Posts tagged gene mutations
Articles and news from the latest research reports.
Gene Technique Identifies Hidden Causes of Brain Malformation
Howard Hughes Medical Institute (HHMI) scientists have developed a strategy for finding disease-causing mutations that lurk in only a small fraction of the body’s cells. Such mutations can cause significant problems, but cannot be detected with traditional methods of genetic testing, as well as newer, more costly genome sequencing technologies.
The scientists report in the August 21, 2014, issue of the New England Journal of Medicine, that they used the technique to find disease-causing mutations in patients with brain malformations whose genetic causes were unknown despite previous testing.
By sequencing hundreds of copies of the genes in a panel of candidate genes, scientists led by HHMI investigator Christopher A. Walsh identified somatic mutations—gene mutations present in some, but nor all, cells – in more than a quarter of patients that could be successfully diagnosed genetically. Walsh and his colleagues, including Saumya Jamuar, a clinical fellow in Walsh’s lab at Boston Children’s Hospital who is now at the KK Women’s and Children’s Hospital in Singapore and Timothy Yu, also at Boston Children’s Hospital, were authors of the study.
Walsh says his team was surprised to discover so many somatic mutations in patients who had already undergone genetic testing. “This tells us just how poorly other methods perform in detecting somatic mutations,” he says. “You’re not going to find these things unless you go looking for them—unless you have a clinical test that is set up to detect them in a sensitive way.”
Somatic mutations are not inherited from parents, but instead, arise sometime after fertilization. They are most often seen in some forms of cancer, in which genetic differences between tumor cells and the rest of the body drive tumor growth and metastasis. But they’ve been implicated in other diseases, as well.
“Somatic mutations have been discovered to cause milder forms of a wide range of diseases, especially neuropsychiatric ones,” Walsh says, citing as examples Rett syndrome and tuberous sclerosis, two disorders that cause seizures and intellectual disability. In his own lab, he had found that some of his patients with double cortex syndrome, a brain malformation that can cause some of the same kinds of neurological problems, have somatic mutations. And in a new study published August 21, 2014, in Cell Reports, Walsh’s team analyzed the genomes of individual cells in healthy and diseased brains and found that large segments of DNA had been duplicated or deleted in most cells. “No neuron’s genome is pristine,” he says. “There’s a lot of variability, and some of these mutations have occurred at a stage where they’re present in more than one cell.”
“We think these somatic mutations are probably more common as causes of intellectual disability, and maybe even some psychiatric conditions, than people have generally realized.” Walsh says. “It’s really time to start investigating that systematically.”
He decided to begin with his own patients. A genetic diagnosis is important for counseling patients and their parents about risks to future children, and can, in some cases, influence treatment decisions. But many patients who had come to Walsh’s lab with neurodevelopmental problems were still without answers. “We’d successfully identified causative mutations in many families. But there remained a subset where—even after 10 or more years of searching—we had been unable to identify the causative genes. This made us wonder whether there might be certain kinds of mutations not well discovered by present methods,” he says.
Walsh’s team questioned whether it had missed somatic mutations in those patients by using traditional methods of genetic testing? It seemed possible. Those techniques are not designed to find mutations that occur only in a small fraction of cells, Walsh says. “Even if you are looking at the right gene, you can still miss the mutation.”
Most diagnostic gene testing is done by sequencing specific genes using a traditional DNA sequencing technique known as the Sanger method. When this strategy fails, the search for mutations is sometimes broadened to all of the protein-coding regions of the genome—the exome—or further, to the entire genome. Both approaches have limitations, Walsh says.
“Whole-exome sequencing tends to sample the genome about 30 or 50 times over,” he explains. “But if a mutation is only in five or 10 percent of the cells, then it’s only going to be in a very small fraction of the data, and it’s hard to separate from the noise. The same is true of Sanger sequencing: it has not been optimized to detect a mutation that’s present in a small fraction of the reads.”
To find the kinds of mutations they were looking for, Walsh’s team knew they would have to deepen their search. They devised a strategy in which they would use next-generation sequencing technology to sequence a panel of genes known or suspected to be associated with brain malformations. “We said we’d shoot to sequence them a thousand times over,” Walsh says. “Even if a mutation is only present in five percent of the cells, it will be obvious that it’s a mutation, because we’ll see that mutation 50 times.”
Jamuar set up a test to screen blood samples from 158 patients whose brain malformations remained unexplained. For each patient, a panel of 14 or 54 genes (depending on the patient’s condition) was sequenced hundreds or thousands of times. The design of the panel and sequencing took about 2-3 months to carry out. He then fine-tuned existing bioinformatics algorithms to search for somatic mutations in the sequences. Though the initial sequencing was fast, follow-up validation of potential somatic mutations took additional months because it remains labor-intensive.
In this way, the team uncovered mutations likely to cause disease—either because their role was already known or because they disrupted protein function—in 27 of the 158 patients in their study. Eight of these were somatic mutations, present in just five to 35 percent of the sequenced DNA. Jamuar confirmed these sequencing findings with laboratory experiments in which the patients’ DNA was replicated in bacterial cells and analyzed by Sanger sequencing.
“We have a genetic diagnosis. This ends the diagnostic odyssey for these eight individuals,” says Jamuar.
Five of the eight somatic mutations that they identified would never have been found with traditional sequencing methods, the scientists say. “All of the mutations that were present at less than about 15 percent of the reads were completely undetectable by Sanger sequencing,” Walsh says. “One of them had been missed by whole-exome sequencing, as well.”
“The gold standard of clinical diagnosis is Sanger sequencing,” Jamuar adds. “But you’re missing a big chunk of patients with mutations in these genes, because you are using a test that’s not designed to look for them.”
Now that they have demonstrated their method’s sensitivity in detecting somatic mutations, Walsh and Jamuar say medical geneticists should consider using the approach before turning to more costly whole-exome sequencing. Neither offers a single solution for all patients, but their complementary strengths give geneticists a more complete set of tools. “Look deep, and you may find the answer,” says Jamuar.
Overhaul of our understanding of why autism potentially occurs
An analysis of autism research covering genetics, brain imaging, and cognition led by Laurent Mottron of the University of Montreal has overhauled our understanding of why autism potentially occurs, develops and results in a diversity of symptoms. The team of senior academics involved in the project calls it the “Trigger-Threshold-Target” model. Brain plasticity refers to the brain’s ability to respond and remodel itself, and this model is based on the idea that autism is a genetically induced plastic reaction. The trigger is multiple brain plasticity-enhancing genetic mutations that may or may not combine with a lowered genetic threshold for brain plasticity to produce either intellectual disability alone, autism, or autism without intellectual disability. The model confirms that the autistic brain develops with enhanced processing of certain types of information, which results in the brain searching for materials that possess the qualities it prefers and neglecting materials that don’t. “One of the consequences of our new model will be to focus early childhood intervention on developing the particular strengths of the child’s brain, rather than exclusively trying to correct missing behaviors, a practice that may be a waste of a once in a lifetime opportunity,” Mottron said.
Mottron and his colleagues developed the model by examining the effect of mutations involved in autism together with the brain activity of autistic people as they undertake perceptual tasks. “Geneticists, using animals implanted with the mutations involved in autism, have found that most of them enhance synaptic plasticity – the capacity of brain cells to create connections when new information is encountered. In parallel, our group and others have established that autism represents an altered balance between the processing of social and non-social information, i.e. the interest, performance and brain activity, in favor of non-social information,” Mottron explained. “The Trigger-Threshold-Target model builds a bridge between these two series of facts, using the neuro cognitive effects of sensory deprivation to resolve the missing link between them.”
The various superiorities that subgroups of autistic people present in perception or in language indicates that an autistic infant’s brain adapts to the information it is given in a strikingly similar way to sensory-deprived people. A blind infant’s brain compensate the lack of visual input by developing enhanced auditory processing abilities for example, and a deaf infant readapts to process visual inputs in a more refined fashion. Similarly, cognitive and brain imaging studies of autistic people work reveal enhanced activity, connectivity and structural modifications in the perceptive areas of the brain. Differences in the domain of information “targeted” by these plastic processes are associated with the particular pattern of strengths and weaknesses of each autistic individual. “Speech and social impairment in some autistic toddlers may not be the result of a primary brain dysfunction of the mechanisms related to these abilities, but the result of their early neglect,” Mottron said. “Our model suggests that the autistic superior perceptual processing compete with speech learning because neural resources are oriented towards the perceptual dimensions of language, neglecting its linguistic dimensions. Alternatively, for other subgroups of autistic people, known as Asperger, it’s speech that’s overdeveloped. In both cases, the overdeveloped function outcompetes social cognition for brain resources, resulting in a late development of social skills.”
The model provides insight into the presence or absence of intellectual disability, which when causative mutation alter the function of brain cell networking. Rather than simply triggering a normal but enhanced plastic reaction, these mutations cause neurons to connect in a way that does not exist in non-autistic people. When brain cell networking functions normally, only the allocation of brain resources is changed.
As is the case with all children, environment and stimulation have an effect on the development and organization of an autistic child’s brain. “Most early intervention programs adopt a restorative approach by working on aspects like social interest. However this focus may monopolize resources in favor of material that the child process with more difficulties, Mottron said. “We believe that early intervention for autistic children should take inspiration from the experience of congenitally deaf children, whose early exposure to sign language has a hugely positive effect on their language abilities. Interventions should therefore focus on identifying and harnessing the autistic child’s strengths, like written language.” By indicating that autistic ‘’restricted interests” result from cerebral plasticity, this model suggest that they have an adaptive value and should therefore be the focus of intervention strategies for autism.
(Source: nouvelles.umontreal.ca)
Brain Response to Appetizing Food Cues Varies Among Obese People
People who have the most common genetic mutation linked to obesity respond differently to pictures of appetizing foods than overweight or obese people who do not have the genetic mutation, according to a new study published in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism (JCEM).
More than one-third of adults are obese. Obesity typically results from a combination of eating too much, getting too little physical activity and genetics. In particular, consumption of appetizing foods that are high in calories can lead to weight gain. Highly palatable foods such as chocolate trigger signals in the brain that give a feeling of pleasure and reward. These cravings can contribute to overeating. Reward signals are processed in specific areas of the brain, where sets of neurons release chemicals such as dopamine. However, very little is known about whether the reward centers of the brain work differently in some people who are overweight or obese.
The most common genetic cause of obesity involves mutations in the melanocortin 4 receptor (MC4R), which occur in about 1 percent of obese people and contribute to weight gain from an early age. The researchers compared three groups of people: eight people who were obese due to a problem in the MC4R gene, 10 people who were overweight or obese without the gene mutation and eight people who were normal weight. They performed functional Magnetic Resonance Imaging (fMRI) scans to look at how the reward centers in the brain were activated by pictures of appetizing food such as chocolate cake compared to bland food such as rice or broccoli and non-food items such as staplers.
“In our study, we found that people with the MC4R mutation responded in the same way as normal weight people, while the overweight people without the gene problem had a lower response,” said lead researcher Agatha van der Klaauw, MD, PhD, of the Wellcome Trust-MRC Institute of Metabolic Science at Addenbrooke’s Hospital in Cambridge, U.K. “In fact, the brain’s reward centers light up when people with the mutation and normal weight people viewed pictures of appetizing foods. But overweight people without the mutation did not have the same level of response.”
The scans revealed that obese people with the MC4R mutation had similar activity in the reward centers of the brain when shown a picture of a dessert like cake or chocolate as normal weight people. The researchers found that, in contrast, the reward centers were underactive in overweight and obese volunteers who did not have the gene mutation. This finding is intriguing as it shows a completely different response in two groups of people of the same age and weight.
“For the first time, we are seeing that the MC4R pathway is involved in the brain’s response to food cues and its underactivity in some overweight people,” van der Klaauw said. “Understanding this pathway may help in developing interventions to limit the overconsumption of highly palatable foods that can lead to weight gain.”
To address the obesity epidemic, the Cambridge team is continuing to study the pathways in the brain that coordinate the need to eat and the reward and pleasure of eating
(Source: endocrine.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)
Genetic legacy from the Ottoman Empire: Single mutation causes rare brain disorder
An international team of researchers have identified a previously unknown neurodegenerative disorder and discovered it is caused by a single mutation in one individual born during the height of the Ottoman Empire in Turkey about 16 generations ago.
(Image caption: An fMRI scan of the brain of a patient with CLP1 mutation reveals severe atrophy of the brainstem (red line) and cerebellum (blue) as well as lack of formation of the corpus callosum (green), which connects both sides of the cerebrum (yellow), which is also atrophied. The lines outline approximately the expected sizes of the brain areas. A study traced the mutation to a single individual born in Turkey during the Ottoman Empire, some 16 generations ago.)
The genetic cause of the rare disorder was discovered during a massive analysis of the individual genomes of thousands of Turkish children suffering from neurological disorders.
“The more we learn about basic mechanisms behind rare forms of neuro-degeneration, the more novel insights we can gain into more common diseases such as Alzheimer’s or Lou Gehrig’s Disease,” said Murat Gunel, the Nixdorff-German Professor of Neurosurgery, and professor of genetics and neurobiology at Yale.
Gunel is a senior co-author of one of two papers published in the April 24 issue of the journal Cell that document the devastating effects of a mutation in the CLP1 gene. Gunel and colleagues at Yale Center for Mendelian Genomics along with Joseph Gleeson’s group at University of California-San Diego compared DNA sequencing results of more than 2,000 children from different families with neurodevelopmental disorders. In four apparently unrelated families, they identified the exact same mutation in the CLP1 gene. Working with the Frank Bass group from the Netherlands, the researchers also studied how CLP1 mutations interfered with the transfer of information encoded within genes to cells’ protein-making machinery.
The discovery of the identical mutation in seemingly unrelated families originally from eastern Turkey suggested an ancestral mutation, dating back several generations, noted the researchers.
Affected children suffer from intellectual disability, seizures, and delayed or absent mental and motor development, and their imaging studies show atrophy affecting the cerebral cortex, cerebellum, and the brain stem.
The second Cell paper by researchers from Baylor School of Medicine and Austria also found the identical founder mutation in CLP1 in another 11 children from an additional five families originally from eastern Turkey.
Gunel said that the high prevalence of consanguineous marriages [between closely related people] in Turkey and the Middle East leads to these rare recessive genetic neurodegenerative disorders. Affected children inherit mutations in the same gene from both of their parents, who are closely related to each other, such as first cousins. Without consanguinity between parents, children are very unlikely to inherit two mutations in the same gene.
“By dissecting the genetic basis of these neurodevelopmental disorders, we are gaining fundamental insight into basic physiological mechanisms important for human brain development and function” Gunel said. “We learn a lot about normal biology by studying what happens when things go wrong.”
(Source: news.yale.edu)
Researcher discovers two new genes linked to intellectual disability
Researchers at the Centre for Addiction and Mental Health have discovered two new genes linked to intellectual disability, according to two research studies published concurrently in early March in the journals Human Genetics and Human Molecular Genetics.
“Both studies give clues to the different pathways involved in normal neurodevelopment,” says CAMH Senior Scientist Dr. John Vincent, who heads the MiND (Molecular Neuropsychiatry and Development) Laboratory in the Campbell Family Mental Health Research Institute at CAMH. “We are building up a body of knowledge that is informing us which kinds of genes are important to, and involved in, intellectual disabilities.”
In the first study, Dr. Vincent and his team used microarray genotyping to map the genes of a large consanguineous (intermarriage within the extended family) Pakistani family, in which five members of the youngest generation were affected with mild to moderate intellectual disability. Dr. Vincent identified a truncation in the FBXO31 gene, which plays a role in the way that proteins are processed during neuronal development, particularly in the cerebellar cortex.
In the second study, using the same techniques, Dr. Vincent and his team analyzed the genes of two consanguineous families, one Austrian and one Pakistani, and identified a disruption in the METTL23 gene linked to mild recessive intellectual disability. The METTL23 gene is involved in methylation—a process important to brain development and function.
About one per cent of children worldwide are affected by non-syndromic (i.e., the absence of any other clinical features) intellectual disability, a condition characterized by an impaired capacity to learn and process new or complex information, leading to decreased cognitive functioning and social adjustment. Although trauma, infection and external damage to the unborn fetus can lead to an intellectual disability, genetic defects are a principal cause.
These studies were part of an ongoing study of affected families in Pakistan, where the cultural tradition of large families and consanguineous marriages among first cousins increases the likelihood of inherited intellectual disability in offspring.
“Although it is easier to find and track genes in consanguineous families, these genes are certainly not limited to them,” Dr. Vincent points out. A recent study estimated that 13–24 per cent of intellectual disability cases among individuals of European descent have autosomal recessive causes, meaning that results of this study are very relevant to populations such as Canada.
Autosomal recessive gene mutations have traditionally been more difficult to trace, resulting in a paucity of research in this area. Parents of affected children show no symptoms, and the child must inherit one defective copy of the gene from each parent, so that only one in four offspring are likely to be affected. Smaller families, therefore, show a decreased incidence and are less amenable to this kind of study.
Dr. Vincent is currently engaged in a study that will screen Canadian populations with autism and intellectual disability for autosomal recessive gene mutations. Results will be available later this year.
A total of 42 genes linked to non-syndromic autosomal recessive forms of intellectual disability have now been identified; estimates suggest that up to 2,500 autosomal genes might be linked with intellectual disability, the majority being recessive.
(Source: camh.ca)
Why ‘Good Hair’ Matters: The first animal model of recent human evolution reveals that a mutation for thick hair does much more
The first animal model of recent human evolution reveals that a single mutation produced several traits common in East Asian peoples, from thicker hair to denser sweat glands, an international team of researchers reports.
The team, led by researchers from Harvard Medical School, Harvard University, the Broad Institute of MIT and Harvard, Massachusetts General Hospital, Fudan University and University College London, also modeled the spread of the gene mutation across Asia and North America, concluding that it most likely arose about 30,000 years ago in what is today central China. The findings are reported in the cover story of the Feb. 14 issue of Cell.
“This interdisciplinary approach yields unique insight into the generation of adaptive variation among modern humans,” said Pardis Sabeti, associate professor in the Center for Systems Biology and Department of Organismic and Evolutionary Biology at Harvard University, and one of the paper’s senior authors. Sabeti is also a senior associate member at the Broad Institute.
“This paper tells a story about human evolution in three parts,” said Cliff Tabin, head of the HMS Department of Genetics and co-senior author. “The mouse model links multiple traits to a single mutation, the related association study finds these traits in humans, and computer models tell us where and when the mutation likely arose and spread.”
Research by scientists from the Centre for Brain Research at the University of Auckland has uncovered new information about the mechanisms underlying autism spectrum disorders (ASDs), to be published in the next issue of the prestigious Journal of Neuroscience.
Principal investigator, Dr Johanna Montgomery, says the findings are highly significant: “We’re moving beyond simply what happens in ASDs and starting to understand how it happens.”
The behavioural manifestations of ASDs are well documented and include impaired communication and socialisation, learning difficulties, and repetitive or stereotyped behaviours. These behavioural characteristics are in turn associated with a wide range of gene mutations. Many of these mutated genes are responsible for the production of specific proteins in the neurons of the brain.
Dr Montgomery and her team took a close look at parts of these neurons – the synapses, which are the structures that enable brain cells to communicate with each other. This cell to cell communication is vital for a healthy brain, and underlies how we learn, remember, move and sense.
In a complex cascade of chemical and electrical signalling, information is transmitted from one neuron to another at the synapses. This process is mediated by several families of protein, some of which form the bedrock of the synapse on the ‘listening’ side. Dr Montgomery’s team chose to investigate one of these proteins, known as Shank3, because it has been identified as vital to the communication process between two neurons, and because it is known to be mutated in ASDs.