Posts tagged genetics
Articles and news from the latest research reports.
Longer Telomeres Linked to Risk of Brain Cancer
New genomic research led by UC San Francisco scientists reveals that two common gene variants that lead to longer telomeres, the caps on chromosome ends thought by many scientists to confer health by protecting cells from aging, also significantly increase the risk of developing the deadly brain cancers known as gliomas.
The genetic variants, in two telomere-related genes known as TERT and TERC, are respectively carried by 51 percent and 72 percent of the general population. Because it is somewhat unusual for such risk-conferring variants to be carried by a majority of people, the researchers propose that in these carriers the overall cellular robustness afforded by longer telomeres trumps the increased risk of high-grade gliomas, which are invariably fatal but relatively rare cancers.
The research was published online in Nature Genetics on June 8, 2014.
“There are clearly high barriers to developing gliomas, perhaps because the brain has special protection,” said Margaret Wrensch, MPH, PhD, the Stanley D. Lewis and Virginia S. Lewis Endowed Chair in Brain Tumor Research at UCSF and senior author of the new study. “It’s not uncommon for people diagnosed with glioma to comment, ‘I’ve never been sick in my life.’”
In a possible example of this genetic balancing act between risks and benefits of telomere length, in one dataset employed in the current study—a massive genomic analysis of telomere length in nearly 40,000 individuals conducted at the University of Leicester in the United Kingdom—shorter telomeres were associated with a significantly increased risk of cardiovascular disease.
“Though longer telomeres might be good for you as a whole person, reducing many health risks and slowing aging, they might also cause some cells to live longer than they’re supposed to, which is one of the hallmarks of cancer,” said lead author Kyle M. Walsh, PhD, assistant professor of neurological surgery and a member of the Program in Cancer Genetics at UCSF’s Helen Diller Family Comprehensive Cancer Center.
In the first phase of the new study, researchers at UCSF and The Mayo Clinic College of Medicine analyzed genome-wide data from 1,644 glioma patients and 7,736 healthy control individuals, including some who took part in The Cancer Genome Atlas project sponsored by the National Cancer Institute and National Human Genome Research Institute. This work confirmed a link between TERT and gliomas that had been made in previous UCSF research, and also identified TERC as a glioma risk factor for the first time.
Since both genes have known roles in regulating the action of telomerase, the enzyme that maintains telomere length, the research team combed the University of Leicester data, and they found that the same TERT and TERC variants associated with glioma risk were also associated with greater telomere length.
UCSF’s Elizabeth Blackburn, PhD, shared the 2009 Nobel Prize in Physiology or Medicine for her pioneering work on telomeres and telomerase, an area of research she began in the mid-1970s. In the ensuing decades, untangling the relationships between telomere length and disease has proved to be complex.
In much research, longer telomeres have been considered a sign of health—for example, Blackburn and others have shown that individuals exposed to chronic stressful experiences have shortened telomeres. But because cancer cells promote their own longevity by maintaining telomere length, drug companies have searched for drugs to specifically target and block telomerase in tumors in the hopes that cancer cells will accumulate genetic damage and die.
Walsh said the relevance of the new research should extend beyond gliomas, since TERT variants have also been implicated in lung, prostate, testicular and breast cancers, and TERC variants in leukemia, colon cancer and multiple myeloma. Variants in both TERT and TERC have been found to increase risk of idiopathic pulmonary fibrosis, a progressive disease of the lungs.
In some of these cases, the disease-associated variants promote longer telomeres, and in others shorter telomeres, suggesting that “both longer and shorter telomere length may be pathogenic, depending on the disease under consideration,” the authors write.
Brain circuit problem likely sets stage for the “voices” that are symptom of schizophrenia
St. Jude Children’s Research Hospital scientists have identified problems in a connection between brain structures that may predispose individuals to hearing the “voices” that are a common symptom of schizophrenia. The work appears in the June 6 issue of the journal Science.
(Image: Getty Images)
Researchers linked the problem to a gene deletion. This leads to changes in brain chemistry that reduce the flow of information between two brain structures involved in processing auditory information.
The research marks the first time that a specific circuit in the brain has been linked to the auditory hallucinations, delusions and other psychotic symptoms of schizophrenia. The disease is a chronic, devastating brain disorder that affects about 1 percent of Americans and causes them to struggle with a variety of problems, including thinking, learning and memory.
The disrupted circuit identified in this study solves the mystery of how current antipsychotic drugs ease symptoms and provides a new focus for efforts to develop medications that quiet “voices” but cause fewer side effects.
“We think that reducing the flow of information between these two brain structures that play a central role in processing auditory information sets the stage for stress or other factors to come along and trigger the ‘voices’ that are the most common psychotic symptom of schizophrenia,” said the study’s corresponding author Stanislav Zakharenko, M.D., Ph.D., an associate member of the St. Jude Department of Developmental Neurobiology. “These findings also integrate several competing models regarding changes in the brain that lead to this complex disorder.”
The work was done in a mouse model of the human genetic disorder 22q11 deletion syndrome. The syndrome occurs when part of chromosome 22 is deleted and individuals are left with one rather than the usual two copies of about 25 genes. About 30 percent of individuals with the deletion syndrome develop schizophrenia, making it one of the strongest risk factors for the disorder. DNA is the blueprint for life. Human DNA is organized into 23 pairs of chromosomes that are found in nearly every cell.
Earlier work from Zakharenko’s laboratory linked one of the lost genes, Dgcr8, to brain changes in mice with the deletion syndrome that affect a structure important for learning and memory. They found evidence that the same mechanism was at work in patients with schizophrenia. Dgcr8 carries instructions for making small molecules called microRNAs that help regulate production of different proteins.
For this study, researchers used state-of-the-art tools to link the loss of Dgcr8 to changes that affect a different brain structure, the auditory thalamus. For decades antipsychotic drugs have been known to work by binding to a protein named the D2 dopamine receptor (Drd2). The binding blocks activity of the chemical messenger dopamine. Until now, however, how that quieted the “voices” of schizophrenia was unclear.
Working in mice with and without the 22q11 deletion, researchers showed that the strength of the nerve impulse from neurons in the auditory thalamus was reduced in mice with the deletion compared to normal mice. Electrical activity in other brain regions was not different.
Investigators showed that Drd2 levels were elevated in the auditory thalamus of mice with the deletion, but not in other brain regions. When researchers checked Drd2 levels in tissue from the same structure collected from 26 individuals with and without schizophrenia, scientists reported that protein levels were higher in patients with the disease.
As further evidence of Drd2’s role in disrupting signals from the auditory thalamus, researchers tested neurons in the laboratory from different brain regions of mutant and normal mice by adding antipsychotic drugs haloperidol and clozapine. Those drugs work by targeting Drd2. Originally nerve impulses in the mutant neurons were reduced compared to normal mice. But the nerve impulses were almost universally enhanced by antipsychotics in neurons from mutant mice, but only in neurons from the auditory thalamus.
When researchers looked more closely at the missing 22q11 genes, they found that mice that lacked the Dgcr8 responded to a loud noise in a similar manner as schizophrenia patients. Treatment with haloperidol restored the normal startle response in the mice, just as the drug does in patients.
Studying schizophrenia and other brain disorders advances understanding of normal brain development and the missteps that lead to various catastrophic diseases, including pediatric brain tumors and other problems.
(Source: stjude.org)
Environmental Influences May Cause Autism in Some Cases
Research by scientists at Albert Einstein College of Medicine of Yeshiva University may help explain how some cases of autism spectrum disorder (ASD) can result from environmental influences rather than gene mutations. The findings, published online today in PLOS Genetics, shed light on why older mothers are at increased risk for having children with ASD and could pave the way for more research into the role of environment on ASD.
The U.S. Centers for Disease Control and Prevention announced in March that one in 68 U.S. children has an ASD—a 30 percent rise from 1 in 88 two years ago. A significant number of people with an ASD have gene mutations that are responsible for their condition. But a number of studies—particularly those involving identical twins, in which one twin has ASD and the other does not—show that not all ASD cases arise from mutations.
In fact, a major study of more than 14,000 children with ASDs published earlier this month in the Journal of the American Medical Association concluded that gene abnormalities could explain only half the risk for developing ASD. The other half of the risk was attributable to “nongenetic influences,” meaning environmental factors that could include the conditions in the womb or a pregnant woman’s stress level or diet.
(Source: einstein.yu.edu)
Citizens help researchers to challenge scientific theory
Science crowdsourcing was used to disprove a widely held theory that “supertasters” owe their special sensitivity to bitter tastes to an usually high density of taste buds on their tongue, according to a study published in the open-access journal Frontiers in Integrative Neuroscience.
Supertasters are people who can detect and are extremely sensitive to phenylthiocarbamide and propylthiouracil, two compounds related to the bitter molecules in certain foods such as broccoli and kale. Supertasting has been used to explain why some people don’t like spicy foods or “hoppy” beers, or why some kids are picky eaters.
The sensitivity to these bitter tastants is partly due to a variation in the taste receptor gene TAS2R38. But some scientists believe that the ability to supertaste is also boosted by a greater-than-average number of “papillae”, bumps on the tongue that contain taste buds. Nicole Garneau, Curator and Chair of the Department of Health Sciences, Denver Museum of Nature & Science, and colleagues tested if this is true.
"There is a long-held belief that if you stick out your tongue and look at the bumps on it, then you can predict how sensitive you are to strong tastes like bitterness in vegetables and strong sensations like spiciness," says Garneau. "The commonly accepted theory has been that the more bumps you have, the more taste buds you have and therefore the more sensitive you are."
Over 3000 visitors to the museum’s Genetics of Taste Lab volunteered to stick their tongue out so that their papillae could be counted and their sensitivity to phenylthiocarbamide and propylthiouracil measured. In total, 394 study subjects were included in the analysis. Cell swabs from volunteers were taken to determine their DNA sequence at TAS2R38. Results confirmed that certain variations in TAS2R38 make it more likely that somebody is sensitive to bitter, but also proved that the number of papillae on the tongue does not affect increased taste sensitivity.
"No matter how we looked at the data, we couldn’t replicate this long held assumption that a high number of papillae equals supertasting," says Garneau.
The authors argue against the continued misuse of the term supertaster, and for the use of the more objective term hypergeusia – abnormally sensitized taste – to describe people who are sensitive to all tastes and sensations from food.
"What we know and understand about how our bodies work improves greatly when we challenge central dogmas of our knowledge. This is the nature of science itself," adds Garneau. "As techniques improve, so too does our ability to do science, and we find that what we accepted as truth 20, 30, or 100 years ago gets replaced with better theories as we gather new data, which advances science. In this case, we’ve proven that with the ‘Denver Papillae Protocol’, our new method for objective analysis for papillae density, we were unable to replicate well-known studies about supertasting."
What make this study unique is that most of the results were collected by citizen scientists including over 130 volunteers who had been specially trained by Garneau and her colleagues. The Genetics of Taste Lab is located in the heart of the museum, uniquely situated to attract volunteers and dedicated citizen scientists who conduct population-based research about human genetics, taste, and health.
Uncovering Clues to the Genetic Cause of Schizophrenia
The overall number and nature of mutations—rather than the presence of any single mutation—influences an individual’s risk of developing schizophrenia, as well as its severity, according to a discovery by Columbia University Medical Center researchers published in the latest issue of Neuron. The findings could have important implications for the early detection and treatment of schizophrenia.
Maria Karayiorgou, MD, professor of psychiatry and Joseph Gogos, MD, PhD, professor of physiology and cellular biophysics and of neuroscience, and their team sequenced the “exome”—the region of the human genome that codes for proteins—of 231 schizophrenia patients and their unaffected parents. Using this data, they demonstrated that schizophrenia arises from collective damage across several genes.
“This study helps define a specific genetic mechanism that explains some of schizophrenia’s heritability and clinical manifestation,” said Dr. Karayiorgou, who is acting chief of the Division of Psychiatric and Medical Genetics at the New York State Psychiatric Institute. “Accumulation of damaged genes inherited from healthy parents leads to higher risk not only to develop schizophrenia but also to develop more severe forms of the disease.”
Schizophrenia is a severe psychiatric disorder in which patients experience hallucination, delusion, apathy and cognitive difficulties. The disorder is relatively common, affecting around 1 in every 100 people, and the risk of developing schizophrenia is strongly increased if a family member has the disease. Previous research has focused on the search for individual genes that might trigger schizophrenia. The availability of new high-throughput DNA sequencing technology has contributed to a more holistic approach to the disease.
The researchers compared sequencing data to look for genetic differences and identify new loss-of-function mutations—which are rarer, but have a more severe effect on ordinary gene function—in cases of schizophrenia that had not been inherited from the patients’ parents. They found an excess of such mutations in a variety of genes across different chromosomes.
Using the same sequencing data, the researchers also looked at what types of mutations are commonly passed on to schizophrenia patients from their parents. It turns out that many of these are “loss-of-function” types. These mutations were also found to occur more frequently in genes with a low tolerance for genetic variation.
“These mutations are important signposts toward identifying the genes involved in schizophrenia,” said Dr. Karayiorgou.
The researchers then looked more deeply into the sequencing data to try to determine the biological functions of the disrupted genes involved in schizophrenia. They were able to verify two key damaging mutations in a gene called SETD1A, suggesting that this gene contributes significantly to the disease.
SETD1A is involved in a process called chromatin modification. Chromatin is the molecular apparatus that packages DNA into a smaller volume so it can fit into the cell and physically regulates how genes are expressed. Chromatin modification is therefore a crucial cellular activity.
The finding fits with accumulating evidence that damage to chromatin regulatory genes is a common feature of various psychiatric and neurodevelopmental disorders. By combining the mutational data from this and related studies on schizophrenia, the authors found that “chromatin regulation” was the most common description for genes that had damaging mutations.
“A clinical implication of this finding is the possibility of using the number and severity of mutations involved in chromatin regulation as a way to identify children at risk of developing schizophrenia and other neurodevelopmental disorders,” said Dr. Gogos. “Exploring ways to reverse alterations in chromatic modification and restore gene expression may be an effective path toward treatment.”
In further sequencing studies, the researchers hope to identify and characterize more genes that might play a role in schizophrenia and to elucidate common biological functions of the genes.
Fruit flies ‘think’ before they act
Oxford University neuroscientists have shown that fruit flies take longer to make more difficult decisions.
In experiments asking fruit flies to distinguish between ever closer concentrations of an odour, the researchers found that the flies don’t act instinctively or impulsively. Instead they appear to accumulate information before committing to a choice.
Gathering information before making a decision has been considered a sign of higher intelligence, like that shown by primates and humans.
'Freedom of action from automatic impulses is considered a hallmark of cognition or intelligence,' says Professor Gero Miesenböck, in whose laboratory the new research was performed. 'What our findings show is that fruit flies have a surprising mental capacity that has previously been unrecognised.'
The researchers also showed that the gene FoxP, active in a small set of around 200 neurons, is involved in the decision-making process in the fruit fly brain.
The team reports its findings in the journal Science. The group was funded by the Wellcome Trust, the Gatsby Charitable Foundation, the US National Institutes of Health and the Oxford Martin School.
The researchers observed Drosophila fruit flies make a choice between two concentrations of an odour presented to them from opposite ends of a narrow chamber, having been trained to avoid one concentration.
When the odour concentrations were very different and easy to tell apart, the flies made quick decisions and almost always moved to the correct end of the chamber.
When the odour concentrations were very close and difficult to distinguish, the flies took much longer to make a decision, and they made more mistakes.
The researchers found that mathematical models developed to describe the mechanisms of decision making in humans and primates also matched the behaviour of the fruit flies.
The scientists discovered that fruit flies with mutations in a gene called FoxP took longer than normal flies to make decisions when odours were difficult to distinguish – they became indecisive.
The researchers tracked down the activity of the FoxP gene to a small cluster of around 200 neurons out of the 200,000 neurons in the brain of a fruit fly. This implicates these neurons in the evidence-accumulation process the flies use before committing to a decision.
Dr Shamik DasGupta, the lead author of the study, explains: ‘Before a decision is made, brain circuits collect information like a bucket collects water. Once the accumulated information has risen to a certain level, the decision is triggered. When FoxP is defective, either the flow of information into the bucket is reduced to a trickle, or the bucket has sprung a leak.’
Fruit flies have one FoxP gene, while humans have four related FoxP genes. Human FoxP1 and FoxP2 have previously been associated with language and cognitive development. The genes have also been linked to the ability to learn fine movement sequences, such as playing the piano.
'We don't know why this gene pops up in such diverse mental processes as language, decision-making and motor learning,' says Professor Miesenböck. However, he speculates: 'One feature common to all of these processes is that they unfold over time. FoxP may be important for wiring the capacity to produce and process temporal sequences in the brain.'
Professor Miesenböck adds: ‘FoxP is not a “language gene”, a “decision-making gene”, even a “temporal-processing” or “intelligence” gene. Any such description would in all likelihood be wrong. What FoxP does give us is a tool to understand the brain circuits involved in these processes. It has already led us to a site in the brain that is important in decision-making.’
New insights could boost treatment for P addiction
A Kiwi researcher’s discovery of new ways methamphetamine can alter the brain could help the development of new drug-based therapies for addiction treatment.
In 2009, New Zealand had one of the highest rates of P users in the world, and today, more than 25,000 Kiwis were estimated to still be using the drug.
Now, new research by a Victoria of University of Wellington graduate has provided valuable insights into how the brain’s natural reward pathways are strongly stimulated following exposure to methamphetamine.
Risk of brain injury is genetic
University researchers have identified a link between injury to the developing brain and common variation in genes associated with schizophrenia and the metabolism of fat.
The study builds on previous research, which has shown that being born prematurely - before 37 weeks - is a leading cause of learning and behavioural difficulties in childhood.
Around half of infants weighing less than 1500g at birth go on to experience difficulties in learning and attention at school age.
Unique collaboration
Scientists at Edinburgh, Imperial College London and King’s College London studied genetic samples and MRI scans of more than 80 premature infants at the time of discharge from hospital.
The tests and scans revealed that variation in the genetic code of genes known as ARVCF and FADS2 influenced the risk of brain injury on MRI in the babies.
Global challenge
Premature births account for 10 per cent of all births worldwide, according to experts.
Earlier research has shown that being born preterm is closely related to abnormal brain development and poor neurodevelopmental outcome.
However, scientists say that they do not fully understand the processes that lead to these problems in some infants.
Researchers add that future studies could look at how changes in these genes may bring about this risk of - or resilience - to brain injury.
Environmental factors such as degree of prematurity at birth and infection play a part, but, as our study has found, they are not the whole story and genetic factors have a role in conferring risk or resilience. We hope that our findings will lead to new understanding about the mechanisms that lead to brain injury and ultimately new neuroprotective treatment strategies for preterm babies.-Dr James Boardman (Scientific director of the Jennifer Brown Research Laboratory at the MRC Centre for Reproductive Health at the University of Edinburgh)
(Image: Thinkstock)
Researchers Identify Genetic Marker Linked to OCD
A group of researchers led by Johns Hopkins scientists say they have identified a genetic marker that may be associated with the development of obsessive-compulsive disorder (OCD), whose causes and mechanisms are among the least understood among mental illnesses.
The results of the research are published online May 13 by the journal Molecular Psychiatry.
“If this finding is confirmed, it could be useful,” says study leader Gerald Nestadt, M.D., M.P.H., a professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and director of Johns Hopkins’ Obsessive-Compulsive Disorder Program. “We might ultimately be able to identify new drugs that could help people with this often disabling disorder, one for which current medications work only 60 to 70 percent of the time.”
Nestadt and his team conducted what is known as a genome-wide association study, scanning the genomes of more than 1,400 people with OCD and more than 1,000 close relatives of people with the mental disorder. A significant association was identified in OCD patients near a gene called protein tyrosine phosphokinase (PTPRD).
OCD is a condition marked by thoughts and images that chronically intrude in the mind and by repetitive behaviors aimed at reducing the associated anxiety. Some of the least disabling forms of the disorder can add an extra hour to the day’s routine, causing distress and interfering with daily life. Some people are so disabled that they can’t leave their homes.
Experts say OCD affects an estimated 1 to 2 percent of the U.S. population, and the World Health Organization has called it one of the more disabling medical conditions worldwide. Antidepressants known as SSRIs work for some people, but not everyone; the same is true of behavioral therapy.
Nestadt says the genome-wide association study findings of a PTRPD-OCD link add to evidence that the genetic region they identified is important. The gene has already been shown in animals to be possibly involved in learning and memory, traits influenced by OCD in humans. Moreover, some cases of attention-deficit hyperactivity disorder (ADHD) have been associated with the gene, and OCD and ADHD have some symptoms in common. He says the gene also works with another gene family, SLITRK, which has also been associated with OCD in animals.
“OCD research has lagged behind other psychiatric disorders in terms of genetics,” Nestadt says. “We hope this interesting finding brings us closer to making better sense of it — and helps us find ways to treat it.”
(Image credit: Jennifer Soo)
Temper trap: the genetics of aggression and self-control
Everyone knows someone with a quick temper – it might even be you. And while scientists have known for decades that aggression is hereditary, there is another biological layer to those angry flare-ups: self-control.
In a paper published earlier this year in the Journal of Cognitive Neuroscience, my colleagues and I found that people who are genetically predisposed toward aggression try hard to control their anger, but have inefficient functioning in brain regions that control emotions.
In other words, self-control is, in part, biological.