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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New Capsicum annuum pepper contains high concentrations of beneficial capsinoids

Researchers have released a new Capsicum annuum pepper germplasm that contains high concentrations of capsinoids. The release was announced in the January 2014 issue of HortScience by researchers Robert L. Jarret from the USDA/Agricultural Research Service in Griffin, Georgia, in collaboration with Jason Bolton and L. Brian Perkins from the Department of Food Science and Human Nutrition at the University of Maine.According to the report, the germplasm called “509-45-1” is a small-fruited Capsicum annuum L. pepper. Fruit of 509-45-1 contain high concentrations of capsiate in both immature and mature fruit. “The release of 509-45-1 will provide researchers and plant breeders with a new source of capsinoids, thus facilitating the production of and further research on these non-pungent biologically active compounds,” Jarret said.Pungent capsaicinoids–the compounds found in the capsicum family of plants that give them their signature heat–have many benefits. Unfortunately, their use as ingredients in foods and pharmaceuticals has been limited by the very characteristic that makes them popular as a spice–their pungency. Non-pungent capsinoids, analogs of capsaicinoids, were first isolated from a sweet pepper cultivar. Capsinoids offer similar types of biological activity as capsaicinoids without the pungency, and are known to provide antioxidant activity, enhance adrenal function, promote metabolism, and suppress body fat accumulation.The scientists began the breeding process in 2005 by screening 120 Capsicum annuum cultivars for the occurrence of capsinoids. …

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Can vitamin A turn back the clock on breast cancer?

A derivative of vitamin A, known as retinoic acid, found abundantly in sweet potato and carrots, helps turn pre-cancer cells back to normal healthy breast cells, according to research published this month in the International Journal of Oncology. The research could help explain why some clinical studies have been unable to see a benefit of vitamin A on cancer: the vitamin doesn’t appear to change the course of full-blown cancer, only pre-cancerous cells, and only works at a very narrow dose.Because cells undergo many changes before they become fully aggressive and metastatic, Sandra V. Fernandez, Ph.D., Assistant Research Professor of Medical Oncology at Thomas Jefferson University, and colleagues, used a model of breast cancer progression composed of four types of cells each one representing a different stage of breast cancer: normal, pre-cancerous, cancerous and a fully aggressive model.When the researchers exposed the four breast cell types to different concentrations of retinoic acid – one of the chemicals that the body converts vitamin A into – they noticed a strong change in the pre-cancerous cells. Not only did the pre-cancerous cells begin to look more like normal cells in terms of their shape, they also changed their genetic signature back to normal. Dr. Fernandez’s pre-cancerous cells had 443 genes that were either up or downregulated on their way to becoming cancerous. All of these genes returned to normal levels after treatment with retinoic acid. “It looks like retinoic acid exerts effects on cancer cells in part via the modulation of the epigenome,” says Fernandez.“We were able to see this effect of retinoic acid because we were looking at four distinct stages of breast cancer,” says Dr. Fernandez. “It will be interesting to see if these results can be applied to patients.”Interestingly, the cells that were considered fully cancerous did not respond at all to retinoic acid, suggesting that there may be a small window of opportunity for retinoic acid to be helpful in preventing cancer progression. …

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New approach to leukemia testing may better define prognosis, treatment

Nearly half of patients with the most common form of adult leukemia are said to have normal chromosomes but appear instead to have a distinct pattern of genetic abnormalities that could better define their prognosis and treatment, researchers report.Using microarray technology that probes millions of genes within chromosomes, researchers found the unique pattern in the leukemia cells of 22 patients diagnosed with cytogenetically normal acute myelogenous leukemia, said Dr. Ravindra Kolhe, molecular pathologist at the Medical College of Georgia at Georgia Regents University.”This is a total game changer,” Kolhe said. “We have to use more sensitive tests to give patients the proper answer.”Kolhe, Director of the Georgia Esoteric, Molecular Labs, LLC, Department of Pathology, presented the findings March 29 during the American College of Medical Genetics and Genomics Annual Clinical Genetics Meeting in Nashville.Acute myelogenous leukemia, the most common type of acute leukemia in adults, has about 20 subtypes, according to the National Cancer Institute. Patients with cytogenetically normal acute myelogenous leukemia experience widely varying outcomes following chemotherapy and bone marrow transplants. Ideally, identifying the causative genes will lead to a more targeted therapy and definitive prognosis, Kolhe said.”The technology we currently use can’t identify specifically what’s wrong,” Kolhe said. Patients have high percentages of cancer-producing cells called blasts in their blood and bone marrow but they do not show the distinctive chromosomal alterations that typically help characterize the leukemia and strategize therapy.Genetic abnormalities, inherited and/or caused by environmental exposures — including previous chemotherapy and radiation treatment — are thought to cause leukemia. The result is that a disproportionate number of stem cells get stuck in the blast, or cancerous, stage, rather than maturing to white blood cells that actually fight cancer and other invaders.Patients often feel tired and feverish and blood tests reveal high blast levels. Pathologists then take about 20 leukemia cells, chemically block their constant division, open the nucleus, and spread the chromosomes on a slide. They examine the chromosomes with a microscope and in-situ hybridization technology, which helps detect small deletions or rearrangements.”(Cytogenetically normal patients) show a normal chromosomal picture but they are clearly sick,” Kolhe said. Frustrated at being unable to give these patients better information, he partnered with California-based Affymetrix to look directly at the genes within chromosomes using CytoScanHD microarray technology.When he put cell contents instead on a computer chip with 2.7 million genetic probes, small, previously undetectable changes in the DNA became apparent in patients who had been classified as cytogenetically normal. …

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Cultural hitchhiking: How social behavior can affect genetic makeup in dolphins

A UNSW-led team of researchers studying bottlenose dolphins that use sponges as tools has shown that social behaviour can shape the genetic makeup of an animal population in the wild.Some of the dolphins in Shark Bay in Western Australia put conical marine sponges on their rostrums (beaks) when they forage on the sea floor — a non-genetic skill that calves apparently learn from their mother.Lead author, Dr Anna Kopps, says sponging dolphins end up with some genetic similarities because the calves also inherit DNA from their mothers. As well, it is likely that sponging dolphins are descendants of a “sponging Eve,” a female dolphin that first developed the innovation.”Our research shows that social learning should be considered as a possible factor that shapes the genetic structure of a wild animal population,” says Dr Kopps.”It is one of the first studies to show this effect — which is called cultural hitchhiking — in animals other than people.”The study is published in the journal Proceedings of the Royal Society B.Dr Kopps and her colleagues identified individual dolphins in western Shark Bay about 850 kilometres north of Perth. They observed them from a boat as they foraged for food, travelled around the bay, rested, and played with other dolphins.Genetic samples were also taken, and analysed for mitochondrial DNA type, which is only inherited from the mother.It was found that the dolphins that lived in shallow waters, where sponges do not grow, mainly fell into a genetic group called Haplotype H.The dolphins living in deep waters, where sponges do grow, were predominantly Haplotype E or Haplotype F.”This striking geographic distribution of a genetic sequence cannot be explained by chance,” says Dr Kopps, who carried out the research while at UNSW and is now at the University of Groningen.As well, the DNA results from 22 dolphins that both lived in deep water and used sponges as tools showed they were all Haplotype E.”For humans we have known for a long time that culture is an important factor in shaping our genetics. Now we have shown for the first time that a socially transmitted behaviour like tool use can also lead to different genetic characteristics within a single animal population, depending on which habitat they live in,” she says.The team includes UNSW’s Professor Bill Sherwin and researchers from the University of Zurich and Murdoch University.Story Source:The above story is based on materials provided by University of New South Wales. Note: Materials may be edited for content and length.

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Link between missing DNA, birth defects confirmed

In 2010, scientists in Italy reported that a woman and her daughter showed a puzzling array of disabilities, including epilepsy and cleft palate. The mother had previously lost a 15-day-old son to respiratory failure, and the research team noted that the mother and daughter were missing a large chunk of DNA on their X chromosome. But the researchers were unable to definitively show that the problems were tied to that genetic deletion.Now a team from the University of Pennsylvania and The Children’s Hospital of Philadelphia has confirmed that those patients’ ailments resulted from the genetic anomaly. Creating mice that lacked the same region of DNA, the Penn and CHOP researchers showed that these animals suffered the same problems that afflicted the mother, daughter and son — cleft palate, epilepsy and respiratory difficulties, a condition called human Xq22.1 deletion syndrome. And, by clarifying the syndrome’s genetic basis, the researchers have laid the foundation for identifying the underlying molecular mechanism of these troubles and potentially treating them at their biological root.”This study has demonstrated that deleting this region in mice causes them to respond like humans with the same deletion,” said P. Jeremy Wang, senior author on the study and professor in the Penn School of Veterinary Medicine’s Department of Animal Biology. “Now that we have a mouse model, we can dissect and try to genetically pinpoint which genes are responsible.”Wang co-led the study with his postdoctoral researcher Jian Zhou. Additional coauthors included Penn Vet’s N. Adrian Leu and CHOP’s Ethan Goldberg, Lei Zhou and Douglas Coulter.The study appears in the journal Human Molecular Genetics.To investigate the effects of missing this portion of DNA, more than 1 million base pairs long, the Penn team crossed existing mice that had particular deletions in their DNA to create a mouse that lacked the entire stretch that the human patients were missing. They quickly observed that all male mice died at birth due to respiratory failure. …

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Free online software helps speed up genetic discoveries

Microarray analysis — a complex technology commonly used in many applications such as discovering genes, disease diagnosis, drug development and toxicological research — has just become easier and more user-friendly. A new advanced software program called Eureka-DMA provides a cost-free, graphical interface that allows bioinformaticians and bench-biologists alike to initiate analyses, and to investigate the data produced by microarrays. The program was developed by Ph.D. student Sagi Abelson of the Rappaport Faculty of Medicine at the Technion-Israel Institute of Technology in Haifa, Israel.DNA microarray analysis, a high-speed method by which the expression of thousands of genes can be analyzed simultaneously, was invented in the late 1980s and developed in the 1990s. Genetic researchers used a glass slide with tiny dots of copies of DNA to test match genes they were trying to identify. Because the array of dots was so small, it was called a “microarray.” There is a strong correlation between the field of molecular biology and medical research, and microarray technology is used routinely in the area of cancer research and other epidemiology studies. Many research groups apply it to detect genetic variations between biological samples and information about aberrant gene expression levels can be used in what is called “personalized medicine.” This includes customized approaches to medical care, including finding new drugs for gene targets where diseases have genetic causes and potential cures are based on an individual’s aberrant gene’s signal.An article written by Abelson published in the current issue of BMC Bioinformatics (2014,15:53) describes the new software tool and provides examples of its uses.”Eureka-DMA combines simplicity of operation and ease of data management with the rapid execution of multiple task analyses,” says Abelson. “This ability can help researchers who have less experience in bioinformatics to transform the high throughput data they generate into meaningful and understandable information.”Eureka-DMA has a distinct advantage over other software programs that only work “behind the scenes” and provide only a final output. It provides users with an understanding of how their actions influence the outcome throughout all the data elucidation steps, keeping them connected to the data, and enabling them to reach optimal conclusions.”It is very gratifying to see the insightful initiative of Sagi Abelson, a leading ‘out-of-the-box’ thoughtful Technion doctorate student whom I have had the privilege of supervising,” said Prof. Karl Skorecki, the Director of the Rappaport Family Institute for Research in the Medical Sciences at the Technion Faculty of Medicine and Director of Medical and Research Development at the Rambam Health Care Campus. …

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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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Look back at US soybeans shows genetic improvement behind increased yields

Soybean improvement through plant breeding has been critical over the years for the success of the crop. In a new study that traces the genetic changes in varieties over the last 80 years of soybean breeding, researchers concluded that increases in yield gains and an increased rate of gains over the years are largely due to the continual release of greater-yielding cultivars by breeders.”This research in some ways looks back and informs us how soybean varieties have changed. It’s useful to document these traits and changes,” said Brian Diers, a University of Illinois plant breeder and researcher on the study. “We can show that we really have been successful at increasing yield.”But this study is also about the future of the soybean crop.”The study has actually created quite a lot of interest among soybean breeders because they want to understand what’s happened, and when we look at physiological traits, we can see what has been changed. This gives us clues about what traits we should focus on in breeding for future increases based what has been inadvertently changed over time as we have selected for yield,” he said.Diers and a multi-institutional team of researchers evaluated historic sets of 60 maturity group (MG) II, 59 MG III, and 49 MG IV soybean varieties, released from 1923 to 2008, in field trials conducted in 17 states and one Canadian province during 2010 to 2011.The experiments included plant introductions (PIs) and public cultivars obtained from the USDA Soybean Germplasm Collection housed at the National Soybean Research Center at the U of I, as well as from varieties provided by Monsanto, Pioneer, and Syngenta.In the process of documenting the genetic changes, the researchers observed an increase in yields over the past 80 years that is equivalent to one-third of a bushel per acre per year increase.Diers said that the researchers estimated that about two-thirds of the yield increases in farmer’s fields are due to new varieties that breeders have introduced with the other third due to other reasons such as improved agronomic practices.”When we compare old varieties to new varieties, the new varieties do yield much better than the old varieties. When we look at the data more closely, the yield increases have actually accelerated starting in the 1960s and 1970s. It’s different for each maturity group, but current yield increases are greater than they were earlier,” Diers said.This research also showed that when compared to old varieties, plants in the new varieties are shorter in height, mature later, lodge less, and have seeds with less protein and greater oil concentration.”The new varieties tend to mature later within these maturity groups, which is something that theoretically shouldn’t happen because we classify these varieties based on when they mature. So theoretically MG II varieties should mature at the same time now as one back in the 1970s, but this is not the case,” Diers said. “Probably over time, people have been selecting varieties that are a little bit later and later, and these changes have accumulated. In some ways, it’s not a bad thing, because farmers are planting earlier than they did back in the 1970s so they actually need varieties that will mature later than back then. …

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Team models photosynthesis, finds room for improvement

Teaching crop plants to concentrate carbon dioxide in their leaves could increase photosynthetic efficiency by 60 percent and yields by as much as 40 percent, researchers report in a new study.The team used a computer model to simulate how adding genes from a type of photosynthetic algae known as cyanobacteria might influence photosynthetic efficiency in plants. Cyanobacteria contain small structures, called carboxysomes, which concentrate carbon dioxide at the site of photosynthesis.”Photosynthesis is the most studied of all plant processes, so we really know this in great detail and can represent it well in silico,” said University of Illinois plant biology professor Stephen Long, who led the study with postdoctoral researcher Justin McGrath. “We’ve modeled the whole system, and added all the components in a cyanobacterial system one at a time to our computer simulation to see if they give us an advantage.”The team found that some of the carboxysome genes hindered, while others greatly enhanced photosynthetic efficiency in crop plants such as soybean, rice and cassava. For example, adding a gene for a bicarbonate transporter, which carries carbon dioxide across the carboxysome membrane, enhances photosynthesis by 6 percent, Long said.”And if we put in about eight components of the carboxysome system, the model says that we could get a 60 percent increase in photosynthesis,” he said.The new findings appear in the journal Plant Physiology.Modeling photosynthesis in crop plants has proven to be an efficient way to determine which kinds of genetic manipulations will be most fruitful, Long said. This prevents a lot of wasted time and money spent trying things in the laboratory that are doomed to fail.The work is very exciting, but will take many years to implement, Long said. “It will take about five years before we have our first test of concept in a model plant. And then, even if everything goes (according) to plan, it might be 15 or 20 years before we see this in any crop,” he said.”The United Nations Food and Agricultural Organization predicts that we’re going to need about 70 percent more primary foodstuffs by the middle of this century,” Long said. “So obviously new innovations like this are needed to try and get there, especially since the approaches of the Green Revolution are now approaching their biological limits.”Story Source:The above story is based on materials provided by University of Illinois at Urbana-Champaign. Note: Materials may be edited for content and length.

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Trigger found for most common form of intellectual disability, autism

A new study led by Weill Cornell Medical College scientists shows that the most common genetic form of mental retardation and autism occurs because of a mechanism that shuts off the gene associated with the disease. The findings, published today in Science, also show that a drug that blocks this silencing mechanism can prevent fragile X syndrome — suggesting similar therapy is possible for 20 other diseases that range from mental retardation to multisystem failure.Fragile X syndrome occurs mostly in boys, causing intellectual disability as well as telltale physical, behavioral and emotional traits. While researchers have known for more than two decades that the culprit behind the disease is an unusual mutation characterized by the excess repetition of a particular segment of the genetic code, they weren’t sure why the presence of a large number of these repetitions — 200 or more — sets the disease process in motion.Using stem cells from donated human embryos that tested positive for fragile X syndrome, the scientists discovered that early on in fetal development, messenger RNA — a template for protein production — begins sticking itself onto the fragile X syndrome gene’s DNA. This binding appears to gum up the gene, making it inactive and unable to produce a protein crucial to the transmission of signals between brain cells.”Until 11 weeks of gestation, the fragile X syndrome gene is active — it produces its messenger RNA and protein normally. Then, all of a sudden it turns off, and stays off for the rest of the patient’s lifetime, causing fragile X syndrome. But scientists have not understood why this gene gets shut off,” says senior author Dr. Samie Jaffrey, a professor of pharmacology at Weill Cornell Medical College. “We discovered that the messenger RNA can jam up one strand of the gene’s DNA, shutting down the gene — which was not known before.”This is new biology — an interaction between the RNA and the DNA of the fragile X syndrome gene causes disease,” Dr. Jaffrey says. “We are coming to understand that RNAs are powerful molecules that can regulate gene expression, but this mechanism is completely novel — and very exciting.”The malfunction occurs suddenly — before the end of the first trimester in humans and after 50 days in laboratory embryonic stem cells. …

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Discovery may help to explain mystery of ‘missing’ genetic risk, susceptibility to common diseases

A new study could help to answer an important riddle in our understanding of genetics: why research to look for the genetic causes of common diseases has failed to explain more than a fraction of the heritable risk of developing them.Susceptibility to common diseases is believed to arise through a combination of many common genetic variants that individually slightly increase the risk of disease, plus a smaller number of rare mutations that often carry far greater risk.However, even when their effects are added together, the genetic variants so far linked to common diseases account for only a relatively small proportion of the risk we know is conveyed by genetics through studies of family history.But the major new study, published in the journal PLOS Genetics, shows for the first time in cancer that some common genetic variants could actually be indicators of the presence of much more influential rare mutations that have yet to be found.Scientists at The Institute of Cancer Research, London, led an international consortium made up of more than 25 leading academic institutions on the study, which was funded by the European Union.The research, involving 20,440 men with prostate cancer and 21,469 without the disease, identified a cluster of four common genetic variants on chromosome 17 that appeared to give rise to a small increase in prostate cancer risk, using the standard statistical techniques for this type of study.But the study found an alternative explanation for the risk signal — a small proportion of the men with these common variants were in fact carriers of a rare mutation in the nearby HOXB13 gene, which is known to be linked to prostate cancer. Under this ‘synthetic association’, the number of people carrying a cancer risk variant was much lower than had been assumed, but those people who did inherit a variant had a much higher risk of prostate cancer than had been realised.The discovery shows that the prevailing genetic theory — that common cancers are predominantly caused by the combined action of many common genetic variants, each with only a very small effect — could potentially underestimate the impact of rare, as yet undiscovered mutations.The results are important because they show that there is a need for renewed effort by geneticists to find the causal variants, whether common or rare, behind the many common cancer-associated variants identified in recent years.Identifying any underlying rare mutations with a big effect on disease risk could improve the genetic screening and clinical management of individuals at greater risk of developing cancer, as well as other diseases.Study co-leader Dr Zsofia Kote-Jarai, Senior Staff Scientist at The Institute of Cancer Research (ICR), said: “As far as we are aware, this is the first known example of a ‘synthetic association’ in cancer genetics. It was exciting to find evidence for this theory, which predicts that common genetic variants that appear to increase risk of disease by only a modest amount may indeed sometimes be detected purely due to their correlation with a rarer variant which confers a greater risk.”Our study does not imply how widespread this phenomenon may be, but it holds some important lessons for geneticists in cancer, and other common diseases. It demonstrates the importance of identifying the causal genetic changes behind the many common variants that have already been shown to influence risk of disease.”Our study also demonstrates that standard methods to identify potential causal variants when fine-mapping genetic associations with disease may be inadequate to assess the contribution of rare variants. Large sequencing studies may be necessary to answer these questions unequivocally.”Study co-leader Professor Ros Eeles, Professor of Oncogenetics at The Institute of Cancer Research and Honorary Clinical Consultant at The Royal Marsden NHS Foundation Trust, said: “One important unanswered question in cancer genetics — and in genetics of common disease more generally — is why the genetic mutations we’ve discovered so far each seem to have such a small effect, when studies of families have shown that our genetic make-up has a very large influence on our risk of cancer.”Our study is an important step forward in our understanding of where we might find this ‘missing’ genetic risk in cancer. At least in part, it might lie in rarer mutations which current research tools have struggled to find, because individually each does not affect a large number of people.”

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Understanding basic biology of bipolar disorder

Scientists know there is a strong genetic component to bipolar disorder, but they have had an extremely difficult time identifying the genes that cause it. So, in an effort to better understand the illness’s genetic causes, researchers at UCLA tried a new approach.Instead of only using a standard clinical interview to determine whether individuals met the criteria for a clinical diagnosis of bipolar disorder, the researchers combined the results from brain imaging, cognitive testing, and an array of temperament and behavior measures. Using the new method, UCLA investigators — working with collaborators from UC San Francisco, Colombia’s University of Antioquia and the University of Costa Rica — identified about 50 brain and behavioral measures that are both under strong genetic control and associated with bipolar disorder. Their discoveries could be a major step toward identifying the specific genes that contribute to the illness.The results are published in the Feb. 12 edition of the Journal JAMA Psychiatry.A severe mental illness that affects about 1 to 2 percent of the population, bipolar disorder causes unusual shifts in mood and energy, and it interferes with the ability to carry out everyday tasks. Those with the disorder can experience tremendous highs and extreme lows — to the point of not wanting to get out of bed when they’re feeling down. The genetic causes of bipolar disorder are highly complex and likely involve many different genes, said Carrie Bearden, a senior author of the study and an associate professor of psychiatry and psychology at the UCLA Semel Institute for Neuroscience and Human Behavior.”The field of psychiatric genetics has long struggled to find an effective approach to begin dissecting the genetic basis of bipolar disorder,” Bearden said. “This is an innovative approach to identifying genetically influenced brain and behavioral measures that are more closely tied to the underlying biology of bipolar disorder than the clinical symptoms alone are.”The researchers assessed 738 adults, 181 of whom have severe bipolar disorder. They used high-resolution 3-D images of the brain, questionnaires evaluating temperament and personality traits of individuals diagnosed with bipolar disorder and their non-bipolar relatives, and an extensive battery of cognitive tests assessing long-term memory, attention, inhibitory control and other neurocognitive abilities.Approximately 50 of these measures showed strong evidence of being influenced by genetics. Particularly interesting was the discovery that the thickness of the gray matter in the brain’s temporal and prefrontal regions — the structures that are critical for language and for higher-order cognitive functions like self-control and problem-solving — were the most promising candidate traits for genetic mapping, based on both their strong genetic basis and association with the disease.”These findings are really just the first step in getting us a little closer to the roots of bipolar disorder,” Bearden said. …

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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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Scientists identify gene linking brain structure to intelligence

For the first time, scientists at King’s College London have identified a gene linking the thickness of the grey matter in the brain to intelligence. The study is published today in Molecular Psychiatry and may help scientists understand biological mechanisms behind some forms of intellectual impairment.The researchers looked at the cerebral cortex, the outermost layer of the human brain. It is known as ‘grey matter’ and plays a key role in memory, attention, perceptual awareness, thought, language and consciousness. Previous studies have shown that the thickness of the cerebral cortex, or ‘cortical thickness’, closely correlates with intellectual ability, however no genes had yet been identified.An international team of scientists, led by King’s, analysed DNA samples and MRI scans from 1,583 healthy 14 year old teenagers, part of the IMAGEN cohort. The teenagers also underwent a series of tests to determine their verbal and non-verbal intelligence.Dr Sylvane Desrivires, from King’s College London’s Institute of Psychiatry and lead author of the study, said: “We wanted to find out how structural differences in the brain relate to differences in intellectual ability. The genetic variation we identified is linked to synaptic plasticity — how neurons communicate. This may help us understand what happens at a neuronal level in certain forms of intellectual impairments, where the ability of the neurons to communicate effectively is somehow compromised.”She adds: “It’s important to point out that intelligence is influenced by many genetic and environmental factors. The gene we identified only explains a tiny proportion of the differences in intellectual ability, so it’s by no means a ‘gene for intelligence’.”The researchers looked at over 54,000 genetic variants possibly involved in brain development. They found that, on average, teenagers carrying a particular gene variant had a thinner cortex in the left cerebral hemisphere, particularly in the frontal and temporal lobes, and performed less well on tests for intellectual ability. The genetic variation affects the expression of the NPTN gene, which encodes a protein acting at neuronal synapses and therefore affects how brain cells communicate.To confirm their findings, the researchers studied the NPTN gene in mouse and human brain cells. …

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Stroke trigger more deadly for African-Americans

Infection is a stronger trigger of stroke death in African- Americans than in whites, a University of Michigan study shows.African-Americans were 39 times more likely to die of a stroke if they were exposed to an infection in the previous month when compared to other time periods while whites were four times more likely and Hispanics were five times more likely to die of stroke after an infection, according to the findings that appear online Feb. 7 in Neurology.The most frequent infections were urinary, skin, and respiratory tract infections and occurred within 30 days of a stroke.”Infection before stroke appears to be most lethal for black Americans,” says lead author Deborah A. Levine, M.D., M.P.H., assistant professor of medicine in the division of general medicine in the U-M Medical School. “We know that African- Americans have a much greater risk of dying from a stroke than white Americans, and we wanted to know if infection — which research suggests is a stroke trigger — might contribute to this disparity.”Infection is believed to promote the formation of blood clots and fat buildup in arteries, which block the artery and stop the flow of blood to the brain causing a stroke.Racial disparities in stroke death continue to widen in the U.S. where blacks are twice as likely to die from stroke as whites. The new findings show that all ethnic and racial groups had a higher risk of stroke following an infection but there were significant disparities in subsequent stroke deaths.Infection appeared to be a trigger of stroke death in whites and Hispanics as well, but it was particularly potent in African-Americans.Infection also occurred more often before stroke death in black Americans, with 70 percent experiencing an infection in the 30 days before stroke death compared to a frequency of 15 percent in months that were not followed by a stroke death. Infection occurred less often before stroke death in white Americans, with 45 percent experiencing an infection in the month before stroke death compared to a frequency of 19 percent in months that were not followed by a stroke death.Although earlier studies suggested that respiratory infections are the most potent triggers of stroke, Levine and colleagues found that urinary tract infections and skin infections seemed to be just as strong of triggers.The study was based on data from the Health and Retirement Study, a nationally-representative sample of older Americans that is conducted by the U-M Institute for Social Research on behalf of the National Institute of Aging.”Because of the higher stroke mortality rate among black Americans, there has been much attention on racial differences in vascular risk factors, like hypertension, and health behaviors but less attention on acute exposures that might contribute to racial differences in stroke deaths,” Levine says.”It is unclear why acute infection is more common, more lethal, or a more powerful trigger for stroke death in black Americans. Genetic risks, clinical, economic or environmental factors, and differences in access to health care are potential reasons. We need further studies to better understand this disparity so we can prevent more black Americans from dying of stroke, particularly after infection,” Levine says.Story Source:The above story is based on materials provided by University of Michigan Health System. Note: Materials may be edited for content and length.

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Click chemistry could provide total chemical DNA synthesis, study shows

An interdisciplinary study led by Dr Ali Tavassoli, a Reader in chemical biology at the University of Southampton, has shown for the first time that ‘click chemistry’ can be used to assemble DNA that is functional in human cells, which paves the way for a purely chemical method for gene synthesis.Writing in Angewandte Chemie International Edition Dr Tavassoli’s team and his collaborators, Dr Jeremy Blaydes and Professor Tom Brown, show that human cells can still read through strands of DNA correctly despite being stitched together using a linker not found in nature.The artificially linked DNA was created by joining oligonucleotides using click chemistry — chemistry tailored to mimic nature which generates substances quickly and reliably by joining small units together.This click technique is highly efficient and boasts a number of advantages over the usual approaches to assembling DNA strands in the lab using a combination of DNA synthesis, PCR amplification and enzymatic ligation.”As chemists we always sought to synthesise long strands of DNA but have been limited by our assumption that the phosphodiester bond is necessary for DNA to function in cells,” says Dr Tavassoli. The DNA backbone is made up of pentose sugars and phosphate groups that stitch the nucleotides together using phosphodiester bonds. This backbone acts as the scaffold for the four bases that make up the genetic code.The click DNA approach relies on a rapid and efficient stitching together of modified DNA strands using the copper-catalysed alkyne-azide cycloaddition reaction. Click-linking DNA leaves behind a triazole group in the backbone and it was feared that cellular machinery would be unable to read these unnaturally joined DNA strands. The new study demonstrated error-free transcription in human cells, the first example of a non-natural DNA linker working correctly in eukaryotic cells.”This is important because it shows that we don’t have to stick to the phosphodiester backbone of the DNA at the site of DNA ligation,” Dr Tavassoli explains. “This suggests that we can replace the enzymatic methods for DNA assembly and DNA ligation with highly efficient chemical reactions.””This is a mind blowing advance that demonstrates chemistry’s power to manipulate nature’s nature,” comments Nobel laureate Barry Sharpless at the Scripps Research Institute, US, who first described the click chemistry process. “I only dreamed I’d get to see click chemistry do this in my lifetime. It is a marvellous achievement.”Story Source:The above story is based on materials provided by University of Southampton. Note: Materials may be edited for content and length.

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‘Severe reduction’ in killer whale numbers during last Ice Age

Whole genome sequencing has revealed a global fall in the numbers of killer whales during the last Ice Age, at a time when ocean productivity may have been widely reduced, according to researchers at Durham University. The scientists studied the DNA sequences of killer whale communities across the world.They found a severe decline in whale numbers leading to a bottleneck and consequent loss of genetic diversity approximately 40,000 years ago when large parts of Earth were covered in ice.The only exception to this was found in a killer whale population off the coast of South Africa that retained high variations in genetic diversity.As greater genetic diversity indicates larger population size, the researchers believe the South African community of killer whales escaped the bottleneck faced by other communities.They said an important factor could have been the Bengeula upwelling system — which delivers nutrient rich cold water to the oceans off South Africa — remaining stable despite the last glacial period.This nutrient rich water would have been able to sustain the supplies of fish and dolphins that killer whales in this part of the world feed on.The researchers added that other major upwelling systems around the world — the California current off North America; Humboldt off South America; and the Canary current off the coast of North Africa — were either disrupted or collapsed altogether during the last glacial or Pleistocene periods (40,000 to 2.5 million years ago).This could potentially have reduced the food supply to killer whales in these areas, leading to the fall in their numbers.Further research looking at the genetic diversity of the ocean’s other top predators, such as sharks, might potentially suggest a negative impact on their numbers too, the researchers suggested.Such a finding could support concerns about the potential impact changes in climate could have on ocean ecosystems in future, the researchers added.The reseach, funded by the Natural Environment Research Council in the UK, is published in the journal Molecular Biology and Evolution.During earlier glacial periods, killer whale populations were likely to have been stable in size, the researchers said.While it was likely that other factors affecting killer whale populations were “overlapping and complex,” the researchers ruled out hunting as an effect on the bottleneck in populations, as hunting by early man could not have happened on a sufficient enough scale to promote the global decline in killer whale numbers during that period.Corresponding author Professor Rus Hoelzel, in the School of Biological and Biomedical Sciences, said: “Killer whales have a broad world-wide distribution, rivalling that of humans. At the same time, they have very low levels of genetic diversity.”Our data suggest that a severe reduction in population size during the coldest period of the last ice age could help explain this low diversity, and that it could have been an event affecting populations around the world.”However, a global event is hard to explain, because regional modern-day killer whale populations seem quite isolated from each other. What could have affected multiple populations from around the world all at the same time?”The uniquely high levels of diversity we found for the population off South Africa suggest a possible explanation. These whales live in an environment that has been highly productive and stable for at least the last million years, while some data suggest that ocean productivity may have been reduced during the last glacial period elsewhere in the world.”If this is the case, then further research may suggest an impact on other ocean top predators during this time. It would also support concerns about the potential for climate disruptions to impact ocean ecosystems in future.”Story Source:The above story is based on materials provided by Durham University. Note: Materials may be edited for content and length.

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Pain sensitivity may be influenced by lifestyle, environment, twin study suggests

Researchers at King’s College London have discovered that sensitivity to pain could be altered by a person’s lifestyle and environment throughout their lifetime. The study is the first to find that pain sensitivity, previously thought to be relatively inflexible, can change as a result of genes being switched on or off by lifestyle and environmental factors — a process called epigenetics, which chemically alters the expression of genes.Published today in Nature Communications, the study has important implications for understanding pain sensitivity and could lead to new treatments aimed at ‘switching off’ certain genes epigenetically.Identical twins share 100 per cent of their genes, whereas non-identical twins share on average only half of the genes that vary between people. Therefore, any difference between identical twins must be due to their environment or epigenetic changes affecting the function of their genes, making them ideal participants for a study of this nature.To identify levels of sensitivity to pain, scientists tested 25 pairs of identical twins using a heat probe on the arm. Participants were asked to press a button when the heat became painful for them, which allowed the researchers to determine their pain thresholds. Using DNA sequencing, the researchers examined over five million epigenetic marks across the whole genome and compared them with a further 50 unrelated individuals to confirm their results.This is the first study to use large numbers of twins with such an in-depth examination of epigenetic signals.The research team found wide variations between people and identified chemical modifications within nine genes involved in pain sensitivity that were different in one twin but not in her identical sister.The chemical changes were most significant within a known pain sensitivity gene, TRPA1, already a therapeutic target in the development of painkillers (analgesics).This is the first time TRPA1 has shown the capacity to be switched on and off epigenetically; finding out how this happens could have major implications for tackling pain relief. It is well established that people who are most sensitive to pain encountered in everyday life are more likely to go on to develop chronic pain.Lead author of the study, Dr Jordana Bell, Department of Twin Research & Genetic Epidemiology at King’s College London, said: ‘The potential to epigenetically regulate the behaviour of TRPA1 and other genes involved in pain sensitivity is very exciting and could lead to a more effective pain relief treatment for patients suffering with chronic pain.’Tim Spector, Professor of Genetic Epidemiology at King’s College London, said: ‘Epigenetic switching is like a dimmer switch for gene expression. This landmark study shows how identical twins, when combined with the latest technology to look at millions of epigenetic signals, can be used to find the small chemical switches in our genes that make us all unique — and in this case respond to pain differently.’Story Source:The above story is based on materials provided by King’s College London. Note: Materials may be edited for content and length.

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