Codon Pair Bias Is a Direct Consequence of Dinucleotide Bias

Kunec, Dušan; Osterrieder, Nikolaus

doi:10.1016/j.celrep.2015.12.011

Cited by 131 publications

(169 citation statements)

References 29 publications

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“…Mice display a strong under-representation of CpG dinucleotide usage compared with Ix. scapularis , while UpA is about equally under-represented in both hosts (Simmen 2008; Kunec and Osterrieder 2016). Therefore, if POWV was adapting toward the host’s preferred codon usage, we would expect to see an increased CpG usage during replication in ticks and decreased usage in mice, as demonstrated for insect-specific and no known vector flaviviruses, respectively (Lobo et al 2009; Blitvich and Firth 2015).…”

Section: Resultsmentioning

confidence: 98%

“…As indicated by d N /d S ratios <1, purifying selection was very strong in mice but became quite variable ( d N /d S = 0.1–1.5) during tick transstadial transmission. We also examined selection for host codon usage specifically based on dicucleotide bias for CpG and UpA (Kunec and Osterrieder 2016). Mice display a strong under-representation of CpG dinucleotide usage compared with Ix.…”

Section: Resultsmentioning

confidence: 99%

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Transmission bottlenecks and RNAi collectively influence tick-borne flavivirus evolution

Grubaugh¹,

Rückert²,

Armstrong

et al. 2016

Virus Evolution

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Arthropod-borne RNA viruses exist within hosts as heterogeneous populations of viral variants and, as a result, possess great genetic plasticity. Understanding the micro-evolutionary forces shaping these viruses can provide insights into how they emerge, adapt, and persist in new and changing ecological niches. While considerable attention has been directed toward studying the population dynamics of mosquito-borne viruses, little is known about tick-borne virus populations. Therefore, using a mouse and Ixodes scapularis tick transmission model, we examined Powassan virus (POWV; Flaviviridae, Flavivirus) populations in and between both the vertebrate host and arthropod vector. We found that genetic bottlenecks, RNAi-mediated diversification, and selective constraints collectively influence POWV evolution. Together, our data provide a mechanistic explanation for the slow, long-term evolutionary trends of POWV, and suggest that all arthropod-borne viruses encounter similar selective pressures at the molecular level (i.e. RNAi), yet evolve much differently due to their unique rates and modes of transmission.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Transmission bottlenecks and RNAi collectively influence tick-borne flavivirus evolution

Grubaugh¹,

Rückert²,

Armstrong

et al. 2016

Virus Evolution

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“…Effects on mRNA stability also can be a factor (9). In addition, recent studies suggested that codon pair bias may be a direct consequence of dinucleotide bias (10), suggesting that the increase in the frequency of CpG and UpA dinucleotides that frequently occurs with CPD may cause attenuation by inducing stronger innate immune responses (11). Regardless of the mechanism of attenuation caused by CPD, the genetic stability of live attenuated virus vaccines is paramount to avoid deattenuation, and thus, it is important to evaluate the genetic and phenotypic stability of such vaccine candidates in detail.…”

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confidence: 99%

Genetic stability of genome-scale deoptimized RNA virus vaccine candidates under selective pressure

Nouën

McCarty

Brown

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Recoding viral genomes by numerous synonymous but suboptimal substitutions provides live attenuated vaccine candidates. These vaccine candidates should have a low risk of deattenuation because of the many changes involved. However, their genetic stability under selective pressure is largely unknown. We evaluated phenotypic reversion of deoptimized human respiratory syncytial virus (RSV) vaccine candidates in the context of strong selective pressure. Codon pair deoptimized (CPD) versions of RSV were attenuated and temperature-sensitive. During serial passage at progressively increasing temperature, a CPD RSV containing 2,692 synonymous mutations in 9 of 11 ORFs did not lose temperature sensitivity, remained genetically stable, and was restricted at temperatures of 34°C/35°C and above. However, a CPD RSV containing 1,378 synonymous mutations solely in the polymerase L ORF quickly lost substantial attenuation. Comprehensive sequence analysis of virus populations identified many different potentially deattenuating mutations in the L ORF as well as, surprisingly, many appearing in other ORFs. Phenotypic analysis revealed that either of two competing mutations in the virus transcription antitermination factor M2-1, outside of the CPD area, substantially reversed defective transcription of the CPD L gene and substantially restored virus fitness in vitro and in case of one of these two mutations, also in vivo. Paradoxically, the introduction into Min L of one mutation each in the M2-1, N, P, and L proteins resulted in a virus with increased attenuation in vivo but increased immunogenicity. Thus, in addition to providing insights on the adaptability of genome-scale deoptimized RNA viruses, stability studies can yield improved synthetic RNA virus vaccine candidates.negative-strand RNA virus | respiratory syncytial virus | live attenuated vaccine | codon pair deoptimization | genetic stability T he availability and affordability of large-scale custom DNA synthesis opened the new field of synthetic biology (1). The combined approach of sequence design and synthetic biology allows the generation of DNA molecules with extensive targeted modifications. Synonymous genome recoding, in which one or more ORFs of a microbial pathogen are modified at the nucleotide level without affecting amino acid coding, currently is being widely evaluated to reduce pathogen fitness and create potential live attenuated vaccines, particularly for RNA viruses (reviewed in ref.2) (3-7). The main strategies for attenuation by synonymous genome recoding are codon deoptimization (CD), codon pair deoptimization (CPD), and increasing the dinucleotide CpG and UpA content (which is usually the result of CD and CPD) (2).The mechanisms of attenuation by these strategies are currently under intensive research. It has been suggested that the primary effect of CD and CPD is to reduce translation efficiency of pathogen mRNAs, thereby providing attenuation (8). Effects on mRNA stability also can be a factor (9). In addition, recent studies suggested that codon pa...

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“…Viruses mimic the codon usage profile of their respective hosts and rely largely on the chaperon apparatus of their hosts for proficient replication and enhanced robustness (Kunec and Osterrieder, 2016). In this pretext, similarity index of a concerned virus with its respective host has been suggested to be an effective tool to properly assess the impact of host genomic influence on the patterns of associated viral codonic signatures.…”

Section: Discussionmentioning

confidence: 99%

HIV Progression Depends on Codon and Amino Acid Usage Profile of Envelope Protein and Associated Host-Genetic Influence

2017

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Acquired immune deficiency syndrome (AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV). Two types of HIV have been characterized: HIV-1 and HIV-2. The present study investigated whether evolutionary selection pressure differs between rapid progressor (RP), slow progressor (SP), and long-term non-progressor (LTNP) of HIV-I infected individuals. An unexpected association between the evolutionary rate of substitution in envelope (env) gene and disease progression is observed. Our present study suggests that env genes of LTNP are subject to unusually strong functional constraint with respect to RP. We also observed that the three categories of env genes i.e., RP, SP, and LTNP, had their own characteristic pattern of amino acid usage and SP and LTNP sequences shared similar patterns of amino acid usage different from RP sequences and evolutionary rate significantly influenced the amino acid usage pattern of the three different types of env gene sequences. It was also noted that the evolutionary rate for the glycosylation sites of LTNP and SP sequences were even significantly less than the RP sequences. Comparative analysis on the influence of human host on the three categories of env genes are well correlated with the rates of disease progression suggesting the adaptive strategies of the viruses for successful residence and infection. Host associated selective constraints appeared most relaxed on the RP sequences and strongest in LTNP sequences. The present study clearly portrays how evolutionary selection pressure differs between three categories of env genes i.e., RP, SP, and LTNP. The env genes, coding for the env glycoproteins, experience severe selection constraints from the host due to their constant exposure to the host immune system. In this perspective it might be suggested that env gene evolution occurs mainly by negative selection with the occurrence of mutation that might not reach fixation in the viral population. This work also confers a deeper insight into the crucial effects of host factors that govern the overall progression of HIV infection.

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Codon Pair Bias Is a Direct Consequence of Dinucleotide Bias

Cited by 131 publications

References 29 publications

Transmission bottlenecks and RNAi collectively influence tick-borne flavivirus evolution

Transmission bottlenecks and RNAi collectively influence tick-borne flavivirus evolution

Genetic stability of genome-scale deoptimized RNA virus vaccine candidates under selective pressure

HIV Progression Depends on Codon and Amino Acid Usage Profile of Envelope Protein and Associated Host-Genetic Influence

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