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

Published version
Peer-reviewed

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Authors

Martincorena, Inigo 
Amato, Roberto 
Lawson, Andrew RJ 
Gerstrung, Moritz 

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 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.

Description

Funder: COG-UK


Funder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265


Funder: NIHR; FundRef: http://dx.doi.org/10.13039/501100000272


Funder: Wellcome; FundRef: http://dx.doi.org/10.13039/100004440

Keywords

Research Article, Epidemiology and Global Health, Genetics and Genomics, SARS-CoV-2, within-host, mutational spectrum, transmission, Other

Journal Title

eLife

Conference Name

Journal ISSN

2050-084X

Volume Title

10

Publisher

eLife Sciences Publications, Ltd
Sponsorship
Wellcome Trust (204016/Z/16/Z)
Wellcome Trust (207498/Z/17/Z)