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Article ; Online: Mutation Rates and Selection on Synonymous Mutations in SARS-CoV-2.

De Maio, Nicola / Walker, Conor R / Turakhia, Yatish / Lanfear, Robert / Corbett-Detig, Russell / Goldman, Nick

2021 Volume 13, Issue 5

Abstract: ... the sequence data from more than 140,000 SARS-CoV-2 genomes, we study mutation rates and selective pressures ... in the SARS-CoV-2 genome, and are possibly the result of APOBEC and ROS activity. These mutations also tend ... of mutation rates and selection, such as ignoring skews in the genetic code, not accounting for recurrent mutations ...

Abstract	The COVID-19 pandemic has seen an unprecedented response from the sequencing community. Leveraging the sequence data from more than 140,000 SARS-CoV-2 genomes, we study mutation rates and selective pressures affecting the virus. Understanding the processes and effects of mutation and selection has profound implications for the study of viral evolution, for vaccine design, and for the tracking of viral spread. We highlight and address some common genome sequence analysis pitfalls that can lead to inaccurate inference of mutation rates and selection, such as ignoring skews in the genetic code, not accounting for recurrent mutations, and assuming evolutionary equilibrium. We find that two particular mutation rates, G →U and C →U, are similarly elevated and considerably higher than all other mutation rates, causing the majority of mutations in the SARS-CoV-2 genome, and are possibly the result of APOBEC and ROS activity. These mutations also tend to occur many times at the same genome positions along the global SARS-CoV-2 phylogeny (i.e., they are very homoplasic). We observe an effect of genomic context on mutation rates, but the effect of the context is overall limited. Although previous studies have suggested selection acting to decrease U content at synonymous sites, we bring forward evidence suggesting the opposite.
MeSH term(s)	COVID-19/virology ; Evolution, Molecular ; Genome, Viral ; Mutation Rate ; Phylogeny ; RNA, Viral/genetics ; SARS-CoV-2/classification ; SARS-CoV-2/genetics ; Selection, Genetic ; Sequence Analysis, RNA ; Silent Mutation/genetics
Chemical Substances	RNA, Viral
Language	English
Publishing date	2021-04-24
Publishing country	England
Document type	Journal Article
ZDB-ID	2495328-3
ISSN	1759-6653 ; 1759-6653
ISSN (online)	1759-6653
ISSN	1759-6653
DOI	10.1093/gbe/evab087
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Mutation rates and selection on synonymous mutations in SARS-CoV-2.

De Maio, Nicola / Walker, Conor R / Turakhia, Yatish / Lanfear, Robert / Corbett-Detig, Russell / Goldman, Nick

bioRxiv : the preprint server for biology

2021

Abstract	The COVID-19 pandemic has seen an unprecedented response from the sequencing community. Leveraging the sequence data from more than 140,000 SARS-CoV-2 genomes, we study mutation rates and selective pressures affecting the virus. Understanding the processes and effects of mutation and selection has profound implications for the study of viral evolution, for vaccine design, and for the tracking of viral spread. We highlight and address some common genome sequence analysis pitfalls that can lead to inaccurate inference of mutation rates and selection, such as ignoring skews in the genetic code, not accounting for recurrent mutations, and assuming evolutionary equilibrium. We find that two particular mutation rates, G→U and C→U, are similarly elevated and considerably higher than all other mutation rates, causing the majority of mutations in the SARS-CoV-2 genome, and are possibly the result of APOBEC and ROS activity. These mutations also tend to occur many times at the same genome positions along the global SARS-CoV-2 phylogeny (i.e., they are very homoplasic). We observe an effect of genomic context on mutation rates, but the effect of the context is overall limited. While previous studies have suggested selection acting to decrease U content at synonymous sites, we bring forward evidence suggesting the opposite.
Language	English
Publishing date	2021-01-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.01.14.426705
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Article ; Online: Mutation rates and selection on synonymous mutations in SARS-CoV-2

De Maio, Nicola / Walker, Conor R / Turakhia, Yatish / Lanfear, Robert / Corbett-Detig, Russell / Goldman, Nick

bioRxiv

Abstract	The COVID-19 pandemic has seen an unprecedented response from the sequencing community. Leveraging the sequence data from more than 140,000 SARS-CoV-2 genomes, we study mutation rates and selective pressures affecting the virus. Understanding the processes and effects of mutation and selection has profound implications for the study of viral evolution, for vaccine design, and for the tracking of viral spread. We highlight and address some common genome sequence analysis pitfalls that can lead to inaccurate inference of mutation rates and selection, such as ignoring skews in the genetic code, not accounting for recurrent mutations, and assuming evolutionary equilibrium. We find that two particular mutation rates, G→U and C→U, are similarly elevated and considerably higher than all other mutation rates, causing the majority of mutations in the SARS-CoV-2 genome, and are possibly the result of APOBEC and ROS activity. These mutations also tend to occur many times at the same genome positions along the global SARS-CoV-2 phylogeny (i.e., they are very homoplasic). We observe an effect of genomic context on mutation rates, but the effect of the context is overall limited. While previous studies have suggested selection acting to decrease U content at synonymous sites, we bring forward evidence suggesting the opposite.
Keywords	covid19
Language	English
Publishing date	2021-01-14
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.01.14.426705
Database	COVID19

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Article ; Online: Trends of mutation accumulation across global SARS-CoV-2 genomes: Implications for the evolution of the novel coronavirus.

Roy, Chayan / Mandal, Santi M / Mondal, Suresh K / Mukherjee, Shriparna / Mapder, Tarunendu / Ghosh, Wriddhiman / Chakraborty, Ranadhir

Genomics

2020 Volume 112, Issue 6, Page(s) 5331–5342

Abstract: To understand SARS-CoV-2 microevolution, this study explored the genome-wide frequency, gene-wise ... indicated that SARS-CoV-2 has already harmonized its replication/transcription machineries with the host ... selection of nonsynonymous mutations (dN/dS >1) in most of the structural, but not the non-structural, genes ...

Abstract	To understand SARS-CoV-2 microevolution, this study explored the genome-wide frequency, gene-wise distribution, and molecular nature of all point-mutations detected across its 71,703 RNA-genomes deposited in GISAID till 21 August 2020. Globally, nsp1/nsp2 and orf7a/orf3a were the most mutation-ridden non-structural and structural genes respectively. Phylogeny of 4618 spatiotemporally-representative genomes revealed that entities belonging to the early lineages are mostly spread over Asian countries, including India, whereas the recently-derived lineages are more globally distributed. Of the total 20,163 instances of polymorphism detected across global genomes, 12,594 and 7569 involved transitions and transversions, predominated by cytidine-to-uridine and guanosine-to-uridine conversions, respectively. Positive selection of nonsynonymous mutations (dN/dS >1) in most of the structural, but not the non-structural, genes indicated that SARS-CoV-2 has already harmonized its replication/transcription machineries with the host metabolism, while it is still redefining virulence/transmissibility strategies at the molecular level. Mechanistic bases and evolutionary/pathogenicity-related implications are discussed for the predominant mutation-types.
MeSH term(s)	Asia ; Evolution, Molecular ; Genome, Viral ; Genomics/methods ; India ; Mutation Accumulation ; Mutation Rate ; Mutation, Missense ; Phylogeny ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus/genetics ; Viral Proteins/genetics ; Viroporin Proteins/genetics
Chemical Substances	ORF3a protein, SARS-CoV-2 ; ORF7a protein, SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; Viral Proteins ; Viroporin Proteins ; spike protein, SARS-CoV-2
Keywords	covid19
Language	English
Publishing date	2020-11-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	356334-0
ISSN	1089-8646 ; 0888-7543
ISSN (online)	1089-8646
ISSN	0888-7543
DOI	10.1016/j.ygeno.2020.11.003
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Article: Comparative Genomic Analyses Reveal a Specific Mutation Pattern Between Human Coronavirus SARS-CoV-2 and Bat-CoV RaTG13.

Lv, Longxian / Li, Gaolei / Chen, Jinhui / Liang, Xinle / Li, Yudong

Frontiers in microbiology

2020 Volume 11, Page(s) 584717

Abstract: ... between SARS-CoV-2 and RaTG13. Further investigation of the mutation pattern mechanism would contribute ... We performed a comprehensive analysis using the available genomes of SARS-CoV-2 and its closely related ... 9.07) between SARS-CoV-2 WIV04 and Bat-CoV RaTG13 was markedly higher than that between ...

Abstract	Background: The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, China, rapidly grew into a global pandemic. How SARS-CoV-2 evolved remains unclear. Methods: We performed a comprehensive analysis using the available genomes of SARS-CoV-2 and its closely related coronaviruses. Results: The ratio of nucleotide substitutions to amino acid substitutions of the spike gene (9.07) between SARS-CoV-2 WIV04 and Bat-CoV RaTG13 was markedly higher than that between other coronaviruses (range, 1.29-4.81); the ratio of non-synonymous to synonymous substitution rates (dN/dS) between SARS-CoV-2 WIV04 and Bat-CoV RaTG13 was the lowest among all the performed comparisons, suggesting evolution under stringent selective pressure. Notably, the relative proportion of the T:C transition was markedly higher between SARS-CoV-2 WIV04 and Bat-CoV RaTG13 than between other compared coronaviruses. Codon usage is similar across these coronaviruses and is unlikely to explain the increased number of synonymous mutations. Moreover, some sites of the spike protein might be subjected to positive selection. Conclusions: Our results showed an increased proportion of synonymous substitutions and the T:C transition between SARS-CoV-2 and RaTG13. Further investigation of the mutation pattern mechanism would contribute to understanding viral pathogenicity and its adaptation to hosts.
Language	English
Publishing date	2020-11-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587354-4
ISSN	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2020.584717
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Article ; Online: Comparative genomic analysis revealed specific mutation pattern between human coronavirus SARS-CoV-2 and Bat-SARSr-CoV RaTG13

Lv, Longxian / Li, Gaolei / Chen, Jinhui / Liang, Xinle / Li, Yudong

bioRxiv

Abstract: ... 29 - 4.81). The elevated synonymous mutations between SARS-CoV-2 and RaTG13, suggesting ... The novel coronavirus SARS-CoV-2 (2019-nCoV) is a member of the family coronaviridae and contains ... we performed comprehensive genomic analysis with newly sequenced SARS-CoV-2 strains and 20 closely related ...

Abstract	The novel coronavirus SARS-CoV-2 (2019-nCoV) is a member of the family coronaviridae and contains a single-stranded RNA genome with positive-polarity. To reveal the evolution mechanism of SARS-CoV-2 genome, we performed comprehensive genomic analysis with newly sequenced SARS-CoV-2 strains and 20 closely related coronavirus strains. Among 98 nucleotide mutations at 93 sites of the genome among different SARS-CoV-2 strains, 58 of them caused amino acid change, indicating a result of neutral evolution. However, the ratio of nucleotide substitutions to amino acid substitutions of spike gene (9.07) between SARS-CoV-2 WIV04 and Bat-SARSr-CoV RaTG13 was extensively higher than those from comparisons between other coronaviruses (range 1.29 - 4.81). The elevated synonymous mutations between SARS-CoV-2 and RaTG13, suggesting they underwent stronger purifying selection. Moreover, their nucleotide substitutions are enriched with T:C transition, which is consistent with the mutation signature caused by deactivity of RNA 3’-to-5’ exoribonuclease (ExoN). The codon usage was similar between SARS-CoV-2 and other strains in beta-coronavirus lineage B, suggesting it had small impact on the mutation pattern. In comparison of SARS-CoV-2 WIV04 with Bat-SARSr-CoV RaTG13, the ratios of non-synonymous to synonymous substitution rates (dN/dS) was the lowest among all performed comparisons, reconfirming the evolution of SARS-CoV-2 under stringent selective pressure. Moreover, some sites of spike protein might be subjected to positive selection. Therefore, our results will help understanding the evolutionary mechanisms contribute to viral pathogenicity and its adaptation with hosts.
Keywords	covid19
Publisher	BioRxiv; MedRxiv; WHO
Document type	Article ; Online
DOI	10.1101/2020.02.27.969006
Database	COVID19

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Article ; Online: Comparative genomic analysis revealed specific mutation pattern between human coronavirus SARS-CoV-2 and Bat-SARSr-CoV RaTG13

Lv, Longxian / Li, Gaolei / Chen, Jinhui / Liang, Xinle / Li, Yudong

bioRxiv

Abstract	The novel coronavirus SARS-CoV-2 (2019-nCoV) is a member of the family coronaviridae and contains a single-stranded RNA genome with positive-polarity. To reveal the evolution mechanism of SARS-CoV-2 genome, we performed comprehensive genomic analysis with newly sequenced SARS-CoV-2 strains and 20 closely related coronavirus strains. Among 98 nucleotide mutations at 93 sites of the genome among different SARS-CoV-2 strains, 58 of them caused amino acid change, indicating a result of neutral evolution. However, the ratio of nucleotide substitutions to amino acid substitutions of spike gene (9.07) between SARS-CoV-2 WIV04 and Bat-SARSr-CoV RaTG13 was extensively higher than those from comparisons between other coronaviruses (range 1.29 - 4.81). The elevated synonymous mutations between SARS-CoV-2 and RaTG13, suggesting they underwent stronger purifying selection. Moreover, their nucleotide substitutions are enriched with T:C transition, which is consistent with the mutation signature caused by deactivity of RNA 39-to-59 exoribonuclease (ExoN). The codon usage was similar between SARS-CoV-2 and other strains in beta-coronavirus lineage B, suggesting it had small impact on the mutation pattern. In comparison of SARS-CoV-2 WIV04 with Bat-SARSr-CoV RaTG13, the ratios of non-synonymous to synonymous substitution rates (dN/dS) was the lowest among all performed comparisons, reconfirming the evolution of SARS-CoV-2 under stringent selective pressure. Moreover, some sites of spike protein might be subjected to positive selection. Therefore, our results will help understanding the evolutionary mechanisms contribute to viral pathogenicity and its adaptation with hosts.
Keywords	covid19
Language	English
Publishing date	2020-03-02
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.02.27.969006
Database	COVID19

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Article ; Online: Rapid and parallel adaptive mutations in spike S1 drive clade success in SARS-CoV-2.

Kistler, Kathryn E / Huddleston, John / Bedford, Trevor

Cell host & microbe

2022 Volume 30, Issue 4, Page(s) 545–555.e4

Abstract: ... a high degree of adaptation in S1 and suggest that SARS-CoV-2 might undergo antigenic drift. ... The SARS-CoV-2 pandemic has resulted in numerous virus variants, some of which have altered ... that are sculpting the evolutionary trajectory of SARS-CoV-2. Adaptive changes in S1 accumulated rapidly ...

Abstract	The SARS-CoV-2 pandemic has resulted in numerous virus variants, some of which have altered receptor-binding or antigenic phenotypes. Here, we quantify the degree to which adaptive evolution is driving the accumulation of mutations across the genome. We correlate clade growth with mutation accumulation, compare rates of nonsynonymous to synonymous divergence, assess temporal clustering of mutations, and evaluate the evolutionary success of individual mutations. We find that spike S1 is the focus of adaptive evolution but also identify positively selected mutations in other proteins (notably Nsp6) that are sculpting the evolutionary trajectory of SARS-CoV-2. Adaptive changes in S1 accumulated rapidly, resulting in a remarkably high ratio of nonsynonymous to synonymous divergence that is 2.5× greater than that observed in influenza hemagglutinin HA1 at the beginning of the 2009 H1N1 pandemic. These findings uncover a high degree of adaptation in S1 and suggest that SARS-CoV-2 might undergo antigenic drift.
MeSH term(s)	COVID-19/virology ; Humans ; Mutation ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus/genetics
Chemical Substances	Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-03-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	2278004-X
ISSN	1934-6069 ; 1931-3128
ISSN (online)	1934-6069
ISSN	1931-3128
DOI	10.1016/j.chom.2022.03.018
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Article: Rapid and parallel adaptive mutations in spike S1 drive clade success in SARS-CoV-2.

Kistler, Kathryn E / Huddleston, John / Bedford, Trevor

bioRxiv : the preprint server for biology

2022

Abstract: ... to synonymous divergence, clustering of mutations across the SARS-CoV-2 phylogeny and degree of convergent ... Given the importance of variant SARS-CoV-2 viruses with altered receptor-binding or antigenic ... in the SARS-CoV-2 genome. Here we assessed adaptive evolution across genes in the SARS-CoV-2 genome ...

Abstract	Given the importance of variant SARS-CoV-2 viruses with altered receptor-binding or antigenic phenotypes, we sought to quantify the degree to which adaptive evolution is driving accumulation of mutations in the SARS-CoV-2 genome. Here we assessed adaptive evolution across genes in the SARS-CoV-2 genome by correlating clade growth with mutation accumulation as well as by comparing rates of nonsynonymous to synonymous divergence, clustering of mutations across the SARS-CoV-2 phylogeny and degree of convergent evolution of individual mutations. We find that spike S1 is the focus of adaptive evolution, but also identify positively-selected mutations in other genes that are sculpting the evolutionary trajectory of SARS-CoV-2. Adaptive changes in S1 accumulated rapidly, resulting in a remarkably high ratio of nonsynonymous to synonymous divergence that is 2.5X greater than that observed in HA1 at the beginning of the 2009 H1N1 pandemic.
Language	English
Publishing date	2022-01-19
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.09.11.459844
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Article ; Online: Evidence for selection on SARS-CoV-2 RNA translation revealed by the evolutionary dynamics of mutations in UTRs and CDSs.

Zhu, Lin / Wang, Qi / Zhang, Weiyu / Hu, Hao / Xu, Kexin

RNA biology

2022 Volume 19, Issue 1, Page(s) 866–876

Abstract: ... For 5'UTR and synonymous mutations in SARS-CoV-2, the selection on TE is evident near start codons. Adaptive ... SARS-CoV-2 sequences during the past year and traced the dynamics of allele frequency of every mutation ... 2, and vice versa. During this evolutionary arms race between human and virus, SARS-CoV-2 tries ...

Abstract	RNA translation is the rate-limiting step when cells synthesize proteins. Elevating translation efficiency (TE) is intuitively beneficial. Particularly, when viruses invade host cells, how to compete with endogenous RNAs for efficient translation is a major issue to be resolved. We collected millions of worldwide SARS-CoV-2 sequences during the past year and traced the dynamics of allele frequency of every mutation. We defined adaptive and deleterious mutations according to the rise and fall of their frequencies along time. For 5'UTR and synonymous mutations in SARS-CoV-2, the selection on TE is evident near start codons. Adaptive mutations generally decrease GC content while deleterious mutations increase GC content. This trend fades away with increasing distance to start codons. Mutations decreasing GC content near start codons would unravel the complex RNA structure and facilitate translation initiation, which are beneficial to SARS-CoV-2, and vice versa. During this evolutionary arms race between human and virus, SARS-CoV-2 tries to improve its
MeSH term(s)	5' Untranslated Regions ; COVID-19/virology ; Codon, Initiator ; Evolution, Molecular ; Humans ; Mutation ; RNA, Viral/genetics ; SARS-CoV-2/genetics ; Selection, Genetic
Chemical Substances	5' Untranslated Regions ; Codon, Initiator ; RNA, Viral
Language	English
Publishing date	2022-06-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2159587-2
ISSN	1555-8584 ; 1555-8584
ISSN (online)	1555-8584
ISSN	1555-8584
DOI	10.1080/15476286.2022.2092351
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