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COVID-19 Infection and Transmission Includes Complex Sequence Diversity

Ernest R. Chan, Lucas D. Jones, Marlin Linger, Jeffrey D. Kovach, Maria M. Torres-Teran, Audric Wertz, Curtis J. Donskey, Peter A. Zimmerman

SARS-CoV-2 whole genome sequencing has played an important role in documenting the emergence of polymorphisms in the viral genome and its continuing evolution during the COVID-19 pandemic. Here we present data from over 360 patients to characterize the complex sequence diversity of individual infections identified during multiple variant surges (e.g., Alpha and Delta). Across our survey, we observed significantly increasing SARS-CoV-2 sequence diversity during the pandemic and frequent occurrence of multiple biallelic sequence polymorphisms in all infections.

Early investigation into the outbreak of the novel pneumonia of unknown cause, from the city of Wuhan in late December 2019, quickly identified the genomic sequence associated with a coronavirus, closely related to the SARS-CoV. The virus, SARS-CoV-2, is now understood to be the causative agent of COVID-19. Sequence variation across the ~30kb positive-strand RNA SARS-CoV-2 genome was reported in the earliest studies, including single nucleotide polymorphisms (SNPs), insertions and deletions (indels).


Ethics statement

The study protocol was approved by the Cleveland VA Medical Center’s Institutional Review Board (IRB protocol number 1584025) with a waiver of consent. This same Institutional Review Board approved the waiver of consent for this study.

Patient enrollment and informed consent
As part of efforts to identify, provide care for infected individuals and limit the spread of COVID-19 within the VA Northeast Ohio Healthcare System, the Infection Control Department collected nasopharyngeal swab specimens from all individuals showing symptoms of a respiratory infection, all patients admitted to the hospital or undergoing invasive medical procedures, and asymptomatic close contacts of COVID-19 cases starting in March 2020 in accordance with Centers for Disease Control and Prevention (CDC) recommendations.

Our study has revealed significant within host infection diversity of SARS-CoV-2 through full genome sequence analysis. We greatly appreciate the work of international data repositories such as GISAID and NextStrain for curating the millions of reported infections and believe that these repositories are a tremendous and invaluable asset for the monitoring of SARS-CoV-2.

We thank the patients, administrators, engineering personnel, scientific and medical staff for their assistance with this study. We acknowledge Simone Edelheit for performing Illumina MiSeq sequencing and thank the staff of the Genomics Core Lab, Case Western Reserve University. We thank Niyati Thosani, Lily Liu and Rounak Fiegelman of Paragon Genomics for their technical assistance in optimizing SARS-CoV- sequencing library preparation and bioinformatic data analysis.

Citation: Chan ER, Jones LD, Linger M, Kovach JD, Torres-Teran MM, Wertz A, et al. (2022) COVID-19 infection and transmission includes complex sequence diversity. PLoS Genet 18(9): e1010200.

Editor: Susana Campino, London School of Hygiene & Tropical Medicine, UNITED KINGDOM

Received: April 15, 2022; Accepted: July 27, 2022; Published: September 8, 2022.

Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Data Availability: All of our sequence data have been reported to GenBank (NCBI – GenBank Accession numbers OM988245-OM988384).

Funding: This work was supported by a Merit Review grant (CX001848) from the US Department of Veterans Affairs to CJD and by a grant from the US Department of Veterans Affairs Office of Research and Development as part of funding for VASeqCURE (grant number N/A) which in turn received funding from the American Rescue Plan Act funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: CJD has received research grants from Clorox, Pfizer, and PDI. All other authors report no conflicts of interest relevant to this article.

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