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

Gerry Tonkin-Hill; Inigo Martincorena; Roberto Amato; Andrew Rj Lawson; Moritz Gerstung; Ian Johnston; David K. Jackson; Naomi Park; Stefanie V. Lensing; Michael A. Quail; Sonia Gonsalves; Cristina 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 G. Caller; Sarah L. Caddy; Theresa Feltwell; Fahad A. Khokhar; Charlotte J. Houldcroft; Martin D. Curran; Surendra Parmar; Rachel Nelson Ewan M. Harrison; John Sillitoe; Stephen D. Bentley; Jeffrey C. Barrett; M. Estee Torok; Ian G. Goodfellow; Cordelia Langford; Dominic Kwiatkowski

doi:10.7554/eLife.66857

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

Gerry Tonkin-Hill^*, Inigo Martincorena^*, Roberto Amato, Andrew Rj Lawson, Moritz Gerstung, Ian Johnston, David K. Jackson, Naomi Park, Stefanie V. Lensing, Michael A. Quail, Sonia Gonsalves, Cristina Ariani, Michael Spencer Chapman, William L. Hamilton, Luke W. Meredith, Grant Hall, Aminu S. Jahun, Yasmin Chaudhry, Myra Hosmillo, Malte L. PinckertIliana Georgana, Anna Yakovleva, Laura G. Caller, Sarah L. Caddy, Theresa Feltwell, Fahad A. Khokhar, Charlotte J. Houldcroft, Martin D. Curran, Surendra Parmar, Rachel Nelson Ewan M. Harrison, John Sillitoe, Stephen D. Bentley, Jeffrey C. Barrett, M. Estee Torok, Ian G. Goodfellow, Cordelia Langford, Dominic Kwiatkowski^*

^*Corresponding author for this work

Cambridge Lab Addenbrookes

Research output: Contribution to journal › Article › peer-review

103 Citations (Scopus)

27 Downloads (Pure)

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.

Original language	English
Article number	66857
Number of pages	25
Journal	eLife
Volume	10
DOIs	https://doi.org/10.7554/eLife.66857
Publication status	Published - 13 Aug 2021

Bibliographical note

Funding Information: This work was funded by COG-UK, supported by funding from the Medical Research Council (MRC) part of UK Research and Innovation (UKRI), the National Institute of Health Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute; the Wellcome Trust (Senior Fellowship to IG ref: 207498/Z/17/Z and PhD Scholarship to GTH ref: 204016/Z/16/Z); the Academy of Medical Sciences and the Health Foundation (Clinician Scientist Fellowship to MET); and the Cambridge NIHR Biomedical Research Centre (MET).

Open Access: This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Publisher Copyright: © Tonkin-Hill et al.

Citation: Tonkin-Hill, Gerry, et al. "Patterns of within-host genetic diversity in SARS-CoV-2." Elife 10 (2021).

DOI: 10.7554/eLife.66857

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.7554/eLife.66857Licence: CC BY

Tonkin-Hill2021PatternsOfWithin-HostGeneticDiversityInSARS-CoV-2eLifeFinal published version, 1.61 MBLicence: CC BY

Cite this

Tonkin-Hill, G., Martincorena, I., Amato, R., Lawson, A. R., Gerstung, M., Johnston, I., Jackson, D. K., Park, N., Lensing, S. V., Quail, M. A., Gonsalves, S., Ariani, C., Spencer Chapman, M., Hamilton, W. L., Meredith, L. W., Hall, G., Jahun, A. S., Chaudhry, Y., Hosmillo, M., ... Kwiatkowski, D. (2021). Patterns of within-host genetic diversity in SARS-COV-2. eLife, 10, Article 66857. https://doi.org/10.7554/eLife.66857

@article{bdbc50f900884988afd186d72ced5c32,

title = "Patterns of within-host genetic diversity in SARS-COV-2",

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.",

author = "Gerry Tonkin-Hill and Inigo Martincorena and Roberto Amato and Lawson, {Andrew Rj} and Moritz Gerstung and Ian Johnston and Jackson, {David K.} and Naomi Park and Lensing, {Stefanie V.} and Quail, {Michael A.} and Sonia Gonsalves and Cristina Ariani and {Spencer Chapman}, Michael and Hamilton, {William L.} and Meredith, {Luke W.} and Grant Hall and Jahun, {Aminu S.} and Yasmin Chaudhry and Myra Hosmillo and Pinckert, {Malte L.} and Iliana Georgana and Anna Yakovleva and Caller, {Laura G.} and Caddy, {Sarah L.} and Theresa Feltwell and Khokhar, {Fahad A.} and Houldcroft, {Charlotte J.} and Curran, {Martin D.} and Surendra Parmar and Harrison, {Rachel Nelson Ewan M.} and John Sillitoe and Bentley, {Stephen D.} and Barrett, {Jeffrey C.} and {Estee Torok}, M. and Goodfellow, {Ian G.} and Cordelia Langford and Dominic Kwiatkowski",

note = "Funding Information: This work was funded by COG-UK, supported by funding from the Medical Research Council (MRC) part of UK Research and Innovation (UKRI), the National Institute of Health Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute; the Wellcome Trust (Senior Fellowship to IG ref: 207498/Z/17/Z and PhD Scholarship to GTH ref: 204016/Z/16/Z); the Academy of Medical Sciences and the Health Foundation (Clinician Scientist Fellowship to MET); and the Cambridge NIHR Biomedical Research Centre (MET). Open Access: This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Publisher Copyright: {\textcopyright} Tonkin-Hill et al. Citation: Tonkin-Hill, Gerry, et al. {"}Patterns of within-host genetic diversity in SARS-CoV-2.{"} Elife 10 (2021). DOI: 10.7554/eLife.66857",

year = "2021",

month = aug,

day = "13",

doi = "10.7554/eLife.66857",

language = "English",

volume = "10",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications Ltd",

}

Tonkin-Hill, G, Martincorena, I, Amato, R, Lawson, AR, Gerstung, M, Johnston, I, Jackson, DK, Park, N, Lensing, SV, Quail, MA, Gonsalves, S, Ariani, C, Spencer Chapman, M, Hamilton, WL, Meredith, LW, Hall, G, Jahun, AS, Chaudhry, Y, Hosmillo, M, Pinckert, ML, Georgana, I, Yakovleva, A, Caller, LG, Caddy, SL, Feltwell, T, Khokhar, FA, Houldcroft, CJ, Curran, MD, Parmar, S, Harrison, RNEM, Sillitoe, J, Bentley, SD, Barrett, JC, Estee Torok, M, Goodfellow, IG, Langford, C & Kwiatkowski, D 2021, 'Patterns of within-host genetic diversity in SARS-COV-2', eLife, vol. 10, 66857. https://doi.org/10.7554/eLife.66857

TY - JOUR

T1 - Patterns of within-host genetic diversity in SARS-COV-2

AU - Tonkin-Hill, Gerry

AU - Martincorena, Inigo

AU - Amato, Roberto

AU - Lawson, Andrew Rj

AU - Gerstung, Moritz

AU - Johnston, Ian

AU - Jackson, David K.

AU - Park, Naomi

AU - Lensing, Stefanie V.

AU - Quail, Michael A.

AU - Gonsalves, Sonia

AU - Ariani, Cristina

AU - Spencer Chapman, Michael

AU - Hamilton, William L.

AU - Meredith, Luke W.

AU - Hall, Grant

AU - Jahun, Aminu S.

AU - Chaudhry, Yasmin

AU - Hosmillo, Myra

AU - Pinckert, Malte L.

AU - Georgana, Iliana

AU - Yakovleva, Anna

AU - Caller, Laura G.

AU - Caddy, Sarah L.

AU - Feltwell, Theresa

AU - Khokhar, Fahad A.

AU - Houldcroft, Charlotte J.

AU - Curran, Martin D.

AU - Parmar, Surendra

AU - Harrison, Rachel Nelson Ewan M.

AU - Sillitoe, John

AU - Bentley, Stephen D.

AU - Barrett, Jeffrey C.

AU - Estee Torok, M.

AU - Goodfellow, Ian G.

AU - Langford, Cordelia

AU - Kwiatkowski, Dominic

N1 - Funding Information: This work was funded by COG-UK, supported by funding from the Medical Research Council (MRC) part of UK Research and Innovation (UKRI), the National Institute of Health Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute; the Wellcome Trust (Senior Fellowship to IG ref: 207498/Z/17/Z and PhD Scholarship to GTH ref: 204016/Z/16/Z); the Academy of Medical Sciences and the Health Foundation (Clinician Scientist Fellowship to MET); and the Cambridge NIHR Biomedical Research Centre (MET). Open Access: This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Publisher Copyright: © Tonkin-Hill et al. Citation: Tonkin-Hill, Gerry, et al. "Patterns of within-host genetic diversity in SARS-CoV-2." Elife 10 (2021). DOI: 10.7554/eLife.66857

PY - 2021/8/13

Y1 - 2021/8/13

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85114386620&partnerID=8YFLogxK

U2 - 10.7554/eLife.66857

DO - 10.7554/eLife.66857

M3 - Article

C2 - 34387545

AN - SCOPUS:85114386620

SN - 2050-084X

VL - 10

JO - eLife

JF - eLife

M1 - 66857

ER -

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

Abstract

Bibliographical note

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this