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Endonuclease fingerprint indicates a synthetic origin of SARS-CoV-2

View ORCID ProfileValentin Bruttel, View ORCID ProfileAlex Washburne, View ORCID ProfileAntonius VanDongen
doi: https://doi.org/10.1101/2022.10.18.512756
Valentin Bruttel
1Department for Obstetrics and Gynecology, University Clinics of Würzburg, Germany
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Alex Washburne
2Selva Analytics, Bozeman, Montana, USA
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  • For correspondence: alex.washburne@joinselva.com
Antonius VanDongen
3Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
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Abstract

To prevent future pandemics, it is important that we understand whether SARS-CoV-2 spilled over directly from animals to people, or indirectly in a laboratory accident. The genome of SARS-COV-2 contains a peculiar pattern of unique restriction endonuclease recognition sites allowing efficient dis- and re-assembly of the viral genome characteristic of synthetic viruses. Here, we report the likelihood of observing such a pattern in coronaviruses with no history of bioengineering. We find that SARS-CoV-2 is an anomaly, more likely a product of synthetic genome assembly than natural evolution. The restriction map of SARS-CoV-2 is consistent with many previously reported synthetic coronavirus genomes, meets all the criteria required for an efficient reverse genetic system, differs from closest relatives by a significantly higher rate of synonymous mutations in these synthetic-looking recognitions sites, and has a synthetic fingerprint unlikely to have evolved from its close relatives. We report a high likelihood that SARS-CoV-2 may have originated as an infectious clone assembled in vitro.

Lay Summary To construct synthetic variants of natural coronaviruses in the lab, researchers often use a method called in vitro genome assembly. This method utilizes special enzymes called restriction enzymes to generate DNA building blocks that then can be “stitched” together in the correct order of the viral genome. To make a virus in the lab, researchers usually engineer the viral genome to add and remove stitching sites, called restriction sites. The ways researchers modify these sites can serve as fingerprints of in vitro genome assembly.

We found that SARS-CoV has the restriction site fingerprint that is typical for synthetic viruses. The synthetic fingerprint of SARS-CoV-2 is anomalous in wild coronaviruses, and common in lab-assembled viruses. The type of mutations (synonymous or silent mutations) that differentiate the restriction sites in SARS-CoV-2 are characteristic of engineering, and the concentration of these silent mutations in the restriction sites is extremely unlikely to have arisen by random evolution. Both the restriction site fingerprint and the pattern of mutations generating them are extremely unlikely in wild coronaviruses and nearly universal in synthetic viruses. Our findings strongly suggest a synthetic origin of SARS-CoV2.

Competing Interest Statement

ADW owns shares of a life insurance company and is a co-founder of Selva.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 20, 2022.
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Endonuclease fingerprint indicates a synthetic origin of SARS-CoV-2
Valentin Bruttel, Alex Washburne, Antonius VanDongen
bioRxiv 2022.10.18.512756; doi: https://doi.org/10.1101/2022.10.18.512756
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Endonuclease fingerprint indicates a synthetic origin of SARS-CoV-2
Valentin Bruttel, Alex Washburne, Antonius VanDongen
bioRxiv 2022.10.18.512756; doi: https://doi.org/10.1101/2022.10.18.512756

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