Posts tagged genetics
Posts tagged genetics
When we get sick it feels natural to try to hasten our recovery by getting some extra shuteye. Researchers from the Perelman School of Medicine at the University of Pennsylvania found that this response has a definite purpose, in fruitflies: enhancing immune system response and recovery to infection. Their findings appear online in two related papers in the journal Sleep, in advance of print editions in May and June.
"It’s an intuitive response to want to sleep when you get sick," notes Center for Sleep and Circadian Neurobiology research associate Julie A. Williams, PhD. "Many studies have used sleep deprivation as a means to understand how sleep contributes to recovery, if it does at all, but there is surprisingly little experimental evidence that supports the notion that more sleep helps us to recover. We used a fruitfly model to answer these questions." Along with post-doctoral fellow, Tzu-Hsing Kuo, PhD, Williams conducted two related studies to directly examine the effects of sleep on recovery from and survival after an infection.
In the first paper, they took a conventional approach by subjecting fruit flies to sleep deprivation before infecting them with either Serratia marcescens or Pseudomonas aeruginosa bacteria. Both the sleep-deprived flies and a non-sleep-deprived control group displayed increased sleep after infection, what the experimenters call an “acute sleep response.”
Unexpectedly, the pre-infection, sleep-deprived flies had a better survival rate. “To our surprise they actually survived longer after the infection than the ones who were not sleep-deprived,” notes Williams. The Penn team found that prior sleep deprivation made the flies sleep for a longer period after infection as compared to the undisturbed controls. They slept longer and they lived longer during the infection. Inducing sleep deprivation after infection rather than before made little difference, as long as the infected flies then got adequate recovery sleep. “We deprived flies of sleep after infection with the idea that if we blocked this sleep, things would get worse in terms of survival,” Williams explains. “Instead they got better, but not until after they had experienced more sleep.”
Sleep deprivation increases activity of an NFkB transcription factor, Relish, which is also needed for fighting infection. Flies without the Relish gene do not experience an acute sleep response and very quickly succumb to infection. But, when these mutants are sleep-deprived before infection, they displayed increased sleep and survival rates after infection. The team then evaluated mutant flies that lacked two varieties of NFkB (Relish and Dif). When flies lacked both types of NFkB genes, sleep deprivation had no effect on the acute sleep response, and the effect on survival was abolished. Flies from both sleep-deprived and undisturbed groups succumbed to infection at equal rates within hours.
"Taken together, all of these data support the idea that post-infection sleep helps to improve survival," Williams says.
In the second study, the researchers manipulated sleep through a genetic approach. They used the drug RU486 to induce expression of ion channels to alter neuronal activity in the mushroom body of the fly brain, and thereby regulate sleep patterns. Compared to a control group, flies that were induced to sleep more, and for longer periods of time for up to two days before infection, showed substantially greater survival rates. The flies with more sleep also showed faster and more efficient rates of clearing the bacteria from their bodies. “Again, increased sleep somehow helps to facilitate the immune response by increasing resistance to infection and survival after infection,” notes Williams.
Because the genetic factors investigated by the Penn team, such as the NFkB pathway, are preserved in mammals, the relative simplicity of the Drosophila model provides an ideal avenue to explore basic functions like sleep. “Investigators have been working on questions about sleep and immunity for more than 40 years, but by narrowing down the questions in the fly we’re now in a good position to identify potentially novel genes and mechanisms that may be involved in this process that are difficult to see in higher animals,” explains Williams.
"These studies provide new evidence of the direct and functional effects of sleep on immune response and of the underlying mechanisms at work. The take-home message from these papers is that when you get sick, you should sleep as much as you can — we now have the data that supports this idea," she concludes.
(Image caption: Researchers have identified a new class of compounds—pharmacologic chaperones—that can stabilize the retromer protein complex (the blue and orange structure shows part of the complex). Retromer plays a vital role in keeping amyloid precursor from being cleaved and producing the toxic byproduct amyloid beta, which contributes to the development of Alzheimer’s. The study found that when the chaperone named R55 (the multicolored molecule) was added to neurons in cell culture, it bound to and stabilized retromer, increasing retromer levels and lowering amyloid-beta levels. Credit: Nature Chemical Biology and lab of Scott A. Small, MD/Columbia University Medical Center.)
A team of researchers from Columbia University Medical Center (CUMC), Weill Cornell Medical College, and Brandeis University has devised a wholly new approach to the treatment of Alzheimer’s disease involving the so-called retromer protein complex. Retromer plays a vital role in neurons, steering amyloid precursor protein (APP) away from a region of the cell where APP is cleaved, creating the potentially toxic byproduct amyloid-beta, which is thought to contribute to the development of Alzheimer’s.
Using computer-based virtual screening, the researchers identified a new class of compounds, called pharmacologic chaperones, that can significantly increase retromer levels and decrease amyloid-beta levels in cultured hippocampal neurons, without apparent cell toxicity. The study was published today in the online edition of the journal Nature Chemical Biology.
“Our findings identify a novel class of pharmacologic agents that are designed to treat neurologic disease by targeting a defect in cell biology, rather than a defect in molecular biology,” said Scott Small, MD, the Boris and Rose Katz Professor of Neurology, Director of the Alzheimer’s Disease Research Center in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at CUMC, and a senior author of the paper. “This approach may prove to be safer and more effective than conventional treatments for neurologic disease, which typically target single proteins.”
In 2005, Dr. Small and his colleagues showed that retromer is deficient in the brains of patients with Alzheimer’s disease. In cultured neurons, they showed that reducing retromer levels raised amyloid-beta levels, while increasing retromer levels had the opposite effect. Three years later, he showed that reducing retromer had the same effect in animal models, and that these changes led to Alzheimer’s-like symptoms. Retromer abnormalities have also been observed in Parkinson’s disease.
In discussions at a scientific meeting, Dr. Small and co-senior authors Gregory A. Petsko, DPhil, Arthur J. Mahon Professor of Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute and Director of the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell Medical College, and Dagmar Ringe, PhD, Harold and Bernice Davis Professor in the Departments of Biochemistry and Chemistry and in the Rosenstiel Basic Medical Sciences Research Center at Brandeis University, began wondering if there was a way to stabilize retromer (that is, prevent it from degrading) and bolster its function. “The idea that it would be beneficial to protect a protein’s structure is one that nature figured out a long time ago,” said Dr. Petsko. “We’re just learning how to do that pharmacologically.”
Other researchers had already determined retromer’s three-dimensional structure. “Our challenge was to find small molecules—or pharmacologic chaperones—that could bind to retromer’s weak point and stabilize the whole protein complex,” said Dr. Ringe.
This was accomplished through computerized virtual, or in silico, screening of known chemical compounds, simulating how the compounds might dock with the retromer protein complex. (In conventional screening, compounds are physically tested to see whether they interact with the intended target, a costlier and lengthier process.) The screening identified 100 potential retromer-stabilizing candidates, 24 of which showed particular promise. Of those, one compound, called R55, was found to significantly increase the stability of retromer when the complex was subjected to heat stress.
The researchers then looked at how R55 affected neurons of the hippocampus, a key brain structure involved in learning and memory. “One concern was that this compound would be toxic,” said Dr. Diego Berman, assistant professor of clinical pathology and cell biology at CUMC and a lead author. “But R55 was found to be relatively non-toxic in mouse neurons in cell culture.”
More important, a subsequent experiment showed that the compound significantly increased retromer levels and decreased amyloid-beta levels in cultured neurons taken from healthy mice and from a mouse model of Alzheimer’s. The researchers are currently testing the clinical effects of R55 in the actual mouse model .
“The odds that this particular compound will pan out are low, but the paper provides a proof of principle for the efficacy of retromer pharmacologic chaperones,” said Dr. Petsko. “While we’re testing R55, we will be developing chemical analogs in the hope of finding compounds that are more effective.”
A major challenge of systems biology is understanding how phenomena at the cellular scale correlate with activity at the organism level. A concerted effort has been made especially in the brain, as scientists are aiming to clarify how neural activity is translated into consciousness and other complex brain activities. One example of the technologies needed is whole-brain imaging at single-cell resolution. This imaging normally involves preparing a highly transparent sample that minimizes light scattering and then imaging neurons tagged with fluorescent probes at different slices to produce a 3D representation. However, limitations in current methods prevent comprehensive study of the relationship. A new high-throughput method, CUBIC (Clear, Unobstructed Brain Imaging Cocktails and Computational Analysis), published in Cell, is a great leap forward, as it offers unprecedented rapid whole-brain imaging at single cell resolution and a simple protocol to clear and transparentize the brain sample based on the use of aminoalcohols.
In combination with light sheet fluorescence microscopy, CUBIC was tested for rapid imaging of a number of mammalian systems, such as mouse and primate, showing its scalability for brains of different size. Additionally, it was used to acquire new spatial-temporal details of gene expression patterns in the hypothalamic circadian rhythm center. Moreover, by combining images taken from opposite directions, CUBIC enables whole brain imaging and direct comparison of brains in different environmental conditions.
CUBIC overcomes a number of obstacles compared with previous methods. One is the clearing and transparency protocol, which involves serially immersing fixed tissues into just two reagents for a relatively short time. Second, CUBIC is compatible with many fluorescent probes because of low quenching, which allows for probes with longer wavelengths and reduces concern for scattering when whole brain imaging while at the same time inviting multi-color imaging. Finally, it is highly reproducible and scalable. While other methods have achieved some of these qualities, CUBIC is the first to realize all.
CUBIC provides information on previously unattainable 3D gene expression profiles and neural networks at the systems level. Because of its rapid and high-throughput imaging, CUBIC offers extraordinary opportunity to analyze localized effects of genomic editing. It also is expected to identify neural connections at the whole brain level. In fact, last author Hiroki Ueda is optimistic about further application to even larger mammalian systems. “In the near future, we would like to apply CUBIC technology to whole-body imaging at single cell resolution.”
In an article published today in PLOS Biology, researchers from the RIKEN Brain Science Institute in Japan report the identification of Chrono, a gene involved in the regulation of the body clock in mammals and that might be a key component of the body’s response to stress.
All organisms, from mammals to fungi, have daily cycles controlled by a tightly regulated internal clock, called the circadian clock. The whole-body circadian clock, influenced by the exposure to light, dictates the wake-sleep cycle. At the cellular level, the clock is controlled by a complex network of genes and proteins that switch each other on and off based on cues from their environment.
Most genes involved in the regulation of the circadian clock have been characterized, but Akihiro Goriki, Toru Takumi and their colleagues from RIKEN and Hiroshima University in Japan and University of Michigan in the United States knew that a key component was missing and sough to uncover it in mammals.
In the study, the team performed a genome-wide chromatin immunoprecipitation analysis for genes that were the target of BMAL1, a core clock component that binds to many other clock genes, regulating their transcription.
The authors characterize a new circadian gene that they name Chrono. They show that CHRONO functions as a transcriptional repressor of the negative feedback loop in the mammalian clock: the protein CHRONO binds to the regulatory region of clock genes, with its repressor function oscillating in a circadian manner. The expression of core clock genes is altered in mice lacking the Chrono gene, and the mice have longer circadian cycles.
"These results suggest that Chrono functions as a core clock repressor,” conclude the authors.
In addition, they demonstrate that the repression mechanism of Chrono is under epigenetic control and links, via a glucocorticoid receptor, to metabolic pathways triggered by behavioral stress.
These findings are confirmed by another study by the University of Pennsylvania, also published in PLOS Biology today. In the study, John Hogenesch and his team prove the existence of Chrono using a computer-based analysis.
Carrying a copy of a gene variant called ApoE4 confers a substantially greater risk for Alzheimer’s disease on women than it does on men, according to a new study by researchers at the Stanford University School of Medicine.
The scientists arrived at their findings by analyzing data on large numbers of older individuals who were tracked over time and noting whether they had progressed from good health to mild cognitive impairment — from which most move on to develop Alzheimer’s disease within a few years — or to Alzheimer’s disease itself.
The discovery holds implications for genetic counselors, clinicians and individual patients, as well as for clinical-trial designers. It could also help shed light on the underlying causes of Alzheimer’s disease, a progressive neurological syndrome that robs its victims of their memory and ability to reason. Its incidence increases exponentially after age 65. An estimated one in every eight people past that age in the United States has Alzheimer’s. Experts project that by mid-century, the number of Americans with Alzheimer’s will more than double from the current estimate of 5-6 million.
According to the Alzheimer’s Association, it is already the nation’s most expensive disease, costing more than $200 million annually. (The epidemiology of mild cognitive impairment is fuzzier, but this gateway syndrome is clearly more widespread than Alzheimer’s.)
The phenomenon has long been known in psychology: traumatic experiences can induce behavioural disorders that are passed down from one generation to the next. It is only recently that scientists have begun to understand the physiological processes underlying hereditary trauma. ”There are diseases such as bipolar disorder, that run in families but can’t be traced back to a particular gene”, explains Isabelle Mansuy, professor at ETH Zurich and the University of Zurich. With her research group at the Brain Research Institute of the University of Zurich, she has been studying the molecular processes involved in non-genetic inheritance of behavioural symptoms induced by traumatic experiences in early life.
Mansuy and her team have succeeded in identifying a key component of these processes: short RNA molecules. These RNAs are synthetized from genetic information (DNA) by enzymes that read specific sections of the DNA (genes) and use them as template to produce corresponding RNAs. Other enzymes then trim these RNAs into mature forms. Cells naturally contain a large number of different short RNA molecules called microRNAs. They have regulatory functions, such as controlling how many copies of a particular protein are made.
Small RNAs with a huge impact
The researchers studied the number and kind of microRNAs expressed by adult mice exposed to traumatic conditions in early life and compared them with non-traumatized mice. They discovered that traumatic stress alters the amount of several microRNAs in the blood, brain and sperm – while some microRNAs were produced in excess, others were lower than in the corresponding tissues or cells of control animals. These alterations resulted in misregulation of cellular processes normally controlled by these microRNAs.
After traumatic experiences, the mice behaved markedly differently: they partly lost their natural aversion to open spaces and bright light and had depressive-like behaviours. These behavioural symptoms were also transferred to the next generation via sperm, even though the offspring were not exposed to any traumatic stress themselves.
Even passed on to the third generation
The metabolism of the offspring of stressed mice was also impaired: their insulin and blood-sugar levels were lower than in the offspring of non-traumatized parents. “We were able to demonstrate for the first time that traumatic experiences affect metabolism in the long-term and that these changes are hereditary”, says Mansuy. The effects on metabolism and behaviour even persisted in the third generation.
“With the imbalance in microRNAs in sperm, we have discovered a key factor through which trauma can be passed on,” explains Mansuy. However, certain questions remain open, such as how the dysregulation in short RNAs comes about. “Most likely, it is part of a chain of events that begins with the body producing too much stress hormones.”
Importantly, acquired traits other than those induced by trauma could also be inherited through similar mechanisms, the researcher suspects. “The environment leaves traces on the brain, on organs and also on gametes. Through gametes, these traces can be passed to the next generation.”
Mansuy and her team are currently studying the role of short RNAs in trauma inheritance in humans. As they were also able to demonstrate the microRNAs imbalance in the blood of traumatized mice and their offspring, the scientists hope that their results may be useful to develop a blood test for diagnostics.
In a groundbreaking York University study, researchers have found that abnormal levels of lipid molecules in the brain can affect the interaction between two key neural pathways in early prenatal brain development, which can trigger autism. And, environmental causes such as exposure to chemicals in some cosmetics and common over-the-counter medication can affect the levels of these lipids, according to the researchers.
“We have found that the abnormal level of a lipid molecule called Prostaglandin E2 in the brain can affect the function of Wnt proteins. It is important because this can change the course of early embryonic development,” explains Professor Dorota Crawford in the Faculty of Health and a member of the York Autism Alliance Research Group.
This is the first time research shows evidence for cross-talk between PGE2 and Wnt signalling in neuronal stem cells, according to the peer reviewed study published at Cell Communication and Signaling.
Lead researcher and York U doctoral student Christine Wong adds, “Using real-time imaging microscopy, we determined that higher levels of PGE2 can change Wnt-dependent behaviour of neural stem cells by increasing cell migration or proliferation. As a result, this could affect how the brain is organized and wired. Moreover, we found that an elevated level of PGE2 can increase expression of Wnt-regulated genes — Ctnnb1, Ptgs2, Ccnd1, and Mmp9. “Interestingly, all these genes have been previously implicated in various autism studies.”
Autism is considered to be the primary disorder of brain development with symptoms ranging from mild to severe and including repetitive behaviour, deficits in social interaction, and impaired language. It is four times more prevalent in boys than in girls and the incidence continues to rise. The US Center for Disease Control and Prevention (CDC) data from 2010 estimates that 1 in 68 children now has autism.
“The statistics are alarming. It’s 30 per cent higher than the previous estimate of 1 in 88 children, up from only two years earlier. Perhaps we can no longer attribute this rise in autism incidence to better diagnostic tools or awareness of autism,” notes Crawford. “It’s even more apparent from the recent literature that the environment might have a greater impact on vulnerable genes, particularly in pregnancy. Our study provides some molecular evidence that the environment likely disrupts certain events occurring in early brain development and contributes to autism.”
According to Crawford, genes don’t undergo significant changes in evolution, so even though genetic factors are the main cause, environmental factors such as insufficient dietary supplementations of fatty acids, exposures to infections, various chemicals or drugs can change gene expression and contribute to autism.
Genes amplify the stress of harsh environments for some children, and magnify the advantage of supportive environments for other children, according to a study that’s one of the first to document how genes interacting with social environments affect biomarkers of stress.
"Our findings suggest that an individual’s genetic architecture moderates the magnitude of the response to external stimuli—but it is the environment that determines the direction" says Colter Mitchell, lead author of the paper and a researcher at the University of Michigan Institute for Social Research (ISR).
The study, published today in the Proceedings of the National Academy of Sciences, uses telomere length as a marker of stress. Found at the ends of chromosomes, telomeres generally shorten with age, and when individuals are exposed to disease and chronic stress, including the stress of living in a disadvantaged environment.
For the study, Mitchell and colleagues used telomere samples from a group of 40 nine-year-old boys from two very different environments – one nurturing and the other harsh. Those in the nurturing environment came from stable families, with nurturing parenting, good maternal mental health, and positive socioeconomic conditions, while those in the harsh environment experienced high levels of poverty, harsh parenting, poor maternal mental health, and high family instability.
For those children with heightened sensitivity in the serotonergic and dopaminergic genetic pathways compared to other children, telomere length was shortest in a disadvantaged environment, and longest in a supportive environment.
Procrastination and impulsivity are genetically linked, suggesting that the two traits stem from similar evolutionary origins, according to research published in Psychological Science, a journal of the Association for Psychological Science. The research indicates that the traits are related to our ability to successfully pursue and juggle goals.
“Everyone procrastinates at least sometimes, but we wanted to explore why some people procrastinate more than others and why procrastinators seem more likely to make rash actions and act without thinking,” explains psychological scientist and study author Daniel Gustavson of the University of Colorado Boulder. “Answering why that’s the case would give us some interesting insights into what procrastination is, why it occurs, and how to minimize it.”
From an evolutionary standpoint, impulsivity makes sense: Our ancestors should have been inclined to seek immediate rewards when the next day was uncertain.
Procrastination, on the other hand, may have emerged more recently in human history. In the modern world, we have many distinct goals far in the future that we need to prepare for – when we’re impulsive and easily distracted from those long-term goals, we often procrastinate.
Thinking about the two traits in that context, it seems logical that people who are perpetual procrastinators would also be highly impulsive. Many studies have observed this positive relationship, but it is unclear what cognitive, biological, and environmental influences are responsible for it.
The most effective way to understand why these traits are correlated is to study human twins. Identical twins — who share 100% of their genes — tend to show greater similarities in behavior than fraternal twins, who only share 50% of their genes (just like any other siblings). Researchers take advantage of this genetic discrepancy to figure out the relative importance of genetic and environmental influences on particular behaviors, like procrastination and impulsivity.
Gustavson and colleagues had 181 identical-twin pairs and 166 fraternal-twin pairs complete several surveys intended to probe their tendencies toward impulsivity and procrastination, as well as their ability to set and maintain goals.
They found that procrastination is indeed heritable, just like impulsivity. Not only that, there seems to be a complete genetic overlap between procrastination and impulsivity — that is, there are no genetic influences that are unique to either trait alone.
That finding suggests that, genetically speaking, procrastination is an evolutionary byproduct of impulsivity — one that likely manifests itself more in the modern world than in the world of our ancestors.
In addition, the link between procrastination and impulsivity also overlapped genetically with the ability to manage goals, lending support to the idea that delaying, making rash decisions, and failing to achieve goals all stem from a shared genetic foundation.
Gustavson and colleagues are now investigating how procrastination and impulsivity are related to higher-level cognitive abilities, such as executive functions, and whether these same genetic influences are related to other aspects of self-regulation in our day-to-day lives.
“Learning more about the underpinnings of procrastination may help develop interventions to prevent it, and help us overcome our ingrained tendencies to get distracted and lose track of work,” Gustavson concludes.
Telomeres are DNA-protein complexes that function as protective caps at the ends of chromosomes. Biologists and veterinarians at the Vetmeduni Vienna recently examined the telomere length of captive African grey parrots. They found that the telomere lengths of single parrots were shorter than those housed with a companion parrot, which supports the hypothesis that social stress can interfere with cellular aging and a particular type of DNA repair. It suggests that telomeres may provide a biomarker for assessing exposure to social stress. The findings have been published in the open access journal PLOS ONE.
In captivity, grey parrots are often kept in social isolation, which can have detrimental effects on their health and wellbeing. So far there have not been any studies on the effects of long term social isolation from conspecifics on cellular aging. Telomeres shorten with each cell division, and once a critical length is reached, cells are unable to divide further (a stage known as ‘replicative senescence’). Although cellular senescence is a useful mechanism to eliminate worn-out cells, it appears to contribute to aging and mortality. Several studies suggest that telomere shortening is accelerated by stress, but until now, no studies have examined the effects of social isolation on telomere shortening.
Using molecular genetics to assess exposure to stress
To test whether social isolation accelerates telomere shortening, Denise Aydinonat, a doctorate student at the Vetmeduni Vienna, conducted a study using DNA samples that she collected from African grey parrots during routine check-ups. African greys are highly social birds, but they are often reared and kept in isolation from other parrots (even though such conditions are illegal in Austria). She and her collaborators compared the telomere lengths of single birds versus pair-housed individuals with a broad range of ages (from 1 to 45 years). Not surprisingly, the telomere lengths of older birds were shorter compared to younger birds, regardless of their housing. However, the important finding of the study was that single-housed birds had shorter telomeres than pair-housed individuals of the same age group.
Reading signs of stress by erosion of DNA
“Studies on humans suggest that people who have experienced high levels of social stress and deprivation have shorter telomeres,” says Dustin Penn from the Konrad Lorenz Institute of Ethology at the Vetmeduni Vienna. “But this study is the first to examine the effects of social isolation on telomere length in any species.” Penn and his team previously conducted experiments on mice, which were the first to show that exposure to crowding stress causes telomere shortening. He points out that this new finding suggests that both extremes of social conditions affect telomere attrition. However, he also cautions “further ‘longitudinal’ studies, in which changes in telomeres of the same individuals over time, are needed to investigate the consequences of stress on telomere shortening and the subsequent effects on health and longevity.”