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First validated canine behavioral genetics, findings of nine fear, aggression traits in dogs

Anxiety disorders are the most common type of mental illness in the United States. And while much is understood about the biochemistry of anxiety, little is known about the genetic variation associated with it.

Recently published in BMC Genetics, a study led by researchers at Nationwide Children’s Hospital reports that genetic predisposition to aggression toward an owner or a familiar dog is distinct from that for fear and aggression directed at unfamiliar humans and dogs. The researchers identified approximately 12 genes associated with these traits.

“Our strongest focus is on specific genes related to aggression toward unfamiliar humans and dogs, which are associated with highly relevant genes at two genome regions,” said Carlos Alvarez, PhD, principal investigator in the Center for Molecular and Human Genetics in The Research Institute at Nationwide Children’s Hospital. “Those genes are consistent with the core fear and aggression neural pathway known as the amygdala to hypothalamic-pituitary-adrenal axis.”

The findings not only relate to the most important dog behavioral problems but are also likely to be highly relevant to human anxiety disorders, according to Dr. Alvarez.

While the most immediate implications are for veterinary behavioral medicine — genetic testing for risk of specific types of fear and aggression, the long term implications for adults and children with anxiety disorders are encouraging.

Because these risk variants are common across dog breeds, the canine veterinary setting provides an ideal testbed for new therapies targeting those biochemical pathways. Once it is determined which neuronal circuits are affected by the risk variation, this will likely reveal drug targets that could be inhibited or activated to increase or decrease the emotional behavioral effects. Those findings can immediately be tested in pet dog patients under owner consent. And, if those therapies are effective in dogs, they can then be applied to humans with similar conditions. Knowledge of the affected pathways will also provide biomarkers that can be used to identify the patients who are most likely to respond to such treatments.

“This project has only just begun,” said Dr. Alvarez. “We are continuing to identify and validate other genes associated with these traits, including the expansion of dog breeds studied and biological validation of the findings. We are excited about what this work will continue to uncover.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/08/160810180908.htm  Original web page at Science Daily

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* Lions in West and Central Africa apparently unique

Lions in West and Central Africa form a unique group, only distantly related to lions in East and Southern Africa. Biologists at Leiden University confirm this in an article published in Scientific Reports.

In this study, the researchers gathered a genetic dataset of lion populations covering a total of 22 countries. This included samples from each remaining lion population in West and Central Africa, a region where lions and other wildlife are rapidly declining as a consequence of the increasing human population. The researchers managed to gather all the information by teaming up with other people in the field and local conservationists.

Based on the genetic data, it was estimated that the split between the two major groups that can be identified in the lion must have occurred 300,000 years ago. To explain what happened in their evolution, the researchers made a reconstruction of African climatological history. It seems that periodic expansions of the rain forest and the desert drove lions into isolated pockets of suitable habitat, where the different genetic lineages originated that can still be observed today.

This influenced not only the patterns we observe in the lion, but also in other large mammals such as giraffe, buffalo, hartebeest, cheetah and spotted hyena. A general pattern is emerging that shows that many large African savannah mammals show very similar arrangements, with unique lineages in West and Central Africa.

The strong declines in wildlife populations in large parts of West and Central Africa are therefore a reason for major concern. The fact that this region seems to harbour a lot of unique genetic lineages makes conservation in the area extremely important. A delegation from Leiden University will participate in the IUCN World Conservation Congress in September 2016, and will lead a Side Event that aims to establish a Species Action Plan for West and Central Africa. The researchers hope that this will facilitate coordination and funding of projects in the region.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/08/160811120559.htm  Original web page at Science Daily

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* Gene therapy treats all muscles in the body in muscular dystrophy dogs

Muscular dystrophy, which affects approximately 250,000 people in the U.S., occurs when damaged muscle tissue is replaced with fibrous, fatty or bony tissue and loses function. For years, scientists have searched for a way to successfully treat the most common form of the disease, Duchenne Muscular Dystrophy (DMD), which primarily affects boys. Now, a team of University of Missouri researchers have successfully treated dogs with DMD and say that human clinical trials are being planned in the next few years.

“This is the most common muscle disease in boys, and there is currently no effective therapy,” said Dongsheng Duan, the study leader and the Margaret Proctor Mulligan Professor in Medical Research at the MU School of Medicine. “This discovery took our research team more than 10 years, but we believe we are on the cusp of having a treatment for the disease.”

Patients with Duchenne muscular dystrophy have a gene mutation that disrupts the production of a protein known as “dystrophin.” Absence of dystrophin starts a chain reaction that eventually leads to muscle cell degeneration and death. Affected boys lose their ability to walk and breathe as they get older. This places significant limitations on individuals afflicted with the disease. Dystrophin also is one of the largest genes in the human body.

“Due to its size, it is impossible to deliver the entire gene with a gene therapy vector, which is the vehicle that carries the therapeutic gene to the correct site in the body,” Duan said. “Through previous research, we were able to develop a miniature version of this gene called a microgene. This minimized dystrophin protected all muscles in the body of diseased mice.”

However, it took the team more than 10 years to develop a strategy that can safely send the micro-dystrophin to every muscle in a dog that is afflicted by the disease. The dog has a body size similar to that of an affected boy. Success in the dog will set the foundation for human tests.

In this latest study, the MU team demonstrated for the first time that a common virus can deliver the microgene to all muscles in the body of a diseased dog. The dogs were injected with the virus when they were two to three months old and just starting to show signs of DMD. The dogs are now six to seven months old and continue to develop normally

“The virus we are using is one of the most common viruses; it is also a virus that produces no symptoms in the human body, making this a safe way to spread the dystrophin gene throughout the body,” Duan said. “These dogs develop DMD naturally in a similar manner as humans. It’s important to treat DMD early before the disease does a lot of damage as this therapy has the greatest impact at the early stages in life.”

https://www.sciencedaily.com/  Science  Daily

https://www.sciencedaily.com/releases/2015/10/151022141722.htm  Original web page at Science Daily

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More evidence that ‘healthy obesity’ may be a myth

The term “healthy obesity” has gained traction over the past 15 years, but scientists have recently questioned its very existence. A study published August 18 in Cell Reports provides further evidence against the notion of a healthy obese state, revealing that white fat tissue samples from obese individuals classified as either metabolically healthy or unhealthy actually show nearly identical, abnormal changes in gene expression in response to insulin stimulation.

“The findings suggest that vigorous health interventions may be necessary for all obese individuals, even those previously considered to be metabolically healthy,” says first author Mikael Rydén of the Karolinska Institutet. “Since obesity is the major driver altering gene expression in fat tissue, we should continue to focus on preventing obesity.”

Obesity has reached epidemic proportions globally, affecting approximately 600 million people worldwide and significantly increasing the risk of heart disease, stroke, cancer, and type 2 diabetes. Since the 1940s, evidence supporting the link between obesity and metabolic and cardiovascular diseases has been steadily growing. But in the 1970s and 80s, experts began to question the extent to which obesity increases the risk for these disorders. Subsequent studies in the late 90s and early 2000s showed that some obese individuals display a relatively healthy metabolic and cardiovascular profile.

Recent estimates suggest that up to 30% of obese individuals are metabolically healthy and therefore may need less vigorous interventions to prevent obesity-related complications. A hallmark of metabolically healthy obesity is high sensitivity to the hormone insulin, which promotes the uptake of blood glucose into cells to be used for energy. However, there are currently no accepted criteria for identifying metabolically healthy obesity, and whether or not such a thing exists is now up for debate.

To address this controversy, Rydén, Carsten Daub, and Peter Arner of the Karolinska Institutet assessed responses to insulin in 15 healthy, never-obese participants and 50 obese subjects enrolled in a clinical study of gastric bypass surgery. The researchers took biopsies of abdominal white fat tissue before and at the end of a two-hour period of intravenous infusion of insulin and glucose. Based on the glucose uptake rate, the researchers classified 21 obese subjects as insulin sensitive and 29 as insulin resistant.

Surprisingly, mRNA sequencing of white fat tissue samples revealed a clear distinction between never-obese participants and both groups of obese individuals. White fat tissue from insulin-sensitive and insulin-resistant obese individuals showed nearly identical patterns of gene expression in response to insulin stimulation. These abnormal gene expression patterns were not influenced by cardiovascular or metabolic risk factors such as waist-to-hip ratio, heart rate, or blood pressure. The findings show that obesity rather than other common risk factors is likely the primary factor determining metabolic health.

“Our study suggests that the notion of metabolically healthy obesity may be more complicated than previously thought, at least in subcutaneous adipose tissue,” Rydén says. “There doesn’t appear to be a clear transcriptomic fingerprint that differentiates obese subjects with high or low insulin sensitivity, indicating that obesity per se is the major driver explaining the changes in gene expression.”

One limitation of the study is that it examined gene expression profiles only in subcutaneous white fat tissue, not other types of fat tissue or other organs. Moreover, all of the obese subjects were scheduled to undergo bariatric surgery, so the findings may only apply to individuals with severe obesity.

In future research, Rydén and his collaborators will track the study participants after bariatric surgery to determine whether weight loss normalizes gene expression responses to insulin. They will also look for specific genes linked to improved metabolic health in these individuals.

In the meantime, the study has an important take-home message. “Insulin-sensitive obese individuals may not be as metabolically healthy as previously believed,” Rydén says. “Therefore, more vigorous interventions may be necessary in these individuals to prevent cardiovascular and metabolic complications.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/08/160818131127.htm  Original web page web page at Science Daily

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CRISPR’s hopeful monsters: gene-editing storms evo-devo labs

A model and fossil of Tiktaalik roseae, a transitional fossil that illustrates how fish began to develop limbs.

Most summers since 1893, young developmental and evolutionary biologists have flocked to Woods Hole, Massachusetts, to master the tricks of their trade. At the world-famous Marine Biological Laboratory there, students in its annual embryology course dissect sea urchins and comb jellies, and graft cells together from different animals. But for the last three years, the keen apprentices have been learning something new: gene editing.

The precise, efficient CRISPR–Cas9 gene-editing technique has already taken life-sciences labs by storm. Now it is sweeping through evo-devo, the field that seeks to explain the developmental changes underlying evolutionary adaptations.

Rather than simply infer what caused historic transitions, such as how fish developed limbs, scientists can check their hypotheses directly with CRISPR. The idea is simple: cut out the fish genes thought to be involved in making fins, and see whether the fish start to form something resembling feet.

That is exactly what researchers report today in Nature, using CRISPR to help explain how fish developed feet and started walking. Others have wielded the technique to determine how butterflies evolved exquisite colour vision, and how crustaceans acquired claws.

“CRISPR is a revolution all across biology, but for evo-devo it’s transformative,” says Arnaud Martin, an evolutionary developmental biologist at George Washington University in Washington DC. “We can do things we were not able to do before.”

Neil Shubin, a palaeontologist and developmental biologist at the University of Chicago in Illinois, has used gene-editing to examine how the tips of fish fins, or rays, were replaced by feet and digits in four-legged land vertebrates, or tetrapods.

While researchers know that ancient fish developed limbs – Shubin led the team that in 2004 discovered a 375-million-year-old fossil that seemed to catch that transition in the act – they also thought that the foot was an evolutionary novelty without an equivalent in fish, because rays and feet are made of different kinds of bone.

But Shubin says gene-editing has changed his mind. His team used CRISPR to engineer zebrafish lacking various combinations of the several hox13 genes they possess – genes that researchers already thought played an important role in laying down fin rays.

None of the mutants grew fully fledged feet, Shubin notes, but some possessed “fingery fins” made of the same kind of bone that builds fingers and toes in tetrapods. “As a palaeontologist I studied and trained thinking these are two different kinds of bones that are completely unrelated developmentally or evolutionarily,” says Shubin. “These results challenge that assumption.”

The zebrafish is a popular model organism, whose genome is regularly manipulated in the lab. But CRISPR vastly sped up the experiments performed by Shubin’s team. One next step will be to knock out hox13 genes in fish species that more closely resemble the ancient fish that gained limbs, say Aditya Saxena and Kimberly Cooper, evolutionary developmental biologists at the University of California, San Diego. Those experiments are now conceivable thanks to CRISPR, they note in a commentary that accompanies Shubin’s article.

Editing crabs and butterflies

There is little reason to think the technique will not work on other, more esoteric species, too. “CRISPR seems to be universally working in any organism,” says Martin, who has successfully applied the technique to a marine crustacean called Parhyale hawaiensis, which is gaining popularity in evo-devo.

In a January Current Biology paper, he and colleague Nipam Patel, at the University of California, Berkeley, found that inactivating different Hox genes in the species messes with the development of specialized appendages such as antennae and claws. If scientists can successfully rear an animal in the lab so they can gain access to its eggs, they should be able to use CRISPR, Martin says.

Such flexibility is important for evo-devo researchers, says Claude Desplan, a developmental neurobiologist at New York University, whose team applied CRISPR to yellow swallowtail butterflies in a Nature paper published last month, to test a theory about how photoreceptors in their eyes detect a broader spectrum of colours than insects such as fruit flies. On-going experiments in his lab have applied gene-editing to wasps and ants.

So far, evo-devo researchers have focused on using CRISPR to eliminate a gene’s activity or to introduce genes, such as the one encoding green fluorescent protein, that make it possible to better track an animal’s development. But Martin expects researchers will soon begin using the tool to precisely alter DNA sequences in animals to test ideas about specific genetic changes. Those could include changes to regulatory DNA sequences that influence where and when a gene is active, which may have contributed to adaptations such as tetrapod limbs.

Researchers could also make an educated guess at the DNA sequences of ancient transitional creatures and insert those into living animals using CRISPR, says Bhart-Anjan Bhullar, a palaeontologist at Yale University in New Haven, Connecticut. Last year, his team used chemicals to modify development pathways in chickens that they thought helped to mould the snouts of theropod dinosaurs into modern birds’ beaks. He hopes to now be able to do such experiments with CRISPR.

Bhullar, who attended last month’s embryology course at Woods Hole, says he’s impressed by the success of gene-editing trials by students there, where scientists had the chance to use CRISPR editing on zebrafish, the crustacean P. hawaiensis, frogs, slipper snails and sea squirts.

With CRISPR, “stuff just works”, Bhullar says. “This is rapidly going to become the standard in evolutionary developmental biology.”

Nature doi:10.1038/nature.2016.20449 Read the related News & Views article, “Fin to limb within our grasp”.

http://www.nature.com/news/index.html  Nature

http://www.nature.com/news/crispr-s-hopeful-monsters-gene-editing-storms-evo-devo-labs-1.20449  Original web page at Nature

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Should the gray wolf keep its endangered species protection?

Research by UCLA biologists published today in the journal Science Advances presents strong evidence that the scientific reason advanced by the U.S. Fish and Wildlife Service to remove the gray wolf from protection under the Endangered Species Act is incorrect.

A key justification for protection of the gray wolf under the act was that its geographic range included the Great Lakes region and 29 Eastern states, as well as much of North America. The Fish and Wildlife Service published a document in 2014 which asserted that a newly recognized species called the eastern wolf occupied the Great Lakes region and eastern states, not the gray wolf. Therefore, the original listing under the act was invalid, and the service recommended that the species (except for the Mexican gray wolf, which is the most endangered gray wolf in North America) should be removed from protection under the act.

A decision by the U.S. Fish and Wildlife Service to remove the gray wolf from protection under the Endangered Species Act may be made as early as this fall.

In the new study, biologists analyzed the complete genomes of North American wolves — including the gray wolf, eastern wolf and red wolf — and coyotes. The researchers found that both the red wolf and eastern wolf are not distinct species, but instead are mixes of gray wolf and coyote.

“The recently defined eastern wolf is just a gray wolf and coyote mix, with about 75 percent of its genome assigned to the gray wolf,” said senior author Robert Wayne, a UCLA professor of ecology and evolutionary biology. “We found no evidence for an eastern wolf that has a separate evolutionary legacy. The gray wolf should keep its endangered species status and be preserved because the reason for removing it is incorrect. The gray wolf did live in the Great Lakes area and in the 29 eastern states.”

Once common throughout North America and among the world’s most widespread mammals, the gray wolf is now extinct in much of the United States, Mexico and Western Europe, and lives mostly in wilderness and remote areas. Gray wolves still lives in the Great lakes area, but not in the eastern states.

Apparently, the two species first mixed hundreds of years ago in the American South, resulting in a population that has become more coyote-like as gray wolves were slaughtered, Wayne said. The same process occurred more recently in the Great Lakes area, as wolves became rare and coyotes entered the region in the 1920s.

The researchers analyzed the genomes of 12 pure gray wolves (from areas where there are no coyotes), three coyotes (from areas where there are no gray wolves), six eastern wolves (which the researchers call Great Lakes wolves) and three red wolves.

There has been a substantial controversy over whether red wolves and eastern wolves are genetically distinct species. In their study, the researchers did not find a unique ancestry in either that could not be explained by inter-breeding between gray wolves and coyotes.

“If you did this same experiment with humans — human genomes from Eurasia — you would find that one to four percent of the human genome has what looks like strange genomic elements from another species: Neanderthals,” Wayne said. “In red wolves and eastern wolves, we thought it might be at least 10 to 20 percent of the genome that could not be explained by ancestry from gray wolves and coyotes. However, we found just three to four percent, on average — similar to that found in individuals from the same species when compared to our small reference set.”

Pure eastern wolves were thought to reside in Ontario’s Algonquin Provincial Park. The researchers studied two samples from Algonquin Provincial Park and found they were about 50 percent gray wolf, 50 percent coyote.

Biologists mistakenly classified the offspring of gray wolves and coyotes as red wolves or eastern wolves, but the new genomic data suggest they are hybrids. “These gray wolf-coyote hybrids look distinct and were mistaken as a distinct species,” Wayne said.

Eventually, after the extinction of gray wolves in the American south, the red wolves could mate only with one another and coyotes, and became increasingly coyote-like.

Red wolves turn out to be about 25 percent gray wolf and 75 percent coyote, while the eastern wolf’s ancestry is approximately 75 percent gray wolf and 25 percent coyote, Wayne said. (Wayne’s research team published findings in the journal Nature in 1991 suggesting red wolves were a mixture of gray wolves and coyotes.)

Although the red wolf, listed as an endangered species in 1973, is not a distinct species, Wayne believes it is worth conserving; it is the only repository of the gray wolf genes that existed in the American South, he said.

The researchers analyzed SNPs (single nucleotide polymorphisms) — tiny variations in a genetic sequence, and used sophisticated statistical approaches. In the more than two dozen genomes, they found 5.4 million differences in SNPs, a very large number.

Wayne said the Endangered Species Act has been extremely effective. He adds, however, that when it was formulated in the 1970s, biologists thought species tended not to inter-breed with other species, and that if there were hybrids, they were not as fit. The scientific view has changed substantially since then. Inter-breeding in the wild is common and may even be beneficial, he said. The researchers believe the Endangered Species Act should be applied with more flexibility to allow protection of hybrids in some cases (it currently does not), and scientists have made several suggestions about how this might be done without a change in the law, Wayne said.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160727150802.htm  Original web page at Science Daily

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Songbirds’ epic migrations connected to a small cluster of genes

Scientists from the University of British Columbia have shown that there is a genetic basis to the migratory routes flown by songbirds, and have narrowed in on a relatively small cluster of genes that may govern the behaviour.

“It’s amazing that the routes and timing of such complex behaviour could be genetically determined and associated with a very small portion of the genome,” said researcher Kira Delmore, lead author of the paper published in Current Biology.

“What’s even more amazing is that differences in this behaviour could be helping to maintain the huge diversity of songbirds we see in the natural world.”

Seasonal migration is one of the most remarkable biological phenomena in the world, with routes spanning thousands of kilometres and involving billions of animals. Songbirds travel up to 15,000 kilometres, despite often weighing under ten grams. They undertake these journeys alone at night and return to the same locations year after year.

Delmore and her colleagues used coin-sized light-level geolocators to track songbirds’ migrations, and next-generation sequencing techniques to get an in-depth view of their genomes. They applied these two recently-developed techniques to two closely related groups of Swainson’s thrushes in B.C., and their hybrids.

While the groups are evolutionarily and genetically related, they take different routes on migration each year. A coastal group migrates down the west coast, southward to Mexico and Central America, while an inland group near Kamloops migrates southeastward to the southeastern USA and then South America. The groups interbreed northeast of Vancouver, in the coastal mountains.

Previous work conducted by the team showed that birds from the hybrid population take intermediary migration routes, which cross deserts and mountainous regions. These inferior routes likely cause hybrids to have lower reproductive success, resulting in less gene flow between the groups and more differentiation between them.

By linking the migratory behavior of hybrids to their genetic makeup, these researchers pinpointed a single cluster of roughly 60 genes on one chromosome that largely accounts for the difference in migration patterns.

The genes play an important role in the birds’ circadian, nervous and cell signalling systems. They are also located in regions of the genome that have reduced movement of genes from one population of thrushes to the other.

“Smaller scale studies have associated some genes in this region with migratory behavior in organisms as diverse as butterflies, fish and other birds,” said UBC zoologist Darren Irwin, senior author of the study. “These results provide even stronger evidence that evolution of this genetic cluster can cause different migratory routes, facilitating the evolution of two species from one.”

Delmore conducted the research while at UBC and is now with the Max Planck Institute for Evolutionary Biology, where she will continue to winnow down the set of genes responsible for migration, and use the same cutting edge techniques to investigate other populations of birds.

https://www.sciencedaily.com/ Sciencè Daily

https://www.sciencedaily.com/releases/2016/07/160728143251.htm Original web page at Science Daily

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Why brain neurons in Parkinson’s disease stop benefiting from levodopa

Though the drug levodopa can dramatically improve Parkinson’s disease symptoms, within five years one-half of the patients using L-DOPA develop an irreversible condition — involuntary repetitive, rapid and jerky movements. This abnormal motor behavior appears only while taking L-DOPA, and it stops if the drug is stopped. However, if L-DOPA is taken again, even many months later, it quickly re-emerges.

In research to prevent this side effect and extend the usefulness of L-DOPA — which is the most effective drug treatment for Parkinson’s disease — University of Alabama at Birmingham researchers have uncovered an essential mechanism of this long-term memory for L-DOPA-induced-dyskinesia, or LID.

They report a widespread reorganization of DNA methylation — a process in which the function of DNA is modified — in brain cells caused by L-DOPA. They also found that treatments that increase or decrease DNA methylation can alter dyskinesia symptoms in an animal model.

Thus, modification of DNA methylation may be a novel therapeutic target to prevent or reverse LID behavior.

“L-DOPA is a very valuable treatment for Parkinson’s, but in many patients its use is limited by dyskinesia,” said David Standaert, M.D., Ph.D., the John N. Whitaker Professor and chair of the Department of Neurology at UAB. “Better means of preventing or reversing LID could greatly extend the use of L-DOPA without inducing intolerable side effects. The treatments we have used here, methionine supplementation or RG-108, are not practical for human use; but they point to the opportunity to develop methylation-based epigenetic therapeutics in Parkinson’s disease.”

The research by David Figge, Karen Eskow Jaunarajs, Ph.D., and corresponding author David Standaert, Center for Neurodegeneration and Experimental Therapeutics, UAB Department of Neurology, was recently published in The Journal of Neuroscience.

Although studies of LID in animal models have shown changes in gene expression and cell signaling, a key unanswered question still remained: Why is the neural sensitization seen in LID persistent when delivery of L-DOPA is transient?

The UAB researchers suspected DNA methylation changes — the attachment of a methyl group onto nucleotides in DNA — because methylation is known to stably alter gene expression in cells as they grow and differentiate. Furthermore, methylation changes in neurons have been shown to be involved during the formation of place memory and the development of addictive behavior after cocaine use.

In general, increased DNA methylation has a silencing effect on nearby gene expression, while removal of the methyl groups enhances gene expression.

Figge and colleagues found that:

L-DOPA treatment of parkinsonian rodents enhanced the expression of two DNA demethylases.

Cells in the dorsal striatum in the LID model showed extensive, location-specific changes in DNA methylation, mostly seen as demethylation.The changes in DNA methylation were near many genes with established functional importance in LID.

Modulating global DNA methylation — either by injecting methionine to increase methylation or applying RG-108, an inhibitor of methylation, to the striatum — modified the dyskinetic behavior of LID, down or up, respectively.

“Together,” the researchers wrote, “these findings demonstrate that L-DOPA induces widespread changes to striatal DNA methylation and that these modifications are required for the development and maintenance of LID.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160728143608.htm  Original web page at Science Daily

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* Scientists warn about health of English bulldog

According to new research it could be difficult to improve the health of the English bulldog, one of the world’s unhealthiest dog breeds, from within its existing gene pool. The findings will be published in the open access journal Canine Genetics and Epidemiology.

The English bulldog’s limited genetic diversity could minimize the ability of breeders to recreate healthy phenotypes from the existing genetic stock, which were created by human-directed selection for specific desired physical traits.

Many large regions of the bulldog’s genome have been altered to attain the extreme changes in its outward appearance. This includes significant loss of genetic diversity in the region of the genome that contains many of the genes that regulate normal immune responses. Despite this, the English bulldog is one of the most popular dog breeds, particularly in the US, where the bulldog was the fourth most popular pure breed in 2015.

Lead author, Niels Pedersen from Center for Companion Animal Health, University of California, US, said: “The English bulldog has reached the point where popularity can no longer excuse the health problems that the average bulldog endures in its often brief lifetime. More people seemed to be enamoured with its appearance than concerned about its health. Improving health through genetic manipulations presumes that enough diversity still exists to improve the breed from within, and if not, to add diversity by outcrossing to other breeds. We found that little genetic ‘wiggle room’ still exists in the breed to make additional genetic changes.”

Pedersen adds: “These changes have occurred over hundreds of years but have become particularly rapid over the last few decades. Breeders are managing the little diversity that still exists in the best possible manner, but there are still many individuals sired from highly inbred parents. Unfortunately eliminating all the mutations may not solve the problem as this would further reduce genetic diversity. We would also question whether further modifications, such as rapidly introducing new rare coat colors, making the body smaller and more compact and adding more wrinkles in the coat, could improve the bulldog’s already fragile genetic diversity.”

This is the first broad-based assessment of genetic diversity in the English bulldog using DNA analysis rather than pedigrees. DNA analysis is needed to measure, monitor and maintain genetic diversity. This has been done in several other breeds including Standard and Miniature Poodles, American Golden Retrievers, and American and European Italian Greyhound.

The researchers sought to identify whether there is enough genetic diversity still existing within the breed to undertake significant improvements from within the existing gene pool. The researchers examined 102 English bulldogs, 87 dogs from the US and 15 dogs from other countries. These were genetically compared with an additional 37 English bulldogs presented to the US Davis Veterinary Clinical Services for health problems, to determine that the genetic problems of the English bulldogs were not the fault of commercial breeders or puppy mills.

Many Swiss breeders have started to outcross the breed with the Olde English Bulldogge (an American breed) to create the Continental Bulldog, hoping to improve the breed’s health. Although outcrossing the English bulldog could improve its health, many breeders feel that any deviations from the original standard will no longer be an English bulldog.

The breed started from a relatively small genetic base with a founder population of 68 individuals after 1835 and has undergone a number of human created artificial bottlenecks (drastic reductions in population size). These could also have greatly diminished genetic diversity.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160729092534.htm  Original web page at Science Daily

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Shorter telomeres reveal stress in migratory birds

The stress of birds’ continent-spanning annual migrations, it appears, leads to faster aging and a potentially earlier death. A new study in The Auk: Ornithological Advances reveals that telomeres, structures on the ends of chromosomes that shorten with age, are shorter in migratory birds than in their non-migratory counterparts.

Migration lets birds take advantage of abundant food resources at high latitudes during the breeding season while escaping the region’s harsh winters. However, it’s also an enormous undertaking, and the benefits that birds gain from it come with a cost. Carolyn Bauer of North Dakota State University and her colleagues compared the telomeres — bits of non-coding DNA that shorten during cell division and stress — of migratory and resident birds from the same species, the Dark-eyed Junco. They found that the migrants had significantly shorter telomeres than birds that stayed put year-round, suggesting that the migratory birds were aging at a faster rate and that the stress of a migratory lifestyle may actually shorten birds’ lifespans.

“Whenever our cells divide, we lose a little bit of DNA on the ends of our chromosomes, and telomeres are simply non-coding regions that act as ‘protective caps,” explains Bauer. Once they reach a certain threshold of shortness, the cell dies. Importantly, exposure to stress can also make telomeres shorten faster. For their study, Bauer and her colleagues collected blood samples from 11 migratory and 21 resident juncos in Virginia, using only first-year birds to ensure that any telomere differences were not simply due to age. “I’ve been interested in measuring telomeres since I was undergraduate at the University of Washington,” says Bauer. “I remember my introductory biology professor lecturing about telomeres and how environmental stress could cause them to shorten.”

If migrating is so stressful, why keep doing it? Bauer and her colleagues believe that the costs of migration must be balanced out by the reproductive boost birds get from nesting in resource-rich northern habitats. They hope that future studies will determine whether shorter telomeres reflect the stress of migration itself or if they’re the result of decreased self-maintenance, as well as whether telomere length is negatively correlated with migratory distance.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/08/160803072812.htm Original web page at Science Daily

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Viruses revealed to be a major driver of human evolution

The constant battle between pathogens and their hosts has long been recognized as a key driver of evolution, but until now scientists have not had the tools to look at these patterns globally across species and genomes. In a new study, researchers apply big-data analysis to reveal the full extent of viruses’ impact on the evolution of humans and other mammals.

Their findings suggest an astonishing 30 percent of all protein adaptations since humans’ divergence with chimpanzees have been driven by viruses.

“When you have a pandemic or an epidemic at some point in evolution, the population that is targeted by the virus either adapts, or goes extinct. We knew that, but what really surprised us is the strength and clarity of the pattern we found,” said David Enard, Ph.D., a postdoctoral fellow at Stanford University and the study’s first author. “This is the first time that viruses have been shown to have such a strong impact on adaptation.”

The study was recently published in the journal eLife and will be presented at The Allied Genetics Conference, a meeting hosted by the Genetics Society of America, on July 14.

Proteins perform a vast array of functions that keep our cells ticking. By revealing how small tweaks in protein shape and composition have helped humans and other mammals respond to viruses, the study could help researchers find new therapeutic leads against today’s viral threats.

“We’re learning which parts of the cell have been used to fight viruses in the past, presumably without detrimental effects on the organism,” said the study’s senior author, Dmitri Petrov, Ph.D., Michelle and Kevin Douglas Professor of Biology and Associate Chair of the Biology Department at Stanford. “That should give us an insight on the pressure points and help us find proteins to investigate for new therapies.”

Previous research on the interactions between viruses and proteins has focused almost exclusively on individual proteins that are directly involved in the immune response — the most logical place you would expect to find adaptations driven by viruses. This is the first study to take a global look at all types of proteins.

“The big advancement here is that it’s not only very specialized immune proteins that adapt against viruses,” said Enard. “Pretty much any type of protein that comes into contact with viruses can participate in the adaptation against viruses. It turns out that there is at least as much adaptation outside of the immune response as within it.”

The team’s first step was to identify all the proteins that are known to physically interact with viruses. After painstakingly reviewing tens of thousands of scientific abstracts, Enard culled the list to about 1,300 proteins of interest. His next step was to build big-data algorithms to scour genomic databases and compare the evolution of virus-interacting proteins to that of other proteins.

The results revealed that adaptations have occurred three times as frequently in virus-interacting proteins compared with other proteins.

“We’re all interested in how it is that we and other organisms have evolved, and in the pressures that made us what we are,” said Petrov. “The discovery that this constant battle with viruses has shaped us in every aspect — not just the few proteins that fight infections, but everything — is profound. All organisms have been living with viruses for billions of years; this work shows that those interactions have affected every part of the cell.”

Viruses hijack nearly every function of a host organism’s cells in order to replicate and spread, so it makes sense that they would drive the evolution of the cellular machinery to a greater extent than other evolutionary pressures such as predation or environmental conditions. The study sheds light on some longstanding biological mysteries, such as why closely-related species have evolved different machinery to perform identical cellular functions, like DNA replication or the production of membranes. Researchers previously did not know what evolutionary force could have caused such changes. “This paper is the first with data that is large enough and clean enough to explain a lot of these puzzles in one fell swoop,” said Petrov.

The team is now using the findings to dig deeper into past viral epidemics, hoping for insights to help fight disease today. For example, HIV-like viruses have swept through the populations of our ancestors as well as other animal species at multiple points throughout evolutionary history. Looking at the effects of such viruses on specific populations could yield a new understanding of our constant war with viruses — and how we might win the next big battle.

were divided into 12 experimental groups and one control group, also impressive, because most studies have two or three experimental groups.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/06/160630102038.htm  Original web page at Science Daily

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No blood vessels without cloche

The decade-long search by researchers worldwide for a gene, which is critical in controlling the formation of blood and blood vessels in the embryo, shows how fascinating science can be. It is more than 20 years since Didier Stainier, director at the Max Planck Institute for Heart and Lung Research in Bad Nauheim, discovered a zebrafish mutant named cloche. This mutant lacks development of both blood vessels and blood cells, and was, until now, a unique phenomenon. Now, his research group has succeeded in finding the gene responsible for it. It had quasi hidden itself at the very end of chromosome 13 and was discovered using the latest molecular biological methods. The discovery of the gene is not only of scientific interest, but could also become important for regenerative medicine.

At a very early stage of embryonic development, blood vessels and blood cells form from common progenitor cells. The timing and manner in which the blood and vessels form is regulated in a genetic program by multiple genes. This program is characterized by a cascade-like activity pattern. In the mid-nineties, during his time in the United States, Didier Stainier, Director of the Department of Developmental Genetics at the Max Planck Institute for Heart and Lung Research in Bad Nauheim, discovered in the model organism zebrafish, a mutant “possessing one of the most exciting developmental defects ever found in zebrafish,” says Sven Reischauer who, together with Oliver Stone and Alethia Villasenor, is one of the main authors of the study. Due to a genetic change in this fish, none of the genes involved in the genetic program for blood and blood vessel cells were activated. Consequently, these cells cannot develop. Stainier named the mutant “cloche” after another unique feature of the mutant, a cloche-like heart shape.

In the last two decades, various laboratories around the world took part in a real hunt for the gene behind the mutant. “Identifying Cloche was, for all of us, like solving a decades-old criminal case of genetics. However, in this case, it was not the perpetrator who was unknown but the victim, the defective gene,” says Reischauer. The Max Planck researchers in Bad Nauheim, together with international partners, have now successfully finished this hunt.

“The search was made extremely complicated due to the fact that the cloche gene is located at the very end of chromosome 13, in a telomeric region,” says Reischauer. Now, with methods, which have only recently become available (for example, CRISPR/Cas9 and TALEN), do we have the tools to analyse these areas. “In addition, we had to assume that the gene is only active prior to the time at which the lack of vascular growth is evident. This made it much more difficult to identify the embryos,” says Reischauer.

First, the Bad Nauheim researchers examined the entire portion of the genome in which they suspected cloche to be located. Analysis of data from 26,000 genes revealed 17 genes, which could be regarded as potential candidates. Then, they deactivated all of these candidate genes separately by producing knockout lines, and examined the blood vessel growth in these embryos. “Only in one case did we find the expected picture, namely that vessel growth failed to be induced. Then we were sure that we had found the cloche gene,” says Reischauer.

In additional experiments, the Max Planck scientists showed how important Cloche is for the development of blood vessels and blood cells in the embryo: It transpired that all genes which were previously known to be involved in vessel formation, are only active after Cloche has been active. Accordingly, Cloche itself controls the activity of the entire program.

This scenario was confirmed in so-called overexpression experiments in which the researchers injected pure cloche mRNA into embryos. This approach enabled them to start the program for vascular and blood cell formation at a time during embryo development at which it is not normally active. “We could, therefore, propose we had found the gene responsible for controlling the developmental program,” says Stainier.

Cloche seems to be highly conserved in nature: The gene is present even in birds. In mammals there is a closely related gene that can take over the function of cloche in the zebrafish model. Therefore, the Bad Nauheim scientists assume “that with the identification of the gene and its function, there will be great opportunities to develop new applications in the context of personalized stem cell therapy,” Stainier says.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160718110936.htm Original web page at Science Daily

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Unsilencing silenced genes by CRISPR/Cas9

Scientists have developed a new technique to unleash silenced genes and change cell fates using CRISPR/Cas9.

The ability to control gene expression in cells allows scientists to understand gene function and manipulate cell fate. Recently, scientists have developed a revolutionary gene-editing tool, called CRIPSR/Cas9, which employs a system naturally used by bacteria as protection against viruses. The tool allows scientists to precisely add, remove or replace specific parts of DNA. CRISPR/Cas9 is the most efficient, inexpensive and easiest gene-editing tool available to date. However, scientists have not yet managed to effectively use it to activate genes in the cells.

A team, led by Toru Kondo at Hokkaido University’s Institute of Genetic Medicine, has developed a powerful new method that does just that.

Genes in cells have their own switches called promoters. A gene is switched off, or silenced, when its promoter is methylated. The team effectively wanted to turn on a switched-off gene.

They combined a DNA repair mechanism, called MMEJ (microhomology-mediated end-joining), with CRISPR/Cas9. They cut out a methylated promoter using CRISPR/Cas9 and then inserted an unmethylated promoter with MMEJ, replacing the off-switch with an on-switch.

The scientists used this tool on the neural cell gene OLIG2 and the embryonic stem cell gene NANOG to test its efficiency in cultured cells. Within five days, they found evidence that the genes were robustly expressed. When they turned on OLIG2 in cultured human stem cells, the cells differentiated to neurons in seven days with high efficiency.

The scientists also found that their editing tool could be used to activate other silenced promoters. In addition, they found that the system didn’t cause unwanted mutations in other non-targeted genes in the cells. The tool has wide potential to be used to manipulate gene expression, create genetic circuits, or to engineer cell fates.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160701120557.htm  Original web page at Science Daily

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Gene-therapy trials must proceed with caution

Jesse Gelsinger was 18 and healthy when he died in 1999 during a gene-therapy experiment. He had a condition called ornithine transcarbamylase deficiency (OTC), but it was under control through a combination of diet and medication. Like others with the disorder, Gelsinger lacked a functional enzyme involved in breaking down ammonia, a waste product of protein metabolism that becomes toxic when its levels become too high. The gene therapy that he received used a viral vector to introduce a normal gene for the enzyme.

Gene therapy remains an obvious route to treat OTC. Simply adding the missing gene has been shown to repair metabolism in mice. But the memory of what happened to Gelsinger has slowed progress in gene therapy for any condition.

That memory was firmly on the agenda at a meeting of the US National Institutes of Health’s Recombinant DNA Advisory Committee (RAC) last week. The RAC evaluates proposals to use modified DNA in human trials, and presenting to it were Cary Harding, a medical geneticist at Oregon Health and Science University in Portland, and Sam Wadsworth, chief scientific officer at Dimension Therapeutics in Cambridge, Massachusetts. The duo were proposing the first new trial of gene therapy for OTC.

Harding and the researchers at Dimension argue that the technology and our understanding of physiology have advanced enough since 1999 to try it again in people. Gelsinger died after his body overreacted to the vector used to introduce the OTC gene. Dimension’s therapy uses a different viral vector, called AAV8, which has been tested numerous times in people with other conditions, with few adverse effects.

Such assurances were not enough for the RAC, and particularly not for its bioethicists and historians. Dawn Wooley, a virologist at Wright State University in Dayton, Ohio, pointed out that an RAC panel raised concerns about Gelsinger’s trial in 1995, but decided to let the test go ahead. “We can’t let it happen again, we cannot,” she says.

Perhaps the greatest indication of how Gelsinger’s death haunts the RAC came when one member suggested that the researchers explain in the consent form to be sent to prospective participants that someone had died in a similar study and attracted media attention.

There are some scientific reasons to be careful. AAV8 can cause mild liver toxicity in healthy people, and the steroids used to treat that could lead to complications in people with OTC. With so little known about these effects, the RAC members suggested that the researchers lower the dose to one that is more likely to be safe, even if it is potentially not effective.

After some discussion, the RAC voted unanimously to approve the trial. However, that came with a long list of conditions, including that the treatment first be tested in a second animal species. The researchers disagree with most of the conditions, believing that more expensive animal trials will add nothing. They feel that they are being held to a different standard from most trials.

Dimension still plans to submit an application to the US Food and Drug Administration (FDA) later this year to start a clinical trial. It is unclear how heavily the RAC’s recommendations weigh into FDA decisions, but Wadsworth says that the company will conduct its trials overseas if necessary. “These patients have been waiting a long time,” he says.

He is right. Therapies can be tested in non-human animals only for so long — at some point, volunteers such as Gelsinger must step forward. Yet the echoes of a trial done 17 years ago cannot be easily silenced. In fact, Gelsinger’s name came up several times at the RAC meeting. Researchers from the University of Pennsylvania in Philadelphia had even mentioned him earlier that morning, when proposing the first human trial of CRISPR gene-editing technology as a treatment for cancer. The RAC approved that proposal, but its implication was clear: take care. Avoidable failures could stymie CRISPR research for decades. History must not repeat itself.

Nature 534, 590 (30 June 2016) doi:10.1038/534590a

http://www.nature.com/news/index.html  Nature

http://www.nature.com/news/gene-therapy-trials-must-proceed-with-caution-1.20186 Original web page at Nature

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On the path to controlled gene therapy

The ability to switch disease-causing genes on and off remains a dream for many physicians, research scientists and patients. Research teams from across the world are busy turning this dream into a reality, including a team of researchers from Charité — Universitätsmedizin Berlin and the Max Planck Institute for Medical Research in Heidelberg. Led by Dr. Mazahir T. Hasan, and working under the auspices of the NeuroCure Cluster of Excellence, the team has successfully programmed a virus to transport the necessary genetic material to affected tissue and nerve cells inside the body.

A report on their new virus-based method, which delivers instructions to the host genome without becoming part of it, has been published in the journal Molecular Therapy Nucleic Acids.

From cancer to Alzheimer’s disease, many life-threatening diseases can only be treated using drug-based treatment options, if at all. Many of these treatments are non-specific in nature, or even ineffective. In some cases, the undesirable side-effects may even outweigh the desirable ones. This is because indiscriminate treatments damage healthy cells, impairing their ability to communicate with other cells; as a result, it is hoped that genetically produced and modified mediators will be able to selectively target diseased cells, and improve the way treatment is delivered. “In the laboratory, we use attenuated, i.e. non-replicating viruses that are known as recombinant adeno-associated viruses (rAAV). We use them to transport genetically encoded material into live organisms affected by disease,” explains Dr. Hasan. “This approach opens up a whole range of options which, in the future, may allow us to treat and heal various diseases.”

By successfully completing the initial step of testing this new method using an animal model, the researchers have laid the groundwork for future genetic treatments for use in humans. Before these can be used, however, they will need to be tested to ensure their safety. It is already known that rAAVs can transport genetically encoded material into any type of cell and tissue, including the brain, and that, once inside the cells, they are capable of repeatedly switching gene therapy applications on and off again. This on/off switch is controlled chemically, via either food intake or drinking water: “The fact that gene function can be switched on and off in this manner is of particular value, and renders the method a perfect candidate for use in controlled gene therapy,” emphasizes Dr. Hasan

The fact that rAAV-infected cells do not trigger any form of measurable immune response and that their genetic material remains completely intact represents an additional benefit. While this does not mean that future gene therapy applications are guaranteed to be successful, the researchers are full of confidence for the future. “We are still at the laboratory stage,” says Dr. Hasan, adding: “Once additional safety options are in place, this development could spearhead innovation, heralding in a time when the transfer of genetically encoded material will be used to heal severe diseases, including neurological ones such as Parkinson’s disease, Alzheimer’s disease and epilepsy.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160719110225.htm  Original web page at Science Daily

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Transmission of genetic disorder Huntington’s disease in normal animals

Mice transplanted with cells grown from a patient suffering from Huntington’s disease (HD) develop the clinical features and brain pathology of that patient, suggests a study published in the latest issue of Acta Neuropathologica by CHA University in Korea, in collaboration with researchers at Université Laval in Québec City, Canada.

“Our findings shed a completely new light onto our current understanding of how HD begins and develops. We believe that they will also lead to the development of a whole new range of therapies for neurodegenerative diseases of the central nervous system,” explains corresponding author of the study Jihwan Song, professor and director of Neural Regeneration and Therapy Group at the CHA Stem Cell Institute of CHA University.

The researchers have now provided further evidence for this new theory by showing that the abnormal protein coded for this genetic disorder can be transmitted to normal animals by the injection of diseased cells into their brain. “This is the first demonstration that cells carrying a genetic disease are capable of spreading into the normal mammalian brain and lead to the manifestation of behavioral abnormalities associated with the disease,” says Francesca Cicchetti, professor at the Université Laval Faculty of Medecine and researcher at Centre de recherche du CHU de Québec-Université Laval.

HD is an inherited chronic degenerative disorder of the brain characterized by major thinking and motor problems as well as psychiatric disturbances. There is no cure for HD and current treatments are of very limited efficacy. It is caused by a single gene abnormality which leads to the production of a mutant form of a protein called huntingtin (mHtt). The production of this protein in a nerve cell eventually kills it but it has long been thought that this protein cannot spread out of the cell and infect and kill neighbouring ones.

However, in recent post mortem analyses of HD patients who received transplants of non-HD tissue in an attempt to repair their brain, the researchers showed that the mHtt can be found in the graft itself. This suggests that the patient with HD transmitted the mHtt from their brain into the transplant.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160531104225.htm  Original web page at Science Daily

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Dogs were domesticated not once, but twice … in different parts of the world

The question, ‘Where do domestic dogs come from?’, has vexed scholars for a very long time. Some argue that humans first domesticated wolves in Europe, while others claim this happened in Central Asia or China. A new paper, published in Science, suggests that all these claims may be right. Supported by funding from the European Research Council and the Natural Environment Research Council, a large international team of scientists compared genetic data with existing archaeological evidence and show that man’s best friend may have emerged independently from two separate (possibly now extinct) wolf populations that lived on opposite sides of the Eurasian continent. This means that dogs may have been domesticated not once, as widely believed, but twice.

A major international research project on dog domestication, led by the University of Oxford, has reconstructed the evolutionary history of dogs by first sequencing the genome (at Trinity College Dublin) of a 4,800-year old medium-sized dog from bone excavated at the Neolithic Passage Tomb of Newgrange, Ireland. The team (including French researchers based in Lyon and at the National Museum of Natural History in Paris) also obtained mitochondrial DNA from 59 ancient dogs living between 14,000 to 3,000 years ago and then compared them with the genetic signatures of more than 2,500 previously studied modern dogs.

The results of their analyses demonstrate a genetic separation between modern dog populations currently living in East Asia and Europe. Curiously, this population split seems to have taken place after the earliest archaeological evidence for dogs in Europe. The new genetic evidence also shows a population turnover in Europe that appears to have mostly replaced the earliest domestic dog population there, which supports the evidence that there was a later arrival of dogs from elsewhere. Lastly, a review of the archaeological record shows that early dogs appear in both the East and West more than 12,000 years ago, but in Central Asia no earlier than 8,000 years ago.

Combined, these new findings suggest that dogs were first domesticated from geographically separated wolf populations on opposite sides of the Eurasian continent. At some point after their domestication, the eastern dogs dispersed with migrating humans into Europe where they mixed with and mostly replaced the earliest European dogs. Most dogs today are a mixture of both Eastern and Western dogs — one reason why previous genetic studies have been difficult to interpret.

The international project (which is combining ancient and modern genetic data with detailed morphological and archaeological research) is currently analysing thousands of ancient dogs and wolves to test this new perspective, and to establish the timing and location of the origins of our oldest pet.

Senior author and Director of Palaeo-BARN (the Wellcome Trust Palaeogenomics & Bio-Archaeology Research Network) at Oxford University, Professor Greger Larson, said: ‘Animal domestication is a rare thing and a lot of evidence is required to overturn the assumption that it happened just once in any species. Our ancient DNA evidence, combined with the archaeological record of early dogs, suggests that we need to reconsider the number of times dogs were domesticated independently. Maybe the reason there hasn’t yet been a consensus about where dogs were domesticated is because everyone has been a little bit right.’

Lead author Dr Laurent Frantz, from the Palaeo-BARN, commented: ‘Reconstructing the past from modern DNA is a bit like looking into the history books: you never know whether crucial parts have been erased. Ancient DNA, on the other hand, is like a time machine, and allows us to observe the past directly.’

Senior author Professor Dan Bradley, from Trinity College Dublin, commented: ‘The Newgrange dog bone had the best preserved ancient DNA we have ever encountered, giving us prehistoric genome of rare high quality. It is not just a postcard from the past, rather a full package special delivery.’

Professor Keith Dobney, co-author and co-director of the dog domestication project from Liverpool University’s Department of Archaeology, Classics and Egyptology, is heartened by these first significant results. ‘With the generous collaboration of many colleagues from across the world-sharing ideas, key specimens and their own data — the genetic and archaeological evidence are now beginning to tell a new coherent story. With so much new and exciting data to come, we will finally be able to uncover the true history of man’s best friend.’

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/06/160602151723.htm  Original web page at Science Daily

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Scientists identify mutation that causes muffs and beards to grow on chickens

The growth of long facial feathers, creating the appearance of muffs and beards on chickens, is caused by a chromosomal rearrangement affecting a gene involved in feather development, report Xiaoxiang Hu of the China Agricultural University in Beijing and colleagues, in a new study published on June 2 in PLOS Genetics.

Unusual plumage and fancy combs aren’t just interesting traits appreciated by poultry fanciers, but opportunities to explore the genetics underlying these striking variations. Scientists investigated the mutation that causes the Muffs and beard characteristic in certain chicken varieties by mapping the trait to the correct location on the chromosome and sequencing that region from chickens with and without Muffs and beard. They found that chickens with the Muffs and beard trait had three duplicated regions of chromosome 27, inserted next to one of the original gene regions. By examining changes in gene expression, they showed that one of the duplicated genes, HOXB8, which is known to function in feather development, was present at high levels in the facial skin of chickens with Muffs and beard, but not in regular chickens.

The scientists suspect that HOXB8 expression may extend the growth phase of the facial feathers, creating the characteristic bearded appearance. Other HOX gene members are linked to feather development, such as HOXC8, which is associated with a crest of feathers on top of the head. The findings present an excellent model for exploring the regulation of HOX genes in different parts of the body during development.

Dr. Guo says: “Muffs and beard in chicken is caused by a structural variation that consists of three duplicated regions on GGA27 and results in the ectopic expression of HOXB8 in facial skin. Our findings show the significance for structural variations on phenotypic diversity and a novel role for HOXB8 in feather formation. In future study, we’ll focus on the regulation of HOX genes in feather cycles.”

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/06/160602151713.htm Original web page at Science

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CRISPR gene-editing system unleashed on RNA

Researchers who discovered a molecular “scissors” for snipping genes have now developed a similar approach for targeting and cutting RNA. The new cutting tool should help researchers better understand RNA’s role in cells and diseases, and some believe it could one day be useful in treatments for illnesses from Huntington’s to heart disease.

To develop the “blades” for the process, researchers led by Feng Zhang at the Broad Institute used CRISPR (clustered regularly interspaced short palindromic repeats)—a system that bacteria evolved to fight off pathogens. CRISPR has previously been used to edit DNA but had been theorized to work on RNA as well.

The new findings, reported Thursday in Science, came from systematically exploring different aspects of that natural defense system that protects bacteria—and may eventually be put to use helping people. “Nature has already invented all these really interesting mechanisms,” Zhang says, comparing himself with a treasure hunter. “We’re just trying to play with that and learn how they work…then turn them into tools that will be useful to us.”

Zhang says the new paper will not affect an ongoing patent dispute over who owns rights to the gene-editing approach known as CRISPR–Cas9. His team was the first to use CRISPR–Cas9 in mammalian cells. Another team—led by Jennifer Doudna, at the University of California, Berkeley, and French researcher Emmanuelle Charpentier—was first to publish on CRISPR–Cas9, showing its activity in bacteria.

Ironically, Doudna was a co-author on a March paper in Cell that used CRISPR–Cas9 to cut RNA in mammalian cells whereas Zhang’s new paper focuses on bacteria. The two RNA manipulation methods may be complementary ways to approach the same ends or one may turn out to be more efficient than the other. In interviews this week each group praised the other’s work while touting the advantages of their own respective approaches.

Zhang says his new method—using the enzyme C2c2 to target RNA—relies on an existing natural system and therefore may be more effective than an approach that requires more manipulation. Gene Yeo, senior author on the Cell paper, says he has collaborated with both Doudna and Zhang, and described the new paper as a continuation of the kind of “friendly competition” that drives science. “There’s always a bit of a race between a lot of the groups, including mine,” he says. “I think scientific competition is good. People tend to push the boundaries more.”

Although Yeo pointed out that the C2c2 system has not yet been shown to work in mammalian cells, Zhang says unpublished results make him optimistic that it will.

Both RNA-targeting approaches have a long way to go before they could be tested in people—but the promise is there, says Yeo, a professor of cellular and molecular medicine at the University of California, San Diego. Targeting RNA may also offer new insights into how changes in RNA lead to changes in biology and the development of disease. “I think we’ll see an avalanche of these tools that will enable us to monitor and study RNA,” Yeo says. “This helps us think about RNA as not just an intermediate molecule between DNA and protein,” but as a therapeutic tool for treating diseases and problems of development.

Genes consist of double-stranded DNA, which makes single-stranded RNA—which in turn makes the proteins needed for life. Many diseases result from too much or too little protein. Theoretically, acting on the RNA could push those protein levels up or down, thereby offering treatments.

Manipulating RNA poses fewer ethical concerns than tinkering with the underlying DNA, although gene editing will remain a better approach for treating some diseases. “The problem with DNA editing is that it’s permanent,” Yeo says. “That could be good, but what if you make a mistake?” In some cases, such as with brain cells, DNA repair mechanisms are so strong that it may be more effective to act on the RNA rather than cutting the DNA, says Yeo, who has started a company that’s still in stealth mode to begin looking at treating diseases with this approach.

The Science paper reports that C2c2 could also be used to add fluorescent tags to RNA as a way to track and better understand its activities.

Zhang says he has long been interested in developing systems to target RNA. His team decided to survey the different kinds of CRISPR systems to figure out their functions. C2c2 turned out to be an RNA-targeting system, according to the new study, which includes researchers from the National Institutes of Health, Rutgers University and the Skolkovo Institute of Science and Technology in Russia, in addition to Harvard University and Massachusetts Institute of Technology. Like the Cas9 system that targets specific DNA, C2c2 can be aimed directly at desired RNA sequences, with seemingly few off-target effects. “The reason that it has evolved is to be able to use RNA guides to target RNA,” Zhang says.

His colleague, Eugene Koonin, a co-author on the new paper, puts it more poetically: “Evolution of life to a very large extent is a story of host–parasite interactions,” says Koonin, an expert in evolutionary genomics at the National Center for Biotechnology Information. “As we explore this arms race between host and parasite, we discover more and more intricate, novel ways in which cellular organisms cope with parasites and parasites counteract.”

Nature doi:10.1038/nature.2016.20030

https://www.sciencedaily.com/ Nature

http://www.nature.com/news/crispr-gene-editing-system-unleashed-on-rna-1.20030  Original web page at Nature

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* Cancer-causing virus strikes genetically vulnerable horses

Sarcoid skin tumors are the most common form of cancer in horses, but little is known about why the papillomavirus behind them strikes some horses and not others. A new study by an international research group led by scientists at the Baker Institute for Animal Health at Cornell’s College of Veterinary Medicine shows genetic differences in immune function between horses partly accounts for these differences. The study, published in the International Journal of Cancer, mirrors findings in humans, as some people have a genetic susceptibility to human papillomavirus, which can cause cervical and other cancers.

“Many therapies have been proposed as the ‘best’ treatment for sarcoids,” says Dr. Doug Antczak, the Dorothy Havemeyer McConville Professor of Equine Medicine, who led the study. In some horses, tumors develop as small bumps under the skin or as scaly lesions that easily can be removed by a veterinarian, but in other horses the problem becomes much more serious. Surgery, cryotherapy (freezing the tissue), laser treatment, injecting the tumors with drugs to kill the cells, radiation treatment and immunotherapy have all been shown to cure these recalcitrant tumors, “but some tumors tend to recur no matter what treatment is used, and there is no universal consensus on a uniformly successful therapy,” says Antczak.

Antczak says it’s been thought for years that bovine papillomavirus (BPV) is the most likely culprit behind sarcoid tumors. Recent work from Europe suggests variants of the BPV have become adapted to horses and are probably the cause of most sarcoids.

With a grant from the Morris Animal Foundation, Antczak, his collaborators Samantha Brooks and Ann Staiger from the University of Florida, and the rest of the team applied a genomewide association study to compare the genetic makeup of horses with and without sarcoid tumors at more than 50,000 sites in the equine genome. They studied 82 sarcoid-bearing horses from the U.S. and United Kingdom and 272 carefully matched controls that did not have sarcoids. They found regions on chromosomes 20 and 22 that tended to be different in horses diagnosed with sarcoids, evidence that a horse’s genes determine, in part, how susceptible it is to sarcoids.

“This is an example of more complicated genetics — multigene susceptibility,” says Antczak. “More than one genetic region is associated with susceptibility to sarcoids, and they don’t completely determine whether or not a horse will develop the disease once it’s exposed to BPV.”

This genetic link implicates the immune system in sarcoid susceptibility. The region of chromosome 20 associated with sarcoid development is within a portion of the genome responsible for immune function called the Major Histocompatibility Complex (MHC) class II region. The MHC type associated with sarcoid susceptibility is very rare among Standardbred horses, a fact that may explain why sarcoid is diagnosed so rarely in this breed.

This complex mix of virus, host genes and tumor development may have relevance to a related human condition. Tumors caused by human papillomaviruses account for more than 5 percent of cancer cases worldwide. In women with cervical cancer, an association with the MHC class II region has also been shown.

“That should make a light bulb go off,” Antczak says. “It suggests there’s a common mechanism in both species for susceptibility to tumor progression that may involve subversion of the host immune response. By studying this phenomenon in horses you can learn about human cancer and vice versa.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/06/160610140652.htm  Original web page at Science Daily

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Human-eating monster crocodile may be Florida’s newest invasive species

Spotting native alligators and crocodiles in Florida is common, but anyone who sees a large reptile may want to take a second look — human-eaters that can grow to 18 feet long and weigh as much as a small car have been found in the Sunshine State.

Using DNA analysis, University of Florida researchers have confirmed the capture of multiple Nile crocodiles in the wild.

The ancient icon eats everything from zebras to small hippos to humans in sub-Saharan Africa. Now three juveniles of the monster crocodile, have been found in South Florida, swimming in the Everglades and relaxing on a house porch in Miami.

The invasive crocodiles were captured between 2000 and 2014, leading UF scientists to analyze their DNA, study their diet and one of the animal’s growth. Scientists verified the animals were Nile crocodiles linked to native populations in South Africa, and confirmed the species can survive in Florida — and potentially thrive, said Kenneth Krysko, herpetology collections manager at the Florida Museum of Natural History on the UF campus.

“The odds that the few of us who study Florida reptiles have found all of the Nile crocs out there is probably unlikely,” said Krysko, co-author of the study published in April in the Journal of Herpetological Conservation and Biology. “We know that they can survive in the Florida wilderness for numerous years, we know that they grow quickly here and we know their behavior in their native range, and there is no reason to suggest that would change here in Florida.”

Nile crocodiles, Crocodylus niloticus, were responsible for at least 480 attacks on people and 123 fatalities in Africa between 2010 and 2014. They are generalist predators and eat a wide variety of prey. In Florida, everything from native birds, fish and mammals to the state’s native crocodile and alligator would be fair game for the carnivorous croc.

The study found one juvenile grew nearly 28 percent faster than wild Nile crocodile juveniles from some parts of their native range. DNA analysis revealed the three similar-size Nile crocodiles were genetically identical, suggesting they were introduced via the same source, but Krysko said the source has not been confirmed. Prior to graduating in 2013, former UF doctoral student and co-author Matthew Shirley extensively sampled DNA of live Nile crocodiles housed in U.S. zoos, including Florida. The DNA of the three crocodiles did not match any of those Shirley sampled, suggesting they were either acquired by a permitted source later, or introduced by someone without a permit.

Study scientists note that over the last decade, large groups of Nile crocodiles have been imported from South Africa and Madagascar for display at places like Disney’s Animal Kingdom and to supply Florida’s flourishing pet trade, with the latter being the most likely introduction pathway, according to the study.

While there is currently no evidence of an established population, study scientists recommend a scientific risk assessment to evaluate the potential for Nile crocodiles to breed and spread across the state. According to the study, Florida’s Atlantic coast and the entire Gulf of Mexico coastline provide favorable climate for Nile crocodiles.

Florida’s subtropical climate is one reason the state has the world’s largest number of invasive species — from the Burmese python that has invested the Everglades to the Cuban tree frog, which has been found as far north as Jacksonville on the East Coast and as far north as Cedar Key on the Gulf Coast.

“My hope as a biologist is that the introduction of Nile crocodiles in Florida opens everyone’s eyes to the problem of invasive species that we have here in our state,” Krysko said. “Now here’s another one, but this time it isn’t just a tiny house gecko from Africa.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160520102244.htm  Original web page at Science Daily

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How do some birds get such bright red feathers?

In the bird world, the color red has special significance. Many species use red signals to attract mates or deter rivals, adding the color to their beaks, feathers, or bare skin. Generally speaking, as far as many birds are concerned, redder is better. Now, two teams of researchers have independently identified an enzyme-encoding gene that allows some bird species to convert yellow pigments from their diets into that remarkable red. Their findings are reported on May 19 in Current Biology.

“To produce red feathers, birds convert yellow dietary pigments known as carotenoids into red pigments and then deposit them in the feathers,” says Miguel Carneiro of Universidade do Porto in Portugal. “Birds also accumulate these same red pigments in one of the cone photoreceptor types in their retina to enhance color vision. We discovered a gene that codes for an enzyme that enables this yellow-to-red conversion in birds.”

“It was known that some birds have the ability to synthesize red ketocarotenoids from the yellow carotenoids that they obtain in their diet, but the gene or enzyme involved, and its anatomical location, have been obscure,” adds Nick Mundy of the University of Cambridge. “Our findings fill this gap and open up many future avenues for research on the evolution and ecology of red coloration in birds.”

Carneiro’s team, including Joseph Corbo of Washington University School of Medicine in St. Louis and Geoffrey Hill of Auburn University, made their discovery thanks to canary fanciers who crossed a yellow canary with a red siskin almost 100 years ago, producing the world’s first red canary. In the new study, the researchers compared the genome sequences of yellow and red canaries to red siskins in search of the gene responsible for the birds’ color differences.

Their search led them to a cytochrome P450 enzyme, dubbed CYP2J19. Further analysis of the gene’s expression showed that the enzyme is expressed at high levels in the skin and liver of red factor canaries, strongly implicating it as the enzyme responsible for red coloration.

In the other report, Mundy and colleagues, including Staffan Andersson of the University of Gothenburg, and Jessica Stapley of the University of Sheffield, found their way to the cytochrome P450 gene cluster through comparisons of standard zebra finches, which have a distinctive red beak, and mutant zebra finches with yellow beaks. Zebra finches have three related cytochrome P450 genes, and the researchers found multiple mutations in this genetic region in the yellowbeak birds. They further found that the enzyme was expressed in almost undetectable levels in the birds’ yellow beaks.

The genetic findings pave the way for new kinds of studies on the red coloration of birds, according to the researchers. They also raise many new and intriguing questions. For example, the gene now identified belongs to a family of genes known to play an important role in detoxification.

“In sexual selection, red color is thought to signal individual quality and one way it can do this is if the type or amount of pigmentation is related to other physiological processes, like detoxification,” Andersson says. “Our results, which link a detoxification gene to carotenoid metabolism, may shed new light on the debated honesty of carotenoid-based signals.”

Corbo says one thing that came as a particular surprise to them was the discovery that the “redness gene” is present in the genomes of many, if not most, bird species, not just those with red feathers.

“Diurnal birds appear to use this gene to produce red pigments in the retina to enhance color vision,” Corbo says. “However, only birds with red feathers additionally express the gene in their skin. These findings suggest that nearly all birds have the latent capacity to make red feathers, but in order to actually do so, they must evolve the means of expressing this gene in the skin in addition to the retina.”

Mundy and Andersson are now returning to the birds where their search for the “red-maker” once began, the African widowbirds and bishops, which show “spectacular differences among different species.” Most intriguingly, Andersson adds, “dazzling red colors have evolved repeatedly in this group, mostly by the mechanism described here, but there are some very interesting exceptions.”

Corbo and colleagues also plan to explore red feathers in many more bird species, to see whether they rely on the same or different mechanisms. They say they also will continue using the canary as a model for uncovering the genetic basis of other interesting traits in birds.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160519130102.htm  Original web page at Science Daily

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* Reintroduction of lynx requires larger numbers to avoid genetic depletion

For successful reintroduction of lynx into the wild, the number of released animals is crucial. If only a few lynx are reintroduced to found a population, the genetic diversity is too low to ensure their long-term sustainability. An international research team has recently published these findings in the scientific journal Conservation Genetics. The researchers highlight the need to strengthen newly established European lynx populations by additional translocations of lynx as well as other conservation measures.

Scientists of the German Leibniz Institute for Zoo and Wildlife Research (IZW), the Bavarian Forest National Park (Germany), the Polish Academy of Sciences (Poland) and the Russian Academy of Sciences (Russia) investigated the genetic status of two lynx populations in the Bohemian-Bavarian and Vosges-Palatinian forests in central Europe.

The Eurasian lynx (Lynx lynx) is the largest European cat species and has been protected in the EU since 1992. Originally spread throughout all of Europe, the species is now mainly limited to protected areas such as national parks. Current populations only exist because countries have invested a considerable effort to protect lynx in Europe or to reintroduced them to suitable habitat in its former range. Reintroduced populations face some specific challenges: “Our results show that these reintroduced populations usually consist of too few individuals to be self-sustaining. Small populations are highly vulnerable to loss of genetic variation because each individual represents a high percentage of the population’s gene pool,” explains Daniel Förster, geneticist at the IZW.

The population in the Bohemian-Bavarian forest was founded by introducing 5 to 10 lynxes in the 1970s and later supplementing them with 18 additional individuals. The population in the Vosges-Palatinian forest was founded by 21 lynxes released between 1983 and 1993. From this already limited number of founders, only some individuals actually produced offspring. “From a genetic point of view this means that the few founder animals represented little genetic variation,” says Jörns Fickel, coauthor of the study and also a geneticist at the IZW. To assess the effect of the reintroduction on the genetic status of these two lynx populations, the scientists compared their genetic diversity with those of naturally occurring lynx populations in Eastern Europe. For this purpose they analysed molecular markers in lynx DNA obtained from fecal, blood, and tissue samples.

The study showed that these two populations displayed very low genetic diversity in comparison with other European lynx populations, with far fewer genetic variants present in the new populations than in the naturally occurring populations. A previous study on a reintroduced lynx population in Slovenia and Croatia already indicated that small reintroduced populations suffer from low genetic diversity. The current study now confirms these findings and thus points towards a more general pattern: Small populations are unlikely to survive in the long term. According to the authors of the study, it is well justified to classify the Bohemian-Bavarian population as “endangered” and the Vosges-Palatinian population as “critically endangered” as is currently done by the International Union for Conservation of Nature and Natural Resources (IUCN Red List). Thus, suitable measures for their ‘genetic reinforcement’ and conservation need to be taken.

Especially for small populations it is crucial that not a single individual dies before it has reproduced — be it of natural causes or poaching. “It is therefore really important to reduce the illegal killing of lynx to establish and maintain a long-term viable population” emphasizes Förster. He and his colleagues also advocate the reintroduction of more lynxes to directly strengthen the genetic variability of the populations. Indirect conservation measures such as setting up wildlife corridors can further facilitate the genetic exchange between neighbouring populations and thus contribute to the strengthening of the overall lynx population as well.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160519082104.htm  Original web page at Science Daily

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Second gene modifies effect of mutation in a dog model of ALS

Degenerative Myelopathy is a naturally occurring, progressive adult onset disorder of the spinal cord that leads to paralysis and death. In 2009, a SOD1 mutation was associated with risk of developing the disease (link to previous press release). However, not all dogs with the mutation became affected, prompting the hypothesis that additional genes could modify disease risk.

Genome-wide association analysis comparing affected and unaffected PWC with the SOD1 mutation identified a haplotype within the gene ‘SP110 nuclear body protein’ that was associated with increased risk of developing DM and early age of onset.

We discovered several variants in SP110 that were more common in the PWCs that developed DM says Emma Ivansson, former PostDoc at Uppsala University leading the study.

Our functional studies revealed that the variants alter expression of SP110 in blood cells continues Sergey Kozyrev, senior scientist at Uppsala University.

Whether SP110 affects the risk of DM also in other dog breeds requires further investigation, says Kate Megquier, veterinarian and PhD student at Uppsala University and Broad Institute.

SP110 is a regulator of gene expression, mainly in immune cells. It is known that the immune response is important in neurodegeneration, but inflammation can be either protective or damaging and the exact mechanisms are still unclear.

Many studies have investigated the role of immunity in ALS, and our finding that a gene regulating the immune response is important in this canine model of ALS could provide a new angle says Emma Ivansson.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160516181035.htm  Original web page at Science Daily

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Why Labrador retrievers are more interested in food than other breeds

Dog owners tell their vets that Labrador retrievers are always interested in food, and new work shows there might be a biological truth to the claim. A May 3 study in Cell Metabolism links a gene alteration specifically found in Labs and related flat coat retrievers to greater food-motivated behavior, describing the first gene associated with canine obesity. The variation also occurs more frequently in Labradors chosen as assistance dogs, and might explain why these canines seem more trainable with food rewards.

Labrador retrievers are more interested in food and tend to be more obese than other breeds, regardless of owner. “Whenever there’s something more common in one breed than another, we think genetics are involved,” says Eleanor Raffan, a veterinary surgeon and geneticist at the University of Cambridge who previously studied human obesity before investigating the canine angle.

Starting with an initial cohort of 15 obese and 18 lean Labrador retrievers, Raffan and her colleagues selected three obesity-related genes to examine, all of which were known to affect weight in humans. This first analysis turned up a variation in a gene called POMC. In more of the obese dogs, a section of DNA was scrambled at the end of the gene. The deletion is predicted to hinder a dog’s ability to produce the neuropeptides β-MSH and β-Endorphin, which are usually involved in switching off hunger after a meal.

In humans, common variants in POMC have been associated with differences in body weight. “There are even some rare obese people who lack a very similar part of the POMC gene to that which is missing in the dogs,” says Stephen O’Rahilly, co-director of the Wellcome Trust-Medical Research Council Institute of Metabolic Science and a senior author on the study.

In a larger sample of 310 Labrador retrievers, Raffan and her colleagues discovered a host of canine behaviors associated with the POMC deletion. Not all Labs with the DNA variation were obese (and some were obese without having the mutation), but in general the deletion was associated with greater weight and, according to an owner survey, affected dogs were more food-motivated–they begged their owners for food more frequently, paid more attention at mealtimes, and scavenged for scraps more often. On average, the POMC deletion was associated with a 2 kg weight increase.

“We’ve found something in about a quarter of pet Labradors that fits with a hardwired biological reason for the food-obsessed behavior reported by owners,” says Raffan. “There are plenty of food-motivated dogs in the cohort who don’t have the mutation, but there’s still quite a striking effect.”

The researchers found that the POMC deletion occurs in roughly 23 percent of Labrador retrievers overall, based on further sampling of 411 dogs from the UK and US. Of 38 other breeds, the deletion only showed up again in flat coat retrievers, related to Labrador retrievers, and weight and behavior were similarly affected.

Notably, the POMC deletion was markedly more common in the 81 assistance Labrador retrievers included in the study, occurring in 76 percent of these dogs. “We had no initial reason to believe that the assistance dogs would be a different cohort,” says Raffan. “It was surprising. It’s possible that these dogs are more food-motivated and therefore more likely to be selected for assistance-dog breeding programs, which historically train using food rewards.”

But, Raffan cautions, the results could also be just a quirk of the data. “We haven’t yet looked at puppies and asked if they’re more likely to qualify as an assistance dog if they have the mutation,” she says.

The study adds to a growing body of knowledge about the biological reasons driving weight. “The behavior of dogs carrying this mutation is different,” says Raffan. “You can keep a dog with this mutation slim, but you have to be a lot more on-the-ball–you have to be more rigorous about portion control, and you have to be more resistant to your dog giving you the big brown eyes. If you keep a really food-motivated Labrador slim, you should give yourself a pat on the back, because it’s much harder for you than it is for someone with a less food-motivated dog.”

Moving forward, Raffan and her colleagues are also investigating the potential therapeutic implications for humans with obesity. The impacts of mutation in POMC have previously been difficult to research because in mice and rats, animals typically used to study obesity, the gene is quite different from the human version. “Further research in these obese Labradors may not only help the well-being of companion animals, but also carry important lessons for human health,” says O’Rahilly.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/05/160503130342.htm Original web page at Science Daily

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Origin of dromedary camel domestication discovered

The dromedary, the one-humped Arabian camel, plays an important role in the countries of North Africa. For thousands of years, the people of North Africa and Asia have used the animal for the transportation of people and goods. It was fundamental to the development of human societies in inhospitable environments. Dromedaries are the largest domesticated livestock species.

“Many open questions remain with regard to the dromedary’s domestication and evolutionary history,” explains Pamela Burger from the Research Institute of Wildlife Ecology at Vetmeduni Vienna. “We have managed to turn the wild dromedary into a domesticate, but we don’t know how and where domestication began and what effect it has had on today’s animals.”

During the domestication process, people usually breed the animals by selecting those parts of the genotype that bring the most benefit. The team around Burger has shown for the first time that this was not the case with the dromedary. Dromedaries exhibit an enormous genetic diversity despite the fact that breeding usually results in a low genetic diversity. This makes dromedaries different from other animals domesticated through breeding.

Burger and her team collected samples from nearly 1,100 extant dromedaries and compared these with archaeological samples from wild and early-domesticated animals. Using DNA analysis, the researchers determined that the dromedary’s genetic diversity is directly related to its use as a transport animal. The forth-and-back movement of the caravans brings different dromedary populations in contact with each other. This leads to a regular gene flow and the maintenance of the genetic diversity. An isolated group is rare. Only one population in East Africa deviated from the genetic diversity of the other dromedaries. This group, however, has been isolated for some time due to geographic obstacles and cultural barriers.

The regular gene flow reflects a genetic diversity that is usually found only in wild animals. But it makes it difficult to determine the wild form from which today’s dromedary is descended and, therefore, where it was domesticated.

Burger and her team succeeded in answering this question. The group of researchers analysed up to 7,000-year-old DNA from bones of wild and early-domesticated dromedaries and compared the samples with the genetic profiles of modern dromedary populations from around the world. For the first time, it was possible to identify the Southeast Arabian Peninsula as the region of first domestication. “Our results appear to confirm that the first domestication of wild dromedaries occurred on the southeast coast. This was followed by repeated breeding of wild dromedaries with the early-domesticated populations,” Burger explains. The wild ancestor of today’s dromedary had a geographically limited range and went extinct around 2,000 years after the first domestication.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160509191839.htm  Original web page at Science Daily

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Human-embryo editing now covered by stem-cell guidelines

The international society that represents stem-cell scientists has updated its research guidelines in the wake of dramatic progress in several fields — in particular in research that involves the manipulation of human embryos. The authors hope that the updated guidelines will allay various ethical concerns, and avoid the need for strict government regulations that could impede the progress of science.

“Self-regulation is the best form of regulation,” says Charles Murry, a member of the committee that updated the guidelines, and a bioengineer at the University of Washington in Seattle. “The biomedical community is best poised to strike the balance between rapid progress and safe, ethical research practice.”

The International Society for Stem Cell Research (ISSCR), which was founded in 2002, has previously released guidelines in 2006 and 2008 on embryonic-stem-cell research and on clinical translation of stem-cell research. The latest guidelines have broader scope, and cover all research on human embryos — including gene-editing of embryos, which has in the past year advanced significantly and generated much controversy.

The revised guidelines recommend that all research involving the manipulation of human embryos now undergo a similar review as experiments that use embryos to create stem-cell lines, which has been one of the most divisive research procedures of recent decades. They suggest that such research be added to the remit of existing embryonic stem cell research oversight (ESCRO) committees.

Scientists previously balked at the introduction of ESCRO committees, and there is likely to be resistance to the idea of adding bureaucratic review to other research areas. “No scientist or physician jumps for joy when new regulations are put in place,” says Murry. But he says that the updates are necessary to avoid “a wild-west environment where sensitive research is done without proper regard for community standards”.

At the same time, the new guidelines attempt to clear the way for more research using induced pluripotent stem (iPS) cells, which, like embryonic stem cells, are able to turn into all cell types in the human body but are not taken from embryos. The authors recommend explicitly excluding the generation of iPS cells from regulations on embryonic stem cell research and relying instead on the existing oversight for donor cell recruitment. Some institutions have been confused about how to classify iPS cells, says George Daley, a stem-cell scientist at the Boston Children’s Hospital in Massachusetts and one of the authors of the new guidelines.

Also included in the guidelines is a call for continued observance of a moratorium on growing human embryos in vitro beyond 14 days — a somewhat arbitrary limit that has become the global standard. Two papers published on 4 May reported experiments that showed that it would soon be possible to breach the limit, sparking debate about whether the rule should be reconsidered.

“The ISSCR deserves credit for bringing up and discussing these important issues,” says stem-cell biologist Ali Brivanlou of the Rockefeller University in New York City, who is a lead author on one of the embryo papers. But he adds that further discussion of the issues is needed.  “We need to get together the positives and negatives of moving forward,” he says.

The authors also take the opportunity to reinforce a warning that the ISSCR has long made — that researchers shouldn’t overstate the clinical implications of stem-cell experiments. Hype surrounding such experiments has enabled a worldwide market for unproven, and often ineffective or dangerous, stem-cell therapies, which has been difficult to regulate. “We take a swipe at hyperbole in scientific communication, essentially asking researchers to ‘take it down a notch’ when they speak about the implications of their work,” says Murry.

Nature doi:10.1038/nature.2016.19909

http://www.nature.com/news/index.html  Nature

http://www.nature.com/news/human-embryo-editing-now-covered-by-stem-cell-guidelines-1.19909  Original web page at Nature

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* Using precision-genetics in pigs to beat cancer

Pigs could be a valuable alternative to rodent models of cancer. The numbers are staggering: more than 40 % is the lifetime risk of developing cancer in the U.S., with only 66 % survival-rates 5 years after diagnosis, for all types of cancer. Trends suggest that in 2015, over 1.6 million new cases were diagnosed in the U.S., with over 580,000 deaths in consequence.

These numbers emphasize the need to better understand and treat the various forms of the disease, but mouse models usually used in cancer research have given us limited answers. However, Senior Scientist Adrienne Watson and colleagues at Recombinetics and the University of Minnesota, say that pigs may turn out to be the best alternative models.

“Many organ systems vary so greatly between rodents and humans that certain types of cancer cannot be accurately modelled,” says Watson, despite the major role mouse models have played in our understanding of the disease. The authors conclude that the five deadliest cancers in the U.S. cannot be modeled in rodents, or have ineffective models for identification of treatments that translate to the clinic.

Cancer is a genetic disease where cells acquire or inherit genetic mutations, which result in malfunctioning proteins that cause uncontrolled growth of cells in the blood or solid organs. “The anatomical, physiological, and genetic similarities between swine and humans are striking, suggesting that disease modeling in this large animal may better represent the development and progression of cancer seen in people.”

The authors explain, in their article that was published recently in Frontiers in Genetics, that new technology in precision-genetics, when applied to pigs, will lead the way, and could become especially advantageous when conducting targeted gene-editing using custom endonucleases, such as TALENs and CRISPRs, and transposon systems. “We can now engineer exact human disease alleles into the pig genome, to make novel models not available in rodents. They are incredibly valuable for their broader preclinical applications.”

Using genetically modified pigs would allow overcoming one of the main drawbacks of rodent models, which is their inability so far to identify safe and effective drugs to treat cancer. For example, the size and ease in handling pigs allows for drugs to be administered in the same way as in patients, and for follow up blood-work over time.

The authors caution that, as for any novel animal model to be useful in cancer research, it must be adopted and fully tested in many laboratories and under many circumstances. But the higher costs involved in handling these animals in the laboratory setting may be well worth the gains in our understanding of this deadly disease.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/05/160513111830.htm  Original web page at Science Daily

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Mice with genetic defect for human stuttering offer new insight into speech disorder

Mice that vocalize in a repetitive, halting pattern similar to human stuttering may provide insight into a condition that has perplexed scientists for centuries, according to a new study by researchers at Washington University School of Medicine in St. Louis and the National Institutes of Health.

The researchers created mice with a mutation in a gene associated with stuttering in humans, and found that they vocalized in an abnormal pattern reminiscent of human stuttering. The animal model of stuttering can help scientists understand the molecular and neurological basis of the disorder, and potentially develop treatments. The research is published online April 14, 2016 in Current Biology.

Once thought to be caused by nervousness, stress or even bad parenting, stuttering is now recognized as primarily biological in origin, although anxiety can exacerbate the condition.

Some people who stutter have a mutation in a gene called Gnptab (for N-acetylglucosamine-1-phosphate transferase alpha and beta). With Dennis Drayna, PhD, and colleagues at the National Institute on Deafness and Other Communication Disorders, the researchers created mice with a corresponding mutation in the same gene and studied their vocalizations for evidence of abnormalities similar to human stuttering.

“Speech is obviously a unique human capacity, but the patterns of speech are built out of a lot of building blocks that are much simpler,” said Tim Holy, PhD, an associate professor of neurosciences and the paper’s senior author. “You have to be able to control the timing of your breath and the fine muscles in your tongue and mouth. You have to be able to initiate movement. Those kinds of things may be shared all the way from mice to people.”

Mice make complex sounds all the time, at pitches too high for the human ear to detect.

“Pups spontaneously vocalize when they are taken from their mom,” said first author Terra Barnes, PhD, a senior scientist in Holy’s lab. “Mice vocalize when they’re in pain, when they meet another mouse or to attract a mate.”

A key characteristic of stuttering is the presence of hesitations that break up the smooth flow of speech. Barnes and colleagues developed an algorithm to analyze the length of pauses in the spontaneous vocalizations of 3- to 8-day-old mouse pups. They found that mice carrying the mutation exhibited longer pauses than those without the mutation.

The researchers applied the same algorithm to recordings of people talking, some of whom stuttered and some did not. The algorithm accurately distinguished people who speak fluently from people who stutter.

The scientists also found that the syllables vocalized by mice with the mutation were less random than those of mice without the mutation. In other words, similar to people who stutter, the mice with the mutation repeated the same syllables more often.

“We found abnormalities that mimic some features of human stuttering,” said Barnes.

Other than in their vocalizations, the mice with the mutation were normal. Co-author David Wozniak, PhD, professor of psychiatry at Washington University, and colleagues put the mice through a battery of tests — to check their balance, strength, coordination, movement initiation, spatial learning, memory, sociability and more — and found no substantial differences between mice with and without the mutation. In this respect, the mice with the mutation are like people who stutter — indistinguishable from nonstutterers in all but speech.

“One of the things we find scientifically interesting about stuttering is that it is so precisely limited to speech,” said Holy. “It’s a very clean defect in an incredibly complex task.”

It is not clear how the gene relates to speech. It is known to be involved in the pathway that degrades molecules inside the cell. Mutations that cause total loss of function result in serious metabolic diseases called mucolipidosis II/III, but the mutations associated with stuttering appear to preserve much of the known function of these genes.

“It’s kind of crazy that this gene that’s involved in digesting the garbage in your cells is somehow linked to something so specific as stuttering,” said Holy. “It could be that the protein has many functions and this mutation affects only one of them. Or the mutation could very mildly compromise the function of the protein, but there’s a set of cells in the brain that is exquisitely sensitive, and if you ever so slightly compromise the function in those cells you get the observable behavioral deficit.”

Now that researchers have a mouse model of stuttering, they are developing ideas to explore the disorder further. “We’re coming up with lots of studies we can do to figure this out,” said Barnes.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/04/160414144205.htm  Original web page at Science Daily

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Gene-editing research in human embryos gains momentum

Experiments are now approved in Sweden, China and the United Kingdom. At the Karolinska Institute in Stockholm, Fredrik Lanner is preparing to edit genes in human embryos. It’s the kind of research that sparked an international frenzy in April last year, when a Chinese team revealed that it had done the world’s first such experiments.

But Lanner doesn’t expect his work, which will explore early human development, to cause such a fuss. A year of discussion about the ethics of embryo-editing research, and perhaps simply the passage of time, seems to have blunted its controversial edge — although such work remains subject to the same ethical anxieties that surround other reproductive-biology experiments. “At least in the scientific community, I sense more support for basic-research applications,” says Lanner, who gained approval for his experiments last June.

His instinct seems to be borne out by the fairly muted reaction to a 6 April report of an experiment to edit human embryos — only the second to be published. A team led by Yong Fan at Guangzhou Medical University in China used the gene-editing technology CRISPR–Cas9 to try to introduce a mutation that makes humans resistant to HIV infection.

“I don’t think there is anything wrong with what these scientists have done,” says Sarah Chan, a bioethicist at the University of Edinburgh, UK. “This work isn’t seeking to do what is still ethically in question. It’s not seeking to create genetically modified human beings.”

The ethics committee of the university-affiliated hospital that approved Fan’s work says that it has green-lighted two other embryo-editing projects; such research is ethically sound because it will lead to improvements in gene-editing technology and could help to prevent diseases, a committee spokesperson says.

Last December, an international summit of scientists and ethicists declared that gene editing should not be done in human embryos that are intended for use in establishing a pregnancy — but it endorsed basic research.

“People are more understanding of this research,” says Fan, who points to UK fertility regulators’ approval in February of a proposal by developmental biologist Kathy Niakan to edit genes in healthy human embryos, at the Francis Crick Institute in London.

Fan’s team began its experiments in early 2014 and originally submitted the paper to Cell Stem Cell, Fan says. By the time the manuscript ended up on the desk of David Albertini, editor-in-chief of the Journal of Assisted Reproduction and Genetics, a different Guanghzou-based team had become the first to report human-embryo-editing experiments. That paper, which tried to correct a mutation that causes a blood disease, fed into a firestorm over the ethics of modifying human reproductive cells (or ‘germline’ modification). Some researchers called for a moratorium even on proof-of-principle research in non-viable embryos.

Albertini, a reproductive biologist at the University of Kansas Medical Center in Kansas City, felt that it was important to publish Fan’s paper to educate scientists and clinicians. He says that the manuscript went through two rounds of review over eight months — twice as long as is normal for the journal — and that he urged the researchers to discuss the ethical issues surrounding germline editing in the paper.

Fan’s paper should help to reassure international observers about the legitimacy of human-embryo-editing research in China, says Robin Lovell-Badge, a developmental biologist at the Crick. More such embryo-editing papers are likely to be published, he adds. “I know that there are papers floating around in review,” he says. “I’d much rather everything was out in the open.” (Fan says that his team is now focusing on improving the efficiency of CRISPR using human stem cells).

Research involving the editing of human embryos will begin soon elsewhere in the world, if it hasn’t done so privately already.

In a Cell paper published on 7 April, Lanner’s team analysed gene expression in 88 early human embryos and is using those data to identify genes to disrupt in embryos using CRISPR–Cas9. Lanner will discuss the work at a meeting on human gene editing organized by the US National Academy of Sciences and National Academy of Medicine this month in Paris. He says that the experiments could begin in the coming months.

Evan Snyder, a stem-cell scientist at the Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California, says that he doesn’t know of anyone in the United States conducting human embryo editing. But he thinks that US scientists will inevitably take on such research, although federal funding of research on human embryos and germline modification is prohibited. It is important for such research to go forward, Snyder adds, to determine whether technical hurdles would prevent clinical applications.

Norms for conducting and publishing human-embryo-editing work are still taking shape. Snyder says that whenever possible, researchers should use alternatives, such as embryos of non-human primates. And when it is not, they should use only surplus embryos that would ordinarily be discarded from in vitro fertilization clinics.

Both Chinese teams used non-viable embryos, but Lovell-Badge says experiments in normal embryos are also important: to see, for instance, whether CRISPR–Cas9 is more or less effective in such cells.

Some scientists contend that gene-editing experiments designed to probe human development, such as those planned by Lanner and Niakan, are more valuable than experiments that are intended to lay the groundwork for creating genetically modified humans. “At the moment, there seems little point in pursuing long-term clinical goals when there’s so much not known about the technique with human embryos,” says Lovell-Badge.

But Chan thinks there should be ethical latitude for both kinds of research to proceed. “We should give the public the credit for being able to understand the difference between research into genetically modified embryos and genetically modifying human beings,” she says. “I think it’s a good thing if the hubbub dies down a bit.”

Nature 532, 289–290 (21 April 2016) doi:10.1038/532289a

http://www.nature.com/news/index.html  Nature

http://www.nature.com/news/gene-editing-research-in-human-embryos-gains-momentum-1.19767  Original web page at Nature