Within-patient genetic diversity of SARS-CoV-2

  1. Jack Kuipers
  2. Aashil A Batavia
  3. Kim Philipp Jablonski
  4. Fritz Bayer
  5. Nico Borgsmüller
  6. Arthur Dondi
  7. Monica-Andreea Drăgan
  8. Pedro Ferreira
  9. Katharina Jahn
  10. Lisa Lamberti
  11. Martin Pirkl
  12. Susana Posada-Céspedes
  13. Ivan Topolsky
  14. Ina Nissen
  15. Natascha Santacroce
  16. Elodie Burcklen
  17. Tobias Schär
  18. Vincenzo Capece
  19. Christiane Beckmann
  20. Olivier Kobel
  21. Christoph Noppen
  22. Maurice Redondo
  23. Sarah Nadeau
  24. Sophie Seidel
  25. Noemie Santamaria de Souza
  26. Christian Beisel
  27. Tanja Stadler
  28. Niko Beerenwinkel
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Abstract

SARS-CoV-2, the virus responsible for the current COVID-19 pandemic, is evolving into different genetic variants by accumulating mutations as it spreads globally. In addition to this diversity of consensus genomes across patients, RNA viruses can also display genetic diversity within individual hosts, and co-existing viral variants may affect disease progression and the success of medical interventions. To systematically examine the intra-patient genetic diversity of SARS-CoV-2, we processed a large cohort of 3939 publicly-available deeply sequenced genomes with specialised bioinformatics software, along with 749 recently sequenced samples from Switzerland. We found that the distribution of diversity across patients and across genomic loci is very unbalanced with a minority of hosts and positions accounting for much of the diversity. For example, the D614G variant in the Spike gene, which is present in the consensus sequences of 67.4% of patients, is also highly diverse within hosts, with 29.7% of the public cohort being affected by this coexistence and exhibiting different variants. We also investigated the impact of several technical and epidemiological parameters on genetic heterogeneity and found that age, which is known to be correlated with poor disease outcomes, is a significant predictor of viral genetic diversity.

Author Summary

Since it arose in late 2019, the new coronavirus (SARS-CoV-2) behind the COVID-19 pandemic has mutated and evolved during its global spread. Individual patients may host different versions, or variants, of the virus, hallmarked by different mutations. We examine the diversity of genetic variants coexisting within patients across a cohort of 3939 publicly accessible samples and 749 recently sequenced samples from Switzerland. We find that a small number of patients carry most of the diversity, and that patients with more diversity tend to be older. We also find that most of the diversity is concentrated in certain regions and positions of the virus genome. In particular, we find that a variant reported to increase infectivity is among the most diverse positions. Our study provides a large-scale survey of within-patient diversity of the SARS-CoV-2 genome.

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