Genome data artifacts and functional studies of deletion repair in the BA.1 SARS-CoV-2 spike protein

Mutations within the N-terminal domain (NTD) of the spike (S) protein are critical for the emergence of successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral lineages. The NTD has been repeatedly impacted by deletions, often exhibiting complex and dynamic patterns, such as th...

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Authors: Alvarez-Herrera, M, Ruiz-Rodriguez, P, Navarro-Domínguez, B, Zulaica, J, Grau, B, Bracho, MA, Guerreiro, M, Aguilar-Gallardo, C, González-Candelas, F, Comas, I, Geller, R, Coscollá, M
Format: article
Status:Published version
Publication Date:2025
Country:España
Institution:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
Repository:r-FISABIO. Repositorio Institucional de Producción Científica
OAI Identifier:oai:fisabio.fundanetsuite.com:p18758
Online Access:https://fisabio.portalinvestigacion.com/publicaciones/18758
Access Level:Open access
Keyword:SARS-CoV-2
spike
transmission
deletion
fusogenicity
antibody neutralization
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spelling Genome data artifacts and functional studies of deletion repair in the BA.1 SARS-CoV-2 spike proteinAlvarez-Herrera, MRuiz-Rodriguez, PNavarro-Domínguez, BZulaica, JGrau, BBracho, MAGuerreiro, MAguilar-Gallardo, CGonzález-Candelas, FComas, IGeller, RCoscollá, MSARS-CoV-2spiketransmissiondeletionfusogenicityantibody neutralizationMutations within the N-terminal domain (NTD) of the spike (S) protein are critical for the emergence of successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral lineages. The NTD has been repeatedly impacted by deletions, often exhibiting complex and dynamic patterns, such as the recurrent emergence and disappearance of deletions in dominant variants. This study investigates the influence of repair of NTD lineage-defining deletions found in the BA.1 lineage (Omicron variant) on viral success. We performed comparative genomic analyses of >10 million SARS-CoV-2 genomes from the Global Initiative on Sharing All Influenza Data (GISAID) EpiCov database to evaluate the detection of viruses lacking S:Delta H69/V70, S:Delta V143/Y145, or both. These findings were contrasted against a screening of publicly available raw sequencing data, revealing substantial discrepancies between data repositories, suggesting that spurious deletion repair observations in GISAID may result from systematic artifacts. Specifically, deletion repair events were approximately an order of magnitude less frequent in the read-run survey. Our results suggest that deletion repair events are rare, isolated events with limited direct influence on SARS-CoV-2 evolution or transmission. Nevertheless, such events could facilitate the emergence of fitness-enhancing mutations. To explore potential drivers of NTD deletion repair patterns, we characterized the viral phenotype of such markers in a surrogate in vitro system. Repair of the S:Delta H69/V70 deletion reduced viral infectivity, while simultaneous repair with S:Delta V143/Y145 led to lower fusogenicity. In contrast, individual S:Delta V143/Y145 repair enhanced both fusogenicity and susceptibility to neutralization by sera from vaccinated individuals. This work underscores the complex genotype-phenotype landscape of the spike NTD in SARS-CoV-2, which impacts viral biology, transmission efficiency, and immune escape potential, offering insights with direct relevance to public health, viral surveillance, and the adaptive mechanisms driving emerging variants.OXFORD UNIV PRESS2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fisabio.portalinvestigacion.com/publicaciones/18758Virus EvolutionISSN: 20571577reponame:r-FISABIO. Repositorio Institucional de Producción Científicainstname:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)Inglésinfo:eu-repo/semantics/openAccessoai:fisabio.fundanetsuite.com:p187582026-06-11T12:45:17Z
dc.title.none.fl_str_mv Genome data artifacts and functional studies of deletion repair in the BA.1 SARS-CoV-2 spike protein
title Genome data artifacts and functional studies of deletion repair in the BA.1 SARS-CoV-2 spike protein
spellingShingle Genome data artifacts and functional studies of deletion repair in the BA.1 SARS-CoV-2 spike protein
Alvarez-Herrera, M
SARS-CoV-2
spike
transmission
deletion
fusogenicity
antibody neutralization
title_short Genome data artifacts and functional studies of deletion repair in the BA.1 SARS-CoV-2 spike protein
title_full Genome data artifacts and functional studies of deletion repair in the BA.1 SARS-CoV-2 spike protein
title_fullStr Genome data artifacts and functional studies of deletion repair in the BA.1 SARS-CoV-2 spike protein
title_full_unstemmed Genome data artifacts and functional studies of deletion repair in the BA.1 SARS-CoV-2 spike protein
title_sort Genome data artifacts and functional studies of deletion repair in the BA.1 SARS-CoV-2 spike protein
dc.creator.none.fl_str_mv Alvarez-Herrera, M
Ruiz-Rodriguez, P
Navarro-Domínguez, B
Zulaica, J
Grau, B
Bracho, MA
Guerreiro, M
Aguilar-Gallardo, C
González-Candelas, F
Comas, I
Geller, R
Coscollá, M
author Alvarez-Herrera, M
author_facet Alvarez-Herrera, M
Ruiz-Rodriguez, P
Navarro-Domínguez, B
Zulaica, J
Grau, B
Bracho, MA
Guerreiro, M
Aguilar-Gallardo, C
González-Candelas, F
Comas, I
Geller, R
Coscollá, M
author_role author
author2 Ruiz-Rodriguez, P
Navarro-Domínguez, B
Zulaica, J
Grau, B
Bracho, MA
Guerreiro, M
Aguilar-Gallardo, C
González-Candelas, F
Comas, I
Geller, R
Coscollá, M
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv SARS-CoV-2
spike
transmission
deletion
fusogenicity
antibody neutralization
topic SARS-CoV-2
spike
transmission
deletion
fusogenicity
antibody neutralization
description Mutations within the N-terminal domain (NTD) of the spike (S) protein are critical for the emergence of successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral lineages. The NTD has been repeatedly impacted by deletions, often exhibiting complex and dynamic patterns, such as the recurrent emergence and disappearance of deletions in dominant variants. This study investigates the influence of repair of NTD lineage-defining deletions found in the BA.1 lineage (Omicron variant) on viral success. We performed comparative genomic analyses of >10 million SARS-CoV-2 genomes from the Global Initiative on Sharing All Influenza Data (GISAID) EpiCov database to evaluate the detection of viruses lacking S:Delta H69/V70, S:Delta V143/Y145, or both. These findings were contrasted against a screening of publicly available raw sequencing data, revealing substantial discrepancies between data repositories, suggesting that spurious deletion repair observations in GISAID may result from systematic artifacts. Specifically, deletion repair events were approximately an order of magnitude less frequent in the read-run survey. Our results suggest that deletion repair events are rare, isolated events with limited direct influence on SARS-CoV-2 evolution or transmission. Nevertheless, such events could facilitate the emergence of fitness-enhancing mutations. To explore potential drivers of NTD deletion repair patterns, we characterized the viral phenotype of such markers in a surrogate in vitro system. Repair of the S:Delta H69/V70 deletion reduced viral infectivity, while simultaneous repair with S:Delta V143/Y145 led to lower fusogenicity. In contrast, individual S:Delta V143/Y145 repair enhanced both fusogenicity and susceptibility to neutralization by sera from vaccinated individuals. This work underscores the complex genotype-phenotype landscape of the spike NTD in SARS-CoV-2, which impacts viral biology, transmission efficiency, and immune escape potential, offering insights with direct relevance to public health, viral surveillance, and the adaptive mechanisms driving emerging variants.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://fisabio.portalinvestigacion.com/publicaciones/18758
url https://fisabio.portalinvestigacion.com/publicaciones/18758
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv OXFORD UNIV PRESS
publisher.none.fl_str_mv OXFORD UNIV PRESS
dc.source.none.fl_str_mv Virus Evolution
ISSN: 20571577
reponame:r-FISABIO. Repositorio Institucional de Producción Científica
instname:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
instname_str Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
reponame_str r-FISABIO. Repositorio Institucional de Producción Científica
collection r-FISABIO. Repositorio Institucional de Producción Científica
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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