Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes

25/01/2010 às 16:53 (Uncategorized)

Cancer Genome Project

Gillian L. Dalgliesh1, Kyle Furge2, Chris Greenman1, Lina Chen1, Graham Bignell1, Adam Butler1, Helen Davies1, Sarah Edkins1, Claire Hardy1, Calli Latimer1, Jon Teague1, Jenny Andrews1, Syd Barthorpe1, Dave Beare1, Gemma Buck1, Peter J. Campbell1, Simon Forbes1, Mingming Jia1, David Jones1, Henry Knott1, Chai Yin Kok1, King Wai Lau1, Catherine Leroy1, Meng-Lay Lin1, David J. McBride1, Mark Maddison1, Simon Maguire1, Kirsten McLay1, Andrew Menzies1, Tatiana Mironenko1, Lee Mulderrig1, Laura Mudie1, Sarah O’Meara1, Erin Pleasance1, Arjunan Rajasingham1, Rebecca Shepherd1, Raffaella Smith1, Lucy Stebbings1, Philip Stephens1, Gurpreet Tang1, Patrick S. Tarpey1, Kelly Turrell1, Karl J. Dykema2, Sok Kean Khoo3, David Petillo3, Bill Wondergem2, John Anema4, Richard J. Kahnoski4, Bin Tean Teh3,5, Michael R. Stratton1,6 & P. Andrew Futreal1

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Laboratory of Computational Biology,
Laboratory of Cancer Genertics, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
Department of Urology, Spectrum Health Hospital, Grand Rapids, Michigan 49503, USA
NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, 169610 Singapore
Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
Correspondence to: Bin Tean Teh3,5Michael R. Stratton1,6P. Andrew Futreal1 Correspondence and requests for materials should be addressed to B.T.T. (Email: Bin.Teh@vai.org), M.R.S. (Email: mrs@sanger.ac.uk) or P.A.F. (Email: paf@sanger.ac.uk).

Top of pageClear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer, characterized by the presence of inactivating mutations in the VHL gene in most cases1, 2, and by infrequent somatic mutations in known cancer genes. To determine further the genetics of ccRCC, we have sequenced 101 cases through 3,544 protein-coding genes. Here we report the identification of inactivating mutations in two genes encoding enzymes involved in histone modification—SETD2, a histone H3 lysine 36 methyltransferase, and JARID1C (also known as KDM5C), a histone H3 lysine 4 demethylase—as well as mutations in the histone H3 lysine 27 demethylase, UTX (KMD6A), that we recently reported3. The results highlight the role of mutations in components of the chromatin modification machinery in human cancer. Furthermore, NF2 mutations were found in non-VHL mutated ccRCC, and several other probable cancer genes were identified. These results indicate that substantial genetic heterogeneity exists in a cancer type dominated by mutations in a single gene, and that systematic screens will be key to fully determining the somatic genetic architecture of cancer.

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Epigenetic control of the variable expression of a Plasmodium falciparum receptor protein for erythrocyte invasion

25/01/2010 às 16:10 (Uncategorized)

Abstract

  1. Lubin Jianga,1,
  2. María José López-Barragána,
  3. Hongying Jianga,
  4. Jianbing Mua,
  5. Deepak Gaura,
  6. Keji Zhaob,
  7. Gary Felsenfeldc, and
  8. Louis H. Millera,1

Plasmodium falciparum can invade erythrocytes by redundant receptors, some of which have variable expression. A P. falciparum clone Dd2 requiring erythrocyte sialic acid for invasion can be switched to a sialic acid-independent progeny clone Dd2NM by growing the Dd2 clone with neuraminidase-treated erythrocytes. The RH4 gene is transcriptionally up-regulated in Dd2NM compared to Dd2, despite the absence of DNA changes in and around the gene. We determined the epigenetic modifications around the transcription start site (TSS) at the time of expression of RH4 in Dd2NM (44 h) and at an earlier time when RH4 is not expressed (24 h). At 44 h, the occupancy of the +1 nucleosome site downstream of the TSS of the active RH4 gene in Dd2NM was markedly reduced compared to Dd2; no difference was observed at 24 h. At 44 h, histone modifications associated with up-regulation were positively correlated to the active RH4 gene of Dd2NM compared to Dd2; no differences were observed at 24 h. Histone H3K9 trimethylation (a marker for silencing) was higher in Dd2 than Dd2NM along the 5′-UTRs of the RH4 gene at both 44 and 24 h. Our data indicate that the failure of Dd2 to express the sialic acid-independent invasion receptor gene RH4 is associated with the epigenetic silencing mark H3K9 trimethylation present throughout the cycle.

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Gene mappers untangling common cold mysteries

25/01/2010 às 16:06 (Diagnóstico Molecular, Medicina, Virus)

“A person can become infected with two viruses, and a third unique virus is formed.”
–Dr. Stephen B. Liggett

By Val Willingham, CNN Medical Producer

(CNN) — A cure for the common cold has eluded scientists since the dawn of mankind.

A close-up of the common cold virus.

Common colds — also known as human rhinovirus — affect billions of people worldwide every year and have more than 100 different, but related, strains. Each of these strains can cause a variety of symptoms in sufferers.

Doctors say that variety is what makes the common cold so hard to understand and so hard to treat.

Last year, researchers from the University of Maryland and the University of Wisconsin-Madison announced that they had taken the first step in finding a cure for rhinovirus by mapping each strain’s entire genome.

Now, those same scientists have found some interesting things about all those different strains.

“We continue to see a new virus that appears to come from two viruses,” said Dr. Stephen B. Liggett, co-leader of the project and a professor of medicine and physiology at the University of Maryland School of Medicine. “So a person can become infected with two viruses, and a third unique virus is formed.”

Why those mutations develop is still a major question, but Liggett says most of them don’t cause any harm. “It’s really more about why they develop … because many are not very strong, but in some cases, they are,” he said. “So we need to better understand them.”

A person can become infected with two viruses, and a third unique virus is formed.

–Dr. Stephen B. Liggett
When the different strains of the common cold were mapped early last year, researchers were looking for ways to develop diagnostic tests and eventually possible treatments.

Since the completion of the mapping, researchers have been working on a diagnostic test for the virus.

Originally, the test was expected to cost about $2,000, but they have perfected the technique and found they can develop a much cheaper test for about $20. That means a test for the cold may one day be common in doctors’ offices.

A fast and inexpensive test is good news for asthmatics and people who have chronic obstructive pulmonary disease, for whom colds can be life-threatening.

“Fifty percent of the exacerbations that occur in patients who have these two diseases are due to a rhinovirus infection,” Liggett notes. “So it’s that group of people we are targeting. Those would be the first group we’d like to help.”

Respiratory infections including colds and the flu are some of the most common causes of asthma flare-ups, especially in young children, according to the American Asthma Foundation.

Although the genetic mapping of the different strains is a positive step, many in the medical community say the virus itself is just too complex to tackle.

But Liggett ignores the naysayers; he says that by mapping the genome of the different strains and assembling the results into a “family tree,” scientists can better understand how virus strains are related, as well as their differences.

Last year, researchers found that human rhinovirus strains are organized into about 15 subgroups, so a “one-drug-fits-all” approach to treat the cold probably won’t work.

But Liggett says he and his fellow researchers hope to streamline those 15 subgroups into five, which would make it easier to treat the virus. “Better to have five treatments than 15,” Liggett said.

“Right now, vaccines and other treatments aren’t our main goal,” Liggett said. “Hopefully, we will be able to design treatments some day. Taking our research little by little will help us understand a virus we’ve never been able to figure out before. And for now, that’s what’s most important.”

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Sequencing Staph: New Genetic Analysis Tracks MRSA Mutations

25/01/2010 às 15:57 (Diagnóstico Molecular, Medicina, Sequenciamento)

As drug-resistant strains of staph sicken people around the globe, high-power genome sequencing promises to trace the spread of this infection

By Katherine Harmon

Resistant strains of the bacteria Staphylococcus aureus are the scourge of hospitals worldwide, frequently sickening and killing patients who were admitted to overcome other ills. And until now, scientists have not been able to closely track the transmission and mutation patterns of single strains.

A new project, using high-throughput, whole-genome sequencing, has begun to demystify MRSA (methicillin-resistant Staphylococcus aureus), revealing how the bacteria tend to spread among patients—and continents. Results of the project were published online January 21 in the journal Science.

The researchers took as their main subject a common strain of the bacteria known as ST239. “We knew that this strain was widespread,” said Sharon Peacock, of the Department of Medicine at the University of Cambridge in England, in a conference call with reporters January 20. “But we had no idea how transmission was occurring.” Given that MRSA has been found worldwide, scientists assumed it was capable of traveling between continents, but just how and where various subtypes were spreading remained obscured by low-resolution data.

Using older analysis techniques, such as multilocus sequence typing (MLST), most isolates of a MRSA strain appeared to have the same genetic profile. Scientists would typically sample DNA sequences in six or seven genes across the whole MRSA genome (which contains some 3,000 genes). At this rough resolution, subtle genetic changes would often go undetected, the researchers behind the new study explained. More rapid, whole-genome sequencing, however, enabled researcher to see “very precise differences” that occur on the level of single-nucleotide changes, Stephen Bentley, from the Wellcome Trust Sanger Institute (WTSI) in Cambridge, and senior study author, said during the teleconference. For instance, dozens of MRSA isolates collected across the globe (from Asia, Australia, Europe, and North and South America) between 1982 and 2003 had appeared identical using the MLST approach, but with the newer, whole-genome analysis, each proved to be genetically distinct.

The more thorough process, when applied to MRSA, has created “a leap in understanding,” which allowed the researchers to construct a rough genetic evolutionary tree for the ST239 strain of MRSA. “It allows us to estimate the date of emergence and trace how it subsequently spread across the world,” Simon Harris, also of WTSI, said during the call. This strain in particular appears to have emerged in Europe in the 1960s—a time when antibiotic use was on the rise in that part of the world.

Mutations on the move
In comparing the genetic sequences of the bacteria samples that had been collected on various continents, the team found that the isolates tended to be strongly clustered geographically, with closely related forms throughout South America, whereas others were more common in Asia. This finding “suggests that intercontinental transmission is a rare event,” Harris said. The paper describing the project highlights some of these apparently infrequent infections, describing one instance, for example, in which a Brazilian line of MRSA cropped up in a Portugal hospital, showing that the infection does occasionally get transmitted between continents.

All of these conclusions are made possible by the newly detailed picture of the genetic changes that the bacterium undergoes across generations. This process of genetic mutation is occurring at the rate of about one core base pair every six weeks, the researchers deduced. It may sound plodding, but this rate is “far faster than was previously thought,” Harris said. This bacterium’s substitution rate is, the authors pointed out, about 1,000 times more rapid than the estimated rate for Escherichia coli.

Beyond the speed of mutations, their accumulation seemed to boost the most problematic aspect of the MRSA—its antibiotic resistance. And mutations that provide resistance appear to have happened on multiple occasions in various lines of a single strain, as Harris explained: “Mutations that confer resistance are occurring around the world.” In particular, the resistance appears specifically tuned to popular antibiotics, which put “an immense selective pressure” on the bacteria, Harris said. In fact, some 29 percent of convergent mutations “can be directly related to evolution of resistance to antibiotic drugs currently in use, confirming clinical practice as a major driver of pathogen evolution,” the researchers concluded in the study.

By studying the origins and transmission patterns of MRSA, researchers hope to be able to recommend more effective ways to stem the spread of this aggressive form of staph—not just within hospitals but also among them and within other settings. With the higher-resolution analysis, “you can see if strains are being transmitted from patient to patient or being brought into the hospital,” Peacock said. Highly diverse samples collected over just seven months from a hospital in Thailand indicate that “there [were] multiple introductions,” Harris said. At this point it is not clear where these introductions are likely coming from, whether it is from workers, patients or visitors who have picked up the infection in other health care or community settings, but it is clear that the map of transmission has expanded beyond wards and hospital walls.

“We think about MRSA in two distinct boxes: hospital-acquired MRSA and community-acquired MRSA,” Peacock said. Increasingly, the two are overlapping, and Peacock noted that the community-acquired side appears to be growing even more prevalent. Although this analysis was conducted on hospital-based cases, an assay could also be done on community-based MRSA, she said.

Read Full Article at Scientific American

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World’s biodiversity ‘crisis’ needs action, says UN

11/01/2010 às 17:11 (Emergency on Planet Earth)

By Richard Black
Environment correspondent, BBC News website

Giant Jewel (Kai Schuette)

The Giant Jewel of West Africa is threatened by loss of forest

The UN has launched the International Year of Biodiversity, warning that the ongoing loss of species around the world is affecting human well-being.

Eight years ago, governments pledged to reduce the rate of biodiversity loss by 2010, but the pledge will not be met.

The expansion of human cities, farming and infrastructure is the main reason.

Speaking at the launch in Berlin, German premier Angela Merkel urged the establishment of a new panel to collate scientific findings on the issue.

Achim Steiner, executive director of the UN Environment Programme (UNEP), urged governments and their leaders to renew their commitment to curbing biodiversity loss even though the 2010 goal will be missed.

The big opportunity during the International Year of Biodiversity is for governments to do for biodiversity what they failed to do for climate change in Copenhagen
Simon Stuart
Conservation International/IUCN

“The urgency of the situation demands that as a global community we not only reverse the rate of loss, but that we stop the loss altogether and begin restoring the ecological infrastructure that has been damaged and degraded over the previous century or so,” he said.

The UN says that as natural systems such as forests and wetlands disappear, humanity loses the services they currently provide for free.

These include purification of air and water, protection from extreme weather events, and the provision of materials for shelter and fire.

With species extinctions running at about 1,000 times the “natural” or “background” rate, some biologists contend that we are in the middle of the Earth’s sixth great extinction – the previous five stemming from natural events such as asteroid impacts.

Cash log

The UN Convention on Biological Diversity (CBD) was agreed at the Rio Earth Summit of 1992, alongside the climate change convention.

FROM BBC WORLD SERVICE

But it acquired its key global pledge during the Johannesburg summit of 2002, when governments agreed to achieve a “significant reduction” in the rate of biological diversity loss by 2010.

Conservation organisations acknowledge that despite some regional successes, the target is not going to be met; some analyses suggest that nature loss is accelerating rather than decelerating.

“We are facing an extinction crisis,” said Jane Smart, director of the biodiversity conservation group with the International Union for the Conservation of Nature (IUCN).

“The loss of this beautiful and complex natural diversity that underpins all life on the planet is a serious threat to humankind now and in the future.”

Mrs Merkel backed the idea of forming a scientific panel to collate and assess research on biodiversity loss, as the Intergovernmental Panel on Climate Change (IPCC) assesses evidence on climatic indicators.

“The question of preserving biological diversity is on the same scale as climate protection,” she said.

“It would be sensible to have an interface between the politics and the science to integrate knowledge.”

Rainforest in Kakum National Park, Ghana

A large on-going UN-sponsored study into the economics of biodiversity suggests that deforestation alone costs the global economy $2-5 trillion each year.

The UN hopes some kind of legally-binding treaty to curb biodiversity loss can be agreed at the CBD summit, held in Japan in October.

One element is due to be a long-awaited protocol under which the genetic resources of financially-poor but biodiversity-rich nations can be exploited in a way that brings benefits to all.

However, given the lack of appetite for legally-binding environmental agreements that key countries displayed at last month’s climate summit in Copenhagen, it is unclear just what kind of deal might materialise on biodiversity.

Political football

The UN has been pursuing new ways of raising public awareness on the issue, including a collaboration with the Cameroon football team taking part in the African Nations Cup finals.

Many environment organisations will be running special programmes and mounting events during the year.

“The big opportunity during the International Year of Biodiversity is for governments to do for biodiversity what they failed to do for climate change in Copenhagen,” said Simon Stuart, a senior science advisor to Conservation International and chair of IUCN’s Species Survival Commission.

“They have the chance to make a major difference; and key to this will be halting species extinctions, the most irreversible aspect of biodiversity loss.”

WWF is highlighting 10 species it considers especially threatened, ranging from commercially significant ones such as bluefin tuna to the Pacific walrus and the monarch butterfly.

In the UK, the national IYB partnership – hosted from the Natural History Museum (NHM) – is asking every citizen to “do one thing for biodiversity” in 2010.

Richard.Black-INTERNET@bbc.co.uk

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Q&A: JCVI’s New Rockville Campus Director Karen Nelson on Current and Future Sequencing Projects

08/01/2010 às 19:17 (Expressão Gênica, GWAS, Medicina, Sequenciamento, Solid, whole transcriptome)

Name: Karen Nelson
Age: 45
Position: Director of the J. Craig Venter Institute Rockville campus, since 2009
Experience and Education:
Other positions, JCVI, since 1996
PhD in microbiology, Cornell University, 1996
MS in animal science, University of Florida, Gainesville, 1992
BS in animal science, University of the West Indies, Trinidad and Tobago, 1987

Karen Nelson was recently named head of the J. Craig Venter Institute’s Rockville, Md., campus. She succeeds Robert Strausberg, who is moving to the Ludwig Institute for Cancer Research as director for collaborative sciences.

Nelson has been with JCVI since 1996, when she came on board as a postdoctoral fellow and the center was still known as the Institute for Genomic Research. She was involved with the institute’s early metagenomic projects, including its first metagenomic analysis, published in 2006, of the microbial diversity found in human fecal matter.

Nelson also led the team that sequenced the bacterium Thermotoga maritime, which lives in 175 ºF water. She eventually became the director of human microbiology and metagenomics in the department of human medicine and genomics at JCVI and has played a large role in the human microbiome project, which aims to characterize and analyze the entire human microbiota.

Recently, Nelson spoke with In Sequence about the future of JCVI’s research and how new sequencing technologies are expanding the scope of what researchers there are able to study.

What are your plans and what projects are you involved in as the new head of JCVI’s Rockville campus?

My training is as a microbiologist, so I’m very excited about looking at the areas of metagenomics, and looking at all the microbial species that we have not been able to culture but now we can access with these new sequencing technologies.

We have a very strong infrastructure in terms of sequencing and data analysis. We have a very strong informatics team involved in the annotation and comparative analysis of these large data sets. So I expect that we will continue to play a major role in terms of the metagenomic analyses of not only the human body but a number of other environments.

We have collaborations looking at the metagenomics of domesticated and wild animals, and we have a huge pipeline analysis of viruses, particularly flu, that’s funded by the NIAID. We’re looking at viruses in the environment and how viruses hop from their natural reservoir into humans.

On the environmental side, we were approached by the University of the West Indies to go to Trinidad and start sampling some of the areas where they have oil reservoirs, to use microbial-based approaches and metagenomic-based approaches to help look at the methane cycle in cleaning up the environment.

So, we have a number of very large-scale studies — both single genomes and large metagenomic studies — that I expect will continue to expand and diversify.

Will you be going in any new directions in the coming years?

I’m hoping to take advantage of the new sequencing technologies, and the whole area that is allowing us to generate larger data sets. We have the tools to analyze the data, but now we can actually generate the data at a reduced cost and in much larger quantities than you could imagine before.

Going beyond gene sequencing, I’m also looking at the transcriptome and the whole area of meta-transcriptomics.

And also, partnering more closely with the traditional microbiologists. The thing that is obviously coming out of sequencing now is that we really can’t culture a lot of these organisms, but we can probably figure out ways to pull them out of the environment, for example, using single-cell approaches. We can now start to figure out how to pull out single cells and get the genome of something that hasn’t been cultivated before and, using a reverse of the traditional approach, figure out how to culture these isolates now. So I think that whole area of using sequencing to pull out uncultured isolates and figure out their physiology and what they’re really about is going to be really exciting. We have a group here that is focused on looking at single-cell isolates — pulling these isolates out, generating their genome, and then hopefully culturing some of these guys.

What sequencing technologies are you using?

We work very closely with the companies that produce the instruments and we’re continuously exploring new avenues and keeping ahead of the newest technologies that are out there. We’re working with Illumina, [Roche’s] 454 [group], Life Technologies. We are also looking at Pacific Biosciences.

We have 454 on campus, and we also have both [Illumina] and SOLiD systems. So we’re working on all different platforms. And also we’re looking into when you merge the datasets and samples and different platforms together — the different platforms have different benefits. Some are longer, some are shorter, some give you much more data than others. We’re constantly looking into exploring those.

[In the human microbiome project], we’re using a combination of all platforms. We’re even doing a little bit of Sanger. We’re doing a lot of 454 and [Illumina] and we’ll be working towards assembling large data sets based on both platforms. The different platforms have different benefits and we’re aiming to take advantage of those. Just as an example, some of the isolates for our reference genome sequencing are closely related. So, you can [sequence one of the isolates] with 454, and then you can do multiple, closely related cousins on different platforms, and you get deeper coverage at reduced cost. We are being very creative in terms of how we merge different platforms of sequencing — it’s not going to be one single platform.

Where are you in the human microbiome project, and what will you be doing going forward?

We have multiple projects. One component is devoted to the four large-scale centers – Baylor [University], JCVI, [the Broad Institute], [Washington University] — and for that part we are sequencing from 15 to18 different body sites. I think it’s close to 600 people now that we have recruited. So, different samples from the body sites are being sent to the centers and they’re all being collated and then hosted by the data analysis and collation center. So we are creating primarily a huge resource for the community.

In addition to that, we are going to be doing between 200 [and] 300 reference genomes with the hope that we will be able to align a lot of this metagenomic data to these reference genomes. The [human microbiome] consortium is doing between 900 [and] 1,000 reference genomes, but just at JCVI, we’re doing 200 to 300. And, for that we get samples from all over the world.

In addition, we were awarded two demonstration projects. So, I have a project at [New York University] with Zhiheng Pei, where we’re following 80 individuals over the next few years and looking at esophageal cancer. We have preliminary information that would suggest that there is a microbial component to cancer of the esophagus. And, another individual at JCVI who works very heavily on the human microbial initiative is Dr. Barbara Methe. She also has a demonstration project from the National Institutes of Health looking at psoriasis in collaboration with Dr. Martin Blaser [at NYU].

You mentioned earlier being excited about taking advantage of the new sequencing technologies. How are these advancements in sequencing technology impacting the scope of what you’re able to do, and the pace of your research?

The scope became much larger. I always tease my colleagues and say that in 2006 you could get on the cover of Nature with two people. And now, it’s like, if you have a hundred, well maybe that gets you in one of the top journals. So things have really changed in the past few years.

I think by virtue of having access to the new technologies, we can adapt questions beyond just our immediate area. For example, we would like to be able to look at diseases in the developing world. And now we can probably do that because costs have come down so much. You can focus on a population beyond just the populations that have been most traditionally studied. So I think it’s really expanding the concept of which diseases we can look at, which health conditions we can look at, and even for the environment, we can now sequence much deeper in the environment, and access microbial diversity far beyond what we could have done five or ten years ago.

But in parallel with that, we’ve had to obviously keep up the pace on the data analysis side and data storage side because you have so much more data coming out. So that’s also been another exciting area for us. We have people like Shibu Yooseph and Granger Sutton. They work very closely with the data and look at the assembly approaches we have to use and the metagenomics tools that have to be adapted.

One of the things to point out is that of the large sequencing centers, JCVI has been at the forefront of metagenomics and has probably processed the largest number of metagenomic data sets just by virtue of when we got on board in the process. So, we’ve really had to keep apace and learn rapidly the new tools — what works, what doesn’t work, and how we have to grow to adapt to new sequencing technologies as they come on board

It’s actually never been dull, but especially in the last few years with the new sequencing technologies, it’s become particularly exciting.

And I think also, we can now ask this question about the rare species in environments. I think because we were limited before by sequencing depth, we were not able to drill down and see what they call the minor players. And now we can actually start to access these organisms. Just to give you an example, Scott Peterson, who is at the [JCVI] Rockville campus, has been looking at oral plaque and he has been able to show you using subtractive hybridization approaches, that when you pull out the dominant players you can see up to 50 to100 species that you have not seen traditionally before as being present in the oral cavity. And that’s because people have not been able to drill down to that depth previously.

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Mammalian Genomes House Non-Retroviral RNA Virus Sequences, Study Finds

07/01/2010 às 08:13 (Diagnóstico Molecular, Medicina, Virus)

NEW YORK (GenomeWeb News)

January 06, 2010
By a GenomeWeb staff reporter

An international research team has garnered evidence that bits of non-retroviral RNA viral elements have made their way into mammalian genomes.

A Japanese and American research team searched through mammalian and other sequence databases for sequences resembling the non-retroviral RNA bornaviruses. Indeed, their search turned up endogenous Borna-like N elements, which they dubbed EBLN elements, in the human genome and genomes of other animals including non-human primates, rodents, and the elephant.

The research, which appeared online today in Nature, offer the first evidence of such non-retroviral sequence incorporation into mammalian genomes — and suggests bornaviruses infected some mammalian species tens of millions of years ago.

“Our results provide the first evidence for endogenization of non-retroviral virus-derived elements in mammalian genomes and give novel insights not only into generation of endogenous elements, but also into a role of bornavirus as a source of genetic novelty in its host,” senior author Keizo Tomonaga, a virology researcher affiliated with Osaka University and the Japan Science and Technology Agency, and colleagues wrote.

Mammalian genomes are known to contain viral sequences. But so far researchers have only found evidence of retroviral sequences in these genomes.

On the contrary, the new study suggests mammalian genomes also contain non-retroviral RNA from bornaviruses, a group of non-segmented, negative sense RNA viruses.

To find these sequences, the researchers first trolled human protein databases for sequences resembling those found in Borna disease viruses. That search yielded two hypothetical proteins with sequence similarity to the bornavirus structural protein nucleoprotein.

After finding these human homologues, the researchers looked for EBLN elements in other mammalian genomes using tblastn searches of NCBI eukaryote and whole-genome shotgun sequence databases and Southern blot hybridization experiments.

In the process, the team found EBLN orthologues in chimpanzee, gorilla, orangutan, macaque, and other primate genomes. Similar sequences also turned up datasets representing the African elephant, cape hyrax, and several rodent species.

In their subsequent experiments, the team started unraveling the phylogenetic relationships between the EBLNs. They also provided evidence supporting the notion that bornavirus sequences can be copied to DNA and incorporated into the genome.

The researchers’ findings suggest EBLN elements have been around in primate genomes for more than 40 million years. In contrast, these elements seem to have become incorporated much more recently in the genome of the thirteen-lined ground squirrel (the only squirrel species in which they found EBLN elements).

Although it’s still unclear exactly how these viral elements got into mammalian genomes, the researchers argue that sequence characteristics suggest retrotransposon related reverse transcriptase may have been involved.

And while most EBLNs seem to occur in pseudogenes, the team noted that some of the elements might have functional roles in their host mammalian genomes — a possibility that requires further exploration.

“This report is the first to provide evidence of endogenous sequences derived from a non-retroviral RNA virus in mammalian sequences,” the team wrote, adding that the findings imply that bornaviruses are the “first non-retroviral RNA virus whose existence in prehistoric times has been confirmed.”

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Penis Microbiome Offers Clues about Circumcision Protection against HIV

07/01/2010 às 08:11 (Uncategorized)

NEW YORK (GenomeWeb News)

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Using a Virus’s Knack for Mutating to Wipe It Out

05/01/2010 às 14:28 (Medicina, Virus)

The New York Times

Published: January 4, 2010
Evolution is a virus’s secret weapon. The virus can rapidly slip on new disguises to evade our immune systems, and it can become resistant to antiviral drugs.

But some scientists are turning the virus’s secret weapon against it. They hope to cure infections by forcing viruses to evolve their way to extinction.

Viruses can evolve because of the mistakes they make when they replicate. All living things can mutate, but viruses are especially prone to these genetic errors. In fact, some species of viruses mutate hundreds of thousands of times faster than we do.

Many of the mutations that strike new viruses are fatal. Others only slow down their growth, and still others have no effect at all. A few mutations are beneficial, and the viruses that inherit those good mutations can swiftly dominate a viral population.

Viruses depend on this rapid evolution to infect a host successfully. Poliovirus, for example, enters the body in the gut and then moves into the bloodstream, muscles and, in a small fraction of cases, the nervous system.

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Evolution at a High Imposed Mutation Rate: Adaptation Obscures the Load in Phage T7

05/01/2010 às 14:22 (Medicina, Virus)

A Publication of The Genetics Society of America

Rachael Springman 1, Thomas Keller 1, Ian Molineux 1 and James J. Bull 1*

1 University of Texas at Austin

Manuscript received August 20, 2009
Manuscript accepted October 20, 2009

Abstract

Evolution at high mutation rates is expected to reduce population fitness deterministically by the accumulation of deleterious mutations. A high enough rate should even cause extinction (lethal mutagenesis), a principle motivating the clinical use of mutagenic drugs to treat viral infections. The impact of a high mutation rate on long-term viral fitness was tested here. A large population of the DNA bacteriophage T7 was grown with a mutagen, producing a genomic rate of 4 non-lethal mutations per generation, 2-3 orders of magnitude above the baseline rate. Fitness – viral growth rate in the mutagenic environment – was predicted to decline substantially; after 200 generations, fitness had increased, rejecting the model. A high mutation load was nonetheless evident from (i) many low- to moderate-frequency mutations in the population (averaging 245 per genome), and (ii) an 80% drop in average burst size. Twenty eight mutations reached high frequency and were thus presumably adaptive, clustered mostly in DNA metabolism genes, chiefly DNA polymerase. Yet blocking DNA polymerase evolution failed to yield a fitness decrease after 100 generations. Although mutagenic drugs have caused viral extinction in vitro under some conditions, this study is the first to match theory and fitness evolution at a high mutation rate. Failure of the theory challenges the quantitative basis of lethal mutagenesis and highlights the potential for adaptive evolution at high mutation rates.

Key Words: adaptation, evolution, lethal mutagenesis, mutation accumulation, virus


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