Bioinformatic Analysis of the Neutrality of Rna Secondary Structure Elements Across Genotypes Reveals Evidence for Direct Evolution of Genetic Robustness in HCV

Churkin, Alexander; Cohen, Moriah; Shemer‐Avni, Yonat; Barash, Danny

doi:10.1142/s0219720010005087

Cited by 12 publications

(12 citation statements)

References 27 publications

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“…These approaches took advantage of a physicochemical model [9] that allows predicting the resulting phenotype (structure) from a given genotype (sequence). Recent computational studies have been mainly focused on precursors of miRNAs [10-13] and on viruses [14-16], and have suggested that natural RNA sequences are robust to mutations. However, as we show in this study, the statistical significance of the results depends on the choice of the reference sample of sequences.…”

Section: Introductionmentioning

confidence: 99%

Describing the structural robustness landscape of bacterial small RNAs

Rodrigo

Fares

2012

BMC Evol Biol

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BackgroundThe potential role of RNA molecules as gene expression regulators has led to a new perspective on the intracellular control and genome organization. Because secondary structures are crucial for their regulatory role, we sought to investigate their robustness to mutations and environmental changes.ResultsHere, we dissected the structural robustness landscape of the small non-coding RNAs (sncRNAs) encoded in the genome of the bacterium Escherichia coli. We found that bacterial sncRNAs are not significantly robust to both mutational and environmental perturbations when compared against artificial, unbiased sequences. However, we found that, on average, bacterial sncRNAs tend to be significantly plastic, and that mutational and environmental robustness strongly correlate. We further found that, on average, epistasis in bacterial sncRNAs is significantly antagonistic, and positively correlates with plasticity. Moreover, the evolution of robustness is likely dependent upon the environmental stability of the cell, with more fluctuating environments leading to the emergence and fixation of more robust molecules. Mutational robustness also appears to be correlated with structural functionality and complexity.ConclusionOur study provides a deep characterization of the structural robustness landscape of bacterial sncRNAs, suggesting that evolvability could be evolved as a consequence of selection for more plastic molecules. It also supports that environmental fluctuations could promote mutational robustness. As a result, plasticity emerges to link robustness, functionality and evolvability.

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Section: Introductionmentioning

confidence: 99%

Describing the structural robustness landscape of bacterial small RNAs

Rodrigo

Fares

2012

BMC Evol Biol

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“…Many of the studies addressing the relevance of genetic robustness on the evolution of RNA molecules are computer analyses and simulated evolution (11,(14)(15)(16)(17). This approach has led to the identification of selection for robustness in hepatitis C virus genomes (18) and microRNA (19).…”

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confidence: 99%

Congruent Evolution of Fitness and Genetic Robustness in Vesicular Stomatitis Virus

Novella

Presloid

Beech

et al. 2013

J Virol

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bQuasispecies theory is a case of mutation-selection balance for evolution at high mutation rates, such as those observed in RNA viruses. One of the main predictions of this model is the selection for robustness, defined as the ability of an organism to remain phenotypically unchanged in the face of mutation. We have used a collection of vesicular stomatitis virus strains that had been evolving either under positive selection or under random drift. We had previously shown that the former increase in fitness while the latter have overall fitness decreases (I. S. Novella, J. B. Presloid, T. Zhou, S. D. Smith-Tsurkan, B. E. Ebendick-Corpus, R. N. Dutta, K. L. Lust, and C. O. Wilke, J. Virol. 84:4960 -4968, 2010). Here, we determined the robustness of these strains and demonstrated that strains under positive selection not only increase in fitness but also increase in robustness. In contrast, strains under drift not only decreased in fitness but also decreased in robustness. There was a good overall correlation between fitness and robustness. We also tested whether there was a correlation between fitness and thermostability, and we observed that the correlation was imperfect, indicating that the fitness effects of mutations are exerted in part at a level other than changing the resistance of the protein to temperature. E rror-prone replication in RNA viruses results in the development of quasispecies populations (1-4), clouds of closely related mutants in mutation-selection balance (5-7). In quasispecies populations, increased genetic robustness can provide a selective advantage (8-11), because a smaller number of offspring are lost to deleterious or lethal mutations. Genetic robustness here is defined as phenotypic invariance despite mutational pressure (12). In terms of fitness landscapes, selection for robustness favors those populations that sit on broad fitness peaks instead of narrow fitness peaks. Studies on digital organisms showed the preference for this type of broad peaks and led to the expression "survival of the flattest" (13). Many of the studies addressing the relevance of genetic robustness on the evolution of RNA molecules are computer analyses and simulated evolution (11,(14)(15)(16)(17). This approach has led to the identification of selection for robustness in hepatitis C virus genomes (18) and microRNA (19).Vesicular stomatitis virus (VSV) provided the first evidence that a low-fitness strain could outcompete a high-fitness strain (20), and these results were confirmed with phage phi-6 (21). One can predict that, all else being equal, the evolution of robustness is a function of the strength of selection, and that environmental factors that diminish selection also result in less robustness. Complementation is one such factor (22-25), because the phenotype of one strain is not always determined by its genetic makeup and, instead, is the result of a gene product from another strain. High levels of complementation, which occur at a high multiplicity of infection (MOI), would result in lower overall...

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“…The main achievement of this system is to use a small portion of genetic information to play a number of different roles. These structural regions, the so-called functional RNA domains, provide a robust genetic background [13][14][15], which overcomes the variable and complex viral pool dynamics. It is noteworthy that the same features that achieve proficient viral fitness also provide a potential tool for destroying them.…”

Section: Introductionmentioning

confidence: 99%

Current and Emerging Themes in the Structural Analysis of Viral RNA Genomes: Applications for the Development of Novel Therapeutic Drugs

Romero-López

Berzal‐Herranz

2015

Genomics Comput Biol

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RNA molecules assume different roles in many different biological processes. This functional diversity is intimately related to RNA folding. In recent years, advances in the field of structure analysis by high-throughput methodologies and the development of novel potent bioinformatic tools have enabled the first structural maps of the eukaryotic transcriptome and the further establishment of novel function-structure relationships. This important progress has been of special relevance in the field of molecular virology. Viral genomes are compact entities that require overlapping coding levels to bear all the genetic information required for viral propagation. This is achieved by the acquisition of functional RNA domains, structurally conserved encoding units that perform essential roles for the consecution of the viral cycle. Interfering with the activity of these structural elements offers a potential means of treating viral infections, such as that caused by the hepatitis C virus, HCV. This review summarizes major achievements in the development of emerging methodologies for the analysis of RNA folding and their application to the study of the HCV genome structure. It will also examine the progress toward the design of novel antiviral compounds based in nucleic acids able to interfere with the folding of functional RNA domains.

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Bioinformatic Analysis of the Neutrality of Rna Secondary Structure Elements Across Genotypes Reveals Evidence for Direct Evolution of Genetic Robustness in HCV

Cited by 12 publications

References 27 publications

Describing the structural robustness landscape of bacterial small RNAs

Describing the structural robustness landscape of bacterial small RNAs

Congruent Evolution of Fitness and Genetic Robustness in Vesicular Stomatitis Virus

Current and Emerging Themes in the Structural Analysis of Viral RNA Genomes: Applications for the Development of Novel Therapeutic Drugs

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