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

2021; eLife Sciences Publications Ltd; Volume: 10; Linguagem: Inglês

10.7554/elife.66857

2050-084X

Gerry Tonkin‐Hill, Iñigo Martincorena, Roberto Amato, Andrew Lawson, Moritz Gerstung, Ian Johnston, David K. Jackson, Naomi Park, Stefanie V. Lensing, Michael A. Quail, Sónia Gonçalves, Cristina V. 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 Caller, Sarah Caddy, Theresa Feltwell, Fahad Khokhar, Charlotte J. Houldcroft, Martin D. Curran, Surendra Parmar, Alex Alderton, Andrew Nelson, Ewan M. Harrison, John Sillitoe, Stephen D. Bentley, Jeffrey C. Barrett, M. Estée Török, Ian Goodfellow, Cordelia Langford, Dominic Kwiatkowski,

Bacteriophages and microbial interactions

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.