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Research Article | Ecological and Evolutionary Science

Rampant C→U Hypermutation in the Genomes of SARS-CoV-2 and Other Coronaviruses: Causes and Consequences for Their Short- and Long-Term Evolutionary Trajectories

P. Simmonds
Martin Schwemmle, Editor
P. Simmonds
aNuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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Martin Schwemmle
University Medical Center Freiburg
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DOI: 10.1128/mSphere.00408-20
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  • FIG 1
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    FIG 1

    Association between sequence divergence and dN/dS ratio. A comparison of dN/dS ratios in recently emerged coronaviruses (red circles), other human coronaviruses and relatives infecting other species (blue circles), and a collection of bat sarbecoviruses (SARS-like) (pink circle). A power law line of best fit showed a significant correlation between divergence and dN/dS ratio (P = 0.000006). Sequences of the three data sets of EBOV control sequences were included (gray triangles).

  • FIG 2
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    FIG 2

    Association of excess C→U transitions with divergence. (A) Numbers of sites in the SARS-CoV-2 genome with each of the four transitions. Bar heights represent the means from the three sequence samples; error bars show one standard deviation (SD). (B) Relationship between sequence diversity and a normalized metric of asymmetry between the numbers of C→U and U→C transitions (where 1.0 is the expected number). Power law regression line was significant at a P value of <0.0001. (C) Association of dN/dS ratio with C→U/U→C asymmetry. The power law regression lines were significant at P values of 0.001 and 0.0004, respectively. Points are colored as in Fig. 1.

  • FIG 3
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    FIG 3

    Positions of C→U transitions in the SARS-CoV-2 genome in each of the three replicate SARS-CoV-2 sequence data sets were matched to a genome diagram of SARS-CoV-2 (using the annotation from the prototype sequence MN908947). The numbers of transitions at each site are shown on a log scale, with the shortest bars indicating individual substitutions.

  • FIG 4
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    FIG 4

    Phylogeny of SARS-CoV-2 and positions of sequences with C→U changes. A neighbor-joining tree of 865 SARS-CoV-2 complete genome sequences was constructed in MEGA6 (41). Labels show the position of sequences containing a selection of C→U transitions at the genome positions indicated in the key.

  • FIG 5
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    FIG 5

    Amino acid changes induced by different nucleotide substitutions. Numbers of individual amino acids changes observed in the combined SARS-CoV-2 data set (864 sequences) at a 5% variability threshold. Bars are colored based on the underlying nucleotide changes. Inset graph shows the relative proportions of transitions leading to amino acid changes.

  • FIG 6
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    FIG 6

    Influence of 5′ and 3′ base contexts on C↔U and G↔A transition frequencies. Totals of each transition in the SARS-CoV-2 sequence data set split into subtotals based on the identity of the 5′ (left) and 3′ (right) base. Bar heights represent the means from the three sequence samples; error bars show standard deviations. A further division into the 16 combinations of 5′ and 3′ base contexts is provided in Fig. S1 in the supplemental material.

  • FIG 7
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    FIG 7

    Base frequencies in different coronaviruses. Relationship between G+C content and frequencies of individual bases in coronaviruses. The associations between C depletion and U enrichment with G+C content were both significant by linear regression at P = 5 × 10−7 and P = 5 × 10−6, respectively. No significant associations were observed between G+C content and G (P = 0.05) or A (P = 0.62) frequencies. Arrows are color coded as for Fig. 1.

  • FIG 8
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    FIG 8

    Suppression of CpG dinucleotides in SARS-CoV-2 and other coronaviruses. Comparison of CpG frequencies of SARS-CoV-2, other coronaviruses, and a set of other mammalian RNA viruses; each data point represents an individual currently classified species; accession numbers are listed in Table S1. CpG frequencies were expressed as the ratio of their observed frequency to the expected frequency based on their G+C content (y axis).

Tables

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  • TABLE 1

    Coronavirus sequence data sets used for the study

    TABLE 1
    • ↵a Mean nucleotide p distances between complete genome sequences.

    • ↵b Frequency of nonsynonymous (dN) to synonymous (dS) p distances.

Supplemental Material

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  • TABLE S1

    Listing of SARS-CoV-2 and EBOV sequences analyzed in the study. Download Table S1, DOCX file, 0.1 MB.

    Copyright © 2020 Simmonds.

    This content is distributed under the terms of the Creative Commons Attribution 4.0 International license.

  • FIG S1

    Frequencies of transitions in all 5′ and 3′ base context combinations. Effects of 5′ and 3′ bases on transition frequencies in SARS-CoV-2 full-genome sequences. Download FIG S1, DOCX file, 0.3 MB.

    Copyright © 2020 Simmonds.

    This content is distributed under the terms of the Creative Commons Attribution 4.0 International license.

  • TABLE S2

    Sequences used for comparison of suppression of CpG in coronaviruses. Download Table S2, DOCX file, 0.1 MB.

    Copyright © 2020 Simmonds.

    This content is distributed under the terms of the Creative Commons Attribution 4.0 International license.

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Rampant C→U Hypermutation in the Genomes of SARS-CoV-2 and Other Coronaviruses: Causes and Consequences for Their Short- and Long-Term Evolutionary Trajectories
P. Simmonds
mSphere Jun 2020, 5 (3) e00408-20; DOI: 10.1128/mSphere.00408-20

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Rampant C→U Hypermutation in the Genomes of SARS-CoV-2 and Other Coronaviruses: Causes and Consequences for Their Short- and Long-Term Evolutionary Trajectories
P. Simmonds
mSphere Jun 2020, 5 (3) e00408-20; DOI: 10.1128/mSphere.00408-20
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KEYWORDS

APOBEC
COVID-19
SARS
SARS coronavirus 2
coronavirus
hypermutation
SARS-CoV-2

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