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

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.
Publication status:
Published
Peer review status:
Peer reviewed

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Publisher copy:
10.1038/s41592-025-02947-1

Authors

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Institution:
University of Oxford
Division:
MSD
Department:
NDM
Role:
Author


Publisher:
Springer Nature
Journal:
Nature Methods More from this journal
Publication date:
2026-02-09
Acceptance date:
2025-08-27
DOI:
EISSN:
1548-7105
ISSN:
1548-7091


Language:
English
Keywords:
Pubs id:
2284602
Local pid:
pubs:2284602
Deposit date:
2025-08-28
ARK identifier:

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