Addressing pandemic-wide systematic errors in the SARS-CoV-2 phylogeny

The majority of SARS-CoV-2 genomes obtained during the pandemic were derived by amplifying overlapping windows of the genome ('tiled amplicons'), reconstructing their sequences and fitting them together. This leads to systematic errors in genomes unless the software is both aware of the amplicon scheme and of the error modes of amplicon sequencing. Additionally, over time, amplicon schemes need to be updated as new mutations in the virus interfere with the primer binding sites at the end of amplicons. Thus, waves of variants swept the world during the pandemic and were followed by waves of systematic errors in the genomes, which had significant impacts on the inferred phylogenetic tree.Here we reconstruct the genomes from all public data as of June 2024 using an assembly tool called Viridian ( https://github.com/iqbal-lab-org/viridian ), developed to rigorously process amplicon sequence data. With these high-quality consensus sequences we provide a global phylogenetic tree of 4,471,579 samples, viewable at https://viridian.taxonium.org . We provide simulation and empirical validation of the methodology, and quantify the improvement in the phylogeny.

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Publication Details

Journal
Nature Methods
Published
2026-02-09
DOI
https://doi.org/10.1038/s41592-025-02947-1
Citations
2
Primary Topic
Genomics and Phylogenetic Studies
Type
article
Field-Weighted Citation Impact
44.47
Controls
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article

Addressing pandemic-wide systematic errors in the SARS-CoV-2 phylogeny

2 citations
Nature Methods
Genomics and Phylogenetic Studies
44.47
article

Addressing pandemic-wide systematic errors in the SARS-CoV-2 phylogeny

article en
2 citations

Abstract

The majority of SARS-CoV-2 genomes obtained during the pandemic were derived by amplifying overlapping windows of the genome ('tiled amplicons'), reconstructing their sequences and fitting them together. This leads to systematic errors in genomes unless the software is both aware of the amplicon scheme and of the error modes of amplicon sequencing. Additionally, over time, amplicon schemes need to be updated as new mutations in the virus interfere with the primer binding sites at the end of amplicons. Thus, waves of variants swept the world during the pandemic and were followed by waves of systematic errors in the genomes, which had significant impacts on the inferred phylogenetic tree.Here we reconstruct the genomes from all public data as of June 2024 using an assembly tool called Viridian ( https://github.com/iqbal-lab-org/viridian ), developed to rigorously process amplicon sequence data. With these high-quality consensus sequences we provide a global phylogenetic tree of 4,471,579 samples, viewable at https://viridian.taxonium.org . We provide simulation and empirical validation of the methodology, and quantify the improvement in the phylogeny.

Nature MethodsVol. 23(3)
National Health Laboratory Service (ZA), Agency for Science, Technology and Research (SG), Birmingham City University (GB), European Bioinformatics Institute (GB), Nebraska Department of Health and Human Services (US), Siriraj Hospital (TH), Centre for Human Genetics (GB), University of Helsinki (FI), University of Ghana (GH), Inserm (FR), University of Cape Town (ZA), University of Freiburg (DE), National University of Singapore (SG), University of Sri Jayewardenepura (LK), University of California, Santa Cruz (US), Université de Montpellier (FR), Singapore General Hospital (SG), University of Sioux Falls (US), University of Cambridge (GB), Robert Koch Institute (DE), University of Health and Allied Sciences (GH), Stellenbosch University (ZA), University of Michigan (US), Leiden University Medical Center (NL), Helsinki University Hospital (FI), The Francis Crick Institute (GB), University Medical Center Freiburg (DE), Tan Tock Seng Hospital (SG), John Radcliffe Hospital (GB), Universidad de Costa Rica (CR), Northumbria University (GB), University of Oxford (GB), Massachusetts General Hospital (US), Clinical Research Institute (US), Düsseldorf University Hospital (DE), Public Health Institute of Malawi (MW), Ministère de la Santé Publique (BI), Centre Hospitalier Universitaire de Montpellier (FR), Biotech Park (IN), World Health Organization - Zimbabwe (ZW), Administración Nacional de Laboratorios e Institutos de Salud (AR), Health Care Foundation (CA), Mahidol Oxford Tropical Medicine Research Unit (TH), Wellcome Centre for Infectious Diseases Research in Africa (ZA), National University Health System (SG), Duke University Hospital (US), Ministère de la Santé Publique (NE), Heinrich Heine University Düsseldorf (DE), Addis Ababa University (ET), Imperial College London (GB), University of Bath (GB), Genome Institute of Singapore (SG), Gdańsk Medical University (PL), Medical University of Vienna (AT), Teesside University (GB), International Centre for Genetic Engineering and Biotechnology (IT), University of KwaZulu-Natal (ZA), University of California, Berkeley (US), Academy of Scientific and Innovative Research (IN)
Good health and well-being
Openalex Percentile: Top 0%
Genomics and Phylogenetic Studies
44.47
DOIOpen Access PDFOpenAlex
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