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

eLife

M Estee Torok¹  William L Hamilton¹  Sarah L Caddy¹  Charlotte J Houldcroft¹  Fahad A Khokhar²  Iliana Georgana³  Myra Hosmillo³  Malte L Pinckert³  Ian G Goodfellow³  Anna Yakovleva³  Theresa Feltwell³  Luke W Meredith³  Laura G Caller³  Aminu S Jahun³  Yasmin Chaudhry³  Grant Hall³  Moritz Gerstrung⁴  Martin D Curran⁵  Surendra Parmar⁵  Sonia Gonçalves⁶  Naomi Park⁶  Andrew RJ Lawson⁶  Michael A Quail⁶  Cristina Ariani⁶  Roberto Amato⁶  Ian Johnston⁶  Michael Spencer Chapman⁶  Gerry Tonkin-Hill⁶  Rachel Nelson⁶  Inigo Martincorena⁶  Jeffrey C Barrett⁶  David K Jackson⁶  Stefanie V Lensing⁶  John Sillitoe⁶  Cordelia Langford⁶  Alex Alderton⁶  Stephen D Bentley⁶  Ewan M Harrison⁷  Dominic P Kwiatowski⁸ 

[1]Department of Medicine, University of Cambridge, Cambridge, United Kingdom

[2]Department of Medicine, University of Cambridge, Cambridge, United Kingdom

[3]Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom

[4]Department of Pathology, University of Cambridge, Cambridge, United Kingdom

[5]European Bioinformatics Institute, Hinxton, United Kingdom

[6]Public Health England, Cambridge, United Kingdom

[7]Wellcome Sanger Institute, Hinxton, United Kingdom

[8]Wellcome Sanger Institute, Hinxton, United Kingdom

[9]European Bioinformatics Institute, Hinxton, United Kingdom

[10]Wellcome Sanger Institute, Hinxton, United Kingdom

[11]Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

关键词: SARS-CoV-2;    within-host;    mutational spectrum;    transmission;    Other;   

DOI  :  10.7554/eLife.66857

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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 1181 SARS-CoV-2 samples sequenced to high depth in duplicate. 95.1% 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.

【 授权许可】

CC BY