Category Archives: Genome

July 3, 2017

The genome sequences of two "false" corals offer a window into the evolution of calcification, which may help their reef-building cousins.

Mushroom polyps. Elephant ear corals. Disc anemones. Whatever you want to call themscientists prefer corallimorphsthese aquarium invertebrates are among the closest known relatives to reef-building corals. A team led by researchers from the Red Sea Research Center at KAUST has now sequenced the entire genomes of two such "naked" coral species, so-called because they don't lay down calcium carbonate skeletons.

DNA maps offer a window into the evolution of calcification and could help scientists save the world's coral reefs from extinction.

"These are the first genomes to be published from this group of organisms," said Manuel Aranda, an Assistant Professor of Marine Science at KAUST who led the genome project. "The resources and analysis we provide are the foundation for future studies aimed at understanding how corals evolved the ability to build one of the most productive and biodiverse ecosystems on our planet."

Aranda teamed up with researchers at the Scientific Centre of Monaco to extract DNA from tissue samples of Amplexidiscus fenestrafer and Discosoma sp., two corallimorphs with a shape like that of terrestrial mushrooms. Xin Wang, a Ph.D. student in Aranda's lab, then worked with technicians at the KAUST Bioscience Core Facility to sequence, assemble and annotate both species' genomes. They pinpointed all the genes in the corallimorph genomes by looking for sequence similarity to known genes found in other species' genomes, including those of two sea anemones and a coral.

In this way, they confirmed that corallimorphs are the closest living relatives of reef-building corals, providing a much-needed genomic resource to fill the evolutionary gap between sea anemones and corals. They also showed that the A. fenestrafer genome is approximately 370-million DNA letters long with 21,372 genes and that the genome of A. Discosoma is 445-million nucleotides in length with 23,199 genes. These sizes are in between those for sea anemones and corals, consistent with the evolutionary history and complexity of this taxonomic grouping.

Scientists everywhere can now freely access and browse both new corallimorph genome maps though an online platform available at corallimorpharia.reefgenomics.org.

Aranda hopes the research community will use the genome sequences to better understand the evolutionary origin of the genes that allowed corals to become the ecosystem builders they are today. In his lab, for example, Aranda and his team are exploring the evolutionary innovations that corals had to make to acquire the ability to calcify. "So far," said Wang, "we have found several genes involved in calcification that have been uniquely duplicated in corals."

Explore further: Gene sequences reveal secrets of symbiosis

Advances in genomic research are helping scientists to reveal how corals and algae cooperate to combat environmental stresses. KAUST researchers have sequenced and compared the genomes of three strains of Symbiodinium, a ...

Single-celled plankton known as dinoflagellates are shown to cope with stress using an unexpected strategy of editing their RNA rather than changing gene expression levels.

Sequencing the genome of an organism allows scientists to investigate its unique genetic make-up, its evolutionary links to other creatures, and how it has adapted to its environment. Researchers at King Abdullah University ...

UH Mnoa scientists at the John A. Burns School of Medicineand the Hawaii Institute of Marine Biology have published new research showing that corals share many of the genes humans possess, especially those that can ...

New genome-sequence data show that Caribbean corals that have survived mass-extinction events caused by environmental change can rebound and expand their populations.

Unique sections of coral DNA can indicate a higher tolerance to environmental stress, researchers have revealed for the first time.

Beech trees should be considered native to Scotland - despite a long-running debate over their national identity, researchers at the University of Stirling and Science and Advice for Scottish Agriculture (SASA) report.

Purdue University scientists released research findings that indicate corn management processes contributing to optimal levels of plant nitrogen uptake could result in fewer nitrous oxide emissions, long identified as one ...

Arizona State University geoscientist Everett Shock has collaborated with a team of life scientists from Montana State University to discover a puzzle at the junction of geochemistry and biology.

Researchers from James Cook University and the Universit catholique de Louvain, Louvain-la-Neuve, Belgium say unprecedented oceanographic conditions in 2016 produced the perfect storm of factors that lead to a mass coral ...

Half a degree Celsius of global warming has been enough to increase heat waves and heavy rains in many regions of the planet, researchers reported Friday.

Oklahomans are no strangers to Mother Nature's whims. From tornadoes and floods to wildfires and winter storms, the state sees more than its share of natural hazards. But prior to 2009, "terra firma" in Oklahoma meant just ...

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Mushroom-like corals get their genomes mapped - Phys.Org

June 29, 2017 A hairpin loop from a pre-mRNA. Highlighted are the nucleobases (green) and the ribose-phosphate backbone (blue). Note that this is a single strand of RNA that folds back upon itself. Credit: Vossman/ Wikipedia

Our genomes are minefields, studded with potentially damaging DNA sequences over which hundreds of thousands of sentries stand guard. These sentries, called epigenetic marks, attach to the double helix at such spots and prevent the underlying DNA sequences from springing into destructive action.

About half the human genome is composed of these damaging sequences. They are places where ancient viruses and parasitic elements called transposons and retrotransposons have incorporated themselves over the long course of evolution. It's astonishing, then, to consider that during two of the most crucial processes in the life cycle, the sentries are removed, leaving the genome naked. The defenders are quickly welcomed back, but only after an interval in which the epigenetic slate is wiped clean.

Today in Cell, a team from Cold Spring Harbor Laboratory (CSHL) describes its discovery of what might be considered emergency replacements for the sentries, shock troops pressed into service across the genome only during these curiously undefended moments. Specifically, these defenders are protecting the genome in mammalian embryos, at the very early point in their development before they are implanted in the wall of the maternal uterus.

The preimplantation embryo is one of two normal settings in which epigenetic marks are wiped clean before being reinscribed. The other setting is a step in the formation of germline cells - sperm and eggswhich have temporary defenders already known to biology, so-called piwi-interacting RNAs (piRNAs). The research published today, led by first author Andrea Schorn, a postdoctoral investigator in the lab of Rob Martienssen, demonstrates that another species of small RNA performs an analogous genome-defending role in preimplantation embryos during an interval of epigenetic reprogramming. Dr. Martienssen is a CSHL Professor and HHMI-Gordon and Betty Moore Foundation investigator.

The newly identified defenders come in two varieties - RNA fragments consisting of 18 and 22 nucleotides. These RNA fragments, Dr. Schorn discovered, are perfect complements of sequences in retrotransposons that must be engaged in order for the genomic parasites to be activated.

This fact led to the discovery. Schorn scrutinized the contents of mouse embryonic stem cells and found many free-floating RNA fragments 18 nucleotides in length. Computer analysis revealed that their sequences perfectly matched sequences within transfer RNAs. tRNAs are ubiquitous, and are involved in the synthesis of proteins. It has been known for decades that tRNAs are hijacked by long terminal repeat (LTR)-retrotransposons, a portion of their sequence docking at a primer binding site (PBS) and initiating a process that activates the genomic parasite.

"Knowing that LTR retrotransposons need tRNAs to replicate, it was very tempting to believe that these 18-nucleotide tRNA fragments we were seeing in preimplantation embryonic stem cells could interfere with that process," says Schorn. "We think the cell is deliberately chopping up full-length tRNAs into smaller fragments precisely because both tRNAs and the fragments cut from them recognize the PBS. This means the small, tRNA-derived fragments would be able to occupy that site and inhibit retrotransposon replication and mobility," Martienssen explains.

The implications, Martienssen says, are potentially profound. This appears to tell us one way in which the genomes of mammals have tolerated vast numbers of transposons and other parasitic elements, even during periods when the genome is wiped clean of repressive epigenetic marks. "It's plausible that this is a very ancient mechanism that cells have found to not only inhibit retrotransposons but help in protection against viruses as well," Martienssen says.

Explore further: Newly identified small-RNA pathway defends genome against the enemy within

More information: "LTR-Retrotransposon Control by tRNA-Derived Small RNAs" appears online in Cell June 29, 2017.

Journal reference: Cell

Provided by: Cold Spring Harbor Laboratory

Reproductive cells, such as an egg and sperm, join to form stem cells that can mature into any tissue type. But how do reproductive cells arise? We humans are born with all of the reproductive cells that we will ever produce. ...

In plant pollen grains, sperm cells, which carry the genetic material to be passed on to progeny, are cocooned within larger "companion" cells that are called pollen vegetative cells. These companions provide sperm with ...

During embryonic development in humans and other mammals, sperm and egg cells are essentially wiped clean of chemical modifications to DNA called epigenetic marks. They are then held in reserve to await fertilization.

Transfer RNAs (tRNAs) are ancient molecules and indispensable components of all living cells - they are found in all three kingdoms of life i.e., in archaea, bacteria and eukaryotes. In a cell, they are part of the machinery ...

Rotifers are tough, microscopic organisms highly resistant to radiation and repeated cycles of dehydration and rehydration. Now Irina Arkhipova, Irina Yushenova, and Fernando Rodriguez of the Marine Biological Laboratory ...

Much like cancer cells, plant cells grown for a long time outside of their normal milieu, in culture dishes, have highly unstable genomes. Changes in gene activity, or how genes are "expressed," help cells cope with challenging ...

Photosynthesis is one of the most complicated and important processesresponsible for kick-starting Earth's food chain. While we have modeled its more-than-100 major steps, scientists are still discovering the purpose of ...

Whether or not society shakes its addiction to oil and gasoline will depend on a number of profound environmental, geopolitical and societal factors.

The actions of a protein used for DNA replication and repair are guided by electrostatic forces known as phosphate steering, a finding that not only reveals key details about a vital process in healthy cells, but provides ...

Worker and queen honeybees exposed to field realistic levels of neonicotinoids die sooner, reducing the health of the entire colony, a new study led by York University biologists has found.

If aliens sent an exploratory mission to Earth, one of the first things they'd noticeafter the fluffy white clouds and blue oceans of our water worldwould be the way vegetation grades from exuberance at the equator ...

Researchers from the Centre for Ecology & Hydrology (CEH) publish results of a large-scale, field-realistic experiment to assess neonicotinoid impacts on honeybees and wild bees across Europe, in the peer-review journal Science ...

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Newly identified small RNA fragments defend the genome when it's ... - Phys.Org

Advances in technology have made it much easier, faster and less expensive to do whole genome sequencingFalling costs have given rise to speculation that it could soon become a routine part of medical care, perhaps as routine as checking your blood pressure.

But will such tests, which can be done for as little as $1,000, prove useful, or needlessly scary?

The first closely-controlled study aimed at answering that question suggests that doctors and their patients can handle the flood of information the tests would produce.

Jason Vassy, a researcher at the VA Boston Healthcare System who led the study,sought to find out what routine testing would look like in a general medicine setting. They studied 100 healthy, middle-aged patients whose primary care physicians randomly asked them if they were interested in having their genomes sequenced.

Among the 50 volunteers who got sequenced, the researchers found that about 1 in 5 had a variant in their genome that was associated with a rare, sometimes serious genetic diseaseMost of them were fine, but what happened next surprised the researchers: Neither the volunteers nor their doctors overreacted.

We were pleasantly surprised to see that primary care physicians were able to manage their patients genetic results appropriately, Vassy says.

[However,] others fear that people who get sequenced could be subject to discrimination.

The GLP aggregated and excerpted this blog/article to reflect the diversity of news, opinion, and analysis. Read full, original post:Routine DNA Sequencing May Be Helpful And Not As Scary As Feared

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Sequencing your genome may become a routine part of family checkup - Genetic Literacy Project

CHICAGO The rise of whole genome sequencing is changing the way state and federal health officials are responding to foodborne illness outbreaks.

Speaking at the May 8-11 Food Safety Summit in Chicago, Matthew Wise, lead for outbreak response team at the Centers for Disease Control and Prevention, said the use of whole genome sequencing is an improvement over DNA sequencing techniques in trying to connect potentially related illnesses.

That DNA fingerprinting system has been very very successful but there are times that it doesnt work very well, Wise said. The whole genome sequencing really has the opportunity to address some of the gap.

Calling whole genome sequencing a much higher resolution picture of the bacteria making people sick, Wise said the CDC can compare the bacteria found in victims with bacteria found in food production environments. It gives us more confidence to be able to (know) that those in fact are connected in some way or another, he said.

For testing of listeria, whole genome sequencing started in 2013 with a pilot project between the Food and Drug Administration, the CDC, the U.S. Department of Agriculture and the National Institutes of Health.

Essentially all the agencies agreed to sequence all the listeria starting in 2013 and now it is a routine part of public health surveillance.

In coming years, Wise said there will be more and more investment by state and local health departments to have sequencing capacity.

We are getting to a point where salmonella and all Shiga toxin-producing E. coli will be sequenced, just as is being done for listeria, he said.

I think potentially this will mean (the ability) to identify a lot more outbreaks, and give us more confidence when starting (outbreak) investigations.Whole genome sequencing is having an impact on the decisions that the CDC makes every day concerning outbreak investigations, he said.

The technology has helped the CDC exclude people that are not a part of an outbreak, and also has demonstrated that some (events) that look like an outbreak actually were not.

The other thing it has showed us is that there are people that might appear unrelated to one another that we wouldnt have thought were connected in the past when we get that high-resolution genomic data we see that they are connected and we should investigate them together.

The technology also has helped the CDC understand the pathology of pathogen reservoirs in the environment of food protection, and whether those trouble spots have been around a long time.

Outbreak response capacity is increasing, with 28 states or jurisdictions getting extra money from the federal government to have more boots on the ground to interview people when they get sick.

The FDA also is giving money to the states to increase the capacity of rapid response teams that give additional resources for state level outbreak investigations, Wise said.

Wise said the growing role of food and environmental isolates in outbreak investigations is largely a function of whole genome sequencing.

Now we have so much more confidence that a food or environmental isolate is linked to cases with that same bacteria. It gives us more of a toehold to ask the right questions about what might be causing the outbreak, he said. In the past, health officials looked for an outbreak by seeing a lot of people get sick at once and interviewing them to try to figure out what happened.

Now we are having more outbreaks where we might find a bacteria in a food or environment and then look backward to see if they are linked to those (illnesses), almost reverse investigations conducted sometimes, he said. Wise said the CDC is really trying to move toward methods of outbreak response that are targeted at getting actionable information quickly.

When we find there is actionable advice that consumers can take to protect themselves, thats the point where we think about pulling the trigger and communicating, he said. We have made a lot of efforts to make that process more systematic and have more identifiable triggers to decide to take that action, he said.

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Influence of Whole Genome Sequencing growing beyond listeria - The Packer

Cancer cells may be streamlining their genome in order to replicate themselves quicker. A new study has found that the cells remove large repetitive chunks of their DNA, which may explain how some drugs work in the battle against certain cancers. The study is published inPLOS Genetics.

As both human and mouse cancer cells grow, the researchers found that they startto extricate large pieces of repetitive sequences known as ribosomal DNA, the bits thathappen to code forthe ribosomes that aid in copying the genome. As this basically shortens the genome, it means that the cancer cells can simply replicate their entire genome much quicker, allowing the cancer to grow and spread at an accelerated speed.

But this removal of DNA sections comes with a cost. Studies have suggested that these portions of repetitive sequences, rather than being a mistake or meaningless, play an important role in allowing cells to survive DNA damage. By taking them out of the genome, it could go some way to explain why certaincancers are sensitive to DNA-damaging treatments.

Drugs that damage DNA are often used to treat cancer, but it's not clear why they would selectively kill cancer cells, explainsteam lead Jennifer L Gerton, an investigator at the Stowers Institute, in a statement.Our results suggest that off-loading copies of ribosomal DNA could create instability in the genome that makes cells particularly susceptible to chemotherapy with DNA-damaging drugs.

It may seem odd that the cancer cells are shedding DNA that codes for such vital components of the cell, particularly when the team expected they would increasecopies of ribosomal DNA as a way to speed up the copying of the genome. However, it turns out that the pressure exerted on the cancerous cells to proliferate is causing changes to the ribosomal DNA, making the cells get rid of the replications.

In experiments on yeast cells, getting rid of these extra copies has been found to makethe genome more sensitive to DNA damage. The team of researchers now plan tosee if this holds true with human cancer cells as well, and if so, whether it could help lead to new chemotherapy treatments in the battle against the disease.

Originally posted here:
Cancer Cells Found To Streamline Their Genome To Replicate Themselves Quicker - IFLScience

When students in Stanford Universitys Introduction to Bioengineering course sit for their final exams, the first question that they have to answer is about our ability to write DNA.

Scientists have fully sequenced the genomes of humans, trees, octopuses, bacteria, and thousands of other species. But it may soon become possible to not just read large genomes but also to write themsynthesizing them from scratch. Imagine a music synthesizer with only four keys, said Stanford professor Drew Endy to the audience at the Aspen Ideas Festival, which is co-hosted by the Aspen Institute and The Atlantic. Each represents one of the four building blocks of DNAA, C, G, and T. Press the keys in sequence and you can print out whatever stretch of DNA you like.

In 2010, one group did this for a bacterium with an exceptionally tiny genome, crafting all million or so letters of its DNA and implanting it into a hollow cell. Another team is part-way through writing the more complex genome of bakers yeast, with 12 million letters. The human genome is 300 times bigger, and as I reported last month, others are trying to build the technology that will allow them to create genomes of this size.

For now, thats prohibitively expensive, but it wont always be that way. In 2003, it cost 4 dollars to press one of the keys on Endys hypothetical synthesizer. This month, it costs just two centsa 200-fold decrease in price in just 14 years. In the same time frame, the cost of tuition at Stanford has doubled, and is now around $50,000. Given all of that, the first question that Stanfords budding bioengineers get is this:

At what point will the cost of printing DNA to create a human equal the cost of teaching a student in Stanford?

And the answer is: 19 years from today.

There are a lot of assumptions built into that answer. It will take a lot of technological advances to print the complex genomes of humans and to keep the costs falling at the same pace as they have done. But bearing those assumptions in mind, the problem is a mathematical one, and the students are graded on their ability to solve it. But the follow-up question is a little more complicated:

If you and your future partner are planning to have kids, would you start saving money for college tuition, or for printing the genome of your offspring?

The question tends to split students down the line, says Endy. About 60 percent say that printing a genome is wrong, and flies against what it means to be a parent. They prize the special nature of education and would opt to save for the tuition. But around 40 percent of the class will say that the value of education may change in the future, and if genetic technology becomes mature, and allows them to secure advantages for them and their lineage, they might as well do that.

There is clearly no right answer to the second question, and students are graded on their reasoning rather than their conclusion. But when both questions are considered together, they suggest, Endy says, that in the order of a human generation, well have to face possibilities that are much stranger than what were prepared for.

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The Moral Question That Stanford Asks Its Bioengineering Students - The Atlantic

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Given that genes make up a paltry 2 percent of the genome, theyve received a disproportionate amount of attention from autism researchers. Slowly, however, the other 98 percent of the genome the so-called dark matter is emerging from the shadows.

Once considered nonfunctional or junk DNA, these non-gene regions are now known to contain instructions for making pieces of RNA that fine-tune the activity of genes. The RNA segments control when and where genes are active. Autism researchers have looked at the role of these RNAs for only about a decade, but they already have tantalizing clues that the segments seem to be involved in the condition.

Its an important field that hasnt really been studied very much yet, says Daniel Campbell, assistant professor of psychiatry at the University of Southern California in Los Angeles.

Evidence so far suggests that some noncoding RNAs are unusually scarce and others unusually abundant in people with autism. A few of the RNAs regulate autism genes or signaling pathways implicated in the condition.

Because of this, noncoding RNAs could also lead to treatments for autism.

When the cause of a disorder is in the regulation of genes, then it might be a better target for intervention than having to repair a gene, says Dorret Boomsma, professor of genetics and psychology at Vrije University in Amsterdam.

There are two major types of noncoding RNA: short stretches called microRNAs, which are roughly 20 nucleotides in length; and so-called long noncoding RNAs (lncRNAs), which have more than 200 nucleotides.

Both types typically turn genes off, but do so in different ways. microRNAs bind to messenger RNA (mRNA), the template for a protein thats created from a gene, and either destabilize it or block the machinery that translates it into protein. lncRNAs target mRNAs, but they can also bind and block microRNAs. And they can influence gene expression by interacting either with proteins that turn genes on or off or with those that control how tightly DNA is packed in the nucleus.

Some noncoding RNAs are more abundant in the brain than in other tissues, and seem to be needed for forming neurons and the connections, or synapses, between them.

Changes to the levels of these RNAs can have serious consequences for brain development and function, says Boryana Stamova, associate adjunct professor of neurology at the University of California, Davis.

For example, altered levels of noncoding RNA in the brains of people with autism track with a drop in the expression of genes important for brain signaling, and a rise in the expression of genes in the immune system. Both pathways are implicated in autism.

However, each study generates a different list of noncoding RNAs linked to autism, and few RNAs have consistently been tied to the condition. Some of these inconsistencies could be due to variable methods for detecting noncoding RNAs. Also, noncoding RNA expression patterns vary with age, sex, brain region and even cell type all factors that could contribute to the inconsistencies.

Some preliminary genetic evidence hints at how the levels of noncoding RNAs may be altered in autism.

For example, large deletions or duplications in the genome often overlap with noncoding RNAs. Roughly 40 such mutations with strong ties to autism contain known microRNAs1.

Smaller mutations can also involve noncoding RNAs. A 2009 study pinpointed a stretch of chromosome 5 as a site for common variants linked to autism. Campbells team explored this region and found that it encodes a lncRNA called MSNP1AS. MSNP1AS turned out to be unusually abundant in the brains of people with autism who carry common variants in this genetic region2.

Campbells team discovered that MSNP1AS turns off a gene called MSN that is involved in brain development. Last year, they reported that excess MSNP1AS decreases the number of signal-receiving branches on cultured neurons3. When the researchers tamped down the levels of MSNP1AS, they found changes in the expression of genes involved in the immune system, protein production and DNA packaging4.

All three of those pathways have been implicated by people looking at protein-coding genes that are mutated in autism, Campbell says.

Campbells team has also reported that CHD8, one of the strongest autism candidate genes, controls the quantity of noncoding RNAs in a cell5.

Some researchers are comprehensively scanning noncoding regions for mutations linked to autism. They are sequencing the whole genomes of people with autism and their unaffected relatives to find spontaneous mutations. Some of the mutations in noncoding RNAs may turn out to contribute to autism, says Ivan Iossifov, associate professor at Cold Spring Harbor Laboratory in New York. Once we get more data, this will become a very important focus, he says.

Other teams are working out the role of noncoding RNAs in animal models.

For example, researchers have found enhanced levels of AK081227, a lncRNA, in a mouse model of Rett syndrome, a condition related to autism. The researchers found that this lncRNA controls the expression of a receptor for gamma-aminobutyric acid, a chemical messenger implicated in autism.

Another study, published in April, showed that Rett mice have increased levels of two microRNAs that impair neuron formation in utero6. Blocking these microRNAs returns neuron formation to normal.

Studies like these hint that manipulating the RNAs might treat autism although that strategy is not straightforward.

You can use specific RNA sequences to overexpress or inhibit microRNAs in a mouse, says Nikolaos Mellios, assistant professor of neuroscience at the University of New Mexico in Albuquerque. But this is difficult for the clinic.

The primary hurdle is delivering the RNAs to the brain, because they typically cannot cross the blood-brain barrier. Even if they could, researchers would need to ensure that the RNAs affect only the intended regions.

There are several clinical trials underway using noncoding RNAs to treat cancer and diabetes. Last year, the U.S. Food and Drug Administration approved an RNA-based treatment for spinal muscular atrophy, which is otherwise fatal. The drug must be injected repeatedly into infants spinal fluid, and so is unlikely to be adopted for less severe conditions. Still, the approval supports the idea that RNAs can be used to treat neurological conditions.

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Genome's 'dark' side steps into spotlight of autism research - Spectrum

A Burmese python superimposed on an analysis of gene expression that uncovers how the species' organs change after feeding. Credit: Todd Castoe

Evolution takes eons, but it leaves marks on the genomes of organisms that can be detected with DNA sequencing and analysis.

As methods for studying and comparing genetic data improve, scientists are beginning to decode these marks to reconstruct the evolutionary history of species, as well as how variants of genes give rise to unique traits.

A research team at the University of Texas at Arlington led by assistant professor of biology Todd Castoe has been exploring the genomes of snakes and lizards to answer critical questions about these creatures' evolutionary history. For instance, how did they develop venom? How do they regenerate their organs? And how do evolutionarily-derived variations in genes lead to variations in how organisms look and function?

"Some of the most basic questions drive our research. Yet trying to understand the genetic explanations of such questions is surprisingly difficult considering most vertebrate genomes, including our own, are made up of literally billions of DNA bases that can determine how an organism looks and functions," says Castoe. "Understanding these links between differences in DNA and differences in form and function is central to understanding biology and disease, and investigating these critical links requires massive computing power."

To uncover new insights that link variation in DNA with variation in vertebrate form and function, Castoe's group uses supercomputing and data analysis resources at the Texas Advanced Computing Center or TACC, one of the world's leading centers for computational discovery.

Recently, they used TACC's supercomputers to understand the mechanisms by which Burmese pythons regenerate their organs including their heart, liver, kidney, and small intestines after feeding.

Burmese pythons (as well as other snakes) massively downregulate their metabolic and physiological functions during extended periods of fasting. During this time their organs atrophy, saving energy. However, upon feeding, the size and function of these organs, along with their ability to generate energy, dramatically increase to accommodate digestion.

Within 48 hours of feeding, Burmese pythons can undergo up to a 44-fold increase in metabolic rate and the mass of their major organs can increase by 40 to 100 percent.

Writing in BMC Genomics in May 2017, the researchers described their efforts to compare gene expression in pythons that were fasting, one day post-feeding and four days post-feeding. They sequenced pythons in these three states and identified 1,700 genes that were significantly different pre- and post-feeding. They then performed statistical analyses to identify the key drivers of organ regeneration across different types of tissues.

What they found was that a few sets of genes were influencing the wholesale change of pythons' internal organ structure. Key proteins, produced and regulated by these important genes, activated a cascade of diverse, tissue-specific signals that led to regenerative organ growth.

Intriguingly, even mammalian cells have been shown to respond to serum produced by post-feeding pythons, suggesting that the signaling function is conserved across species and could one day be used to improve human health.

"We're interested in understanding the molecular basis of this phenomenon to see what genes are regulated related to the feeding response," says Daren Card, a doctoral student in Castoe's lab and one of the authors of the study. "Our hope is that we can leverage our understanding of how snakes accomplish organ regeneration to one day help treat human diseases."

Making Evolutionary Sense of Secondary Contact

Castoe and his team used a similar genomic approach to understand gene flow in two closely related species of western rattlesnakes with an intertwined genetic history.

The two species live on opposite sides of the Continental Divide in Mexico and the U.S. They were separated for thousands of years and evolved in response to different climates and habitat. However, over time their geographic ranges came back together to the point that the rattlesnakes began to crossbreed, leading to hybrids, some of which live in a region between the two distinct climates.

The work was motivated by a desire to understand what forces generate and maintain distinct species, and how shifts in the ranges of species (for example, due to global change) may impact species and speciation.

The researchers compared thousands of genes in the rattlesnakes' nuclear DNA to study genomic differentiation between the two lineages. Their comparisons revealed a relationship between genetic traits that are most important in evolution during isolation and those that are most important during secondary contact, with greater-than-expected overlap between genes in these two scenarios.

However, they also found regions of the rattlesnake genome that are important in only one of these two scenarios. For example, genes functioning in venom composition and in reproductive differences distinct traits that are important for adaptation to the local habitat likely diverged under selection when these species were isolated. They also found other sets of genes that were not originally important for diversification of form and function, that later became important in reducing the viability of hybrids. Overall, their results provide a genome-scale perspective on how speciation might work that can be tested and refined in studies of other species.

The team published their results in the April 2017 issue of Ecology and Evolution.

The Role of Supercomputing in Genomics Research

The studies performed by members of the Castoe lab rely on advanced computing for several aspects of the research. First, they use advanced computing to create genome assemblies putting millions of small chunks of DNA in the correct order.

"Vertebrate genomes are typically on the larger side, so it takes a lot of computational power to assemble them," says Card. "We use TACC a lot for that."

Next, the researchers use advanced computing to compare the results among many different samples, from multiple lineages, to identify subtle differences and patterns that would not be distinguishable otherwise.

Castoe's lab has their own in-house computers, but they fall short of what is needed to perform all of the studies the group is interested in working on.

"In terms of genome assemblies and the very intensive analyses we do, accessing larger resources from TACC is advantageous," Card says. "Certain things benefit substantially from the general output from TACC machines, but they also allow us to run 500 jobs at the same time, which speeds up the research process considerably."

A third computer-driven approach lets the team simulate the process of genetic evolution over millions of generations using synthetic biological data to deduce the rules of evolution, and to identify genes that may be important for adaptation.

For one such project, the team developed a new software tool called GppFst that allows researchers to differentiate genetic drift a neutral process whereby genes and gene sequences naturally change due to random mating within a population from genetic variations that are indicative of evolutionary changes caused by natural selection.

The tool uses simulations to statistically determine which changes are meaningful and can help biologists better understand the processes that underlie genetic variation. They described the tool in the May 2017 issue of Bioinformatics.

Lab members are able to access TACC resources through a unique initiative, called the University of Texas Research Cyberinfrastructure, which gives researchers from the state's 14 public universities and health centers access to TACC's systems and staff expertise.

"It's been integral to our research," said Richard Adams, another doctoral student in Castoe's group and the developer of GppFst. "We simulate large numbers of different evolutionary scenarios. For each, we want to have hundreds of replicates, which are required to fully vet our conclusions. There's no way to do that on our in-house systems. It would take 10 to 15 years to finish what we would need to do with our own machines frankly, it would be impossible without the use of TACC systems."

Though the roots of evolutionary biology can be found in field work and close observation, today, the field is deeply tied to computing, since the scale of genetic material tiny but voluminous -- cannot be viewed with the naked eye or put in order by an individual.

"The massive scale of genomes, together with rapid advances in gathering genome sequence information, has shifted the paradigm for many aspects of life science research," says Castoe.

"The bottleneck for discovery is no longer the generation of data, but instead is the analysis of such massive datasets. Data that takes less than a few weeks to generate can easily take years to analyze, and flexible shared supercomputing resources like TACC have become more critical than ever for advancing discovery in our field, and broadly for the life sciences."

This article has been republished frommaterialsprovided byUniversity of Texas at Austin. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference

Adams, R. H., Schield, D. R., Card, D. C., Blackmon, H., & Castoe, T. A. (2016). GppFst: Genomic posterior predictive simulations of FST and dXY for identifying outlier loci from population genomic data. Bioinformatics, 33(9), 1414-1415.

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Secrets of the Genome: How pythons regenerate their organs - Technology Networks

New gene editing tools transform disease models and future therapies CRISPR gene editing is taking biomedical research by storm. Providing the ultimate toolbox for genetic manipulation, many new applications for this technology are now being investigated and established. CRISPR systems are already delivering superior genetic models for fundamental disease research, drug screening and therapy development, rapid diagnostics, in vivo editing and correction of heritable conditions and now the first human CRISPR clinical trials.

The continuing patent battle for CRISPR-Cas9 licensing rights and the emergence of new editing systems such as Cpf1 has so far done nothing to slow the advance of CRISPR-Cas9 as the leading gene editing system. There are weekly press releases and updates on new advances and discoveries made possible with this technology; the first evidence is now emerging that CRISPR-Cas9 could provide cures for major diseases including cancers and devastating human viruses such as HIV-1.

The key to CRISPR-Cas9s uptake is its ease of application and design, with retargeting only a matter of designing new guide RNA. It has quickly surpassed TALENs (Transcription Activator-Like Effector Nucleases) and ZFNs (Zinc Finger Nucleases) where editing, now possible with CRISPR, was previously prohibitively complex and time-consuming. As well as correcting gene mutations with scar-less modifications, with CRISPR-Cas9 it is possible to control the expression of entire genes offering longer term expression alteration compared to other methods such as RNAi.

LNA GapmeRs are highly effective antisense oligonucleotides for knockdown of mRNA and lncRNA in vivo or in vitro. Designed using advanced algorithms, the RNase H-activating LNA gapmers offer excellent performance and a high success rate.

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CRISPR-Cas9 systems, tools and basic methodology are very accessible as ready to go toolkits that anyone with lab space and an idea can pick up and start working with. This is thanks largely to the efforts of Addgene and commercial service and product providers. Alongside CRISPR research there are innovations in companion technologies and design software. In response to a growing need, companies such as Desktop Genetics have developed open access software to accelerate CRISPR experimentation and analysis.

It is not all about CRISPR-Cas9 though. Like Cas9, Cpf1 is a DNA-targeting CRISPR enzyme that is also recruited to the target site by sequence homology but with slightly different site requirements. Cpf1 has been reported to be efficient and highly specific in human cells, with low off-target cleavage suggesting a role for Cpf1 in therapeutic applications down the line. Cas13a is an RNA-targeting CRISPR enzyme which is showing promise as a rapid diagnostic tool. Unlike Cas9, the enzyme continues to cut after it has acted on its intended RNA target, a characteristic which has been exploited to develop diagnostic technology for the likes of Zika and Dengue virus. The group behind SHERLOCK (Specific High Sensitivity Enzymatic Reporter UnLOCKing) combined this collateral effect of Cas13a with isothermal amplification and produced rapid DNA or RNA detection at attomolar sensitivity and with single-base mismatch specificity.

A particularly active area of CRISPR activity is the genetic manipulation of patient-derived stem cells to create models for diseases including Parkinsons, cystic fibrosis, cardiomyopathy and ischemic heart disease, to name but a few. With CRISPR it is now possible for researchers to correct disease-causing mutations in patient-derived pluripotent stem cells to create isogenic cell lines to differentiate to any cell type of interest for disease research. Generating these isogenic lines is making it possible, for the first time, to unambiguously show the contribution of gene mutations to a disease phenotype.

Dr Lise Munsie leads the pluripotent stem cell program at CCRM, a Canadian, not-for-profit organisation supporting the development of foundational technologies to support the commercialisation of cell and gene therapies, and regenerative medicine.

Gene editing technology now provides unlimited genetic flexibility to stem cell manipulation. You can target anywhere in the genome with relative ease and make it scar-less, saidDr Munsie.

Dr Munsies program is using CRISPR-Cas9 to produce reporter cell lines (for example with fluorescent protein inserted at a target gene) and isogenic lines from patient iPSCs. In stem cells, CRISPR-Cas9 is introduced with the Cas9 nuclease expressed from plasmid DNA or as purified Cas9 protein and the components are introduced into the cells by transfection or electroporation.

Dr Bjrn Brndl and his colleagues at the Lab for Integrative Biology at the Zentrum fr Integrative Psychiatrie, Universitatsklinikum Schleswig-Holstein, Germany, are also using stem cell gene editing to generate model systems for studying complex neurological disease such as Parkinsons and dyskinesia by correcting mutation in patient lines and introducing these mutations in control cells lines.

One of the biggest contributions of CRISPR to research is the ability to create isogenic stem cell lines. With these, we can create relevant disease models with near-perfect negative controls with the same genomic context varying only in the region of interest. Our goal is to compare disease patient lines with corrected lines by differentiating the induced pluripotent stem cells into neurons and studying differences in the phenotypes. In the biomedical field, we currently have a reproducibility crisis, so with clean and effective tools like isogenic pluripotent stem cells lines, we can improve the reproducibility and validity of our findings. One of the biggest challenges is working with the stem cells which are delicate and much more sensitive to the manipulations required for successful gene editing compared to standard cell lines.

CRISPR has completed upended how cell biology is approached. Being able to copy/paste DNA into the genomes has introduced a lot of ways of thinking about a problem. Genome editing has introduced engineering into the cell biology toolbox. saidDr Brndl.

An alarming number of bacteria are now resistant to our most effective antibiotics. The antibiotic resistance crisis has been given more of the attention it deserves thanks to initiatives from the WHO, UN, NICE and others but, in truth, the situation has been critical for over a decade. No new antibiotics have come out of pharma companies in the last 10 years and interest in their development has waned. Pharma companies are reluctant to invest the large sums required to develop new antimicrobials because of the inevitable resistant strains that will quickly follow and subsequent restrictions on their usage to preserve efficacy.

In short, we need a miracle, but the answer could come from CRISPR. Companies such as Nemesis Bioscience and Eligo Bioscience are developing antimicrobial technology and treatments made possible by CRISPR technology. Both technologies use modified bacteriophage as delivery vehicles for CRISPR-Cas9 gene editing systems that target and inactivate either virulence genes or the resistance genes themselves, leaving the rest of the microbiome intact.

Nemesis Bioscience employs CRISPR to target known bacterial resistance genes to deactivate them in situ and re-sensitise virulent bacteria making existing antibiotics effective again. Dr Frank Massam, CEO at Nemesis Biosciences explains, Killing bacteria stimulates resistance mutations we reasoned it would make more sense to inactivate bacterias ability to resist antibiotics and therefore make existing antibiotics work again. This approach would also mean that newly developed antibiotic assets could be protected from resistance, thereby increasing pharmas ROI and so making antibiotic development attractive again.

Nemesis Biosciences Symbiotics are based on modified CRISPR-Cas9 which enables highly multiplexed guide RNA targeting. Our first expression cassettes encode the S. pyogenes Cas9 plus a CRISPR array encoding guide RNAs that can target for inactivation members of 8 families of beta-lactamase genes. We call them the VONCKIST families, these are: VIM, OXA, NDM, CTX-M, IMP, SHV and TEM. The beta-lactamases encoded by these families are able to degrade >100 different types of beta-lactam antibiotics saidDr Massam.

The symbiotics are delivered by phage Transmids delivery vehicles based on phage architecture that deliver the DNA and then drop off. Once the Symbiotic is inside the bacteria, it can then spread further by conjugation from the edited bacteria to others it encounters, remaining invisible to the immune system. This provides both therapeutic applications as well as prophylactic ones in a probiotic delivery system to disarm the microbiome of antimicrobial-resistant bacteria. The technology is applicable to all bacteria, all antibiotic classes and all known resistance mechanisms and Nemesis have initially targeted resistant E. coli for in vivo testing.

Traditional small-molecule antibiotics target conserved bacterial cellular pathways or growth functions and therefore cannot selectively kill specific members of a complex microbial population. Eligo Biosciences flagship technology SSAMS eligobiotics, uses reprogrammed Cas9 targeted to bacterial virulence or resistance genes delivered by phagemids to produce selective killing of virulent and antibiotic resistant bacteria, leaving all other bacteria unaffected. The Eligo platform is being adapted for other microbial applications including in situ detection of specific live bacterial strains in complex microbiome samples and in situ expression of therapeutics protein to modulate and engineer host-microbiome interactions.

CRISPR-based therapies for human diseases could bring profound benefits to medicine, but there are many hurdles still to overcome. Despite the high degree of specificity of the CRISPR system, the induction of off-target mutations, at sites other than the intended target, is still a major concern especially in the context of therapeutic applications for heritable disease, and there are still considerable safety concerns about using CRISPR in humans. Assays for investigating the intended (on-target) and unintended (off-target) effects of CRISPR guides on in vitro and in vivo models are still in their infancy. The second major challenge is the development of safe carrier systems for CRISPR-Cas9 delivery to human cells in vivo.

Nonetheless, exciting progress is being made in the application of CRISPR gene editing to the treatment of heritable diseases for which there are only symptomatic treatments available, such as retinal myopathy where demonstrated recovery has been reported in a mouse model, and Duchenne muscular dystrophy, where the disease phenotype is reversed in mouse cells in vivo. We will also soon see the completion of the first clinical trials using CRISPR to try and correct genetic defects in vivo, the results of which are eagerly awaited.

There are a growing number of researchers from many disciplines collaborating to bring ambitious CRISPR-based insight, technology and therapeutics into the clinic. As CRISPR continues to undergo technical improvements, the prospects for these applications continues to look promising and as they move rapidly towards reality.

References

1. Yin, C., Zhang, T., Qu, X., Zhang, Y., Putatunda, R., Xiao, X., ... & Qin, X. (2017). In vivo excision of HIV-1 provirus by saCas9 and multiplex single-guide RNAs in animal models. Molecular Therapy.)

2. Hough SH, Kancleris K, Brody L, Humphryes-Kirilov N, Wolanski J, Dunaway K, Ajetunmobi A, Dillard V. Guide Picker is a comprehensive design tool for visualizing and selecting guides for CRISPR experiments. BMC bioinformatics. 2017 Mar 14;18(1):167.

3. Zetsche, B., Gootenberg, J. S., Abudayyeh, O. O., Slaymaker, I. M., Makarova, K. S., Essletzbichler, P., ... & Koonin, E. V. (2015). Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR-Cas system. Cell, 163(3), 759-771.

4. Kleinstiver, B. P., Tsai, S. Q., Prew, M. S., Nguyen, N. T., Welch, M. M., Lopez, J. M., ... & Joung, J. K. (2016). Genome-wide specificities of CRISPR-Cas Cpf1 nucleases in human cells. Nature biotechnology, 34(8), 869-874.

5. Gootenberg JS, Abudayyeh OO, Lee JW, Essletzbichler P, Dy AJ, Joung J, Verdine V, Donghia N, Daringer NM, Freije CA, Myhrvold C. Nucleic acid detection with CRISPR-Cas13a/C2c2. Science. 2017 Apr 13:eaam9321

6. Bikard, D., Euler, C. W., Jiang, W., Nussenzweig, P. M., Goldberg, G. W., Duportet, X., ... & Marraffini, L. A. (2014). Exploiting CRISPR-Cas nucleases to produce sequence-specific antimicrobials. Nature biotechnology, 32(11), 1146-1150.

7. Zhang, X. H., Tee, L. Y., Wang, X. G., Huang, Q. S., & Yang, S. H. (2015). Off-target effects in CRISPR/Cas9-mediated genome engineering. Molecular Therapy-Nucleic Acids, 4, e264.

8. Yu, W., Mookherjee, S., Chaitankar, V., Hiriyanna, S., Kim, J. W., Brooks, M., ... & Swaroop, A. (2017). Nrl knockdown by AAV-delivered CRISPR/Cas9 prevents retinal degeneration in mice. Nature Communications, 8.

9. Long, C., Amoasii, L., Mireault, A. A., McAnally, J. R., Li, H., Sanchez-Ortiz, E., ... & Olson, E. N. (2016). Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science, 351(6271), 400-403.

10. Nelson, C. E., Hakim, C. H., Ousterout, D. G., Thakore, P. I., Moreb, E. A., Rivera, R. M. C., ... & Asokan, A. (2016). In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science, 351(6271), 403-407.

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CRISPR: Emerging applications for genome editing technology - Technology Networks

Euan Ashley and his collaborators used long-read genome sequencing to diagnose a rare condition in a Stanford patient. It's the first time the technique has been used in a clinical setting. Steve Fisch

Stanford scientists have used a next-generation technology called long-read sequencing to diagnose a patients rare genetic condition that current technology failed to diagnose.

When Ricky Ramon was 7, he went for a routine checkup. The pediatrician, who lingered over his heartbeat, sent him for a chest X-ray, which revealed a benign tumor in the top-left chamber of his heart. For Ramon, it was the beginning of a long series of medical appointments, procedures and surgeries that would span nearly two decades.

During this time, noncancerous tumors kept reappearing in Ramons heart and throughout his body in his pituitary gland, adrenal glands above his kidneys, nodules in his thyroid.

The trouble was, doctors couldnt diagnose his condition.

When Ramon was 18, doctors thought his symptoms were suggestive of Carney complex, a genetic condition caused by mutations in a gene called PRKAR1A. However, evaluation of Ramons DNA revealed no disease-causing variations in this gene.

Now, eight years later, researchers at the Stanford University School of Medicine have used a next-generation technology long-read sequencing to secure a diagnosis for Ramon. Its the first time long-read, whole-genome sequencing has been used in a clinical setting, the researchers report in a paper published online June 22 in Genetics in Medicine.

Genome sequencing involves snipping DNA into pieces, reading the fragments, and then using a computer to patch the sequence together. DNA carries our genetic blueprint in a double-stranded string of molecular letters called nucleotides, or base pairs. The four types of nucleotides are each represented by a letter C for cytosine and G for guanine, for example and they form links across the two strands to hold DNA together.

Illuminating a dark corner

Current sequencing technologies cut DNA into words that are about 100 base-pairs, or letters, long, according to the studys senior author, Euan Ashley, DPhil, FRCP, professor of cardiovascular medicine, of genetics and of biomedical data science. Long-read sequencing, by comparison, cuts DNA into words that are thousands of letters long.

This allows us to illuminate dark corners of the genome like never before, Ashley said. Technology is such a powerful force in medicine. Its mind-blowing that we are able to routinely sequence patients genomes when just a few years ago this was unthinkable.

The study was conducted in collaboration with Pacific Biosciences, a biotechnology company in Menlo Park, California, that has pioneered a type of long-read sequencing. Lead authorship of the paper is shared by Jason Merker, MD, PhD, assistant professor of pathology and co-director of the Stanford Clinical Genomics Service, and Aaron Wenger, PhD, of Pacific Biosciences.

The type of long-read sequencing developed by the research teams collaborators at the company can continuously spool long threads of DNA for letter-by-letter analysis, limiting the number of cuts needed.

This is exciting, said Ashley, because instead of having 100-base-pair words, you now have 7,000- to 8,000-letter words.

Falling cost

Thanks to technological advances and increased efficiency, the cost of long-read sequencing has been falling dramatically. Ashley estimated the current cost of the sequencing used for this study at between $5,000 and $6,000 per genome.

Though the cost of short-read sequencing is now below $1,000, according to Ashley, parts of the genome are not accessible when cutting DNA into small fragments. Throughout the genome, series of repeated letters, such as GGCGGCGGC, can stretch for hundreds of base pairs. With only 100-letter words, it is impossible to know how long these stretches are, and the length can critically determine someones predisposition to disease.

Additionally, some portions of the human genome are redundant, meaning there are multiple places a 100-base pair segment could potentially fit in, said Ashley. This makes it impossible to know where to place those segments when reassembling the genome. With longer words, that happens much less often.

Given these issues, 5 percent of the genome cannot be uniquely mapped, the researchers wrote. And any deletions or insertions longer than about 50 letters are too long to detect.

For patients with undiagnosed conditions, short-read sequencing can help doctors provide a diagnosis in about one-third of cases, said Ashley. But Ramons case was not one of those.

The technique initially used to analyze Ramons genes failed to identify a mutation in the gene responsible for Carney complex, though Ashley said co-author Tam Sneddon, DPhil, a clinical data scientist at Stanford Health Care who browsed through the database of Ramons sequenced genome by hand, did notice something looked wrong. Ultimately, the long-read sequencing of Ramons genome identified a deletion of about 2,200 base-pairs and confirmed that a diagnosis of Carney complex was indeed correct.

This work is an example of Stanford Medicines focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.

An exceedingly rare condition

Carney complex arises from mutations in the PRKAR1A gene, and is characterized by increased risk for several tumor types, particularly in the heart and hormone-producing glands, such as ovaries, testes, adrenal glands, pituitary gland and thyroid. According to the National Institutes of Health, fewer than 750 individuals with this condition have been identified.

The most common symptom is benign heart tumors, or myxomas. Open heart surgery is required to remove cardiac myxomas; by the time Ramon was 18 years old, hed had three such surgeries. He is under consideration for a heart transplant, and having the correct diagnosis for his condition was important for the transplant team. Beyond the typical screening for a transplant, Ashley said the team needed to ensure there werent other health issues that could be exacerbated by immune suppressants, which heart transplant patients must take to avoid rejection of the donated organ.

Though it helps his medical team to have a confirmed diagnosis of Carney complex, Ramon has found it disheartening to face the fact that he cannot escape his condition. I was pretty sad, he said. It took me a while to come to terms with the fact that Ill have this until the day I die.

He tries not to dwell on it, though. Live one day at a time, he said. The bad days are temporary storms, and theyll pass.

His story is quite incredible, said Ashley, who said it was a privilege to be working on Ramons team. To have such a burden on such young shoulders, and to decide whether or not he wants a transplant, requires incredible courage.

Because he couldnt wait any longer for a transplant, Ramon recently underwent his fourth surgery to remove three tumors in his heart. Joseph Woo, MD, professor and chair of cardiothoracic surgery, performed the operation at Stanford Hospital. It is exceedingly rare to have tumors in the heart, said Ashley. It was a particularly heroic operation. Though Ramon is still under consideration for a transplant, the need is less urgent now.

Im in good hands, Ramon said of the Stanford team. Im glad to be here.

A future in the clinic?

Ashley said he and many other doctors believe that long-read technology is part of the future of genomics.

Now we get to see how to do it better, said Ashley. If we can get the cost of long-read sequencing down to where its accessible for everyone, I think it will be very useful.

This article has been republished frommaterialsprovided by Stanford University. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference

Merker, J., Wenger, A. M., Sneddon, T., Grove, M., Waggott, D., Utiramerur, S., ... & Korlach, J. (2016). Long-read whole genome sequencing identifies causal structural variation in a Mendelian disease. bioRxiv, 090985.

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Long-read Genome Sequencing Used for First Time in a Patient - Technology Networks