predicted to be covariant in our 161 strains with residues in the ORF1ab, E, M, N, ORF3a, ORF6, ORF7, ORF8, which suggest there is an evolutionary relationship between these areas. And from Figure 1C For the 17 residues in RBD interfaces with Angiotensin-Converting Enzyme 2 (ACE2) 5 , eight were mutated in the different variants. In detail, K417N was observed in the Omicron, Beta and Gamma variants, which reduces ACE2 binding significantly 6, 7 . Whereas N501Y, which exhibit increased ACE2 binding affinity 8,9 , was detected in all other 6 variants except Delta and Lambda. In addition, five residues only occurred in the Omicron, G446S, Q493R, G496S, Q498R and Y505H.

The Cryo-EM structure of spike protein of Omicron variant showed that new salt bridges and hydrogen bonds formed by mutated residues R493, S496 and R498 in reuse, remix, or adapt this material for any purpose without crediting the original authors. preprint (which was not certified by peer review) in the Public Domain. It is no longer restricted by copyright. Anyone can legally share,

The copyright holder has placed this this version posted March 6, 2022. ; https://doi.org/10.1101/2022.03.03.22271159 doi: medRxiv preprint the RBD with ACE2 likely make spike-ACE2 binding stronger, which appear to compensate other Omicron mutations such as K417N known to reduce ACE2 binding affinity 10 . However, a recent in vitro study11 showed that the Omicron variant exhibited reduced infectivity in human lung epithelia-derived CaLu-3 cells compared to other variants.

To further describe the relationship between the spike mutations and epitopes of the SARS-CoV-2, a total of 163 reported epitopes were downloaded from the Immune Epitope Database (IEDB) (http://www.iedb.org/) (Supplementary Table2). Among these epitopes, 161 are discontinuous, and 2 are linear epitopes. 52.6% (41/78) of spike mutations are located within the epitopes ( Figure 1D ). Especially in the Omicron, 64.1% (25/39) of the mutations are located within the epitopes, which was significantly higher than other variants except for the Delta ( Figure 1E ). 64.0% 

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 Table 1 . List of the SARS-CoV-2 strains retrieved from the reuse, remix, or adapt this material for any purpose without crediting the original authors. preprint (which was not certified by peer review) in the Public Domain. It is no longer restricted by copyright. Anyone can legally share,The copyright holder has placed this this version posted March 6, 2022. ; https://doi.org/10.1101/2022.03.03.22271159 doi: medRxiv preprint GISAID database used in this study.

The reported epitopes of the SARS-CoV-2 spike. reuse, remix, or adapt this material for any purpose without crediting the original authors. preprint (which was not certified by peer review) in the Public Domain. It is no longer restricted by copyright. Anyone can legally share,The copyright holder has placed this this version posted March 6, 2022. ; https://doi.org/10.1101/2022.03.03.22271159 doi: medRxiv preprint