SARS-CoV-2 and other human coronavirus show genome patterns previously associated to reduced viral recognition and altered immune response

AbstractA new pandemic caused by the betacoronavirus SARS-CoV-2 originated in China in late 2019. Although often asymptomatic, a relevant percentage of affected people can develop severe pneumonia. Initial evidence suggests that dysregulation of the immune response could contribute to the pathogenesis, as previously demonstrated for SARS-CoV. The presence of genome composition features involved in delaying viral recognition is herein investigated for human coronaviruses (HCoVs), with a special emphasis on SARS-CoV-2. A broad collection of HCoVs polyprotein, envelope, matrix, nucleocapsid and spike coding sequences was downloaded and several statistics representative of genome composition and codon bias were investigated. A model able to evaluate and test the presence of a significant under- or over-representation of dinucleotide pairs while accounting for the underlying codon bias and protein sequence was also implemented. The study revealed the significant under-representation of CpG dinucleotide pair in all HcoV, but especially in SARS-CoV and even more in SARS-CoV-2. The presence of forces acting to minimize CpG content was confirmed by relative synonymous codon usage pattern. Codons containing the CpG pair were severely under-represented, primarily in the polyprotein and spike coding sequences of SARS-CoV-2. Additionally, a significant under-representation of the TpA pair was observed in the N and S region of SARS-CoV and SARS-CoV-2. Increasing experimental evidence has proven that CpG and TpA are targeted by innate antiviral host defences, contributing both to RNA degradation and RIG-1 mediated interferon production. The low content of these dinucleotides could contribute to a delayed interferon production, dysregulated immune response, higher viral replication and poor outcome. Significantly, the RIG-1 signalling pathway was proven to be defective in elderlies, suggesting a likely interaction between limited viral recognition and lower responsiveness in interferon production that could justify the higher disease severity and mortality in older patients.

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SARS-CoV-2 And Other Human Coronavirus Show Genome Patterns Previously Associated to Reduced Viral Recognition and Altered Immune Response

10.21203/rs.3.rs-287307/v1 ◽

2021 ◽

Author(s):

Giovanni Franzo

Keyword(s):

Immune Response ◽

Codon Bias ◽

Synonymous Codon ◽

Rna Degradation ◽

Codon Usage Pattern ◽

Interferon Production ◽

Genome Composition ◽

Coding Sequences ◽

Spike Coding ◽

Viral Recognition

Abstract A new pandemic caused by the betacoronavirus SARS-CoV-2 originated in China in late 2019. Although often asymptomatic, a relevant percentage of affected people can develop severe pneumonia. Initial evidence suggests that dysregulation of the immune response could contribute to the pathogenesis, as previously demonstrated for SARS-CoV. The presence of genome composition features involved in delaying viral recognition is herein investigated for human coronaviruses (HCoVs), with a special emphasis on SARS-CoV-2. A broad collection of HCoVs polyprotein, envelope, matrix, nucleocapsid and spike coding sequences was downloaded and several statistics representative of genome composition and codon bias were investigated. A model able to evaluate and test the presence of a significant under- or over-representation of dinucleotide pairs while accounting for the underlying codon bias and protein sequence was also implemented. The study revealed the significant under-representation of CpG dinucleotide pair in all HcoV, but especially in SARS-CoV and even more in SARS-CoV-2. The presence of forces acting to minimize CpG content was confirmed by relative synonymous codon usage pattern. Codons containing the CpG pair were severely under-represented, primarily in the polyprotein and spike coding sequences of SARS-CoV-2. Additionally, a significant under-representation of the TpA pair was observed in the N and S region of SARS-CoV and SARS-CoV-2. Increasing experimental evidence has proven that CpG and TpA are targeted by innate antiviral host defences, contributing both to RNA degradation and RIG-1 mediated interferon production. The low content of these dinucleotides could contribute to a delayed interferon production, dysregulated immune response, higher viral replication and poor outcome. Significantly, the RIG-1 signalling pathway was proven to be defective in elderlies, suggesting a likely interaction between limited viral recognition and lower responsiveness in interferon production that could justify the higher disease severity and mortality in older patients.

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The features of SARS-CoV-2 and other human coronavirus genomes could affect interferon production and immune response

10.21203/rs.3.rs-25640/v1 ◽

2020 ◽

Author(s):

Giovanni Franzo

Keyword(s):

Immune Response ◽

Codon Bias ◽

Synonymous Codon ◽

Rna Degradation ◽

Codon Usage Pattern ◽

Interferon Production ◽

Genome Composition ◽

Coding Sequences ◽

Spike Coding ◽

Viral Recognition

Abstract A new pandemic caused by the betacoronavirus SARS-CoV-2 originated in China in late 2019. Although often asymptomatic, a relevant percentage of affected people can develop severe pneumonia. Initial evidence suggests that dysregulation of the immune response could contribute to the pathogenesis, as previously demonstrated for SARS-CoV. The presence of genome composition features involved in delaying viral recognition is herein investigated for human coronaviruses (HCoVs), with a special emphasis on SARS-CoV-2. A broad collection of HCoVs polyprotein, envelope, matrix, nucleocapsid and spike coding sequences was downloaded and several statistics representative of genome composition and codon bias were investigated. A model able to evaluate and test the presence of a significant under- or over-representation of dinucleotide pairs while accounting for the underlying codon bias and protein sequence was also implemented.The study revealed the significant under-representation of CpG dinucleotide pair in all HcoV, but especially in SARS-CoV and even more in SARS-CoV-2. The presence of forces acting to minimize CpG content was confirmed by relative synonymous codon usage pattern. Codons containing the CpG pair were severely under-represented, primarily in the polyprotein and spike coding sequences of SARS-CoV-2. Additionally, a significant under-representation of the TpA pair was observed in the N and S region of SARS-CoV and SARS-CoV-2.Increasing experimental evidence has proven that CpG and TpA are targeted by innate antiviral host defences, contributing both to RNA degradation and RIG-1 mediated interferon production. The low content of these dinucleotides could contribute to a delayed interferon production, dysregulated immune response, higher viral replication and poor outcome. Significantly, the RIG-1 signalling pathway was proven to be defective in elderlies, suggesting a likely interaction between limited viral recognition and lower responsiveness in interferon production that could justify the higher disease severity and mortality in older patients.

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Effect of genome composition and codon bias on infectious bronchitis virus evolution and adaptation to target tissues

BMC Genomics ◽

10.1186/s12864-021-07559-5 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Giovanni Franzo ◽

Claudia Maria Tucciarone ◽

Matteo Legnardi ◽

Mattia Cecchinato

Keyword(s):

Codon Usage ◽

Codon Bias ◽

Synonymous Codon ◽

Synonymous Codon Usage ◽

Accessory Proteins ◽

Effective Number ◽

Genome Composition ◽

Infectious Bronchitis ◽

Selective Forces ◽

Effective Number Of Codons

Abstract Background Infectious bronchitis virus (IBV) is one of the most relevant viruses affecting the poultry industry, and several studies have investigated the factors involved in its biological cycle and evolution. However, very few of those studies focused on the effect of genome composition and the codon bias of different IBV proteins, despite the remarkable increase in available complete genomes. In the present study, all IBV complete genomes were downloaded (n = 383), and several statistics representative of genome composition and codon bias were calculated for each protein-coding sequence, including but not limited to, the nucleotide odds ratio, relative synonymous codon usage and effective number of codons. Additionally, viral codon usage was compared to host codon usage based on a collection of highly expressed genes in IBV target and nontarget tissues. Results The results obtained demonstrated a significant difference among structural, non-structural and accessory proteins, especially regarding dinucleotide composition, which appears under strong selective forces. In particular, some dinucleotide pairs, such as CpG, a probable target of the host innate immune response, are underrepresented in genes coding for pp1a, pp1ab, S and N. Although genome composition and dinucleotide bias appear to affect codon usage, additional selective forces may act directly on codon bias. Variability in relative synonymous codon usage and effective number of codons was found for different proteins, with structural proteins and polyproteins being more adapted to the codon bias of host target tissues. In contrast, accessory proteins had a more biased codon usage (i.e., lower number of preferred codons), which might contribute to the regulation of their expression level and timing throughout the cell cycle. Conclusions The present study confirms the existence of selective forces acting directly on the genome and not only indirectly through phenotype selection. This evidence might help understanding IBV biology and in developing attenuated strains without affecting the protein phenotype and therefore immunogenicity.

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Analysis of Synonymous Codon Usage Bias in Potato Virus M and Its Adaption to Hosts

Viruses ◽

10.3390/v11080752 ◽

2019 ◽

Vol 11 (8) ◽

pp. 752 ◽

Cited By ~ 8

Author(s):

Zhen He ◽

Haifeng Gan ◽

Xinyan Liang

Keyword(s):

Natural Selection ◽

Codon Usage ◽

Potato Virus ◽

Synonymous Codon ◽

Synonymous Codon Usage ◽

Economic Losses ◽

Codon Usage Pattern ◽

Usage Pattern ◽

Coding Sequences ◽

Potato Virus M

Potato virus M (PVM) is a member of the genus Carlavirus of the family Betaflexviridae and causes large economic losses of nightshade crops. Several previous studies have elucidated the population structure, evolutionary timescale and adaptive evolution of PVM. However, the synonymous codon usage pattern of PVM remains unclear. In this study, we performed comprehensive analyses of the codon usage and composition of PVM based on 152 nucleotide sequences of the coat protein (CP) gene and 125 sequences of the cysteine-rich nucleic acid binding protein (NABP) gene. We observed that the PVM CP and NABP coding sequences were GC-and AU-rich, respectively, whereas U- and G-ending codons were preferred in the PVM CP and NABP coding sequences. The lower codon usage of the PVM CP and NABP coding sequences indicated a relatively stable and conserved genomic composition. Natural selection and mutation pressure shaped the codon usage patterns of PVM, with natural selection being the most important factor. The codon adaptation index (CAI) and relative codon deoptimization index (RCDI) analysis revealed that the greatest adaption of PVM was to pepino, followed by tomato and potato. Moreover, similarity Index (SiD) analysis showed that pepino had a greater impact on PVM than tomato and potato. Our study is the first attempt to evaluate the codon usage pattern of the PVM CP and NABP genes to better understand the evolutionary changes of a carlavirus.

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Phylodynamics and Codon Usage Pattern Analysis of Broad Bean Wilt Virus 2

Viruses ◽

10.3390/v13020198 ◽

2021 ◽

Vol 13 (2) ◽

pp. 198

Author(s):

Zhen He ◽

Zhuozhuo Dong ◽

Lang Qin ◽

Haifeng Gan

Keyword(s):

Codon Usage ◽

Broad Bean ◽

Synonymous Codon ◽

Similarity Index ◽

Full Length ◽

Codon Usage Pattern ◽

Usage Pattern ◽

Coding Sequences ◽

Wilt Virus ◽

Broad Bean Wilt Virus

Broad bean wilt virus 2 (BBWV-2), which belongs to the genus Fabavirus of the family Secoviridae, is an important pathogen that causes damage to broad bean, pepper, yam, spinach and other economically important ornamental and horticultural crops worldwide. Previously, only limited reports have shown the genetic variation of BBWV2. Meanwhile, the detailed evolutionary changes, synonymous codon usage bias and host adaptation of this virus are largely unclear. Here, we performed comprehensive analyses of the phylodynamics, reassortment, composition bias and codon usage pattern of BBWV2 using forty-two complete genome sequences of BBWV-2 isolates together with two other full-length RNA1 sequences and six full-length RNA2 sequences. Both recombination and reassortment had a significant influence on the genomic evolution of BBWV2. Through phylogenetic analysis we detected three and four lineages based on the ORF1 and ORF2 nonrecombinant sequences, respectively. The evolutionary rates of the two BBWV2 ORF coding sequences were 8.895 × 10−4 and 4.560 × 10−4 subs/site/year, respectively. We found a relatively conserved and stable genomic composition with a lower codon usage choice in the two BBWV2 protein coding sequences. ENC-plot and neutrality plot analyses showed that natural selection is the key factor shaping the codon usage pattern of BBWV2. Strong correlations between BBWV2 and broad bean and pepper were observed from similarity index (SiD), codon adaptation index (CAI) and relative codon deoptimization index (RCDI) analyses. Our study is the first to evaluate the phylodynamics, codon usage patterns and adaptive evolution of a fabavirus, and our results may be useful for the understanding of the origin of this virus.

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Codon Usage Bias Covaries With Expression Breadth and the Rate of Synonymous Evolution in Humans, but This Is Not Evidence for Selection

Genetics ◽

10.1093/genetics/159.3.1191 ◽

2001 ◽

Vol 159 (3) ◽

pp. 1191-1199

Author(s):

Araxi O Urrutia ◽

Laurence D Hurst

Keyword(s):

Codon Usage ◽

Codon Bias ◽

Synonymous Codon ◽

Nucleotide Composition ◽

Synonymous Codon Usage ◽

Synonymous Substitutions ◽

Numerous Species ◽

Nucleotide Content ◽

Expression Breadth ◽

Human Genes

Abstract In numerous species, from bacteria to Drosophila, evidence suggests that selection acts even on synonymous codon usage: codon bias is greater in more abundantly expressed genes, the rate of synonymous evolution is lower in genes with greater codon bias, and there is consistency between genes in the same species in which codons are preferred. In contrast, in mammals, while nonequal use of alternative codons is observed, the bias is attributed to the background variance in nucleotide concentrations, reflected in the similar nucleotide composition of flanking noncoding and exonic third sites. However, a systematic examination of the covariants of codon usage controlling for background nucleotide content has yet to be performed. Here we present a new method to measure codon bias that corrects for background nucleotide content and apply this to 2396 human genes. Nearly all (99%) exhibit a higher amount of codon bias than expected by chance. The patterns associated with selectively driven codon bias are weakly recovered: Broadly expressed genes have a higher level of bias than do tissue-specific genes, the bias is higher for genes with lower rates of synonymous substitutions, and certain codons are repeatedly preferred. However, while these patterns are suggestive, the first two patterns appear to be methodological artifacts. The last pattern reflects in part biases in usage of nucleotide pairs. We conclude that we find no evidence for selection on codon usage in humans.

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Analysis of synonymous codon usage inShigella flexneri2a strain 301 and otherShigellaandEscherichia colistrains

Canadian Journal of Microbiology ◽

10.1139/w11-095 ◽

2011 ◽

Vol 57 (12) ◽

pp. 1016-1023 ◽

Cited By ~ 2

Author(s):

Xue Lian Luo ◽

Jian Guo Xu ◽

Chang Yun Ye

Keyword(s):

Codon Usage ◽

Codon Usage Bias ◽

Synonymous Codon ◽

Shigella Flexneri ◽

Synonymous Codon Usage ◽

Codon Usage Pattern ◽

Mutational Pressure ◽

E Coli ◽

Shigella Flexneri 2A ◽

Usage Patterns

In this study, we analysed synonymous codon usage in Shigella flexneri 2a strain 301 (Sf301) and performed a comparative analysis of synonymous codon usage patterns in Sf301 and other strains of Shigella and Escherichia coli . Although there was a significant variety in codon usage bias among different Sf301 genes, there was a slight but observable codon usage bias that could primarily be attributable to mutational pressure and translational selection. In addition, the relative abundance of dinucleotides in Sf301 was observed to be independent of the overall base composition but was still caused by differential mutational pressure; this also shaped codon usage. By comparing the relative synonymous codon usage values across different Shigella and E. coli strains, we suggested that the synonymous codon usage pattern in the Shigella genomes was strain specific. This study represents a comprehensive analysis of Shigella codon usage patterns and provides a basic understanding of the mechanisms underlying codon usage bias.

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Presyncodon, a Web Server for Gene Design with the Evolutionary Information of the Expression Hosts

International Journal of Molecular Sciences ◽

10.3390/ijms19123872 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3872 ◽

Cited By ~ 2

Author(s):

Jian Tian ◽

Qingbin Li ◽

Xiaoyu Chu ◽

Ningfeng Wu

Keyword(s):

High Frequency ◽

Synonymous Codon ◽

Low Frequency ◽

Synonymous Codon Usage ◽

Codon Usage Pattern ◽

Evolutionary Information ◽

Specific Expression ◽

Synonymous Codons ◽

New Genes ◽

And Function

In the natural host, most of the synonymous codons of a gene have been evolutionarily selected and related to protein expression and function. However, for the design of a new gene, most of the existing codon optimization tools select the high-frequency-usage codons and neglect the contribution of the low-frequency-usage codons (rare codons) to the expression of the target gene in the host. In this study, we developed the method Presyncodon, available in a web version, to predict the gene code from a protein sequence, using built-in evolutionary information on a specific expression host. The synonymous codon-usage pattern of a peptide was studied from three genomic datasets (Escherichia coli, Bacillus subtilis, and Saccharomyces cerevisiae). Machine-learning models were constructed to predict a selection of synonymous codons (low- or high-frequency-usage codon) in a gene. This method could be easily and efficiently used to design new genes from protein sequences for optimal expression in three expression hosts (E. coli, B. subtilis, and S. cerevisiae). Presyncodon is free to academic and noncommercial users; accessible at http://www.mobioinfor.cn/presyncodon_www/index.html.

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Intragenomic variation in mutation biases causes underestimation of selection on synonymous codon usage

10.1101/2021.10.29.466462 ◽

2021 ◽

Author(s):

Alexander L Cope ◽

Premal Shah

Keyword(s):

Population Genetics ◽

Natural Selection ◽

Codon Usage ◽

Codon Bias ◽

Synonymous Codon ◽

Synonymous Codon Usage ◽

Mutation Bias ◽

Biased Gene Conversion ◽

Intragenomic Variation ◽

The Impact

Patterns of non-uniform usage of synonymous codons (codon bias) varies across genes in an organism and across species from all domains of life. The bias in codon usage is due to a combination of both non-adaptive (e.g. mutation biases) and adaptive (e.g. natural selection for translation efficiency/accuracy) evolutionary forces. Most population genetics models quantify the effects of mutation bias and selection on shaping codon usage patterns assuming a uniform mutation bias across the genome. However, mutation biases can vary both along and across chromosomes due to processes such as biased gene conversion, potentially obfuscating signals of translational selection. Moreover, estimates of variation in genomic mutation biases are often lacking for non-model organisms. Here, we combine an unsupervised learning method with a population genetics model of synonymous codon bias evolution to assess the impact of intragenomic variation in mutation bias on the strength and direction of natural selection on synonymous codon usage across 49 Saccharomycotina budding yeasts. We find that in the absence of a priori information, unsupervised learning approaches can be used to identify regions evolving under different mutation biases. We find that the impact of intragenomic variation in mutation bias varies widely, even among closely-related species. We show that the overall strength and direction of selection on codon usage can be underestimated by failing to account for intragenomic variation in mutation biases. Interestingly, genes falling into clusters identified by machine learning are also often physically clustered across chromosomes, consistent with processes such as biased gene conversion. Our results indicate the need for more nuanced models of sequence evolution that systematically incorporate the effects of variable mutation biases on codon frequencies.

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Analysis of codon usage bias of classical swine fever virus

Veterinary World ◽

10.14202/vetworld.2021.1450-1458 ◽

2021 ◽

pp. 1450-1458

Author(s):

Sharanagouda S. Patil ◽

Uma Bharathi Indrabalan ◽

Kuralayanapalya Puttahonnappa Suresh ◽

Bibek Ranjan Shome

Keyword(s):

Codon Usage ◽

Codon Usage Bias ◽

Synonymous Codon ◽

Principal Component ◽

Infectious Agent ◽

Classical Swine Fever ◽

Economic Loss ◽

Codon Usage Pattern ◽

Usage Pattern ◽

Coding Regions

Background and Aim: Classical swine fever (CSF), caused by CSF virus (CSFV), is a highly contagious disease in pigs causing 100% mortality in susceptible adult pigs and piglets. High mortality rate in pigs causes huge economic loss to pig farmers. CSFV has a positive-sense RNA genome of 12.3 kb in length flanked by untranslated regions at 5' and 3' end. The genome codes for a large polyprotein of 3900 amino acids coding for 11 viral proteins. The 1300 codons in the polyprotein are coded by different combinations of three nucleotides which help the infectious agent to evolve itself and adapt to the host environment. This study performed and employed various methods/techniques to estimate the changes occurring in the process of CSFV evolution by analyzing the codon usage pattern. Materials and Methods: The evolution of viruses is widely studied by analyzing their nucleotides and coding regions/ codons using various methods. A total of 115 complete coding regions of CSFVs including one complete genome from our laboratory (MH734359) were included in this study and analysis was carried out using various methods in estimating codon usage bias and evolution. This study elaborates on the factors that influence the codon usage pattern. Results: The effective number of codons (ENC) and relative synonymous codon usage showed the presence of codon usage bias. The mononucleotide (A) has a higher frequency compared to the other mononucleotides (G, C, and T). The dinucleotides CG and CC are underrepresented and overrepresented. The codons CGT was underrepresented and AGG was overrepresented. The codon adaptation index value of 0.71 was obtained indicating that there is a similarity in the codon usage bias. The principal component analysis, ENC-plot, Neutrality plot, and Parity Rule 2 plot produced in this article indicate that the CSFV is influenced by the codon usage bias. The mutational pressure and natural selection are the important factors that influence the codon usage bias. Conclusion: The study provides useful information on the codon usage analysis of CSFV and may be utilized to understand the host adaptation to virus environment and its evolution. Further, such findings help in new gene discovery, design of primers/probes, design of transgenes, determination of the origin of species, prediction of gene expression level, and gene function of CSFV. To the best of our knowledge, this is the first study on codon usage bias involving such a large number of complete CSFVs including one sequence of CSFV from India.

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