Evidence for Strong Mutation Bias toward, and Selection against, U Content in SARS-CoV-2: Implications for Vaccine Design

Abstract Large-scale re-engineering of synonymous sites is a promising strategy to generate vaccines either through synthesis of attenuated viruses or via codon-optimized genes in DNA vaccines. Attenuation typically relies on deoptimization of codon pairs and maximization of CpG dinucleotide frequencies. So as to formulate evolutionarily informed attenuation strategies that aim to force nucleotide usage against the direction favored by selection, here, we examine available whole-genome sequences of SARS-CoV-2 to infer patterns of mutation and selection on synonymous sites. Analysis of mutational profiles indicates a strong mutation bias toward U. In turn, analysis of observed synonymous site composition implicates selection against U. Accounting for dinucleotide effects reinforces this conclusion, observed UU content being a quarter of that expected under neutrality. Possible mechanisms of selection against U mutations include selection for higher expression, for high mRNA stability or lower immunogenicity of viral genes. Consistent with gene-specific selection against CpG dinucleotides, we observe systematic differences of CpG content between SARS-CoV-2 genes. We propose an evolutionarily informed approach to attenuation that, unusually, seeks to increase usage of the already most common synonymous codons. Comparable analysis of H1N1 and Ebola finds that GC3 deviated from neutral equilibrium is not a universal feature, cautioning against generalization of results.

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Evidence for strong mutation bias towards, and selection against, T/U content in SARS-CoV2: implications for attenuated vaccine design

10.1101/2020.05.11.088112 ◽

2020 ◽

Cited By ~ 3

Author(s):

Alan M. Rice ◽

Atahualpa Castillo Morales ◽

Alexander T. Ho ◽

Christine Mordstein ◽

Stefanie Mühlhausen ◽

...

Keyword(s):

Large Scale ◽

Mutation Bias ◽

Cpg Dinucleotides ◽

Synonymous Codons ◽

Universal Feature ◽

Neutral Equilibrium ◽

Synonymous Sites ◽

Selection For ◽

Attenuated Viruses ◽

Codon Pairs

ABSTRACTLarge-scale re-engineering of synonymous sites is a promising strategy to generate attenuated viruses for vaccines. Attenuation typically relies on de-optimisation of codon pairs and maximization of CpG dinculeotide frequencies. So as to formulate evolutionarily-informed attenuation strategies, that aim to force nucleotide usage against the estimated direction favoured by selection, here we examine available whole-genome sequences of SARS-CoV2 to infer patterns of mutation and selection on synonymous sites. Analysis of mutational profiles indicates a strong mutation bias towards T with concomitant selection against T. Accounting for dinucleotide effects reinforces this conclusion, observed TT content being a quarter of that expected under neutrality. A significantly different mutational profile at CDS sites that are not 4-fold degenerate is consistent with contemporaneous selection against T mutations more widely. Although selection against CpG dinucleotides is expected to drive synonymous site G+C content below mutational equilibrium, observed G+C content is slightly above equilibrium, possibly because of selection for higher expression. Consistent with gene-specific selection against CpG dinucleotides, we observe systematic differences of CpG content between SARS-CoV2 genes. We propose an evolutionarily informed gene-bespoke approach to attenuation that, unusually, seeks to increase usage of the already most common synonymous codons. Comparable analysis of H1N1 and Ebola finds that GC3 deviated from neutral equilibrium is not a universal feature, cautioning against generalization of results.

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Variability in codon usage in Coronaviruses is mainly driven by mutational bias and selective constraints on CpG dinucleotide

10.1101/2021.01.26.428296 ◽

2021 ◽

Author(s):

J. Daron ◽

I.G. Bravo

Keyword(s):

Codon Usage ◽

Codon Usage Bias ◽

Synonymous Codon ◽

Synonymous Codon Usage ◽

Mutational Bias ◽

Cpg Dinucleotides ◽

Neutral Equilibrium ◽

History Of ◽

Cpg Dinucleotide ◽

Human Coronaviruses

AbstractThe Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third virus within the Orthocoronavirinae causing an emergent infectious disease in humans, the ongoing coronavirus disease 2019 pandemic (COVID-19). Due to the high zoonotic potential of these viruses, it is critical to unravel their evolutionary history of host species shift, adaptation and emergence. Only such knowledge can guide virus discovery, surveillance and research efforts to identify viruses posing a pandemic risk in humans. We present a comprehensive analysis of the composition and codon usage bias of the 82 Orthocoronavirinae members, infecting 47 different avian and mammalian hosts. Our results clearly establish that synonymous codon usage varies widely among viruses and is only weakly dependent on the type of host they infect. Instead, we identify mutational bias towards AT-enrichment and selection against CpG dinucleotides as the main factors responsible of the codon usage bias variation. Further insight on the mutational equilibrium within Orthocoronavirinae revealed that most coronavirus genomes are close to their neutral equilibrium, the exception is the three recently-infecting human coronaviruses, which lie further away from the mutational equilibrium than their endemic human coronavirus counterparts. Finally, our results suggest that while replicating in humans SARS-CoV-2 is slowly becoming AT-richer, likely until attaining a new mutational equilibrium.

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The Evolution of Isochores: Evidence From SNP Frequency Distributions

Genetics ◽

10.1093/genetics/162.4.1805 ◽

2002 ◽

Vol 162 (4) ◽

pp. 1805-1810 ◽

Cited By ~ 1

Author(s):

Martin J Lercher ◽

Nick G C Smith ◽

Adam Eyre-Walker ◽

Laurence D Hurst

Keyword(s):

Population Genetics ◽

Large Scale ◽

Gc Content ◽

Nucleotide Composition ◽

Compositional Variation ◽

Mutation Bias ◽

Single Nucleotide ◽

Frequency Distributions ◽

Noncoding Regions ◽

Standard Population

AbstractThe large-scale systematic variation in nucleotide composition along mammalian and avian genomes has been a focus of the debate between neutralist and selectionist views of molecular evolution. Here we test whether the compositional variation is due to mutation bias using two new tests, which do not assume compositional equilibrium. In the first test we assume a standard population genetics model, but in the second we make no assumptions about the underlying population genetics. We apply the tests to single-nucleotide polymorphism data from noncoding regions of the human genome. Both models of neutral mutation bias fit the frequency distributions of SNPs segregating in low- and medium-GC-content regions of the genome adequately, although both suggest compositional nonequilibrium. However, neither model fits the frequency distribution of SNPs from the high-GC-content regions. In contrast, a simple population genetics model that incorporates selection or biased gene conversion cannot be rejected. The results suggest that mutation biases are not solely responsible for the compositional biases found in noncoding regions.

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