Viruses and Bioinformatics from Virology.uvic.ca
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Genomic Variation in Seven Khoe-San Groups Reveals Adaptation and Complex African History

"The history of click-speaking Khoe-San, and African populations in general, remains poorly understood. We genotyped ∼2.3 million SNPs in 220 southern Africans and found that the Khoe-San diverged from other populations ≥100,000 years ago, but structure within the Khoe-San dated back to about 35,000 years ago. Genetic variation in various sub-Saharan populations did not localize the origin of modern humans to a single geographic region within Africa; instead, it indicated a history of admixture and stratification. We found evidence of adaptation targeting muscle function and immune response, potential adaptive introgression of UV-light protection, and selection predating modern human diversification involving skeletal and neurological development. These new findings illustrate the importance of African genomic diversity in understanding human evolutionary history."

 

Ex Africa, semper aliquid novi...or old, in this case!

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Viruses and Bioinformatics from Virology.uvic.ca
Virus and bioinformatics articles with some microbiology and immunology thrown in for good measure
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Bioinformatics: indispensable, yet hidden in plain sight?

Bioinformatics: indispensable, yet hidden in plain sight? | Viruses and Bioinformatics from Virology.uvic.ca | Scoop.it
Bioinformatics has multitudinous identities, organisational alignments and disciplinary links. This variety allows bioinformaticians and bioinformatic work to contribute to much (if not most) of life science research in profound ways. The multitude of bioinformatic work also translates into a multitude of credit-distribution arrangements, apparently dismissing that work. We report on the epistemic and social arrangements that characterise the relationship between bioinformatics and life science. We describe, in sociological terms, the character, power and future of bioinformatic work. The character of bioinformatic work is such that its cultural, institutional and technical structures allow for it to be black-boxed easily. The result is that bioinformatic expertise and contributions travel easily and quickly, yet remain largely uncredited. The power of bioinformatic work is shaped by its dependency on life science work, which combined with the black-boxed character of bioinformatic expertise further contributes to situating bioinformatics on the periphery of the life sciences. Finally, the imagined futures of bioinformatic work suggest that bioinformatics will become ever more indispensable without necessarily becoming more visible, forcing bioinformaticians into difficult professional and career choices. Bioinformatic expertise and labour is epistemically central but often institutionally peripheral. In part, this is a result of the ways in which the character, power distribution and potential futures of bioinformatics are constituted. However, alternative paths can be imagined.
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Hepatitis Delta Virus: Replication Strategy and Upcoming Therapeutic Options for a Neglected Human Pathogen

The human Hepatitis Delta Virus (HDV) is unique among all viral pathogens. Encoding only one protein (Hepatitis Delta Antigen; HDAg) within its viroid-like self-complementary RNA, HDV constitutes the smallest known virus in the animal kingdom. To disseminate in its host, HDV depends on a helper virus, the human Hepatitis B virus (HBV), which provides the envelope proteins required for HDV assembly. HDV affects an estimated 15–20 million out of the 240 million chronic HBV-carriers and disperses unequally in disparate geographical regions of the world. The disease it causes (chronic Hepatitis D) presents as the most severe form of viral hepatitis, leading to accelerated progression of liver dysfunction including cirrhosis and hepatocellular carcinoma and a high mortality rate. The lack of approved drugs interfering with specific steps of HDV replication poses a high burden for gaining insights into the molecular biology of the virus and, consequently, the development of specific novel medications that resiliently control HDV replication or, in the best case, functionally cure HDV infection or HBV/HDV co-infection. This review summarizes our current knowledge of HBV molecular biology, presents an update on novel cell culture and animal models to study the virus and provides updates on the clinical development of the three developmental drugs Lonafarnib, REP2139-Ca and Myrcludex B.
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Unexpected complexity in the interference activity of a cloned influenza defective interfering RNA

Unexpected complexity in the interference activity of a cloned influenza defective interfering RNA | Viruses and Bioinformatics from Virology.uvic.ca | Scoop.it
Defective interfering (DI) viruses are natural antivirals made by nearly all viruses. They have a highly deleted genome (thus being non-infectious) and interfere with the replication of genetically related infectious viruses. We have produced the first potential therapeutic DI virus for the clinic by cloning an influenza A DI RNA (1/244) which was derived naturally from genome segment 1. This is highly effective in vivo, and has unexpectedly broad-spectrum activity with two different modes of action: inhibiting influenza A viruses through RNA interference, and all other (interferon-sensitive) respiratory viruses through stimulating interferon type I. We have investigated the RNA inhibitory mechanism(s) of DI 1/244 RNA. Ablation of initiation codons does not diminish interference showing that no protein product is required for protection. Further analysis indicated that 1/244 DI RNA interferes by replacing the cognate full-length segment 1 RNA in progeny virions, while interfering with the expression of genome segment 1, its cognate RNA, and genome RNAs 2 and 3, but not genome RNA 6, a representative of the non-polymerase genes. Our data contradict the dogma that a DI RNA only interferes with expression from its cognate full-length segment. There is reciprocity as cloned segment 2 and 3 DI RNAs inhibited expression of RNAs from a segment 1 target. These data demonstrate an unexpected complexity in the mechanism of interference by this cloned therapeutic DI RNA.
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Visibiome: an efficient microbiome search engine based on a scalable, distributed architecture

Visibiome: an efficient microbiome search engine based on a scalable, distributed architecture | Viruses and Bioinformatics from Virology.uvic.ca | Scoop.it
Given the current influx of 16S rRNA profiles of microbiota samples, it is conceivable that large amounts of them eventually are available for search, comparison and contextualization with respect to novel samples. This process facilitates the identification of similar compositional features in microbiota elsewhere and therefore can help to understand driving factors for microbial community assembly. We present Visibiome, a microbiome search engine that can perform exhaustive, phylogeny based similarity search and contextualization of user-provided samples against a comprehensive dataset of 16S rRNA profiles environments, while tackling several computational challenges. In order to scale to high demands, we developed a distributed system that combines web framework technology, task queueing and scheduling, cloud computing and a dedicated database server. To further ensure speed and efficiency, we have deployed Nearest Neighbor search algorithms, capable of sublinear searches in high-dimensional metric spaces in combination with an optimized Earth Mover Distance based implementation of weighted UniFrac. The search also incorporates pairwise (adaptive) rarefaction and optionally, 16S rRNA copy number correction. The result of a query microbiome sample is the contextualization against a comprehensive database of microbiome samples from a diverse range of environments, visualized through a rich set of interactive figures and diagrams, including barchart-based compositional comparisons and ranking of the closest matches in the database. Visibiome is a convenient, scalable and efficient framework to search microbiomes against a comprehensive database of environmental samples. The search engine leverages a popular but computationally expensive, phylogeny based distance metric, while providing numerous advantages over the current state of the art tool.
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Virus found in a boreal lake links ssDNA and dsDNA viruses

Proc Natl Acad Sci U S A. 2017 Jul 17. pii: 201703834. doi: 10.1073/pnas.1703834114. [Epub ahead of print]
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Ancient proteins block modern viruses

Ancient proteins block modern viruses | Viruses and Bioinformatics from Virology.uvic.ca | Scoop.it
Thioredoxin from E. coli is an essential part of the DNA polymerase complex of the bacteriophage T7 (pictured – image credit). This virus does not form plaques on E. coli lacking the two thioredoxin genes. The only ancient thioredoxin gene that allows phage T7 plaque formation is from the last common ancestor of cyanobacterial, deinococcus, and thermus groups, which is about 2.5 billion years old and has 57% amino acid identity with the E. coli enzyme. But the effienciency of plaque formation was very poor – about 100 million times worse than on regular  E. coli. None of the older thioredoxins worked.

Why would an ancient thioredoxin work for E. coli but not for bacteriophage T7? Over billions of years, thioredoxin evolves but it must still be able to carry out its function for E. coli. The viruses that infected bacteria 4 billion years ago were very different from contemporary viruses, and so the ancient thioredoxin does not work for modern viruses. Today’s thioredoxin could change so that it would not support T7 replication – as long as the enzyme still works for E. coli.

The authors of this work view it as a proof of principle: that virus growth is not supported by an ancient version of a modern protein required for virus replication. They would like to apply this approach to produce plants that are resistant to viruses, which have serious effects on global agricultural productivity.

I think the work is amazing not only because an ancient protein can be made, but it supports growth of the host and not that of a virus. It might therefore be possible to reconstruct the host-virus arms race, starting from ancient proteins. In this race, the gene encoding an essential cell protein can evolve so that it no longer supports virus replication. Next, the viral genome changes to adapt to the altered cell protein. And so the game goes back and forth.

The authors have shown that they can select mutant bacteriophage T7 isolates that replicate in the present of an ancient thioredoxin. This result suggests that it might be possible to reconstruct host-virus arms races beginning with an ancestral host protein. If we can make an ancient protein, could we also make an ancient virus? Why not?
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Interesting!
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New video on the NCBI YouTube channel: How You and Your Journal Club Can Contribute Using PubMed Commons

New video on the NCBI YouTube channel: How You and Your Journal Club Can Contribute Using PubMed Commons | Viruses and Bioinformatics from Virology.uvic.ca | Scoop.it

The newest video on the NCBI YouTube channel discusses how eligible individuals and journal clubs can join PubMed Commons and contribute comments.

PubMed Commons enables members to post comments about publications, which appear directly below abstracts in PubMed.

Subscribe to the NCBI YouTube channel to watch and receive alerts about new videos ranging from quick tips to full presentations.

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Did you know NCBI has their own Youtube channel?!
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NucDiff: in-depth characterization and annotation of differences between two sets of DNA sequences

NucDiff: in-depth characterization and annotation of differences between two sets of DNA sequences | Viruses and Bioinformatics from Virology.uvic.ca | Scoop.it
Comparing sets of sequences is a situation frequently encountered in bioinformatics, examples being comparing an assembly to a reference genome, or two genomes to each other. The purpose of the comparison is usually to find where the two sets differ, e.g. to find where a subsequence is repeated or deleted, or where insertions have been introduced. Such comparisons can be done using whole-genome alignments. Several tools for making such alignments exist, but none of them 1) provides detailed information about the types and locations of all differences between the two sets of sequences, 2) enables visualisation of alignment results at different levels of detail, and 3) carefully takes genomic repeats into consideration. We here present NucDiff, a tool aimed at locating and categorizing differences between two sets of closely related DNA sequences. NucDiff is able to deal with very fragmented genomes, repeated sequences, and various local differences and structural rearrangements. NucDiff determines differences by a rigorous analysis of alignment results obtained by the NUCmer, delta-filter and show-snps programs in the MUMmer sequence alignment package. All differences found are categorized according to a carefully defined classification scheme covering all possible differences between two sequences. Information about the differences is made available as GFF3 files, thus enabling visualisation using genome browsers as well as usage of the results as a component in an analysis pipeline. NucDiff was tested with varying parameters for the alignment step and compared with existing alternatives, called QUAST and dnadiff. We have developed a whole genome alignment difference classification scheme together with the program NucDiff for finding such differences. The proposed classification scheme is comprehensive and can be used by other tools. NucDiff performs comparably to QUAST and dnadiff but gives much more detailed results that can easily be visualized. NucDiff is freely available on
https://github.com/uio-cels/NucDiff

under the MPL license.
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A bioinformatics pipeline to search functional motifs within whole-proteome data: a case study of poxviruses

Proteins harbor domains or short linear motifs, which facilitate their functions and interactions. Finding functional motifs in protein sequences could predict the putative cellular roles or characteristics of hypothetical proteins. In this study, we present Shetti-Motif, which is an interactive tool to (i) map UniProt and PROSITE flat files, (ii) search for multiple pre-defined consensus patterns or experimentally validated functional motifs in large datasets protein sequences (proteome-wide), (iii) search for motifs containing repeated residues (low-complexity regions, e.g., Leu-, SR-, PEST-rich motifs, etc.). As proof of principle, using this comparative proteomics pipeline, eleven proteomes encoded by member of Poxviridae family were searched against about 100 experimentally validated functional motifs. The closely related viruses and viruses infect the same host cells (e.g. vaccinia and variola viruses) show similar motif-containing proteins profile. The motifs encoded by these viruses are correlated, which explains why poxviruses are able to interact with wide range of host cells. In conclusion, this in silico analysis is useful to establish a dataset(s) or potential proteins for further investigation or compare between species.
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Respiratory syncytial virus–Host interaction in the pathogenesis of bronchiolitis and its impact on respiratory morbidity in later life

Respiratory syncytial virus–Host interaction in the pathogenesis of bronchiolitis and its impact on respiratory morbidity in later life | Viruses and Bioinformatics from Virology.uvic.ca | Scoop.it
Respiratory syncytial virus (RSV) is the most common agent of severe airway disease in infants and young children. Large epidemiologic studies have demonstrated a clear relationship between RS

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Evolution and Vaccination of Influenza Virus

In this study, we present an application paradigm in which an unsupervised machine learning approach is applied to the high-dimensional influenza genetic sequences to investigate whether vaccine is a driving force to the evolution of influenza virus. We first used a visualization approach to visualize the evolutionary paths of vaccine-controlled and non-vaccine-controlled influenza viruses in a low-dimensional space. We then quantified the evolutionary differences between their evolutionary trajectories through the use of within- and between-scatter matrices computation to provide the statistical confidence to support the visualization results. We used the influenza surface Hemagglutinin (HA) gene for this study as the HA gene is the major target of the immune system. The visualization is achieved without using any clustering methods or prior information about the influenza sequences. Our results clearly showed that the evolutionary trajectories between vaccine-controlled and non-vaccine-controlled influenza viruses are different and vaccine as an evolution driving force cannot be completely eliminated.
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Viral infection: Packing to leave

Viral infection: Packing to leave | Viruses and Bioinformatics from Virology.uvic.ca | Scoop.it
An essential feature of the life cycle of hepatitis B virus (HBV) is the packaging of the viral RNA pre-genome (pgRNA) into virions. It has been hypothesized that pgRNA is specifically packaged into viral nucleocapsids; however, the HBV assembly pathway remains incompletely understood. In a recent study, Patel, White et al. discover that the HBV pgRNA contains specific nucleotide motifs that mediate interactions with the viral capsid protein to drive nucleocapsid assembly.
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Identical Protein Groups: Non-redundant access to protein records

Identical Protein Groups: Non-redundant access to protein records | Viruses and Bioinformatics from Virology.uvic.ca | Scoop.it
  Have you ever searched the NCBI Protein database and been overwhelmed with the number of sequences returned? Have you tried searching with a protein name, thinking that would greatly limit the results, only to still be presented with many sequences (all with the same name)? It’s a common problem in this time of greatly…
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Latency, Integration, and Reactivation of Human Herpesvirus-6

Human herpesvirus-6A (HHV-6A) and human herpesvirus-6B (HHV-6B) are two closely related viruses that infect T-cells. Both HHV-6A and HHV-6B possess telomere-like repeats at the terminal regions of their genomes that facilitate latency by integration into the host telomeres, rather than by episome formation. In about 1% of the human population, human herpes virus-6 (HHV-6) integration into germline cells allows the viral genome to be passed down from one generation to the other; this condition is called inherited chromosomally integrated HHV-6 (iciHHV-6). This review will cover the history of HHV-6 and recent works that define the biological differences between HHV-6A and HHV-6B. Additionally, HHV-6 integration and inheritance, the capacity for reactivation and superinfection of iciHHV-6 individuals with a second strain of HHV-6, and the role of hypomethylation of human chromosomes during integration are discussed. Overall, the data suggest that integration of HHV-6 in telomeres represent a unique mechanism of viral latency and offers a novel tool to study not only HHV-6 pathogenesis, but also telomere biology. Paradoxically, the integrated viral genome is often defective especially as seen in iciHHV-6 harboring individuals. Finally, gaps in the field of HHV-6 research are presented and future studies are proposed.
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Telomerase Induction in HPV Infection and Oncogenesis

Telomerase Induction in HPV Infection and Oncogenesis | Viruses and Bioinformatics from Virology.uvic.ca | Scoop.it
Telomerase extends the repetitive DNA at the ends of linear chromosomes, and it is normally active in stem cells. When expressed in somatic diploid cells, it can lead to cellular immortalization. Human papillomaviruses (HPVs) are associated with and high-risk for cancer activate telomerase through the catalytic subunit of telomerase, human telomerase reverse transcriptase (hTERT). The expression of hTERT is affected by both high-risk HPVs, E6 and E7. Seminal studies over the last two decades have identified the transcriptional, epigenetic, and post-transcriptional roles high-risk E6 and E7 have in telomerase induction. This review will summarize these findings during infection and highlight the importance of telomerase activation as an oncogenic pathway in HPV-associated cancer development and progression.
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The Reproducibility Of Research And The Misinterpretation Of P Values

bioRxiv - the preprint server for biology, operated by Cold Spring Harbor Laboratory, a research and educational institution
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Cow antibodies yield important clues for developing a broadly effective AIDS vaccine

Cow antibodies yield important clues for developing a broadly effective AIDS vaccine | Viruses and Bioinformatics from Virology.uvic.ca | Scoop.it
Credit: IAVI LA JOLLA - Cows are leaving the pasture and entering the field...of HIV vaccine research. As outlined in a study published today in Nature, lead author Devin Sok, Director, Antibody Di..

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Two-amino acids change in the nsp4 of SARS coronavirus abolishes viral replication

Infection with coronavirus rearranges the host cell membrane to assemble a replication/transcription complex in which replication of the viral genome and transcription of viral mRNA occur. Although coexistence of nsp3 and nsp4 is known to cause membrane rearrangement, the mechanisms underlying the interaction of these two proteins remain unclear. We demonstrated that binding of nsp4 with nsp3 is essential for membrane rearrangement and identified amino acid residues in nsp4 responsible for the interaction with nsp3. In addition, we revealed that the nsp3-nsp4 interaction is not sufficient to induce membrane rearrangement, suggesting the participation of other factors such as host proteins. Finally, we showed that loss of the nsp3-nsp4 interaction eliminated viral replication by using an infectious cDNA clone and replicon system of SARS-CoV. These findings provide clues to the mechanism of the replication/transcription complex assembly of SARS-CoV and could reveal an antiviral target for the treatment of betacoronavirus infection.
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Molecular Mechanisms of Human Papillomavirus Induced Skin Carcinogenesis

nfection of the cutaneous skin with human papillomaviruses (HPV) of genus betapapillomavirus (βHPV) is associated with the development of premalignant actinic keratoses and squamous cell carcinoma. Due to the higher viral loads of βHPVs in actinic keratoses than in cancerous lesions, it is currently discussed that these viruses play a carcinogenic role in cancer initiation. In vitro assays performed to characterize the cell transforming activities of high-risk HPV types of genus alphapapillomavirus have markedly contributed to the present knowledge on their oncogenic functions. However, these assays failed to detect oncogenic functions of βHPV early proteins. They were not suitable for investigations aiming to study the interactive role of βHPV positive epidermis with mesenchymal cells and the extracellular matrix. This review focuses on βHPV gene functions with special focus on oncogenic mechanisms that may be relevant for skin cancer development.
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CRISPR gene editing controversy - does it cause unexpected mutations?

CRISPR gene editing controversy - does it cause unexpected mutations? | Viruses and Bioinformatics from Virology.uvic.ca | Scoop.it
Just over a month ago, a short paper appeared in Nature Methods saying that the gene editing technique known as CRISPR-Cas9 has a bi
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Rift Valley fever virus NSs protein functions and the similarity to other bunyavirus NSs proteins

Rift Valley fever virus NSs protein functions and the similarity to other bunyavirus NSs proteins | Viruses and Bioinformatics from Virology.uvic.ca | Scoop.it
Rift Valley fever is a mosquito-borne zoonotic disease that affects both ruminants and humans. The nonstructural (NS) protein, which is a major virulence factor for Rift Valley fever virus (RVFV), is encoded on the S-segment. Through the cullin 1-Skp1-Fbox E3 ligase complex, the NSs protein promotes the degradation of at least two host proteins, the TFIIH p62 and the PKR proteins. NSs protein bridges the Fbox protein with subsequent substrates, and facilitates the transfer of ubiquitin. The SAP30-YY1 complex also bridges the NSs protein with chromatin DNA, affecting cohesion and segregation of chromatin DNA as well as the activation of interferon-β promoter. The presence of NSs filaments in the nucleus induces DNA damage responses and causes cell-cycle arrest, p53 activation, and apoptosis. Despite the fact that NSs proteins have poor amino acid similarity among bunyaviruses, the strategy utilized to hijack host cells are similar. This review will provide and summarize an update of recent findings pertaining to the biological functions of the NSs protein of RVFV as well as the differences from those of other bunyaviruses.
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Taming the BEAST - A community teaching material resource for BEAST 2. - PubMed - NCBI

Taming the BEAST - A community teaching material resource for BEAST 2. - PubMed - NCBI | Viruses and Bioinformatics from Virology.uvic.ca | Scoop.it
Syst Biol. 2017 Jun 29. doi: 10.1093/sysbio/syx060. [Epub ahead of print]
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Pathways to zoonotic spillover

Zoonotic spillover, which is the transmission of a pathogen from a vertebrate animal to a human, presents a global public health burden but is a poorly understood phenomenon. Zoonotic spillover requires several factors to align, including the ecological, epidemiological and behavioural determinants of pathogen exposure, and the within-human factors that affect susceptibility to infection. In this Opinion article, we propose a synthetic framework for animal-to-human transmission that integrates the relevant mechanisms. This framework reveals that all zoonotic pathogens must overcome a hierarchical series of barriers to cause spillover infections in humans. Understanding how these barriers are functionally and quantitatively linked, and how they interact in space and time, will substantially improve our ability to predict or prevent spillover events. This work provides a foundation for transdisciplinary investigation of spillover and synthetic theory on zoonotic transmission.
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