Where did ‘weird’ Omicron come from?

Kupferschmidt, Kai

doi:10.1126/science.acx9738

Cited by 154SARS-CoV-2 and COVID-19 ResearchEvolution and Genetic DynamicsCOVID-19 epidemiological studies

Where did ‘weird’ Omicron come from?

Kupferschmidt, Kai·2021·Science

DOI 10.1126/science.acx9738

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Abstract

but WHO skipped the letters Nu and Xi, it said, “because Nu is too easily confounded with ‘new’ and Xi was not used because it is a common surname.”) One reason for concern about Omicron is that sequenced samples indicate it has rapidly replaced other variants in South Africa. But that picture might be skewed. For one, sequencing might have been focused on possible cases of the new variant in recent days, which could make it appear more frequent than it is. PCR data provide broader coverage and a less biased view, but there, too, samples with the S gene failure indicate a rapid rise of Omicron. The rising frequency could still be due in part to chance. In San Diego, a series of superspreading events at a university resulted in an explosion of one particular strain of SARS-CoV-2 earlier this year, Andersen says: “It was thousands of cases and they were all the same virus.” But the virus wasn’t notably more infectious. South Africa has seen relatively few cases recently, so a series of superspreading events could have led to the rapid increase of Omicron. “I suspect that a lot of that signal is explained by that and I desperately hope so,” Andersen says. Based on a comparison of different Omicron genomes, Andersen estimates the virus emerged sometime around late September or early October, which suggests it might be spreading more slowly than it appears to have. The other reason to be concerned is Omicron’s confusing genome. Its spike protein, which latches on to receptors on h…

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The rising level of SARS-CoV-2 exposure in South Africa in 2020-2021 would be expected to promote the fitness advantage of immune escape variants over earlier variants.
“While there are different hypotheses addressing the evolutionary origins of Omicron BA.1's emergence and this variant's unusual number of mutations 25 , the rising level of SARS-CoV-2 exposure in South Africa in 2020-2021 would be expected to promote the fitness advantage of immune escape variants over earlier variants.”
From Rapidly shifting immunologic landscape and severity of SARS-CoV-2 in the Omicron era in South Africa (2023) · cites this paper as [25]

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Background
Role of the Pangolin in Origin of SARS-CoV-2: An Evolutionary Perspective
Gupta, S. K., Minocha, R., Thapa, P. J., Srivastava, M., & Dandekar, T. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169115 · Cited by 13 · see citing works
Artificial Intelligence: A Next-Level Approach in Confronting the COVID-19 Pandemic
Mahalakshmi, V. J., Balobaid, A. S., Kanisha, B., Sasirekha, R., & Raja, M. R. (2023) · Healthcare · doi:10.3390/healthcare11060854 · Cited by 12 · see citing works
An evolutionary insight into Severe Acute Respiratory Syndrome Coronavirus 2 Omicron variant of concern.
Paz, M., Aldunate, F., Arce, R., Ferreiro, I., & Cristina, J. (2022) · Virus Research · doi:10.1016/j.virusres.2022.198753 · Cited by 11 · see citing works
The frequency of defective genomes in Omicron differs from that of the Alpha, Beta and Delta variants
de Campos, C. F., Colomer‐Castell, S., García‐Cehic, D., Gregori, J., Andrés, C., Piñana, M., Gónzalez‐Sánchez, A., Borràs-Bermejo, B., Parés‐Badell, O., Adombi, C. M., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-24918-8 · Cited by 11 · see citing works
Status and Developing Strategies for Neutralizing Monoclonal Antibody Therapy in the Omicron Era of COVID-19
Ren, Z., Shen, C., & Peng, J. (2023) · Viruses · doi:10.3390/v15061297 · Cited by 11 · see citing works
Risk assessment of SARS-CoV-2 replicating and evolving in animals
Zhao, J., Kang, M., Wu, H., Sun, B., Baele, G., He, W., Lu, M., Suchard, M. A., Ji, X., He, N., et al. (2023) · Trends in Microbiology · doi:10.1016/j.tim.2023.07.002 · Cited by 11 · see citing works
Raman Fingerprints of SARS-CoV-2 Omicron Subvariants: Molecular Roots of Virological Characteristics and Evolutionary Directions
Pezzotti, G., Ohgitani, E., Fujita, Y., Imamura, H., Pappone, F., Grillo, A., Nakashio, M., Shin‐Ya, M., Adachi, T., Yamamoto, T., et al. (2023) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.3c00312 · Cited by 11 · see citing works
Complexity of Viral Epitope Surfaces as Evasive Targets for Vaccines and Therapeutic Antibodies
Miller, N. L., Raman, R., Clark, T., & Sasisekharan, R. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.904609 · Cited by 11 · see citing works
Bayesian Molecular Dating Analyses Combined with Mutational Profiling Suggest an Independent Origin and Evolution of SARS-CoV-2 Omicron BA.1 and BA.2 Sub-Lineages
Kumar, N., Kaushik, R., Singh, A., Uversky, V. N., Zhang, K. Y. J., Sahu, U., Bhatia, S., & Sanyal, A. (2022) · Viruses · doi:10.3390/v14122764 · Cited by 12 · see citing works
The Spread of SARS-CoV-2 Omicron Variant in CALABRIA: A Spatio-Temporal Report of Viral Genome Evolution
Veneziano, C., Marascio, N., Marco, C. D., Quaresima, B., Biamonte, F., Trecarichi, E. M., Santamaria, G., Quirino, A., Torella, D., Quattrone, A., et al. (2023) · Viruses · doi:10.3390/v15020408 · Cited by 10 · see citing works
Seasonal effects decouple SARS-CoV-2 haplotypes worldwide
Tomaszewski, T., Ali, M. A., Caetano-Anollés, K., & Caetano‐Anollés, G. (2023) · F1000Research · doi:10.12688/f1000research.131522.1 · Cited by 11 · see citing works
“Discussion VOC emergence There appears to be no ‘transparent’ path of transmission from viral ancestors to VOCs nor an explanation for themassive mutant constellation that characterizes the current VOC Omicron wave of the pandemic (Kupferschmidt, 2021; Mallapaty, 2022).”
Background
Mapping Data to Deep Understanding: Making the Most of the Deluge of SARS-CoV-2 Genome Sequences
Sokhansanj, B., & Rosen, G. L. (2022) · mSystems · doi:10.1128/msystems.00035-22 · Cited by 6 · see citing works
“The Omicron variant has such a long branch divergence, indicating that it may have emerged in an immunocompromised host or after incubating in a nonhuman host such as mice (41, 42).”
Background
Immunogenicity and protective potential of chimeric virus-like particles containing SARS-CoV-2 spike and H5N1 matrix 1 proteins
Chen, J., Wang, X., Li, L., Yi, L., Jiang, Y., Hao, P., Xu, Z., Zou, W., Li, P., Gao, Z., et al. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.967493 · Cited by 9 · see citing works
“A phylogenetic tree based on the mutations in the S1 subunit of viral Spike showed that the Omicron is far from other variants, indicating that Omicron evolved in parallel with other variants (Kupferschmidt, 2021).”
Background
Intrinsic Severity of the SARS-CoV-2 Omicron Variant
Bhattacharyya, R. P., & Hanage, W. P. (2022) · New England Journal of Medicine · doi:10.1056/nejmc2203679 · Cited by 9 · see citing works
Early pathogenesis profiles across SARS-CoV-2 variants in K18-hACE2 mice revealed differential triggers of lung damages
Aw, Z., Mok, C.-K., Wong, Y., Chen, H.-X., Mak, T., Lin, R., Lye, D., Tan, K.-S., & Chu, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.950666 · Cited by 7 · see citing works
Effective virus-specific T-cell therapy for high-risk SARS-CoV-2 infections in hematopoietic stem cell transplant recipients: initial case studies and literature review
Gopcsa, L., Réti, M., Andrikovics, H., Bobek, I., Bekő, G., Bogyó, J., Ceglédi, A., Dobos, K., Giba-Kiss, L., Jankovics, I., et al. (2023) · GeroScience · doi:10.1007/s11357-023-00858-7 · Cited by 8 · see citing works
“In addition to life threatening outcomes, a persistent SARS-CoV-2 infection in immunocompromised hosts also carries the risk of giving rise to series of mutations in the viral genome [15–18].”
Background
Omicron variant receptor-binding domain phylogenetics and molecular dynamics
Kandeel, M. K., & El‐Deeb, W. (2022) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2022.105633 · Cited by 8 · see citing works
“Because of Africa’s low vaccination rate, the Omicron variant may have more readily circulated [25].”
SARS-CoV-2 Omicron variant (B.1.1.529): A concern with immune escape
Sanyaolu, A. O., Marinkovic, A., Prakash, S., Haider, N., Williams, M., Okorie, C., Badaru, O., & Smith, S. I. (2022) · World Journal of Virology · doi:10.5501/wjv.v11.i3.137 · Cited by 8 · see citing works
SARS-CoV-2 variants of concerns in animals: An unmonitored rising health threat
Saied, A. A., & Metwally, A. A. (2022) · VirusDisease · doi:10.1007/s13337-022-00794-8 · Cited by 8 · see citing works
Epistasis at the SARS-CoV-2 RBD Interface and the Propitiously Boring Implications for Vaccine EscapePreprint
Rochman, N. D., Faure, G., Wolf, Y. I., Freddolino, P. L., Zhang, F., & Koonin, E. V. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.08.30.458225 · Cited by 8 · see citing works
“425 At the time of writing, the origins of the Omicron variant are unclear and is suspected to 426 have evolved over an extended period of time within an immunocompromised 427 individual(s) or an animal reservoir(30).”
Background
COVID-19 epidemic in New York City: development of an age group-specific mathematical model to predict the outcome of various vaccination strategies
Li, M., Zu, J., Zhang, Y., Ma, L., Shen, M., Li, Z., & Ji, F. (2022) · Virology Journal · doi:10.1186/s12985-022-01771-9 · Cited by 7 · see citing works
Structural basis and analysis of hamster ACE2 binding to different SARS-CoV-2 spike RBDs
Niu, S., Zhao, Z., Liu, Z., Rong, X., Chai, Y., Bai, B., Han, P., Shang, G., Ren, J., Wang, Y., et al. (2024) · Journal of Virology · doi:10.1128/jvi.01157-23 · Cited by 7 · see citing works
“As reported, omicron variants evolved independently of all other SARS-CoV-2 variants, and a possible animal origin was proposed to be related to rodents such as mice and rats (41).”
Background
Modeling of ACE2 and antibodies bound to SARS-CoV-2 provides insights into infectivity and immune evasion
Lubin, J. H., Markosian, C., Balamurugan, D., Ma, M. T., Chen, C.-H., Liu, D., Pasqualini, R., Arap, W., Burley, S. K., & Khare, S. D. (2023) · JCI Insight · doi:10.1172/jci.insight.168296 · Cited by 26 · see citing works
In silico genomic surveillance by CoVerage predicts and characterizes SARS-CoV-2 variants of interest
Norwood, K., Deng, Z.-L., Reimering, S., Robertson, G., Foroughmand-Araabi, M.-H., Goliaei, S., Hölzer, M., Klawonn, F., & McHardy, A. C. (2025) · Nature Communications · doi:10.1038/s41467-025-60231-4 · Cited by 10 · see citing works
“• Line 273: Could statistical significance (e.g., Wilcoxon test) be tested for differences between designated and non-designated pVOIs?”
Viral syncytia evolve to resist interferon
Li, T., Kang, I., Ye, J., Hu, Z., Gibbs, J. S., Ye, C., Takeda, K., Košík, I., Shi, G., Hollý, J., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-74676-8 · Cited by 6 · see citing works
Additional Evidence for Commonalities between COVID-19 and Radiation Injury: Novel Insight into COVID-19 Candidate Drugs
Geng, F., Chen, J., Tang, S., Azzam, E. I., Zhang, J., & Zhang, S. (2022) · Radiation Research · doi:10.1667/rade-22-00058.1 · Cited by 6 · see citing works
A SARS-CoV-2 vaccine based on conjugation of SARS-CoV-2 RBD with IC28 peptide and mannan
He, Y., Yu, W., Shen, L., Yan, W., Xiao, L., Qi, J., & Hu, T. (2022) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2022.09.180 · Cited by 6 · see citing works
Current status of mucosal vaccines against SARS-CoV2: a hope for protective immunity
García-Silva, I., Govea‐Alonso, D. O., & Rosales‐Mendoza, S. (2023) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2022.2156284 · Cited by 6 · see citing works
Indoor Air Quality Measurements in Enclosed Spaces Combining Activities with Different Intensity and Environmental Conditions
Urbina-Garcia, O., Fernández‐Gámiz, U., Zulueta, E., Ugarte-Anero, A., & Portal-Porras, K. (2024) · Buildings · doi:10.3390/buildings14041007 · Cited by 7 · see citing works
Shell Disorder Models Detect That Omicron Has Harder Shells with Attenuation but Is Not a Descendant of the Wuhan-Hu-1 SARS-CoV-2
Goh, G. K., Dunker, A. K., Foster, J. A., & Uversky, V. N. (2022) · Biomolecules · doi:10.3390/biom12050631 · Cited by 6 · see citing works
The Omicron Sub-Variant BA.4 Displays a Remarkable Lack of Clinical Signs in a Golden Syrian Hamster Model of SARS-CoV-2 Infection
Davies, E. R., Ryan, K. A., Bewley, K. R., Coombes, N. S., Salguero, F. J., Carnell, O. T., Biddlecombe, S. M., Charlton, M., Challis, A., Cross, E. S., et al. (2023) · Viruses · doi:10.3390/v15051133 · Cited by 5 · see citing works
Investigating the structural impact of Omicron RBD mutation on antibody escape and receptor management
Saini, S., Pareekh, S., & Kumar, Y. (2023) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2023.2222174 · Cited by 5 · see citing works
“However, some studies suggest evolution of antigenic shifts in variants could be attributed to rigorous viral amplification in patients who are immunocompromised (Cameroni et al., 2022; Corey et al., 2021; Kupferschmidt, 2021).”
Background
A Comparative Experimental and Computational Study on the Nature of the Pangolin-CoV and COVID-19 Omicron
Wei, L., Song, L., Dunker, A. K., Foster, J. A., Uversky, V. N., & Goh, G. K. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25147537 · Cited by 5 · see citing works
“[ 23–25, 29 – Omicrons became available [26,34].”
Background
A Study on the Nature of SARS-CoV-2 Using the Shell Disorder Models: Reproducibility, Evolution, Spread, and Attenuation
Goh, G. K., Dunker, A. K., Foster, J. A., & Uversky, V. N. (2022) · Biomolecules · doi:10.3390/biom12101353 · Cited by 5 · see citing works
Structural basis for antibody resistance to SARS-CoV-2 omicron variantPreprint
Cerutti, G., Guo, Y., Liu, L., Zhang, Z., Liu, L., Luo, Y., Huang, Y., Wang, H. H., Ho, D. D., Sheng, Z., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.12.21.473620 · Cited by 5 · see citing works
“Some have proposed that it developed in a chronically infected individual with an impaired immune response, whereas others think it developed in parallel with other variants in a population not monitored by sequencing (Kupferschmidt, 2021).”
Background
What Learned from Omicron Sub-Variants BQ.1 and BQ.1.1Preprint
Mustafa, M. I., & Makhawi, A. M. (2022) · Preprints.org · doi:10.20944/preprints202210.0361.v1 · Cited by 5 · see citing works

Authors: Kupferschmidt, K.
Corresponding author: Kupferschmidt, Kai
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2021-12-03
Volume: 374
Issue: 6572
Pages: 1179-1179
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.acx9738
OpenAlex: W3215456302
Cited by: 154
References: 0
Citations by year: 2026: 2 · 2025: 5 · 2024: 14 · 2023: 30 · 2022: 86 · 2021: 17
FWCI: 11.63
Type: journal article
Language: en
Open access: closed
Locations: Science (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
Physical Sciences › Mathematics › Modeling and Simulation › COVID-19 epidemiological studies
Keywords: Omicron variant, SARS-CoV-2, viral evolution, COVID-19 pandemic
MeSH terms: Vaccination Coverage, COVID-19, SARS-CoV-2, COVID-19 Vaccines, Persistent Infection, Animals, Humans, Mutation, Genome, Viral, Immunocompromised Host, Evolution, Molecular

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