Posts tagged genomics
Posts tagged genomics
Researchers at Washington University School of Medicine in St. Louis have identified a new set of genetic markers for Alzheimer’s that point to a second pathway through which the disease develops.
Much of the genetic research on Alzheimer’s centers on amyloid-beta, a key component of brain plaques that build up in the brains of people with the disease.
In the new study, the scientists identified several genes linked to the tau protein, which is found in the tangles that develop in the brain as Alzheimer’s progresses and patients develop dementia. The findings may help provide targets for a different class of drugs that could be used for treatment.
The researchers report their findings online April 24 in the journal Neuron.
“We measured the tau protein in the cerebrospinal fluid and identified several genes that are related to high levels of tau and also affect risk for Alzheimer’s disease,” says senior investigator Alison M. Goate, DPhil, the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry. “As far as we’re aware, three of these genes have no effect on amyloid-beta, suggesting that they are operating through a completely different pathway.”
A fourth gene in the mix, APOE, had been identified long ago as a risk factor for Alzheimer’s. It has been linked to amyloid-beta, but in the new study, APOE appears to be connected to elevated levels of tau. Finding that APOE is influencing more than one pathway could help explain why the gene has such a big effect on Alzheimer’s disease risk, the researchers say.
“It appears APOE influences risk in more than one way,” says Goate, also a professor of genetics and co-director of the Hope Center for Neurological Disorders. “Some of the effects are mediated through amyloid-beta and others by tau. That suggests there are at least two ways in which the gene can influence our risk for Alzheimer’s disease.”
The new research by Goate and her colleagues is the largest genome-wide association study (GWAS) yet on tau in cerebrospinal fluid. The scientists analyzed points along the genomes of 1,269 individuals who had undergone spinal taps as part of ongoing Alzheimer’s research.
Whereas amyloid is known to collect in the brain and affect brain cells from the outside, the tau protein usually is stored inside cells. So tau usually moves into the spinal fluid when cells are damaged or die. Elevated tau has been linked to several forms of non-Alzheimer’s dementia, and first author Carlos Cruchaga, PhD, says that although amyloid plaques are a key feature of Alzheimer’s disease, it’s possible that excess tau has more to do with the dementia than plaques.
“We know there are some individuals with high levels of amyloid-beta who don’t develop Alzheimer’s disease,” says Cruchaga, an assistant professor of psychiatry. “We don’t know why that is, but perhaps it could be related to the fact that they don’t have elevated tau levels.”
In addition to APOE, the researchers found that a gene called GLIS3, and the genes TREM2 and TREML2 also affect both tau levels and Alzheimer’s risk.
Goate says she suspects changes in tau may be good predictors of advancing disease. As tau levels rise, she says people may be more likely to develop dementia. If drugs could be developed to target tau, they may prevent much of the neurodegeneration that characterizes Alzheimer’s disease and, in that way, help prevent or delay dementia.
The new research also suggests it may one day be possible to reduce Alzheimer’s risk by targeting both pathways.
“Since two mechanisms apparently exist, identifying potential drug targets along these pathways could be very useful,” she says. “If drugs that influence tau could be added to those that affect amyloid, we could potentially reduce risk through two different pathways.”
Children with autism have increased levels of genetic change in regions of the genome prone to DNA rearrangements, so called “hotspots,” according to a research discovery to be published in the print edition of the journal Human Molecular Genetics. The research indicates that these genetic changes come in the form of an excess of duplicated DNA segments in hotspot regions and may affect the chances that a child will develop autism — a behavioral disorder that affects about 1 of every 88 children in the United States, according to the Centers for Disease Control.
Earlier work had identified, in children with autism, a greater frequency of rare DNA deletions or duplications, known as DNA copy number changes. These rare and harmful events are found in approximately 5 to 10 percent of cases, raising the question as to what other genetic changes might contribute to the disorders known as autism spectrum disorders.
The new research shows that children with autism have — in addition to these rare events — an excess of duplicated DNA including more common variants not exclusively found in children with autism, but are found at elevated levels compared to typically developing children. The research collaboration includes groups led at Penn State by Scott Selleck; at the University of California Davis/MIND Institute by Isaac Pessah, Irva Hertz-Picciotto, Flora Tassone, and Robin Hansen; and at the University of Washington by Evan Eichler.
The investigators also found that the balance of DNA duplications and deletions in children with autism was different from that found in more severe developmental disorders, such as intellectual disability or multiple congenital anomalies, where the levels of both deletions and duplications are increased compared to controls, and are even higher than in children with autism.
They also found that children who had more difficulty with daily living skills also had the greatest level of copy number change throughout their genome. “These measures of adaptive behavior provide an indication of the severity of the impairment in the children with autism. These behaviors were significantly correlated with the amount of DNA copy number change,” Selleck said, emphasizing that the research revealed “clear and graded effects of the genetic change.”
“These results beg the question as to the origin of this genetic change,” Selleck said. “The increased levels of both rare and common variants suggests the possibility that these individuals are predisposed to genetic alteration.”
A vigorous debate is ongoing in the research community about the degree of genetic versus environmental contributions to autism. Selleck said the finding of an overall increase in genetic change in children with autism heightens the need to search for the basis of this variation. “We know that environmental factors can affect the stability of the genome, but we don’t know if the DNA copy number change we detect in these children is a result of environmental exposures, nutrition, medical factors, lifestyle, genetic susceptibility, or combinations of many elements together,” Selleck said. “The elevated levels of common variants is telling us something. It suggests that pure selection of randomly generated variants may not be the whole story.”
The Penn State team includes Department of Biochemistry and Molecular Biology Associate Professor Marylyn Ritchie and Assistant Professor Santhosh Girirajan. “The relationship between the level of copy number change and the degree of neurodevelopmental disability is something we have noted previously for large, rare variants” says Girirajan, “but this work extends those observations to common copy number variants, suggesting the level of copy number change in children with autism is larger than we had appreciated.” Girirajan, the first author of the study, coordinated the effort between the Penn State and University of Washington researchers.
Disorders characterized by expansion of an unstable nucleotide repeat account for a number of inherited neurological diseases. Here, we review examples of unstable repeat disorders that nicely illustrate three of the major pathogenic mechanisms associated with these diseases: loss of function typically by disrupting transcription of the mutated gene, RNA toxic gain of function, and protein toxic gain of function. In addition to providing insight into the mechanisms underlying these devastating neurological disorders, the study of these unstable microsatellite repeat disorders has provided insight into very basic aspects of neuroscience.
For the first time, an international team of researchers has found that a combination of a particular virus in the mother and a specific gene variant in the child increases the risk of the child developing schizophrenia.
Viruses and genes interact in a way that may increase the risk of developing schizophrenia significantly. This happens already in the developing foetus.
An international team of scientists led by Aarhus University, Denmark, has made this discovery. As the first in the world, they scanned the entire genome of hundreds of sick and healthy people to see if there is an interaction between genes and a very common virus - cytomegalovirus - and to see whether the interaction influences the risk of developing schizophrenia.
And it does.
Women that have been infected by the virus - and around 70% has - will have a statistically significant increased risk of giving birth to a child who later develops schizophrenia if the child also has the aforementioned gene variant. This variant is found in 15 percent. The risk is five times higher than usual, the researchers report in Molecular Psychiatry.
No cause for alarm
People infected with cytomegalovirus most often do not know it, as the infection by the virus, which belongs to the herpes virus family, is usually very mild. But the researchers stress that there is no cause for alarm - even if both risk factors are present in mother and child, there may be a variety of other factors that prevents disease development in the child.
But as schizophrenia affects 1 per cent of the global population, this new knowledge is very important.
“In the longer term, the development of an effective vaccine against cytomegalovirus may help to prevent many cases of schizophrenia,” says Professor of Medical Genetics at Aarhus University, Anders Børglum.
“And our discovery emphasizes that mental disorders such as schizophrenia may arise in the context of an interaction between genes and biological environmental factors very early in life.”
Last month, the National Institutes of Health announced a new collaborative initiative that aims to accelerate the search for biomarkers — changes in the body that can be used to predict, diagnose or monitor a disease — in Parkinson’s disease, in part by improving collaboration among researchers and helping patients get involved in clinical studies. As part of this program, launched by the National Institute of Neurological Disorders and Stroke (NINDS), part of the NIH, Clemens Scherzer, MD, a neurologist and researcher at Brigham and Women’s Hospital (BWH), was awarded $2.6 million over five years to work on the development of biomarkers and facilitate NINDS-wide access to one of the largest data and biospecimens bank in the world for Parkinson’s available at BWH. This NINIDS initiative is highlighted in an editorial in the March issue of Lancet Neurology.
“There is a critical gap in the research that leads to lack of treatment for diseases like Parkinson’s,” said Scherzer. “Biomarkers are desperately needed to make clinical trials more efficient, less expensive and to monitor disease and treatment response. We are hopeful that this initiative will fast track new discoveries in this area.”
According to Scherzer, most of our knowledge of the human brain is based on the analysis of just 1.5 percent of the human genome that encodes proteins. The first part of Scherzer’s project will examine the function of the remaining 98.5 percent of the genome that, so far, has been unexplored in the human brain. While this remainder had been previously dismissed as “junk”, it is now becoming clearer that parts of it actively regulate cell biology. Scherzer and colleagues believe that “dark matter” RNA transcribed from stretches of so called “junk” DNA is active in brain cells and contributes to the complexity of normal dopamine neurons and, when corrupted, Parkinson’s disease.
“This offers a potentially ground breaking opportunity for biomarker development. Initially, the team will search for these RNAs associated in brain tissue of individuals at earliest stages of the disease. Then, this team will look for related biomarkers in the bloodstream and cerebrospinal fluid in both healthy brains and those with Parkinson’s,” Scherzer said.
Scherzer’s lab has been spearheading biomarker research in this field since 2004 and the team already has 2,000 patients enrolled and being followed in a longitudinal study with rich clinical data and one of the largest biobanks in the world for Parkinson’s tissue with support from the Harvard NeuroDiscovery Center. The biobank was designed as an incubator for Parkinson’s research and until now was chiefly available for research collaborations within the Harvard-affiliated community. As part of this new project, this vast resource will be open to all NIH-funded investigators.
“Our ultimate goal is to personalize treatment for our patients with Parkinson’s.” said Scherzer. “By opening up this vast collection of specimens, we are exploding the resources that are available to NIH-funded investigators looking at this disease. We hope to harness the power of collaboration to speed up biomarkers discovery.”
The ability of some animals to regenerate tissue is generally considered to be an ancient quality of all multicellular animals. A genetic analysis of newts, however, now suggests that it evolved much more recently.
Tiny and delicate it may be, but the red spotted newt (Notophthalmus viridescens) has tissue-engineering skills that far surpass the most advanced biotechnology labs. The newt can regenerate lost tissue, including heart muscle, components of its central nervous system and even the lens of its eye.
Doctors hope that this skill relies on a basic genetic program that is common — albeit often in latent form — to all animals, including mammals, so that they can harness it in regenerative medicine. Mice, for instance, are able to generate new heart cells after myocardial injury.
The newt study, by Thomas Braun at the Max Planck Institute for Heart and Lung Research in Bad Nauheim, Germany, and his colleagues, suggest that it might not be so simple.
Attempts to analyse the genetics of newts in the same way as for humans, mice and flies have so far been hampered by the enormous size of the newt genome, which is ten times larger than our own. Braun and his colleagues therefore looked at the RNA produced when genes are expressed — known as the transcriptome — and used three analytical techniques to compile their data.
The team compiled the first catalogue of all the RNA transcripts expressed in N. viridescens, looking at both primary and regenerated tissue in the heart, limbs and eyes of both embryos and larvae.
The researchers found more than 120,000 RNA transcripts, of which they estimate 15,000 code for proteins. Of those, 826 were unique to the newt. What is more, several of those sequences were expressed at different levels in regenerated tissue than in primary tissue. Their results are published in Genome Biology.
Future research into the underlying causes of neurological disorders such as autism, epilepsy and schizophrenia, should greatly benefit from a first-of-its-kind atlas of gene-enhancers in the cerebrum (telencephalon). This new atlas, developed by a team led by researchers with the U.S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab) is a publicly accessible Web-based collection of data that identifies and locates thousands of gene-regulating elements in a region of the brain that is of critical importance for cognition, motor functions and emotion.
“Understanding how the brain develops and functions, and how it malfunctions in neurological disorders, remains one of the most daunting challenges in contemporary science,” says Axel Visel, a geneticist with Berkeley Lab’s Genomics Division. “We’ve created a genome-wide digital atlas of gene enhancers in the human brain – the switches that tell genes when and where they need to be switched on or off. This enhancer atlas will enable other scientists to study in more detail how individual genes are regulated during development of the brain, and how genetic mutations may impact human neurological disorders.”
Visel is the corresponding author of a paper in the journal Cell that describes this work. The paper is titled “A High-Resolution Enhancer Atlas of the Developing Telencephalon.”
Nearly the entire genetic landscape of the most common form of brain tumor can be explained by abnormalities in just five genes, an international team of researchers led by Yale School of Medicine scientists report online in the Jan. 24 edition of the journal Science. Knowledge of the genomic profile of the tumors and their location in the brain make it possible for the first time to develop personalized medical therapies for meningiomas, which currently are only managed surgically.
Meningioma tumors affect about 170,000 patients in the United States. They are usually benign but can turn malignant in about 10 percent of cases. Even non-cancerous tumors can require surgery if they affect the surrounding brain tissue and disrupt neurological functions.
Approximately half of the tumors have already been linked to a mutation or deletion of a gene called neurofibromin 2, or NF2. The origins of the rest of the meningiomas had remained a mystery.
The Yale team conducted genomic analyses of 300 meningiomas and found four new genetic suspects, each of which yields clues to the origins and treatment of the condition. Tumors mutated with each of these genes tend to be located in different areas of the brain, which can indicate how likely they are to become malignant.
“Combining knowledge of these mutations with the location of tumor growth has direct clinical relevance and opens the door for personalized therapies,” said Dr. Murat Gunel, the Nixdorff-German Professor of Neurosurgery, professor of genetics and of neurobiology, and senior author of the study. Gunel is also a member of Yale Cancer Center’s Genetics and Genomics Research Program.
(Image: U.S. Dept. of Energy Office of Science)
The amount of time and money needed to sequence genomes continued to fall this year, perhaps to no one’s surprise. But while the field seemed to be finally approaching the heralded $1,000 human genome, the implications of reaching that milestone are not clear. Without expert analysis, the result of sequencing a human genome is just a large file of letters. You still need to manipulate and understand what those letters mean. Different companies announced services to help, from initial processing and storage of data to interpretation of the genetic data into medical meaning.
As human genomics garnered more attention from the medical community, the technology attracted new business opportunities. In April, the company behind the most widely used DNA sequencer, Illumina, fought off a hostile bid from pharmaceutical giant Roche. Just seven months later, Illumina tried to take over Complete Genomics, a company with technology well suited to medical genomics but which has never achieved financial success. That offer followed what seemed to be an all-but-assured purchased of Complete Genomics by China’s BGI. Illumina and BGI continue to fight over Complete Genomics.
Still, the medical community is only at the cusp of its understanding of how genome sequences can be used to help patients. Two branches of medicine that seem to be at the forefront of bringing on board DNA technology are reproductive medicine and cancer. Early in the summer, scientists at the University of Washington in Seattle reported a technique for determining the genome sequence of a fetus by analyzing DNA in the mother’s blood and from the father. Illumina’s CEO Jay Flatley said that prenatal diagnostics will be a major focus for the company, which has been expanding its business from sequencer manufacturing to broad DNA analysis service. In September, Illumina purchased BlueGnome, a chromosome-focused diagnostic company whose technology can detect abnormal numbers of chromosomes in IVF embryos. DNA analysis could also help prior to conception, according to a start-up called GenePeeks. That company announced it would offer predictive genome analysis for sperm bank clients to help guide them away from risky donor matches.
Cancer patients and their doctors were also early adopters of medical genome science this year. Cancer is a disease of the genome: genetic mutations lead to abnormal cellular proliferation and behavior. Each person’s tumor and even different cells within a single tumor can have a unique profile of mutations, which makes finding the right drug to treat each patient difficult. Cambridge, Massachusetts-based Foundation Medicine offered a sequencing service that searches for mutations that can be addressed with drugs in a patient’s tumor. Another Cambridge company, H3 Biomedicine, is using public databases of tumor sequences to find new drug targets specific to certain patient populations.
Genetic medicines also got a boost with the first Western approval of gene therapy in November. Amsterdam-based Uniqure will begin selling its virus-mediated gene correction for a rare metabolic disorder sometime next year. The announcement could be good news for other companies trying to develop gene therapies as well as other groups developing molecular medicines, such as gene-silencing RNAi treatments that continue to move through clinical trials.
Although still untested in patients, another genetic manipulation is proving to be a powerful tool for neuroscientists. With optogenetics, scientists can manipulate neuron activity with flashes of light, and this year a group demonstrated for the first time that primate behavior could be controlled with the technique. Lab animal studies this year suggest optogenetics might one day help patients with blindness caused by retinal degeneration.
The melding of mind and machine was also big this year. Scientists in Winston-Salem, North Carolina, demonstrated that a brain implant could replace some cognitive function in primates, which could one day help people with brain damage. On the flip side, two research groups published the first accounts of quadriplegic people using brain implants to control robotic limbs. The implants recorded the participants’ intentions to move, which were translated by a computer into instructions for a robotic arm. The idea is that one day people with severe paralysis or amputations could use such neural prosthetics at home to help with the tasks of daily life.
Brain electronics were also implanted into Alzheimer’s patients this year in an attempt to slow a disease that has so far evaded pharmaceutical treatment. The urgency for treatment is growing, but the community still doesn’t know what sets into motion the cascade of molecular events that robs people of their memory and thinking skills. With better diagnostic tools and the discovery that there are warnings decades before symptoms, scientists are turning to treating patients with a genetic predisposition for the disease before they start having symptoms. Perhaps this will be the key to treatments in future years.
Would you make your DNA and health data public if it may help cure disease?
The 39-year-old Toronto professional is the brave or, perhaps, foolhardy Canadian volunteer who will be first to go public this week in a project that will reveal the coded secrets hidden in her genome, the six billion chemical units of her DNA.
They may include not only her susceptibility to diseases such as cancer but the levels of her propensities to alcoholism, depression or obesity, or even personality traits such as risk-taking. She will also provide the personal context required to make sense of the biological data – her age, height, weight; medical records; details about how she lives, works and plays; and even her photo if she’s game.
This information – everything but her name and address – will be placed on an online database that will be open and available to anyone in the world. Even in this digital age of perpetual show and tell, exposing oneself so completely amounts to a molecular full monty: Even without a name attached, any participant might be identifiable.
Ms. Davies is making a leap of faith that at least 100,000 of her fellow citizens are also being asked to take – even though Canadian law has no strict guidelines on how this confidential knowledge might be used or misused by any insurance company, employer, police force or identity thief.