Within-host diversity improves phylogenetic and transmission reconstruction of SARS-CoV-2 outbreaks

  1. Arturo Torres Ortiz  Is a corresponding author
  2. Michelle Kendall
  3. Nathaniel Storey
  4. James Hatcher
  5. Helen Dunn
  6. Sunando Roy
  7. Rachel Williams
  8. Charlotte Williams
  9. Richard A Goldstein
  10. Xavier Didelot
  11. Kathryn Harris
  12. Judith Breuer
  13. Louis Grandjean  Is a corresponding author
  1. Imperial College London, United Kingdom
  2. University of Warwick, United Kingdom
  3. Great Ormond Street Hospital, United Kingdom
  4. University College London, United Kingdom

Abstract

Accurate inference of who infected whom in an infectious disease outbreak is critical for the delivery of effective infection prevention and control. The increased resolution of pathogen whole-genome sequencing has significantly improved our ability to infer transmission events. Despite this, transmission inference often remains limited by the lack of genomic variation between the source case and infected contacts. Although within-host genetic diversity is common among a wide variety of pathogens, conventional whole-genome sequencing phylogenetic approaches exclusively use consensus sequences, which consider only the most prevalent nucleotide at each position and therefore fail to capture low frequency variation within samples. We hypothesized that including within-sample variation in a phylogenetic model would help to identify who infected whom in instances in which this was previously impossible. Using whole-genome sequences from SARS-CoV-2 multi-institutional outbreaks as an example, we show how within-sample diversity is partially maintained among repeated serial samples from the same host, it can transmitted between those cases with known epidemiological links, and how this improves phylogenetic inference and our understanding of who infected whom. Our technique is applicable to other infectious diseases and has immediate clinical utility in infection prevention and control.

Data availability

Samples sequenced as part of this study have been submitted to the European Nucleotide Archive under accession PRJEB53224.Sample metadata is included in Supplementary file 1.All custom code used in this article can be accessed at https://github.com/arturotorreso/scov2_withinHost.git.

The following data sets were generated

Article and author information

Author details

  1. Arturo Torres Ortiz

    Department of Infectious Diseases, Imperial College London, London, United Kingdom
    For correspondence
    a.ortiz@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2492-0958
  2. Michelle Kendall

    Department of Statistics, University of Warwick, Coventry, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7344-7071
  3. Nathaniel Storey

    Department of Microbiology, Great Ormond Street Hospital, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. James Hatcher

    Department of Microbiology, Great Ormond Street Hospital, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Helen Dunn

    Department of Microbiology, Great Ormond Street Hospital, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Sunando Roy

    Department of Infection, Immunity and Inflammation, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Rachel Williams

    UCL Genomics, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Charlotte Williams

    UCL Genomics, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Richard A Goldstein

    UCL Genomics, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5148-4672
  10. Xavier Didelot

    Department of Statistics, University of Warwick, Coventry, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1885-500X
  11. Kathryn Harris

    Department of Microbiology, Great Ormond Street Hospital, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Judith Breuer

    Department of Infection, Immunity and Inflammation, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8246-0534
  13. Louis Grandjean

    Department of Infection, Immunity and Inflammation, University College London, London, United Kingdom
    For correspondence
    l.grandjean@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Funding

Wellcome Trust (201470/Z/16/Z)

  • Louis Grandjean

National Institute of Allergy and Infectious Diseases (1R01AI146338)

  • Louis Grandjean

NIHR

  • Xavier Didelot

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. James M McCaw, University of Melbourne, Australia

Version history

  1. Preprint posted: June 7, 2022 (view preprint)
  2. Received: October 22, 2022
  3. Accepted: September 20, 2023
  4. Accepted Manuscript published: September 21, 2023 (version 1)
  5. Version of Record published: October 26, 2023 (version 2)

Copyright

© 2023, Torres Ortiz et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Arturo Torres Ortiz
  2. Michelle Kendall
  3. Nathaniel Storey
  4. James Hatcher
  5. Helen Dunn
  6. Sunando Roy
  7. Rachel Williams
  8. Charlotte Williams
  9. Richard A Goldstein
  10. Xavier Didelot
  11. Kathryn Harris
  12. Judith Breuer
  13. Louis Grandjean
(2023)
Within-host diversity improves phylogenetic and transmission reconstruction of SARS-CoV-2 outbreaks
eLife 12:e84384.
https://doi.org/10.7554/eLife.84384

Share this article

https://doi.org/10.7554/eLife.84384

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