Gene mutation leads to impairment of 2 senses: Touch and hearing

People with good hearing also have a keen sense of touch; people with impaired hearing generally have an impaired sense of touch. Extensive data supporting this hypothesis was presented by Dr. Henning Frenzel and Professor Gary R. Lewin of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Germany.

The two researchers showed that both senses – hearing and touch – have a common genetic basis. In patients with Usher syndrome, a hereditary form of deafness accompanied by impaired vision, they discovered a gene mutation that is also causative for the patients' impaired touch sensitivity. The examination was preceded by various studies, including studies with healthy identical and non-identical human twins (PLoS Biology). In total, the researchers assessed sensory function in 518 volunteers.

In all vertebrates, and consequently also in humans, hearing and touch represent two distinct sensory systems that both rely on the transformation of mechanical force into electrical signals. When we hear, sound waves trigger vibrations that stimulate the hair-like nerve endings in the cochlea in the inner ear. These then transform the mechanical stimuli into electrical signals, which are transmitted to the brain via the auditory nerve. When we touch something a similar process takes place: The mechanical stimulus - sliding the fingers over a rough or smooth surface, the perception of vibrations - is taken up via sensors in the skin, converted into an electrical stimulus and transmitted to the brain.

Twin study with 100 pairs of twins

In recent years about 70 genes have been identified in humans, mutations in which trigger hearing loss or deafness. "Surprisingly, no genes have been found that negatively influence the sense of touch," Professor Lewin said. To see whether the sense of touch also has a hereditary component, the researchers first studied 100 pairs of twins - 66 pairs of monozygotic twins and 34 dizygotic pairs of twins. Monozygotic twins are genetically completely identical; dizygotic twins are genetically identical to 50 percent. The tests showed that the touch sensitivity of the subjects was determined to more than 50 percent by genes. Furthermore, hearing and touch tests showed that there is a correlation between the sense of hearing and touch.

The researchers therefore suspected that genes that influence the sense of hearing may also have an influence on the sense of touch. In a next step, they recruited test subjects at a school in Berlin for students with hearing impairments. There they assessed the touch sensitivity in a cohort of 39 young people who suffered from severe congenital hearing impairment. The researchers compared these findings with the data from their twin study and discovered that not all of the young people with hearing loss had impaired tactile acuity. "Strikingly, however, many of these young people did indeed have poor tactile acuity," Professor Lewin explained.

The researchers decided it would take too much time to analyze which of the approximately 70 genes that adversely affect the sense of hearing may also negatively affect the sense of touch. Therefore, the researchers focused specifically on patients with the Usher syndrome, a hereditary form of hearing impairment, in which the patients progressively become blind. Usher syndrome patients have varying degrees of hearing impairment, and the disease is genetically very well studied. There are nine known Usher genes carrying mutations which cause the disease.

The researchers examined one cohort of patients in a special consultation at the Charité - Universitätsmedizin Berlin for Usher patients from all over Germany. A second cohort was recruited at the university hospital La Fe in Valencia, Spain. The studies revealed that not all patients with Usher-syndrome have poor tactile acuity and touch sensitivity. The researchers showed that only patients with Usher syndrome who have a mutation in the gene USH2A have poor touch sensitivity. This mutation is also responsible for the impaired hearing of 19 patients. The 29 Usher-syndrome patients in whom the mutation could not be detected had a normal sense of touch. The researchers thus demonstrated that there is a common genetic basis for the sense of hearing and touch. They suspect that even more genes will be discovered in the future that influence both mechanosensory traits.

Women hear better than men and have a finer sense of touch

The researchers discovered another interesting detail during their five-year study. "When women complain that their men are not really listening to them, there is some truth in that," Professor Lewin said. "The studies with a total of 518 individuals including 295 women have actually shown that women hear better and they also have a finer sense of touch than men; in short woman hear and feel more than men!"

More information: PLoS Biology doi:10.1371/journal.pbio.1001318

Provided by Helmholtz Association of German Research Centres

"Gene mutation leads to impairment of 2 senses: Touch and hearing." May 1st, 2012. http://medicalxpress.com/news/2012-05-gene-mutation-impairment.html

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Robert Karl Stonjek

Devastating disease provides insight into development and death of motor neurons

Researchers at UCLA have been searching for the cause of a rare disease that virtually no one has ever heard: PCH1, or pontocerebellar hypoplasia type 1, which attacks the brain and the spine.

It's a particularly cruel disorder, occurring mostly in infants, who begin manifesting symptoms at or soon after birth, with poor muscle tone, difficulty feeding, growth retardation and global developmental delay.

Now, thanks to the cooperation of a California family stricken by the disorder and a state-of-the-art genomic sequencing lab at UCLA, Dr. Joanna Jen, a UCLA professor of neurology, and colleagues discovered a specific mutation of a gene that is responsible for PCH1 in this family, then confirmed mutations in the same gene in several other PCH1 families around the world.

The study appears in the April 29 in the online edition of the journal Nature Genetics.

The diagnosis of PCH1 is often delayed or never made because the combination of cerebellar and spinal motor-neuron degeneration is very rare and not commonly recognized. The discovery of the gene, EXOSC3 (exosome component 3), showed that it is critically important in the normal development and survival of neurons, especially in the cerebellum, and for motor neurons in the spine, which innervate or stimulate muscles.

Five years ago, Jen began working with a family living in Southern California with four boys who were neurologically afflicted. They were floppy at birth, suffered from progressive muscle wasting and were never able to stand, walk or speak. Today, they range in age from 9 to the teens, and none weighs more than 50 pounds.

The family was referred to Jen because of her special interest in rare neurological disorders. As Jen reviewed the medical history and examined the children to reach a clinical diagnosis, she began searching for the causative gene in collaboration with Dr. Stanley Nelson, a professor and vice chair of the UCLA Department of Human Genetics.

Nelson, who also directs the UCLA Clinical Genomics Center, and his graduate student Michael Yourshaw, used a new technique called exome sequencing. The exome is the part of the genome that directs those proteins that are actually expressed — that is, it provides the genetic blueprint for functional genes. Exome sequencing searches just the protein-coding regions in the genome to pinpoint disease-causing mutations. In this way, they were able to quickly survey some 22,000 protein-encoding genes to identify a defect in the EXOSC3 gene in this single California family.

To confirm their finding, Jen reached out to other neurologists around the world, eventually verifying the presence of the same defective gene in eight other families stricken with PCH1. And by using a model of the disease in zebrafish, Jijun Wan, a UCLA research scientist in neurology, found that preventing the EXOSC3 gene from expressing in zebrafish caused embryonic maldevelopment and poor movement reminiscent of human clinical features. These symptoms were largely reversed when the researchers injected normal EXOSC3, suggesting that it was indeed the mutations that disrupted normal function.

The EXOSC3 gene encodes a core component of the RNA exosome complex, which is essential for all organisms and which is emerging as the major cellular machinery in the processing of RNA to regulate gene expression, Jen said. There is increasing appreciation for the diversity of RNAs, she noted, as it is becoming clear that the majority of genomic information is transcribed into RNA.

"When we began this study, mutations in the RNA exosome had not been associated with any human disease," Jen said. "Relatively little is known about the human RNA exosome. It is surprising that a gene that is expressed in every cell should have such a selective detrimental impact on the cerebellar and spinal motor neurons.

There is increasing focus on RNA metabolism in motor neuron diseases such as amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, and spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, Jen said. The discovery of defects in the RNA exosome causing combined SMA and PCH further emphasizes the importance of the regulation of RNA metabolism.

"The discovery may lead to potential targets for treatment and in addition enhances our understanding of the biological function of the RNA exosome," said Jen. She is working with other neurologists to better define the clinical spectrum of EXOSC3-associated PCH1.

"It is remarkable that all of the affected children in this family have survived beyond infancy. We are grateful for the generosity of the family in sharing their experience and participating in research to improve the lives of other children who are similarly affected," said Jen.

Provided by University of California, Los Angeles

"Devastating disease provides insight into development and death of motor neurons." April 30th, 2012. http://medicalxpress.com/news/2012-04-devastating-disease-insight-death-motor.html

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Robert Karl Stonjek

Heart disease genes no death sentence

THE UNIVERSITY OF OTAGO

Share on print While genetic variants linked to heart disease can cause the disease to develop at a younger age, it doesn't appear to reduce an individual's life expectancy after a heart attack. Image: Dkart/iStockphoto Inheriting gene variants that increase the risk of developing coronary heart disease does not necessarily mean an individual is going to have reduced life expectancy if he or she suffers a heart attack. Two research papers revealing these findings by Dr Katrina Ellis and colleagues at the University of Otago, Christchurch have been highlighted in the leading international cardiology journal Circulation, along with 42 other papers from cardiac researchers around the world. “These results have attracted considerable international attention as we found for the first time that the most likely gene variants for risk of developing coronary heart disease didn’t have a major negative effect on survival after heart attack, as might have been expected by the medical and scientific community,” explains Dr Ellis. “When we examined the progress of patients with four key gene variants, who were admitted to Christchurch Hospital with either angina or heart attack, we found little or no effect on their subsequent survival eight to 15 years after a heart attack compared with those carrying the more common form of the gene sequence. “However we noted those who carried these gene variants tended to develop heart disease at a younger age or have more risk factors, like high cholesterol.” As the head of the research group Professor Vicky Cameron says: “This is good news for those patients, and of high interest to medical science as it would be expected that gene variants associated with a greater risk for having a heart attack would also indicate a negative rather than positive prognosis.” Research into gene variants and their relationship to heart attacks has rapidly progressed since 2007 when it became possible to examine all 23,000 genes in humans relatively quickly using new computerised technology. This lead to ‘genome-wide association studies’ which identify those gene variants most strongly linked to the development of coronary heart disease, and subsequent survival after treatment. Coronary heart disease is the leading cause of death world-wide and in New Zealand, with sixteen people dying each day from this condition. Risks include environmental or lifestyle factors such as smoking and obesity, but about 50% of heart disease is actually inherited through our genetic make-up and gene variants. “For many this means our genes make us more susceptible to lifestyle risk factors, such as bad diet or lack of exercise,” says Professor Cameron. Dr Ellis is now moving to the prestigious Mt Sinai School of Medicine in New York. However her research is continuing at the University of Otago, Christchurch under Professor Cameron. A new research project, ‘The Family Heart Study’, is looking at the specific genetic risk factors that contribute to early coronary heart disease in New Zealanders. This will enable identification of genetic factors, such as gene variants, which put people at risk of heart attack and will enable even earlier intervention and better chances of survival. Editor's Note: Original news release can be found here.

Genetic link to fractures found

THE UNIVERSITY OF WESTERN AUSTRALIA

The study found that variants in 56 regions of the genome influenced bone mineral density, while 14 of these variants increased the risk of bone fracture. Image: skhoward/iStockphoto A large number of genetic variants have for the first time been linked to the risk of osteoporosis and bone fracture, according to a major new international study. Osteoporosis is a silent but devastating age-related disease that kills half of those who fracture their hip after the age of 80 within 12 months.  Women aged over 65 are at greater risk of death after hip fracture than from breast cancer. Researchers around the world, including from The University of Western Australia, found that variants in 56 regions of the genome influenced bone mineral density, while 14 of these variants increased the risk of bone fracture. Bone mineral density is the most widely used measurement to diagnose osteoporosis and assess the risk of fracture, with higher density associated with lower risk of fracture. In the largest genetic study of osteoporosis to date, investigators from more than 50 studies across Europe, North America, East Asia and Australia studied more than 80,000 individuals. The study, led by researchers from Holland's Erasmus University Medical Centre in Rotterdam, was published in the leading international journal Nature Genetics. Co-author Professor Richard Prince, from UWA's Bone and Vascular Research Group, said osteoporosis was strongly related to gene variation. "We have found new genes strongly related to bone structure.  This latest research has helped pinpoint many factors in critical molecular pathways that may lead to therapeutic treatments. "This research also leads to better understanding of the biology of skeletal health and fracture susceptibility." Researchers also found that women with an excess of bone mineral density-decreasing genetic variants had up to 56 per cent higher risk osteoporosis and a 60 per cent higher risk of all types of fractures. The Bone and Vascular Research Group, within UWA's School of Medicine and Pharmacology, is focused on bone and joint disease, including genetic epidemiology, using a longitudinal study of 1500 elderly West Australian women. Editor's Note: Original news release can be found here.

Gene hunt is on for mental disability

Pioneering clinical genome-sequencing projects focus on patients with developmental delay.

Ewen Callaway

 

 

Exome sequencing could help to identify the causes of intellectual disability in children such as Siebe.

Han Brunner

Medical geneticists are giving genome sequencing its first big test in the clinic by applying it to some of their most baffling cases. By the end of this year, hundreds of children with unexplained forms of intellectual disability and developmental delay will have had their genomes decoded as part of the first large-scale, national clinical sequencing projects.

These programmes, which were discussed last month at a rare-diseases conference hosted by the Wellcome Trust Sanger Institute near Cambridge, UK, aim to provide a genetic diagnosis that could end years of uncertainty about a child’s disability. In the longer term, they could provide crucial data that will underpin efforts to develop therapies. The projects are also highlighting the logistical and ethical challenges of bringing genome sequencing to the consulting room. “The overarching theme is that genome-based diagnosis is now hitting mainstream medicine,” says Han Brunner, a medical geneticist at the Radboud University Nijmegen Medical Centre in the Netherlands, who leads one of the projects.

About 2% of children experience some form of intellectual disability. Many have disorders such as Down’s syndrome and fragile X syndrome, which are linked to known genetic abnormalities and so are easily diagnosed. Others have experienced environmental risk factors, such as fetal alcohol exposure, that rule out a simple genetic explanation. However, a large proportion of intellectual disability cases are thought to be the work of single, as-yet-unidentified mutations.

Scientists estimate that about 1,000 genes are involved in the function of the healthy brain. “There are so many genes that can go wrong and give you intellectual disability,” says André Reis, a medical geneticist at Erlangen University Hospital in Germany. Reis’s group, the German Mental Retardation Network, has already sequenced the exomes — the 1–2% of the genome that contains instructions for building proteins — of about 50 patients with severe intellectual disability.

Joining the hunt is a UK-based programme called Deciphering Developmental Disorders, which expects to sequence 1,000 exomes by the year’s end, with an ultimate goal of diagnosing up to 12,000 British children with developmental delay. A Canadian project called FORGE (finding of rare disease genes) aims to sequence children and families with 200 different disorders this year. And in the United States, the National Human Genome Research Institute in Bethesda, Maryland, recently funded three Mendelian Disorders Sequencing Centers that will apply genome sequencing to diagnosing thousands of patients with a wider range of rare diseases, including intellectual disability and developmental delay.

First glance

Early results are coming in from Brunner’s team, which has already sequenced about 100 exomes of children with intellectual disability. By comparing the children’s exomes with those of the parents, the researchers have identified new mutations — potential causes of the disorder — in as many as 40% of the cases. The other programmes are having similar success at making possible genetic diagnoses.

In most cases, identifying mutations will not point to medical treatments, let alone cures. But scientists say the importance of a diagnosis should not be discounted. “Parents have been struggling with the delay of their children for years. They have gone from one doctor to the next, had all kinds of tests done on their children looking for an explanation,” Reis says. Knowing that the mutation causing a child’s intellectual disability is new rather than inherited can also reassure parents that other children they conceive are unlikely to have the same disease.

Treatments could eventually follow. The projects are guiding research in mice, zebrafish and fruitflies, with the goal of unpicking the mechanisms of mental disorders. But it will undoubtedly be a long time before any potential therapies are tried in humans: an early-stage clinical trial of a drug to treat fragile X syndrome, for example, was published last year (S. Jacquemont et al. Sci. Transl. Med. 3, 64ra1; 2011), some two decades after the gene underlying the condition, FMR1, was identified.

The work is also throwing up a fresh challenge: how can scientists be sure that a specific mutation is the cause of a particular form of mental disability? “It’s not clear what is the threshold of evidence at which you can say this is the causal variant in this patient,” says Daniel MacArthur, a geneticist at Massachusetts General Hospital in Boston. In a recent Science paper, his team estimated that the average healthy genome contains about 100 gene-disabling mutations. Such ‘background noise’ could lead scientists astray in their hunt for causal mutations.

Brunner says that about half of the mutations his team has identified have previously been seen in other patients with similar forms of intellectual disability, offering enough assurance to make a diagnosis. Circumstantial evidence, such as indications that the mutation disrupts a gene expressed in the brains of animals, ties the other half of the mutations to intellectual disability. But making a solid case often requires identifying second, third and fourth patients with similar mutations and symptoms.

Scientists are already forging these connections on an informal basis. At the Sanger Institute meeting, several groups reported mutations in a gene called ARID1B in patients with intellectual disability. James Lupski, a medical geneticist at Baylor College of Medicine in Houston, Texas, says that when his team identifies a potentially disease-causing mutation in a patient genome, he e-mails other scientists to see whether they have found similar mutations.

But researchers agree that they need a more formalized way to make these connections. To that end, the US National Center for Biotechnology Information in Bethesda is developing a database, ClinVar, to integrate clinical and genetic data; others, such as DECIPHER, run by the Sanger Institute, handle genetic data such as chromosome rearrangements that can disrupt genes.

The first clinical sequencing projects are also grappling with what they should or shouldn’t tell patients. “We don’t want people coming into our clinic for intellectual disability and coming out with a cancer gene; this is not what they came for,” says Reis.

Brunner’s team once had to face just that situation. The researchers identified a mutation in a gene in one patient that could increase the risk of colon cancer as an adult. The project’s ethical review board had determined that if families wanted to know of mutations potentially underlying a child’s intellectual disability, they must also be willing to receive such incidental findings, and so the child’s parents were told. But clinical sequencing projects vary in their approach to incidental results. For the time being, Deciphering Developmental Disorders will not inform families about such findings. For FORGE Canada, the policy varies from province to province.

A working group convened by the American College of Medical Genetics and Genomics in Bethesda recently suggested drawing up a list of gene mutations that ought to be routinely reported back to patients. The list would include mutations strongly linked to conditions for which a medical intervention is available.

“This is a fast-changing ethical environment,” says Matt Hurles, a geneticist at the Sanger Institute and one of the leaders of Deciphering Developmental Disorders. His team is conducting a web-based survey to gauge the attitudes of parents, physicians and the general public towards disclosing incidental genomic findings. Lupski admits, “We’re learning as we go along. People don’t want to hear that, but that’s the truth of the matter.”

Scientists and clinicians hope that the lessons learned in these initial large-scale clinical sequencing projects will inform genomic medicine as it reaches more patients and moves to other specialities, such as neurology and cardiology, and even to routine health care. “If in five years time this project hasn’t catalysed the adoption of genomic technologies which have been shown to be useful, in some degree we will have failed,” says Hurles.

Nature 484, 302–303

( 19 April 2012 )

doi :10.1038/484302a

 

Source: Nature
http://www.nature.com/news/gene-hunt-is-on-for-mental-disability-1.10463

 

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Robert Karl Stonjek

Major study finds memory in adults impacted by versions of four genes

In studying a gene that drives cell growth, Project ENIGMA scientists found a variant that boosted gene expression levels (shown as colored dots), which also enlarged the brain's memory centers (shaded in green). Credit: UCLA

Two research studies, co-led by UC Davis neurologist Charles DeCarli and conducted by an international team that included more than 80 scientists at 71 institutions in eight countries, has advanced understanding of the genetic components of Alzheimer's disease and of brain development. Both studies appear in the April 15 edition of the journal Nature Genetics.

The first study, based on a genetic analysis of more than 9,000 people, has found that certain versions of four genes may speed shrinkage of a brain region involved in making new memories. The brain area, known as the hippocampus, normally shrinks with age, but if the process speeds up, it could increase vulnerability to Alzheimer's disease, the research suggests.

The second paper identifies two genes associated with intracranial volume — the space within the skull occupied by the brain when the brain is fully developed in a person's lifespan, usually around age 20.

DeCarli is an internationally renowned pioneer in the field of neuroimaging of the aging brain who has been at the forefront of developing and using quantifiable imaging techniques to define the relationship between structure and function in the healthy aging brain and to characterize the changes associated with vascular and Alzheimer's dementias. He is professor of neurology and director of the UC Davis Alzheimer's Disease Center and the UC Davis Imaging of Dementia and Aging Laboratory.

Genetic variants of hippocampus study

The gene variants identified in the first study do not cause Alzheimer's, but they may rob the hippocampus of a kind of "reserve" against the disease, which is known to cause cell destruction and dramatic shrinkage of this key brain site. The result is severe loss of memory and cognitive ability.

Scientists calculated that hippocampus shrinkage in people with these gene variants accelerates by about four years on average. The risk of Alzheimer's doubles every five years beginning at age 65, so a person of that age would face almost twice the Alzheimer's risk if he or she had these versions of the gene.

Looked at another way, if a person with one of these variants did get Alzheimer's, the disease would attack an already compromised hippocampus and so would lead to a more severe condition at a younger age than otherwise, the research suggests.

"This is definitely a case of 'bigger is better,'" said DeCarli. "We already know that Alzheimer's disease causes much of its damage by shrinking hippocampus volume. If someone loses a greater-than-average amount of volume due to the gene variants we've identified, the hippocampus is more vulnerable to Alzheimer's."

Why the aging hippocampus normally decreases in volume is unclear. The new research shows that the genes most strongly linked to shrinkage are involved in maturation of the hippocampus and in apoptosis, or programmed cell death – a continual process by which older cells are removed from active duty.

The scientists suggest that if the gene variants they identified do affect either maturation or the rate at which cells die, this could underlie at least some of the increased rates of hippocampus shrinkage.

"Either by making more or healthier hippocampal neurons or preventing them from dying with advancing age, the healthy versions of these genes influence how people remember as they get older," said DeCarli. "The alternate versions of the genes may not fully provide these benefits."

The researchers hope that they can find ways to protect the hippocampus from premature shrinkage or slow its decline by studying the normal regulation of the proteins coded by these genes.

The genetic analysis draws on what is known as a genome-wide association study -- research aimed at finding the common genetic variants associated with specific diseases or other conditions. Different versions of a gene usually come down to changes in just one of the tens of thousands of DNA "letters" that make up genes. These one-letter differences are known as single-nucleotide polymorphisms, or SNPs.

The research involved more than 80 scientists at 71 institutions in 8 countries. Many researchers are needed for such a study in order to put together the large samples, or cohorts, of people whose genetic makeup is to be investigated, to measure the hippocampus from magnetic resonance pictures of the brain and for the labor-intensive statistical analysis of the findings.

The study used a very large assemblage of genetic and disease data called the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, or CHARGE. The consortium brings together several population-based cohorts in the United States and Europe.

The cohort was made up of 9,232 dementia-free volunteers with an average age of 67. The study identified four different gene variants associated with hippocampus volume decline. One, known as rs7294919, showed a particularly strong link to a reduced hippocampus volume, suggesting that this gene is very important to hippocampus development or health.

The findings were then assessed in two other cohorts. One, including both normal and cognitively compromised people with an average age of 40, showed that three of the suspect SNPs were linked to reduced hippocampus volume. Analysis of results from the third group, comprised primarily of older people, showed a significant association between one of the SNPs and accelerated memory loss.

"With this study, we have new evidence that aging, the hippocampus and memory are influenced by specific genes," DeCarli said. "Understanding how these genes affect the development and aging of the hippocampus may give us new tools to delay memory loss with advanced age and possibly reduce the impact of such diseases as Alzheimer's disease."

Genetic variants of Intracranial-volume study

While the first study deals with the genetic associations with brain shrinkage, the second deals with associations impacting intracranial volume, which is an indirect measure of the size of the brain at full development.

Though brain volume and intracranial volume are both highly heritable, the genetic influences on these measures may differ. To assess the genetic influence on these two measures, researchers in the second study performed a genome-wide association study on cross-sectional measures of intracranial volume and brain volume in 8,175 elderly in the CHARGE consortium.

They found no associations for brain volume, but they did discover that intracranial volume was significantly associated with two loci: rs4273712, a known height locus on chromosome 6q22, and rs9915547, tagging the inversion on chromosome 17q21.

"Since geneticists are already familiar with the other functions of these same genes, associating these particular genes with intracranial volume may help us better understand brain development in general," said DeCarli. "For instance, we know that one of these genes has played a unique evolutionary role in human development, and perhaps we as a species are selecting this gene as a way of providing further advances in brain development."

Provided by University of California - Davis

"Major study finds memory in adults impacted by versions of four genes." April 15th, 2012. http://medicalxpress.com/news/2012-04-major-memory-adults-impacted-versions.html

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Robert Karl Stonjek

Genetic Bar Code Search Can Use RNA to Pick Out Individuals From Huge Gene Pools

Even without a DNA sample

By Rebecca Boyle

RNA Wikipedia

DNA databases are highly protected resources, because they contain the most detailed fingerprint that can be used to identify a person — from genetic predisposition to cancer, to paternity tests, to criminal histories. But apparently RNA databases, derived from large genome studies, can also be used to pinpoint a person’s identity, according to a new study. These databases are published in journals and are publicly available, and contain genetic information from thousands of people around the world.

Given these findings, scientists could use RNA and other deep personal data to improve patients’ health and serve the greater good, the researchers argue. But it also raises some questions about genomic privacy.

The study, conducted at Mount Sinai School of Medicine in New York, turns the process of RNA detection inside out. Researchers Eric E. Schadt and Ke Hao figured out how to infer a person’s DNA using RNA data; most studies use DNA sequences and then determine how RNA relays that genetic information.

The researchers looked at levels of RNA, which works as a messenger carrying out DNA’s instructions, in samples of liver tissue that were collected in two separate studies. One study looked at samples from liver donors, and the other studied people who were undergoing gastric bypass surgery. The Mount Sinai team looked for markers called expression quantitative trait loci, or eQTLs, which are locations on the genome that regulate expression of certain proteins or RNAs. They used algorithms that matched these eQTL patterns to variations in DNA bases, extrapolating the DNA sequences. Schadt describes it as “hearing a symphony and deducing which instruments are in the orchestra, essentially unwinding the developmental process to trace tissue samples back to RNA and the gene that instructed it.”

With this DNA inference, you could theoretically use RNA levels to match an individual to an independently obtained DNA sample — like scanning a barcode to see if two items match.

“DNA collected at a crime scene could be genotyped and then searched against the barcodes derived from the gene expression studies represented, say, in the GEO database, enabling investigators to potentially link unknown individuals at the crime scene to individuals who participated in a particular study,” the researchers write.

This finding rings some alarm bells about privacy — if you have stomach-shrinking surgery, and you’ve never donated DNA to a crime database, should the authorities really be able to track you down via your medical history? What about obtaining warrants for this information, when it’s technically already in the public domain? In a Mount Sinai news release, Schadt hints that the age of medical privacy may be drawing to a close.

“Rather than developing ways to further protect an individual's privacy given the ability to collect mountains of information on him or her, we would be better served by a society that accepts the fact that new types of high-dimensional data reflect deeply on who we are,” he said. "We need to accept the reality that it is difficult—if not impossible—to shield personal information from others. It is akin to trying to protect privacy regarding appearances, for example, in a public place.”

The research appears in the online edition of Nature Genetics.

Men respond more aggressively than women to stress and it's all down to a single gene

The pulse quickens, the heart pounds and adrenalin courses through the veins, but in stressful situations is our reaction controlled by our genes, and does it differ between the sexes? Australian scientists, writing in BioEssays, believe the SRY gene, which directs male development, may promote aggression and other traditionally male behavioural traits resulting in the fight-or-flight reaction to stress.

Research has shown how the body reacts to stress by activating the adrenal glands which secrete catecholamine hormones into the bloodstream and trigger the aggressive fight-or-flight response. However, the majority of studies into this process have focused on men and have not considered different responses between the sexes.

"Historically males and females have been under different selection pressures which are reflected by biochemical and behavioural differences between the sexes," said Dr Joohyung Lee, from the Prince Henry's Institute in Melbourne. "The aggressive fight-or-flight reaction is more dominant in men, while women predominantly adopt a less aggressive tend-and-befriend response."

Dr Lee and co-author Professor Vincent Harley, propose that the Y-chromosome gene SRY reveals a genetic underpinning for this difference due to its role in controlling a group of neurotransmitters known as catecholamines. Professor Harley's earlier research had shown that SRY is a sex-determining gene which directs the prenatal development of the testes, which in turn secrete hormones which masculinise the developing body.

"If the SRY gene is absent the testes do not form and the foetus develops as a female. People long thought that SRY's only function was to form the testes" said Professor Harley. "Then we found SRY protein in the human brain and with UCLA researchers led by Professor Eric Vilain, showed that the protein controls movement in males via dopamine."

"Besides the testes, SRY protein is present in a number of vital organs in the male body, including the heart, lungs and brain, indicating it has a role beyond early sex determination," said Dr Lee. "This suggests SRY exerts male-specific effects in tissues outside the testis, such as regulating cardiovascular function and neural activity, both of which play a vital role in our response to stress."

The authors propose that SRY may prime organs in the male body to respond to stress through increased release of catecholamine and blood flow to organs, as well as promoting aggression and increased movement which drive fight-or-flight in males. In females oestrogen and the activation of internal opiates, which the body uses to control pain, may prevent aggressive responses.

The role of SRY regulation of catecholamines also suggests the gene may have a role in male-biased disorders such as Parkinson's disease.

"New evidence indicates that the SRY gene exerts 'maleness' by acting directly on the brain and peripheral tissues to regulate movement and blood pressure in males," concluded Lee. "This research helps uncover the genetic basis to explain what predisposes men and women to certain behavioural phenotypes and neuropsychiatric disorders."

More information: Lee. J, Harley. V, “The male fight-flight response: A result of SRY regulation of catecholamines?” Bioessays, Wiley-Blackwell, March 2012, DOI: 10.1002/bies.201100159

Provided by Wiley

"Men respond more aggressively than women to stress and it's all down to a single gene." March 7th, 2012. http://medicalxpress.com/news/2012-03-men-aggressively-women-stress-gene.html

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Robert Karl Stonjek

'REST' is crucial for the timing of brain development

Researchers have just shown that the molecule REST acts as an adapter in stem cells, and hope that future studies of REST will contribute to the development of new types of treatments for diseases such as cancer.

Upon fertilisation, a single cell is formed when egg and sperm fuse. Our entire body, with more than 200 specialised cell types and billions of cells are formed from this single cell. It is a scientific mystery how the early stem cells know what cell type to become, but a precise timing of the process is crucial for correct development and function of our body. Researchers across the world chase knowledge about our stem cells, as this knowledge holds great promises for development of treatment against several major diseases. Researchers from BRIC, University of Copenhagen, have just shown that the molecule REST acts as an adapter in stem cells, coupling molecular on-off switches with neural genes and thereby times neuronal development.

"REST secure neuronal genes to be turned off in our stem cells until the correct time point in fetal life, where the molecule is lost and development of the nervous system begins. Our results are very important for the understanding of how genes are turned on and off during fetal development, but also relates to disease development such as cancer. Hopefully, our future studies of REST will contribute to the development of new types of treatments," says Associate Professor and Group Leader at BRIC, Klaus Hansen.

Genetic switches

All our cells contain the same DNA, yet they can develop into specialised cells with different shapes and functions. This ability is due to only selective genes being turned on in for example neuronal cells and other genes in liver cells and skin cells. Postdoc Nikolaj Dietrich from Klaus Hansen's laboratory has been the main driver of the investigation:

"Our results show that REST act as an adapter for the protein complexes called PRCs, connecting these complexes to neuronal genes. The PRCs are genetic switches turning off genes and therefore REST and the PRCs act in concert to shutdown neuronal genes. A similar mechanism has previously been described in fruit flies, but until now, no one has been able to identify such adapter-molecules in humans or other mammals. This has led to various biological hypotheses, but now we are able to show that this genetic mechanism has been conserved trough out evolution," says Nikolaj Dietrich.

Brain damage and brain tumors

REST and PRC are attached to neuronal genes in the early fetal stem cells, keeping neuronal genes turned off. During fetal development, REST disappears in cells that are determined to develop into neuronal cells, whereas the molecule is preserved in other cell types. REST is also preserved in special neuronal stem cells, ensuring that these cells maintain their stem cell properties. This is crucial if we experience damage to our nervous system later in life, as only the neuronal stem cells can repair the damage by giving rise to new neurons and thereby secure vital body functions. However, REST also appears to be associated with a higher risk of cancer:

"An increased amount of REST has been found in the brain tumor form called neuroblastoma. Some of our results indicate that REST may be involved in cancer, as the molecule can turn off some growth-inhibitory and cancer-protective genes called tumor suppressors. This possible action of REST is the focus of ongoing studies," says Nikolaj Dietrich.

More information: The results have just been published in the international scientific journal PLoS Genetics: REST-Mediated Recruitment of Polycomb Repressor Complexes in Mammalian Cells, Dietrich et al. March 1, 2012.

Provided by University of Copenhagen

"'REST' is crucial for the timing of brain development." March 2nd, 2012. http://medicalxpress.com/news/2012-03-rest-crucial-brain.html

Posted by
Robert Karl Stonjek