Evidence for a mouse origin of the SARS-CoV-2 Omicron variant

Changshuo Wei; Ke-Jia Shan; Weiguang Wang; Shuya Zhang; Qing Huan; Wenfeng Qian

doi:10.1016/j.jgg.2021.12.003

Volume 48 Issue 12

Dec. 2021

Turn off MathJax

Article Contents

Article Navigation > Journal of Genetics and Genomics > 2021 > 48(12): 1111-1121

PDF( 1894 KB)

Evidence for a mouse origin of the SARS-CoV-2 Omicron variant

doi: 10.1016/j.jgg.2021.12.003

a. State Key Laboratory of Plant Genomics, Institute of Genetics and Developmental Biology, Innovation Academy for Seed Design, Chinese Academy of Sciences, Beijing 100101, China;
b. University of Chinese Academy of Sciences, Beijing 100049, China

Funds:

We thank Dr. Xionglei He from Sun Yat-sen University and Dr. Mingkun Li from Beijing Institute of Genomics CAS for discussion. We acknowledge the authors and laboratories for generating and submitting the sequences to GISAID Database on which this research is based. The list is detailed in Table S3. This work was supported by grants from the National Natural Science Foundation of China (31922014).

Received Date: 2021-12-14
Revised Date: 2021-12-20
Accepted Date: 2021-12-20
Publish Date: 2021-12-20

Abstract

Abstract

The rapid accumulation of mutations in the SARS-CoV-2 Omicron variant that enabled its outbreak raises questions as to whether its proximal origin occurred in humans or another mammalian host. Here, we identified 45 point mutations that Omicron acquired since divergence from the B.1.1 lineage. We found that the Omicron spike protein sequence was subjected to stronger positive selection than that of any reported SARS-CoV-2 variants known to evolve persistently in human hosts, suggesting a possibility of host-jumping. The molecular spectrum of mutations (i.e., the relative frequency of the 12 types of base substitutions) acquired by the progenitor of Omicron was significantly different from the spectrum for viruses that evolved in human patients but resembled the spectra associated with virus evolution in a mouse cellular environment. Furthermore, mutations in the Omicron spike protein significantly overlapped with SARS-CoV-2 mutations known to promote adaptation to mouse hosts, particularly through enhanced spike protein binding affinity for the mouse cell entry receptor. Collectively, our results suggest that the progenitor of Omicron jumped from humans to mice, rapidly accumulated mutations conducive to infecting that host, then jumped back into humans, indicating an inter-species evolutionary trajectory for the Omicron outbreak.
- SARS-CoV-2,
- Omicron,
- Evolutionary origins,
- Molecular spectrum of mutations,
- Spike-ACE2 interaction,
- Receptor-binding domain

FullText(HTML)

References(47)

References

Ashkenazy, H., Penn, O., Doron-Faigenboim, A., Cohen, O., Cannarozzi, G., Zomer, O., Pupko, T., 2012. FastML: a web server for probabilistic reconstruction of ancestral sequences. Nucleic Acids Res. 40, W580-W584.

Blanc, V., Davidson, N.O., 2010. APOBEC-1-mediated RNA editing. Wiley Interdiscip. Rev. Syst. Biol. Med. 2, 594-602.

Callaway, E., 2021. Heavily mutated Omicron variant puts scientists on alert. Nature. https://doi.org/10.1038/d41586-021-03552-w.

Cameroni, E., Bowen, J.E., Rosen, L.E., Saliba, C., Zepeda, S.K., Culap, K., Pinto, D., VanBlargan, L.A., Marco, A.D., Di Iulio, J., et al., 2021. Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift. Nature. https://doi.org/10.1038/d41586-021-03825-4.

Chandler, J.C., Bevins, S.N., Ellis, J.W., Linder, T.J., Tell, R.M., Jenkins-Moore, M., Root, J.J., Lenoch, J.B., Robbe-Austerman, S., DeLiberto, T.J., et al., 2021. SARS-CoV-2 exposure in wild white-tailed deer (Odocoileus virginianus). Proc. Natl. Acad. Sci. U. S. A. 118, e2114828118.

De Maio, N., Walker, C.R., Turakhia, Y., Lanfear, R., Corbett-Detig, R., Goldman, N., 2021. Mutation rates and selection on synonymous mutations in SARS-CoV-2. Genome Biol. Evol. 13, evab087.

Deng, S., Xing, K., He, X., 2021. Mutation signatures inform the natural host of SARS-CoV-2. Natl. Sci. Rev. https://doi.org/10.1093/nsr/nwab220.

Edgar, R.C., 2004. MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinf. 5, 113.

Gu, H., Chen, Q., Yang, G., He, L., Fan, H., Deng, Y.Q., Wang, Y., Teng, Y., Zhao, Z., Cui, Y., et al., 2020. Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy. Science 369, 1603-1607.

Hadfield, J., Megill, C., Bell, S.M., Huddleston, J., Potter, B., Callender, C., Sagulenko, P., Bedford, T., Neher, R.A., 2018. Nextstrain: real-time tracking of pathogen evolution. Bioinformatics 34, 4121-4123.

Harris, R.S., Dudley, J.P., 2015. APOBECs and virus restriction. Virology 479-480, 131-145.

Hatcher, E.L., Zhdanov, S.A., Bao, Y., Blinkova, O., Nawrocki, E.P., Ostapchuck, Y., Schaffer, A.A., Brister, J.R., 2017. Virus variation resource -improved response to emergent viral outbreaks. Nucleic Acids Res. 45, D482-D490.

Huang, K., Zhang, Y., Hui, X., Zhao, Y., Gong, W., Wang, T., Zhang, S., Yang, Y., Deng, F., Zhang, Q., et al., 2021. Q493K and Q498H substitutions in Spike promote adaptation of SARS-CoV-2 in mice. EBioMedicine 67, 103381.

Huang, Y., Yang, C., Xu, X.F., Xu, W., Liu, S.W., 2020. Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta Pharmacol. Sin. 41, 1141-1149.

Kastritis, P.L., Bonvin, A.M., 2010. Are scoring functions in protein-protein docking ready to predict interactomes? Clues from a novel binding affinity benchmark. J. Proteome Res. 9, 2216-2225.

Kemp, S.A., Collier, D.A., Datir, R.P., Ferreira, I., Gayed, S., Jahun, A., Hosmillo, M., Rees-Spear, C., Mlcochova, P., Lumb, I.U., et al., 2021. SARS-CoV-2 evolution during treatment of chronic infection. Nature 592, 277-282.

Kim, D., Lee, J.Y., Yang, J.S., Kim, J.W., Kim, V.N., Chang, H., 2020. The architecture of SARS-CoV-2 transcriptome. Cell 181, 914-921.

Kong, Q., Lin, C.L., 2010. Oxidative damage to RNA: mechanisms, consequences, and diseases. Cell. Mol. Life Sci. 67, 1817-1829.

Kumar, S., Stecher, G., Suleski, M., Hedges, S.B., 2017. TimeTree: a resource for timelines, timetrees, and divergence times. Mol. Biol. Evol. 34, 1812-1819.

Kupferschmidt, K., 2021. Where did ‘weird’ Omicron come from? Science 374, 1179.

Lam, S.D., Bordin, N., Waman, V.P., Scholes, H.M., Ashford, P., Sen, N., van Dorp, L., Rauer, C., Dawson, N.L., Pang, C.S.M., et al., 2020. SARS-CoV-2 spike protein predicted to form complexes with host receptor protein orthologues from a broad range of mammals. Sci. Rep. 10, 16471.

Lan, J., Ge, J., Yu, J., Shan, S., Zhou, H., Fan, S., Zhang, Q., Shi, X., Wang, Q., Zhang, L., et al., 2020. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 581, 215-220.

Leist, S.R., Dinnon 3rd, K.H., Schafer, A., Tse, L.V., Okuda, K., Hou, Y.J., West, A., Edwards, C.E., Sanders, W., Fritch, E.J., et al., 2020. A mouse-adapted SARS-CoV-2 induces acute lung injury and mortality in standard laboratory mice. Cell 183, 1070-1085.

Li, Q., Nie, J., Wu, J., Zhang, L., Ding, R., Wang, H., Zhang, Y., Li, T., Liu, S., Zhang, M., et al., 2021. SARS-CoV-2 501Y. V2 variants lack higher infectivity but do have immune escape. Cell 184, 2362-2371.

Li, Z., Wu, J., Deleo, C.J., 2006. RNA damage and surveillance under oxidative stress. IUBMB Life 58, 581-588.

Martinez-Flores, D., Zepeda-Cervantes, J., Cruz-Resendiz, A., Aguirre-Sampieri, S., Sampieri, A., Vaca, L., 2021. SARS-CoV-2 vaccines based on the spike glycoprotein and implications of new viral variants. Front. Immunol. 12, 701501.

Montagutelli, X., Prot, M., Jouvion, G., Levillayer, L., Conquet, L., Reyes-Gomez, E., Donati, F., Albert, M., van der Werf, S., Jaubert, J., et al., 2021. A mouse-adapted SARS-CoV-2 strain replicating in standard laboratory mice. bioRxiv. https://doi.org/10.1101/2021.07.10.451880.

Nelson, G., Buzko, O., Spilman, P., Niazi, K., Rabizadeh, S., Soon-Shiong, P., 2021. Molecular dynamic simulation reveals E484K mutation enhances spike RBD-ACE2 affinity and the combination of E484K, K417N and N501Y mutations (501Y. V2 variant) induces conformational change greater than N501Y mutant alone, potentially resulting in an escape mutant. bioRxiv. https://doi.org/10.1101/2021.01.13.426558.

Oude Munnink, B.B., Sikkema, R.S., Nieuwenhuijse, D.F., Molenaar, R.J., Munger, E., Molenkamp, R., van der Spek, A., Tolsma, P., Rietveld, A., Brouwer, M., et al., 2021. Transmission of SARS-CoV-2 on mink farms between humans and mink and back to humans. Science 371, 172-177.

Panchin, A.Y., Panchin, Y.V., 2020. Excessive G-U transversions in novel allele variants in SARS-CoV-2 genomes. PeerJ 8, e9648.

Ren, W., Zhu, Y., Wang, Y., Shi, H., Yu, Y., Hu, G., Feng, F., Zhao, X., Lan, J., Wu, J., et al., 2021. Comparative analysis reveals the species-specific genetic determinants of ACE2 required for SARS-CoV-2 entry. PLoS Pathog. 17, e1009392.

Rodrigues, J., Barrera-Vilarmau, S., J, M.C.T., Sorokina, M., Seckel, E., Kastritis, P.L., Levitt, M., 2020. Insights on cross-species transmission of SARS-CoV-2 from structural modeling. PLoS Comput. Biol. 16, e1008449.

Shan, K.J., Wei, C., Wang, Y., Huan, Q., Qian, W., 2021. Host-specific asymmetric accumulation of mutation types reveals that the origin of SARS-CoV-2 is consistent with a natural process. Innovation (N Y). 2, 100159.

Shu, Y., McCauley, J., 2017. GISAID: global initiative on sharing all influenza data -from vision to reality. Euro Surveill. 22, 30494.

Smyth, D.S., Trujillo, M., Gregory, D.A., Cheung, K., Gao, A., Graham, M., Guan, Y., Guldenpfennig, C., Hoxie, I., Kannoly, S., et al., 2021. Tracking cryptic SARSCoV-2 lineages detected in NYC wastewater. medRxiv. https://doi.org/10.1101/2021.07.26.21261142.

Sun, S., Gu, H., Cao, L., Chen, Q., Ye, Q., Yang, G., Li, R.T., Fan, H., Deng, Y.Q., Song, X., et al., 2021. Characterization and structural basis of a lethal mouseadapted SARS-CoV-2. Nat. Commun. 12, 5654.

Telenti, A., Arvin, A., Corey, L., Corti, D., Diamond, M.S., Garcia-Sastre, A., Garry, R.F., Holmes, E.C., Pang, P.S., Virgin, H.W., 2021. After the pandemic: perspectives on the future trajectory of COVID-19. Nature 596, 495-504.

Truong, T.T., Ryutov, A., Pandey, U., Yee, R., Goldberg, L., Bhojwani, D., AguayoHiraldo, P., Pinsky, B.A., Pekosz, A., Shen, L., et al., 2021. Increased viral variants in children and young adults with impaired humoral immunity and persistent SARS-CoV-2 infection: a consecutive case series. EBioMedicine 67, 103355.

van Zundert, G.C.P., Rodrigues, J., Trellet, M., Schmitz, C., Kastritis, P.L., Karaca, E., Melquiond, A.S.J., van Dijk, M., de Vries, S.J., Bonvin, A., 2016. The HADDOCK2.2 web server: user-friendly integrative modeling of biomolecular complexes. J. Mol. Biol. 428, 720-725.

Venkatakrishnan, A., Anand, P., Lenehan, P., Suratekar, R., Raghunathan, B., Niesen, M.J., Soundararajan, V., 2021. Omicron variant of SARS-CoV-2 harbors a unique insertion mutation of putative viral or human genomic origin. OSF Preprints. https://doi.org/10.31219/osf.io/f7txy.

Waterhouse, A., Bertoni, M., Bienert, S., Studer, G., Tauriello, G., Gumienny, R., Heer, F.T., de Beer, T.A.P., Rempfer, C., Bordoli, L., et al., 2018. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 46, W296-W303.

Wei, C., Chen, Y.M., Chen, Y., Qian, W., 2021. The missing expression levelevolutionary rate anticorrelation in viruses does not support protein function as a main constraint on sequence evolution. Genome Biol. Evol. 13, evab049.

Wong, L.Y.R., Zheng, J., Wilhelmsen, K., Li, K., Ortiz, M.E., Schnicker, N.J., Pezzulo, A.A., Szachowicz, P.J., Klumpp, K., Aswad, F., et al., 2021. Eicosanoid signaling as a therapeutic target in middle-aged mice with severe COVID-19. bioRxiv. https://doi.org/10.1101/2021.04.20.440676.

Wu, F., Zhao, S., Yu, B., Chen, Y.M., Wang, W., Song, Z.G., Hu, Y., Tao, Z.W., Tian, J.H., Pei, Y.Y., et al., 2020a. A new coronavirus associated with human respiratory disease in China. Nature 579, 265-269.

Wu, S., Zhong, G., Zhang, J., Shuai, L., Zhang, Z., Wen, Z., Wang, B., Zhao, Z., Song, X., Chen, Y., et al., 2020b. A single dose of an adenovirus-vectored vaccine provides protection against SARS-CoV-2 challenge. Nat. Commun. 11, 4081.

Zhang, Y., Huang, K., Wang, T., Deng, F., Gong, W., Hui, X., Zhao, Y., He, X., Li, C., Zhang, Q., et al., 2021. SARS-CoV-2 rapidly adapts in aged BALB/c mice and induces typical pneumonia. J. Virol. 95 e02477-20.

Zhou, P., Yang, X.L., Wang, X.G., Hu, B., Zhang, L., Zhang, W., Si, H.R., Zhu, Y., Li, B., Huang, C.L., et al., 2020. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270-273.

Relative Articles

Supplements(0)

Cited By

Proportional views