Posts tagged genes
Articles and news from the latest research reports.
Genes exhibit different behaviours in different stages of development
The effect that genes have on our brain depends on our age. These are the findings of a group of researchers from the MedUni Vienna. It has been known for a number of years that particular genetic variations are of importance for the functioning of neural circuits in the brain. Just how these effects differ in the various stages of life has until recently not been fully understood. This international study has been able to demonstrate that genetic variations at different times in our lives can actually have opposite effects on the brain, which provides an explanation for the differences that clinicians observe in the psychiatric symptoms and response to medications of adolescents and adults.
The group of researchers from Vienna, in collaboration with international cooperation partners, has shown that the effect of a psychiatric risk gene on a resting state network in the forebrain depends greatly on the patient’s age.
The human forebrain is crucial for planning and action, which are closely interwoven with concentration, attention and memory functions. The nerve transmitter substance dopamine orchestrates the activity of neurons in the forebrain in order to ensure an ideal level of functioning. The amount of dopamine in the brain is not constant for life, however. Instead, it rises until adolescence and then falls by the time the individual reaches early adulthood to a much lower level. When the dopaminergic control function collapses, serious mental illnesses such as schizophrenia, depression or attention deficit / hyperactivity disorder (ADHD) can result that usually start around the period of transition to adulthood.
For a number of years, doctors have known that a risk gene involved in dopamine metabolism (COMT) can affect neuronal regulation of the forebrain in adults. Carriers of risk gene variants are more prone to dopaminergic mental illness.
The interaction of genes and stages of development
As part of the study, carried out at the MedUni Vienna’s University Department of Psychiatry and Psychotherapy (led by Siegfried Kasper), the study team used magnetic resonance imaging data from a large random sample of over 200 test subjects to analyse the complex interaction between stages of development and genetic variations in the COMT gene and how it affects the resting state network of the forebrain.
Some of the magnetic resonance scans were performed in Vienna (Centre of Excellent, High-Field MR, Department of MR Physics, Head: Ewald Moser) and some as part of an EU project (Institute of Psychiatry, London, Head: Gunther Schumann). Gene analyses (COMT Val158Met) were carried out in Vienna (Univ. Dept. of Laboratory Medicine, Harald Esterbauer and colleagues) or as part of the EU project.
"Our age has a crucial influence on the effects of psychiatric risk genes. A gene that has positive effects during puberty can be bad for us in adulthood," says study leader Lukas Pezawas, describing the results. In the study, adolescents exhibited contrary gene effects on the brain compared to adults.
The study highlights the dynamism of gene effects on brain function throughout the various stages of life such as adolescence or adulthood. “These results are important for understanding the onset of illness in conditions such as schizophrenia, depression or ADHD, which mostly occur at the threshold of adulthood. Our results also show that there are fundamental differences in the dopamine system between adolescents and adults, which we need to take into account in future treatments”, explains Pezawas.
(Source: meduniwien.ac.at)
Applying Proteomics to Parkinson’s
Scientists studying two genes that are mutated in an early-onset form of Parkinson’s disease have deciphered how normal versions of these genes collaborate to help rid cells of damaged mitochondria. Mitochondria are the cell’s primary energy source, and maintaining their health is critical for cellular function. Mitochondrial dysfunction may underlie multiple neurodegenerative diseases, including Parkinson’s.
(Image caption: PARKIN (green) is localized on damaged mitochondria. Image: Harper Lab)
In their analysis published in Molecular Cell, Harvard Medical School researchers used powerful quantitative mass spectrometry and live-cell imaging approaches to elucidate a multistep mechanism by which the two proteins mutated in Parkinson’s disease—PINK1 and PARKIN—mark mitochondria as damaged by attaching chains of a small protein called ubiquitin. This work paves the way for a deeper understanding of what molecular steps are defective when these proteins are mutated in patients with Parkinson’s disease.
“The PINK1-PARKIN pathway has been studied for many years, yet its mechanisms weren’t clearly defined,” said Wade Harper, Bert and Natalie Vallee Professor of Molecular Pathology in the Department of Cell Biology at HMS and senior author of the paper. “Combining imaging and advanced mass spectrometry approaches has allowed us for the first time to determine with molecular precision the biochemical output of the PINK1-PARKIN pathway in living cells.”
One hypothesis about the origin of Parkinson’s disease suggests that neurons place high energy demands on their mitochondria. When mitochondria become damaged and their energy production falls, they must be cleared away; if not, cell death results when the damaged mitochondria create harmful chemicals called reactive oxygen species.
People who have certain early-onset mutations in PINK1 or PARKIN genes may live normal lives until they enter their 30s when movement disorders begin to appear, reflecting the loss of neurons that make the neurotransmitter dopamine. These neurons seem to be the cells that are the most sensitive to an inability to remove damaged mitochondria.
Only in the last few years have scientists understood that the enzymes PARKIN and PINK1 work together to remove damaged mitochondria. The PINK1 kinase, an enzyme that transfers phosphate to other proteins, is activated specifically on damaged mitochondria where it then functions to promote accumulation of PARKIN on the mitochondrial surface. Once there, PARKIN—a ubiquitin ligase— marks numerous proteins on the surface of the mitochondria with chains of ubiquitin, which in turn target the damaged mitochondria for removal from the cell.
In their new work, Harper’s team identifies a multistep “feed-forward” mechanism that involves intertwined ubiquitylation and phosphorylation in a sequence of reactions that successively build on one another. To the authors’ knowledge, this is the first report of a feed-forward mechanism of this type.
The team, led by postdoctoral fellow Alban Ordureau, found that PINK1 actually has two functions in a multistep pathway. First, PINK1 phosphorylates PARKIN, greatly stimulating its ability to attach ubiquitin to mitochondrial substrates. Second, PINK1 phosphorylates ubiquitin chains that PARKIN has just built. Unexpectedly, these phosphorylated ubiquitin chains then bind tightly to activated PARKIN, thereby facilitating its retention on the mitochondrial surface and furthering ubiquitin chain assembly through a feed-forward mechanism. Eventually these chains become so dense that the damaged mitochondria are marked for degradation.
“Our finding that PARKIN binds phosphorylated-ubiquitin chains as its mechanism of retention on damaged mitochondria was completely unexpected,” Harper said. “Ubiquitin has been studied for almost 40 years, but only recently has regulation of ubiquitin by phosphorylation emerged as a major focus for the field.”
Methods employed in this study have their origins in prior work of Steven Gygi, HMS professor of cell biology and a co-author of the paper, who developed ways to quantify ubiquitin chains more than a decade ago. Harper says there is “enormous potential in the application of these approaches to understand how defects in the ubiquitin system lead to disease.”
The team also included Brenda Schulman, a Howard Hughes Medical Institute investigator, the co-director of the Cancer Genetics, Biochemistry and Cell Biology Program at St. Jude Children’s Research Hospital and a leading expert on ubiquitin biochemistry.
“This is a very intricate pathway,” Ordureau said. “We were surprised by our findings at every step.”
(Source: hms.harvard.edu)
(Image caption: The hair cells of mice missing just Hey2 are neatly lined up in four rows (left) while those missing Hey1 and Hey2 are disorganized (right). The cells’ hairlike protrusions (pink) can be misoriented, too. Credit: Angelika Doetzlhofer)
Hey1 and Hey2 ensure inner ear ‘hair cells’ are made at the right time, in the right place
Two Johns Hopkins neuroscientists have discovered the “molecular brakes” that time the generation of important cells in the inner ear cochleas of mice. These “hair cells” translate sound waves into electrical signals that are carried to the brain and are interpreted as sounds. If the arrangement of the cells is disordered, hearing is impaired.
A summary of the research will be published in The Journal of Neuroscience on Sept. 16.
"The proteins Hey1 and Hey2 act as brakes to prevent hair cell generation until the time is right," says Angelika Doetzlhofer, Ph.D., an assistant professor of neuroscience. "Without them, the hair cells end up disorganized and dysfunctional."
The cochlea is a coiled, fluid-filled structure bordered by a flexible membrane that vibrates when sound waves hit it. This vibration is passed through the fluid in the cochlea and sensed by specialized hair cells that line the tissue in four precise rows. Their name comes from the cells’ hairlike protrusions that detect movement of the cochlear fluid and create electrical signals that relay the sound to the brain.
During development, “parent cells” within the cochlea gradually differentiate into hair cells in a precise sequence, starting with the cells at the base of the cochlea and progressing toward its tip. The signaling protein Sonic Hedgehog was known to be released by nearby nerve cells in a time- and space-dependent pattern that matches that of hair cell differentiation. But the mechanism of Sonic Hedgehog’s action was unclear.
Doetzlhofer and postdoctoral fellow Ana Benito Gonzalez bred mice whose inner ear cells were missing Hey1 and Hey2, two genes known to be active in the parent cells but turned off in hair cells. They found that, without those genes, the cells were generated too early and were abnormally patterned: Rows of hair cells were either too many or too few, and their hairlike protrusions were often deformed and pointing in the wrong direction.
"While these mice didn’t live long enough for us to test their hearing, we know from other studies that mice with disorganized hair cell patterns have serious hearing problems," says Doetzlhofer.
Further experiments demonstrated the role of Sonic Hedgehog in regulating the two key genes.
"Hey1 and Hey2 stop the parent cells from turning into hair cells until the time is right," explains Doetzlhofer. "Sonic Hedgehog applies those ‘brakes,’ then slowly releases pressure on them as the cochlea develops. If the brakes stop working, the hair cells are generated too early and end up misaligned."
She adds that Sonic Hedgehog, Hey1 and Hey2 are found in many other parent cell types throughout the developing nervous system and may play similar roles in timing the generation of other cell types.
Schizophrenia not a single disease but multiple genetically distinct disorders
New research shows that schizophrenia isn’t a single disease but a group of eight genetically distinct disorders, each with its own set of symptoms. The finding could be a first step toward improved diagnosis and treatment for the debilitating psychiatric illness.
The research at Washington University School of Medicine in St. Louis is reported online Sept. 15 in The American Journal of Psychiatry.
About 80 percent of the risk for schizophrenia is known to be inherited, but scientists have struggled to identify specific genes for the condition. Now, in a novel approach analyzing genetic influences on more than 4,000 people with schizophrenia, the research team has identified distinct gene clusters that contribute to eight different classes of schizophrenia.
“Genes don’t operate by themselves,” said C. Robert Cloninger, MD, PhD, one of the study’s senior investigators. “They function in concert much like an orchestra, and to understand how they’re working, you have to know not just who the members of the orchestra are but how they interact.”
Cloninger, the Wallace Renard Professor of Psychiatry and Genetics, and his colleagues matched precise DNA variations in people with and without schizophrenia to symptoms in individual patients. In all, the researchers analyzed nearly 700,000 sites within the genome where a single unit of DNA is changed, often referred to as a single nucleotide polymorphism (SNP). They looked at SNPs in 4,200 people with schizophrenia and 3,800 healthy controls, learning how individual genetic variations interacted with each other to produce the illness.
In some patients with hallucinations or delusions, for example, the researchers matched distinct genetic features to patients’ symptoms, demonstrating that specific genetic variations interacted to create a 95 percent certainty of schizophrenia. In another group, they found that disorganized speech and behavior were specifically associated with a set of DNA variations that carried a 100 percent risk of schizophrenia.
“What we’ve done here, after a decade of frustration in the field of psychiatric genetics, is identify the way genes interact with each other, how the ‘orchestra’ is either harmonious and leads to health, or disorganized in ways that lead to distinct classes of schizophrenia,” Cloninger said.
Although individual genes have only weak and inconsistent associations with schizophrenia, groups of interacting gene clusters create an extremely high and consistent risk of illness, on the order of 70 to 100 percent. That makes it almost impossible for people with those genetic variations to avoid the condition. In all, the researchers identified 42 clusters of genetic variations that dramatically increased the risk of schizophrenia.
“In the past, scientists had been looking for associations between individual genes and schizophrenia,” explained Dragan Svrakic, PhD, MD, a co-investigator and a professor of psychiatry at Washington University. “When one study would identify an association, no one else could replicate it. What was missing was the idea that these genes don’t act independently. They work in concert to disrupt the brain’s structure and function, and that results in the illness.”
Svrakic said it was only when the research team was able to organize the genetic variations and the patients’ symptoms into groups that they could see that particular clusters of DNA variations acted together to cause specific types of symptoms.
Then they divided patients according to the type and severity of their symptoms, such as different types of hallucinations or delusions, and other symptoms, such as lack of initiative, problems organizing thoughts or a lack of connection between emotions and thoughts. The results indicated that those symptom profiles describe eight qualitatively distinct disorders based on underlying genetic conditions.
The investigators also replicated their findings in two additional DNA databases of people with schizophrenia, an indicator that identifying the gene variations that are working together is a valid avenue to explore for improving diagnosis and treatment.
By identifying groups of genetic variations and matching them to symptoms in individual patients, it soon may be possible to target treatments to specific pathways that cause problems, according to co-investigator Igor Zwir, PhD, research associate in psychiatry at Washington University and associate professor in the Department of Computer Science and Artificial Intelligence at the University of Granada, Spain.
And Cloninger added it may be possible to use the same approach to better understand how genes work together to cause other common but complex disorders.
“People have been looking at genes to get a better handle on heart disease, hypertension and diabetes, and it’s been a real disappointment,” he said. “Most of the variability in the severity of disease has not been explained, but we were able to find that different sets of genetic variations were leading to distinct clinical syndromes. So I think this really could change the way people approach understanding the causes of complex diseases.”
(Source: news.wustl.edu)
Children’s drawings indicate later intelligence
How 4-year old children draw pictures of a child is an indicator of intelligence at age 14, according to a study by the Institute of Psychiatry at King’s College London, published today in Psychological Science.
The researchers studied 7,752 pairs of identical and non-identical twins (a total of 15,504 children) from the Medical Research Council (MRC) funded Twins Early Development Study (TEDS), and found that the link between drawing and later intelligence was influenced by genes.
At the age of 4, children were asked by their parents to complete a ‘Draw-a-Child’ test, i.e. draw a picture of a child. Each figure was scored between 0 and 12 depending on the presence and correct quantity of features such as head, eyes, nose, mouth, ears, hair, body, arms etc. For example, a drawing with two legs, two arms, a body and head, but no facial features, would score 4. The children were also given verbal and non-verbal intelligence tests at ages 4 and 14.
The researchers found that higher scores on the Draw-a-Child test were moderately associated with higher scores of intelligence at ages 4 and 14. The correlation between drawing and intelligence was moderate at ages 4 (0.33) and 14 (0.20).
Dr Rosalind Arden, lead author of the paper from the MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre at the Institute of Psychiatry at King’s College London, says: “The Draw-a-Child test was devised in the 1920’s to assess children’s intelligence, so the fact that the test correlated with intelligence at age 4 was expected.What surprised us was that it correlated with intelligence a decade later.”
“The correlation is moderate, so our findings are interesting, but it does not mean that parents should worry if their child draws badly. Drawing ability does not determine intelligence, there are countless factors, both genetic and environmental, which affect intelligence in later life.”
The researchers also measured the heritability of figure drawing. Identical twins share all their genes, whereas non-identical twins only share about 50 percent, but each pair will have a similar upbringing, family environment and access to the same materials.
Overall, at age 4, drawings from identical twins pairs were more similar to one another than drawings from non-identical twin pairs. Therefore, the researchers concluded that differences in children’s drawings have an important genetic link. They also found that drawing at age 4 and intelligence at age 14 had a strong genetic link.
Dr Arden explains: “This does not mean that there is a drawing gene – a child’s ability to draw stems from many other abilities, such as observing, holding a pencil etc. We are a long way off understanding how genes influence all these different types of behaviour.”
Dr Arden adds: “Drawing is an ancient behaviour, dating back beyond 15,000 years ago. Through drawing, we are attempting to show someone else what’s in our mind. This capacity to reproduce figures is a uniquely human ability and a sign of cognitive ability, in a similar way to writing, which transformed the human species’ ability to store information, and build a civilisation.”
Our genes determine the traces that stress leaves behind on our brains
Our individual genetic make-up determines the effect that stress has on our emotional centres. These are the findings of a group of researchers from the MedUni Vienna. Not every individual reacts in the same way to life events that produce the same degree of stress. Some grow as a result of the crisis, whereas others break down and fall ill, for example with depression. The outcome is determined by a complex interaction between depression gene versions and environmental factors.
The Vienna research group, together with international cooperation partners, have demonstrated that there are interactions between stressful life events and certain risk gene variants that subsequently change the volume of the hippocampus forever.
The hippocampus is a switching station in the processing of emotions and acts like a central interface when dealing with stress. It is known to react very sensitively to stress. In situations of stress that are interpreted as a physical danger (‘distress’), it shrinks in size, which is a phenomenon observed commonly in patients with depression and one which is responsible for some of their clinical symptoms. By contrast, positive stress (‘eustress’), of the kind that can occur in emotionally exciting social situations can actually cause the hippocampus to increase in size.
According to the results of the study, just how stressful life events impact on the size of the hippocampus depends on more than just environmental factors. There are genes that determine whether the same life event causes an increase or decrease in the volume of the hippocampus, and which therefore defines whether the stress is good or bad for our brain. The more risk genes an individual has, the more negative an impact the “life events” have on the size of the hippocampus. Where there are no or only a few risk genes, this life event can actually have a positive effect.
Examining life crises
As part of the study, carried out at the University Department of Psychiatry and Psychotherapy (led by Siegfried Kasper), the study team obtained quantitative information from healthy test subjects about stressful life events, such as deaths in the family, divorce, unemployment, financial losses, relocations, serious illnesses or accidents.
A high-resolution anatomical magnetic resonance scan was also carried out (at the High-Field MR Centre of Excellence, Department of MR Physics, led by Ewald Moser). The University Department of Laboratory Medicine (Harald Esterbauer and colleagues) carried out the gene analyses (COMT Val158Met, BDNF Val66Met, 5-HTTLPR). At the University Department of Psychiatry and Psychotherapy, primary author Ulrich Rabl measured the volume of the test subjects’ hippocampi using computer-assisted techniques and analysed the results in the context of the genetic and environmental data.
"People with the three gene versions believed to encourage depression had a smaller hippocampus than those with fewer or none of these gene versions, even though they had the same number of stressful life events," says study leader Lukas Pezawas, describing the results. People with only one or even none of the risk genes, on the other hand, had an enlarged hippocampus with similar life events.
The study highlights the importance of gene and environment interaction as a determining factor for the volume of the hippocampus. “These results are important for understanding neurobiological processes in stress-associated illnesses such as depression or post-traumatic stress disorder. It is ultimately our genes that determine whether stress makes us psychologically unwell or whether it encourages our mental health,” explains Pezawas.
The study, published in the highly respected “Journal of Neuroscience”, was funded by a special research project of the FWF (Austrian Science Fund) (SFB-35, led by Harald Sitte) and presented as a highlight at the international conference on “Organization for Human Brain Mapping”.
(Source: meduniwien.ac.at)
Schizophrenia and cannabis use may share common genes
Genes that increase the risk of developing schizophrenia may also increase the likelihood of using cannabis, according to a new study led by King’s College London, published today in Molecular Psychiatry.
Previous studies have identified a link between cannabis use and schizophrenia, but it has remained unclear whether this association is due to cannabis directly increasing the risk of the disorder.
The new results suggest that part of this association is due to common genes, but do not rule out a causal relationship between cannabis use and schizophrenia risk.
The study is a collaboration between King’s and the Queensland Institute of Medical Research in Australia, partly funded by the UK Medical Research Council (MRC).
Mr Robert Power, lead author from the MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre at the Institute of Psychiatry at King’s, says: “Studies have consistently shown a link between cannabis use and schizophrenia. We wanted to explore whether this is because of a direct cause and effect, or whether there may be shared genes which predispose individuals to both cannabis use and schizophrenia.”
Cannabis is the most widely used illicit drug in the world, and its use is higher amongst people with schizophrenia than in the general population. Schizophrenia affects approximately 1 in 100 people and people who use cannabis are about twice as likely to develop the disorder. The most common symptoms of schizophrenia are delusions (false beliefs) and auditory hallucinations (hearing voices). Whilst the exact cause is unknown, a combination of physical, genetic, psychological and environmental factors can make people more likely to develop the disorder.
Previous studies have identified a number of genetic risk variants associated with schizophrenia, each of these slightly increasing an individual’s risk of developing the disorder.
The new study included 2,082 healthy individuals of whom 1,011 had used cannabis. Each individual’s ‘genetic risk profile’ was measured – that is, the number of genes related to schizophrenia each individual carried.
The researchers found that people genetically pre-disposed to schizophrenia were more likely to use cannabis, and use it in greater quantities than those who did not possess schizophrenia risk genes.
Power says: “We know that cannabis increases the risk of schizophrenia. Our study certainly does not rule this out, but it suggests that there is likely to be an association in the other direction as well – that a pre-disposition to schizophrenia also increases your likelihood of cannabis use.”
“Our study highlights the complex interactions between genes and environments when we talk about cannabis as a risk factor for schizophrenia. Certain environmental risks, such as cannabis use, may be more likely given an individual’s innate behaviour and personality, itself influenced by their genetic make-up. This is an important finding to consider when calculating the economic and health impact of cannabis.”
(Source: kcl.ac.uk)
Cancer by remote-control: Overlooked DNA shuffling drives deadly paediatric brain tumour
One of the deadliest forms of paediatric brain tumour, Group 3 medulloblastoma, is linked to a variety of large-scale DNA rearrangements which all have the same overall effect on specific genes located on different chromosomes. The finding, by scientists at the European Molecular Biology Laboratory (EMBL), the German Cancer Research Centre (DKFZ), both in Heidelberg, Germany, and Sanford-Burnham Medical Research Institute in San Diego, USA, is published online today in Nature.
To date, the only gene known to play an important role in Group 3 medulloblastoma was a gene called MYC, but that gene alone couldn’t explain some of the unique characteristics of this particular type of medulloblastoma, which has a higher metastasis rate and overall poorer prognosis than other types of this childhood brain tumour. To tackle the question, Jan Korbel’s group at EMBL and collaborators at DKFZ tried to identify new genes involved, taking advantage of the large number of medulloblastoma genome sequences now known.
“We were surprised to see that in addition to MYC there are two other major drivers of Group 3 medulloblastoma – two sister genes called GFI1B and GFI1,” says Korbel. “Our findings could be relevant for research on other cancers, as we discovered that those genes had been activated in a way that cancer researchers don’t usually look for in solid tumours.”
Rather than take the usual approach of looking for changes in individual genes, the team focused on large-scale rearrangements of the stretches of DNA that lie between genes. They found that the DNA of different patients showed evidence of different rearrangements: duplications, deletions, inversions, and even complex alterations involving many ‘DNA-shuffling’ events. This wide array of genetic changes had one effect in common: they placed GFI1B close to highly active enhancers – stretches of DNA that can dramatically increase gene activity. So large-scale DNA changes relocate GFI1B, activating this gene in cells where it would normally be switched off. And that, the researchers surmise, is what drives the tumour to form.
“Nobody has seen such a process in solid cancers before,” says Paul Northcott from DKFZ, “although it shares similarities with a phenomenon implicated in leukaemias, which has been known since the 80s.”
GFI1B wasn’t affected in all cases studied, but in many patients where it wasn’t, a related gene with a similar role, GFI1, was. GFI1B and GFI1 sit on different chromosomes, and interestingly, the DNA rearrangements affecting GFI1 put it next to enhancers sitting on yet other chromosomes. But the overall result was identical: the gene was activated, and appeared to drive tumour formation.
To confirm the role of GFI1B and GFI1 in causing medulloblastoma, the Heidelberg researchers turned to the expertise of Robert Wechsler-Reya’s group at Sanford-Burnham. Wechsler-Reya’s lab genetically modified neural stem cells to have either GFI1B or GFI1 turned on, together with MYC. When they inserted those modified cells into the brains of healthy mice, the rodents developed aggressive, metastasising brain tumours that closely resemble Group 3 medulloblastoma in humans.
These mice are the first to truly mimic the genetics of the human version of Group 3 medulloblastoma, and researchers can now use them to probe further. The mice could, for instance, be used to test potential treatments suggested by these findings. One interesting option to explore, the scientists say, is that highly active enhancers – like the ones they found were involved in this tumour – can be vulnerable to an existing class of drugs called bromodomain inhibitors. And, since neither GFI1B nor GFI1 is normally active in the brain, the study points to possible routes for diagnosing this brain tumour, too.
But the mice also raised another question the scientists are still untangling. For the rodents to develop medulloblastoma-like tumours, activating GFI1 or GFI1B was not enough; MYC also had to be switched on. In human patients, however, scientists have found a statistical link between MYC and GFI1, but not between MYC and GFI1B, so the team is now following up on this partial surprise.
“What we’re learning from this study is that clearly one has to think outside the box when trying to understand cancer genomes,” Korbel concludes.
(Source: embl.de)
(Image caption: Brain scans show high activity in the medial prefrontal cortex (top) and striatum (bottom) while playing a competitive game. UC Berkeley and UIUC researchers have now found genetic variations in dopamine-regulating genes in the prefrontal cortex and striatum associated with differences in belief learning and reinforcement learning, respectively. Credit: Ming Hsu)
Your genes affect your betting behavior
Investors and gamblers take note: your betting decisions and strategy are determined, in part, by your genes.
Researchers from the University of California, Berkeley, National University of Singapore and University of Illinois at Urbana-Champaign (UIUC) have shown that betting decisions in a simple competitive game are influenced by the specific variants of dopamine-regulating genes in a person’s brain.
Dopamine is a neurotransmitter – a chemical released by brain cells to signal other brain cells – that is a key part of the brain’s reward and pleasure-seeking system. Dopamine deficiency leads to Parkinson’s disease, while disruption of the dopamine network is linked to numerous psychiatric and neurodegenerative disorders, including schizophrenia, depression and dementia.
While previous studies have shown the important role of the neurotransmitter dopamine in social interactions, this is the first study tying these interactions to specific genes that govern dopamine functioning.
“This study shows that genes influence complex social behavior, in this case strategic behavior,” said study leader Ming Hsu, an assistant professor of marketing in UC Berkeley’s Haas School of Business and a member of the Helen Wills Neuroscience Institute. “We now have some clues about the neural mechanisms through which our genes affect behavior.”
The implications for business are potentially vast but unclear, Hsu said, though one possibility is training workforces to be more strategic. But the findings could significantly affect our understanding of diseases involving dopamine, such as schizophrenia, as well as disorders of social interaction, such as autism.
“When people talk about dopamine dysfunction, schizophrenia is one of the first diseases that come to mind,” Hsu said, noting that the disease involves a very complex pattern of social and decision making deficits. “To the degree that we can better understand ubiquitous social interactions in strategic settings, it may help us understand how to characterize and eventually treat the social deficits that are symptoms of diseases like schizophrenia.”
Hsu, UIUC graduate student Eric Set and their colleagues, including Richard P. Ebstein and Soo Hong Chew from the National University of Singapore, will publish their findings the week of June 16 in the online early edition of the Proceedings of the National Academy of Sciences.
Two brain areas involved in competition
Hsu established two years ago that when people engage in competitive social interactions, such as betting games, they primarily call upon two areas of the brain: the medial prefrontal cortex, which is the executive part of the brain, and the striatum, which deals with motivation and is crucial for learning to acquire rewards. Functional magnetic resonance imaging (fMRI) scans showed that people playing these games displayed intense activity in these areas.
“If you think of the brain as a computing machine, these are areas that take inputs, crank them through an algorithm, and translate them into behavioral outputs,” Hsu said. “What is really interesting about these areas is that both are innervated by neurons that use dopamine.”
Hsu and Set of UIUC’s Department of Economics wanted to determine which genes involved in regulating dopamine concentrations in these brain areas were associated with strategic thinking, so they enlisted as subjects a group of 217 undergraduates at the National University of Singapore, all of whom had had their genomes scanned for some 700,000 genetic variants. The researchers focused on only 143 variants within 12 genes involved in regulating dopamine. Some of the 12 are primarily involved in regulating dopamine in the prefrontal cortex, while others primarily regulate dopamine in the striatum.
The competition was a game called patent race, commonly used by social scientists to study social interactions. It involves one person betting, via computer, with an anonymous opponent.
“We know from brain imaging studies that when people compete against one another, they actually engage in two distinct types of learning processes,” Set said, referring to Hsu’s 2012 study. “One type involves learning purely from the consequences of your own actions, called reinforcement learning. The other is a bit more sophisticated, called belief learning, where people try to make a mental model of the other players, in order to anticipate and respond to their actions.”
Trial-and-error learning vs belief learning
Using a mathematical model of brain function during competitive social interactions, Hsu and Set correlated performance in reinforcement learning and belief learning with different variants or mutations of the 12 dopamine-related genes, and discovered a distinct difference.
They found that differences in belief learning – the degree to which players were able to anticipate and respond to the actions of others, or to imagine what their competitor is thinking and respond strategically – was associated with variation in three genes which primarily affect dopamine functioning in the medial prefrontal cortex.
In contrast, differences in trial-and-error reinforcement learning – how quickly they forget past experiences and how quickly they change strategy – was associated with variation in two genes that primarily affect striatal dopamine.
Hsu said that the findings correlate well with previous brain studies showing that the prefrontal cortex is involved in belief learning, while the striatum is involved in reinforcement learning.
“We were surprised by the degree of overlap, but it hints at the power of studying the neural and genetic levels under a single mathematical framework, which is only beginning in this area,” he said.
Hsu is currently collaborating with other scientists to correlate career achievements in older adults with genes and performance on competitive games, to see which brain regions and types of learning are most important for different kinds of success in life.
Research in the News: Brain at rest yields clues to origins of mental illness
While at rest, multiple regions of the brain remain engaged in a highly heritable, stable pattern of activity called the default mode network. Researchers have found that this network is often disrupted in people with schizophrenia and bipolar disorder, which appear to share underlying genetic causes. This network is often abnormal in their unaffected close relatives, suggesting common genetic roots.
Now researchers at the Yale University School of Medicine and the Institute of Living in Hartford have devised a method to simultaneously identify many genes that play a role in disrupting this network. “Previous studies have identified small numbers of different genes which each contribute in a small way to schizophrenia and bipolar disorder but tell us little overall about the development of psychosis in an individual,” said Godfrey Pearlson, professor of psychiatry and neurobiology and senior author of the study. “Now we have begun to identify markers for these conditions that consist of hundreds of such genes acting simultaneously in recognized pathways that will eventually help in our designing novel ways to intervene in the disease process.”
The study was published April 28 in the Proceedings of the National Academy of Sciences.