Transcription, mRNA export and immune evasion shape the codon usage of viruses
TL;DR: This paper analyzed the patterns of codon usage in 1,520 vertebrate-infecting viruses, focusing on parameters known to be under selection and associated with gene regulation, and found that GC content, dinucleotide content, and splicing and m6A modification-related sequence motifs are associated with the type of genetic material (DNA or RNA), strandedness, and replication compartment of viruses.
Abstract: The nucleotide composition, dinucleotide composition, and codon usage of many viruses differs from their hosts. These differences arise because viruses are subject to unique mutation and selection pressures that do not apply to host genomes; however, the molecular mechanisms that underlie these evolutionary forces are unclear. Here, we analysed the patterns of codon usage in 1,520 vertebrate-infecting viruses, focusing on parameters known to be under selection and associated with gene regulation. We find that GC content, dinucleotide content, and splicing and m6A modification-related sequence motifs are associated with the type of genetic material (DNA or RNA), strandedness, and replication compartment of viruses. In an experimental follow-up, we find that the effects of GC content on gene expression depend on whether the genetic material is delivered to the cell as DNA or mRNA, whether it is transcribed by endogenous or exogenous RNA polymerase, and whether transcription takes place in the nucleus or cytoplasm. Our results suggest that viral codon usage cannot be explained by a simple adaptation to the codon usage of the host - instead, it reflects the combination of multiple selective and mutational pressures, including the need for efficient transcription, export, and immune evasion.
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TL;DR: In this article, it was shown that the SARS-CoV-2 mutation rate is at least 49-67% higher than would be estimated based on the rate of appearance of variants in sampled genomes.
Abstract: Owing to a lag between a deleterious mutation's appearance and its selective removal, gold-standard methods for mutation rate estimation assume no meaningful loss of mutations between parents and offspring. Indeed, from analysis of closely related lineages, in SARS-CoV-2 the Ka/Ks ratio was previously estimated as 1.008, suggesting no within-host selection. By contrast, we find a higher number of observed SNPs at 4-fold degenerate sites than elsewhere and, allowing for the virus's complex mutational and compositional biases, estimate that the mutation rate is at least 49-67% higher than would be estimated based on the rate of appearance of variants in sampled genomes. Given the high Ka/Ks one might assume that the majority of such intra-host selection is the purging of nonsense mutations. However, we estimate that selection against nonsense mutations accounts for only â¼10% of all the "missing" mutations. Instead, classical protein-level selective filters (against chemically disparate amino acids and those predicted to disrupt protein functionality) account for many missing mutations. It is less obvious why for an intracellular parasite, amino acid cost parameters, notably amino acid decay rate, are also significant. Perhaps most surprisingly, we also find evidence for real time selection against synonymous mutations that move codon usage away from that of humans. We conclude that there is common intra-host selection on SARS-CoV-2 that acts on nonsense, missense and possibly synonymous mutations. This has implications for methods of mutation rate estimation, for determining times to common ancestry and the potential for intra-host evolution including vaccine escape.
27 citations
TL;DR: In this paper, the authors used a variety of genetic methods to identify the ancestor of SARS-CoV-2 and showed that trends in codon usage across chiroptera-hosted CoVs are collaboratively driven by geographically different host-species and temporal-spatial distribution.
Abstract: Many viruses that cause serious diseases in humans and animals, including the betacoronaviruses (beta-CoVs), such as SARS-CoV, MERS-CoV, and the recently identified SARS-CoV-2, have natural reservoirs in bats. Because these viruses rely entirely on the host cellular machinery for survival, their evolution is likely to be guided by the link between the codon usage of the virus and that of its host. As a result, specific cellular microenvironments of the diverse hosts and/or host tissues imprint peculiar molecular signatures in virus genomes. Our study is aimed at deciphering some of these signatures. Using a variety of genetic methods we demonstrated that trends in codon usage across chiroptera-hosted CoVs are collaboratively driven by geographically different host-species and temporal-spatial distribution. We not only found that chiroptera-hosted CoVs are the ancestors of SARS-CoV-2, but we also revealed that SARS-CoV-2 has the codon usage characteristics similar to those seen in CoVs infecting the Rhinolophus sp. Surprisingly, the envelope gene of beta-CoVs infecting Rhinolophus sp., including SARS-CoV-2, had extremely high CpG levels, which appears to be an evolutionarily conserved trait. The dissection of the furin cleavage site of various CoVs infecting hosts revealed host-specific preferences for arginine codons; however, arginine is encoded by a wider variety of synonymous codons in the murine CoV (MHV-A59) furin cleavage site. Our findings also highlight the latent diversity of CoVs in mammals that has yet to be fully explored.
12 citations
TL;DR: In this paper, a comprehensive investigation was carried out to reveal the systematic evolutionary processes of synonymous codon usage and host-adapted evolution phenotype of PEDV genome, and the authors found a low codon use bias (CUB) in PEDVs genome.
Abstract: Porcine epidemic diarrhea virus (PEDV), which classified in the genus Alphacoronavirus, family Coronaviridae, is one of the most important pathogens that cause heavy economic losses in pig industry. Although intensive mutation and recombination analysis of PEDV strains were provided, systematic genome analysis were needed to elucidate the evolution mechanism and codon usage adaptation profiles of the pathogen. Here, a comprehensive investigation was carried out to reveal the systematic evolutionary processes of synonymous codon usage and host-adapted evolution phenotype of PEDV genome. We found a low codon usage bias (CUB) in PEDV genome and that nucleotide compositions, natural selection, mutation pressure and geographical diversity shapes the codon usage patterns of PEDV, with natural selection dominated the overall codon usage bias in PEDV than the others. By using the relative codon deoptimization index (RCDI) and similarity index (SiD) analysis, we observed that genotype II PEDV strains showed the highest level of adaptation phenotype to Sus scrofa than another divergent clade. To the best of our knowledge, this is the first comprehensive report elaborating the codon usage and host adaptation of PEDV. The findings offer an insight into our understanding of factors involved in PEDV evolution, adaptation and fitness towards their hosts.
10 citations
TL;DR: In this article , a mini-review of the evolution of plant RNA viruses in view of compositional biases and explore how they adapt to the host is presented, and it appears that adenine rich (A-rich) coding sequences, low CpG and UpA dinucleotide frequencies and lower codon usage patterns were found in the vast majority of plant IR viruses.
Abstract: During recent decades, many new emerging or re-emerging RNA viruses have been found in plants through the development of deep-sequencing technology and big data analysis. These findings largely changed our understanding of the origin, evolution and host range of plant RNA viruses. There is evidence that their genetic composition originates from viruses, and host populations play a key role in the evolution and host adaptability of plant RNA viruses. In this mini-review, we describe the state of our understanding of the evolution of plant RNA viruses in view of compositional biases and explore how they adapt to the host. It appears that adenine rich (A-rich) coding sequences, low CpG and UpA dinucleotide frequencies and lower codon usage patterns were found in the vast majority of plant RNA viruses. The codon usage pattern of plant RNA viruses was influenced by both natural selection and mutation pressure, and natural selection mostly from hosts was the dominant factor. The codon adaptation analyses support that plant RNA viruses probably evolved a dynamic balance between codon adaptation and deoptimization to maintain efficient replication cycles in multiple hosts with various codon usage patterns. In the future, additional combinations of computational and experimental analyses of the nucleotide composition and codon usage of plant RNA viruses should be addressed.
7 citations
TL;DR: In this article , a systemic analysis of 107 SMV strains was performed to explore the genome-wide codon usage profile and the various factors influencing the codon use patterns of SMV, which provides insight into its molecular evolution and elucidates its unknown host adaptation pattern.
3 citations
References
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TL;DR: It is shown that guanosine (G)- and uridine (U)-rich ssRNA oligonucleotides derived from human immunodeficiency virus–1 (HIV-1) stimulate dendritic cells and macrophages to secrete interferon-α and proinflammatory, as well as regulatory, cytokines, and these data suggest that ssRNA represents a physiological ligand for TLR7 and TLR8.
Abstract: Double-stranded ribonucleic acid (dsRNA) serves as a danger signal associated with viral infection and leads to stimulation of innate immune cells. In contrast, the immunostimulatory potential of single-stranded RNA (ssRNA) is poorly understood and innate immune receptors for ssRNA are unknown. We report that guanosine (G)- and uridine (U)-rich ssRNA oligonucleotides derived from human immunodeficiency virus-1 (HIV-1) stimulate dendritic cells (DC) and macrophages to secrete interferon-alpha and proinflammatory, as well as regulatory, cytokines. By using Toll-like receptor (TLR)-deficient mice and genetic complementation, we show that murine TLR7 and human TLR8 mediate species-specific recognition of GU-rich ssRNA. These data suggest that ssRNA represents a physiological ligand for TLR7 and TLR8.
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TL;DR: It is shown that m6A is selectively recognized by the human YTH domain family 2 (YTHDF2) ‘reader’ protein to regulate mRNA degradation and established the role of YTH DF2 in RNA metabolism, showing that binding of Y THDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies.
Abstract: N(6)-methyladenosine (m(6)A) is the most prevalent internal (non-cap) modification present in the messenger RNA of all higher eukaryotes. Although essential to cell viability and development, the exact role of m(6)A modification remains to be determined. The recent discovery of two m(6)A demethylases in mammalian cells highlighted the importance of m(6)A in basic biological functions and disease. Here we show that m(6)A is selectively recognized by the human YTH domain family 2 (YTHDF2) 'reader' protein to regulate mRNA degradation. We identified over 3,000 cellular RNA targets of YTHDF2, most of which are mRNAs, but which also include non-coding RNAs, with a conserved core motif of G(m(6)A)C. We further establish the role of YTHDF2 in RNA metabolism, showing that binding of YTHDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies. The carboxy-terminal domain of YTHDF2 selectively binds to m(6)A-containing mRNA, whereas the amino-terminal domain is responsible for the localization of the YTHDF2-mRNA complex to cellular RNA decay sites. Our results indicate that the dynamic m(6)A modification is recognized by selectively binding proteins to affect the translation status and lifetime of mRNA.
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TL;DR: It is hypothesized that the presence of a rare codon, marked by the synonymous polymorphism, affects the timing of cotranslational folding and insertion of P-gp into the membrane, thereby altering the structure of substrate and inhibitor interaction sites.
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