New hope for powdery mildew resistant barley

New research at the University of Adelaide has opened the way for the development of new lines of barley with resistance to powdery mildew.In Australia, annual barley production is second only to wheat with 7-8 million tonnes a year. Powdery mildew is one of the most important diseases of barley.Senior Research Scientist Dr Alan Little and team have discovered the composition of special growths on the cell walls of barley plants that block the penetration of the fungus into the leaf.The research, by the ARC Centre of Excellence in Plant Cell Walls in the University’s School of Agriculture, Food and Wine in collaboration with the Leibniz Institute of Plant Genetics and Crop Plant Research in Germany, will be presented at the upcoming 5th International Conference on Plant Cell Wall Biology and published in the journal New Phytologist.”Powdery mildew is a significant problem wherever barley is grown around the world,” says Dr Little. “Growers with infected crops can expect up to 25% reductions in yield and the barley may also be downgraded from high quality malting barley to that of feed quality, with an associated loss in market value.”In recent times we’ve seen resistance in powdery mildew to the class of fungicide most commonly used to control the disease in Australia. Developing barley with improved resistance to the disease is therefore even more important.”The discovery means researchers have new targets for breeding powdery mildew resistant barley lines.”Powdery mildew feeds on the living plant,” says Dr Little. “The fungus spore lands on the leaf and sends out a tube-like structure which punches its way through cell walls, penetrating the cells and taking the nutrients from the plant. The plant tries to stop this penetration by building a plug of cell wall material — a papillae — around the infection site. Effective papillae can block the penetration by the fungus.”It has long been thought that callose is the main polysaccharide component of papilla. But using new techniques, we’ve been able to show that in the papillae that block fungal penetration, two other polysaccharides are present in significant concentrations and play a key role.”It appears that callose acts like an initial plug in the wall but arabinoxylan and cellulose fill the gaps in the wall and make it much stronger.”In his PhD project, Jamil Chowdhury showed that effective papillae contained up to four times the concentration of callose, arabinoxylan and cellulose as cell wall plugs which didn’t block penetration.”We can now use this knowledge find ways of increasing these polysaccharides in barley plants to produce more resistant lines available for growers,” says Dr Little.Story Source:The above story is based on materials provided by University of Adelaide. Note: Materials may be edited for content and length.

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Function found for mysterious heart disease gene

A new study from researchers at the University of Ottawa Heart Institute (UOHI), published today in Cell Reports, sheds light on a mysterious gene that likely influences cardiovascular health. After five years, UOHI researchers now know how one genetic variant works and suspect that it contributes to the development of heart disease through processes that promote chronic inflammation and cell division.Researchers at the Ruddy Canadian Cardiovascular Genetics Centre had initially identified a variant in a gene called SPG7 as a potential contributor to coronary artery disease several years ago, but its role in multiple health processes made it difficult to tease out how it affects heart disease.The gene holds instructions for producing a protein called SPG7. This protein resides in mitochondria — the small power plants of cells that produce the energy cells need to function. SPG7’s role is to help break down and recycle other damaged proteins within the mitochondria.Normally, SPG7 requires a partner protein to activate itself and start this breakdown process. But, in people who carry the genetic variant in question, SPG7 can activate itself in certain circumstances, leading to increased production of free radicals and more rapid cell division. These factors contribute to inflammation and atherosclerosis.”We think this variant would definitely heighten the state of inflammation, and we know that inflammation affects diabetes and heart disease,” said Dr. Stewart, Principal Investigator in the Ruddy Canadian Cardiovascular Genetics Centre and senior author of the study. “Interestingly, the variant also makes people more resistant to the toxic side effects of some chemotherapy drugs.”From an evolutionary perspective, this resistance could help such a genetic variant gain a stable place in the human genome. Between 13 and 15 per cent of people of European descent possess this variant.”The idea of mitochondria contributing to inflammation isn’t new,” concluded Dr. Stewart. …

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Genetic evidence for single bacteria cause of sepsis identified for the first time by academic team

An international team of academics, including Professor Marco Oggioni from the University of Leicester’s Department of Genetics, has studied how localized infections can turn into the dangerous systematic disease sepsis — and has identified for the first time through genetic evidence that a single bacteria could be the cause.The study, which has been published in the academic journal PLOS Pathogens, examined the events that lead to sepsis by Streptococcus pneumoniae (pneumococcus), a major human pathogen, in mice. They found that in most cases the bacteria causing sepsis was started by a single pneumococcal cell.The study was an interdisciplinary collaboration between the Departments of Genetics, Infection Immunity and Inflammation and Mathematics at the University of Leicester, Professor Richard Moxon at the University of Oxford and scientists from overseas including the University of Siena.Professor Oggioni said: “Our data in experimental infection models indicate that we do not need only strategies which target many bacteria when it is too late, but that early intervention schemes which prevent the one-single cell that starts the disease process might provide substantial benefit to the patient.”In this work we have for the first time provided genetic evidence for a single cell origin of bacterial invasive infection. The scenario was hypothesized over 50 years ago, but so far only phenotypic and statistical evidence could be obtained for this event.”Under normal circumstances, when different bacteria are used in models of experimental infection of hosts who have not previously encountered the same pathogen, the vast majority is destroyed rapidly by the host’s innate immune system.In the researcher’s model, a dose of one million bacteria is needed to induce systemic disease in about half of the hosts in the study.This is in stark contrast to a much lower number of bacteria thought to make up the starting “seed” that leads to the development of systemic infection — and the assumption is that there must be one or more “bottlenecks” in the development of the disease.To investigate these bottlenecks, the researchers injected mice with a mix of three different variants of S. pneumoniae. About half of the mice developed sepsis and in almost all cases the bacteria causing sepsis were derived from only one of the three variants used in the initial challenge.Using statistical analysis as well as direct DNA sequencing, the researchers could show that in most cases the bacterial population causing sepsis was started by a single pneumococcal cell.When the researchers looked closer at how the immune system resists most injected bacteria, they found that macrophages, a type of immune cell that can gobble up bacteria, and specifically macrophages in the spleen, are the main contributors to an efficient immune response to this pathogen.Their findings suggest that if bacteria survive this initial counter-attack, a single ‘founder’ bacterium multiplies and re-enters the bloodstream, where its descendants come under strong selective pressure that dynamically shapes the subsequent bacterial population — resulting in the sepsis.The data also suggests that the single bacterium leading to sepsis has no obvious characteristics that give it an advantage over the 999,999 others, but that random events determine which of the injected bacteria survives and multiplies to cause disease.It is believed that the findings, suggesting that the development of sepsis starting from a single founding cell which survives the immune system’s initial counter-attack in mice, could also potentially apply to human systemic infections.This information could prove vital to understanding sepsis, as the causes of the disease are still largely unknown to the scientific community.Dr Oggioni added: “Knowing that there is a moment when a single bacterial cell escapes “normal” immune surveillance at the beginning of each invasive infection is an important paradigm and essential information which, in our opinion, should lead to changes in therapeutic protocols in order to maximise success of treatment outcome.”Story Source:The above story is based on materials provided by University of Leicester. Note: Materials may be edited for content and length.

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New theory on cause of endometriosis

Changes to two previously unstudied genes are the centerpiece of a new theory regarding the cause and development of endometriosis, a chronic and painful disease affecting 1 in 10 women.The discovery by Northwestern Medicine scientists suggests epigenetic modification, a process that enhances or disrupts how DNA is read, is an integral component of the disease and its progression. Matthew Dyson, research assistant professor of obstetrics and gynecology at Northwestern University Feinberg School of Medicine and and Serdar Bulun, MD, chair of obstetrics and gynecology at Feinberg and Northwestern Memorial Hospital, also identified a novel role for a family of key gene regulators in the uterus.”Until now, the scientific community was looking for a genetic mutation to explain endometriosis,” said Bulun, a member of the Center for Genetic Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “This is the first conclusive demonstration that the disease develops as a result of alterations in the epigenetic landscape and not from classical genetic mutations.”The findings were recently published in PLoS Genetics.Women develop endometriosis when cells from the lining of the uterus, usually shed during menstruation, grow in other areas of the body. The persistent survival of these cells results in chronic pelvic pain and infertility. Although the cause of the disease has remained unknown on a cellular level, there have been several different models established to explain its development.Endometriosis only occurs in menstruating primates, suggesting that the unique evolution behind uterine development and menstruation are linked to the disease. Scientists consider retrograde menstruation — cells moving up the fallopian tubes and into the pelvis — as one probable cause. Previous models, however, have been unable to explain why only 10 percent of women develop the disease when most experience retrograde menstruation at some point. Nor do they explain instances of endometriosis that arise independent of menstruation.Bulun and Dyson propose that an epigenetic switch permits the expression of the genetic receptor GATA6 rather than GATA2, resulting in progesterone resistance and disease development.”We believe an overwhelming number of these altered cells reach the lining of the abdominal cavity, survive and grow,” Bulun said. “These findings could someday lead to the first noninvasive test for endometriosis.”Clinicians could then prevent the disease by placing teenagers predisposed to this epigenetic change on a birth control pill regimen, preventing the possibility of retrograde menstruation in the first place, Bulun said.Dyson will also look to use the epigenetic fingerprint resulting from the presence of GATA6 rather than GATA2 as a potential diagnostic tool, since these epigenetic differences are readily detectable.”These findings have the potential to shift how we view and treat the disease moving forward,” Bulun said.Story Source:The above story is based on materials provided by Northwestern University. …

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Protective mutations for type 2 diabetes pinpointed

An international team led by researchers at the Broad Institute and Massachusetts General Hospital (MGH) has identified mutations in a gene that can reduce the risk of developing type 2 diabetes, even in people who have risk factors such as obesity and old age. The results focus the search for developing novel therapeutic strategies for type 2 diabetes; if a drug can be developed that mimics the protective effect of these mutations, it could open up new ways of preventing this devastating disease.Type 2 diabetes affects over 300 million people worldwide and is rising rapidly in prevalence. Lifestyle changes and existing medicines slow the progression of the disease, but many patients are inadequately served by current treatments. The first step to developing a new therapy is discovering and validating a “drug target” — a human protein that, if activated or inhibited, results in prevention and treatment of the disease.The current study breaks new ground in type 2 diabetes research and guides future therapeutic development in this disease. In the new study, researchers describe the genetic analysis of 150,000 patients showing that rare mutations in a gene called SLC30A8 reduce risk of type 2 diabetes by 65 percent. The results were seen in patients from multiple ethnic groups, suggesting that a drug that mimics the effect of these mutations might have broad utility around the globe. The protein encoded by SLC30A8 had previously been shown to play an important role in the insulin-secreting beta cells of the pancreas, and a common variant in that gene was known to slightly influence the risk of type 2 diabetes. However, it was previously unclear whether inhibiting or activating the protein would be the best strategy for reducing disease risk — and how large an effect could be expected.”This work underscores that human genetics is not just a tool for understanding biology: it can also powerfully inform drug discovery by addressing one of the most challenging and important questions — knowing which targets to go after,” said co-senior author David Altshuler, deputy director and chief academic officer at the Broad Institute and a Harvard Medical School professor at Massachusetts General Hospital.The use of human genetics to identify protective mutations holds great potential. Mutations in a gene called CCR5 were found to protect against infection with HIV, the virus that causes AIDS; drugs have been developed that block the CCR5 protein. A similar protective association for heart disease set off a race to discover new cholesterol-lowering drugs when mutations in the gene PCSK9 were found to lower cholesterol levels and heart disease risk. …

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Manipulating heat, drought tolerance in cowpeas

Cowpeas, known as black-eyed peas in the U.S., are an important and versatile food legume grown in more than 80 countries. Texas A&M University scientists are working to map the genes controlling drought and heat tolerance in recent varieties.New and improved varieties of cowpeas have numerous adaptive traits of agronomic importance, such as 60-70 day maturity, drought tolerance, heat tolerance, aphid resistance and low phosphorus tolerance, said Dr. Meiping Zhang, Texas A&M AgriLife Research associate research scientist in College Station.Under a National Institute for Food and Agriculture grant of $500,000, Zhang and other Texas A&M scientists will take advantage of the recently developed DNA sequencing technology to map and ultimately clone the genes controlling drought and heat tolerance for molecular studies and deployment of these genes in other crops, she said.Joining Zhang on the project are Dr. Hongbin Zhang, Texas A&M professor of plant genomics and systems biology and director of the Laboratory for Plant Genomics and Molecular Genetics; Dr. B.B. Singh, a visiting scholar and cowpea breeder with the Texas A&M soil and crop sciences department; and Dr. Dirk Hays, Texas A&M associate professor of physiological and molecular genetics, all in College Station.The goal of the study is to develop single nucleotide polymorphisms or SNP markers, the latest DNA marker technology, enabling efficient manipulation of heat and drought tolerances in cowpeas and related species, Zhang said.Cowpeas were chosen for the study because they are a high protein grain, vegetable, fodder and high nitrogen-fixing legume that can be intercropped with corn, cotton and other crops in many countries, including the U.S., Zhang said.”We know it is highly tolerant to drought, heat and several other biotic and abiotic stresses,” she said. “This research will use high-throughput site-associated DNA sequencing to map the genes controlling drought and heat tolerance and to develop SNP markers, enabling efficient manipulation of heat and drought tolerances in cowpea and related species.”Zhang said they have already developed a mapping population of 110 recombinant inbred lines from a cross of two cowpea lines that are highly tolerant or susceptible to both drought and high temperature. This population is being augmented into more than 200 recombinant inbred lines for the new project.”We will not only map drought and heat tolerant genes, but also develop a platform for mapping genes controlling several other biotic and abiotic stress tolerances such as aphid resistance and low phosphorus tolerance, both of which are also of extreme significance for agricultural production of many crops.”The drought and heat tolerant genes, once defined and cloned, will significantly advance understanding of the molecular basis underlying plant tolerances to these stresses, Zhang said.This will help researchers design tools to effectively combine multiple traits into new cultivars adapted to the globally changing climate in this and related crops, thus supporting the long-term genetic improvement and sustainability of U.S. agriculture and food systems, she said.Story Source:The above story is based on materials provided by Texas AgriLife Research. …

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Mixed genes: Interactive world map of human genetic history reveals likely genetic impacts of historical events

When individuals from different groups interbreed, their offspring’s DNA becomes a mixture of the DNA from each admixing group. Pieces of this DNA are then passed along through subsequent generations, carrying on all the way to the present day. Researchers from the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, Oxford University and University College London (UCL) have now produced a global map detailing the genetic histories of 95 different populations across the world, spanning the last four millennia.The interactive world map that is accessible via the internet, details the histories of genetic mixing between each of the 95 populations across Europe, Africa, Asia and South America. It shows likely genetic impacts of historical events including European colonialism, the Mongol Empire, the Arab slave trade and European traders near the Silk Road mixing with people in China.The study, published this week in Science, is the first to simultaneously identify, date and characterise genetic mixing between populations. To do this, the researchers developed sophisticated statistical methods to analyse the DNA of 1490 individuals in 95 populations around the world. “DNA really has the power to tell stories and uncover details of humanity’s past,” said Simon Myers of Oxford University’s Department of Statistics and Wellcome Trust Centre for Human Genetics, co-senior author of the study. “Because our approach uses only genetic data, it provides information independent from other sources. Many of our genetic observations match historical events, and we also see evidence of previously unrecorded genetic mixing. For example, the DNA of the Tu people in modern China suggests that in around 1200CE, Europeans similar to modern Greeks mixed with an otherwise Chinese-like population. Plausibly, the source of this European-like DNA might be merchants travelling the nearby Silk Road.”The powerful technique, christened ‘Globetrotter’, provides insight into past events such as the genetic legacy of the Mongol Empire. …

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Revolutionary new view on heritability in plants: Complex heritable traits not only determined by changes in DNA sequence

Complex heritable traits are not only determined by changes in the DNA sequence. Scientists from the University of Groningen Bioinformatics Centre, together with their French colleagues, have shown that epigenetic marks can affect traits such as flowering time and architecture in plants. Furthermore, these marks are passed on for many generations in a stable manner. Their results were published in Science on the 6th of February 2014. It seems that a revision of genetics textbooks is now in order.We’ve all been taught that DNA is the physical foundation of heredity. Our genes are spelled out in the four famous letters A, T, C and G, which together form the genetic code. A single letter change in this code can lead to a gene ceasing to function or failing to work properly.The fact that the functioning of our genes is also affected by epigenetic marks has been known for decades. For example, the nucleotide cytosine (the C in the genetic code) can be changed into a methylcytosine. This cytosine methylation, which is one type of epigenetic mark, is typically associated with repression of gene activity.Epigenetic inheritance’While in mammals epigenetic marks are typically reset every generation, in plants no such dramatic resetting takes place. This opens the door to epigenetic inheritance in plants: epigenetic changes that are acquired in one generation tend to be stably passed on to the next generation’, explains Frank Johannes, assistant professor at the GBIC and co-lead scientist for the Science study.Johannes’s French colleagues have produced inbred strains of the model plant Arabidopsis, in which the epigenetic marks vary between strains although the DNA sequence is almost identical. …

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Ranking disease-causal mutations within whole genome sequences

Researchers from the University of Washington and the HudsonAlpha Institute for Biotechnology have developed a new method for organizing and prioritizing genetic data. The Combined Annotation-Dependent Depletion, or CADD, method will assist scientists in their search for disease-causing mutation events in human genomes.The new method is the subject of a paper titled “A general framework for estimating the relative pathogenicity of human genetic variants,” published in Nature Genetics.Current methods of organizing human genetic variation look at just one or a few factors and use only a small subset of the information available. For example, the Encyclopedia Of DNA Elements, or ENCODE, catalogs various types of functional elements in human genomes, while sequence conservation looks for similar or identical sequences that have survived across different species through hundreds of millions of years of evolution. CADD brings all of these data together, and more, into one score in order to provide a ranking that helps researchers discern which variants may be linked to disease and which ones may not.”CADD will substantially improve our ability to identify disease-causal mutations, will continue to get better as genomic databases grow, and is an important analytical advance needed to better exploit the information content of whole-genome sequences in both clinical and research settings,” said Gregory M. Cooper, Ph.D., faculty investigator at HudsonAlpha and one of the collaborators on CADD.The goal in developing the new approach was to take the overwhelming amount of data available and distill it down into a single score that can be more easily evaluated by a researcher or clinician. To accomplish that, CADD compares and contrasts the properties of 15 million genetic variants separating humans from chimpanzees with 15 million simulated variants. Variants observed in humans have survived natural selection, which tends to remove harmful, disease-causing variants, while simulated variants are not exposed to selection. Thus, by comparing observed to simulated variants, CADD is able to identify those properties that make a variant harmful or disease-causing. C scores have been pre-computed for all 8.6 billion possible single nucleotide variants and are freely available for researchers.”We didn’t know what to expect,” Cooper said, “but we were pleasantly surprised that CADD was able not only to be applicable to mutations everywhere in the genome but in fact do a substantially better job in nearly every test that we performed than other metrics.”The CADD method is unique from other algorithms in that it assigns scores to mutations anywhere in human genomes, not just the less-than two percent that encode proteins (the “exome”). This unique attribute will be crucial as whole-genome sequencing becomes routine in both clinical and research settings.Story Source:The above story is based on materials provided by HudsonAlpha Institute for Biotechnology. …

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Horse gaits controlled by genetic mutation spread by humans

From the Faroe Pony to the Spanish Mustang, fewer animals have played such a central role in human history as the horse. New research in Animal Genetics reveals that a horse’s gait, an attribute central to its importance to humans, is influenced by a genetic mutation, spread by humans across the world.The team, led by Dr. Leif Andersson from the Swedish University of Agricultural Sciences, explored the distribution of a mutation in the DMRT3 gene which affects the gait of horses, known as the ‘gait keeper.'”All over the world, horses have been used for everyday transportation, in military settings, cattle herding and agricultural power, pulling carriages and carts, pleasure riding or racing,” said Dr. Andersson. “Over the centuries, horse populations and breeds have been shaped by humans based on the different purposes for which the animals were used.”The DMRT3 gene is central to the utility of horses to humans, as it controls a range of gaits as well as pace. From racing to pleasure riding, many species have been bred to encourage smoothness of gait.”For example, the Paso Fino is a breed from Latin America in which the frequency of the ‘gait keeper’ mutation is nearly 100%. It is claimed that the Paso Fino gait is so smooth that you can have a glass of wine in your hand without letting it spill,” said Dr. Andersson.The team analyzed 4,396 horses from 141 breeds around the world and found that the ‘gait keeper’ mutation is spread across Eurasia from Japan in the East, to the British Isles in West, on Iceland, in both South and North America, and also in breeds from South Africa.”Humans have spread this mutation across the world primarily because horses carrying this mutation are able to provide a very smooth ride, in some breeds referred to as a running walk,” said Dr. Andersson. “During such ambling gaits the horse has at least one foot on the ground that means that the vertical movement of the rider is minimal.”Story Source:The above story is based on materials provided by Wiley. …

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Childhood depression may increase risk of heart disease by teen years

Children with depression are more likely to be obese, smoke and be inactive, and can show the effects of heart disease as early as their teen years, according to a newly published study by University of South Florida Associate Professor of Psychology Jonathan Rottenberg.The research, by Rottenberg and his colleagues at Washington University and the University of Pittsburgh, suggests that depression may increase the risk of heart problems later in life. The researchers also observed higher rates of heart disease in the parents of adolescents that had been depressed as children. The research is published online in Psychosomatic Medicineand will be included in the medical journal’s February 2014 issue.”Given that the parents in this sample were relatively young, we were quite surprised to find that the parents of the affected adolescents were reporting a history of heart attacks and other serious events,” Rottenberg explained.Cardiologists and mental health professionals have long known a link exists between depression and heart disease. Depressed adults are more likely to suffer a heart attack, and if they do have a heart attack, it’s more likely to be fatal.However it was unclear when the association between clinical depression and cardiac risk develops, or how early in life the association can be detected. These findings suggest improved prevention and treatment of childhood depression could reduce adult cardiovascular disease.Heart disease is the leading cause of death for men and women- accounting for one in every four deaths in the United States every year, according to the Centers for Disease Control and Prevention.During the study, Rottenberg and his colleagues followed up on Hungarian children who had participated in a 2004 study of the genetics of depression. The researchers compared heart disease risk factors — such as smoking, obesity, physical activity level, and parental history — across three categories of adolescents.The investigators surveyed more than 200 children with a history of clinical depression, as well as about 200 of their siblings who have never suffered from depression. They also gathered information from more than 150 unrelated children of the same age and gender with no history of depression.Rottenberg plans to conduct additional research in order to understand why depression early in life may put people at increased risk for cardiovascular disease. Further studies planned with the Hungarian group will also examine whether any early warning signs of heart disease are present as these adolescents move into young adulthood.Story Source:The above story is based on materials provided by University of South Florida (USF Health). The original article was written by Adam Freeman. Note: Materials may be edited for content and length.

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Researchers advance toward engineering ‘wildly new genome’

Oct. 17, 2013 — In two parallel projects, researchers have created new genomes inside the bacterium E. coli in ways that test the limits of genetic reprogramming and open new possibilities for increasing flexibility, productivity and safety in biotechnology.In one project, researchers created a novel genome — the first-ever entirely genomically recoded organism — by replacing all 321 instances of a specific “genetic three-letter word,” called a codon, throughout the organism’s entire genome with a word of supposedly identical meaning. The researchers then reintroduced a reprogramed version of the original word (with a new meaning, a new amino acid) into the bacteria, expanding the bacterium’s vocabulary and allowing it to produce proteins that do not normally occur in nature.In the second project, the researchers removed every occurrence of 13 different codons across 42 separate E. coli genes, using a different organism for each gene, and replaced them with other codons of the same function. When they were done, 24 percent of the DNA across the 42 targeted genes had been changed, yet the proteins the genes produced remained identical to those produced by the original genes.”The first project is saying that we can take one codon, completely remove it from the genome, then successfully reassign its function,” said Marc Lajoie, a Harvard Medical School graduate student in the lab of George Church. “For the second project we asked, ‘OK, we’ve changed this one codon, how many others can we change?'”Of the 13 codons chosen for the project, all could be changed.”That leaves open the possibility that we could potentially replace any or all of those 13 codons throughout the entire genome,” Lajoie said.The results of these two projects appear today in Science. The work was led by Church, Robert Winthrop Professor of Genetics at Harvard Medical School and founding core faculty member at the Wyss Institute for Biologically Inspired Engineering. Farren Isaacs, assistant professor of molecular, cellular, and developmental biology at Yale School of Medicine, is co-senior author on the first study.Toward safer, more productive, more versatile biotechRecoded genomes can confer protection against viruses — which limit productivity in the biotech industry — and help prevent the spread of potentially dangerous genetically engineered traits to wild organisms.”In science we talk a lot about the ‘what’ and the ‘how’ of things, but in this case, the ‘why’ is very important,” Church said, explaining how this project is part of an ongoing effort to improve the safety, productivity and flexibility of biotechnology.”These results might also open a whole new chemical toolbox for biotech production,” said Isaacs. “For example, adding durable polymers to a therapeutic molecule could allow it to function longer in the human bloodstream.”But to have such an impact, the researchers said, large swaths of the genome need to be changed all at once.”If we make a few changes that make the microbe a little more resistant to a virus, the virus is going to compensate. …

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In a surprise finding, gene mutation found linked to low-risk bladder cancer

Oct. 13, 2013 — An international research team led by scientists from Georgetown Lombardi Comprehensive Cancer Center has discovered a genetic mutation linked to low-risk bladder cancer. Their findings are reported online today in Nature Genetics.The investigators identified STAG2 as one of the most commonly mutated genes in bladder cancer, particularly in tumors that do not spread. The finding suggests that checking the status of the gene may help identify patients who might do unusually well following cancer treatment, says the study’s senior investigator, cancer geneticist Todd Waldman, MD, PhD, a professor of oncology at Georgetown Lombardi.”Most bladder cancers are superficial tumors that have not spread to other parts of the body, and can therefore be easily treated and cured. However, a small fraction of these superficial tumors will recur and metastasize even after treatment,” he says.Because clinicians have been unable to definitively identify those potentially lethal cancers, all bladder cancers patients — after surgery to remove tumors — must undergo frequent endoscopic examinations of their bladder to look for signs of recurrence, says Waldman. This procedure, called cystoscopy, can be uncomfortable and is expensive.”Our data show that STAG2 is one of the earliest initiating gene mutations in 30-40 percent of superficial or ‘papillary-type’ bladder tumors, and that these tumors are unlikely to recur,” says David Solomon, MD, PhD, a lead author on the study. Solomon is a graduate of the Georgetown MD/PhD program and is currently a pathology resident at the University of California, San Francisco.”We have developed a simple test for pathologists to easily assess the STAG2 status of these tumors, and are currently performing a larger study to determine if this test should enter routine clinical use for predicting the likelihood that a superficial bladder cancer will recur,” Solomon says.For the study, the researchers examined 2,214 human tumors from virtually all sites of the human body for STAG2 inactivation and found that STAG2 was most commonly inactivated in bladder cancer, the fifth most common human cancer. In follow up work, they found that 36 percent of low risk bladder cancers — those that never invaded the bladder muscle or progressed — had mutated STAG2. That suggests that testing the STAG2 status of the cancer could help guide clinical care, Waldman says. “A positive STAG2 mutation could mean that patient is at lower risk of recurrence.”The researchers also found that 16 percent of the bladder cancers that did spread, or metastasize, had mutated STAG2.STAG2 mutations have been found in a number of cancers, and this finding in bladder cancer adds new information, he says.

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Previously unstudied gene is essential for normal nerve development

Oct. 10, 2013 — Our ability to detect heat, touch, tickling and other sensations depends on our sensory nerves. Now, for the first time, researchers at Albert Einstein College of Medicine of Yeshiva University have identified a gene that orchestrates the crucially important branching of nerve fibers that occurs during development. The findings were published online today in the journal Cell.The research focuses on dendrites, the string-like extensions of sensory nerves that penetrate tissues of the skin, eyes and other sensory organs. “The formation of dendritic branches — ‘arbors’ as we call them — is vital for allowing sensory nerves to collect information and sample the environment appropriately,” said Hannes Buelow, Ph.D., senior author of the Cell paper and associate professor of genetics at Einstein. “These arbors vary greatly in shape and complexity, reflecting the different types of sensory input they receive. The loss of dendritic complexity has been linked to a range of neurological problems including Alzheimer’s disease, schizophrenia and autism spectrum disorders.” Dr. Buelow is also associate professor in the Dominick P. Purpura Department of Neuroscience.The Human Genome Project, completed in 2003, revealed that humans possess some 20,500 genes and determined the DNA sequence of each. But for many of those genes, their function in the body has remained unknown. …

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Genes linked to being right- or left-handed identified

Sep. 12, 2013 — A genetic study has identified a biological process that influences whether we are right handed or left handed.Scientists at the Universities of Oxford, St Andrews, Bristol and the Max Plank Institute in Nijmegen, the Netherlands, found correlations between handedness and a network of genes involved in establishing left-right asymmetry in developing embryos.’The genes are involved in the biological process through which an early embryo moves on from being a round ball of cells and becomes a growing organism with an established left and right side,’ explained first author William Brandler, a PhD student in the MRC Functional Genomics Unit at Oxford University.The researchers suggest that the genes may also help establish left-right differences in the brain, which in turn influences handedness.They report their findings in the open-access journal PLOS Genetics.Humans are the only species to show such a strong bias in handedness, with around 90% of people being right-handed. The cause of this bias remains largely a mystery.The researchers, led by Dr Silvia Paracchini at the University of St Andrews, were interested in understanding which genes might have an influence on handedness, in order to gain an insight into the causes and evolution of handedness.The team carried out a genome-wide association study to identify any common gene variants that might correlate with which hand people prefer using.The most strongly associated, statistically significant variant with handedness is located in the gene PCSK6, which is involved in the early establishment of left and right in the growing embryo.The researchers then made full use of knowledge from previous studies of what PCSK6 and similar genes do in mice to reveal more about the biological processes involved.Disrupting PCSK6 in mice causes ‘left-right asymmetry’ defects, such as abnormal positioning of organs in the body. They might have a heart and stomach on the right and their liver on the left, for example.The researchers found that variants in other genes known to cause left-right defects when disrupted in mice were more likely to be associated with relative hand skill than you would expect by chance.While the team has identified a role for genes involved in establishing left from right in embryo development, William Brandler cautioned that these results do not completely explain the variation in handedness seen among humans. He said: ‘As with all aspects of human behaviour, nature and nurture go hand-in-hand. The development of handedness derives from a mixture of genes, environment, and cultural pressure to conform to right-handedness.’

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Early-onset Parkinson’s disease linked to genetic deletion

Sep. 9, 2013 — Scientists at the Centre for Addiction and Mental Health (CAMH) and University Health Network (UHN) have found a new link between early-onset Parkinson’s disease and a piece of DNA missing from chromosome 22. The findings help shed new light on the molecular changes that lead to Parkinson’s disease.The study appears online today in JAMA Neurology.Among people aged 35 to 64 who were missing DNA from a specific part of chromosome 22, the research team found a marked increase in the number of cases of Parkinson’s disease, compared to expected rates of Parkinson’s disease in the general population from the same age group.The deletion, which occurs when a person is born with about 50 genes missing on one chromosome 22, is associated with 22q11.2 deletion syndrome. People with this condition may have heart or other birth defects, learning or speech difficulties, and some develop schizophrenia. It occurs in an estimated 1 in 2,000 to 4,000 births, but is believed to be under-diagnosed.”22q11.2 deletion syndrome has been fairly well studied in childhood and adolescence, but less is known about its effects as people age,” said Dr. Anne Bassett, Director of CAMH’s Clinical Genetics Research Program and Director of the Dalglish Family Hearts and Minds Clinic at UHN, the world’s first clinic dedicated to adults with 22q11.2 deletion syndrome. A few cases of patients with the syndrome who had Parkinson’s disease symptoms had been previously reported, which suggested that the two conditions might be linked.Parkinson’s disease is one of the most common neurodegenerative disorders worldwide, typically affecting people over the age of 65. Earlier onset of Parkinson’s disease, before age 50, is rare and has been associated with several other genetic changes that are not on chromosome 22.The researchers studied 159 adults with 22q11.2 deletion syndrome to discover how many had been clinically diagnosed with Parkinson’s disease. For three individuals with the deletion and Parkinson’s disease who were deceased, brain tissue was also examined.”Through a post-mortem examination, we were able to show that all three patients had a loss of neurons that was typical of that seen in Parkinson’s disease. The examination also helped to show that the symptoms of Parkinson’s disease were not related to side effects of the medications commonly used to treat schizophrenia,” added Dr.Rasmus Kiehl, neuropathologist in UHN’s Laboratory Medicine Program, who co-authored the report with CAMH graduate student Nancy Butcher. …

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Genetic cause of childhood leukemia identified

Sep. 8, 2013 — For the first time, a genetic link specific to risk of childhood leukemia has been identified, according to a team of researchers from Memorial Sloan-Kettering Cancer Center, St. Jude Children’s Research Hospital, University of Washington, and other institutions. The discovery was reported online today in the journal Nature Genetics.”We’re in uncharted territory,” said study author Kenneth Offit, MD, MPH, Chief of the Clinical Genetics Service at Memorial Sloan-Kettering. “At the very least this discovery gives us a new window into inherited causes of childhood leukemia. More immediately, testing for this mutation may allow affected families to prevent leukemia in future generations.”The mutation was first observed in a family treated at Memorial Sloan-Kettering of which several family members of different generations had been diagnosed with childhood acute lymphoblastic leukemia (ALL). A second, non-related, leukemia-prone family cared for at a different hospital was later found to have the same mutation. A series of experiments were conducted confirming that the observed mutation compromised the normal function of the gene, which may increase the risk of developing ALL.The inherited genetic mutation is located in a gene called PAX5, which is known to play a role in the development of some B cell cancers, including ALL. PAX5, a transcription factor or “master gene,” regulates the activity of several other genes and is essential for maintaining the identity and function of B cells. In all study participants, one of the two copies of the PAX5 gene was missing, leaving only the mutated version. …

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Multiple mutations often needed to make TB bacteria drug resistant

Sep. 1, 2013 — Tuberculosis (TB) drug resistance is not an all-or-none phenomenon, according to new research from Rutgers, The State University of New Jersey. Rather, TB-causing bacteria often accumulate mutations in a step-wise fashion, with the initial mutation having minimal impact but poising the bug to later develop high-level resistance upon acquisition of other mutations. The study appears in Nature Genetics .Share This:The anti-TB drug ethambutol blocks bacterial genes required for synthesis of the bug’s protective cell wall. Several mutations in these bacterial genes (collectively called the embCAB operon) have been identified in drug-resistant strains of TB, and single mutations are widely thought to confer resistance in one fell swoop. But not all bugs carrying embCAB mutations become ethambutol-resistant and not all resistance strains contain these mutations, suggesting that the story is much more complicated.David Alland, director of the Center for Emerging and Re-Emerging Pathogens at Rutgers New Jersey Medical School, and colleagues had previously shown expressing single embCAB mutations in drug sensitive bugs rendered them only slightly more drug resistant than normal and failed to explain full-blown resistance. The group now identifies new mutations that contribute to drug resistance, with the level of resistance depending on the unique combination of mutations in a given bacterial isolate.One of the newly identified mutations — in a bacterial gene called Rv3806c — ramps up production of a substrate used by the embCAB-encoded enzymes to generate the bug’s cell wall. This excess substrate then binds to the enzymes, potentially limiting the amount of drug that can bind. However, the Rv3806c mutation alone only modestly increased drug resistance. But when combined with other mutations, it generated high-level ethambutol resistance. …

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Potential molecular defense against Huntington’s disease

Aug. 25, 2013 — Leicester geneticists have discovered a potential defence against Huntington’s disease — a fatal neurodegenerative disorder which currently has no cure.The team of University of Leicester researchers identified that glutathione peroxidase activity — a key antioxidant in cells — protects against symptoms of the disease in model organisms.They hope that the enzyme activity — whose protective ability was initially observed in model organisms such as yeast — can be further developed and eventually used to treat people with the genetically-inherited disease.The disease affects around 12 people per 100,000.Their paper, Glutathione peroxidase activity is neuroprotective in models of Huntington’s disease, was published in Nature Genetics on 25 August.A team of experts from the University’s Department of Genetics carried out research for more than six years to identify new potential drug targets for the disease.They used model systems, such as baker’s yeast, fruit flies, and cultured mammalian cells to help uncover potential mechanisms underlying disease at the cellular level.They initially screened a genome-wide collection of yeast genes and found several candidates which protected against Huntington’s related symptoms in yeast. They then validated their findings in fruit flies and mammalian cells.They found that glutathione peroxidase activity is robustly protective in these models of Huntington’s disease.Importantly, there are drug-like compounds available that mimic this activity that have already been tested in human clinical trials for other disorders — which potentially means the approach could be used to treat people with the disease.The team now aim to further validate the observations regarding glutathione peroxidase activity, in order to understand whether this could have therapeutic relevance for Huntington’s.In addition, they have identified many additional genes that are protective — and aim to further explore these to see if there are any additional therapeutic possibilities suggested by their research.Dr Flaviano Giorgini, Reader in Neurogenetics of the University’s Department of Genetics and senior author of the paper, said: “We are taking advantage of genetic approaches in simple model organisms in order to better understand Huntington’s disease, with the aim of uncovering novel ways to treat this devastating disorder.”It appears that glutathione peroxidase activity is a robustly protective antioxidant approach which may have relevance for Huntington’s disease.”Dr Robert Mason, Research Associate in the Department of Genetics, and first author of the study, said: “In addition to glutathione peroxidase, this study has identified many genes that improve Huntington’s ‘symptoms’ in yeast. These genes provide valuable information on the underlying mechanisms leading to Huntington’s, and further study will likely uncover additional approaches that could be beneficial in treating this terrible disease.”Dr Giorgini stated: “We are excited by the work because it uncovers a potential new route for therapeutics in Huntington’s disease. I am also proud that all of this work has been conducted at the Department of Genetics at the University of Leicester.”The study was performed in collaboration with Prof Charalambos Kyriacou, also of the Department of Genetics at Leicester. Massimiliano Casu, Nicola Butler, Dr Carlo Breda, Dr Susanna Campesan, Dr Jannine Clapp, Dr Edward Green and Devyani Dhulkhed also contributed to the research study.The research was primarily funded by CHDI Foundation and the Huntington’s Disease Association.

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New tool enhances the search for genetic mutations

Aug. 25, 2013 — Concealed within the vastness of the human genome, (composed of some 3 billion base pairs), mutations are commonplace. While the majority of these appear to have neutral effect on human health, many others are associated with diseases and disease susceptibility.Reed Cartwright, a researcher at Arizona State University’s Biodesign Institute, along with colleagues at ASU, Washington University and the Wellcome Trust Sanger Institute, Cambridge, UK, report on a new software tool known as DeNovoGear, which uses statistical probabilities to help identify mutations and more accurately pinpoint their source and their possible significance for health.Improvements in the accuracy of mutation identification and validation could have a profound impact on the diagnosis and treatment of mutation-related diseases.”These techniques are being considered in two different realms,” Cartwright says. “The first is for pediatric diseases.” Here, a child with an unusual genetic disease may undergo genomic sequencing to see if the mutations observed have been acquired from the parents or are instead, unique to the child. “We can identify these mutations and try to detect which gene may be broken,” he says.The second application is for cancer research, where tumor tissues are genetically compared with normal tissue. Many now believe that the identification of a specific cancer mutation may eventually permit clinicians to customize a treatment for that tissue type. “We are developing methods to allow researchers to make those types of analyses, using advanced, probabilistic methods,” Cartwright says. “We actually model the whole process.”Indeed, the method described provides the first model-based approach for ferreting out certain types of mutations. The group’s research results appear in today’s issue of the journal Nature Methods.One of the primary goals in genetics is to accurately characterize genetic variation and the rate at which it occurs. Searching for DNA mutations through genetic sequencing is an important ingredient in this quest, but many challenges exist. …

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