Showing posts with label viral integration. Show all posts

Viruses in genome important for our brain -- ScienceDaily

"The genes that control the production of various proteins in the body represent a smaller proportion of our DNA than endogenous retroviruses. They account for approximately 2 per cent, while retroviruses account for 8-10 per cent of the total genome. If it turns out that they are able to influence the production of proteins, this will provide us with a huge new source of information about the human brain," says Johan Jakobsson.

And this is precisely what the researchers discovered. They have determined that several thousands of the retroviruses that have established themselves in our genome may serve as "docking platforms" for a protein called TRIM28. This protein has the ability to "switch off" not only viruses but also the standard genes adjacent to them in the DNA helix, allowing the presence of ERV to affect gene expression.

This switching-off mechanism may behave differently in different people, since retroviruses are a type of genetic material that may end up in different places in the genome. This makes it a possible tool for evolution, and even a possible underlying cause of neurological diseases. In fact, there are studies that indicate a deviating regulation of ERV in several neurological diseases such as ALS, schizophrenia and bipolar disorder.

Redefining the invertebrate RNA virosphere : Nature : Nature Research

"Current knowledge of RNA virus biodiversity is both biased and fragmentary, reflecting a focus on culturable or disease-causing agents. Here we profile the transcriptomes of over 220 invertebrate species sampled across nine animal phyla and report the discovery of 1,445 RNA viruses, including some that are sufficiently divergent to comprise new families. The identified viruses fill major gaps in the RNA virus phylogeny and reveal an evolutionary history that is characterized by both host switching and co-divergence. The invertebrate virome also reveals remarkable genomic flexibility that includes frequent recombination, lateral gene transfer among viruses and hosts, gene gain and loss, and complex genomic rearrangements. Together, these data present a view of the RNA virosphere that is more phylogenetically and genomically diverse than that depicted in current classification schemes and provide a more solid foundation for studies in virus ecology and evolution."

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Study adds to evidence that viruses are alive -- ScienceDaily

Small Things Considered: Polintons; A Viral Missing Link?

The line between viruses and parasitic elements of the genome is thin and delicate, and probably often crossed. Parasitic elements that acquire the means to escape the host cell become viruses and, conversely, viruses can lose this ability and return to a more limited lifestyle as transposable elements (TEs). This back-and-forth occurs alongside a propensity for gene exchange, with genes acquired horizontally from various hosts, and at various periods of evolution.The result is that, although viruses and other "selfish" elements are obviously related, their relationship cannot be represented by the satisfying, graceful branches seen on phylogenetic trees depicting the evolution of more pedestrian organisms such as primates, for example. Instead, a virus or TE is like a quilt whose patches were added by different quilters, at different times.

PLOS Genetics: Reactivation of Chromosomally Integrated Human Herpesvirus-6 by Telomeric Circle Formation

More than 95% of the human population is infected with human herpesvirus-6 (HHV-6) during early childhood and maintains latent HHV-6 genomes either in an extra-chromosomal form or as a chromosomally integrated HHV-6 (ciHHV-6). In addition, approximately 1% of humans are born with an inheritable form of ciHHV-6 integrated into the telomeres of chromosomes. Immunosuppression and stress conditions can reactivate latent HHV-6 replication, which is associated with clinical complications and even death. We have previously shown that Chlamydia trachomatis infection reactivates ciHHV-6 and induces the formation of extra-chromosomal viral DNA in ciHHV-6 cells. Here, we propose a model and provide experimental evidence for the mechanism of ciHHV-6 reactivation. Infection with Chlamydia induced a transient shortening of telomeric ends, which subsequently led to increased telomeric circle (t-circle) formation and incomplete reconstitution of circular viral genomes containing single viral direct repeat (DR). Correspondingly, short t-circles containing parts of the HHV-6 DR were detected in cells from individuals with genetically inherited ciHHV-6. Furthermore, telomere shortening induced in the absence of Chlamydia infection also caused circularization of ciHHV-6, supporting a t-circle based mechanism for ciHHV-6 reactivation.

Paleovirology: inferring viral evolution from host genome sequence data

Paleovirology is the study of ancient viruses, typically over prehistoric or geological timescales. There is no physical ‘fossil record’ of viruses; virions persist for short time periods, and rapidly degrade leaving no direct trace of their existence. Many viruses can enter the genomes of their hosts—some, such as retroviruses, do so as an obligate step during their replication process, and others can occasionally do so, either by accident or as a latent part of their life cycle. When viral integrations occur in the germline of their host, they can be passed on to the next generation, potentially fixing in the host population. When this occurs, the integrated endogenous virus genomes evolve at host rates of mutation, and their sequence is relatively stably preserved. The study of this genomic ‘fossil record’ has led to the burgeoning field of paleovirology, which uses these endogenous viruses to disentangle the long-term evolutionary history of virus–host interactions.

Ancient viruses that function in early human development may play role in cancer

Up to 98 percent of human genomic matter is known as "junk" or "dark matter" non-coding DNA, and had for years attracted little interest among scientists who doubted its role in human health and disease. Recent research has begun to identify that part of that non-coding DNA is used by the cell to make RNA such as vlincRNA, highly tissue-specific RNA chains of unusually large lengths, many of which are only found in embryonic or cancerous cells. VlincRNAs found in these two types of cells tend to be expressed based upon genetic signals from ancient viruses that invaded our ancestors' genome millions of years ago and were gradually "domesticated" over evolutionary time. The number of vlincRNAs expressed by these domesticated viral sequences correlates with both embryonic development and malignant cancers.

Transposable element recruitments in the mammalian placenta: impacts and mechanisms

Transposable elements (TEs) are mobile DNA elements found at high frequency in mammalian genomes. Although these elements are generally perceived as genomic parasites, they have the potential to influence host genome function in many beneficial ways. This article discusses the role TEs have played in the evolution of the placenta and pregnancy in viviparous mammals. Using examples from our own research and the literature, we argue that frequent recruitment of TEs, in particular of retroelements, has facilitated the extreme diversification of tissues at the maternal–fetal interface. We also discuss the mechanisms by which TEs have been recruited for functions during pregnancy. We argue that retroelements are pre-adapted to becoming cis-regulatory elements for host genomes because they need to utilize host regulatory signals for their own life cycle. However, although TEs contain some of the signals necessary for host functions upon insertion, they often require modification before acquiring a biological role in a host tissue. We discuss the process by which one TE was transformed into a promoter for prolactin expression in the endometrium, describing a model for TE domestication called ‘epistatic capture’.

Antiviral therapy of two patients with chromosomally-integrated human herpesvirus-6A presenting with cognitive dysfunction.

Human herpesvirus 6 (HHV-6) is a neurotropic virus implicated in central nervous system (CNS) dysfunction, multiple sclerosis, seizures and encephalitis. Inherited or "chromosomally integrated" HHV-6 (CIHHV-6) is a condition characterized by high DNA loads and germ line transmission of HHV-6 genomes, which are integrated into the telomere.OBJECTIVES:We previously reported that integrated HHV-6 can be reactivated by trichostatin A in vitro. Therefore, we hypothesized that a broad array of neurological symptoms of CIHHV-6 patients may respond to antiviral drug treatment.STUDY DESIGN:The patients have been treated with antiviral drugs and monitored for viral load, late mRNA, and clinical improvement.RESULTS:Antiviral therapy of two CIHHV patients resulted in successful clinical resolution. However, both patients relapsed on multiple occasions within 4-6 months of cessation of antiviral therapy.CONCLUSIONS:Successful antiviral drug treatment suggests that clinical symptoms of these patients were due to symptomatic reactivation of CIHHV-6. Alternatively, some CIHHV-6 patients may have a reduced resistance to community-acquired HHV-6 strains due to tolerance leading to persistent infections.

Non-Random Integration of the HPV Genome in Cervical Cancer.

HPV DNA integration into the host genome is a characteristic but not an exclusive step during cervical carcinogenesis. It is still a matter of debate whether viral integration contributes to the transformation process beyond ensuring the constitutive expression of the viral oncogenes. There is mounting evidence for a non-random distribution of integration loci and the direct involvement of cellular cancer-related genes. In this study we addressed this topic by extending the existing data set by an additional 47 HPV16 and HPV18 positive cervical carcinoma. We provide supportive evidence for previously defined integration hotspots and have revealed another cluster of integration sites within the cytogenetic band 3q28. Moreover, in the vicinity of these hotspots numerous microRNAs (miRNAs) are located and may be influenced by the integrated HPV DNA. By compiling our data and published reports 9 genes could be identified which were affected by HPV integration at least twice in independent tumors. In some tumors the viral-cellular fusion transcripts were even identical with respect to the viral donor and cellular acceptor sites used. However, the exact integration sites are likely to differ since none of the integration sites analysed thus far have shown more than a few nucleotides of homology between viral and host sequences. Therefore, DNA recombination involving large stretches of homology at the integration site can be ruled out. It is however intriguing that by sequence alignment several regions of the HPV16 genome were found to have highly homologous stretches of up to 50 nucleotides to the aforementioned genes and the integration hotspots. One common region of homologies with cellular sequences is between the viral gene E5 and L2 (nucleotides positions 4100 to 4240). We speculate that this and other regions of homology are involved in the integration process. Our observations suggest that targeted disruption, possibly also of critical cellular genes, by HPV integration remains an issue to be fully resolved.

Dr.VIS Human Disease-Related Viral Integration Sites Database

Dr.VIS collects and locates human disease-related viral integration sites. So far, about 600 sites covering 5 virus organisms and 11 human diseases are available. Integration sites in Dr.VIS are located against chromesome, cytoband, gene and refseq position as specific as possible. Viral-cellular junction sequences are extracted from papers and nucleotide databases, and linked to cooresponding integration sites Graphic views summarizing distribution of viral integration sites are generated according to chromosome maps. It is free to browse and download data in Dr.VIS.

Scientists unravel mechanism that causes liver cancer

Scientists at the Genome Institute of Singapore (GIS) have unraveled the mechanism that causes liver cancer (hepatocellular carcinoma, HCC), one of the most common solid tumors worldwide. Essentially, the Hepatitis B virus (HBV) integrates its own DNA into human genes: Their analyses revealed that the incidences of HBV integrations were high – 76 of the 88 patients had HBV integration. Specifically, they discovered that the HBV will integrate into genes CCNE1, SENP5 and ROCK1, causing an increase in the expression levels in these genes, and subsequently enhancing the tumor growth. This discovery is in addition to the previously reported integration into the TERT and MLL4 genes.

Study reveals how ancient viruses became genomic 'superspreaders'

Scientists have uncovered clues as to how our genomes became riddled with viruses. The study, supported by the Wellcome Trust, reveals important information about the so–called 'dark matter' of our genome.For years scientists have been struggling with the enigma that more than 90 percent of every mammal's genome has no known function. A part of this 'dark matter' of genetic material is known to harbour pieces of DNA from ancient viruses that infected our ancestors going back as far as the age of the dinosaurs.

Metagenomic Study Uncovers Apparent RNA-DNA Hybrid Virus | GenomeWeb Daily News | Sequencing | GenomeWeb

Results from a metagenomic study described online today in the journal Biology Direct are challenging the notion that viruses exchange sequences exclusively with viruses of the same type.

Endogenous viruses: insights into viral evolution and impact on host biology : Abstract : Nature Reviews Genetics

Recent studies have uncovered myriad viral sequences that are integrated or 'endogenized' in the genomes of various eukaryotes. Surprisingly, it appears that not just retroviruses but almost all types of viruses can become endogenous. We review how these genomic 'fossils' offer fresh insights into the origin, evolutionary dynamics and structural evolution of viruses, which are giving rise to the burgeoning field of palaeovirology. We also examine the multitude of ways through which endogenous viruses have influenced, for better or worse, the biology of their hosts. We argue that the conflict between hosts and viruses has led to the invention and diversification of molecular arsenals, which, in turn, promote the cellular co-option of endogenous viruses.

Mammals Made By Viruses | The Loom | Discover Magazine

Viruses have insinuated themselves into the genome of our ancestors for hundreds of millions of years. They typically have gotten there by infecting eggs or sperm, inserting their own DNA into ours.

Dr.VIS: a database of human disease-related viral integration sites.

Viral integration plays an important role in the development of malignant diseases. Viruses differ in preferred integration site and flanking sequence. Viral integration sites (VIS) have been found next to oncogenes and common fragile sites. Understanding the typical DNA features near VIS is useful for the identification of potential oncogenes, prediction of malignant disease development and assessing the probability of malignant transformation in gene therapy. Therefore, we have built a database of human disease-related VIS (Dr.VIS, http://202.120.189.88/drvis/) to collect and maintain human disease-related VIS data, including characteristics of the malignant disease, chromosome region, genomic position and viral-host junction sequence. The current build of Dr.VIS covers about 600 natural VIS of 5 oncogenic viruses representing 11 diseases. Among them, about 200 VIS have viral-host junction sequence

Parasites Or Not? Transposable Elements In Fruit Flies

Many living organisms suffer from parasites, which use the hosts' resources for their own purposes. The problem of parasitism occurs at all levels right down to the DNA scale. Genomes may contain up to 80% "foreign" DNA but details of the mechanisms by which this enters the host genome and how hosts attempt to combat its spread are still the subject of conjecture. Important new information comes from the group of Christian Schlotterer at the University of Veterinary Medicine, Vienna. The findings are published in the prestigious journal PLoS Genetics.

Pathogens don't just have acute effects : their DNA may integrate our genomes and have effects on our genes and those of our descendants .

Defending the genome from viral integration

Small, mobile sequences of DNA left over from viruses, called transposons or "jumping genes" because of their ability to move around the genome, pose a significant threat to the genetic integrity and stability of an organism. Considered genetic parasites, these transposable elements are believed to comprise as much as 50 percent of the human genome. Because of the damage transposons can do to an organism's DNA, an immune-like response has evolved to turn off, or silence, the transposons.

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