Categories
News

* Surface mutation lets canine parvovirus jump to other species

Canine parvovirus, or CPV, emerged as a deadly threat to dogs in the late 1970s, most likely the result of the direct transfer of feline panleukopenia or a similar virus from domesticated cats.

CPV has since spread to wild forest-dwelling animals, including raccoons, and the transfer of the virus from domesticated to wild carnivores has been something of a mystery.

“The underlying issue is, how do viruses jump from one animal to another and what controls viral host range?” said Colin Parrish, the John M. Olin Professor of Virology and director of the Baker Institute for Animal Health at Cornell University.

Parrish co-authored a research paper, published in the Journal of Virology, with Susan Daniel, associate professor in Cornell’s Robert Frederick Smith School of Chemical and Biomolecular Engineering, which contends that a key mutation in the protein shell of CPV — a single amino acid substitution — plays a major role in the virus’ ability to infect hosts of different species.

That was a critical step,” he said. “It took a lot of changes to allow that to happen.”

He said another key factor in CPV’s infectivity is adhesion strengthening during TfR binding.

“There’s an initial attachment, which is probably relatively weak,” he said. “The thing just grabs on and holds on a little bit, sort of like using your fingertips. And then it looks like there’s a second attachment that is much stronger, where it’s like you grab on and hold on with both hands and won’t let go.”

“We think that the second event, this structural interaction that occurs in a small proportion of the binding cases, seems to be critical,” he said. “We think that it actually causes a change in the virus, that it triggers a small shift in the virus that actually makes it able to infect successfully.”

One of Daniel’s specialties is the investigation of chemically patterned surfaces that interact with soft matter, including biological materials such as cells, viruses, proteins and lipids. Her lab has pioneered a method called single-particle tracking — placing artificial cell membranes into microfluidics devices, fabricated at the CNF, to study the effect of single virus particles on a variety of membrane host receptors, in this case from both dogs and raccoons.

“The nice thing about these materials is that we can design them to have all different kinds of chemistries,” she said. “So in this particular study, we can put the receptor of interest in there, isolated from everything else so we can look at the specific effect of that receptor on a particular virus interaction.”

Daniel’s lab also developed the precision imaging devices used in the study. “Another piece of this paper is how the parvovirus actually sits down and binds even stronger over time with that receptor,” Daniel said. “That was kind of a new result that came out of the technique itself, being able to look at individual binding events.”

“When this virus infects a young animal, it can be fatal,” Parrish said. “It’s very unpleasant, and if you own a puppy or a kitten, that’s why you should vaccinate.”

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

https://www.sciencedaily.com/releases/2016/04/160414122007.htm  Original web page at Science Daily

Categories
News

Island foxes may be ‘least variable’ of all wild animals

In comparison to their relatives on the mainland, the Channel Island foxes living on six of California’s Channel Islands are dwarves, at two-thirds the size. The island foxes most likely evolved from gray foxes brought to the northern islands by humans over 7,000 years ago. Some think island foxes may have been partially domesticated by Native Americans. Like many island species, they have little fear of humans.

Now a new study reported in the Cell Press journal Current Biology on April 21 finds that the foxes also show a surprising absence of genetic variation. The study offers the first complete genome sequences of an island species that is a model for long-term conservation of small, endangered populations, the researchers say.

“We find a dramatic reduction of genetic variation, far lower than most other animal species,” says Jacqueline Robinson of the University of California, Los Angeles (UCLA).

One population in particular living on San Nicolas Island has an order of magnitude lower variation than any other known species, including the severely endangered African cheetah, Mountain gorilla, and Tasmanian devil, she says. Such near absence of genetic variation doesn’t bode well for the foxes. But it also presents a puzzle as to how the foxes have managed as well as they have.

“The degree to which the San Nicolas foxes have lost genetic variation is remarkable, upholding a previous observation that they may be the least genetically variable population of wild animals known,” says Robert Wayne, also of UCLA. “It suggests that under some conditions, genetic variation is not absolutely essential for the persistence of endangered populations.”

The researchers sequenced DNA samples representing each of the Channel Island fox populations and one mainland gray fox from southern California. Researchers originally collected the island fox samples back in 1988, prior to subsequent population declines due to predation and disease in four of the island populations

Theory holds that small populations will not only lose variation, but will also accumulate deleterious variation as the normal process of natural selection fails. Indeed, the complete genomes of the island foxes show dramatic, 3- to 84-fold declines in heterozygosity. (Heterozygosity refers to places in the genome where an individual has inherited different variants of the same gene from their mother and father.) The foxes also show sharp increases in genes for which they carried two copies of a variant deemed to be harmful or deleterious in some way.

The San Nicolas Island population of foxes has a near absence of variation, the researchers report, demonstrating a unique “genetic flatlining.” The only variation found in those foxes occurs at “heterozygosity hotspots,” enriched for olfactory receptor genes and other genes with high levels of ancestral variation.

The researchers say the new findings need to be taken into careful consideration in plans for the foxes’ future, including the removal of their federal endangered species protection status.

“The island fox populations suffer from both a lack of genetic diversity and the accumulation of damaging genetic variants, which is likely to worsen over time,” Wayne says. Island foxes are also susceptible to population crashes from disease and non-native predators, such as golden eagles.

Additional research is needed to understand how the foxes may compensate for their decreased variation and the accumulation of deleterious variants. Wayne and Robinson say they’d like to explore gene expression and regulation in the foxes, to find out whether these factors may act to alleviate some of the effects of deleterious variants.

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

https://www.sciencedaily.com/releases/2016/04/160421133636.htm  Original web page at Science Daily

Categories
News

Evolution of Darwin’s finches tracked at genetic level

Researchers are pinpointing the genes that lie behind the varied beaks of Darwin’s finches – the iconic birds whose facial variations have become a classic example of Charles Darwin’s theory of natural selection.

Last year, researchers identified a gene that helps to determine the shape of the birds’ beaks. Today in Science, they report a different gene that controls beak size. Shifts in this gene underlay an evolutionary change that researchers watched in 2004–05, during a drought that ravaged the Galapagos Islands, where the finches live. The beak sizes of one population of finches shrank, so as to avoid competing for food sources with a different kind of finch – and their genetics changed accordingly.

“A big question was, ‘Is it possible to identify genes underlying such evolution in action, even in a natural population?’,” says Leif Andersson, a geneticist at Uppsala University in Sweden and one of the study’s authors. “We were able to nail down genes that have directly played a role in this evolutionary change.”

The story begins about two million years ago, when the common ancestor of all Darwin’s finches arrived on the Galapagos Islands. By the time of Charles Darwin’s visit in 1835, the birds had diversified into more than a dozen species, each adapted to different ecological niches. Some had massive beaks for cracking seeds, some had delicate beaks for snatching insects, and some even had sharp beaks for feeding on blood.

To examine the genetic basis for this variation, the researchers compared the genomes of 60 birds representing six species of Darwin’s finches, along with 120 specimens from other species to help them tease out phylogenetic relationships. As expected, closely related species had the most similar genomes.

But in those six finch species one region of the genome correlated more with bird size than with relatedness. Small species had one variation of this genomic region, large species had another and medium-sized species had a mixture of the two, suggesting that at least one of the genes in this region affected size. The most likely candidate was HMGA2, which is known to affect size and face structure in other animals. Further analysis showed that in Darwin’s finches, the HMGA2 region is especially important in controlling the size of the beak.

The researchers then looked at the role of HMGA2 in a dramatic evolutionary event. After drought struck the Galapagos in 2003, many of the medium ground finches (Geospiza fortis) with larger-than-average beaks starved to death. They couldn’t compete with a bigger species (Geospiza magnirostris) that had recently colonized the island and was better at eating large seeds. After the drought, the medium ground finches that managed to survive had smaller beaks than those that had perished, probably because they were better suited to eating the small seeds that their competitors avoided.

By analysing DNA from medium ground finches that lived around the time of the drought, the researchers found that the large-beak HMGA2 variant was more common in birds that starved to death, while the small-beak variant was more common in birds that survived. This genetic shift is likely responsible for some of the reduction in beak size, the researchers say.

The discovery opens up new questions for biologists to explore, such as when gene variants arise and how they contribute to splits between species, says Dolph Schluter, an evolutionary biologist at the University of British Columbia in Vancouver, Canada.

“On the one hand it doesn’t change anything, in that we already knew there was an evolutionary response to competition during that drought,” says Schluter. “But on the other hand, it changes everything, because we can point to a physical, material basis for that change.”

Nature doi:10.1038/nature.2016.19795

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

http://www.nature.com/news/evolution-of-darwin-s-finches-tracked-at-genetic-level-1.19795 Original web page at Nature

Categories
News

Breakthrough made in cleft lip and palate research

Leading scientists have identified an important gene that is associated with cleft lip and palate. Experts say the discovery is a step closer to understanding how this birth defect arises, and will help in the development of medical approaches to prevent the disfiguring condition.

An international team, led by Newcastle University, UK, and the University of Bonn in Germany, has found that variants near a gene called GREM1 (Gremlin1) significantly increase the risk for cleft lip and palate.

A cleft is a gap in the upper lip, the roof of the mouth, or sometimes both. Each year, approximately 250,000 babies worldwide are born with a cleft, equating to about two babies a day in the UK.

Dr Heiko Peters, who works at Newcastle University’s Institute of Genetic Medicine, is senior author of the research paper published in the journal, PLoS Genetics.

He said: “The findings reveal a link between GREM1 and specific clinical characteristics that arise in the formation of a cleft lip and palate.

“This is very important in this research area as it helps to decipher the complex interplay between genes required for the different steps and in different tissues during lip and palate development.

“A cleft lip can occur with or without a cleft palate and the genetic factors that predispose to palate involvement are largely unknown.”

The research team carried out analyses on genetic and clinical data from three large patient cohorts and identified a strong association between a region on chromosome 15 and cleft lip and palate.

Experts carried out studies on mice to investigate where GREM1 is normally active in the development of the face and how alterations in the gene’s activity may affect the lip and palate.

Results indicate that it is not the loss of GREM1 function but rather its increased activity that causes the condition.

It is the second gene which has been shown to be linked to a condition in which a cleft of the lip and a cleft of the secondary palate occur together.

Dr Peters added: “These findings provide a framework for further analyses of GREM1 in human cell systems and model organisms, broadening our understanding of the processes that regulate the face’s shape.”

Although not life-threatening for patients with access to postnatal surgery, cleft lip and palate requires additional multidisciplinary care by specialists, including ear, nose and throat experts, orthodontists and speech therapists.

Children with the condition can have dental issues, speech problems and are at increased risk of serious ear infections and hearing loss.

Currently, scientists only have a fragmented picture about which genes are required for lip and palate development, and how environmental factors might interact with genetic risk factors.

To establish effective prevention strategies scientists must identify genetic risk factors and understand how gene-gene and gene-environment interactions interfere with lip and palate development.

As the use of personalized medicine increases, understanding how genetic changes alter fetal development will become increasingly relevant.

This is particularly important for conditions such as cleft lip and palate that appear to be caused by a combination of genetic and environmental factors, such as smoking or certain medicines used by the mother.

Further studies will focus on identifying genes and environmental factors that interact with GREM1.

Dr Laura Yates, consultant in clinical genetics at Newcastle upon Tyne Hospitals NHS Foundation Trust, said: “The families we meet in genetic clinics on a daily basis generally have two common questions.

“Firstly, what is the cause of the developmental anomaly affecting their child or themselves, and secondly, can it be treated or prevented in future pregnancies?

“Studies such as this contribute vital pieces of information that enable clinicians to provide patients with answers that are relevant to them and their family, not just general statistics.

“Our understanding of how genetic factors in both mother and fetus, and external or environmental influences impact on fetal development in the womb, is far from complete.

“This study takes us one step closer to being able to identify genetic changes that increase the chance of a particular form of cleft lip and palate re-occurring in a family, therefore to studying what can be done to reduce the chance of this happening in individuals who have this genetic change.”

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

https://www.sciencedaily.com/releases/2016/03/160324104802.htm  Original web page at Science Daily

Categories
News

* Analysis of dog genome will provide insight into human disease

An important model in studying human disease, the non-coding RNA of the canine genome is an essential starting point for evolutionary and biomedical studies, according to a new study led by The Genome Analysis Centre (TGAC).

New research published today in PLOS ONE reveals an improved annotation of microRNAs in the dog genome to further understand its biological role. Providing a platform for future studies into biomedicine, evolution and the domestication of important animals including dogs, cows, horses and pigs.

MicroRNAs (miRNAs) are small non-coding RNA molecules that play a crucial role in regulating gene expression in animals and plants. Using the latest dog genome assembly and small RNA sequences of nine different dog tissues including skin, blood, ovaries and testes, scientists from TGAC have identified 91 novel miRNAs.

This discovery provides a significant opportunity not only to enhance our understanding of how miRNAs regulate a variety of biological processes in an important model species for studying human diseases, but can lead to further, similar research into the role that miRNAs play in animal domestication.

Lead researcher, Dr Luca Penso Dolfin from TGAC’s Vertebrate & Health Genomics Group, said: “As miRNAs are so important in orchestrating a variety of cellular processes, the discovery of these 91 novel miRNAs provides a vital starting point to explore their potentially major effects on gene regulation.”

Overall, 811 miRNAs were analysed by Dr Penso-Dolfin: 91 novel microRNA sequences and 720 conserved (that is, common to other organisms). Among these conserved loci, 207 had not previously been identified as canine microRNAs.

Dr Penso-Dolfin, added: “Our results represent a clear improvement in our knowledge of the dog genome, paving the way for further research on the evolution of gene regulation, and the contribution of microRNAs to pathological conditions. We are now looking at additional data for dog and a variety of farm animals, combining microRNA discovery to the investigation of their possible role in domestication.”

The domestic dog, Canis familiaris, is the result of wolf (Canis lupus) domestication, which started around 10,000 years ago. Since then, hundreds of dog breeds have been artificially selected, leading to very high levels of morphological and behavioural variation. Having shared the environment with humans ever since its appearance, the dog has been exposed to similar pathogens, and therefore represents an important model system for the study of human diseases.

The publication of the latest Canine genome build and annotation, CanFam3.1 provides an opportunity to enhance our understanding of gene regulation across tissues in the dog model system.

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

https://www.sciencedaily.com/releases/2016/04/160427164134.htm  Original web page at Science Daily

Categories
News

Genomes of chimpanzee parasite species reveal evolution of human malaria

Understanding the origins of emerging diseases — as well as more established disease agents — is critical to gauge future human infection risks and find new treatment and prevention approaches. This holds true for malaria, which kills more than 500,000 people a year. Symptoms, including severe anemia, pregnancy-associated malaria, and cerebral malaria, have been linked to the parasite’s ability to cause infected red blood cells to bind to the inner lining of blood vessels.

An international team led by Beatrice Hahn, MD, a professor of Medicine and Microbiology from the Perelman School of Medicine at the University of Pennsylvania, and MD/PhD student Sesh Sundararaman, used a selective amplification technique to sequence the genomes of two divergent Plasmodium species, Plasmodium reichenowi and Plasmodium gaboni, from miniscule volumes of chimpanzee blood to find clues about the evolution and pathogenicity of Plasmodium falciparum, the deadliest malaria parasite that affects people. Their findings appear this week in Nature Communications.

African apes harbor at least six Plasmodium species that have been classified into a separate subgenus, called Laverania. Three of these Laverania species, including Plasmodium reichenowi and Plasmodium gaboni, reside in chimps, while three others, including Plasmodium praefalciparum that gave rise to Plasmodium falciparum, reside in gorillas. The gorilla origin of Plasmodium falciparum was discovered several years ago by this same international group of investigators.

“We want to know why Plasmodium falciparum is so deadly,” Hahn said. “The answer must lie in the blueprint — the genome — of its chimpanzee and gorilla cousins. We also want to know how and when the gorilla precursor of Plasmodium falciparum jumped into humans, and why this happened only once.”

Parasites infecting humans and great apes share genes that allow them to hide from the host’s immune system, adhere to tissues, and cause disease. Better understanding the evolution of human malaria virulence provides potential new targets for drugs and vaccines.

Coauthor Dustin Brisson, PhD, a professor of Biology at Penn, initially developed the selective amplification method to sequence bacterial genomes. Sundararaman calls applying this new approach to malaria research “one of the paper’s most important contributions.” Using this technique, the team was able to generate high quality Laverania genome sequences by using small amounts of unprocessed blood collected from chimpanzees living in sanctuaries during routine health screens.

The chimpanzee parasite genomes contain a goldmine of information about the evolutionary origins of the malaria parasites infecting humans. One of the first things to emerge from genome-wide analyses was that the parasites indeed represent distinct, non-interbreeding species.

In addition, members of each chimpanzee parasite species display about 10 times more genetic diversity than do human parasites. “The chimpanzee parasites really highlight the lack of diversity in Plasmodium falciparum,” said co-author Paul Sharp, PhD, an evolutionary biologist from the University of Edinburgh and long-term collaborator of the Hahn team. “This is most likely because these parasites went through a severe bottleneck when first transmitted to humans, perhaps within the past 10,000 years.”

By comparing the different parasite genomes the team also found an expansion of a multi-gene family, which governs red blood cell remodeling and therefore helps the parasite to evade host immune cells as well as clearance by the spleen. “The remodeling process is a key part of severe malaria pathology in human Plasmodium falciparum infections,” explained coauthor Julian Rayner, PhD, a malaria researcher at the Wellcome Trust Sanger Institute and long-term member of the research team. “The expansion of this gene family from a single gene in all other Plasmodium parasites to up to 21 genes in Laverania suggests that remodeling evolved early in the radiation of this group of primate parasites and contributed not only to their unique biology but perhaps also to their successful expansion.”

“‘We also found a short region of the genome, including two essential invasion genes, where Plasmodium falciparum was much more different from its close relatives than we expected,” said Lindsey Plenderleith, PhD, a postdoctoral fellow at the University of Edinburgh, who together with Sundararaman compared and annotated the various parasite genomes. Further analysis yielded the surprising finding that this fragment of DNA was horizontally transferred — from one species to another — into the gorilla ancestor of Plasmodium falciparum.

“It is tempting to speculate that this unusual event somehow predisposed the precursor of Plasmodium falciparum to colonize humans,” added Hahn. “However, this gene transfer clearly is not the entire story.”

Although the origin of Plasmodium falciparum is now well-established from past research by this group, nothing is known about the circumstances that led to its emergence. “Coaxing entire parasite genome sequences out of small quantities of unprocessed ape blood will help us to better understand what happened and whether it can happen again,” Sundararaman said.

“It’s an exciting time to study Plasmodium species that cannot be cultured and have thus been neglected because of the difficulty of obtaining sufficient quantities of DNA for whole genome sequencing,” Hahn said. The team plans, as a next step, to use the now validated select genome amplification technique to sequence additional ape parasite genomes to identify host-specific interactions and transmission requirements, thereby uncovering vulnerabilities that can be exploited to combat human malaria.

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

https://www.sciencedaily.com/releases/2016/03/160322080523.htm  Original web page at Science Daily

Categories
News

Fungal pathogen sheds gene silencing machinery and becomes more dangerous

For more than a decade, a rare but potentially deadly fungus called Cryptococcus deuterogatti has taken up residence in the Pacific Northwest and Vancouver Island. Unlike its cousin Cryptococcus neoformans, which mostly infects patients with compromised immune systems, this fungus has sickened hundreds of otherwise healthy people.

Now, researchers have found that the pathogen tossed aside over a dozen different genes on its way to becoming a new, more virulent species. Surprisingly, most of these discarded genes play a part in RNA interference or RNAi, a defense mechanism employed by fungi and other organisms to protect the integrity of their genomes. The study was published March 4 in PLOS Genetics.

“Genome instability is a bad thing in terms of human health, because it is linked to cancer and other diseases,” said Blake Billmyre, lead study author and a graduate student in Joseph Heitman’s lab at Duke University School of Medicine. “But it could be good thing for single-celled organisms like Cryptococcus, because it enables them to mutate, evolve and adapt to survive under different conditions.”

Cryptococcus deuterogatti was largely confined to tropical climates until 1999, when it showed up on Vancouver Island and began spreading throughout southwest Canada and into Washington and Oregon. The emerging fungal pathogen causes severe pulmonary and central nervous system infections, and is fatal if left untreated.

Five years ago, researchers in the Heitman lab participated in an international collaborative consortium to sequence the genome of this outbreak species and discovered that it had lost two genes involved in RNAi, a process previously thought to be key to its survival.

The RNAi gene-silencing machinery normally shreds the genetic instructions for harmful viruses or silences rogue genes that might contaminate the fungus’ genome. But Cryptococcus deuterogatti had holes in its genome where the two RNAi genes should have been.

Armed with this information, Billmyre hypothesized that other genes in this missing set of genes might also function in RNAi. He and his colleagues compared the genomes of Cryptococcus deuterogatti with less potent cousins like Cryptococcus neoformans, which predominantly infects immunocompromised individuals. They found that C. deuterogatti has lost 14 genes compared to the other, less pathogenic, species.

The researchers then conducted a number of genetic and molecular analyses to determine if any of these lost genes played a role in RNAi. They mutated each of the genes in Cryptococcus neoformans, which has fully functioning RNAi machinery, to see if these genes were needed for the fungi to silence extra genetic material.

Joseph Heitman, the James B. Duke professor and chair of Molecular Genetics and Microbiology, said he expected to find maybe one or two other genes involved in RNAi. To his surprise, they found that 11 of the 14 missing genes they surveyed were involved in gene silencing.

“We could have imagined that the species lost a couple of RNAi genes, and then a smattering of genes involved in all other kinds of processes,” said Heitman. “Instead, the one glaring difference between these more and less virulent species seems to be the loss of the RNAi pathway.”

Though the researchers don’t know why shedding the RNAi machinery could help Cryptococcus assume a deadlier form, they do have some ideas. It could enable the fungi to cohabitate with killer viruses that pump out powerful toxins to poison competing organisms. Or it could allow them to accumulate mutations or even extra chromosomes to gain resistance against antifungal medications.

Whatever the reason, the discovery could pave the way for future studies using comparative genomics to identify other sets of related genes. Once one gene in a pathway is lost, the researchers hypothesize that an organism can find itself on a slippery evolutionary slope as other genes that are no longer of benefit are lost in quick succession. Only a few other examples of this system-wide pattern of gene loss, called systems polymorphisms, have been described so far.

“There is so much you can learn from looking for things that are missing,” said Billmyre. “It’s true what they say, you don’t know what you’ve got ’till it’s gone.”

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

https://www.sciencedaily.com/releases/2016/03/160304160348.htm  Original web page At Science Daily

Categories
News

CRISPR everywhere

Just under a year ago, a molecular-biology technique was thrust onto the world stage. Researchers in China announced that they had used the nascent gene-editing tool CRISPR–Cas9 to modify the genomes of human embryos, triggering a major ethics debate.

Yet while this controversy has been playing out, researchers the world over have rushed to use the tool to tinker with the genomes of human somatic cells, viruses, bacteria, animals and plants, and it’s in these contexts that the technique promises to have more immediate impact. This issue of Nature examines what’s going on at the CRISPR frontiers.

Biologists are using CRISPR–Cas9 to better understand genomes — not just by editing DNA, but by devising variations on the technique to precisely manipulate the activity of genes. And, armed for the first time with a method that can easily introduce genetic changes to many animals, researchers have edited a veritable menagerie of beasts — from ferrets to elephants to koi carp — in an attempt to combat disease, improve agriculture and even make designer pets.

Such advances in gene editing are creating upheaval for regulatory bodies that are responsible for approving genetically engineered products — it’s a “powder keg waiting to explode”, writes Jennifer Kuzma, a science-policy researcher at North Carolina State University in Raleigh. She calls for more openness and honesty than has characterized past discussions of biotechnology, and for a regulatory system that better factors in societal views as well as science.

CRISPR–Cas9 may be democratizing gene editing in the laboratory, but Todd Kuiken, who studies science policy at the Wilson Center, a think tank in Washington DC, argues that the revolution has not yet swept into home workshops or citizen-science community spaces. Contrary to reports in the popular media, he says, few CRISPR creations are likely to come from the labs of do-it-yourself biologists any time soon. However, this group is arguably ahead of the scientific establishment when it comes to thinking about how to use the technology safely.

For better or for worse, CRISPR–Cas9 is transforming biology. We are now at the dawn of the gene-editing age.

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

http://www.nature.com/news/crispr-everywhere-1.19511  Original web page at Nature

Categories
News

Link made between genetics, aging

Scientists at the University of Georgia have shown that a hormone instrumental in the aging process is under genetic control, introducing a new pathway by which genetics regulates aging and disease.

Previous studies have found that blood levels of this hormone, growth differentiation factor 11, decrease over time. Restoration of GDF11 reverses cardiovascular aging in old mice and leads to muscle and brain rejuvenation, a discovery that was listed as one of the top 10 breakthroughs in science in 2014.

Scientists in the UGA College of Family and Consumer Sciences have now discovered that levels of this hormone are determined by genetics, representing another potential mechanism by which aging is encoded in the genome.

Future studies will seek to reveal why GDF11 levels decrease later in life and whether they can be sustained to prevent disease.

“Finding that GDF11 levels are under genetic control is of significant interest. Since it is under genetic control, we can find the genes responsible for GDF11 levels and its changes with age,” said the study’s senior author Rob Pazdro, an assistant professor in the college’s department of foods and nutrition.

The study confirmed results from previous experiments showing that GDF11 levels decrease over time and also showed that most of the depletion occurs by middle age.

In addition, the study examined the relationship between GDF11 levels and markers of aging such as lifespan in 22 genetically diverse inbred mice strains. Of note, the strains with the highest GDF11 levels tended to live the longest

Using gene mapping, Pazdro’s team then identified seven candidate genes that may determine blood GDF11 concentrations at middle age, demonstrating for the first time that GDF11 levels are highly heritable.

“Essentially, we found a missing piece of the aging/genetics puzzle,” Pazdro said. “Very generally, we’ve made an important step toward learning about aging and why we age and what are the pathways that drive it. It’s the first step down a long road, but it’s an important step.”

The study, “Circulating Concentrations of Growth Differentiation Factor 11 are heritable and correlate with life span,” was published in the Jan. 16 issue of the Journals of Gerontology Series A Biological Sciences and Medical Sciences.

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

https://www.sciencedaily.com/releases/2016/02/160219111513.htm  Original web page at Science Daily

Categories
News

* Newly found genomic causes of severe compulsiveness in dogs could aid study of human OCD

Research led by investigators in veterinary and human medicine has identified genetic pathways that exacerbate severity of canine compulsive disorder in Doberman pinschers, a discovery that could lead to better therapies for obsessive compulsive disorder in people. The discovery appears online in advance of print on Feb. 29, 2016 in the International Journal of Applied Research in Veterinary Medicine.

“Dogs naturally suffer complex diseases, including mental disorders that are similar to those in humans. Among those is canine compulsive disorder (CCD), the counterpart to human obsessive compulsive disorder (OCD),” says the study’s first and corresponding author Nicholas Dodman, BVMS, DACVA, DACVB, professor in clinical sciences and section head and program director of animal behavior at Cummings School of Veterinary Medicine at Tufts University.

OCD is one of the world’s most common neuropsychiatric disorders, affecting an estimated 1 to 3 percent of people and listed by the World Health Organization as among the 20 most disabling diseases. OCD is often characterized by distressing thoughts and time-consuming, repetitive behaviors, while canine compulsions may include repetitive tail chasing, excessive grooming and flank and blanket sucking. Current OCD therapies are not as effective as they could be; medicinal treatment benefits only about half of all human patients. No previously recorded study in humans or dogs has addressed the factors that drive severity in OCD and CCD.

“Genomic research on human neuropsychiatric disorders can be challenging due to the genetic heterogeneity of disease in humans,” says neurologist Edward Ginns, MD, PhD, professor of psychiatry, neurology, pediatrics and clinical pathology, and director, program in medical genetics at the University of Massachusetts Medical School and a co-author on the new study. “Canine compulsive disorder shares behavioral hallmarks, pharmacological responsiveness, and brain structural homology with human OCD, and thus is expected to be an important animal model.”

The research team compared whole genome sequencing of 70 Doberman pinschers to search for inherited factors that exacerbate CCD. Researchers identified two loci on chromosomes that were strongly correlated with severe CCD, as well as a third locus that showed evidence of association.

The locus most strongly associated with severe CCD was found on chromosome 34 — a region containing three serotonin receptor genes.

“This is particularly significant because drugs that work on the serotonin system are the mainstay treatment for OCD in humans, which demonstrates further correlation between the human and animal models,” says Dodman.

The second locus significantly correlated with severe CCD was on chromosome 11, the same chromosome that contains a gene thought to increase the risk of schizophrenia in humans. This discovery, along with suggestive evidence found on chromosome 16 linking CCD to stress tolerance, may also be relevant to the pathophysiology of OCD, according to the study authors. “Comparative genomics is a particularly attractive approach to reveal the molecular underpinnings of disease in inbred animals with the hope of gaining new insights into these diseases in dogs and humans,” says Ginns.

The study builds on more than a decade of research from Cummings School of Veterinary Medicine and the University of Massachusetts Medical School that in 2010 initially found the neural cadherin (CDH2) gene on canine chromosome 7 appeared to coincide with an increased risk of OCD. Additionally, 2013 MRI research from Cummings School of Veterinary Medicine at Tufts University and McLean Imaging Center at McLean Hospital showed that the structural brain abnormalities of Doberman pinschers afflicted with canine compulsive disorder (CCD) were similar to those of humans with OCD.

“If the canine construct is fully accepted by other OCD researchers, this spontaneously-occurring model of the condition in humans, right down to the biological pathways involved, could help point the way to novel and more effective treatments for such a debilitating condition,” Dodman says.

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

https://www.sciencedaily.com/releases/2016/02/160226125311.htm  Original web page at Science Daily

Categories
News

A new method to dramatically improve the sequencing of metagenomes

An international team of computer scientists developed a method that greatly improves researchers’ ability to sequence the DNA of organisms that can’t be cultured in the lab, such as microbes living in the human gut or bacteria living in the depths of the ocean. They published their work in the Feb. 1 issue of Nature Methods.

The method, called TruSPADES, generates via computer so-called Synthetic Long Reads, segments that are about 10,000 base pairs of the genome, from the commonly used short reads of just 300 base pairs produced by machines from San Diego-based Illumina.

Using Synthetic Long Reads instead of short reads to assemble a genome is like using entire chapters rather than single sentences to assemble a book, researchers said. So there is a strong incentive to improve sequencing with long reads.

“This is the next generation of sequencing technologies,” said Pavel Pevzner, a professor of computer science at the University of California, and the lead author on the study. “It will make a significant impact on the practice of metagenomics sequencing.”

Currently, the leaders in the long-read sequencing market, Pacific Biosciences and Oxford Nanopore, generate long reads that can be inaccurate and difficult to use in complex sequencing problems, such as assembling metagenomes–whole colonies of microbes sampled from their natural environment. By contrast, the Synthetic Long Reads are 100 times more accurate and can be rapidly generated on a massive scale to cover a large fraction of bacteria in metagenomes.

To develop their new method, researchers took the shorter reads, 100 to 300 base pairs, equipped with barcodes. They then assembled the short reads together into Synthetic Long Reads by representing them using a de Brujin graph, a method often used in short read sequencing. The graph allows researchers to determine which reads are connected together, resulting in the longer and more accurate Synthetic Long Reads.

The next step is to apply this method to the study of various microbial communities ranging from human to marine microbiomes. Pevzner and co-author Anton Bankevich from St. Petersburg State University, are working with Christopher Dupont, a researcher at the J. Craig Venter Institute, to do just that.

Metagenomics is especially challenging because researchers do not study a single species of bacteria but hundreds of them that live together in a community. When they extract a sample from the community and sequence it, they end up with bits of bacterial genomes from all the organisms in the community. It’s very much like trying to solve hundreds of puzzles without knowing which pieces belong to which puzzle. TruSPADES and Synthetic Long Reads will help researchers solve these puzzles.

“This method gives us better results at a much smaller cost,” said Dupont. “We are now assembling genomes for organisms we didn’t even know existed.”

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

https://www.sciencedaily.com/releases/2016/02/160216181453.htm  Original web page at Science Daily

Categories
News

* Are we losing the fight against antibiotic resistance?

Tackling antibiotic resistance on only one front is a waste of time because resistant genes are freely crossing environmental, agricultural and clinical boundaries, new research has shown.

Analysis of historic soil archives dating back to 1923 has revealed a clear parallel between the appearance of antibiotic resistance in medicine and similar antibiotic resistant genes detected over time in agricultural soils treated with animal manure.

Collected in Denmark — where antibiotics were banned in agriculture from the 1990s for non-therapeutic use — the soil archives provide an ‘antibiotic resistance timeline’ that reflects resistant genes found in the environment and the evolution of the same types of antibiotic resistance in medicine.

Led by Newcastle University, UK, the study also showed that the repeated use of animal manure and antibiotic substitutes can increase the capacity of soil bacteria to mobilise, or ready themselves, and acquire resistance genes to new antibiotics.

Publishing their findings in the academic journal Scientific Reports, the study’s authors say the data highlights the importance of reducing antibiotic use across all sectors if we are to reduce global antibiotic resistance.

Lead author David Graham, Professor of Ecosystems Engineering at Newcastle University, said: “The observed bridge between clinical and agricultural antibiotic resistance means we are not going to solve the resistance problem just by reducing the number of antibiotics we prescribe in our GP clinics.

“To reduce the global rise in resistance we need to reduce use and improve antibiotic stewardship across all sectors.

“If this is not done, antibiotic resistance from imprudent sectors will cross-contaminate the whole system and we will quickly find ourselves in a situation where our antibiotics are no longer effective.”

Antibiotics have been used in medicine since the 1930s, saving millions of lives. Two decades later they were introduced into agricultural practices and Denmark was among the leaders in employing antibiotics to increase agricultural productivity and animal production.

However, a growing awareness of the antibiotic resistance crisis and continued debate over who and which activities are most responsible led to the EU calling for the use of antibiotics in non-therapeutic settings to be phased out and Denmark led the way.

The Askov Long-Term Experiment station in Denmark was originally set up in 1894 to study the role of animal manure versus inorganic fertilisers on soil fertility.

Analysing the samples, the team — involving experts from Newcastle University, the University of Strathclyde and Aarhus University — were able to measure the relative abundance of specific β-lactam antibiotic resistant genes, which can confer resistance to a class of antibiotics that are of considerable medical importance.

Prior to 1960, the team found low levels of the genes in both the manured soil and that treated with inorganic fertiliser. However, by the mid 1970’s, levels of selected β-lactam genes started to increase in the manured soils, with levels peaking in the mid 1980’s. No increase or change was detected in the soil treated with inorganic fertiliser.

“We chose these resistant genes because their appearance and rapid increase in hospitals from 1963 to 1989 is well-documented,” explains Professor Graham.

“By comparing the two timelines, we saw the appearance of each specific gene in the soil samples was consistent with the evolution of similar types of resistance in medicine. So the question now is not which came first, clinical or environmental resistance, but what do we do about it?”

Following the ban on non-therapeutic antibiotic use in Danish agriculture, farmers substituted metals for antibiotics, such as copper, and levels of the key β-lactam genes in the manured soils declined rapidly, reaching pre-industrialisation levels by 2010.

However, at the same time the team measured a 10-fold rise in Class 1 Integrons. These are gene carrier and exchange molecules — transporters which allow bacteria to readily share genes, including resistance genes.

These findings suggest the application of manure and antibiotic substitutes, such as copper, may be ‘priming’ the soils, readying them for increased resistance transmission in the future.

“Once antibiotics were banned, operators substituted them with copper which has natural antibiotic properties,” explains Professor Graham.

“More research is needed but our findings suggest that by substituting antibiotics for metals such as copper we may have increased the potential for resistance transmission.

“Unless we reduce use and improve stewardship across all sectors — environmental, clinical and agricultural — we don’t stand a chance of reducing antibiotic resistance in the future.”

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

https://www.sciencedaily.com/releases/2016/02/160216143053.htm  Original web page at Science Daily

Categories
News

* Songbird’s reference genome illuminate key role of epigenetics in evolution of memory and learning

A well-known songbird, the great tit, has revealed its genetic code, offering researchers new insight into how species adapt to a changing planet. Their initial findings suggest that epigenetics — what’s on rather than what’s in the gene — may play a key role in the evolution of memory and learning. And that’s not just true for birds. An international research team led by the Netherlands Institute of Ecology (NIOO-KNAW) and Wageningen University will publish these findings in Nature Communications on Monday.

“People in our field have been waiting for this for decades,” explain researchers Kees van Oers and Veronika Laine from the Netherlands Institute of Ecology. The reference genome of their favourite model species, the great tit, is “a powerful toolbox that all ecologists and evolutionary biologists should know about.”

Coming from a single Dutch bird, the genetic code of the assembled reference genome will help to reveal the genetic basis of phenotypic evolution. This is essential for understanding how wild species adapt to our changing planet.

In addition to looking at the genome, the research team have also determined the so-called transcriptome and methylome. The latter belongs to the field of epigenetics: the study of what you can inherit not in but ‘on’ your genes. Specific DNA sequences in the genome can be ‘methylated’: methyl groups are added to them, modifying how the genes function.

The research team sequenced the complete genomes of a further 29 great tit individuals from different parts of Europe. This enabled them to identify regions in the great tit’s genome that have been under selection during recent evolution of the bird. These regions appeared to be overrepresented for genes related to learning and cognition.

“The great tit has evolved to be smart,” says Van Oers. “Very smart.” It’s not your average bird, as it belongs to the top 3% smartest birds when it comes to learning new behaviour. That makes it a perfect candidate for research into the evolution of learning, memory and cognitive processes.

What that research has revealed are so-called conserved patterns of methylation in those same regions, present not only in birds but also in humans and other mammals. It’s evidence of a correlation between epigenetic processes such as methylation and the rate of molecular evolution: “the more methylation, the more evolution.”

And so the great tit has once more proved that its role as a model species in a variety of biological research fields for over 60 years is by no means coincidental.

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

http://www.sciencedaily.com/releases/2016/01/160125090617.htm  Original web page at Science Daily

Categories
News

Don’t blame grey squirrels: their British invasion had much more to do with us

DNA profiling reveals grey squirrels are not as good invaders as we think, and that humans played a much larger role in spreading them through the UK.

Grey squirrels were imported to the UK from the 1890s onward, and the traditional view is that they spread rapidly across the UK due to their ability cope with new landscapes. Different populations of grey squirrels were thought to have interbred into a ‘supersquirrel’ that was better able to adapt and spread.

However, new research shows greys may not be as hardy as once thought, and were helped much more by humans in their conquest of the British Isles. Dr Lisa Signorile compiled a DNA database of nearly 1,500 grey squirrels in the UK and Italy during her PhD studies at Imperial College London and the Zoological Society of London (ZSL).

She was able to show that different squirrel populations are still genetically distinct, meaning they did not interbreed much and did not create a supersquirrel. The difference between populations also means Dr Signorile and coauthors were able to trace where populations in new areas had come from.

In many cases, new populations of grey squirrels are not related to nearby populations, and instead have come from a long way away. The only way they could have travelled so far was by human intervention. For example, the population in Aberdeen is most closely related to populations in Hampshire, around the New Forest area.

“It has been thought since the 1930s that grey squirrels were all the same, spreading across the country as one invasion front. After a century, genetics has proved that this isn’t correct. They are not that good at breeding and mixing — in fact there are clear signs of inbreeding,” said Dr Signorile.

“Grey squirrels are not as crazy invaders as we think — their spread is far more our own fault.” The research is published in two papers, in the journals Biological Conservation and Diversity and Distributions.

Dr Signorile also discovered that one of the worst offenders at spreading grey squirrels was the 11th Duke of Bedford, Herbrand Russell. Russell was involved in many successful animal conservation projects, but released and gifted many grey squirrels around the UK from his home at Woburn Park. Russell also released populations in Regent’s Park, likely creating the London epidemic of greys. “It was a time when we didn’t know invasive species could cause so much damage,” said Dr Signorile.

Although not as good invaders as previously thought, greys still outcompete native red squirrels for resources, and carry diseases that kills reds but not greys. Greys have largely displaced reds in England and Wales. “Eradication or control programs are still needed, in particular in areas where red squirrels are present,” said Dr Signorile.

Scotland is one of the last places to be invaded, but humans are still helping grey squirrels move into new areas today, albeit more unwittingly. Dr Signorile also investigated where recently-spotted greys have come from.

She found that one individual that was captured on the Isle of Skye in 2010 had come from Glasgow. In this case, genetic profiling confirmed a report that the squirrel had stowed away under a car bonnet and escaped on Skye.

Dr Signorile also examined the case in Italy, where grey squirrels are more of a recent introduction and could be sold as pets until 2012. Her analysis of populations in different regions of the country confirmed an illegal trade in grey squirrels. “It illustrates that ‘attractive and cute’ species are often spread further by people,” said Dr Signorile.

Aside from revealing the surprising result that the success of grey squirrels is in part based on our help, Dr Signorile said the study also suggests new approaches are needed to tackle their spread. “We put a lot of money into controlling grey squirrel numbers, but nobody is trying to prevent their movement and discourage people from picking them up. Decision-makers should look into preventing spreading of greys by human hands.

“The public also needs to be aware of the risk of even accidentally moving squirrels. People think grey squirrels are already everywhere, so it is not a problem, but it can be, especially in areas of Scotland where there are not yet established populations.”

The findings of the genetic study could also be applied to other invasive species, said Dr Signorile, especially where human movements may play more of an important role. These include the more ‘ornamental’ species that are considered attractive, such as London’s ring-necked parakeets and Chinese water deer.

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

http://www.sciencedaily.com/releases/2016/01/160126090057.htm  Original web page at Science Daily

Categories
News

* New way to detect human-animal diseases tested in lemurs

Advances in genetic sequencing are uncovering emerging diseases in wildlife that other diagnostic tests can’t detect.

In a study led by Duke University, researchers used a technique called whole-transcriptome sequencing to screen for blood-borne diseases in wild lemurs, distant primate cousins to humans.

The animals were found to carry several strains or species of parasites similar to those that cause Lyme disease and other infections in humans. This is the first time these parasites have been reported in lemurs or in Madagascar, the only place on Earth where lemurs live in the wild outside of zoos and sanctuaries, the researchers report in the Jan. 27, 2016 issue of Biology Letters.

The approach could pave the way for earlier, more accurate detection of future outbreaks of zoonotic diseases that move between animals and people. “We can detect pathogens we might not expect and be better prepared to deal with them,” said co-author Anne Yoder, director of the Duke Lemur Center.

In 2012, Duke Lemur Center veterinarian Cathy Williams and colleagues started performing physical exams on lemurs in the rainforests surrounding a mine site in eastern Madagascar to help monitor the impacts of such activities on lemur health.

“Lemur populations are becoming increasingly small and fragmented because of human activities like mining, logging and clearing forests to make way for cattle grazing and rice paddies,” Williams said. “If an infectious disease wipes out a lemur population it could be a huge blow to the species.”

Researchers took small amounts of blood and tested them for evidence of exposure to known viruses and pathogens, but nothing turned up.

The problem is that standard diagnostic tests tend to target known pathogens, Williams said. You can check for antibodies to certain viruses, or look for specific snippets of genetic material in an animal’s blood, “but you have to know what you’re looking for.”

The end result is that new or exotic diseases often go undetected. And with hundreds of thousands of viral and bacterial species that lemurs and other mammals harbor still awaiting discovery, “we could be looking for anything,” Williams said.

Lead author Peter Larsen, senior research scientist at Duke, analyzed blood samples from six lemurs in two species, the indri and the diademed sifaka, both of which are considered critically endangered by the International Union for Conservation of Nature (IUCN).

With advances in high-throughput sequencing, the ability to read genetic code rapidly, Larsen was able to look at all the gene readouts, or RNA transcripts, that were present in each animal — an alphabet soup containing billions of nucleotide bases.

The team found more than just lemur RNA in the animals’ blood. Using computer algorithms that compared the genetic material to sequences already catalogued in existing databases, they discovered several new types of parasites that had never been reported in lemurs.

These included a new form of the protozoa responsible for babesiosis, a disease spread by bites from infected ticks, and a new kind of Borrelia closely related to the bacterium that causes Lyme disease. They also found the first known case in Madagascar of a bacterium called Candidatus Neoehrlichia, which can be deadly in humans

Further analyses revealed that the new types of Babesia and Borrelia they found didn’t begin in lemurs, but were likely introduced to Madagascar in infected pets and livestock such as cattle and then spilled over to lemurs.

The researchers don’t yet know if the new parasites are actually dangerous to lemurs. But they caution that what is infecting lemurs could potentially infect people, too. Human health officials and veterinarians in Madagascar may want to consider screening their patients to see if any test positive for the same parasites, the researchers say.

The majority of emerging infectious diseases that affect humans, including recent outbreaks of SARS, Ebola and bird flu, are zoonotic — they can spread among wildlife, domestic animals and humans.

“Next-generation sequencing will be an important tool to identify emerging pathogens, particularly vector-borne diseases,” said Barbara Qurollo, a research assistant professor at the N.C. State College of Veterinary Medicine who was not affiliated with the study.

“A clinician cannot treat an infection that he or she does not know exists,” said veterinarian and infectious diseases researcher Edward Breitschwerdt, also of the N.C. State College of Veterinary Medicine. “The kindest form of therapy is an accurate diagnosis.”

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

http://www.sciencedaily.com/releases/2016/01/160127121205.htm  Original web page at Science Daily

Categories
News

Orangutans: Lethal aggression between females

Researchers have for the first time witnessed the death of a female orangutan at the hands of another female. Even more extraordinary is that the perpetrator recruited a male orangutan as a hired gun to help her corner and attack the victim. Before this observation, lethal fights between females had never been observed in orangutans; in other primates such fights occur mainly between males, according to Anna Marzec of the University of Zurich in Switzerland. She is the lead author of a report on the fatal incident, which appears in Springer’s journal Behavioral Ecology and Sociobiology.

Aggression serves ultimately to gain access to limited resources. Although aggression among primates is frequent, lethal attacks are very rare, especially among female individuals. Female Bornean orangutans live alone and typically settle in or near the area where they were born, whereas males generally disperse. The two sexes regularly associate only during the few months before a female orangutan is ready to conceive, which happens approximately every seven years.

The research team around Marzec had been following a population of Bornean orangutans (Pongo pygmaeus wurmbill) in the swamp forests of Indonesia’s Mawas Reserve since 2003 and already collected over 26,000 hours of information on the adult females alone when they observed the fatal attack in July 2014. During this period, only six female-female attacks had been observed, none of which had caused visible injuries. Other long-term studies of orangutans similarly have never reported such violent female attacks.

The case involved Kondor, a young female who had lost her infant just weeks before, and Sidony, a much older resident female who did not interact much with neighbouring apes. The two females had a history of aggressive interaction: a few years earlier the researchers had witnessed an encounter between them during which Sidony hit and bit Kondor, who had apparently approached Sidony’s seven-year-old daughter.

In the week before the lethal attack, Kondor was seen with a male called Ekko. The two of them encountered Sidony and her dependent son. After Ekko sexually inspected Sidony, he returned to Kondor to mate with her. Kondor interrupted these sexual activities when Sidony started to move away, and attacked her.

Ekko joined the fight, which lasted 33 minutes. They continuously attacked as a coordinated team. While one attacked, the other blocked the victim’s escape route. Kondor instigated two further shorter attacks. Ekko, who had long canines typical of a male, inflicted the most serious injuries and effectively prevented Sidony’s escape.

The dynamics changed when another male, Guapo, arrived and chased Ekko away. Guapo then mated with Sidony. Kondor continued to harass and bite her. Whenever Sidony screamed, Guapo positioned himself between the females or escorted the older ape away. Sidony sustained major injuries in the first part of the attack. Although Guapo successfully protected her from further damaging attacks, Sidony died two weeks later.

The case does not comfortably fit into the pattern of joint coalitional killings normally seen in primates. The attack involved between-sex coalitions, with the males being either the back-up or bodyguard of a female.

“This is quite unexpected, as in wild orangutans males and females have never been reported to form coalitions before,” says Marzec. “It is also the first report of males supporting females in their conflicts, with lethal outcome.”

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

http://www.sciencedaily.com/releases/2016/02/160203110924.htm  Original web page at Science Daily

Categories
News

* Dog domestication may have increased harmful genetic changes, biologists report

The domestication of dogs may have inadvertently caused harmful  genetic changes, a UCLA-led study suggests. Domesticating dogs from gray wolves more than 15,000 years ago involved artificial selection and inbreeding, but the effects of these processes on dog genomes have been little-studied.

UCLA researchers analyzed the complete genome sequences of 19 wolves; 25 wild dogs from 10 different countries; and 46 domesticated dogs from 34 different breeds. They found that domestication may have led to a rise in the number of harmful genetic changes in dogs, likely as a result of temporary reductions in population size known as bottlenecks.

“Population bottlenecks tied to domestication, rather than recent inbreeding, likely led to an increased frequency of deleterious genetic variations in dogs,” said Kirk Lohmueller, senior author of the research and assistant professor of ecology and evolutionary biology in the UCLA College.

“Our research suggests that such variants may have piggybacked onto positively selected regions, which were also enriched in disease-related genes,” Lohmueller said. “Thus, the use of small populations artificially bred for desired traits, such as smaller body size or coat color, may have led to an accumulation of harmful genetic variations in dogs.”

Such variations, Lohmueller said, could potentially lead to a number of different developmental disorders and other health risks.

Selective breeding programs, particularly those aimed at conserving rare and endangered species, may need to include and maintain large populations to minimize the inadvertent enrichment of harmful genetic changes, he said.

The research was published recently in the journal Proceedings of the National Academy of Sciences.

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

http://www.sciencedaily.com/releases/2016/01/160111162701.htm  Original web page at Science Daily

Categories
News

Attention: Terrapin! Invasive pond slider on the move

Using genetic methods, scientists of the Senckenberg Research Institute in Dresden discovered that the introduced pond slider is capable of reproducing in Europe even outside of the Mediterranean region. The turtle, originally from North America, poses a significant threat to the native turtle fauna and, according to the authors of the study recently published in the scientific journal “Conservation Genetics,” should be intercepted in Europe.

The pond slider (Trachemys scripta) is the world’s most widely distributed species beyond its native range. These turtles with a shell length of up to 30 centimeters are native to the Southeastern U.S. – but today, they are found on all continents, except for Antarctica and a few oceanic islands. “The turtle can be found in the wild in practically all European countries.” explains Dr. Melita Vamberger of the Senckenberg Natural History Collections in Dresden, and she continues, “These reptiles owe their wide-spread distribution to the captive animal trade.”

The species is considered a threat to native turtles, since it is in direct competition with them regarding food as well as nesting and basking sites. Moreover, the introduced reptiles are potential carriers of parasites and other pathogens. Since the 1990s, the import of these popular pets with their vividly orange to red head stripes has been outlawed in Europe. “However, in some countries, in particular in the Balkan states, the illegal trade continues to flourish,” adds Vamberger, and she goes on to say, “But for a long time, it was not clear whether the species could become invasive in Europe.” Until now, the successful reproduction and establishment of these animals had only been documented in the Mediterranean region.

The Slovenian-German team of researchers around Dr. Vamberger and the director of Senckenberg Dresden, Professor Dr. Uwe Fritz has now been able to demonstrate by means of genetic studies that the turtles also reproduce in Slovenia. The biologists took samples of 77 turtles from three sites and could show that they reproduce in all areas examined in Slovenia. “We selected the sites based on climatic differences,” explains Fritz, and he adds, “Unfortunately, the pond slider also reproduce and spread in the vicinity of Ljubljana – a temperate, continental climate.”

For the first time, the researchers were thus able to offer genetic proof that Trachemys scripta can also reproduce outside the Mediterranean region with its mild climate. Around Ljubljana, the capital of Slovenia, fewer animals were found that were related to each other than in the warmer regions, which could indicate that the turtles reproduce less frequently here. “However, it is likely that more animals with new genetic material are being released near the city, which necessarily leads to fewer related animals,” cautions Vamberger.

Due to the potential for expansion beyond the Mediterranean region and the potential threat to native species, the sliders should be classified as invasive, according to the biologists from Dresden. “In addition, we recommend to intercept the pond slider, at least in habitats occupied by native turtle species, in order to prevent the spread of the invasive turtle and the displacement of the native inhabitants,” says Fritz in closing.

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

http://www.sciencedaily.com/releases/2016/01/160122122729.htm  Original web page at Science Daily

Categories
News

* When chickens go wild

“Don’t look at them directly,” Rie Henriksen whispers, “otherwise they get suspicious.” The neuroscientist is referring to a dozen or so chickens loitering just a few metres away in the car park of a scenic observation point for Opaekaa Falls on the island of Kauai, Hawaii.

The chickens have every reason to distrust Henriksen and her colleague, evolutionary geneticist Dominic Wright, who have travelled to the island from Linköping University in Sweden armed with traps, drones, thermal cameras and a mobile molecular-biology lab to study the birds.

As the two try to act casual by their rented car, a jet-black hen with splashes of iridescent green feathers pecks its way along a trail of bird feed up to a device called a goal trap. Wright tugs at a string looped around his big toe and a spring-loaded net snaps over the bird. After a moment of stunned silence, the hen erupts into squawking fury.

Opaekaa Falls, like much of Kauai, is teeming with feral chickens — free-ranging fowl related both to the domestic breeds that lay eggs or produce meat for supermarket shelves and to a more ancestral lineage imported to Hawaii hundreds of years ago.

These modern hybrids inhabit almost every corner of the island, from rugged chasms to KFC car parks. They have clucked their way into local lore and culture and are both beloved and reviled by Kauai’s human occupants. Biologists, however, see in the feral animals an improbable experiment in evolution: what happens when chickens go wild?

The process of domestication has moulded animals and their genomes to thrive in human environments. Traits that ensure survival in the wild often give way to qualities that benefit humans, such as docility and fast growth. Feralization looks, on its surface, like domestication in reverse. But closer inspection suggests that the chickens of Kauai are evolving into something quite different from their wild predecessors, gaining some traits that reflect that past, but maintaining others that had been selected by humans. In this way, they are similar to other populations of animals, including dogs, pigs and sheep, that have broken free of captivity and flourished.

By looking at feral animals, some evolutionary biologists hope to determine how domestic animals and their genes change in response to natural pressures. The research could also help to inform tricky conservation questions about how such animals affect native species, and ultimately whether and how to control them.

The natural history of the Kauai fowl makes them an important test case. “People have a really complicated relationship with the chickens,” says Eben Gering, an evolutionary ecologist at Michigan State University’s Kellogg Biological Station in Hickory Corners, who is in Kauai with Henriksen and Wright. “Some people absolutely want them gone. Some consider them an integral part of the local culture.”

The Polynesian mariners who first settled the Hawaiian Islands about 1,000 years ago brought what they needed to start civilization anew. Staple plants such as taro, sweet potato and coconut palm made the trans-Pacific voyage, as did domestic dogs, pigs and, naturally, their prized chickens.

The Polynesian poultry probably bore little resemblance to the birds that provide much of the world’s protein today. Archaeological and genetic evidence suggests that they were more like red junglefowl (Gallus gallus) — small, furtive birds that still roam the forests of southeast Asia and are ancestral to all domestic chickens.

By the time that Captain James Cook landed in Waimea in southern Kauai in 1778, the Polynesian chickens had already, in essence, become feral. They wandered freely between Native Hawaiian villages and the neighbouring forest. Later, European and US settlers imported predators such as mongooses, which devastated birds of all kinds. Polynesian chickens were all but wiped out everywhere but Kauai and neighbouring Niihau, where the predators were never introduced.

On Kauai, chickens flourished. Although the birds’ numbers have not been tracked precisely, many residents contend that the population surged after hurricanes in 1982 and 1992 blew modern chickens from people’s back yards into the forests, where they encountered the descendants of the Polynesian chickens.

Gering says it is possible that interbreeding between the two populations allowed the birds’ numbers to swell. And during his first trip to the island in 2013, he and Wright noticed1 that many of the feral chickens they encountered had flecks of the white feathers common in modern domestic breeds, in addition to the darker plumage usually seen in wild populations. Many had yellow legs (red-junglefowl legs are grey). And some of the roosters’ crows sounded conspicuously like the drawn out cock-a-doodle-doo of their barnyard brethren, rather than the truncated calls of red junglefowl.

DNA from 23 chickens revealed just how far domestic-chicken genes had infiltrated1. The birds’ nuclear genomes seemed to be a mixture of genes from red-junglefowl-like Polynesian chickens and domestic chickens, whereas their maternally inherited mitochondrial markers traced back to European and Pacific domestic poultry. Gering and Wright think that a single hybrid population of feral chickens now roams Kauai, bearing a mixture of traits from modern and ancient birds.

In unpublished work, the two have scoured the birds’ genomes for stretches of DNA with very little variation across the population. This homogeneity suggests that a gene has surged through the population in the recent past, probably because it offers some benefit. If feralization were domestication played backwards, then these ‘selective sweeps’ might appear around the DNA sequences that distinguish domestic chickens from red junglefowl. Instead, the researchers have found that most of the swiftest-evolving genes in the Kauai chickens are distinct from those suspected involved in modern domestication.

In some cases, genes from the Polynesian chickens are helping the hybrid feral chickens to adapt to Kauai’s habitats. For example, modern domestic fowl have been bred not to sit on, or brood, their eggs (making the eggs easier to collect). But in the wild, this trait puts unhatched chicks at risk. Wright and Gering found that feral chickens possess red-junglefowl gene variants that are linked to brooding.

But some genes of domestication do seem to be handy outside the coop. A variant linked to increased growth rates and reproduction in domestic chickens, for example, persists in the Kauai population, even though the average adult feral chicken is half the weight of a month-old bird bred for meat.

“You won’t see a bird as healthy-looking as that,” Wright says of the hen that he and Henriksen had captured at Opaekaa Falls. “Her plumage is perfect.” In the basement of a rented house on Kauai, the researchers have set up a makeshift laboratory where they photograph the bird, draw its blood and then kill it and prepare it for dissection. Wright starts with the hen’s Brazil-nut-sized brain.

Their unpublished research has shown that the brains of domestic chickens are smaller than those of junglefowl, relative to their body size, and organized differently. The team hopes to identify the genes responsible for these changes and others, such as the diminished visual-processing systems of domestic birds. Life in the wild has also altered the reproductive systems of the feral chickens. Domestic breeds lay eggs almost daily, but breeding seasonally could allow feral chickens to reapportion the minerals devoted to eggs (which come from spongy tissue in the centre of their bones) to making their skeletons more robust. The researchers sample the hen’s femur and also find that its ovaries are empty of egg follicles, which could be a sign of seasonal breeding.

Feralization has garnered much less attention from scientists than domestication (which gets a nod in chapter one of Charles Darwin’s 1859 On the Origin of Species). But swapping of domestic and wild genes has been happening all over the world for thousands of years. A feral-sheep population that has lived on the island of St Kilda in the Scottish Outer Hebrides for as long as 4,000 years acquired beneficial alleles that determine coat colour from a modern domestic sheep breed some 150 years ago. A 2009 study in Science found that some wolves in Yellowstone National Park, Wyoming, carry a domestic-dog version of a gene linked to dark coats that shows hallmarks of positive selection, possibly helping wolves from the Arctic to adapt to forested environments. “People would have thought that genes to live in a farm and house aren’t going to be any good in the wild, but that’s not necessarily true,” says Jonathan Losos, an evolutionary ecologist at Harvard University in Cambridge, Massachusetts.

And like Kauai’s feral chickens, other feral animals such as dingoes in Australia and urban pigeons practically everywhere have not evolved back to the state of their wild ancestors — even if certain traits may trend in that direction.

Like chickens, other domesticated animals tend to have smaller brains than their wild cousins, relative to body size. And brain regions involved in processing things such as sight, sound and smell are among the most diminished, perhaps because humans bred animals to be docile and less wary of their surroundings. Feral pigs in Sardinia seem to have regained large brains and high densities of neurons involved in olfaction, but not the abilities that come with them: their neurons do not express a protein that has been linked to the exquisite sense of smell in closely related wild boars. Likewise, feral dogs, cats and pigs often lack the savvy of their wild brethren and still depend on human niches for their survival, notes Melinda Zeder, an archaeologist at the Smithsonian Institution’s National Museum of Natural History in Washington DC. Packs of feral dogs, for instance, do not form the complex hierarchies that make wolves such fearsome predators. “There’s no leadership the way you get in a wolf pack. It’s just a bunch of shitty friends ,” says Greger Larson, an evolutionary geneticist at the University of Oxford, UK, who is part of a team examining the mixed ancestry of Kauai’s feral pigs.

Wright and Henriksen take less than an hour to dissect the captured hen and preserve samples of its brain, bone, liver and other tissue for gene-expression studies. They will use the RNA molecules expressed in different tissues to come up with a list of genes that might influence traits that distinguish the feral chickens from domestic birds and red junglefowl. They are eager to add to their study sample, and they jump at an offer to visit a nearby farm to collect more chickens.

“They are a scourge. They are vermin. They cost us thousands and thousands of dollars every year,” says the farm’s owner (who asked not to be named). The birds scratch at tree saplings on his orchard, exposing the roots and killing fruit trees before they can mature. He patrols his property in a beaten-up luxury sedan with a high-powered air rifle and a hired hand who gets US$5 per kill. Every few months, he invites hunters with night-vision goggles to visit and pick off the birds as they roost.

Few Kauaians share his malice towards feral chickens. Many locals give them a ‘no-big-deal’ shrug when asked. And the island’s many tourists tend to view the birds with curiosity followed by mild annoyance after a couple of 3 a.m. wake-up calls. Feral-chicken merchandise — postcards, kitchen chopping boards, T-shirts — are ubiquitous. A popular children’s television show hosted by a character called Russell the Rooster has been on air for nearly two decades.

“Before deciding how important it is to conserve them, manage them or cull them, it would at least be good to know about their impact.”

As descendants of the birds imported by the Polynesians, Kauai’s feral chickens occupy a zoological purgatory somewhere between native plants and animals and the dreaded invasive species that plague island habitats such as Hawaii. “It’s much more complicated than just a feralized chicken,” says Gering. “Even though junglefowl were not here before the Polynesians colonized the island, they have been a part of this ecosystem for much longer than the domestic chickens.”

The chickens enjoy semi-official protection as ‘wild chickens’ in nature preserves. But if the same birds wander into developed areas or private property, they are considered ‘free-flying domestic chickens’ with no sanctuary. “Locals are free to take them (if they come onto your property) and put them in the pot,” says a State of Hawaii website. (Gering and Wright, with a freezer full of the animals, consider making ‘feral coq au vin’.)

Kauai may have no shortage of feral chickens now, but if mongooses arrive on the island or political winds change, they could be at risk. Hawaii’s most populous island, Oahu, has mounted a controversial culling campaign against its feral chickens (whose ancestry is uncertain). But Gering thinks that the Kauai chickens’ long tenure and unique cultural position makes some form of conservation worth considering. “Before deciding how important it is conserve them, manage them or cull them, it would be good to at least know about their impact,” he says. Researchers want to know about everything from the animals and plants that the birds eat to how they alter landscapes — information that Gering hopes to gather on future trips to the island.

Kauai’s chickens are hardly the only creatures to occupy a nebulous space between native and alien. When Przewalski’s horses, which live on the Mongolian steppe, were first described in the late nineteenth century, they were believed to be the planet’s last wild, undomesticated horses. But a 2015 genome study found that the 2,100 or so remaining horses carry substantial amounts of domestic-horse DNA. They also show significant signs of inbreeding, owing to a captive-breeding programme begun in the 1940s.

Some conservationists view domestic genes as pollutants that are tarnishing the genomes of wild animals such as wolves, coyotes and even the red junglefowl native to southeast Asia. Some even contend that there are no ‘pure’ red junglefowl left.

“What feral animals make us do is reconsider this all-too-obvious, all-too-easy and all-too-wrong dichotomy between wild and domestic,” says Larson. And the ability of supposedly wild animals to thrive in a world increasingly altered by human activity may be due in part to the domestic genes that they now carry. What better way to adapt to human-moulded environments than to borrow traits from human-moulded creatures?

“Cock-a-doodle-doo,” announces a rooster masked by dense forest in Kokee State Park, an achingly beautiful nature reserve on Kauai’s western coast, on a sunny autumn morning. A faint but unmistakable “cock-a-doodle-doo” volleys back, from maybe a kilometre away.

“What feral animals make us do is consider this all-too-easy dichotomy between wild and domestic.” Although the birds are a fixture even in this rich and remote landscape, most of the chickens in the reserve stick near the car parks and picnic areas, where human hand-outs are easy to come by. The park’s birds are among the most brazen and comfortable around humans in all of Kauai, and it’s hard to enjoy a meal in Kokee’s central meadow without attracting the attention of a flock or two. But “give them a chase and they’ll disappear down a 300-metre ravine that’s so thick with vegetation it’s impossible to follow”, says Gering. “That’s not something I think about barnyard chickens as being able to do.”

A park website discourages visitors from feeding the chickens, in the hope of reducing their numbers and their dependence on humans. This interest in ‘rewilding’ the feral chickens is probably motivated by the desire to reduce their numbers through methods other than culling. It may well be a matter of time before feral animals fully shed their yokes and evolve into creatures less dependent on humans — but perhaps it will never happen. “The environmental niches that feralized animals are exploiting are very different and bear a human stamp that wasn’t there when their ancestors developed,” says Zeder. “Why should anyone expect a feralized animal to go out and become the noble savage animal again?” Wright, however, thinks there is a possibility that if the chickens in Kokee are left alone for long enough, they may well become not a facsimile of their red-junglefowl ancestors, but some other kind of creature just as deserving of being called wild. Whatever wild means.

Nature 529, 270–273 (21 January 2016) doi:10.1038/529270a

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

http://www.nature.com/news/when-chickens-go-wild-1.19195  Original web page at Nature

Categories
News

* A horse of a different color: Genetics of camouflage and the dun pattern

Most horses today are treasured for their ability to run, work, or be ridden, but have lost their wild-type camouflage: pale hair with zebra-like dark stripes known as the Dun pattern. Now an international team of scientists has discovered what causes the Dun pattern and why it is lost in most horses. The results, published in Nature Genetics, reveal a new mechanism of skin and hair biology, and provide new insight into horse domestication.

Pale hair colour in Dun horses provides camouflage as it makes a horse in the wild less conspicuous. In contrast, domestic horses, as well as many other domestic animals, have been selected over many generations to be more conspicuous, more appealing or simply different than the wild type. The pale hair colour in Dun horses does not affect all parts of the body; most Dun horses have a dark stripe along their back, and often show zebra-like leg stripes. However, the majority of domestic horses are non-dun and show a more intense pigmentation that is uniformly distributed.

“Dun is clearly one of the most interesting coat colour variants in domestic animals because it does not just change the colour but the colour pattern,” states Leif Andersson, whose group led the genetic analysis. We were really curious to understand the underlying molecular mechanism why Dun pigment dilution did not affect all parts of the body, continues Leif.

“Unlike the hair of most well studied mammals, the dilute coloured hairs from Dun horses are not evenly pigmented the whole way around. They have a section of intense pigmentation along the length of the hair, on the side that faces out from the body of the horse, whilst the rest of the hair has more or less no pigment,” explains Freyja Imsland, the lead author for the genetic analysis, and a PhD student in Andersson’s group. The hairs from the dark areas of Dun horses are in contrast intensely pigmented all around each individual hair. In spite of scientists having studied hair pigmentation in detail for a very long time, this kind of pigmentation is novel to science, and quite unlike that seen in rodents, primates and carnivores.

Genetic analysis and DNA sequencing revealed that Dun versus non-dun colour is determined by a single gene that codes for the T-box 3 (TBX3) transcription factor. In humans, inactivation of the TBX3 gene causes a constellation of birth defects known as Ulnar-Mammary Syndrome. But in horses that have lost their Dun colour, TBX3 mutations do not inactivate TBX3 protein function and instead only affect where the gene is expressed in the growing hair.

“Previous studies in humans and laboratory mice show that TBX3 controls several critical processes in development that affect bones, breast tissue, and cardiac conduction,” explains Greg Barsh, whose group led the tissue analysis. We were surprised to find that TBX3 also plays a critical role in skin and hair development.

The team discovered two forms of dark, non-dun colour, non-dun1 and non-dun2, caused by different mutations.

“Non-dun horses have much more vibrant colour than Dun horses. Non-dun1 horses tend to show primitive markings similar to Dun horses, whereas non-dun2 horses generally don’t show primitive markings. These primitive markings in non-dun1 horses can sometimes lead horse owners to think that their intensely pigmented non-dun1 horses are Dun,” states Freyja Imsland.

To understand how TBX3 affects hair colour, they measured TBX3 distribution in individual hairs relative to other molecules previously known to regulate pigmentation.

“In growing hairs, TBX3 mirrors the distribution of melanocytes, the cells that produce pigment,” explains Kelly McGowan, a senior scientist in the Barsh group. “Our results suggest that TBX3 affects differentiation of specific cells in the hair, creating a microenvironment that inhibits melanocytes from living in the “inner” half of the hair.”

The group speculates that the signals governing where TBX3 is expressed could help to explain zebra stripes. “The region of the body where TBX3 is expressed may account for the stripe pattern,” says McGowan, “whereas the region of the hair where TBX3 is expressed may account for colour intensity.”

The results of the present study indicates that the non-dun2 variant occurred recently most likely after domestication. In contrast, both the Dun and non-dun1 variants predate domestication, which is evident from the observation that ancient DNA from a horse that lived about 43,000 years ago, long before horses were domesticated, carried both Dun and non-dun1 variants.

“This demonstrates that horse domestication involved two different colour morphs (Dun and non-dun1) and future studies of ancient DNA will be able to reveal the geographic distribution and the abundance of the two morphs,” ends Leif Andersson.

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

http://www.sciencedaily.com/releases/2015/12/151221133612.htm  Original web page at Science Daily

Categories
News

Innovation sheds light on how genetic information travels from cell’s nucleus

Discovery science led by the University of Alberta’s Faculty of Medicine & Dentistry is opening a window on cell biology rarely seen before. New research featured in the Journal of Cell Biology has revealed a real-time look at how genetic information travels within a living cell.

The discovery, observed through a specially designed high-powered microscope, significantly alters current understanding of how RNA is transported from a cell’s nucleus–findings that researchers believe will lead to medical advances.

“You need to understand the system so that when it’s broken, you know how to fix it,” says Ben Montpetit, senior author of the study and an assistant professor in the Department of Cell Biology at the U of A. “I often use the analogy of a mechanic. If your car breaks down, you bring it to the mechanic because they understand how the car works, where to look and how to diagnose the issue. But if they didn’t understand how the car works and, say, your car didn’t start, would the mechanic spend an hour looking at the ashtray?”

“We really need to understand the system, and this technology is allowing us to do that now,” adds Azra Lari, lead author of the study and a PhD candidate in the Department of Cell Biology.

Until now, scientists observing how RNA travelled from the nucleus would rely on a still image, giving them only a static snapshot of what was happening. New technology developed for the study allowed the research team to observe particles nanometres in size–a billionth of a metre–over just milliseconds in a living yeast cell. By recording the events, they observed the route and time taken for the RNA to be transported from the nucleus to the cytoplasm, where it is then used to encode proteins–the workhorses of the cell. They also observed how that changed after introducing a mutation into the system.

“With the old technology, we could tell there was a defect but could not tell where it was happening. Now we can see the errors occurring in real time,” says Montpetit. “And already with this new imaging technique we’re seeing defects that we didn’t expect–that the models we have wouldn’t have predicted. It just highlights how useful this new technology is going to be.”

“Discovery research is really the driving force that leads to new innovation. It fuels new discovery and is the type of research that solves big problems.” The research team’s work will continue on two fronts–pressing on with their efforts to study mutations and other factors that affect RNA transport, while also honing the imaging technology that made their groundbreaking research possible. They believe this innovative technology will soon help scientists gain an unprecedented understanding of the cell.

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

http://www.sciencedaily.com/releases/2015/12/151223130538.htm  Original web page at Science Daily

Categories
News

* Scientists prevent, reverse diabetes-related kidney destruction in animal model

Diabetes is the leading cause of kidney failure, and scientists have found that infusing just a small dose of a cytokine, thought to help cause that failure, can instead prevent or reverse it.

The cytokine IL-17A has long been considered a classic promoter of inflammation, which plays a major role in progression of diabetes-related kidney disease, or diabetic nephropathy, said Dr. Ganesan Ramesh, kidney pathologist at the Vascular Biology Center at the Medical College of Georgia at Augusta University.

His lab was pursuing its role in kidney damage but found that when they deleted the IL-17 gene in mice, then induced diabetes, it resulted in increased kidney injury, Ramesh said. They looked next at patients with severe diabetic nephropathy, and found levels of IL-17A reduced in their blood and urine.

In follow-up studies in animal models of both type 1 and type 2 diabetes, IL-17A’s surprising role grew: When researchers infused a small amount of IL-17A every 48 hours for several weeks, it prevented or reversed diabetic nephropathy in their diabetes models. In fact, the therapy worked best in late-stage diabetic nephropathy, Ramesh said. IL-17A therapy also reduced high levels of fat in the blood, a hallmark of type 2 diabetes that is believed to contribute to related kidney and cardiovascular problems.

“It clearly indicates that IL-17A is protective,” Ramesh said. “It does well for the kidney in suppressing damage in response to diabetes.” Ramesh is corresponding author of the study, published in the Journal of the American Society of Nephrology, which is the first to look at IL-17’s role in chronic kidney disease.

IL-17A seems to protect kidney cells multiple ways, including inducing the anti-inflammatory molecule AMWAP, or activated microglia/macrophage WAP domain protein. The cytokine also appeared to aid survival and regeneration of key kidney cells, including podocytes and epithelial cells in the tubules. Podocytes help the kidney retain important large molecules such as protein, and epithelial cells line tubules where these essentials are reabsorbed.

To date, the MCG research team has seen no ill effects from overexpressing IL-17A in mice kidneys and to some extent in their circulation. Currently, there are no drugs available to increase patients’ IL-17A levels, but there are inhibitors for the cytokine that is considered causative in autoimmune diseases such as Crohn’s. Emerging laboratory and clinical trial data indicate there may need to be drugs that do both.

As examples, in a clinical trial of an antibody for IL-17A in patients with Crohn’s, the drug did not seem to help patients, and, in fact, some patients reported worsening symptoms. However, the National Psoriasis Foundation reports good experience with the use of biologics that block 1L-17 for the skin disorder. Meanwhile, French researchers have shown that giving IL-17A to mice suppressed the development of atherosclerosis, while a deficiency in the cytokine gene accelerated development of the arterial disease associated with inflammation.

The MCG researchers note that whether IL-17 promotes or suppresses inflammation may be related to the level and length of time it’s stimulated. Response may also depend on which of the six different forms of IL-17 is activated, the receptors activated and resulting downstream signaling. In their studies, for example, increasing IL-17C and IL-17E levels did not have the same positive effect on diabetic nephropathy as IL-17A as well as IL-17F.

In follow up to the therapy’s particular success with advanced disease, next steps include examining its impact on essentially destroyed kidneys. “If you can recover function from the dead kidney, you could save millions of people from a lifetime of dialysis,” Ramesh said.

A primary way physicians check kidney function is looking for signs of patients excreting the protein albumin in their urine. Albumin, which is made by the liver, is a major protein in the blood that helps keep blood from leaking out of blood vessels and helps keep other vital substances such as nutrients and hormones in the blood. Well-functioning kidneys retain albumin, and, even on dialysis, patients with diabetic nephropathy secrete a lot of protein in their urine.

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

http://www.sciencedaily.com/releases/2015/12/151228161255.htm  Original web page at Science Daily

Categories
News

* Gene-editing technique successfully stops progression of Duchenne muscular dystrophy

Using a new gene-editing technique, a team of scientists from UT Southwestern Medical Center stopped progression of Duchenne muscular dystrophy (DMD) in young mice.

If efficiently and safely scaled up in DMD patients, this technique could lead to one of the first successful genome editing-based treatments for this fatal disease, researchers said.

DMD, the most common and severe form of muscular dystrophy among boys, is characterized by progressive muscle degeneration and weakness. It is caused by mutations in the X-linked DMD gene that encodes the protein dystrophin. The disease affects one in 3,500 to 5,000 boys, according to the Centers for Disease Control and Prevention and other estimates, and often leads to premature death by the early 30s.

Although the genetic cause of DMD has been known for nearly 30 years, no effective treatments exist. The disease breaks down muscle fibers and replaces them with fibrous or fatty tissue, causing the muscle to gradually weaken. This condition often results in heart muscle disease, or cardiomyopathy, the leading cause of death in these patients.

In the study published in Science, UTSW researchers used a gene-editing approach to permanently correct the DMD mutation that causes the disease in young mice.

“This is different from other therapeutic approaches, because it eliminates the cause of the disease,” said senior author Dr. Eric Olson, Chairman of Molecular Biology, and Co-Director of the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center at UT Southwestern.

In 2014, Dr. Olson’s team first used this technique — called CRISPR/Cas9-mediated genome editing — to correct the mutation in the germ line of mice and prevent muscular dystrophy. This paved the way for novel genome editing-based therapeutics in DMD. It also raised several challenges for clinical applications of gene editing. Since germ line editing is not feasible in humans, strategies would need to be developed to deliver gene-editing components to postnatal tissues.

To test this out, researchers delivered gene-editing components to the mice via adeno-associated virus 9 (AAV9). DMD mice treated with this technique produced dystrophin protein and progressively showed improved structure and function of skeletal muscle and heart.

“AAV9 can efficiently infect humans in a tissue-specific manner, but it does not cause human disease or toxicity. It’s a molecular missile for gene therapy,” said Dr. Leonela Amoasii, a postdoctoral researcher in the Olson lab and co-lead author of the study with Dr. Chengzu Long, Instructor of Molecular Biology.

“The CRISPR/Cas9 system is an adaptive immune system of single-celled organisms against invading virus. Ironically, this system was hijacked, we packaged it into a nonpathogenic virus, and corrected a genetic mutation in an animal model,” added Dr. Long.

The CRISPR genome-editing technology, which was developed by a researcher at University of California at Berkeley, was picked as the “Breakthrough of the Year” scientific development by Science.

“This study represents a very important translational application of genome editing of DMD mutations in young mice. It’s a solid step toward a practical cure for DMD,” said Dr. Rhonda Bassel-Duby, Professor of Molecular Biology and Co-Principal Investigator of a genomic editing project with Dr. Olson at the Wellstone Center.

“Importantly, in principle, the same strategy can be applied to numerous types of mutations within the human DMD patients,” added Dr. Olson, who also serves as Director of the Hamon Center for Regenerative Science and Medicine, and holds the Annie and Willie Nelson Professorship in Stem Cell Research, the Pogue Distinguished Chair in Research on Cardiac Birth Defects, and the Robert A. Welch Distinguished Chair in Science.

Now, the research team is working to apply this gene-editing technique to cells from DMD patients and in larger preclinical animal models.

This marks the first major finding of the UTSW Wellstone Center, which was recently established with $7.8 million in funding from the National Institutes of Health. UTSW is one of six Wellstone Centers across the country, which work to translate scientific findings and technological developments into novel treatments for muscular dystrophy, and to promote basic, translational, and clinical research. UT Southwestern’s Wellstone Center focuses on Duchenne muscular dystrophy.

“The recent groundbreaking discoveries from the Olson laboratory using genome editing to correct the genetic mutation that causes DMD have accelerated the race to find a cure for this deadly disease,” said Dr. Pradeep Mammen, Associate Professor of Internal Medicine and Co-Director of the UTSW Wellstone Center. “The challenge now lies before Wellstone Center researchers to translate these discoveries in the mouse model of DMD into a therapy for patients with DMD.”

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

http://www.sciencedaily.com/releases/2016/01/160104080259.htm  Original web page at  Science Daily

Categories
News

DNA repair enzyme identified as a potential brain cancer drug target

Rapidly dividing cells rely on an enzyme called Dicer to help them repair the DNA damage that occurs as they make mistakes in copying their genetic material over and over for new cells. UNC Lineberger Comprehensive Cancer Center researchers have built on the discovery of Dicer’s role in fixing DNA damage to uncover a new potential strategy to kill rapidly dividing, cancerous cells in the brain.

In the journal Cell Reports, researchers report that when they removed Dicer from preclinical models of medulloblastoma, a common type of brain cancer in children, they found high levels of DNA damage in the cancer cells, leading to the cells’ death. The tumor cells were smaller, and also more sensitive to chemotherapy.

“This is the first time that the specific function of Dicer for DNA damage has been looked at in the context of the developing brain or even in brain tumors, despite that the fact that the protein has been extensively studied,” said Mohanish Deshmukh, PhD, a UNC Lineberger member and professor in the UNC School of Medicine Department of Cell Biology and Physiology and also the Neuroscience Center. “We have found that targeting Dicer could be an effective therapy to either prevent cancer development or to actually sensitize tumors to chemotherapy.”

Scientists have understood for more than a decade that Dicer plays an important role in the cell for processing microRNAs, which regulate the expression of genes in cells. But Deshmukh said it was in 2012 that scientists discovered a direct role of Dicer in repairing DNA damage. And that function, he said, is of importance for cancer research. That’s because rapidly dividing cells — such as cancer cells — incur DNA damage as they divide. And chemotherapy and radiation treatments often work by damaging the cells’ DNA, leading to cell death. Removing a key enzyme that repairs DNA in cancerous cells could help prevent DNA repair.

“We found that cancerous cells upregulate Dicer,” said Vijay Swahari, MBBS, MS, a postdoctoral fellow at the UNC Neuroscience Center and the first author of this study. “We think tumors upregulate Dicer because its function is to repair DNA.”

In their study, Deshmukh and his team studied the effect of deleting Dicer in several types of rapidly dividing cells, including of preclinical brain cancer models. They deleted Dicer in the normal, rapidly dividing developing brain cells in the cerebellum of animal models, finding spontaneous DNA damage in the brain cells, leading to severe degeneration of the cerebellum. They also tested whether Dicer had a similar effect on rapidly dividing cells outside of the brain. Upon deleting Dicer from embryonic stem cells, the authors found a similar effect.

To test whether they could exploit the role of Dicer to kill cancerous cells, Swahari and his collaborators also deleted Dicer in medulloblastoma models, and found that these cells also had high DNA damage levels and degeneration. The tumor load was lower, and the cells were more sensitive to chemotherapy.

“We found that when you delete Dicer, these tumors are more sensitive to DNA damage,” Swahari said. “We also took the next step by injecting chemotherapy into models where Dicer was deleted, finding that not only are the tumors smaller, but the tumors are also more sensitive to chemotherapy.”

Based on their findings, the researchers believe that Dicer could be investigated as a potential drug target for medulloblastoma and other types of brain cancer. “We are excited about these results because of the implication that Dicer inhibitors could be developed as a potential therapy for treating rapidly-dividing tumors like medulloblastoma,” Deshmukh said.

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

http://www.sciencedaily.com/releases/2016/01/160105112336.htm  Original web page at Science Daily

Categories
News

Genetically modified mice reveal the secret to a painless life

Researchers have discovered the pharmaceutical recipe for painlessness. People born with a rare genetic mutation are unable to feel pain, but previous attempts to recreate this effect with drugs have had surprisingly little success. Using mice modified to carry the same mutation, UCL researchers funded by the MRC and Wellcome Trust have now discovered the recipe for painlessness.

‘Channels’ that allow messages to pass along nerve cell membranes are vital for electrical signalling in the nervous system. In 2006, it was shown that sodium channel Nav1.7 is particularly important for signalling in pain pathways and people born with non-functioning Nav1.7 do not feel pain. Drugs that block Nav1.7 have since been developed but they had disappointingly weak effects.

The new study, published in Nature Communications, reveals that mice and people who lack Nav1.7 also produce higher than normal levels of natural opioid peptides.

To examine if opioids were important for painlessness, the researchers gave naloxone, an opioid blocker, to mice lacking Nav1.7 and found that they became able to feel pain. They then gave naloxone to a 39-year-old woman with the rare mutation and she felt pain for the first time in her life.

“After a decade of rather disappointing drug trials, we now have confirmation that Nav1.7 really is a key element in human pain,” says senior author Professor John Wood (UCL Medicine). “The secret ingredient turned out to be good old-fashioned opioid peptides, and we have now filed a patent for combining low dose opioids with Nav1.7 blockers. This should replicate the painlessness experienced by people with rare mutations, and we have already successfully tested this approach in unmodified mice.”

Broad-spectrum sodium channel blockers are used as local anaesthetics, but they are not suitable for long-term pain management as they cause complete numbness and can have serious side-effects over time. By contrast, people born without working Nav1.7 still feel non-painful touch normally and the only known side-effect is the inability to smell.

Opioid painkillers such as morphine are highly effective at reducing pain, but long-term use can lead to dependence and tolerance. As the body becomes used to the drug it becomes less effective so higher doses are needed for the same effect, side effects become more severe, and eventually it stops working altogether.

“Used in combination with Nav1.7 blockers, the dose of opioid needed to prevent pain is very low,” explains Professor Wood. “People with non-functioning Nav1.7 produce low levels of opioids throughout their lives without developing tolerance or experiencing unpleasant side-effects. We hope to see our approach tested in human trials by 2017 and we can then start looking into drug combinations to help the millions of chronic pain patients around the world.”

The findings were made possible by the use of ‘transgenic’ mice, meaning they were modified to carry genetic material from another organism — in this case, the mutation that prevents humans from feeling pain. Precise physiological experiments showed that the nervous systems of the transgenic mice contained around twice the levels of naturally-produced opioids as unmodified mice from the same litter.

“Our results reaffirm the clinical relevance of transgenic mouse models for human diseases,” says Professor Wood. “Studying the mice showed us what was going on in the nervous system that led to painlessness and our findings were directly translatable to humans, as confirmed by the painless patient. Without the work in transgenic mice, none of this would have been possible and we still wouldn’t know how to replicate the effects to help people suffering from chronic pain.”

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

http://www.sciencedaily.com/releases/2015/12/151204090034.htm  Original web page at Science Daily

Categories
News

* European seafood fraud? Largest genetic study of fish labeling accuracy

Tough new policies to combat fish fraud across Europe appear to be working, according to new evidence. The largest multi-species survey of fish labelling accuracy to date indicates a marked and sudden reduction of seafood mislabelling in supermarkets, markets and fishmongers in the EU.

Scientists in six European countries tracked samples of the mostly commonly consumed fish, including cod, tuna, hake and plaice, after a series of studies going back 5 years had shown mislabelling in up to 40% of cases.

It is thought that more transparent seafood supply chains can lead to more sustainable exploitation and healthier oceans. The study is part of the LABELFISH project, supported by the EU Atlantic Area Programme and the Department for Environment, Food and Rural Affairs.

Principal Investigator Stefano Mariani, professor of conservation genetics at the University of Salford, said he was surprised at the progress made but that much remains to be investigated about the complexities of global seafood supply. Mariani and his collaborators carried out genetic testing of seafood sold in supermarkets, traditional markets and fishmongers in 19 European cities between 2013 and 2014, including Cardiff, Glasgow, Plymouth and Manchester, Dublin, Madrid, Marseille, Lisbon and Hamburg.

Species verification was carried out on fresh, frozen and tinned products labelled as cod, tuna, haddock, plaice, sole, swordfish, anchovy, hake and monkfish. Of the 1,563 DNA sequence samples examined, just 77 (4.9%) proved to be mislabelled. Most commonly mislabelled was anchovy (15.5%), hake (11.1%) and tuna (6.8%). By contrast only 3.5% of cod and 3% of haddock was mislabelled. None of the monkfish, plaice or swordfish samples was substituted with other species.

The study found little or no difference in tinned, fresh or frozen products and no significant country-associated trends. According to the samples taken, Spain had the highest rate of incorrect labelling (8.9%), followed by Portugal (6.7%), Germany (6.2%), Ireland (3.9%), the UK (3.3%) and France (2.7%).

The study, which is published (01/12/2015) in Frontiers in Ecology and the Environment, argues that the trend is due to a combination of transnational legislation, governance and public outreach, which has forced new regulation and self-regulation, and it contrasts the European ‘turn-around’ with the experience of the United States, where improvements appear more sluggish.

Professor Mariani added: “Genetic identification methods have progressively exposed the inadequacies of the seafood supply chain, raising awareness among the public, and serving as a warning to industry that malpractice will be detected. “This evidence indicates we are now on the road to greater transparency, which should help the management of exploited stocks worldwide, but further standardised studies on a greater range of food provision channels, such as restaurants and auctions, are warranted, in order to have a complete understanding of the current state of the trade.”

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

http://www.sciencedaily.com/releases/2015/12/151201093722.htm  Original web page at Science Daily

Categories
News

US government approves transgenic chicken

Transgenic chickens are the latest animals engineered to produce ‘farmaceutical’ drugs.

The US Food and Drug Administration (FDA) has approved a chicken that has been genetically engineered to produce a drug in its eggs. The drug, Kanuma (sebelipase alfa), is a recombinant human enzyme marketed by Alexion Pharmaceuticals. It replaces a faulty enzyme in people with a rare, inherited condition that prevents the body from breaking down fatty molecules in cells.

Following its approval by the FDA on 8 December, Kanuma joins a small group of ‘farmaceuticals’ on the US market. In 2009, the agency approved genetically modified goats that produce an anticoagulant called ATryn (antithrombin) in their milk. And last year, the FDA authorized a drug for treating hereditary angioedema that is produced by transgenic rabbits.

The FDA’s latest decision “shows that the ATryn goats weren’t just a one-off”, says Jay Cormier, a lawyer at Hyman, Phelps and McNamara in Washington DC and a former scientific reviewer for the FDA. “The process can function for more than just one particular unique case.”

The agency moved quickly to consider Kanuma, giving it a priority review, orphan-drug status and a breakthrough-therapy designation. The disease that it is designed to treat, lysosomal acid lipase deficiency, causes fat to accumulate in the liver, spleen and vasculature. A form of the disease that strikes infants is quickly fatal. A second form that affects older patients causes liver enlargement, fibrosis and cirrhosis, as well as cardiovascular disease.

“Before we had this drug, we didn’t have any treatment for the patients that really addressed the underlying biochemical defect in the disorder,” says Barbara Burton, a paediatrician with the Northwestern University Feinberg School of Medicine in Chicago, Illinois. Clinicians could only provide nutrition and supportive care to infants, says Burton, who worked with Alexion to conduct the clinical trials. Older patients are treated with statins — which do not address the fatty build-up in the liver.

Unlike the genetically engineered AquAdvantage salmon that was approved by the FDA last month, the transgenic chickens that produce Kanuma are not intended to enter the food supply. But just as with the AquAdvantage salmon, the FDA considers the chicken’s genetic modifications to be an ‘animal drug’.

Because every cell in the modified chicken contains altered DNA, the FDA “asserts its jurisdiction over the entire chicken”, says Cormier. Under its process for considering animal drugs, the FDA examined whether altering the chickens’ DNA would harm them, and whether the modified DNA was stable as it passed to new generations of chickens. The FDA says that the chickens are not likely to accidentally enter the food supply or adversely affect the environment because they are raised in indoor facilities.

William Muir, a geneticist at Purdue University in West Lafayette, Indiana, praised the FDA’s decision to approve the transgenic chickens. “The floodgates are opening,” he says, “and I can’t wait to see what comes next.”

Nature doi:10.1038/nature.2015.18985

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

http://www.nature.com/news/us-government-approves-transgenic-chicken-1.18985  Original web page at Nature

Categories
News

Urban swans’ genes make them plucky

Researchers have discovered that swans’ wariness is partly determined by their genes. The research, which is published in the open access journal BMC Evolutionary Biology, suggests that swans which are genetically predisposed to be timid are more likely to live in non-urban areas, and the findings could have important implications for releasing animals bred in captivity into the wild

It is often assumed that animals that live in urban areas become less wary of humans through habituation, but until now, no research has been conducted which tests whether animals’ preference for an urban or non-urban environment might be genetically determined.

A team of researchers from Victoria University, Deakin University and The University of Melbourne, Australia, conducted a series of tests to establish the wariness of two separate populations of black swans (Cygnus atratus). One population of 80 swans were living in an urban parkland setting, where they frequently encountered humans, while a second population of 20 swans were living around 30km away in a non-urban area, much less frequented by people.

The researchers quantified the birds’ wariness by walking slowly towards them, and then measuring the distance at which the bird flew away, called the Flight Initiation Distance (FID). Separately, they also took blood samples from the two populations of birds so that they could look for variations in two sets of genes — DRD4 and SERT — typically associated with behaviours related to anxiety and harm avoidance in animals.

As expected, the swans living in an urban setting were much bolder than their rural counterparts, with an average FID of 13 meters, compared to 96 meters for the non-urban swans. The genetic tests revealed no significant differences between the two populations in SERT genotypes, but they found five different variants of DRD4 which were associated with different levels of wariness.

The vast majority (88.8%) of the urban swans shared the most common genotype for DRD4, whereas only 60% of the rural swans exhibited this genotype. Of all the swans, 83% with the most common DRD4 genotype had a shorter average FID, suggesting that the birds’ wariness is at least partly determined by their genes.

As swans are typically highly mobile, and have the ability to migrate between different habitats, the researchers conclude that wary swans may be more likely to choose to inhabit a non-urban site, with bolder swans colonising urban areas.

Lead researcher, Wouter van Dongen, says: “Growing global urbanisation means that wild animals are increasingly settling near to humans. Although we often assume that animals become less wary of humans by simply getting used to them, our results suggest that at least part of this response might be genetically determined. This has important implications for conservation, particularly for the introduction of animals bred in captivity, which could in future be screened for genotypes that are associated with wariness, allowing them to be released to a location commensurate with their expected wariness.”

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

http://www.sciencedaily.com/releases/2015/12/151211130113.htm  Original  web page at Science Daily

Categories
News

Study uncovers hard-to-detect cancer mutations

New research shows that current approaches to genome analysis systematically miss detecting a certain type of complex mutation in cancer patients’ tumors. Further, a significant percentage of these complex mutations are found in well-known cancer genes that could be targeted by existing drugs, potentially expanding the number of cancer patients who may benefit.

The study, from Washington University School of Medicine in St. Louis, appeared Dec. 14 in the journal Nature Medicine.

“The idea of not catching a targetable mutation in a patient’s tumor is devastating,” said senior author Li Ding, PhD, associate professor of medicine and assistant director of the McDonnell Genome Institute at Washington University. “We developed a software tool for finding a certain type of genetic error that has been consistently missed by cancer genome studies. We identified a large number of such events in critical cancer genes. The ability to discover such events is crucial for cancer research and for clinical practice.”

Mutations in the genome happen in a variety of ways. Perhaps the simplest is a change in a single “letter” of the DNA code. Among the more complex types of mutations are those that involve deleting or inserting a few letters. In the new study of 8,000 cancer cases, the investigators focused on mutations involving letters that are inserted at the same time that other letters are deleted.

“We call this type of mutation a complex indel because insertion and deletion is happening at the same time, in the same genomic location,” Ding said. “It is very difficult to capture such events because conventional approaches were designed to catch one or the other, not both types at the same time and place.”

To find the complex indels, the researchers developed specialized computer software and verified its accuracy in genome sequences into which they purposely introduced these complex mutations.

Then, the researchers looked at cancer genomes that already had been sequenced and found 285 complex indels in genes known to be associated with cancer. About 81 percent of these complex indel events had been missed on the first analysis using conventional approaches. And another 18 percent had been misidentified as some other type of mutation.

Ding emphasized the importance of developing special tools to find these complex indels, as the data suggest they go almost completely undetected by existing tools and appear to cluster in important cancer genes more often than can be attributed to random chance. This information is particularly valuable when indels are found in genes that already have drugs designed to counter the effects of mutation.

In particular, the researchers identified complex indels in the gene EGFR, which is implicated in lung cancer. If such an indel is found in this gene, Ding and her colleagues suggest a patient may benefit from an EFGR inhibitor, such as erlotinib, regardless of the tumor type. The investigators also found complex indels in a gene called KIT, which appears to play a role in melanoma. The analysis suggests that patients with complex indels in KIT would benefit from drugs such as imatinib, sunitnib and sorafenib, which target mutations in this gene.

The new software the investigators developed specifically to find complex indels is called Pindel-C. It was built on top of existing software called Pindel, which was published in 2009 by the study’s first author, Kai Ye, PhD, assistant professor of genetics. Both versions of the software are freely available online for download.

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

http://www.sciencedaily.com/releases/2015/12/151214130353.htm  Original web page at Science Daily

Categories
News

China’s bold push into genetically customized animals

New kinds of dogs, goats, monkeys and pigs are being made quickly, though scientists voice worries about ethics.

China’s western Shaanxi Province is known for rugged windswept terrain and its coal and wool, but not necessarily its science. Yet at the Shaanxi Provincial Engineering and Technology Research Center for Shaanbei Cashmere Goats, scientists have just created a new kind of goat, with bigger muscles and longer hair than normal. The goats were made not by breeding but by directly manipulating animal DNA—a sign of how rapidly China has embraced a global gene-changing revolution.

Geneticist Lei Qu wants to increase goatherd incomes by boosting how much meat and wool each animal produces. For years research projects at his lab in Yulin, a former garrison town along the Great Wall, stumbled along, Qu’s colleagues say. “The results were not so obvious, although we had worked so many years,” his research assistant, Haijing Zhu, wrote in an e-mail.

That changed when the researchers adopted the new gene-customizing technology called CRISPR–Cas9, a technique developed in the U.S. about three years ago. CRISPR uses enzymes to precisely locate and snip out segments of DNA, much like a word-processor finding and deleting a given phrase—a process known as “gene-editing.” Although it is not the first tool scientists have used to tweak DNA, it is by far more precise and cheaper than past technologies. The apparent ease of this powerful method now raises both tantalizing possibilities and pressing ethical questions.

Once the goat team began to deploy CRISPR, their progress was rapid. In September Qu and 25 other collaborating scientists in China published the details of their research in Nature’s Scientific Reports. In early-stage goat embryos they had successfully deleted two genes that suppressed both hair and muscle growth. The result was 10 goat kids exhibiting both larger muscles and longer fur—designer livestock—that, so far, show no other abnormalities. “We believed gene-modified livestock will be commercialized after we demonstrate that it is safe,” predicts Qu, who envisions this work as a simple way to boost the sale of goat meat and cashmere sweaters from Shaanxi.

The research is just one of a recent flurry of papers by Chinese scientists that describe CRISPR-modified goats, sheep, pigs, monkeys and dogs, among other mammals. In October, for instance, researchers from the country discussed their work to create unusually muscled beagles in the Journal of Molecular Cell Biology. Such research has been supported via grants from the National Natural Science Foundation of China, Ministry of Agriculture, Ministry of Science and Technology as well as provincial governments.

Dozens, if not hundreds, of Chinese institutions in both research hubs like Beijing and far-flung provincial outposts have enthusiastically deployed CRISPR. “It’s a priority area for the Chinese Academy of Sciences,” says Minhua Hu, a geneticist at the Guangzhou General Pharmaceutical Research Institute and one of the beagle researchers. A colleague, Liangxue Lai of the Guangzhou Institutes of Biomedicine and Health, adds that “China’s government has allocated a lot of financial support in genetically modified animals in both the agriculture field and the biomedicine field.

This is raising a number of ethical worries about making new life forms. Unlike past gene therapies, changes made using CRISPR to zygotes or embryos can become “permanent”—that is, they are made to the DNA that will be passed onto future generations. For each zygote or embryo that scientists successfully transform, typically dozens, if not hundreds, of others do not work. But the technology is rapidly improving. “What is different about CRISPR is that the technology is vastly more efficient and so the possibility of it being practiced widely is that much more real,” says George Daley, a stem-cell biologist at Harvard Medical School. Past efforts to manipulate the genetic code of life have been slower, more cumbersome and more unpredictable. “The ethical concerns are now upon us because the technology is real,” he adds.

This applies to CRISPR experiments to “edit” the DNA of all plants and animals—as well as in the future, perhaps, humans, if scientists like Qu further hone the technique. Unlike past gene therapies, changes made using CRISPR to zygotes or embryos become “permanent”; that is, they enter the germ line and will be passed onto future generations. “As with any intervention, there’s always a trade-off in issues between human welfare and animal welfare and gauging the environmental impacts,” says Daley, referring the quest for “improved” livestock, a current focus of China’s gene-editing research. And on the even more complicated topic of potential CRISPR experiments involving human DNA, he wonders, “Can we draw a clear line between what might be allowable for medical research or applications and what we must strictly prohibit?” Finding an answer that the whole world can agree on is geneticists’ and ethicists’ next big task.

China is not the birthplace of CRISPR (currently there’s an ongoing patent battle between scientists at Massachusetts Institute of Technology and the University of California, Berkeley, for that claim). China, however, has been an extremely rapid adopter, aided by a fast-growing research budget and the sheer scale of China’s science establishment, which is largely state-affiliated. Between 2008 and 2012 China’s research and development spending fully doubled, according to the Organization for Economic Cooperation and Development’s Science, Technology and Industry Outlook 2014. (Now second in the world, China’s research budget may surpass the U.S. by 2019, the report projects.) Yet despite its strengths, “China is a relative newcomer to international scientific community and doesn’t have the same institutional-review traditions in place,” says Daley, adding that scientists in the U.S. and Europe are now keenly watching how Chinese scientists will deploy such powerful tools.

The level and sophistication of work in China using CRISPR is already “about the same” as in Europe and the U.S., where the technology was codeveloped, says George Church, a professor of genetics at Harvard Medical School. An analysis by Thomson Innovation, a division of London-based Thomson Reuters, found that more than 50 Chinese research institutions have filed gene-editing patents.

Some experiments in China, as in the U.S. and U.K., are aimed at potential biomedical applications. For instance, scientists at Yunnan Key Laboratory of Primate Biomedical Research have used CRISPR to augment the neurological development of monkeys in an effort to test the feasibility of creating primate disease models for better understanding human conditions like autism, schizophrenia and Alzheimer’s disease. Many experiments, like the one on cashmere goats and a similar experiment that deleted the gene-inhibiting muscle growth in sheep, are aimed at transforming animal husbandry—more muscled livestock could help satiate China’s fast-growing middle-class appetite for meat.

But what first brought widespread global attention, or infamy, to China’s ambitions was a recent published experiment on human embryos, the first in the world. In April China became a lightning rod for criticism and anxiety when a team of Chinese scientists published a paper online in the journal Protein & Cell detailing attempts to use CRISPR to modify nonviable human embryos, obtained with consent from a fertility clinic. Their aim had been to delete a gene linked to a blood disorder called beta-thalassemia without creating other mutations, but the experiment failed on 85 attempted embryos.

The research was legal within China, which bans experiments on human embryos more than 14 days old, and was supported in part by government grants. (Such research is not banned in most U.S. states but is probably ineligible for federal funding.)

Many international observers reacted with sharp rebuke, attributing nefarious intentions to the Chinese scientists. “No researcher has the moral warrant to flout the globally widespread policy agreement against altering the human germ line,” Marcy Darnovsky, executive director of the California-based Center for Genetics and Society, a nonprofit advocacy group, wrote in a statement reacting to the report. Respected news organizations ran ominous headlines: “Chinese Scientists Edit Genes of Human Embryos, Raising Concerns” appeared in The New York Times and “Editing Humanity” in The Economist.

Because China is new to global scientific stage, its institutional standards for approving research projects are not fully transparent to the world, Daley says. Moreover, the researchers involved were not the heads of well-known global institutions, like the Broad Institute of M.I.T. and Harvard University or the Francis Crick Institute in London, whom global research community knows well and understands their motivations. Daley adds that now China’s scientific establishment is “responsibly stepping up to discussion.”

The controversy may have been a bit overblown. The Chinese scientists say they were not trying to edit human germ line or develop clinical uses. Junjiu Huang, co-author of the paper and a geneticist at Sun Yat-sen University in Guangzhou, wrote in an e-mail to Scientific American that “It is forbidden to do germ-line editing in clinic.” Yet he defended the potential to learn about human diseases through future CRISPR experiments. “Using CRISPR–Cas9 technology, scientists could learn more about what are the real functions of key genes in the human preimplantation period. … We can also figure out the mechanism of gene repairing, which could lead to a new understanding of how genetic diseases occur during early development.

Later appraisals credit the carefulness of their method, including the choice to deliberately use nonviable embryos that could never become babies, Harvard’s Church says. But the flap itself pointed to both the seriousness of the stakes and concern over whether Chinese scientists will accept same ethical principles as Westerners.

In early December scientists from the U.S., U.K. and China will meet at the U.S. National Academy of Sciences in Washington, D.C., in an effort to codify international consensus on editing DNA, focusing on the human germ line. Church, who has participated in preliminary meetings with Chinese and U.S. counterparts, says that the important takeaway from these debates may not be that China is an ethical outlier but rather that public discussion and clarification of guidelines, especially regarding the human germ line, is dearly needed. “I think China is behaving just as responsibly as others. I would not characterize China as being problematic in any way. Chinese scientists worked well within the legal system of most countries but I think there might have been some misunderstandings about consensus at that time,” he says. “I think it’s important to talk about it. I think many people want every opportunity to discuss this issue—sometimes you need an event to make it newsworthy.

Although scientists today offer a range of views on what is acceptable, the essential divide may not be between East and West. In September a researcher at the London-based Francis Crick Institute, Kathy Niakan, filed an application with U.K. regulators “to use new [CRISPR] ‘genome editing’ techniques on human embryos,” according to an institution statement. “The work carried out at the Crick will be for research purposes and will not have a clinical application. However, the knowledge acquired from the research will be very important for understanding how a healthy human embryo develops.

Meanwhile Chinese scientists point out that the country is having its own internal debates about the ethics of editing DNA.

Whatever the discussions in Washington yield, Yaofeng Zhao at the State Key Laboratory of Agrobiotechnology, a geneticist working on sheep, says that China is also grappling with its own internal ethical and safety debates about moving CRISPR experiments, for agriculture and biomedicine, beyond the lab. “I think there are different viewpoints on gene modification. Even in China there are different viewpoints on this issue. Some people in the general public, they are scared. But for most academics, I think most scientists support this kind of research—we need to do something for the future,” he says. In contrast to Qu, the cashmere-goat specialist, Zhao doesn’t think designer meat will be soon be on dinner plates. “If you want to use modified animals in agriculture, you must consider the public opinion—Can they accept this? Even if the technology is quite safe, it depends on many factors if you want to commercialize this kind of animal in agriculture.” There is already precedent for the Chinese government spending heavily on GMO crop research, including improved corn, wheat and rice, but delaying commercialization due to fierce public resistance.

In areas where science advances faster than regulation it may be possible for individual scientists or labs—in China or any country—to act outside of national consensus. At the Shenzhen International Biotech Leaders Summit on September 23, the private genomics firm BGI–Shenzhen, a maverick in the field, announced that it would begin selling gene-edited micro pigs as pets; the smaller pigs were originally created with the intention of biomedical research. Yong Li, technical director of BGI’s animal science platform, who turned down an interview request about the pigs for Scientific American, previously told Nature that he wanted to “evaluate the market.” (Pets are less regulated than agriculture, and do not supply national markets.) Some Chinese researchers clearly disapprove. Lai, co-author of the beagle paper, says he believes scientists should “not use CRISPR technique to create pets with special traits to satisfy some pet owner’s special favor.”

Lai’s own work does not involve human embryos but he offered his opinion on the larger ongoing debate: If safety and efficacy issues can first be addressed, he is open to the future possibility of therapeutic uses, but not to eugenics. “In human beings CRISPR could be used to correct the mutation, which cause genetic human diseases, and it should not be used to generate any particular traits which some people may favor.” Other Chinese scientists working with CRISPR expressed similar views but none purported to predict the future—in China or elsewhere. Huang notes, “The gene-editing technology is very hot all over the world.”

Public debate over any powerful new technology reflects preexisting public hopes and fears, Church says. In the case of CRISPR that includes the desire to eliminate hereditary diseases as well as concerns about the commodification of parenting, the privileges of rich over poor and, newly, the rise of China.

Nature doi:10.1038/nature.2015.18826

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

http://www.nature.com/news/china-s-bold-push-into-genetically-customized-animals-1.18826  Original web page at Nature