1. Genetic study links tendency to undervalue future rewards with ADHD

    December 5, 2017 by Ashley

    From the University of California – San Diego press release:

    Researchers at University of California San Diego School of Medicine have found a genetic signature for delay discounting — the tendency to undervalue future rewards — that overlaps with attention-deficit/hyperactivity disorder (ADHD), smoking and weight.

    In a study published December 11 in Nature Neuroscience, the team used data of 23andme customers who consented to participate in research and answered survey questions to assess delay discounting. In all, the study included the data of more than 23,000 people to show that approximately 12 percent of a person’s variation in delay discounting can be attributed to genetics — not a single gene, but numerous genetic variants that also influence several other psychiatric and behavioral traits.

    “Studying the genetic basis of delay discounting is something I’ve wanted to do for the entirety of my 20 years of research, but it takes a huge number of people for a genetics study to be meaningful,” said senior author Abraham Palmer, PhD, professor of psychiatry and vice chair for basic research at UC San Diego School of Medicine. “By collaborating with a company that already has the genotypes for millions of people, all we needed was for them to answer a few questions. It would have been difficult to enroll and genotype this many research participants on our own in academia — it would’ve taken years and been cost prohibitive. This is a new model for science.”

    According to Palmer, every complicated nervous system needs a way of assessing the value of current versus delayed rewards. Most people think of the “marshmallow experiment,” he said, referring to the classic experiment where children were tested for their ability to delay gratification by giving them the choice between one marshmallow now or two marshmallows a few minutes later.

    “A person’s ability to delay gratification is not just a curiosity, it’s integrally important to physical and mental health,” Palmer said. “In addition, a person’s economic success is tied to delay discounting. Take seeking higher education and saving for retirement as examples — these future rewards are valuable in today’s economy, but we’re finding that not everyone has the same inclination to achieve them.”

    For the study, the team looked at data from 23andMe research participants who answered survey questions that could be used to assess delay discounting. For example, customers were asked to choose between two options: “Would you rather have $55 today or $75 in 61 Days?”

    “In less than four months, we had responses from more than 23,000 research participants,” said Pierre Fontanillas, PhD, a senior statistical geneticist at 23andMe. “This shows the power of our research model to quickly gather large amounts of phenotypic and genotypic data for scientific discovery.”

    By comparing participants’ survey responses to their corresponding genotypes and complementary data from other studies, Palmer’s team found a number of genetic correlations.

    “We discovered, for the first time, a genetic correlation between ADHD and delay discounting,” said first author Sandra Sanchez-Roige, PhD, a postdoctoral researcher in Palmer’s lab. “People with ADHD place less value in delayed rewards. That doesn’t mean that everyone with ADHD will undervalue future rewards or vice versa, just that the two factors have a common underlying genetic cause.”

    The researchers also found that delay discounting is genetically correlated with smoking initiation. In other words, people who undervalue future rewards may be more likely to start smoking and less likely to quit if they did.

    Body weight, as determined by body mass index (BMI), was also strongly correlated with delay discounting, suggesting that people who don’t place a high value on future rewards tend to have a higher BMI.

    The team determined that delay discounting negatively correlated with three cognitive measures: college attainment, years of education and childhood IQ. In other words, the genetic factors that predict delay discounting also predict these outcomes.

    In many studies that rely on surveys, particularly for those in which the participants are paid to fill out the survey, there’s always a chance that some answered randomly or carelessly. Palmer’s survey included three questions to assess how carefully the research participants were answering the questions. For example, one asked “Would you rather have $60 today or $20 today?” There’s only one correct answer and the team saw only 2.1 percent of participants get even one of those three questions wrong, assuring them that the vast majority were answering the questions carefully.

    “We are very thankful to the 23andMe research participants who took the time to complete our survey — they weren’t paid to do it, they are citizen-scientists volunteering their help,” Palmer said. “It’s quite a feeling to think that so many people were willing to help out in this interest of ours.”

    Palmer hopes to expand the study to a larger and more diverse population to strengthen their findings.

    “An even larger study would help start identifying specific genes with a higher level of confidence,” he said. “Then we can do hypothesis-driven studies of this trait with animal or cellular models.”

    While most research studies begin in test tubes, cells grown in the laboratory and animal models before moving to humans, the opposite is true here. After starting with these human observations, Palmer’s team is now studying the same delay discounting-related genetic traits in rodent models. They want to determine if changing those genes experimentally changes rodent behavior as expected. If it does, they will be able to use the animals to study how those delay discounting-related genes lead to those behaviors, at a molecular level.


  2. Theory linking cognition, genes and income refuted

    November 29, 2017 by Ashley

    From the Northwestern University press release:

    Researchers have cast doubt on a widely-held belief that connects family income with cognitive development, according to a new study published in Proceedings of the National Academy of Sciences.

    A popular theory holds that genes play a larger role in brain development for children from advantaged environments than in those from poorer backgrounds, especially in the United States.

    But in the largest study to date using matched birth and school records, the researchers from Northwestern University, Stanford University and the University of Florida found family income won’t necessarily mitigate the effects of genetics on cognitive outcomes.

    While children from higher socio-economic status backgrounds have much better cognitive outcomes on average than those from lower socio-economic status households, genetics appear to matter just as much for both groups,” said Northwestern economist David Figlio, study lead author and dean of the School of Education and Social Policy. “Genes matter. Environment matters. But we find no evidence that the two interact.”

    Some studies suggest that the difference in genetic influence between rich and poor families is particularly pronounced in the U.S., but the Florida data, which includes records of siblings and twins, calls this idea into question, the researchers said.

    The finding mildly surprised Figlio, but he said it falls in line with his previous work published in American Economic Review, which indicated that heavier babies do better in school. In that study of Florida children, Figlio and his coauthors found that those who were heavier at birth scored higher on math and reading tests in the third to eighth grades, and that the relationship between birth weight and test scores is essentially the same for everybody.

    “It’s definitely still true that, from the point of view of test scores, you’d rather be a tiny baby from a wealthy family than a big baby from a poor family,” said Figlio, faculty fellow at Northwestern’s Institute for Policy Research. “But birth weight matters, and it matters for everyone. It seems the same effect is at play here.”

    A full understanding of how genes interact with the environment for cognition is more complex and elusive than previously supposed, the researchers said.

    “Being able to say that ‘genes’ matter more for this group versus that group is appealing partly for its simplicity,” said study co-author Jeremy Freese of Stanford. “We suspect the truth is more complicated: Some genes may matter more in richer families and other genes may matter in poorer families. There’s no overall characterization.”

    Freese emphasized that genetic differences do matter in cognitive development. “But we are still far from understanding how in any useful way,” he said. “Meanwhile, we know poor children face many social disadvantages, and there is much we can do to address those to help promote the flourishing of all children.”


  3. Study suggests potential treatment for autism, intellectual disability

    November 26, 2017 by Ashley

    From the University of Nebraska Medical Center (UNMC) press release:

    A breakthrough in finding the mechanism and a possible therapeutic fix for autism and intellectual disability has been made by a University of Nebraska Medical Center researcher and his team at the Munroe-Meyer Institute (MMI).

    Woo-Yang Kim, Ph.D., associate professor, developmental neuroscience, led a team of researchers from UNMC and Creighton University into a deeper exploration of a genetic mutation that reduces the function of certain neurons in the brain.

    Dr. Kim’s findings were published in this week’s online issue of Nature Neuroscience.

    “This is an exciting development because we have identified the pathological mechanism for a certain type of autism and intellectual disability,” Dr. Kim said.

    Recent studies have shown that the disorder occurs when a first-time mutation causes only one copy of the human AT-rich interactive domain 1B (ARID1B) gene to remain functional, but it was unknown how it led to abnormal cognitive and social behaviors.

    Autism spectrum disorder (ASD) impairs the ability of individuals to communicate and interact with others. About 75 percent of individuals with ASD also have intellectual disability, which is characterized by significant limitations in cognitive functions and adaptive behaviors.

    There are no drugs or genetic treatments to prevent ASD or intellectual disability; the only treatment options focus on behavioral management and educational and physical therapies.

    The team created and analyzed a genetically modified mouse and found that a mutated Arid1b gene impairs GABA neurons, the ‘downer’ neurotransmitter, leading to an imbalance of communication in the brain.

    GABA blocks impulses between nerve cells in the brain. Low levels of GABA may be linked to anxiety or mood disorders, epilepsy and chronic pain. It counters glutamate (the upper neurotransmitter), as the two mediate brain activation in a Yin and Yang manner. People take GABA supplements for anxiety.

    “In normal behavior, the brain is balanced between excitation and inhibition,” Dr. Kim said. “But when the inhibition is decreased, the balance is broken and the brain becomes more excited causing abnormal behavior.

    “We showed that cognitive and social deficits induced by an Arid1bmutation in mice are reversed by pharmacological treatment with a GABA receptor modulating drug. And, now we have a designer mouse that can be used for future studies.”

    Next steps for Dr. Kim and his team are to even further refine the specific mechanism for autism and intellectual disability and to identify which of the many GABA neurons are specifically involved.


  4. Study uses stem cells to explore the causes of autism

    November 17, 2017 by Ashley

    From the Elsevier press release:

    Using human induced pluripotent stem cells (iPSCs) to model autism spectrum disorder (ASD), researchers at the University of São Paulo, Brazil and University of California, San Diego have revealed for the first time that abnormalities in the supporting cells of the brain, called astrocytes, may contribute to the cause of the disorder. The findings, published in Biological Psychiatry, help explain what happens at a biological level to produce ASD behavior, and may help researchers identify new treatments for patients with the disorder.

    Astrocytes play an important role in the development and function of the nervous system. But until now, iPSC models of autism have neglected their contribution. The new study, led by Dr. Patricia Beltrão-Braga and Dr. Alysson Muotri, used iPSCs to generate neurons and astrocytes to model the interaction between these brain cells and better understand how the brain forms in the disorder.

    “This new use of pluripotent stem cells suggests that neurobiological approaches to autism based solely on abnormal neuronal development may fail to account for complex interplay of neurons and astrocytes that may be an underappreciated component of the biology of this disorder,” said Dr. John Krystal, Editor of Biological Psychiatry.

    Induced pluripotent stem cell technology allows researchers to reprogram human cells into any cell in the body. In the study, first authors Dr. Fabiele Russo and Beatriz Freitas and colleagues used cells from three patients diagnosed with ASD and three healthy individuals to generate neurons and astrocytes. Neurons derived from ASD patients had less complex structure than healthy neurons, but adding healthy astrocytes to the ASD neurons improved their poorly developed structure. In reverse, pairing ASD astrocytes with healthy neurons interfered with their development, making them look more like the neurons from ASD patients.

    “The article highlights for the first time the influence of astrocytes in ASD, revealing that astrocytes play a fundamental role in neuronal structure and function,” said Beltrão-Braga.

    The researchers further investigated how the astrocytes exert their influence, and pegged a substance that astrocytes produce called IL-6, already suggested as a player in ASD, as the culprit for the defects. Astrocytes from the patients with ASD appeared to be producing too much of the substance, and the findings suggest that reducing IL-6 could be a beneficial treatment for neurons in ASD.

    Importantly, ASD has been a challenging disease to model using iPSCs because of its complexity. Several genes have been linked to ASD, but their contributions remain unknown, and genetic differences between patients have made it difficult to understand the cause and develop treatments for the disorder. But in this study, the ASD subjects were selected because they shared similar behaviors, rather than similar genes. According to Beltrão-Braga, this means the findings could provide a new alternative strategy for treating ASD symptoms, independent of the patient’s genotype.


  5. Twin study finds genetics affects where children look, shaping mental development

    November 16, 2017 by Ashley

    From the Indiana University press release:

    A new study co-led by Indiana University that tracked the eye movement of twins finds that genetics plays a strong role in how people attend to their environment.

    Conducted in collaboration with researchers from the Karolinska Institute in Sweden, the study offers a new angle on the emergence of differences between individuals and the integration of genetic and environmental factors in social, emotional and cognitive development. This is significant because visual exploration is also one of the first ways infants interact with the environment, before they can reach or crawl.

    “The majority of work on eye movement has asked ‘What are the common features that drive our attention?'” said Daniel P. Kennedy, an assistant professor in the IU Bloomington College of Arts and Sciences’ Department of Psychological and Brain Sciences. “This study is different. We wanted to understand differences among individuals and whether they are influenced by genetics.”

    Kennedy and co-author Brian M. D’Onofrio, a professor in the department, study neurodevelopmental problems from different perspectives. This work brings together their contrasting experimental methods: Kennedy’s use of eye tracking for individual behavioral assessment and D’Onofrio’s use of genetically informed designs, which draw on data from large population samples to trace the genetic and environmental contributions to various traits. As such, it is one of the largest-ever eye-tracking studies.

    In this particular experiment, the researchers compared the eye movements of 466 children — 233 pairs of twins (119 identical and 114 fraternal) — between ages 9 and 14 as each child looked at 80 snapshots of scenes people might encounter in daily life, half of which included people. Using an eye tracker, the researchers then measured the sequence of eye movements in both space and time as each child looked at the scene. They also examined general “tendencies of exploration”; for example, if a child looked at only one or two features of a scene or at many different ones.

    Published Nov. 9 in the journal Current Biology, the study found a strong similarity in gaze patterns within sets of identical twins, who tended to look at the same features of a scene in the same order. It found a weaker but still pronounced similarity between fraternal twins.

    This suggests a strong genetic component to the way individuals visually explore their environments: Insofar as both identical and fraternal twins each share a common environment with their twin, the researchers can infer that the more robust similarity in the eye movements of identical twins is likely due to their shared genetic makeup. The researchers also found that they could reliably identify a twin with their sibling from among a pool of unrelated individuals based on their shared gaze patterns — a novel method they termed “gaze fingerprinting.”

    “People recognize that gaze is important,” Kennedy said. “Our eyes are moving constantly, roughly three times per second. We are always seeking out information and actively engaged with our environment, and ultimately where you look affects your development.”

    After early childhood, the study suggests that genes influence at the micro-level — through the immediate, moment-to-moment selection of visual information — the environments individuals create for themselves.

    “This is not a subtle statistical finding,” Kennedy said. “How people look at images is diagnostic of their genetics. Eye movements allow individuals to obtain specific information from a space that is vast and largely unconstrained. It’s through this selection process that we end up shaping our visual experiences.

    “Less known are the biological underpinnings of this process,” he added. “From this work, we now know that our biology affects how we seek out visual information from complex scenes. It gives us a new instance of how biology and environment are integrated in our development.”

    “This finding is quite novel in the field,” D’Onofrio said. “It is going to surprise people in a number of fields, who do not typically think about the role of genetic factors in regulating such processes as where people look.”


  6. Study suggests malfunctions in communication between brain cells could be at root of autism

    November 11, 2017 by Ashley

    From the Washington University School of Medicine press release:

    A defective gene linked to autism influences how neurons connect and communicate with each other in the brain, according to a study from Washington University School of Medicine in St. Louis. Rodents that lack the gene form too many connections between brain neurons and have difficulty learning.

    The findings, published Nov. 2 in Nature Communications, suggest that some of the diverse symptoms of autism may stem from a malfunction in communication among cells in the brain.

    “This study raises the possibility that there may be too many synapses in the brains of patients with autism,” said senior author Azad Bonni, MD, PhD, the Edison Professor of Neuroscience and head of the Department of Neuroscience at Washington University School of Medicine in St. Louis. “You might think that having more synapses would make the brain work better, but that doesn’t seem to be the case. An increased number of synapses creates miscommunication among neurons in the developing brain that correlates with impairments in learning, although we don’t know how.”

    Autism is a neurodevelopmental disorder affecting about one out of every 68 children. It is characterized by social and communication challenges.

    Among the many genes linked to autism in people are six genes that attach a molecular tag, called ubiquitin, to proteins. These genes, called ubiquitin ligases, function like a work order, telling the rest of the cell how to deal with the tagged proteins: This one should be discarded, that one should be rerouted to another part of the cell, a third needs to have its activity dialed up or down.

    Patients with autism may carry a mutation that prevents one of their ubiquitin genes from working properly. But how problems with tagging proteins affect how the brain is hardwired and operates, and why such problems may lead to autism, has remained poorly understood.

    To understand the role of ubiquitin genes in brain development, Bonni, first author Pamela Valnegri, PhD, and colleagues removed the ubiquitin gene RNF8 in neurons in the cerebellum of young mice. The cerebellum is one of the key brain regions affected by autism.

    The researchers found that neurons that lacked the RNF8 protein formed about 50 percent more synapses — the connections that allow neurons to send signals from one to another — than those with the gene. And the extra synapses worked. By measuring the electrical signal in the receiving cells, the researchers found that the strength of the signal was doubled in the mice that lacked the protein.

    The cerebellum is indispensable for movement and learning motor skills such as how to ride a bicycle. Some of the recognizable symptoms of autism — such as motor incoordination and a tendency to walk tippy-toed — involve control of movement.

    The animals missing the RNF8 gene in the neurons of their cerebellum did not have any obvious problems with movement: They walked normally and appeared coordinated. When the researchers tested their ability to learn motor skills, however, the mice without RNF8 failed miserably.

    The researchers trained the mice to associate a quick puff of air to the eye with the blinking of a light. Most mice learn to shut their eyes when they see the light blink, to avoid the irritation of the coming air puff. After a week of training, mice with a functioning copy of the gene closed their eyes in anticipation more than three quarters of the time, while mice without the gene shut their eyes just a third of the time.

    While it is best known for its role in movement, the cerebellum is also important in higher cognitive functions such as language and attention, both of which are affected in autism. People with autism often have language delays and pay unusually intense attention to objects or topics that interest them. The cerebellum may be involved not only in motor learning but in other features of autism as well, the researchers said.

    Of course, there is a world of difference between a mouse that can’t learn to shut its eyes and a person with autism who struggles to communicate. But the researchers said the findings suggest that changing how many connections neurons make with each other can have important implications for behavior.

    Since this paper was written, Bonni and colleagues have tested the other autism-associated ubiquitin genes. Inhibition of all genes tested cause an increase in the number of synapses in the cerebellum.

    “It’s possible that excessive connections between neurons contribute to autism,” Bonni said. “More work needs to be done to verify this hypothesis in people, but if that turns out to be true, then you can start looking at ways of controlling the number of synapses. It could potentially benefit not just people who have these rare mutations in ubiquitin genes but other patients with autism.”


  7. Study suggests gene therapy protecting against age-related cognitive, memory deficits

    November 4, 2017 by Ashley

    From the Universitat Autònoma de Barcelona press release:

    Researchers from the Institute of Neurosciences at the Universitat Autònoma de Barcelona (INc-UAB) and the Vall d’Hebron Research Institute (VHIR) are the first to demonstrate that regulation of the brain’s Klotho gene using gene therapy protects against age-related learning and memory problems in mice.

    The study, published in Molecular Psychiatry (Nature group), opens the door to advancing in the research and development of therapies based on this neuroprotective gene.

    Researchers from the UAB demonstrated in a previous study that Klotho regulates age-associated processes, increasing life expectancy when over-expressed and accelerating the development of learning and memory deficiencies when inhibited.

    Now they have demonstrated in vivo for the first time that one dose of this gene injected into the central nervous system prevents the cognitive decline associated with aging in old animals which were treated at a younger age.

    The results, which form part of the PhD thesis of Anna Massó, first author of the article, are part of a study led by INc-UAB researchers Dr Miguel Chillón, ICREA researcher at the Department of Biochemistry and Molecular Biology of the UAB and the VHIR; Dr Lydia Giménez-Llort from the Department of Psychiatry and Legal Medicine of the UAB; and with the collaboration of Dr Assumpció Bosch, also from the Department of Biochemistry and Molecular Biology.

    “The therapy is based on an increase in the levels of this protein in the brain using an adeno-associated viral vector (AAV). Taking into account that the study was conducted with animals which aged naturally, we believe this could have the therapeutic ability to treat dementia and neurodegenerative disorders such as Alzheimer’s or multiple sclerosis, among others,” Miguel Chillón points out.

    The researchers patented their therapy and have licensed it to Kogenix Therapeutics. The company includes UAB participation and is based in the United States. It was launched by Dr Miguel Chillón and Dr Assumpció Bosch, together with the entrepreneur Menachem Abraham and Dr Carmela Abraham, professor of Biochemistry and Pharmacology at the Boston University School of Medicine, a pioneering centre in the study of Klotho in the central nervous system for more than a decade.

    The objective of Kogenix is to achieve the initial capital needed to advance in the pre-clinical trials already being conducted with animal models of Alzheimer’s disease. This will give way to the development of a drug to be used in gene therapy against neurodegenerative diseases based on small molecules which enhance the expression of the gene and/or the use of fragments of the Klotho protein itself.

    “In basic research studies and clinical trials the AAVs have shown to be safe and effective in the implementation of a central nervous system gene therapy. In fact, the Food and Drug Administration made the first gene therapy available in the United States in August and additional approvals are expected,” Dr Assumpció Bosch states.


  8. Prenatal exposure to BPA at low levels can affect gene expression in developing rat brain

    November 2, 2017 by Ashley

    From the North Carolina State University press release:

    New research from North Carolina State University reveals that prenatal exposure to bisphenol A (BPA) at levels below those currently considered safe for humans affects gene expression related to sexual differentiation and neurodevelopment in the developing rat brain.

    BPA is a chemical used in a variety of consumer and household products including some food containers. Experimental data has also suggested a link between the chemical and mood or anxiety-related behaviors in children. Currently, the U.S. Food and Drug Administration (FDA) No Observed Adverse Effect Level (NOAEL) for BPA is 50 micrograms per kilogram of body weight per day.

    Heather Patisaul, professor of biology at NC State, with Ph.D. candidate Sheryl Arambula, conducted a study exposing gestating rats to levels of BPA both above and below those currently considered to have no adverse effect — including levels as low as 2.5 and 25 micrograms per kilogram of body weight per day — and looked at effects in the brains of their newborn pups.

    Arambula and Patisaul found that prenatal BPA exposure, even at the lowest levels, changed the expression of numerous hormone receptors including those for androgen, estrogen, oxytocin and vasopressin in the newborns’ amygdala, a brain structure involved in a wide range of stress and emotional behaviors. Oxytocin, for example, is important for affiliation and pair-bonding, while vasopressin is involved in stress responses. The changes varied depending upon the sex of the newborn and the amount of exposure. Significantly, disruption of genes critical for synaptic transmission and neurodevelopment were also found to be altered, with females appearing to be more sensitive than males.

    “Uniquely, we found that low level prenatal BPA exposure can change androgen receptor expression levels in the amygdala,” says Arambula. “In humans, this gene is important for forming differences between male and female brains, which suggests this could be a way by which BPA exposure might alter sex differences in the human brain.”

    Patisaul is among a consortium of researchers involved in a multi-year, multi-disciplinary project called CLARITY-BPA, a research initiative that includes the FDA, the National Toxicology Program, the National Institute of Environmental Health Sciences (NIEHS), and 13 academic labs. CLARITY-BPA seeks to understand how BPA affects multiple organ systems. Patisaul’s focus is on brain and behavior. All rats in the study were housed at the National Center for Toxicological Research and followed FDA protocols for exposure. CLARITY-BPA experiments were specifically conceived and conducted to provide the FDA with data it could use to make decisions about human health risks.

    “In our previous work, including work for this consortium, we found similar changes in other brain regions including the hypothalamus and hippocampus.” says Patisaul. “There is now a wealth of data showing that BPA can alter neurodevelopment. There is no question that prenatal BPA exposure at levels currently considered safe for humans affects hormone-sensitive gene expression in the developing rodent brain, suggesting that what we consider ‘safe’ for human brains may need to be re-evaluated.”

    The researchers’ findings appear in NeuroToxicology. Arambula is first author and Patisaul is corresponding author of the work. Dereje Jima, a specialist with NC State’s Center for Human Health and the Environment, did the bioinformatics analysis. The research was funded by the NIEHS (grants P30ES025128 and U011ES020929).


  9. Mysterious DNA modification seen in stress response

    October 25, 2017 by Ashley

    From the Emory Health Sciences press release:

    With advances in genomics, scientists are discovering additional components of the DNA alphabet in animals. Do these unusual chemical modifications of DNA have a special meaning, or are they just signs that cellular machines are making mistakes?

    Geneticists at Emory University School of Medicine led by Peng Jin, PhD have been studying a modification of DNA that is not well understood in animals: methylation of the DNA letter A (adenine). They’ve found that it appears more in the brain under conditions of stress, and may have a role in neuropsychiatric disorders.

    The results are scheduled for publication in Nature Communications.

    Methylation on the DNA letter C (cytosine) generally shuts genes off and is an important part of epigenetic regulation, a way for cells to change how the DNA code is read without altering the DNA letters themselves. Methylation describes a mark consisting of an extra carbon atom and three hydrogens: -CH3.

    What if methylation appears on adenine? In bacteria, N6-methyladenine is part of how they defend themselves against invasion by phages (viruses that infect bacteria). The same modification was recently identified as present in the DNA of insects and mammals, but this epigenetic flourish has been awaiting a full explanation of its function.

    Just to start, having that extra -CH3 jutting out of the DNA could get in the way of proteins that bind DNA and direct gene activity. For C-methylation, scientists know a lot about the enzymes that grab it, add it or erase it. For A-methylation, less is known.

    “We found that 6-methyl A is dynamic, which could suggest a functional role,” Jin says. “That said, the enzymes that recognize, add and erase this type of DNA methylation are still mysterious.”

    It does appear that the enzymes that add methyl groups to A when it is part of RNA are not involved, he adds.

    First author Bing Yao, PhD, assistant professor of human genetics, recently established his own laboratory at Emory to examine these and other emerging parts of the DNA alphabet. Jin is vice chair of research in the Department of Human Genetics.

    In the Nature Communications paper, Yao, Jin and their colleagues looked at the prefrontal cortex region of the brain in mice that were subjected to stress, in standard models for the study of depression (forced swim test and tail suspension test).

    Under these conditions, the abundance of N6-methyladenine in the brain cells’ DNA rose four-fold, the scientists found. The DNA modification was detected with two sensitive techniques: liquid chromatography/mass spectrometry and binding to an antibody against N6-methyladenine. The peak abundance is about 25 parts per million, which isn’t that high — but it appears to be confined to certain regions of the genome.

    The methyl-A modification tended to appear more in regions that were between genes and was mostly excluded from the parts of the genome that encode proteins. The loss of methyl-A correlates with genes that are upregulated with stress, suggesting that something removes it around active genes. There does seem to be some “cross talk” between A and C methylation, Jin adds.

    Genes bearing stress-induced 6mA changes overlapped with those associated with neuropsychiatric disorders; a relationship that needs more investigation. The scientists speculate that aberrant 6mA in response to stress could contribute to neuropsychiatric diseases by ectopically recruiting DNA binding proteins.

    The research was supported in part by the National Institute of Neurological Disorders and Stroke (NS051630, NS097206) and the National Institute of Mental Health (MH102690).


  10. Study suggests genetic influences on the brain’s reward, stress systems underlie co-occurring alcohol use disorder, chronic pain

    October 21, 2017 by Ashley

    From the Research Society on Alcoholism press release:

    Alcohol use disorder (AUD) often co-occurs with chronic pain (CP), yet the relationship between the two is complex — involving genetic, neurophysiological, and behavioral elements — and is poorly understood. This review addressed the genetic influences on brain reward and stress systems that neurological research suggests may contribute to the co-occurrence of AUD and CP.

    Candidate gene association studies (CGAS) and genome-wide association studies (GWAS) have provided initial evidence suggesting that a similar dysregulation of reward and stress pathways contribute to AUD and CP, and that genetic influences on these pathways may contribute to both conditions. More specifically, genetic association studies that have looked at AUD and CP independently have identified a number of single-nucleotide polymorphisms (SNPs) — DNA sequence variations — suggestively associated with AUD and CP, with several of these SNPs being located in or near a common set of genes. These common genes are either directly or indirectly related to the reward and stress systems, and are also more broadly involved with the central nervous system (CNS).

    The authors suggested that these results must be interpreted with caution until studies with sufficient statistical power are conducted and replicated. Further, the co-occurrence of AUD and CP reflect a common genetic basis that will likely involve CNS processes other than reward and stress mechanisms in AUD-CP co-occurrence. As the field of molecular genetics continues to advance, if such shared genetic contributions to AUD and CP may be identified, this knowledge can help inform understanding of the underlying mechanisms that contribute to the etiologies of each disorder and their co-occurrence. This would refine and improve the diagnosis and treatment of AUD and CP.