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Patterns of within-host genetic diversity in SARS-CoV-2

View ORCID ProfileGerry Tonkin-Hill, Inigo Martincorena, Roberto Amato, Andrew R J Lawson, Moritz Gerstung, Ian Johnston, David K Jackson, Naomi R Park, Stefanie V Lensing, Michael A Quail, Sónia Gonçalves, Cristina Ariani, Michael Spencer Chapman, William L Hamilton, Luke W Meredith, Grant Hall, Aminu S Jahun, Yasmin Chaudhry, Myra Hosmillo, Malte L Pinckert, Iliana Georgana, Anna Yakovleva, Laura G Caller, Sarah L Caddy, Theresa Feltwell, Fahad A Khokhar, Charlotte J Houldcroft, Martin D Curran, Surendra Parmar, The COVID-19 Genomics UK (COG-UK) Consortium, Alex Alderton, Rachel Nelson, Ewan Harrison, John Sillitoe, Stephen D Bentley, Jeffrey C Barrett, M. Estee Torok, Ian G Goodfellow, Cordelia Langford, View ORCID ProfileDominic Kwiatkowski, Wellcome Sanger Institute COVID-19 Surveillance Team
doi: https://doi.org/10.1101/2020.12.23.424229
Gerry Tonkin-Hill
1Wellcome Sanger Institute, Hinxton, United Kingdom
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Inigo Martincorena
1Wellcome Sanger Institute, Hinxton, United Kingdom
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  • For correspondence: im3@sanger.ac.uk dominic@sanger.ac.uk
Roberto Amato
1Wellcome Sanger Institute, Hinxton, United Kingdom
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Andrew R J Lawson
1Wellcome Sanger Institute, Hinxton, United Kingdom
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Moritz Gerstung
2European Bioinformatics Institute, Hinxton, United Kingdom
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Ian Johnston
1Wellcome Sanger Institute, Hinxton, United Kingdom
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David K Jackson
1Wellcome Sanger Institute, Hinxton, United Kingdom
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Naomi R Park
1Wellcome Sanger Institute, Hinxton, United Kingdom
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Stefanie V Lensing
1Wellcome Sanger Institute, Hinxton, United Kingdom
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Michael A Quail
1Wellcome Sanger Institute, Hinxton, United Kingdom
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Sónia Gonçalves
1Wellcome Sanger Institute, Hinxton, United Kingdom
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Cristina Ariani
1Wellcome Sanger Institute, Hinxton, United Kingdom
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Michael Spencer Chapman
1Wellcome Sanger Institute, Hinxton, United Kingdom
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William L Hamilton
3Department of Medicine, University of Cambridge
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Luke W Meredith
4Department of Pathology, University of Cambridge
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Grant Hall
4Department of Pathology, University of Cambridge
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Aminu S Jahun
4Department of Pathology, University of Cambridge
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Yasmin Chaudhry
4Department of Pathology, University of Cambridge
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Myra Hosmillo
4Department of Pathology, University of Cambridge
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Malte L Pinckert
4Department of Pathology, University of Cambridge
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Iliana Georgana
4Department of Pathology, University of Cambridge
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Anna Yakovleva
4Department of Pathology, University of Cambridge
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Laura G Caller
4Department of Pathology, University of Cambridge
5The Francis Crick Institute, London
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Sarah L Caddy
3Department of Medicine, University of Cambridge
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Theresa Feltwell
4Department of Pathology, University of Cambridge
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Fahad A Khokhar
3Department of Medicine, University of Cambridge
6Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge
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Charlotte J Houldcroft
3Department of Medicine, University of Cambridge
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Martin D Curran
7Public Health England, Cambridge, UK
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Surendra Parmar
7Public Health England, Cambridge, UK
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Alex Alderton
1Wellcome Sanger Institute, Hinxton, United Kingdom
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Rachel Nelson
1Wellcome Sanger Institute, Hinxton, United Kingdom
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Ewan Harrison
1Wellcome Sanger Institute, Hinxton, United Kingdom
2European Bioinformatics Institute, Hinxton, United Kingdom
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John Sillitoe
1Wellcome Sanger Institute, Hinxton, United Kingdom
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Stephen D Bentley
1Wellcome Sanger Institute, Hinxton, United Kingdom
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Jeffrey C Barrett
1Wellcome Sanger Institute, Hinxton, United Kingdom
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M. Estee Torok
3Department of Medicine, University of Cambridge
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Ian G Goodfellow
4Department of Pathology, University of Cambridge
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Cordelia Langford
1Wellcome Sanger Institute, Hinxton, United Kingdom
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Dominic Kwiatkowski
1Wellcome Sanger Institute, Hinxton, United Kingdom
8Nuffield Department of Medicine, University of Oxford
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  • ORCID record for Dominic Kwiatkowski
  • For correspondence: im3@sanger.ac.uk dominic@sanger.ac.uk
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Abstract

Monitoring the spread of SARS-CoV-2 and reconstructing transmission chains has become a major public health focus for many governments around the world. The modest mutation rate and rapid transmission of SARS-CoV-2 prevents the reconstruction of transmission chains from consensus genome sequences, but within-host genetic diversity could theoretically help identify close contacts. Here we describe the patterns of within-host diversity in 1,181 SARS-CoV-2 samples sequenced to high depth in duplicate. 95% of samples show within-host mutations at detectable allele frequencies. Analyses of the mutational spectra revealed strong strand asymmetries suggestive of damage or RNA editing of the plus strand, rather than replication errors, dominating the accumulation of mutations during the SARS-CoV-2 pandemic. Within and between host diversity show strong purifying selection, particularly against nonsense mutations. Recurrent within-host mutations, many of which coincide with known phylogenetic homoplasies, display a spectrum and patterns of purifying selection more suggestive of mutational hotspots than recombination or convergent evolution. While allele frequencies suggest that most samples result from infection by a single lineage, we identify multiple putative examples of co-infection. Integrating these results into an epidemiological inference framework, we find that while sharing of within-host variants between samples could help the reconstruction of transmission chains, mutational hotspots and rare cases of superinfection can confound these analyses.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵† https://www.cogconsortium.uk - A full list of consortium names and affiliations is included in the supplementary material

  • ↵‡ https://www.sanger.ac.uk/covid-team

  • https://github.com/gtonkinhill/SC2_withinhost

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 25, 2020.
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Patterns of within-host genetic diversity in SARS-CoV-2
Gerry Tonkin-Hill, Inigo Martincorena, Roberto Amato, Andrew R J Lawson, Moritz Gerstung, Ian Johnston, David K Jackson, Naomi R Park, Stefanie V Lensing, Michael A Quail, Sónia Gonçalves, Cristina Ariani, Michael Spencer Chapman, William L Hamilton, Luke W Meredith, Grant Hall, Aminu S Jahun, Yasmin Chaudhry, Myra Hosmillo, Malte L Pinckert, Iliana Georgana, Anna Yakovleva, Laura G Caller, Sarah L Caddy, Theresa Feltwell, Fahad A Khokhar, Charlotte J Houldcroft, Martin D Curran, Surendra Parmar, The COVID-19 Genomics UK (COG-UK) Consortium, Alex Alderton, Rachel Nelson, Ewan Harrison, John Sillitoe, Stephen D Bentley, Jeffrey C Barrett, M. Estee Torok, Ian G Goodfellow, Cordelia Langford, Dominic Kwiatkowski, Wellcome Sanger Institute COVID-19 Surveillance Team
bioRxiv 2020.12.23.424229; doi: https://doi.org/10.1101/2020.12.23.424229
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Patterns of within-host genetic diversity in SARS-CoV-2
Gerry Tonkin-Hill, Inigo Martincorena, Roberto Amato, Andrew R J Lawson, Moritz Gerstung, Ian Johnston, David K Jackson, Naomi R Park, Stefanie V Lensing, Michael A Quail, Sónia Gonçalves, Cristina Ariani, Michael Spencer Chapman, William L Hamilton, Luke W Meredith, Grant Hall, Aminu S Jahun, Yasmin Chaudhry, Myra Hosmillo, Malte L Pinckert, Iliana Georgana, Anna Yakovleva, Laura G Caller, Sarah L Caddy, Theresa Feltwell, Fahad A Khokhar, Charlotte J Houldcroft, Martin D Curran, Surendra Parmar, The COVID-19 Genomics UK (COG-UK) Consortium, Alex Alderton, Rachel Nelson, Ewan Harrison, John Sillitoe, Stephen D Bentley, Jeffrey C Barrett, M. Estee Torok, Ian G Goodfellow, Cordelia Langford, Dominic Kwiatkowski, Wellcome Sanger Institute COVID-19 Surveillance Team
bioRxiv 2020.12.23.424229; doi: https://doi.org/10.1101/2020.12.23.424229

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