Lamb, K. D., Luka, M. M., Saathoff, M., Orton, R. J. , Phan, M. V.T., Cotten, M. , Yuan, K. and Robertson, D. L. (2024) Mutational signature dynamics indicate SARS-CoV-2's evolutionary capacity is driven by host antiviral molecules. PLoS Computational Biology, 20(1), e1011795. (doi: 10.1371/journal.pcbi.1011795) (PMID:38271457) (PMCID:PMC10868779)
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Abstract
The COVID-19 pandemic has been characterised by sequential variant-specific waves shaped by viral, individual human and population factors. SARS-CoV-2 variants are defined by their unique combinations of mutations and there has been a clear adaptation to more efficient human infection since the emergence of this new human coronavirus in late 2019. Here, we use machine learning models to identify shared signatures, i.e., common underlying mutational processes and link these to the subset of mutations that define the variants of concern (VOCs). First, we examined the global SARS-CoV-2 genomes and associated metadata to determine how viral properties and public health measures have influenced the magnitude of waves, as measured by the number of infection cases, in different geographic locations using regression models. This analysis showed that, as expected, both public health measures and virus properties were associated with the waves of regional SARS-CoV-2 reported infection numbers and this impact varies geographically. We attribute this to intrinsic differences such as vaccine coverage, testing and sequencing capacity and the effectiveness of government stringency. To assess underlying evolutionary change, we used non-negative matrix factorisation and observed three distinct mutational signatures, unique in their substitution patterns and exposures from the SARS-CoV-2 genomes. Signatures 1, 2 and 3 were biased to C→T, T→C/A→G and G→T point mutations. We hypothesise assignments of these mutational signatures to the host antiviral molecules APOBEC, ADAR and ROS respectively. We observe a shift amidst the pandemic in relative mutational signature activity from predominantly Signature 1 changes to an increasingly high proportion of changes consistent with Signature 2. This could represent changes in how the virus and the host immune response interact and indicates how SARS-CoV-2 may continue to generate variation in the future. Linkage of the detected mutational signatures to the VOC-defining amino acids substitutions indicates the majority of SARS-CoV-2's evolutionary capacity is likely to be associated with the action of host antiviral molecules rather than virus replication errors.
| Item Type: | Articles |
|---|---|
| Additional Information: | The authors acknowledge funding from the Medical Research Council (MRC, MC_UU_12014/12 to DLR, MC_UU_00034/5 to DLR and a Doctoral Training Programme in Precision Medicine studentship for KDL, MR/N013166/1 to KY and DLR), the Wellcome Trust (220977/Z/20/Z to MC, KY, DLR), the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement (MC_PC_20010 to MC), Engineering and Physical Sciences Research Council (EPSRC, EP/R018634/1 to KY), and the European Union’s Horizon 2020 research and innovation programme project PANCAIM (101016851 to KY). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Saathoff, Ms Megan and Robertson, Professor David and Orton, Dr Richard and Luka, Ms Martha and Lamb, Mr Kieran and Cotten, Professor Matthew and Yuan, Dr Ke |
| Creator Roles: | Lamb, K.Conceptualization, Formal analysis, Investigation, Methodology, Resources, Software, Visualization, Writing – original draft, Writing – review and editing Luka, M.Formal analysis, Investigation, Writing – original draft, Writing – review and editing Saathoff, M.Formal analysis, Writing – original draft Orton, R.Data curation Cotten, M.Funding acquisition, Supervision, Writing – review and editing Yuan, K.Conceptualization, Funding acquisition, Investigation, Methodology, Supervision, Writing – review and editing Robertson, D.Conceptualization, Funding acquisition, Investigation, Supervision, Writing – review and editing |
| Authors: | Lamb, K. D., Luka, M. M., Saathoff, M., Orton, R. J., Phan, M. V.T., Cotten, M., Yuan, K., and Robertson, D. L. |
| College/School: | College of Medical Veterinary and Life Sciences College of Medical Veterinary and Life Sciences > School of Infection & Immunity College of Science and Engineering > School of Computing Science |
| Journal Name: | PLoS Computational Biology |
| Publisher: | Public Library of Science |
| ISSN: | 1553-7358 |
| Copyright Holders: | Copyright © 2024 The Authors |
| First Published: | First published in PLoS Computational Biology 20(1):e1011795 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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