Exceptional enrichment of rare C-to-G transversions in the SARS-CoV-2 Delta spike

Exceptional enrichment of rare C-to-G transversions in the SARS-CoV-2 Delta spike | 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 Short Report Exceptional enrichment of rare C-to-G transversions in the SARS-CoV-2 Delta spike Hideki This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8722653/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract SARS-CoV-2 evolution is constrained by strong mutational biases, with C→G transversions being exceptionally rare. We show that this constraint is uniquely violated in the Delta variant spike, where C→G substitutions are significantly enriched compared with inter- and intra-lineage backgrounds. This deviation highlights an unusual evolutionary trajectory with potential epidemiologic significance. Systems Biology Virology Biostatistics Bioinformatics Evolutionary Genetics Molecular Genetics Infectious Diseases Molecular Biology SARS-CoV-2 Delta variant C→G transversion Mutation spectrum Spike protein Figures Figure 1 Introduction SARS-CoV-2 evolution is governed by strong intrinsic mutational biases. Across hosts, lineages, and epidemiological settings, nucleotide substitutions are dominated by transitions, particularly C→U [1], whereas transversions occur less frequently. Among transversions, C→G substitutions are consistently the rarest. Although some saltation variants exhibit elevated transversion rates, C→G substitutions are rarely observed during lineage transitions. This constraint has been observed even under conditions of strong immune selection. A longitudinal analysis of prolonged SARS-CoV-2 infections documented extensive accumulation of spike mutations associated with immune escape, yet no C→G substitutions were detected [2]. Similarly, SARS-CoV-2 exhibits the lowest frequency of C→G substitutions among all single-nucleotide changes in genomic surveillance data [3,4] as well as in patients treated with molnupiravir [5] or in vitro experiments [6]. Together, these findings indicate that near absence of C→G substitutions is a robust feature of SARS-CoV-2 evolution. It is also noteworthy that C→G substitutions are the rarest among coronaviruses infecting diverse animal hosts [7]. Moreover, C→G substitutions are consistently rare in other viruses, such as MERS-CoV [8], Ebola, and Influenza A viruses [9]. To assess whether this constraint is maintained across viral diversification, we examined nucleotide substitution spectra in spike and genome-wide mutations across multiple evolutionary contexts, as shown in Figure 1. Spike and genome-wide mutations were defined as fixed, lineage-defining nucleotide substitutions relative to their respective immediate ancestral reference sequences (e.g., B.1 for Delta), excluding insertions and deletions. Substitutions were classified into the twelve possible single-nucleotide categories. Mutation spectrum generation was performed using Python custom scripts (Supplementary Material). First, we analyzed inter-lineage spike and genome-wide evolution, including early variants of concern and major evolutionary transitions leading to Omicron sublineages (BA.1, BA.2.75, BA.2.86, and BA.3.2). Regarding the early variants, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Epsilon (B.1.427), Eta (B.1.525), Iota (B.1.526), and Lambda (C.37) were selected for the analyses. Across these contexts excluding Delta, C→G substitutions were completely absent from spike mutations (0/162). This absence persisted despite extensive spike remodeling during major evolutionary jumps. In contrast, the Delta variant carried two C→G substitutions among seven spike substitutions. To estimate background substitution frequencies within a single lineage, we analyzed spike evolution within lineage B.1.1. Among 179 spike point mutations accumulated within this lineage, only a single C→G substitution was observed (1/179, 0.56%), confirming that C→G substitutions are strongly suppressed even during prolonged diversification within a lineage. The Delta spike contained two C→G substitutions (2/7, 28.6%), in contrast to the consistent suppression of C→G substitutions across non-Delta inter-lineage spike evolution (0/162) and within-lineage B.1.1 spike evolution (1/179, 0.56%). This represents a significant enrichment of C→G substitutions in the Delta spike compared with non-Delta inter-lineage spike evolution (Fisher’s exact test, one-sided, p = 0.00148) and compared with within-lineage B.1.1 spike evolution (Fisher’s exact test, one-sided, p = 0.00360). Among the seven substitutions in the Delta spike, four resulted in substitutions to basic residues, which elevate the positive charge and are considered to have enhanced its transmissibility [10]. The two C→G substitutions both contributed to this basic-residue enrichment, giving rise to T19R and P681R, respectively. Table 1 shows the spike mutations in the Delta variant. Because sequences carrying multiple Delta-defining mutations were rare prior to Delta emergence (with no sequences carrying four or more such mutations), recombination among pre-existing lineages is unlikely to account for the assembly of the Delta mutation constellation. P681R is known to enhance furin-mediated S1/S2 cleavage. The Alpha and early Omicron variants carry P681H substitutions, which also enhance S1/S2 cleavage. Later, R681 reappeared in Omicron BA.2.86. Starting from an H681 background, R681 can be achieved via an additional G→A substitution. However, it is unlikely that the Delta variant is a descendant of the Alpha variant, since the only shared mutation between them is D614G, which is common to all major variants of concern. T19R disappeared after the Delta variant, although another substitution at the same position, T19I, appeared in Omicron. The absence of T19R in other variants suggests that this mutation does not confer a strong selective advantage for long-term prevalence. It therefore remains enigmatic why a C→G substitution occurred to generate this mutation under apparently weak selection pressure. Taken together, these results identify the Delta spike protein as a clear outlier in SARS-CoV-2 mutational spectra. Given the strong and consistent suppression of C→G substitutions across evolutionary contexts, their enrichment in the Delta spike is unlikely to reflect mutational bias alone and instead suggests the presence of an unusual selective context and/or lineage-specific evolutionary process acting on spike evolution. Monitoring deviations from conserved mutational constraints may provide a complementary signal in genomic surveillance for identifying atypical evolutionary trajectories. Declarations Conflicts of interest The author declares no conflict of interest exists. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Ethical Approval Not applicable. Declaration of generative AI and AI-assisted technologies in the manuscript preparation process During the preparation of this work, the author used ChatGPT (OpenAI; version 5.2) to debug source code and to improve language and readability. After using this tool, the author reviewed and edited the content as needed and takes full responsibility for the content of the published article. Data Availability All data used in this study are publicly available from GenBank and GISAID. The source code used for this study is available at https://github.com/visual-media-lab/SARS-CoV-2-HMV https://github.com/visual-media-lab/BA3 Acknowledgement We gratefully acknowledge all data contributors to GenBank and GISAID. References Simmonds P. Rampant C→U hypermutation in the genomes of SARS-CoV-2 and other coronaviruses: causes and consequences for their short- and long-term evolutionary trajectories. mSphere. 2020;5(3):e00408-20. doi: 10.1128/mSphere.00408-20. Voloch CM, et al. Intra-host evolution during SARS-CoV-2 prolonged infection. Virus Evol. 2021;7(2):veab078. doi:10.1093/ve/veab078. Yi K, Kim SY, Bleazard T, et al. Mutational spectrum of SARS-CoV-2 during the global pandemic. Exp Mol Med. 2021;53(8):1229–37. doi:10.1038/s12276-021-00658-z. Rice AM, Morales AC, Ho AT, et al. Evidence for strong mutation bias toward, and selection against, U content in SARS-CoV-2: implications for vaccine design. Mol Biol Evol. 2021;38(1):67–83. doi:10.1093/molbev/msaa188. Sanderson T, Hisner R, Donovan-Banfield I, et al. A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes. Nature. 2023;623:594-600. doi:10.1038/s41586-023-06649-6. Amicone M, Borges V, Alves MJ, et al. Mutation rate of SARS-CoV-2 and emergence of mutators during experimental evolution. Evol Med Public Health. 2022;10(1):142-155. doi:10.1093/emph/eoac010. Wei C, Shan KJ, Wang W, et al. Evidence for a mouse origin of the Omicron variant. J Genet Genomics. 2021;48(12):1111-1121. doi:10.1016/j.jgg.2021.10.003. Di Giorgio S, Martignano F, Torcia MG, Mattiuz G, Conticello SG. Evidence for host-dependent RNA editing in the transcriptome of SARS-CoV-2. Sci Adv. 2020;6(25):eabb5813. doi: 10.1126/sciadv.abb5813. Shan KJ, Wei C, Wang Y, et al. Host-specific asymmetric accumulation of mutation types reveals that the origin of SARS-CoV-2 is consistent with a natural process. Innovation (Camb). 2021;2(4):100159. doi:10.1016/j.xinn.2021.100159. Cotten M, Phan MVT. Evolution of increased positive charge on the SARS-CoV-2 spike protein may be adaptation to human transmission. iScience. 2023;26(3):106230. doi:10.1016/j.isci.2023.106230. Table Table 1. Characteristics of mutations in the Delta variant. (A) Spike amino acid substitutions defining the emergence of the Delta variant (B.1→B.1.617.2) and their corresponding nucleotide substitutions. C→G substitutions are shown in bold. (B) GISAID submission counts of sequences carrying Delta spike substitutions and combinations of these substitutions before the first Delta sequence was submitted (March 23, 2021). (C) Earliest submission dates of sequences carrying the Delta spike substitutions and substitution combinations listed in panel (B). (A) Amino Acid T19R G142D R158D L452R T478K P681R D950N Nucleotide C21618G G21987A U22917G C22995A A23403G C23604G G24410A (B) total w/ G142D w/ R158D w/ L452R w/ T478K w/ P681R w/ D950N T19R 48 0 0 0 0 0 0 G142D 1,072 4 274 11 7 0 R158D 18 1 0 0 0 L452R 18,478 1 32 0 T478K 4,419 0 0 P681R 1,530 0 D950N 56 * G142D+L452R+P681R: 6; Total number of GISAID sequences before emergence of Delta: 850,214. (C) G142D L452R D950N T478K P681R T19R G142D T478K R158D G142D P681R G142D R158D L452R P681R G142D L452R P681R R158D L452R L452R T478K 4/13/20 4/23 5/12 7/8 7/27 9/23 10/22 11/3 11/5 1/8/21 1/15 3/5 3/12 3/16 Additional Declarations The authors declare no competing interests. Supplementary Files Supplement.docx Cite Share Download PDF Status: Posted 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8722653","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":582139464,"identity":"35b67ac3-2eaf-49ef-8230-4f3b705c574a","order_by":0,"name":"Hideki","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7klEQVRIiWNgGAWjYBACCQY2BoYPBhJgDmMDwwGYMH4tjDMMJMBaidfCzAO1DaEFH5BsP5b42KbAoo5Bvv2Z5My2O/IM7IcfMFjuwK1FmiftsHEO2GE8ZpIb254ZNvCkGTBInsGtRY4hvU0aqoVN8mHbYaDjcoCWt+HRwv+8/bcFWAv7M5AW+wb+N/i1SEukHWNmgIQYyGGHExskCNgiOeNZsmSPgYRkG1uOseWMc8+S2ySeGRzA5xeJ82mGH378qePnZz7+8GZP2R3bfv7kh48l8YQYHLAhMw5LNhChBQUwfiRZyygYBaNgFAxjAABOwEdBkeCiSgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-3788-9133","institution":"Kakeya","correspondingAuthor":true,"prefix":"","firstName":"","middleName":"","lastName":"Hideki","suffix":""}],"badges":[],"createdAt":"2026-01-28 15:24:26","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-8722653/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8722653/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101470168,"identity":"e5b57a7c-dec3-475b-8f3e-3854206f7308","added_by":"auto","created_at":"2026-01-30 05:10:48","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":101257,"visible":true,"origin":"","legend":"\u003cp\u003eMutation spectra (substitution counts) for lineage transitions and within-lineage evolution. Mutation spectra were compiled for (A) early variant transitions (B.1.1→B.1.1.7, B.1.1→P.1, B.1→B.1.427, B.1→B.1.525, B.1→B.1.526, and B.1.1→C.37), (B) major Omicron transitions (B.1.1→BA.1, BA.2→BA.2.75, BA.2→BA.2.86, and BA.3→BA.3.2), (C) within-lineage evolution in B.1.1, and (D) the Delta transition (B.1→B.1.617.2). Spike (blue) and non-spike (gray) substitutions are shown. C→G substitutions are boxed in red. Source data were obtained from GenBank, except for BA.3.2. Due to limited data availability, BA.2.86.1 sequences from GenBank were used as a proxy for BA.2.86, and BA.3.2.2 sequences from GISAID were used as a proxy for BA.3.2. The BA.3 consensus sequence was generated from BA.3 sequences registered in GISAID in 2021 or earlier.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8722653/v1/a119bf2fcdb16b1903fbc393.jpeg"},{"id":101751930,"identity":"e533f232-611b-4492-ae38-05975f2d8970","added_by":"auto","created_at":"2026-02-03 10:24:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":552739,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8722653/v1/526d8979-f35a-4043-9752-6152a967adb2.pdf"},{"id":101470170,"identity":"896c9ca4-ce88-4b06-b950-394e7f2e573e","added_by":"auto","created_at":"2026-01-30 05:10:48","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18547,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement.docx","url":"https://assets-eu.researchsquare.com/files/rs-8722653/v1/37f2e97e96d283915eeea5a4.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eExceptional enrichment of rare C-to-G transversions in the SARS-CoV-2 Delta spike\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSARS-CoV-2 evolution is governed by strong intrinsic mutational biases. Across hosts, lineages, and epidemiological settings, nucleotide substitutions are dominated by transitions, particularly C→U [1], whereas transversions occur less frequently. Among transversions, C→G substitutions are consistently the rarest. Although some saltation variants exhibit elevated transversion rates, C→G substitutions are rarely observed during lineage transitions.\u003c/p\u003e\n\u003cp\u003eThis constraint has been observed even under conditions of strong immune selection. A longitudinal analysis of prolonged SARS-CoV-2 infections documented extensive accumulation of spike mutations associated with immune escape, yet no C→G substitutions were\u0026nbsp;detected [2]. Similarly, SARS-CoV-2 exhibits the lowest frequency of C→G substitutions among all single-nucleotide changes in genomic surveillance data [3,4] as well as in patients treated with molnupiravir [5] or in vitro experiments [6]. Together, these findings indicate that near absence of C→G substitutions is a robust feature of SARS-CoV-2 evolution. It is also noteworthy that C→G substitutions are the rarest among coronaviruses infecting diverse animal hosts [7]. Moreover, C→G substitutions are consistently rare in other viruses, such as MERS-CoV [8], Ebola, and Influenza A viruses [9].\u003c/p\u003e\n\u003cp\u003eTo assess whether this constraint is maintained across viral diversification, we examined nucleotide substitution spectra in spike and genome-wide mutations across multiple evolutionary contexts, as shown in Figure 1. Spike and genome-wide mutations were defined as fixed, lineage-defining nucleotide substitutions relative to their respective immediate ancestral reference sequences (e.g., B.1 for Delta), excluding insertions and deletions. Substitutions were classified into the twelve possible single-nucleotide categories. Mutation spectrum generation was performed using Python custom scripts (Supplementary Material).\u003c/p\u003e\n\u003cp\u003eFirst, we analyzed inter-lineage spike and genome-wide evolution, including early variants of concern and major evolutionary transitions leading to Omicron sublineages (BA.1, BA.2.75, BA.2.86, and BA.3.2). Regarding the early variants, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Epsilon (B.1.427), Eta (B.1.525), Iota (B.1.526), and Lambda (C.37) were selected for the analyses.\u003c/p\u003e\n\u003cp\u003eAcross these contexts excluding Delta, C→G substitutions were completely absent from spike mutations (0/162). This absence persisted despite extensive spike remodeling during major evolutionary jumps. In contrast, the Delta variant carried two C→G substitutions among seven spike substitutions.\u003c/p\u003e\n\u003cp\u003eTo estimate background substitution frequencies within a single lineage, we analyzed spike evolution within lineage B.1.1. Among 179 spike point mutations accumulated within this lineage, only a single C→G substitution was observed (1/179, 0.56%), confirming that C→G substitutions are strongly suppressed even during prolonged diversification within a lineage.\u003c/p\u003e\n\u003cp\u003eThe Delta spike contained two C→G substitutions (2/7, 28.6%), in contrast to the consistent suppression of C→G substitutions across non-Delta inter-lineage spike evolution (0/162) and within-lineage B.1.1 spike evolution (1/179, 0.56%). This represents a significant enrichment of C→G substitutions in the Delta spike compared with non-Delta inter-lineage spike evolution (Fisher’s exact test, one-sided, p = 0.00148) and compared with within-lineage B.1.1 spike evolution (Fisher’s exact test, one-sided, p = 0.00360).\u003c/p\u003e\n\u003cp\u003eAmong the seven substitutions in the Delta spike, four resulted in substitutions to basic residues, which elevate the positive charge and are considered to have enhanced its transmissibility [10]. The two C→G substitutions both contributed to this basic-residue enrichment, giving rise to T19R and P681R, respectively.\u003c/p\u003e\n\u003cp\u003eTable 1 shows the spike mutations in the Delta variant. Because sequences carrying multiple Delta-defining mutations were rare prior to Delta emergence (with no sequences carrying four or more such mutations), recombination among pre-existing lineages is unlikely to account for the assembly of the Delta mutation constellation.\u003c/p\u003e\n\u003cp\u003eP681R is known to enhance furin-mediated S1/S2 cleavage. The Alpha and early Omicron variants carry P681H substitutions, which also enhance S1/S2 cleavage. Later, R681 reappeared in Omicron BA.2.86. Starting from an H681 background, R681 can be achieved via an additional G→A substitution. However, it is unlikely that the Delta variant is a descendant of the Alpha variant, since the only shared mutation between them is D614G, which is common to all major variants of concern.\u003c/p\u003e\n\u003cp\u003eT19R disappeared after the Delta variant, although another substitution at the same position, T19I, appeared in Omicron. The absence of T19R in other variants suggests that this mutation does not confer a strong selective advantage for long-term prevalence. It therefore remains enigmatic why a C→G substitution occurred to generate this mutation under apparently weak selection pressure.\u003c/p\u003e\n\u003cp\u003eTaken together, these results identify the Delta spike protein as a clear outlier in SARS-CoV-2 mutational spectra. Given the strong and consistent suppression of C→G substitutions across evolutionary contexts, their enrichment in the Delta spike is unlikely to reflect mutational bias alone and instead suggests the presence of an \u003cstrong\u003eunusual selective context and/or lineage-specific evolutionary process\u003c/strong\u003e acting on spike evolution. Monitoring deviations from conserved mutational constraints may provide a complementary signal in genomic surveillance for identifying atypical evolutionary trajectories.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author declares no conflict of interest exists.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of generative AI and AI-assisted technologies in the manuscript preparation process\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the preparation of this work, the author used ChatGPT (OpenAI; version 5.2) to debug source code and to improve language and readability. After using this tool, the author reviewed and edited the content as needed and takes full responsibility for the content of the published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data used in this study are publicly available from GenBank and GISAID. The source code used for this study is available at\u003cbr\u003ehttps://github.com/visual-media-lab/SARS-CoV-2-HMV\u003cbr\u003e\u0026nbsp;https://github.com/visual-media-lab/BA3\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe gratefully acknowledge all data contributors to GenBank and GISAID.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSimmonds P. Rampant C\u0026rarr;U hypermutation in the genomes of SARS-CoV-2 and other coronaviruses: causes and consequences for their short- and long-term evolutionary trajectories. mSphere. 2020;5(3):e00408-20. doi: 10.1128/mSphere.00408-20.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eVoloch CM, et al. Intra-host evolution during SARS-CoV-2 prolonged infection. Virus Evol. 2021;7(2):veab078. doi:10.1093/ve/veab078.\u003c/li\u003e\n \u003cli\u003eYi K, Kim SY, Bleazard T, et al. Mutational spectrum of SARS-CoV-2 during the global pandemic. Exp Mol Med. 2021;53(8):1229\u0026ndash;37. doi:10.1038/s12276-021-00658-z.\u003c/li\u003e\n \u003cli\u003eRice AM, Morales AC, Ho AT, et al. Evidence for strong mutation bias toward, and selection against, U content in SARS-CoV-2: implications for vaccine design. Mol Biol Evol. 2021;38(1):67\u0026ndash;83. doi:10.1093/molbev/msaa188.\u003c/li\u003e\n \u003cli\u003eSanderson T, Hisner R, Donovan-Banfield I, et al. A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes. Nature. 2023;623:594-600. doi:10.1038/s41586-023-06649-6.\u003c/li\u003e\n \u003cli\u003eAmicone M, Borges V, Alves MJ, et al. Mutation rate of SARS-CoV-2 and emergence of mutators during experimental evolution. Evol Med Public Health. 2022;10(1):142-155. doi:10.1093/emph/eoac010.\u003c/li\u003e\n \u003cli\u003eWei C, Shan KJ, Wang W, et al. Evidence for a mouse origin of the Omicron variant. J Genet Genomics. 2021;48(12):1111-1121. doi:10.1016/j.jgg.2021.10.003.\u003c/li\u003e\n \u003cli\u003eDi Giorgio S, Martignano F, Torcia MG, Mattiuz G, Conticello SG. Evidence for host-dependent RNA editing in the transcriptome of SARS-CoV-2. Sci Adv. 2020;6(25):eabb5813. doi: 10.1126/sciadv.abb5813.\u003c/li\u003e\n \u003cli\u003eShan KJ, Wei C, Wang Y, et al. Host-specific asymmetric accumulation of mutation types reveals that the origin of SARS-CoV-2 is consistent with a natural process. Innovation (Camb). 2021;2(4):100159. doi:10.1016/j.xinn.2021.100159.\u003c/li\u003e\n \u003cli\u003eCotten M, Phan MVT. Evolution of increased positive charge on the SARS-CoV-2 spike protein may be adaptation to human transmission. iScience. 2023;26(3):106230. doi:10.1016/j.isci.2023.106230.\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003e\u003cstrong\u003eTable 1. \u003cstrong\u003eCharacteristics of mutations in the Delta variant.\u003c/strong\u003e\u003c/strong\u003e (A) Spike amino acid substitutions defining the emergence of the Delta variant (B.1\u0026rarr;B.1.617.2) and their corresponding nucleotide substitutions. \u003cstrong\u003eC\u0026rarr;G substitutions are shown in bold.\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e(B) GISAID submission counts of sequences carrying Delta spike substitutions and combinations of these substitutions \u003cstrong\u003ebefore the first Delta sequence was submitted (March 23, 2021).\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e(C) \u003cstrong\u003eEarliest submission dates\u003c/strong\u003e of sequences carrying the Delta spike substitutions and substitution combinations listed in panel (B).\u003c/p\u003e\n\u003cp\u003e(A)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAmino Acid\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT19R\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003eG142D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003eR158D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003eL452R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003eT478K\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP681R\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003eD950N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNucleotide\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eC21618G\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003eG21987A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003eU22917G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003eC22995A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003eA23403G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eC23604G\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003eG24410A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e(B)\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"567\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2676%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003etotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003ew/ G142D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003ew/ R158D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003ew/ L452R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003ew/ T478K\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003ew/ P681R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003ew/ D950N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2676%;\"\u003e\n \u003cp\u003eT19R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2676%;\"\u003e\n \u003cp\u003eG142D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e1,072\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e274\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2676%;\"\u003e\n \u003cp\u003eR158D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2676%;\"\u003e\n \u003cp\u003eL452R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e18,478\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2676%;\"\u003e\n \u003cp\u003eT478K\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e4,419\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2676%;\"\u003e\n \u003cp\u003eP681R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e1,530\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2676%;\"\u003e\n \u003cp\u003eD950N\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.6761%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*\u0026nbsp;G142D+L452R+P681R: 6; Total number of GISAID sequences before emergence of Delta: 850,214.\u003c/p\u003e\n\u003cp\u003e(C)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"618\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 8.22581%;\"\u003e\n \u003cp\u003eG142D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.93548%;\"\u003e\n \u003cp\u003eL452R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.25806%;\"\u003e\n \u003cp\u003eD950N\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.93548%;\"\u003e\n \u003cp\u003eT478K\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.25806%;\"\u003e\n \u003cp\u003eP681R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.77419%;\"\u003e\n \u003cp\u003eT19R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.41935%;\"\u003e\n \u003cp\u003eG142D\u003cbr\u003e\u0026nbsp;T478K\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.25806%;\"\u003e\n \u003cp\u003eR158D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.41935%;\"\u003e\n \u003cp\u003eG142D\u003cbr\u003e\u0026nbsp;P681R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.41935%;\"\u003e\n \u003cp\u003eG142D\u003cbr\u003e\u0026nbsp;R158D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.77419%;\"\u003e\n \u003cp\u003eL452R\u003cbr\u003e\u0026nbsp;P681R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.77419%;\"\u003e\n \u003cp\u003eG142D\u003cbr\u003e\u0026nbsp;L452R\u003cbr\u003e\u0026nbsp;P681R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.77419%;\"\u003e\n \u003cp\u003eR158D\u003cbr\u003e\u0026nbsp;L452R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.77419%;\"\u003e\n \u003cp\u003eL452R\u003cbr\u003e\u0026nbsp;T478K\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 8.22581%;\"\u003e\n \u003cp\u003e4/13/20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.93548%;\"\u003e\n \u003cp\u003e4/23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.25806%;\"\u003e\n \u003cp\u003e5/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.93548%;\"\u003e\n \u003cp\u003e7/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.25806%;\"\u003e\n \u003cp\u003e7/27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.77419%;\"\u003e\n \u003cp\u003e9/23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.41935%;\"\u003e\n \u003cp\u003e10/22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.25806%;\"\u003e\n \u003cp\u003e11/3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.41935%;\"\u003e\n \u003cp\u003e11/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.41935%;\"\u003e\n \u003cp\u003e1/8/21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.77419%;\"\u003e\n \u003cp\u003e1/15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.77419%;\"\u003e\n \u003cp\u003e3/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.77419%;\"\u003e\n \u003cp\u003e3/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.77419%;\"\u003e\n \u003cp\u003e3/16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"University of Tsukuba","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"SARS-CoV-2, Delta variant, C→G transversion, Mutation spectrum, Spike protein","lastPublishedDoi":"10.21203/rs.3.rs-8722653/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8722653/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSARS-CoV-2 evolution is constrained by strong mutational biases, with C\u0026rarr;G transversions being exceptionally rare. We show that this constraint is uniquely violated in the Delta variant spike, where C\u0026rarr;G substitutions are significantly enriched compared with inter- and intra-lineage backgrounds. This deviation highlights an unusual evolutionary trajectory with potential epidemiologic significance.\u003c/p\u003e","manuscriptTitle":"Exceptional enrichment of rare C-to-G transversions in the SARS-CoV-2 Delta spike","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-30 05:10:33","doi":"10.21203/rs.3.rs-8722653/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f7dd27bf-b0ef-42aa-9b10-7b43682e26bb","owner":[],"postedDate":"January 30th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":61933525,"name":"Systems Biology"},{"id":61933526,"name":"Virology"},{"id":61933527,"name":"Biostatistics"},{"id":61933528,"name":"Bioinformatics"},{"id":61933529,"name":"Evolutionary Genetics"},{"id":61933530,"name":"Molecular Genetics"},{"id":61933531,"name":"Infectious Diseases"},{"id":61933532,"name":"Molecular Biology"}],"tags":[],"updatedAt":"2026-01-30T05:10:33+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-30 05:10:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8722653","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8722653","identity":"rs-8722653","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}