scholarly journals Evaluation of Conserved RNA Secondary Structures within and between Geographic Lineages of Zika Virus

2021 ◽  
Author(s):  
Kevin Calderon Gallegos ◽  
Johan Fabian Galindo ◽  
Clara Isabel Bermudez-Santana
Keyword(s):  
Zika Virus ◽  
Rna Structure ◽  
Genome Structure ◽  
Past Century ◽  
Rna Structures ◽  
Genome Variability ◽  
Vital Functions ◽  
Host Cell Interactions ◽  
Rna Genome ◽  
Genomic Regions

Zika virus (ZIKV), without a vaccine or no effective treatment approved as yet, have globally spread since the past century. The infection caused by ZIKV in humans has changed progressively from mild to subclinical in the last years, causing epidemics with greater infectivity, tropism towards new tissues, and other related symptoms as a product of various emergent ZIKV-host cell interactions. However, it is still unknown why or how the RNA genome structure impacts those interactions in differential evolutionary origin strains. Moreover, genomic comparison of ZIKV strains from the sequence-based phylogenetic analysis is well known, but differences from RNA structure comparisons are less known. Thus, in order to understand the RNA genome variability of lineages of various geographic distributions better, 412 complete genomes in a phylogenomic scanning were used for studying the conservation of structured RNAs. We found specific genomic regions, which highlight their patterns of conserved RNA structures at the level of inter-geographical comparisons. We have proposed these structures as candidates for further experimental validation to establish their potential role in vital functions of the viral cycle of ZIKV and their possible associations with the singularities of different outbreaks that occurred in specific geographic regions.

scholarly journals Evaluation of Conserved RNA Secondary Structures within and between Geographic Lineages of Zika Virus

Life ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 344
Author(s):  
Kevin Nicolas Calderon ◽  
Johan Fabian Galindo ◽  
Clara Isabel Bermudez-Santana
Keyword(s):  
Zika Virus ◽  
Rna Structure ◽  
Potential Role ◽  
Genome Structure ◽  
Nucleotide Substitutions ◽  
Genomic Comparison ◽  
Genome Variability ◽  
Vital Functions ◽  
Host Cell Interactions ◽  
Rna Genome

Zika virus (ZIKV), without a vaccine or an effective treatment approved to date, has globally spread in the last century. The infection caused by ZIKV in humans has changed progressively from mild to subclinical in recent years, causing epidemics with greater infectivity, tropism towards new tissues and other related symptoms as a product of various emergent ZIKV–host cell interactions. However, it is still unknown why or how the RNA genome structure impacts those interactions in differential evolutionary origin strains. Moreover, the genomic comparison of ZIKV strains from the sequence-based phylogenetic analysis is well known, but differences from RNA structure comparisons have barely been studied. Thus, in order to understand the RNA genome variability of lineages of various geographic distributions better, 410 complete genomes in a phylogenomic scanning were used to study the conservation of structured RNAs. Our results show the contemporary landscape of conserved structured regions with unique conserved structured regions in clades or in lineages within circulating ZIKV strains. We propose these structures as candidates for further experimental validation to establish their potential role in vital functions of the viral cycle of ZIKV and their possible associations with the singularities of different outbreaks that lead to ZIKV populations to acquire nucleotide substitutions, which is evidence of the local structure genome differentiation.

scholarly journals The global and local distribution of RNA structure throughout the SARS-CoV-2 genome

2020 ◽  
Author(s):  
Rafael de Cesaris Araujo Tavares ◽  
Gandhar Mahadeshwar ◽  
Anna Marie Pyle
Keyword(s):  
Rna Structure ◽  
Drug Targets ◽  
Structural Complexity ◽  
Viral Agent ◽  
Rna Structures ◽  
Viral Rnas ◽  
Functional Regions ◽  
Structural Density ◽  
Rna Genome ◽  
High Base

AbstractSARS-CoV-2 is the causative viral agent of COVID-19, the disease at the center of the current global pandemic. While knowledge of highly structured regions is integral for mechanistic insights into the viral infection cycle, very little is known about the location and folding stability of functional elements within the massive, ~30kb SARS-CoV-2 RNA genome. In this study, we analyze the folding stability of this RNA genome relative to the structural landscape of other well-known viral RNAs. We present an in-silico pipeline to locate regions of high base pair content across this long genome and also identify well-defined RNA structures, a method that allows for direct comparisons of RNA structural complexity within the several domains in SARS-CoV-2 genome. We report that the SARS-CoV-2 genomic propensity to stable RNA folding is exceptional among RNA viruses, superseding even that of HCV, one of the most highly structured viral RNAs in nature. Furthermore, our analysis reveals varying levels of RNA structure across genomic functional regions, with accessory and structural ORFs containing the highest structural density in the viral genome. Finally, we take a step further to examine how individual RNA structures formed by these ORFs are affected by the differences in genomic and subgenomic contexts. The conclusions reported in this study provide a foundation for structure-function hypotheses in SARS-CoV-2 biology, and in turn, may guide the 3D structural characterization of potential RNA drug targets for COVID-19 therapeutics.

scholarly journals The global and local distribution of RNA structure throughout the SARS-CoV-2 genome

2020 ◽  
Author(s):  
Rafael de Cesaris Araujo Tavares ◽  
Gandhar Mahadeshwar ◽  
Han Wan ◽  
Nicholas C. Huston ◽  
Anna Marie Pyle
Keyword(s):  
In Silico ◽  
Rna Structure ◽  
Drug Targets ◽  
Rna Folding ◽  
Rna Viruses ◽  
Viral Agent ◽  
Rna Structures ◽  
Viral Rnas ◽  
Viral Genomes ◽  
Rna Genome

SARS-CoV-2 is the causative viral agent of COVID-19, the disease at the center of the current global pandemic. While knowledge of highly structured regions is integral for mechanistic insights into the viral infection cycle, very little is known about the location and folding stability of functional elements within the massive, ∼30kb SARS-CoV-2 RNA genome. In this study, we analyze the folding stability of this RNA genome relative to the structural landscape of other well-known viral RNAs. We present an in-silico pipeline to predict regions of high base pair content across long genomes and to pinpoint hotspots of well-defined RNA structures, a method that allows for direct comparisons of RNA structural complexity within the several domains in SARS-CoV-2 genome. We report that the SARS-CoV-2 genomic propensity for stable RNA folding is exceptional among RNA viruses, superseding even that of HCV, one of the most structured viral RNAs in nature. Furthermore, our analysis suggests varying levels of RNA structure across genomic functional regions, with accessory and structural ORFs containing the highest structural density in the viral genome. Finally, we take a step further to examine how individual RNA structures formed by these ORFs are affected by the differences in genomic and subgenomic contexts, which given the technical difficulty of experimentally separating cellular mixtures of sgRNA from gRNA, is a unique advantage of our in-silico pipeline. The resulting findings provide a useful roadmap for planning focused empirical studies of SARS-CoV-2 RNA biology, and a preliminary guide for exploring potential SARS-CoV-2 RNA drug targets. Importance The RNA genome of SARS-CoV-2 is among the largest and most complex viral genomes, and yet its RNA structural features remain relatively unexplored. Since RNA elements guide function in most RNA viruses, and they represent potential drug targets, it is essential to chart the architectural features of SARS-CoV-2 and pinpoint regions that merit focused study. Here we show that RNA folding stability of SARS-CoV-2 genome is exceptional among viral genomes and we develop a method to directly compare levels of predicted secondary structure across SARS-CoV-2 domains. Remarkably, we find that coding regions display the highest structural propensity in the genome, forming motifs that differ between the genomic and subgenomic contexts. Our approach provides an attractive strategy to rapidly screen for candidate structured regions based on base pairing potential and provides a readily interpretable roadmap to guide functional studies of RNA viruses and other pharmacologically relevant RNA transcripts.

scholarly journals Trends of genetic changes uncovered by Env- and Eigen-GWAS in wheat and barley

2020 ◽  
Author(s):  
Rajiv Sharma ◽  
James Cockram ◽  
Keith A. Gardner ◽  
Joanne Russell ◽  
Luke Ramsay ◽  
...  
Keyword(s):  
Plant Breeding ◽  
Crop Improvement ◽  
Genome Structure ◽  
Genomic Relationship Matrix ◽  
Past Century ◽  
Relationship Matrix ◽  
Crop Breeding ◽  
Phenotypic Data ◽  
Improvement Programs ◽  
Genomic Regions

AbstractThe process of crop breeding over the last century has delivered new varieties with increased genetic gains, resulting in higher crop performance and yield. However in many cases, the underlying alleles and genomic regions that have underpinned this success remain unknown. This is due, in part, to the difficulty in generating sufficient phenotypic data on large numbers of historical varieties to allow such analyses to be undertaken. Here we demonstrate the ability to circumvent such bottlenecks by identifying genomic regions selected over 100 years of crop breeding using the age of a variety as a surrogate for yield. Using ‘environmental genome-wide association scans’ (EnvGWAS) on variety age in two of the world’s most important crops, wheat and barley, we found strong signals of selection across the genomes of our target crops. EnvGWAS identified 16 genomic regions in barley and 10 in wheat with contrasting patterns between spring and winter types of the two crops. To further examine changes in genome structure in wheat and barley over the past century, we used the same genotypic data to derive eigenvectors for deployment in EigenGWAS. This resulted in the detection of seven major chromosomal introgressions that contributed to adaptation in wheat. The deployment of both EigenGWAS and EnvGWAS based on variety age avoids costly phenotyping and will facilitate the identification of genomic tracts that have been under selection during plant breeding in underutilized historical cultivar collections. Our results not only demonstrate the potential of using historical cultivar collections coupled with genomic data to identify chromosomal regions that have been under selection but to also guide future plant breeding strategies to maximise the rate of genetic gain and adaptation in crop improvement programs.Significance Statement100 years of plant breeding have greatly improved crop adaptation, resilience, and productivity. Generating the trait data required for these studies is prohibitively expensive and can be impossible on large historical traits. This study reports using variety age and eigenvectors of the genomic relationship matrix as surrogate traits in GWAS to locate the genomic regions that have undergone selection during varietal development in wheat and barley. In several cases these were confirmed as associated with yield and other selected traits. The success and the simplicity of the approach means it can easily be extended to other crops with a recent recorded history of plant breeding and available genomic resources.

scholarly journals RNA thermoswitches modulate Staphylococcus aureus adaptation to ambient temperatures

2021 ◽  
Vol 49 (6) ◽  
pp. 3409-3426
Author(s):  
Arancha Catalan-Moreno ◽  
Marta Cela ◽  
Pilar Menendez-Gil ◽  
Naiara Irurzun ◽  
Carlos J Caballero ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Rna Structure ◽  
Cold Shock ◽  
Mrna Translation ◽  
Site Directed Mutagenesis ◽  
Rna Structures ◽  
Double Stranded Rna ◽  
Ambient Temperatures ◽  
Shock Proteins ◽  
Rna Hairpin

Abstract Thermoregulation of virulence genes in bacterial pathogens is essential for environment-to-host transition. However, the mechanisms governing cold adaptation when outside the host remain poorly understood. Here, we found that the production of cold shock proteins CspB and CspC from Staphylococcus aureus is controlled by two paralogous RNA thermoswitches. Through in silico prediction, enzymatic probing and site-directed mutagenesis, we demonstrated that cspB and cspC 5′UTRs adopt alternative RNA structures that shift from one another upon temperature shifts. The open (O) conformation that facilitates mRNA translation is favoured at ambient temperatures (22°C). Conversely, the alternative locked (L) conformation, where the ribosome binding site (RBS) is sequestered in a double-stranded RNA structure, is folded at host-related temperatures (37°C). These structural rearrangements depend on a long RNA hairpin found in the O conformation that sequesters the anti-RBS sequence. Notably, the remaining S. aureus CSP, CspA, may interact with a UUUGUUU motif located in the loop of this long hairpin and favour the folding of the L conformation. This folding represses CspB and CspC production at 37°C. Simultaneous deletion of the cspB/cspC genes or their RNA thermoswitches significantly decreases S. aureus growth rate at ambient temperatures, highlighting the importance of CspB/CspC thermoregulation when S. aureus transitions from the host to the environment.

scholarly journals Integrative Analysis of Zika Virus Genome RNA Structure Reveals Critical Determinants of Viral Infectivity

2018 ◽  
Vol 24 (6) ◽  
pp. 875-886.e5 ◽  
Author(s):  
Pan Li ◽  
Yifan Wei ◽  
Miao Mei ◽  
Lei Tang ◽  
Lei Sun ◽  
...  
Keyword(s):  
Zika Virus ◽  
Rna Structure ◽  
Virus Genome ◽  
Integrative Analysis ◽  
Viral Infectivity

Preparation of His-Tagged Armored RNA particles as positive controls for Real-Time RT-PCR Detection of Zika virus

2021 ◽  
Vol 31 (4) ◽  
pp. 18-27
Author(s):  
Do Thi Quynh Nga ◽  
Ha Thi Phuong Mai ◽  
Tran Thi Hai Au ◽  
Vu Thi Kim Lien ◽  
Vu Thi Bich Hau ◽  
...  
Keyword(s):  
Real Time ◽  
Zika Virus ◽  
Room Temperature ◽  
Virus Detection ◽  
Positive Control ◽  
Reverse Transcription Pcr ◽  
His Tag ◽  
Armored Rna ◽  
Genomic Regions ◽  
Positive Controls

Armored RNA (AR) is a good candidate for creating nuclease-resistant RNA positive controls in the nucleic acid - based assay for RNA viruses. To simplify the production and purifcation of armored RNA, a single plasmid double – expressing His6-tag system was designed. His-tag armored RNA particles were purifed using his-tag affnity. A genomic fragment of the zika virus consisting of the encoding sequences of flavi-M, flavi-E-C protein targeted for zika virus was selected to prepare a positive control. In this study, we have successfully produced His-taged MS2- phage like particles carrying specifc genomic regions (M and E genes) to monitor the procedures of real-time Reverse transcription-PCR for Zika virus detection in one plasmid double expression. AR-ZIKA is completely resistant to DNase and RNase, stable in normal human EDTA plasma at room temperature for at least 60 and 15 days at 40C and room temperature respectively.

Quantitative Structure Activity Relationship (QSAR) study predicts small molecule binding to RNA structure

2021 ◽  
Author(s):  
Zhengguo Cai ◽  
Martina Zafferani ◽  
Olanrewaju Akande ◽  
Amanda Hargrove
Keyword(s):  
High Resolution ◽  
Small Molecules ◽  
Small Molecule ◽  
Rna Structure ◽  
Quantitative Structure ◽  
Rna Structures ◽  
Qsar Study ◽  
Structure Activity ◽  
Qsar Models ◽  
Hiv 1

The diversity of RNA structural elements and their documented role in human diseases make RNA an attractive therapeutic target. However, progress in drug discovery and development has been hindered by challenges in the determination of high-resolution RNA structures and a limited understanding of the parameters that drive RNA recognition by small molecules, including a lack of validated quantitative structure-activity relationships (QSAR). Herein, we developed QSAR models that quantitatively predict both thermodynamic and kinetic-based binding parameters of small molecules and the HIV-1 TAR model RNA system. A set of small molecules bearing diverse scaffolds was screened against the HIV-1-TAR construct using surface plasmon resonance, which provided the binding kinetics and affinities. The data was then analyzed using multiple linear regression (MLR) combined with feature selection to afford robust models for binding of diverse RNA-targeted scaffolds. The predictivity of the model was validated on untested small molecules. The QSAR models presented herein represent the first application of validated and predictive 2D-QSAR using multiple scaffolds against an RNA target. We expect the workflow to be generally applicable to other RNA structures, ultimately providing essential insight into the small molecule descriptors that drive selective binding interactions and, consequently, providing a platform that can exponentially increase the efficiency of ligand design and optimization without the need for high-resolution RNA structures.

scholarly journals Intrinsic Regulatory Role of RNA Structural Arrangement in Alternative Splicing Control

2020 ◽  
Vol 21 (14) ◽  
pp. 5161 ◽  
Author(s):  
Katarzyna Taylor ◽  
Krzysztof Sobczak
Keyword(s):  
Alternative Splicing ◽  
Rna Structure ◽  
The Other ◽  
Splicing Regulation ◽  
Rna Structures ◽  
Structural Arrangement ◽  
Biological Functionality ◽  
Cis And Trans ◽  
Structural Aspects

Alternative splicing is a highly sophisticated process, playing a significant role in posttranscriptional gene expression and underlying the diversity and complexity of organisms. Its regulation is multilayered, including an intrinsic role of RNA structural arrangement which undergoes time- and tissue-specific alterations. In this review, we describe the principles of RNA structural arrangement and briefly decipher its cis- and trans-acting cellular modulators which serve as crucial determinants of biological functionality of the RNA structure. Subsequently, we engage in a discussion about the RNA structure-mediated mechanisms of alternative splicing regulation. On one hand, the impairment of formation of optimal RNA structures may have critical consequences for the splicing outcome and further contribute to understanding the pathomechanism of severe disorders. On the other hand, the structural aspects of RNA became significant features taken into consideration in the endeavor of finding potential therapeutic treatments. Both aspects have been addressed by us emphasizing the importance of ongoing studies in both fields.

scholarly journals Advances in Diagnostic Methods for Zika Virus Infection

2018 ◽  
Vol 12 (4) ◽  
Author(s):  
Carlos A. Herrada ◽  
Md. Alamgir Kabir ◽  
Rommel Altamirano ◽  
Waseem Asghar
Keyword(s):  
Reverse Transcription ◽  
Zika Virus ◽  
Vaccine Development ◽  
Genome Structure ◽  
Diagnostic Methods ◽  
World Health ◽  
Health Concern ◽  
Localized Surface Plasmon ◽  
Enzyme Linked Immunosorbent Assay ◽  
Health Organization

The Zika virus (ZIKV) is one of the most infamous mosquito-borne flavivirus on recent memory due to its potential association with high mortality rates in fetuses, microcephaly and neurological impairments in neonates, and autoimmune disorders. The severity of the disease, as well as its fast spread over several continents, has urged the World Health Organization (WHO) to declare ZIKV a global health concern. In consequence, over the past couple of years, there has been a significant effort for the development of ZIKV diagnostic methods, vaccine development, and prevention strategies. This review focuses on the most recent aspects of ZIKV research which includes the outbreaks, genome structure, multiplication and propagation of the virus, and more importantly, the development of serological and molecular detection tools such as Zika IgM antibody capture enzyme-linked immunosorbent assay (Zika MAC-ELISA), plaque reduction neutralization test (PRNT), reverse transcription quantitative real-time polymerase chain reaction (qRT-PCR), reverse transcription-loop mediated isothermal amplification (RT-LAMP), localized surface plasmon resonance (LSPR) biosensors, nucleic acid sequence-based amplification (NASBA), and recombinase polymerase amplification (RPA). Additionally, we discuss the limitations of currently available diagnostic methods, the potential of newly developed sensing technologies, and also provide insight into future areas of research.

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