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Challenges in Harnessing Shared Within-Host Severe Acute Respiratory Syndrome Coronavirus 2 Variation for Transmission Inference

BACKGROUND: The limited variation observed among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) consensus sequences makes it difficult to reconstruct transmission linkages in outbreak settings. Previous studies have recovered variation within individual SARS-CoV-2 infections but have n...

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Autores principales: Walter, Katharine S, Kim, Eugene, Verma, Renu, Altamirano, Jonathan, Leary, Sean, Carrington, Yuan J, Jagannathan, Prasanna, Singh, Upinder, Holubar, Marisa, Subramanian, Aruna, Khosla, Chaitan, Maldonado, Yvonne, Andrews, Jason R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9898879/
https://www.ncbi.nlm.nih.gov/pubmed/36751652
http://dx.doi.org/10.1093/ofid/ofad001
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author Walter, Katharine S
Kim, Eugene
Verma, Renu
Altamirano, Jonathan
Leary, Sean
Carrington, Yuan J
Jagannathan, Prasanna
Singh, Upinder
Holubar, Marisa
Subramanian, Aruna
Khosla, Chaitan
Maldonado, Yvonne
Andrews, Jason R
author_facet Walter, Katharine S
Kim, Eugene
Verma, Renu
Altamirano, Jonathan
Leary, Sean
Carrington, Yuan J
Jagannathan, Prasanna
Singh, Upinder
Holubar, Marisa
Subramanian, Aruna
Khosla, Chaitan
Maldonado, Yvonne
Andrews, Jason R
author_sort Walter, Katharine S
collection PubMed
description BACKGROUND: The limited variation observed among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) consensus sequences makes it difficult to reconstruct transmission linkages in outbreak settings. Previous studies have recovered variation within individual SARS-CoV-2 infections but have not yet measured the informativeness of within-host variation for transmission inference. METHODS: We performed tiled amplicon sequencing on 307 SARS-CoV-2 samples, including 130 samples from 32 individuals in 14 households and 47 longitudinally sampled individuals, from 4 prospective studies with household membership data, a proxy for transmission linkage. RESULTS: Consensus sequences from households had limited diversity (mean pairwise distance, 3.06 single-nucleotide polymorphisms [SNPs]; range, 0–40). Most (83.1%, 255 of 307) samples harbored at least 1 intrahost single-nucleotide variant ([iSNV] median, 117; interquartile range [IQR], 17–208), above a minor allele frequency threshold of 0.2%. Pairs in the same household shared significantly more iSNVs (mean, 1.20 iSNVs; 95% confidence interval [CI], 1.02–1.39) than did pairs in different households infected with the same viral clade (mean, 0.31 iSNVs; 95% CI, .28–.34), a signal that decreases with increasingly stringent minor allele frequency thresholds. The number of shared iSNVs was significantly associated with an increased odds of household membership (adjusted odds ratio, 1.35; 95% CI, 1.23–1.49). However, the poor concordance of iSNVs detected across sequencing replicates (24.8% and 35.0% above a 0.2% and 1% threshold) confirms technical concerns that current sequencing and bioinformatic workflows do not consistently recover low-frequency within-host variants. CONCLUSIONS: Shared within-host variation may augment the information in consensus sequences for predicting transmission linkages. Improving sensitivity and specificity of within-host variant identification will improve the informativeness of within-host variation.
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spelling pubmed-98988792023-02-06 Challenges in Harnessing Shared Within-Host Severe Acute Respiratory Syndrome Coronavirus 2 Variation for Transmission Inference Walter, Katharine S Kim, Eugene Verma, Renu Altamirano, Jonathan Leary, Sean Carrington, Yuan J Jagannathan, Prasanna Singh, Upinder Holubar, Marisa Subramanian, Aruna Khosla, Chaitan Maldonado, Yvonne Andrews, Jason R Open Forum Infect Dis Major Article BACKGROUND: The limited variation observed among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) consensus sequences makes it difficult to reconstruct transmission linkages in outbreak settings. Previous studies have recovered variation within individual SARS-CoV-2 infections but have not yet measured the informativeness of within-host variation for transmission inference. METHODS: We performed tiled amplicon sequencing on 307 SARS-CoV-2 samples, including 130 samples from 32 individuals in 14 households and 47 longitudinally sampled individuals, from 4 prospective studies with household membership data, a proxy for transmission linkage. RESULTS: Consensus sequences from households had limited diversity (mean pairwise distance, 3.06 single-nucleotide polymorphisms [SNPs]; range, 0–40). Most (83.1%, 255 of 307) samples harbored at least 1 intrahost single-nucleotide variant ([iSNV] median, 117; interquartile range [IQR], 17–208), above a minor allele frequency threshold of 0.2%. Pairs in the same household shared significantly more iSNVs (mean, 1.20 iSNVs; 95% confidence interval [CI], 1.02–1.39) than did pairs in different households infected with the same viral clade (mean, 0.31 iSNVs; 95% CI, .28–.34), a signal that decreases with increasingly stringent minor allele frequency thresholds. The number of shared iSNVs was significantly associated with an increased odds of household membership (adjusted odds ratio, 1.35; 95% CI, 1.23–1.49). However, the poor concordance of iSNVs detected across sequencing replicates (24.8% and 35.0% above a 0.2% and 1% threshold) confirms technical concerns that current sequencing and bioinformatic workflows do not consistently recover low-frequency within-host variants. CONCLUSIONS: Shared within-host variation may augment the information in consensus sequences for predicting transmission linkages. Improving sensitivity and specificity of within-host variant identification will improve the informativeness of within-host variation. Oxford University Press 2023-01-07 /pmc/articles/PMC9898879/ /pubmed/36751652 http://dx.doi.org/10.1093/ofid/ofad001 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Major Article
Walter, Katharine S
Kim, Eugene
Verma, Renu
Altamirano, Jonathan
Leary, Sean
Carrington, Yuan J
Jagannathan, Prasanna
Singh, Upinder
Holubar, Marisa
Subramanian, Aruna
Khosla, Chaitan
Maldonado, Yvonne
Andrews, Jason R
Challenges in Harnessing Shared Within-Host Severe Acute Respiratory Syndrome Coronavirus 2 Variation for Transmission Inference
title Challenges in Harnessing Shared Within-Host Severe Acute Respiratory Syndrome Coronavirus 2 Variation for Transmission Inference
title_full Challenges in Harnessing Shared Within-Host Severe Acute Respiratory Syndrome Coronavirus 2 Variation for Transmission Inference
title_fullStr Challenges in Harnessing Shared Within-Host Severe Acute Respiratory Syndrome Coronavirus 2 Variation for Transmission Inference
title_full_unstemmed Challenges in Harnessing Shared Within-Host Severe Acute Respiratory Syndrome Coronavirus 2 Variation for Transmission Inference
title_short Challenges in Harnessing Shared Within-Host Severe Acute Respiratory Syndrome Coronavirus 2 Variation for Transmission Inference
title_sort challenges in harnessing shared within-host severe acute respiratory syndrome coronavirus 2 variation for transmission inference
topic Major Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9898879/
https://www.ncbi.nlm.nih.gov/pubmed/36751652
http://dx.doi.org/10.1093/ofid/ofad001
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