Posts tagged genetics
Posts tagged genetics
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.”
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.
Vast gene-expression map yields neurological and environmental stress insights
A consortium led by scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) has conducted the largest survey yet of how information encoded in an animal genome is processed in different organs, stages of development, and environmental conditions. Their findings paint a new picture of how genes function in the nervous system and in response to environmental stress.
They report their research this week in the Advance Online Publication of the journal Nature.
The scientists studied the fruit fly, an important model organism in genetics research. Seventy percent of known human disease genes have closely related genes in the fly, yet the fly genome is one-thirtieth the size of ours. Previous fruit fly research has provided insights on cancer, birth defects, addictive behavior, and neurological diseases. It has also advanced our understanding of processes common to all animals such as body patterning and synaptic transmission.
In the latest scientific fruit from the fruit fly, the consortium, led by Susan Celniker of Berkeley Lab’s Life Sciences Division, generated the most comprehensive map of gene expression in any animal to date. Scientists from the University of California at Berkeley, Indiana University at Bloomington, the University of Connecticut Health Center, and several other institutions contributed to the research.