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Intra-host mutation rate of acute SARS-CoV-2 infection during the initial pandemic wave

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Abstract

SARS-CoV-2 mutation is minimized through a proofreading function encoded by NSP-14. Most estimates of the SARS-CoV-2 mutation rate are derived from population based sequence data. Our understanding of SARS-CoV-2 evolution might be enhanced through analysis of intra-host viral mutation rates in specific populations. Viral genome analysis was performed between paired samples and mutations quantified at allele frequencies (AF) ≥ 0.25, ≥ 0.5 and ≥ 0.75. Mutation rate was determined employing F81 and JC69 evolution models and compared between isolates with (ΔNSP-14) and without (wtNSP-14) non-synonymous mutations in NSP-14 and by patient comorbidity. Forty paired samples with median interval of 13 days [IQR 8.5–20] were analyzed. The estimated mutation rate by F81 modeling was 93.6 (95%CI 90.8–96.4], 40.7 (95%CI 38.9–42.6) and 34.7 (95%CI 33.0–36.4) substitutions/genome/year at AF ≥ 0.25, ≥ 0.5, ≥ 0.75 respectively. Mutation rate in ΔNSP-14 were significantly elevated at AF ≥ 0.25 vs wtNSP-14. Patients with immune comorbidities had higher mutation rate at all allele frequencies. Intra-host SARS-CoV-2 mutation rates are substantially higher than those reported through population analysis. Virus strains with altered NSP-14 have accelerated mutation rate at low AF. Immunosuppressed patients have elevated mutation rate at all AF. Understanding intra-host virus evolution will aid in current and future pandemic modeling.

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Acknowledgements

We appreciate Daniel H. Farkas, PhD and Charles Foster MD for their kind insight and thoughtful review of the project

Funding

This research was supported through the Ellen and Steven Ross Fellowship Research Award, Cleveland Clinic Children’s IF-110077. This project was supported in part by NSF IIS-2027667 and NSF CCF-2200255 (JL and FE), NSF CCF-2006780 (JL), NSF CCF-1815139 (JL) and through unrestricted funds from the Robert J. Tomsich Pathology and Laboratory Medicine Institute. Ellen and Steven Ross Fellowship Research Award, IF-110077, IF-110077, IF-110077, IF-110077, IF-110077,IF-110077, National Science Foundation,CCF-1815139, National Science Foundation,United States, CCF-2006780, CCF-2200255

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Authors and Affiliations

  1. Center for Pediatric Infectious Disease, Cleveland Clinic Children’s, R3, 9500 Euclid Avenue, Cleveland, 44195 , OH, USA

    Kim El-Haddad & Frank P. Esper

  2. Department of Computer and Data Sciences, Case Western Reserve University, Cleveland, OH, USA

    Thamali M. Adhikari, Xiaoyi Leng, Xiangyi Zhang & Jing Li

  3. Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA

    Zheng Jin Tu, Yu-Wei Cheng, Daniel Rhoads, Jennifer S. Ko & Brian P. Rubin

  4. Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA

    Sarah Worley

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  1. Kim El-Haddad
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Contributions

KEH, FE, and BR conceptualized and directed this research. TA, XL, XZ and JL, developed methodology, and performed evolutionary modeling and mutation statistics. TJ and YC assisted in sample acquisition, Illumina sequencing and pipeline development. DR and JK assisted in study design, sample identification and acquisition. SW assisted in statistics review. All authors contributed to discussions and manuscript preparation.

Corresponding authors

Correspondence to Kim El-Haddad or Frank P. Esper.

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Competing interests

DDR performs collaborative research that is sponsored by industry collaborators: BD, bioMerieux, Cepheid, Cleveland Diagnostics, Hologic, Luminex, Q-Linea, Qiagen, Roche, Specific Diagnostics, Thermo Fisher, and Vela. DDR is or has been on advisory boards for Luminex, Talis Biomedical, and Thermo Fisher. FE has served as a consultant to Proctor & Gamble. The remaining authors have or do not have an association that might pose a conflict of interest.

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El-Haddad, K., Adhikari, T.M., Tu, Z. et al. Intra-host mutation rate of acute SARS-CoV-2 infection during the initial pandemic wave. Virus Genes 59, 653–661 (2023). https://doi.org/10.1007/s11262-023-02011-0

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