Systematic surveillance of SARS-CoV-2 reveals dynamics of variant mutagenesis and transmission in a large urban population

Systematic surveillance of SARS-CoV-2 reveals dynamics of variant mutagenesis and transmission in a large urban population | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Systematic surveillance of SARS-CoV-2 reveals dynamics of variant mutagenesis and transmission in a large urban population Jeff Wrana, Marie-Ming Aynaud, Lauren Caldwell, Khalid Al-Zahrani, and 25 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4797694/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Dec, 2024 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Highly mutable pathogens generate viral diversity that impacts virulence, transmissibility, treatment, and thwarts acquired immunity. We previously described C19-SPAR-Seq, a high-throughput, next-generation sequencing platform to detect SARS-CoV-2 that we deployed to systematically profile variant dynamics of SARS-CoV-2 for over 3 years in a large, North American urban environment (Toronto, Canada). Sequencing of the ACE2 receptor binding motif and polybasic furin cleavage site of Spike in over 70,000 patients revealed that population sweeps of canonical variants of concern (VOCs) occurred in repeating wavelets. Furthermore, we found that subvariants and putative quasi-species with alterations characteristic of future VOCs and/or predicted to be functionally important arose frequently, but always extinguished. Systematic screening of functionally relevant domains in pathogens could thus provide a powerful tool for monitoring spread and mutational trajectories, particularly those with zoonotic potential. Biological sciences/Microbiology/Virology/SARS-CoV-2 Biological sciences/Computational biology and bioinformatics/High-throughput screening Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryData.zip Dataset 1, Dataset 2, Dataset 3, Dataset 4, SupplementaryInformation.pdf Cite Share Download PDF Status: Published Journal Publication published 30 Dec, 2024 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4797694","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":334286669,"identity":"34afd89c-83d4-4adb-b028-ed5939c9251b","order_by":0,"name":"Jeff 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Percentage of top reads with a mutation detected in a given amino acid in S-Rbm and S-Pbs. The percentage of a point mutation at each amino acid position is shown. Canonical VOCs mutations are indicated in grey. The binding site of S-Rbm with hACE2 (black tiles) and \u0026nbsp;\u0026nbsp;neutralizing antibodies are shown (white-purple scale, with darker purple indicating \u0026nbsp;contact with more antibodies)32, 33, 34 939 , as well as the S-Pbs cleavage site (S1 subunit \u0026nbsp;940 indicated in purple, S2 subunit indicated in yellow) b. Heatmap of case counts of the top \u0026nbsp;941 14 key subvariants and the circulation time (time from the 1st-last case) are plotted with \u0026nbsp;942 functional subvariants shown in red and non-functional subvariants shown in light blue.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4797694/v1/7b91f0f49d18c28093b2154b.png"},{"id":61811294,"identity":"b131b357-4816-4ef9-bcf6-ace3e0a5cb72","added_by":"auto","created_at":"2024-08-05 20:25:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":59624,"visible":true,"origin":"","legend":"\u003cp\u003eResults of an Improved C19-SPAR-Seq V2 pipeline. Line graph of the total number of cases for each canonical VOC from December 2020 to March 2023 (upper panel). Percentage of the weekly cases of the variants, the peaks and cross-over are indicated with dot and dashed lines respectively (lower panel).\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4797694/v1/58f08abde0086a32803821aa.png"},{"id":61809913,"identity":"f718f189-6008-46a8-a3c8-9728927c5d13","added_by":"auto","created_at":"2024-08-05 20:17:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":66142,"visible":true,"origin":"","legend":"\u003cp\u003eVariant dynamic and Non-Pharmaceutical Interventions (NPIs). a. Schematic of the procedure to track the dynamic spread of the virus (see Methods) showing the proportion of Alpha, Delta and Omicron cases with representation of linear models along sliding 5 days windows (red line) (upper panel). Slopes from each linear model (lower panel). b. Dynamic spread using slopes of WT, Alpha, Delta and Omicron B1.1.529. NPIs are plotted (red lines indicate closures or restrictions and green lines indicate openings; see Supplementary Table 6)\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4797694/v1/d9c3886173fe664c26b50adc.png"},{"id":61811820,"identity":"1af2e441-9062-4614-ae59-7394602ff681","added_by":"auto","created_at":"2024-08-05 20:33:31","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":109063,"visible":true,"origin":"","legend":"\u003cp\u003ePopulation-level surveillance of variant dynamics by C19-SPAR-Seq. a. \u0026nbsp;Quantitation of all major mutations observed in the pilot cohort. The frequency of each observed mutation is plotted and color-coded based on their location in the SARS-CoV2 genome b. Phylogenetic tree of the WT strain and the early variants. c. Binary heat map of each canonical VOC and non-canonical VOC ordered by date of first detection. Withineach coloured box is each mutant that shares a common VOC sequence trace. d. Foreach variant, the percentage of canonical VOC is shown with a solid line, and thepercentage of mutant VOC is represented with a dash-line.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4797694/v1/eabc1bdbc16b3d281c656c07.png"},{"id":61809915,"identity":"c05924a6-fbbe-476f-ad08-c6514d3c9088","added_by":"auto","created_at":"2024-08-05 20:17:31","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":64635,"visible":true,"origin":"","legend":"\u003cp\u003eMajor VOC subvariants within the S-Rbm and S-Pbs sequences. a. Percentage of top reads with a mutation detected in a given amino acid in S-Rbm and S-Pbs. The percentage of a point mutation at each amino acid position is shown. Canonical VOCs mutations are indicated in grey. The binding site of S-Rbm with hACE2 (black tiles) and \u0026nbsp;\u0026nbsp;9 neutralizing antibodies are shown (white-purple scale, with darker purple indicating \u0026nbsp;contact with more antibodies)32, 33, 34 , as well as the S-Pbs cleavage site (S1 subunit \u0026nbsp;940 indicated in purple, S2 subunit indicated in yellow) b. Heatmap of case counts of the top 14 key subvariants and the circulation time (time from the 1st-last case) are plotted with functional subvariants shown in red and non-functional subvariants shown in light blue.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-4797694/v1/00964ad2162a4915b774ddbc.png"},{"id":61809917,"identity":"588f87ea-9e2c-4f0b-9e94-cb9b0d54991e","added_by":"auto","created_at":"2024-08-05 20:17:31","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":98638,"visible":true,"origin":"","legend":"\u003cp\u003eDetection of putative quasispecies by C19-SPAR-Seq. a. Schematic of pQS detection. b. Percentage of putative quasispecies detected in S-Rbm and S-Pbs sequences on WT, Alpha, Delta, and Omicron B.1.1.529 samples. c. S-Rbm and S-Pbs putative quasispecies sequences.\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-4797694/v1/88ca7f23c7a226a3303ed83d.png"},{"id":61811296,"identity":"9eea3cf7-b3c9-41f7-bd89-a88cc0d21f50","added_by":"auto","created_at":"2024-08-05 20:25:31","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":128424,"visible":true,"origin":"","legend":"\u003cp\u003eFunctional Impact of VOC subvariants and putative quasispecies. a. Summary of all mutations and/or putative quasispecies found in S-Rbm and S-Pbs. S-Rbm and S-Pbs reference sequences are indicated with VOC-associated changes highlighted in red. \u0026nbsp;\u0026nbsp;At top left, the binding site of S-Rbm with hACE2 (black tiles) and 9 neutralizing antibodies \u0026nbsp;953 are shown (white-purple scale, with darker purple indicating contact with more \u0026nbsp;antibodies)32, 33, 34, as well as the S-Pbs cleavage site at top right (S1 subunit indicated in purple, S2 subunit indicated in yellow). 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We previously described C19-SPAR-Seq, a high-throughput, next-generation sequencing platform to detect SARS-CoV-2 that we deployed to systematically profile variant dynamics of SARS-CoV-2 for over 3 years in a large, North American urban environment (Toronto, Canada). Sequencing of the ACE2 receptor binding motif and polybasic furin cleavage site of Spike in over 70,000 patients revealed that population sweeps of canonical variants of concern (VOCs) occurred in repeating wavelets. Furthermore, we found that subvariants and putative quasi-species with alterations characteristic of future VOCs and/or predicted to be functionally important arose frequently, but always extinguished. 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