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13 Gene Regions Newly Associated with Coronary Atherosclerosis in Massive Study

Thirteen new gene regions have been convincingly associated with coronary atherosclerosis in a massive, new, international genetics study involving investigators from the Stanford University School of Medicine and researchers from other major institutions around the world. The results of the study, published online March 6 in Nature Genetics, provide 13 vital new clues on the etiology of this disease, the most common cause of death worldwide. The study doubles the number of gene regions previously known to predispose people to this condition. Coronary atherosclerosis is the process by which plaque builds up in the wall of heart vessels, eventually leading to chest pain and potentially lethal heart attacks. The study was conducted by an international consortium, which pooled resources to analyze data from 14 genome-wide association studies. Consortium investigators examined the complete genetic profiles of more than 22,000 people of European descent with coronary heart disease or a heart attack history and 60,000 healthy people — close to 10 times more than the next-largest whole-genome study to date. "These new discoveries will allow scientists worldwide to eventually better understand the root causes of coronary atherosclerosis, possibly leading to important new drug therapies that may profoundly reduce the risk of having a heart attack," said Dr. Thomas Quertermous, the William G. Irwin Professor in Cardiovascular Medicine at Stanford. Dr. Quertermous is the principal investigator of the Stanford/Kaiser ADVANCE study of heart disease, which joined this consortium early in its formation. Investigators were able to examine an average of 2.5 million common single nucleotide polymorphisms, or SNPs, in each of the 14 genome-wide association studies. SNPs are genetic variants at specific locations on individual chromosomes.

Gene for Rare Osteoporosis Disorder Identified

Scientists have identified a single mutated gene that causes Hajdu-Cheney syndrome (HCS), a disorder of the bones causing progressive bone loss and osteoporosis. The study, published online in Nature Genetics on March 6, 2011, gives vital insight into possible causes of osteoporosis and highlights the identified gene (NOTCH2) as a potential target for treating the condition. There are only 50 reported cases of HCS, of which severe osteoporosis is a main feature. Osteoporosis is a condition leading to reduction in bone strength and susceptibility to fractures. It is the most common bone disease, with one in two women and one in five men over 50 in the UK fracturing a bone because of the condition. This represents a major public health problem yet, until this study, possible genetic causes of osteoporosis have been poorly understood. The team of researchers, led by the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre (BRC) at King's College London and Guy's and St Thomas', set out to investigate the genetic cause of HCS in order to detect clues to the role genes might play in triggering osteoporosis. Using a cutting edge technique for identifying disease-causing genes, known as exome sequencing, the team was able to identify NOTCH2 as the causative gene using DNA from just three unrelated HCS patients. The team then confirmed their findings in an additional 12 affected families, 11 of whom had an alteration in the identical portion of the same gene. Senior author Professor Richard Trembath, Head of King's College London's Division of Genetics and Molecular Medicine and Medicine Director of the NIHR BRC, said: "Up until now, we knew very little about the genetic mechanisms of severe bone disease.

Cryo-Microscope Allows High-Res 3-D Model of Salmonella’s Needle Complex

Some of the most dread diseases in the world such as plague, typhoid, and cholera are caused by bacteria that have one thing in common: they possess an infection apparatus which is a nearly unbeatable weapon. When attacking a cell of the body, they develop numerous hollow-needle-shaped structures that project from the bacterial surface. Through these needles, the bacteria inject signal substances into the host cells, which re-program these cells and thereby overcome their defense. The pathogens can then invade the cells unimpeded and in large numbers. The biochemist and biophysicist Dr. Thomas Marlovits, a group leader at the Vienna Institutes IMP (Research Institute of Molecular Pathology) and IMBA (Institute of Molecular Biotechnology) has been occupied for several years with the infection complex of salmonellae. As early as in 2006 Dr. Marlovits showed how the needle complex of Salmonella typhimurium develops. Together with his doctoral student Oliver Schraidt, he has now been able to demonstrate the three-dimensional structure of this complex at extremely high resolution. The team was able to show details with dimensions of just 5 to 6 angstroms, which are nearly atomic orders of magnitude. Their work is presented in the March 4, 2011 issue of Science. Never before has the infection tool of salmonellae been presented in such precision. This was achieved by the combined use of high-resolution cryo-electron microscopy and specially developed imaging software. "Austria's coolest microscope" makes it possible to shock-freeze biological samples at minus 196 degrees centigrade and view them in almost unchanged condition.

Novel Mechanism for Control of Gene Expression

Researchers at Boston University have discovered a novel, evolutionarily conserved mechanism for the regulation of gene expression. The new work by Dr. David Levin and Dr. Ki-Young Kim is reported in the March 4, 2011 issue of Cell. Normal cell growth, embryonic development, and responses to stress, require proper spatial and temporal control of gene expression. Studies on control of transcription (RNA biosynthesis) are typically centered on understanding how the RNA polymerase is recruited to the promoter, the control region of a gene. However, the new work has revealed the existence of a second level of control in a yeast model system. The researchers found that genes expressed solely under certain stress conditions are normally maintained in a silent state by a process called transcriptional attenuation. In attenuation, the RNA polymerase initiates transcription of the gene, but its progress is terminated prematurely by a termination complex that binds to the polymerase. Attenuation occurs commonly in bacteria, but was not previously known to operate in eukaryotic cells (those with a nucleus). “In response to an inducing stress signal, attenuation must be overcome so that a target gene can be expressed,” said Dr. Levin. “The way that works in this instance is that an activating transcription factor, called Mpk1, serves double duty—it is first responsible for recruitment of the RNA polymerase to the promoter, but Mpk1 then binds to the transcribing polymerase to block association of the termination complex.” Mutations in a human protein, called Senataxin, which is related to a component of the yeast termination complex, are responsible for causing juvenile-onset forms of ALS and ataxia, two neuromuscular degenerative diseases. In their new research, Dr. Levin and Dr.

New Details on Key Protein in Lou Gehrig’s Disease

Amyotrophic lateral sclerosis, known as ALS or more popularly, Lou Gehrig's disease, is a notorious neurodegenerative condition characterized by the progressive deterioration of brain and spinal cord neurons, resulting in the gradual but catastrophic loss of muscle control and ultimately, death. In a new paper, published in the Feb. 27 advance online edition of the journal Nature Neuroscience, a team of scientists at the University of California, San Diego School of Medicine and colleagues describe the profound and pervasive role of a key RNA-binding protein called TDP-43 in ALS pathology. It has previously been shown that, when mutated, TDP-43 can cause ALS. The new work on TDP-43 was led by Dr. Don W. Cleveland, professor and chair of the UCSD Department of Cellular and Molecular Medicine and head of the Laboratory of Cell Biology at the Ludwig Institute for Cancer Research and Dr. Gene Yeo, assistant professor in the Department of Cellular and Molecular Medicine. In normal cells, TDP-43 is found in the nucleus where it helps maintain proper levels of RNA. In the majority of ALS patients, however, TDP-43 accumulates in the cell's cytoplasm and thus is excluded from the nucleus, which prevents it from performing its normal duties. Using a mouse model, the researchers made three new important findings: First, employing a comprehensive genome-wide RNA-binding mapping strategy, they discovered that more than one-third of the genes in the mouse brain are direct targets of TDP-43. In other words, the roles and functions of these genes are impacted by the presence – or absence – of normal TDP-43. Second, the genes most affected had numerous TDP-43 binding sites on very long introns. Introns are the non-coding portions of a gene that are not used to make proteins.

Possible Liver Origin of Alzheimer’s Plaques

Unexpected results from a Scripps Research Institute and ModGene, LLC study could completely alter scientists' ideas about Alzheimer's disease—pointing to the liver instead of the brain as the source of the "amyloid" that deposits as brain plaques associated with this devastating condition. The findings could offer a relatively simple approach for Alzheimer's prevention and treatment. The study was published online on March 3, 2011, in The Journal of Neuroscience Research. In the study, the scientists used a mouse model for Alzheimer's disease to identify genes that influence the amount of amyloid that accumulates in the brain. They found three genes that protected mice from brain amyloid accumulation and deposition. For each gene, lower expression in the liver protected the mouse brain. One of the genes encodes presenilin—a cell membrane protein believed to contribute to the development of human Alzheimer's. "This unexpected finding holds promise for the development of new therapies to fight Alzheimer's," said Scripps Research Professor Greg Sutcliffe, who led the study. "This could greatly simplify the challenge of developing therapies and prevention." In trying to help solve the Alzheimer's puzzle, in the past few years Dr. Sutcliffe and his collaborators have focused their research on naturally occurring, inherited differences in neurological disease susceptibility among different mouse strains, creating extensive databases cataloging gene activity in different tissues, as measured by mRNA accumulation. These data offer up maps of trait expression that can be superimposed on maps of disease modifier genes. As is the case with nearly all scientific discovery, Dr. Sutcliffe's research builds on previous findings.

“David and Goliath” Viruses May Shed Light on Origin of Jumping Genes

University of British Columbia researchers have identified a small virus that attacks another virus more than 100 times its own size, rescuing the infected zooplankton from certain death. The discovery may provide clues to the evolutionary origin of some jumping genes found in other organisms. The study, by UBC marine microbiologist Dr. Curtis Suttle and Ph.D. student Matthias Fischer, was published online March 3, 2011, in Science Express. It describes the marine virus Mavirus and its interaction with marine zooplankton Cafeteria roenbergenesis and CroV, the world’s largest marine virus. “It’s a microbial version of the David and Goliah story where, after infecting Cafeteria roenbergeneis, Mavirus protects it against infection by CroV, while ensuring its own survival,” said Dr. Suttle. Viruses rely on host cells to replicate; in the case of Mavirus, its host is another virus, making it only the second known virophage. It needs CroV to replicate, and in the process suppresses the propagation of CroV. “What makes this interaction significant to evolutionary biology is that the closest genetic relatives to Mavirus are mobile genetic elements found in single-celled and higher organisms,” said Dr. Suttle. “This implies that over evolutionary time, organisms have co-opted the DNA from ancient relatives of Mavirus into their own genomes, presumably so that they could acquire immunity against giant viruses like CroV. Transposons, or jumping genes, are bits of DNA that can move or “transpose” themselves to new positions within an organism’s genome. Researchers have suspected that a subset of transposons – called Maverick transposons – have a viral origin because of the nature of their DNA sequences. Suttle and Fischer’s latest work on Mavirus provides the first concrete evidence of this connection.

Varying Enzyme Activity Enhances/Erases Long-Term Memories in Rats

Even long after it is formed, a memory in rats can be enhanced or erased by increasing or decreasing the activity of a particular brain enzyme, say researchers reporting in the March 4 issue of Science. "Our study is the first to demonstrate that, in the context of a functioning brain in a behaving animal, a single molecule, PKMzeta, is both necessary and sufficient for maintaining long-term memory," explained Dr. Todd Sacktor, of the SUNY Downstate Medical Center, New York City, an author of the study, which was partially funded by the NIH. Unlike other recently discovered approaches to memory enhancement, the PKMzeta mechanism appears to work any time. It is not dependent on exploiting time-limited windows when a memory becomes temporarily fragile and changeable – just after learning and upon retrieval – which may expire as a memory grows older, said Dr. Sacktor. "This pivotal mechanism could become a target for treatments to help manage debilitating emotional memories in anxiety disorders and for enhancing faltering memories in disorders of aging," said National Institute of Mental Health (NIMH) Director Dr. Thomas R. Insel, who was not involved in the study. In earlier studies, Dr. Sacktor's team had shown that even weeks after rats learned to associate a nauseating sensation with saccharin and shunned the sweet taste, their sweet tooth returned within a couple of hours after rats received a chemical that blocked the enzyme PKMzeta in the brain's outer mantle, or neocortex, where long-term memories are stored. In the new study, the researchers paired genetic engineering with the same aversive learning model to both confirm the earlier studies and to demonstrate, by increasing PKMzeta, the opposite effect.

DNA Testing Links Habitat Quality to Diet in Bats

New DNA testing technology has allowed scientists to compare the diets of bats consuming food from agricultural environments versus those of bats consuming food from conservation environments. The results indicate that bats feeding in agricultural environments have more restricted diets than do bats feeding in conservation environments. Working at three sites in Southern Ontario (Canada) the research team of students and scientists monitored the diet of little brown bats (Myotis lucifugus) from colonies living on agricultural land and at a conservation site. Guano (bat feces) was continually collected under each roost from May to August. Back in the lab at the Biodiversity Institute of Ontario in Canada, the team extracted insect DNA from the material and sequenced a "DNA barcode" which is a small region of DNA that can be used to identify animal species. The team then matched these unknown insect sequences in bat guano to a library of known sequences to identify which insect prey the bats were eating. "This technology is very new," said lead author Dr. Elizabeth Clare of the University of Bristol's School of Biological Sciences. "It gives us an entirely new insight into the bats' behavior. Instead of just finding they ate a moth or a mayfly, we now know exactly what species of insect it was, providing us with important information on their habitat." Using this technique, the team found that the bats rely heavily on insects from aquatic environments. They were also able to identify the exact species of insect prey, which revealed that different colonies exploit different source water, sometimes rivers and streams, sometimes ponds, depending on the local landscape. "Some of the insects they eat come from very specific habitats and have specific pollution tolerances.

Scientists Identify Genetic Susceptibility Factor for Bipolar Disorder

A genome-wide association study has revealed that genetic variation in the neurocan (NCAN) gene is significantly associated with bipolar disorder in thousands of patients. Importantly, in a follow-up study, these findings were replicated in tens of thousands of individual samples of bipolar disorder. The researchers went on to show that the mouse version of this gene, which is written Ncan and is thought to be involved in neuronal adhesion and migration, is strongly expressed in brain areas associated with cognition and the regulation of emotions. Although mice without functional Ncan did not exhibit obvious defects in brain structure or basic cell communication, there did appear to be some perturbation in mechanisms associated with learning and memory, mechanisms that have been associated with the cognitive deficits observed in bipolar disorder. However, the authors caution that Ncan-deficient mice need to be re-examined for more subtle brain changes and behavioral abnormalities. "Our results provide strong evidence that genetic variation in the gene NCAN is a common risk factor for bipolar disorder," concluded Dr. Sven Cichon of the University of Bonn, one of the leaders of the study. "Further work is needed now to learn more about the biological processes that NCAN is involved in and how NCAN variants disturb neuronal processes in patients with bipolar disorder." The NCAN work was published online on February 24, 2011, in the American Journal of Human Genetics. [Press release] [AJHG abstract]

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